THE RAT NERVOUS SYSTEM THIRD EDITION
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THE RAT NERVOUS SYSTEM THIRD EDITION Edited by
GEORGE PAXINOS Prince of Wales Medical Research Institute The University of New South Wales Sydney, Australia
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Cover image: Figure 17.12, Panel A: illustrates the mixing of neurons that stain with antiserum against ORX (brown) and with a digoxygenin-labeled probe for MCH mRNA (blue) in the perifornical region of a rat. Although the two types of neurons cluster closely with one another around the edge of the fornix, there is virtually no colocalization within individual neurons. Modified from Elias, C.F., Saper, C.B., Maratos-Flier, E., Tritos, N.A., Lee, C., Kelly, J., Tatro, J.B., Hoffman, G.E., Ollmann, M.M., Barsh, G.S., Sakurai, T., Yanagisawa, M., and Elmquist, J.K. (1998b). Chemically defined projections linking the mediobasal hypothalamus and the lateral hypothalamic area. J. Comp. Neurol. 402, 442–459.
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This book is dedicated to: Babis and Kalliopi
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Contents
II
Contributors xiii Foreword xvii
PERIPHERAL NERVOUS SYSTEM AND SPINAL CORD 3. Autonomic Nervous System
I
GIORGIO GABELLA
DEVELOPMENT
Localization of Autonomic Ganglia 77 Structure of Autonomic Ganglia and Nerves 84
1. Gene Maps and Related Histogenetic Domains in the Forebrain and Midbrain
4. Primary Afferent Projections to the Spinal Cord
LUIS PUELLES, SALVADOR MARTÍNEZ, MARGARET MARTÍNEZ-DE-LA-TORRE, AND JOHN L. R. RUBENSTEIN
GUNNAR GRANT AND BRITA ROBERTSON
Projection of Primary Afferent Fibers to Different Laminae and Some Spinal Cord Nuclei 112 Somatotopic Organization of Primary Afferent Projections 114
Molecular Versus Anatomical Distinction of Brain Subdivisions: The Specification State 3 Sharing of Molecularly Distinct Brain Domains Among Vertebrates 5 Differential Aspects of Histogenesis 6 The Bauplan of the Brain 7 The Neural Plate Subdivisions 11 The Closed Neural Tube 13 Basal Plate Regions 14 Alar Plate Regions 16 Telencephalic Patterns 17 About Mechanisms 20 Relevant Genetic Mechanisms 20
5. Spinal Cord Cytoarchitecture GUNNAR GRANT AND H. RICHARD KOERBER
Lamina I 121 Lamina II 122 Lamina III 122 Lamina IV 122 Lamina V 123 Lamina VI 123 Lamina VII 123 Lamina VIII 124 Lamina IX 124 Area X 125 Lateral Spinal Nucleus 126 Lateral Cervical Nucleus 126
2. Development of the Telencephalon: Neural Stem Cells, Neurogenesis, and Neuronal Migration SHIRLEY A. BAYER AND JOSEPH ALTMAN
Neurogenetic Timetables in the Telencephalon 28 Maps of Stem Cell Mosaics in the Telencephalic Neuroepithelium 36 Development of the Lateral, Rostral, and Dentate Migratory Streams 66 Stem Cell Dynamics in Cortical Germinal Zones 68
6. Substantia Gelatinosa of the Spinal Cord ALFREDO RIBEIRO-DA-SILVA
Definition 129 Characteristics of Neurons of the Superficial Laminae of the Spinal Cord 130
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CONTENTS
Ultrastructure of the Spinal Dorsal Horn 133 Neurochemistry of the Dorsal Horn 136 Final Remarks 143
Efferent Projections of LC Neurons 277 Other Metencephalic Noradrenergic Neurons (A5 and A7 Cell Groups) 284 Conclusions 284
7. Ascending and Descending Pathways in the Spinal Cord
12. Oromotor Nuclei
DAVID TRACEY
JOSEPH B. TRAVERS
Ascending Pathways 149 Descending Pathways 154
III BRAINSTEM AND CEREBELLUM 8. Precerebellar Nuclei and Red Nucleus TOM J. H. RUIGROK
Pontine Nuclei 167 Lateral Reticular Nucleus 174 Inferior Olivary Nucleus 180 Red Nucleus 187
9. Cerebellum JAN VOOGD
The Gross Anatomy of the Cerebellum 205 The Cerebellar Nuclei and Their Efferent Pathways 208 Longitudinal, Zonal Organization of Purkinje Cells in the Cerebellar Cortex: Chemoarchitecture and Connections 216 Afferent Mossy Fiber Systems 229 Terminations of Mossy Fiber Systems in Different Regions of the Cerebellum 231
Motor Trigeminal Nucleus 295 Facial Nucleus 301 Hypoglossal Nucleus 305 Summary and Conclusions 311
13. Central Nervous System Control of Micturition GERT HOLSTEGE
Motoneurons Innervating Bladder and Urethral Sphincter 321 Sacral Cord Micturition Reflexes 323 Brain Stem–Spinal Cord Pathways Coordinate Bladder and Sphincter Motoneurons 323 Afferent Systems 324 Forebrain Involvement in the Control of Micturition 325 Micturition Control in Humans 326 Conclusions 327
IV DIENCEPHALON, BASAL GANGLIA, AMYGDALA AND SEPTUM
10. Periaqueductal Gray
14. Anatomical Substrates of Hypothalamic Integration
KEVIN A. KEAY AND RICHARD BANDLER
RICHARD B. SIMERLY
PAG Columnar Organization 244 Anatomical Studies 247 The PAG And Parallel Circuits for Emotional Coping 249 Conclusions 253
11. Locus Coeruleus, A5 and A7 Noradrenergic Cell Groups GARY ASTON-JONES
Cytoarchitecture 259 Afferents to the Nucleus Locus Coeruleus 263 The Pericoerulear Region: The “Extranuclear LC” 274
Morphological Organization of the Hypothalamus 336 Hypothalamic Integration 352
15. Hypothalamic Supraoptic and Paraventricular Nuclei WILLIAM E. ARMSTRONG
Pituitary Gland 369 Supraoptic Nucleus 370 Paraventricular Nucleus 375 Accessory Magnocellular Neurosecretory Neurons 382 Conclusion 382
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16. Circumventricular Organs BRIAN J. OLDFIELD AND MICHAEL J. MCKINLEY
General Features 389 Subfornical Organ 390 Vascular Organ of the Lamina Terminalis 394 Area Postrema 397 Median Eminence and Neurohypophysis 398 Subcommissural Organ 399 Pineal Gland 400 Choroid Plexus 400
17. Thalamus HENK J. GROENEWEGEN AND MENNO P. WITTER
Some General Aspects of Thalamic Organization 408 Principal Thalamic “Relay” Nuclei 411 Association Thalamic Nuclei 425 Midline and Intralaminar Thalamic Nucle 433 Reticular Nucleus 441
18. Basal Ganglia CHARLES R. GERFEN
Cortical Input to the Striatum 458 Striatum 464 Indirect Pathway 478 Basal Ganglia Outputs 482 Dual Output Systems of Striatal Output Pathways 484 Nigrostriatal Dopamine System 488 Striatal Patch/Matrix Compartments 490 Summary 497
19. Amygdala and Extended Amygdala of the Rat: A Cytoarchitectonical, Fibroarchitectonical, and Chemoarchitectonical Survey JOSE S. DE OLMOS, CARLOS A. BELTRAMINO, AND GEORGE ALHEID
General Topography and Terminology 510 Description: Observation Procedures 514 Organization of the Rat Amygdaloid Complex and Extended Amygdala 514 The Extended Amygdala (EXA) 547 The Laterobasal Nuclear Complex (LBNC) 572 Unclassified Cell Groups in the Amygdala and Bed Nucleus of the Stria Terminalis 588
20. The Septal Region P. Y. RISOLD
Development of the Septal Region 602 Morphological Overviews and Cytoarchitecture of the Septal Nuclei 603
The Chemoarchitecture of the Septal Region 606 Connections of the Septal Region 615 Functional Organization of the Septal Region 621
V CORTEX 21. Hippocampal Formation MENNO P. WITTER AND DAVID G. AMARAL
Dentate Gyrus 637 Hippocampus 647 Overview of the Subiculum, Presubiculum, and Parasubiculum 658 Subiculum 660 Presubiculum 666 Parasubiculum 669 Entorhinal Cortex 670 Perirhinal and Postrhinal Cortices 684 Conclusions: The Organization of Hippocampal Circuitry and the Flow of Information Processing 687
22. Cingulate Cortex and Disease Models BRENT A. VOGT, LESLIE VOGT, AND NURI B. FARBER
Regional Organization 704 Is “Infra” Limbic Area IL Ventral to Limbic Cortex? 705 Cytology of Limbic Area 25 705 Modified Brodmann Nomenclature 705 Cytology of the Perigenual Anterior and Midcingulate Regions 707 Cytology of Retrosplenial Cortex 708 Opioid Architecture: Regional Differences and Neuronal Expression Patterns 709 Area 24B: Movement, Vision, and Pain Behaviors 710 Cortical Connections of Retrosplenial Cortex and Role in Visuospatial Function 711 Thalamic Afferents 712 NMDA Receptor Antagonist-Induced Neurotoxicity in Retrosplenial Cortex 714 Polysynaptic Circuit Disinhibition Underlies NRHypo Neurotoxicity 717 NRHypo-Induced Psychosis 719 NRHypo and Neurodegeneration in Alzheimer’s Disease 719 Comparison of Medial Cortex in Rat and Monkey 720 Rodent Models of Disease 721
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23. Isocortex
28. Gustatory System
NICOLA PALOMERO-GALLAGHER AND KARL ZILLES
ROBERT F. LUNDY, JR. AND RALPH NORGREN
Isocortex 728 Transition Regions Between Isocortex and Allocortex 747
VI SYSTEMS 24. Central Autonomic System CLIFFORD B. SAPER
Medullospinal Level: Reflex Control 761 Mesopontine Level: Modulation and Integration of Reflex Control and Arousal 766 Forebrain Level: Behavioral and Metabolic Integration of Autonomic Control and Arousal 774 Summary and Conclusion 784
25. Somatosensory System DAVID TRACEY
Somatosensory Receptors 795 Cell Bodies and Central Processes of Somatosensory Receptors 797 Ascending Spinal Pathways 798 Medullary Relay Nuclei 799 Somatosensory Thalamus 802 Somatosensory Cortex 803
26. Trigeminal Sensory System P. M. E. WAITE
Adult Sensory Trigeminal System 815 Development of the Trigeminal System 834
27. Pain System WILLIAM D. WILLIS, KARIN N. WESTLUND, AND SUSAN M. CARLTON
Nociceptors 853 Dorsal Horn Interneurons 856 Ascending Nociceptive Pathways 862 Thalamus and Cortex 866 Descending Control Systems 866 Plastic Changes in Pathological Conditions 868
Peripheral Anatomy 890 Central Organization 891 Cytoarchitecture 903 Neurochemistry 905 Functional Considerations 908 Conclusion 911
29. Olfactory System MICHAEL T. SHIPLEY, MATTHEW ENNIS, AND ADAM PUCHE
The Olfactory Epithelium 922 The Main Olfactory Bulb 925 Primary Olfactory Cortex 935 The Accessory Olfactory System 946 “Nonolfactory” Modulatory Inputs to the Olfactory System 950
30. Vestibular System PIERRE-PAUL VIDAL AND ALAIN SANS
The Vestibular Message: From the Periphery to the Center 964 The Vestibular Nuclear Complex: Morphofunctional Properties 966 Neurotransmitters and Neuromodulators of Central Vestibular Neurons 975 Conclusion 985
31. Auditory System MANUEL S. MALMIERCA AND MIGUEL A. MERCHÁN
The Organ of Corti 996 The Cochlear Nuclear Complex 1001 The Superior Olivary Complex 1011 The Nuclei of the Lateral Lemniscus 1018 The Inferior Colliculus 1027 He Medial Geniculate Body 1039 The Auditory Cortex 1049 The Descending Auditory Pathway 1056
32. Visual System ANN JERVIE SEFTON, BOGDAN DREHER, AND ALAN HARVEY
Visual Pathways 1082 Retinal Output 1084 Retino-Recipient Nuclei 1087 Associated Visual Nuclei 1119 Visual Cortex 1121
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33. Cerebral Vascular System OSCAR U. SCREMIN
Methodology 1165 Cerebral Blood Vessels 1166 Spinal Cord Blood Vessels 1190 Vascular Innervation 1192 Functional Localization With Blood Flow 1193
VII NEUROTRANSMITTERS 34. The Serotonin and Tachykinin Systems ANTONY HARDING, GEORGE PAXINOS, AND GLENDA HALLIDAY
Serotonin System 1203 Tachykinin System 1212
Coexistence of Serotonin and Tachykinins 1244 Functional Interaction Between Serotonin and Tachykinins 1245
35. Cholinergic Neurons and Networks Revisited LARRY L. BUTCHER AND NANCY J. WOOLF
Cholinergic Neuroanatomy in the Context of Function 1257 Central Cholinergic Neurons: Modes of Operation 1262 Genesis of Alzheimer’s Disease: A Hypothesis 1263
36. Glutamate JONAS BROMAN, ERIC RINVIK, MARCO SASSOE-POGNETTO, HOSSEIN KHALKHALI SHANDIZ, AND OLE PETTER OTTERSEN
Anatomical Systems 1269 Conclusion 1280
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Contributors
Numbers in parentheses indicate the pages on which the authors’ contributions begin. Alheid, George, (509) Department of Physiology and Institute for Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA Altman, Joseph, (27), Department of Biology, Purdue University, Indianapolis, Indiana, USA Amaral, David G., (635), Department of Psychiatry, California National Primate Research Center and The M.I.N.D. Institute, University of California, Davis, California, USA Armstrong, Willaim E., (369), Department of Anatomy and Neurobiology, University of Tennessee, Memphis, Tennessee, USA Aston-Jones, Gary, (259), Laboratory of Neuromodulation and Behavior, Department of Psychiatry University of Pennsylvania School of Medicine, Philadelphia, USA Bandler, Richard, (243), Department of Anatomy and Histology, University of Sydney, Sydney, Australia Bayer, Shirley A., (27), Department of Biology, Purdue University, Indianapolis, Indiana, USA Beltramino, Carlos A., (509) Department de Neurofisiologia y Psicofisiologia, Facultad de Psicologia, Universidad Nacional De Cordoba, Cordoba, Argentina Broman, Jonas, (1269), Dept of Physiological Sciences, Lund University, Lund, Sweden Butcher, Larry L., (1257), Department of Psychology UCLA, Los Angeles, California, USA Carlton, Susan M., (853), Department of Anatomy, Neuroscience, Marine Biomedicine Institute, University of Texas Medical Branch, Galveston, Texas, USA
DeOlmos, Jose, S., (509), Instituo de Investigacion Medica, Mercedes y Martin Ferreyra, Cordoba, Argentina Dreher, Bogdan, (1083), Department of Physiology, University of Sydney, Sydney, Australia Ennis, Matthew, (923), Dept Anatomy and Neurobiology, University Maryland School of Medicine Baltimore, Maryland, USA Farber, Nuri B., (705), Department of Psychiatry, Washington University, St. Louis, Missouri Gabella, Giorgio, (77), Department of Anatomy and Developmental Biology, University College London, London, UK Gerfen, Charles, R., (455), Laboratory of Systems Neuroscience, Bethesda, Maryland, USA Grant, Gunnar, (111, 121), Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden Groenewegen, Henk J., (407), Department of Anatomy, Vrije Universiteit, Amsterdam, The Netherlands Halliday, Glenda, (1205), Prince of Wales Medical Research Institute, Randwick, Australia Harding, Antony, (1205), Prince of Wales Medical Research Institute, Randwick, Australia Harvey, Alan, (1083), School of Anatomy and Human Biology, The University of Western, Crawley, Australia Holstege, Gert, (321, 1269), Department of Anatomy and Embryology, University Groningen Oostersingel, Groningen, The Netherlands Keay, Kevin A., (243), Department of Anatomy and Histology, University of Sydney, Sydney, Australia
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CONTRIBUTORS
Koerber, Richard, (121), Deparment of Neuroscience, Karolinska Institute, Stockholm, Sweden Lundy, Robert F., Jr. (891), Department of Behavioral Science, Pennsylvania State University, College of Medicine, Hershey, Pennsylvania, USA Malmierca, Manuel S., (997), Laboratory for the Neurobiology of Hearing, The Institute of Neuroscience of Castilla y Leon Faculty of Medicine, University of Salamanca, Salamanca, Spain Martinez, Salvador, (3), Department of Anatomy, University of Murcia, Murcia, Spain Martínez-de-la-Torre, Margaret, (3), Department of Morphological Sciences, University of Murcia, Murcia, Spain McKinley, Michael J., (389), Howard Florey Institute, University of Melbourne, Parkville, Australia Merchán, Miguel A., (997), Laboratory for the Neurobiology of Hearing, The Institute of Neuroscience of Castilla y Leon Faculty of Medicine, University of Salamanca, Salamanca, Spain Norgren, Ralph, (891), Department of Behavioral Science, Pennsylvania State University, College of Medicine, Hershey, Pennsylvania, USA Oldfield, Brian J., (389), Howard Florey Institute, University of Melbourne, Parkville, Australia Ottersen, Ole Petter, (1269), Centre for Molecular Biology and Neuroscience, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway Palomero-Gallagher, Nicola, (729), Institute of Medicine, Research Center, Julich, Germany Paxinos, George, (1205), School of Psychology, The University of New South Wales, Sydney, Australia Puche, Adam, (923), Dept Anatomy and Neurobiology, University Maryland School of Medicine Baltimore, Maryland, USA Puelles, Luis, (3), Department of Morphological Sciences, University of Murcia, Murcia, Spain Ribeiro-da-Silva, Alfredo, (129), Department of Pharmacology and Therapeutics, McGill University Montreal, Quebec, Canada Rinvik, Eric, (1269), Centre for Molecular Biology and Neuroscience, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway Risold, P. Y., (605), Laboratoire d’Histologie, Fac. Med. Université Franche-Comte, Besancon, France Robertson, Brita, (111), Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
Rubenstein, John L. R., (3), University of California, San Francisco, California Ruigrok, Tom J. H., (167), Department of Anatomy, Erasmus University, Rotterdam, The Netherlands Sans, Alain, (965), INSERM Unite 432, Neurobiologie et Developpement du Systeme Vestibulaire, Universite Montpellier II, Place Eugene Bataillon F34095 Montpellier, France Saper, Clifford B., (761), Department of Neurology, Beth Israel Hospital, Boston, Massachusetts, USA Sassoe-Pognetto, Marco, (1269), Dipartimento di Anatomia, Farmacologia e Medicina Legale, University of Turin, Italy Scremin, Oscar U., (1167), Veterans Affairs Greater Los Angeles Healthcare System, and Department of Physiology, UCLA School of Medicine, Los Angeles, California, USA Sefton, Ann Jervie, (1083), Department of Physiology, University of Sydney, Sydney, Australia Shandiz, Hossein Khalkhali, (1269), Centre for Molecular Biology and Neuroscience, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway Shipley, Michael T., (923), Dept Anatomy and Neurobiology, University Maryland School of Medicine Baltimore, Maryland, USA Simerly, Richard B., (335), Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Sciences University, Beaverton, Oregon Tracey, David, (149, 797), School of Medical Sciences, University of New South Wales, Sydney, Australia Travers, Joseph B., (259), Section of Oral Biology, OSU College of Dentistry, Columbus, Ohio, USA Vidal, Pierre Paul, (965), Laboratoire de Neurobiologie des Reseaux Sensorimoteurs, Universiteˇ Paris V, Paris, France Vogt, Brent A., (705), Cingulum Neurosciences Institute, Manlius, New York, USA Vogt, Leslie, (705), Cingulum Neurosciences Institute, Manlius, New York, USA Voogd, Jan, (205), Department of Anatomy, Erasmus University, Rotterdam, The Netherlands Waite, P. M. E, (817), School of Anatomy, The University of New South Wales, Sydney, Australia Westlund, Karin N., (853), Department of Anatomy, Neuroscience, Marine Biomedicine Institute, University of Texas Medical Branch, Galveston, Texas, USA
CONTRIBUTORS
Willis, William D., (853), Department of Anatomy, Neuroscience, Marine Biomedicine Institute, University of Texas Medical Branch, Galveston, Texas, USA
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Witter, Menno P, (407, 635), Department of Anatomy, Vrije Universiteit, Amsterdam, The Netherlands Zilles, Karl, (729), Vogt Brain Research Institute, University of Dusseldorf, Dusseldorf, Germany
1. SECTION TITLE
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Foreword
The structure of the nervous is the backbone of neuroscience. The aim of this book is to describe all parts of the rat nervous system in the context of modern hypotheses of structural and functional organization. No individual scientist could write with ultimate authority on every part of the brain, spinal cord and peripheral nervous system. It is for this reason that experts on different regions were asked to contribute to this book. The reader will notice that many of these
experts generated major hypotheses and original observations that today guide research in their field. It is hoped that the combined effort of contributors to the third edition of The Rat Nervous System will make this one an even friendlier and helpful companion to the graduate student or scientist wanting to learn the highlights and fundamentals of the structure of the nervous system. George Paxinos, Sydney January 2004
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SECTION
I
DEVELOPMENT
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C H A P T E R
1 Gene Maps and Related Histogenetic Domains in the Forebrain and Midbrain LUIS PUELLES1, SALVADOR MARTÍNEZ2, MARGARET MARTÍNEZ-DE-LA-TORRE1 and JOHN L. R. RUBENSTEIN3 1
Department of Human Anatomy and Psychobiology University of Murcia, Murcia, Spain
2
Institute of Neuroscience/CSIC, University Miguel Hernandez San Juan de Alicante, Spain 3
Nina Ireland Laboratory of Developmental Neurobiology Langley Porter Psychiatric Institute, UCSF, San Francisco, USA
brain and midbrain patterns. To keep this essay within manageable size, we refer mainly to selected transcription factor genes, i.e., those whose coded proteins enter the cell nucleus and interact with DNA to regulate further genetic transcription into RNA. They belong to the class of “developmental genes,” influential in the generation of embryonic pattern, and whose lack of function can lead to profound alterations in the development of specific brain regions. Secreted morphogens and structural products, such as cell-adhesion proteins, are mentioned occasionally. We do not address “housekeeping” genes involved in metabolism, or genes that are generally related to neuronal and glial differentiation, as they tend to be broadly expressed and therefore provide little or no regional morphological information.
The developing neural tube shows over time an increasing number of regional subdivisions. These are known to us primarily as morphological entities (i.e., vesicles, neuromeres, lobes, gyri, eminences, recesses), but also can be characterized by their patterns of gene expression. We allude to the latter properties by the term “molecular brain subdivision,” referring the reader to a rapidly growing new field of neuromorphology. In recent years many observations have accumulated showing that such combined molecular topographies frequently show reproducible boundaries and are topologically invariant during ontogenesis (though some genes do show changing expression patterns over time), and many early patterns are remarkably resistant to evolutionary change. The largescale comparability of mouse brain gene patterns with counterparts in human, avian, amphibian, teleost, and agnathan species is providing a substantial new impulse to comparative neuroanatomy (i.e., SmithFernandez et al., 1998; Puelles et al., 2000; Bachy et al., 2001; Murakami et al., 2001; Hauptmann et al., 2002). This also accounts for the singularity of this mousebased chapter in a rat brain book. Space and time limitations have led us to concentrate upon the fore-
The Rat Nervous System, Third Edition
MOLECULAR VERSUS ANATOMICAL DISTINCTION OF BRAIN SUBDIVISIONS: THE SPECIFICATION STATE Molecular brain subdivisions start to appear at neural plate stages, earlier than morphological parts
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LUIS PUELLES ET AL.
can be distinguished (Fig. 1) (Shimamura et al., 1995; Rubenstein et al., 1998). Various transcription factors and morphogen-coding genes are expressed either homogeneously or gradientally within distinct anteroposterior (AP) and dorsoventral (DV) neuroectoderm regions, usually symmetrically relative to the midline. At each stage of development, the genes that are active in a locus (known genes plus unknown ones) are jointly held to represent the molecular specification state of the local tissue. The specification state at any stage may be more or less reversible, being sensitive to various microenvironmental aspects, particularly at early stages (activities of surrounding cells; composition of the intercellular matrix and fluid). Each state evolves with time as a result of ongoing intrinsic genetic regulations (genes up- or downregulated) and of epigenetic shortor long-range intercellular signaling effects; these phenomena are all encompassed in the concept of “patterning.” So-called planar neural patterning occurs by signal communication spreading within the ectoderm itself (the neuroepithelium and adjacent nonneural ectoderm, normally within a limited spatial range), whereas vertical patterning is imposed by signals emitted by tissues adjacent to the neural primordium, i.e., derivatives of mesoderm or endoderm. Fate-map analysis suggests that early differential specification of various regions and subregions in the neural plate and neural tube often correlates with prospective fates, or at least with specified levels of developmental “competence.” A state of competence implies a partial advance into a developmental route that still allows multiple outcomes (thus implying a partially unstable specification state), but some alternative developmental routes are now largely excluded. Prospective fate, referred usually to a grossly defined later morphological entity, like the “eye field” or the “telencephalon” (see Fig. 2), simply suggests that under normal circumstances the early region is on its way to produce the corresponding later brain part, without implications as regards competence or determination (the same cells might be able to do something completely different if grafted elsewhere). Fate maps (i.e., Inoue et al., 2000; Cobos et al., 2001; Fernández-Garre et al., 2002) thus apparently locate topologically invariant causal environments where capable cells usually achieve a particular developmental result, whereas specification maps identify the cells actually progressing along a definite developmental route, as they change their competence. Prospective fate can be determined before much molecular specification has taken place (i.e., at blastula stages). Therefore, correspondence of a prospectivefate region with a particular gene expression, or a
molecular constellation, is merely indicative of what may be the first steps in the specification of the correlative later brain part. As the neural primordium progresses through successive stages, following ever more diverse specification routes (reminiscent of the epigenetic landscape of Waddington, 1957), new differentially specified regional subdivisions are introduced. In contrast to the very dynamic changes at the earlier stages, more stable specification states tend to characterize the “definitive” determined fate of each particular subregion. This genetic identity of each locus, articulated with local epigenetic constraints, influences all aspects of histogenesis (proliferation properties, types of neurons and glia cells differentiated, cell adhesivity, and intercellular matrix composition—with consequences in cell migration and axonal navigation—and even differential synaptogenetic and trophic interaction capacities). A fully determined state cannot be proven in principle, since only limited testing conditions can be employed to show that the tissue cannot change its fate. The primary patterning mechanisms, by causing diverse genetic programs to be followed at different loci of the neural wall, lead to secondary histogenetic processes (proliferation, migration, differentiation, establishment of connections) characteristic for each genetic program and locus. Neurohistogenesis produces the characteristic neuronal and glial populations of each brain part and thereby mediates in a complex way the differential growth in surface and thickness of the neural wall. As a consequence of these varied developmental processes, where literally thousands of molecules and millions of cells participate, the anatomical landmarks that were studied in classical neuroembryology and neuroanatomy appear and are further transformed into adult shape. Brain morphogenesis is accordingly a tertiary process, consequent to fine-grain histogenetic and molecular phenomena in the brain wall. Brain wall shape is not directly related to (is not used for) functional fitness of the animal, whereas the local microscopic cellular structure—brain texture—clearly is strongly relevant for fitness. Thus, during evolution, patterning, histogenesis, and functional capacities are the essential aspects of brain development that are fixed in the genes by natural selection, whereas morphogenesis is an epiphenomenon. In some cases it is possible to directly correlate given anatomical landmarks with underlying details of molecular specification (Puelles and Rubenstein, 1993; Puelles, 1995, 2001a). However, there are also cases where anatomical landmarks widely taken as boundaries do not correlate precisely with molecular bound-
I. DEVELOPMENT
1. GENE MAPS AND RELATED HISTOGENETIC DOMAINS IN THE FOREBRAIN AND MIDBRAIN
aries. This is often the case with brain ventricular sulci, i.e., the sulcus limitans of His, or Herrick’s thalamic sulci (Puelles and Rubenstein, 1993). Another clear example is the “pons,” whose apparent upper and lower “limits,” at least as described in classical anatomy, lack a precise correlation with rhombomeric differential molecular identities (Rubenstein and Puelles, 1994; Marin and Puelles, 1995) (see Fig. 2). It is remarkable that pontine nuclei originate widely in the medullary rhombic lip and reach via rostralward tangential migration the pontine region in rhombomeres 2–3, whereas the cerebellum largely forms in the isthmus and rhombomere 1. This knowledge clearly disrupts the traditional concept of the metencephalon or pontocerebellum as a fundamental morphological unit of the hindbrain. Moreover, molecular boundaries sometimes cross a seemingly undivided anatomical region (i.e., no corresponding anatomical boundary was described there before) (Rubenstein and Puelles, 1994). In these comparisons, it seems reasonable to think that the molecular boundaries, which likely represent fate-determining primary causal mechanisms, weigh more as regards defining significant subdivisions than the tertiary anatomical landmarks. After all, differentially specified adjacent brain regions with independent histogenesis do not need to develop morphologically visible boundaries (i.e., the case of individual cortical areas or pallial and subpallial parts of the septum). Conversely, morphologic bulges or sulci tend to be rather variable ontoand phylogenetically, since they are not themselves fixed by genetic information and may depend heavily on epigenesis. Such landmarks often are subjects of vague and preconceived definition and thus can be traced somewhat tendentiously (it is surprising to see the variety of ventricular relief that has been taken as a “sulcus” in the literature; Kuhlenbeck once mentioned a “ridge-like” sulcus). When ventricular or surface sulci are mapped accurately, they tend to show a changing relationship relative to the topologically static molecular boundaries. Exceptions to this rule result when there is direct causal interaction of landmark-forming structures with the molecular boundaries, as occurs in the growth of some axonal tracts parallel to a molecular boundary. The axonal growth cones often are influenced by the underlying molecular discontinuity (i.e., growth-permissive versus nonpermissive substrates, as apparently occurs with the posterior commissure and the retroflex tract; see also Marin et al., 2002). Sometimes the boundary itself, by virtue of specific differentiation of its cells, acquires a mature ridge-like or sulcus-like appearance (i.e., the zona limitans intrathalamica or the hindbrain median raphe).
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SHARING OF MOLECULARLY DISTINCT BRAIN DOMAINS AMONG VERTEBRATES Accumulating comparative results over the last decade strongly indicate that in large measure there is a common pattern of differentially specified neural regions among all vertebrates (Smith-Fernandez et al., 1998; Puelles et al., 2000; Hauptmann and Gerster, 2000; Hauptmann et al., 2002; Bachy et al., 2001; Murakami et al., 2001). This shared pattern, where the relative topology of neighboring differentially specified radial histogenetic fields remains constant despite substantial quantitative differences in field size or in growth, cell migration, and differentiation properties, may be conceived as representing a topological neural tube molecular Bauplan common to all vertebrates. Its existence implies a developmentally constrained process of primary anatomical regionalization of the brain that underlies the overt morphological Bauplan, irrespective of its various modulations in different vertebrate lineages. It is possible to understand how this occurs. In different vertebrates, embryonic neuroepithelial domains with comparable topological positions express spatially and temporally characteristic sets of genes, thus acquiring sequentially the same (causally comparable) specification states. As a result, the neuroepithelial precursors and the neuronal or glial derivatives of these domains become similarly patterned as regards their fundamental proliferative and differentiative properties. A given shared gene combination thus instructs the relevant set of neuroepithelial cells to form a distinct histogenetic subdivision of the neural wall (a morphogenetic field) which is “the same” from diverse points of view: relative position (topology), significant causal mechanisms, overall field fate, and field competence. This situation is known as a field homology (see Puelles and Medina, 2002). Such widely shared molecular regionalization entails first large primary expression domains at neural plate and early neural tube stages, which secondarily become subdivided by intersection with other expression domains, as new genes are upregulated or downregulated selectively via cell-to-cell interactions along the anteroposterior (AP) and dorsoventral (DV) dimensions of the neural primordium or via cellautonomous genetic regulation of transcription. This accounts for implementation of a common Bauplan and for the existence of structural and functional homologies across vertebrates and particularly for the existence of developmental and anatomic similarity across those species that are closely related evolutionarily (i.e., among rodents; see Fig. 3 for the brain territory covered in this chapter).
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DIFFERENTIAL ASPECTS OF HISTOGENESIS The subsequent histogenetic development of each distinct field in the Bauplan under species-specific parameter and variable values—i.e., variant patterns of proliferation, genesis, differentiation, migration, neurite growth, synaptogenesis, and cell death of daughter cells—has important morphogenetic consequences which frequently are species-specific, both intrinsically and considered in the wider context of the other fields in the immediate neighborhood (Puelles and Medina, 2002). The more expansive fields of the neural wall will tend to compress or deform morphogenetically the less expansive adjacent ones, with various shaping results, depending on quantitative differences in the mechanical forces generated and the particular equilibrium states reached typically in each species (i.e., tangential expansion or compression, increase or decrease in thickness, protrusion at the surface or at the ventricle, bending of the radial dimension). This probably accounts for most species-specific aspects of brain structure and form. Normally the histogenesis and morphogenesis of each histogenetic field leads, via the predominant radial migration of derivatives into the local mantle layer, to a characteristic, more or less deformed radial block of the mature brain wall. Each “bidimensional” field of the undifferentiated neural tube wall (if we abstract the thickness of the neuroepithelium) transforms into a tridimensional block, or radial domain, of the mature brain wall (concept comparable to the migration areas of Berquist and Källén, 1954). The radial domains logically extend from the ventricular lining to the pial surface (along lines conceptually radiating from the central axis in the cavity of the neural tube). Frequently, we can distinguish superficial (subpial), intermediate, and periventricular strata of the derived mantle structure, though in some cases most neurons accumulate in only one or two of these positions, allowing space in the rest for fasciculated fiber tracts (i.e., deeply in the cortex or superficially in the spinal cord). Radial layering of neurons relative to their birthdates varies in different radial domains (inside-out, outside-in, or mixed patterns). There is also the heterochronic property of some differentially specified histogenetic fields that nevertheless share some properties. In such cases neighboring radial domains may implement similar programs with different relative timing, i.e., heterochrony of even and odd rhombomeres collaborating in plurisegmental longitudinal structures such as the sensory or motor columns of the cranial nerves (even segments are precocious relative to the adjacent odd rhombomeres). In contrast, different neocortical
areas tend to form continuous gradients of maturation across their boundaries (boundaries clearly may have various sorts of molecular and histological characteristics). Gradiental distribution of differentiation timetables across the brain surface is nevertheless regionspecific in orientation and magnitude. The boundaries of such heterochronic phenomena do correlate easily with underlying molecular boundaries (i.e., the isthmomesencephalic boundary separates mirror-image neurogenetic gradients in the AP dimension of the midbrain and the rostral hindbrain, and many segmental boundaries are transverse loci of minimal proliferation). There are special cases, nevertheless, where derivatives from a given histogenetic field migrate tangentially to a different location in the brain wall, colonizing, so to speak, one or several ectopic histogenetic domains, and thus also depleting variably the population of their original radial domain (such tangentially migrating neurons often keep at least partially their original molecular identity). One recently investigated example is the migration of populations of inhibitory interneurons from the telencephalic ganglionic eminences into the overlying pallium (Anderson et al., 1997, 2001; Marin and Rubenstein, 2001). Extreme cases are known where all the derivatives of one region seem to move away tangentially, as occurs for instance at the rhombic lip in relation to the formation of the inferior olive, the pons, and the external granular layer of the cerebellum. The olfactory bulb is a contrary extreme case in that most of its cells—except the mitral and tufted projection neurons—come from outside its histogenetic field proper (the interneurons come from the ganglionic eminences via the rostral migration stream). A special case of differences obtained among vertebrates, notably among mammals, relates to the number of areal fields one can distinguish within the cerebral cortex. Comparative data suggest that the areas increase in number in proportion to the overall size of the cortex. This apparently bespeaks of developmental constraints limiting the maximal size of a cortical area. It is unclear at the moment whether such constraints relate to regulation of proliferation and fate determination (patterning) or to histogenesis, or both. Protracted patterning might cause more regionalization when the morphogenetic fields overstep a given size limit—note that the intercellular signaling mechanisms involved in patterning have limited effective ranges and probably are sensitive to primordium size. As regards the histogenetic mechanisms, at the moment neither glia-guided radial cell migration or layer-specific neuronal differentiation seem candidates for such effects, since it is unclear how they would be affected by overall size. Possibly there may be size-related limits to the establishment of
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THE BAUPLAN OF THE BRAIN
ordered sets of projections—note that cortical areas thought to have subdivided evolutionarily typically show mirror-image topographic connection patterns relative to their mutual boundaries (Krubitzer, 2000). This interesting arealization phenomenon is a mechanism that converts quantitative changes in cell population into qualitative changes in emergent functional properties. It may operate not only in cortical areas but also in complex nuclear regions (i.e., nuclear subdivisions in the thalamus, the amygdala, or the pons). Understanding of the peculiar histogenetic and morphogenetic properties of the diverse anatomical regions of the brain is thus promoted by correlating the local histogenetic processes both with the underlying molecular specification history and the resulting formation of anatomical landmarks and functionally distinct structures. Comparative analysis of these issues across a range of animals wider than the usual rat– monkey–human spectrum frequently results revealing (Puelles, 2001a).
RP
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There are clear reasons for conceiving of the brain as an elongated tubular formation with DV and AP subdivisions. The precursor of the neural tube is the neural plate (here the prospective DV dimension appears flattened into symmetric mediolateral dimension; Fig. 1). The neural plate starts as a radially symmetrical area around the primary organizer (the planar radial dimension corresponds to the future DV axis of the neural tube) and then elongates dramatically, leading to secondary appearance of the AP axis (see review of clonal data in Rubenstein et al., 1998). Subsequent neurulation rolls up the edges of the neural plate and closes the tube, building the roof plate (Fig. 1). The most anterior end of the roof plate overlies the anterior commissure in the mature brain (Rubenstein et al., 1998; Inoue et al., 2000; Cobos et al., 2001) (see Fig. 2), whereas the anterior end of the floor plate corresponds to the locus of the neurohypophysis
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FIGURE 1 Graphic schematic representation of the neurulation process viewed from the rostrolateral end of the brain. Nonneural structures of the head primordium are not shown. As the borders of the neural plate approach each other and fuse at the dorsal midline, the eye vesicles evaginate and the forebrain and midbrain (delimited by a transverse dash-line) gradually acquire their characteristic shape. The schema ends when the telencephalic vesicles (Tel) start to evaginate and the rostral neuropore closes. The fundamental four-tiered longitudinal structure of the CNS has its simplest form at initial neural plate stages. The drawings display the topology of the prospective floor plate (FP), basal plate (BP), alar plate (AP), and roof plate (RP) longitudinal domains, which are continuous from left to right across the midline at the front of the neural plate. The initial eye field, which is conceived to lie within the alar plate, also bridges the rostral midline. The anterior neural ridge (ANR) is postulated as a secondary organizer for the forebrain. We base the represented size of this hypotetic organizer area on the early expression of Hesx1 and Six3 genes. As neurulation proceeds, the mutual topologic relationships of these longitudinal domains are not altered. The rostral end of the roof plate will form choroidal tissue at the roof of the third ventricle and at the caudomedial wall of the lateral ventricles (Tel). The ANR persists as the telencephalic commissural plate (median septum), continuing into the lamina terminalis and the prospective optic chiasm. The rostral-most floor plate area is the site where the neurohypophysis will develop, surrounded by the median eminence (compare with Fig. 2).
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FIGURE 2 Fate map of the mouse neural plate (right side; based on data from Inoue et al., 2000, and extrapolating some chicken data from Fernández-Garre et al., 2002; Cobos-Sillero et al., 2001; and Marín and Puelles, 1995).. The fate map appears divided in longitudinal domains, corresponding to the early floor, basal, alar, and roof plates (choroidal roof plate in dark gray; see Fig. 1), as well as in transversal domains (rhombomeres, isthmus, midbrain, prosomeres, secondary prosencephalon). The floor region is divided into a prechordal part (rostral and caudal hypothalamus, RH, CH, plus Mam), and an epichordal part (note distinct AP parts for diencephalon proper and midbrain, and for hindbrain). These epichordal floor subdivisions correspond to two plurisegmental domains: the ventral tegmental area (VTA, underlying the nigral tegmentum in the mes–diencephalic basal plate) and the hindbrain raphe domain. These two domains are differentially characterized by the formation of dopaminergic and serotoninergic neurons, respectively. The midbrain and isthmic basal plate areas contain the oculomotor and trochlear nuclei (III, IV). The main prospective areas derived from the alar plate are indicated. The alar hypothalamus (AH) surrounds the eye domain and includes caudally the peduncular area (which is also known as the supraoptoparaventricular area, because it contains the paraventricular and supraoptic nuclei; the name used here refers to its nature as bed of the telencephalic peduncle; Marín et al., 2002). Rostral to the midbrain, a series of dorsal specialized territories like the subcommissural organ (Sco; under the posterior commissure) and the epithalamus and pineal gland (Eth, Pin) are continuous rostrally with the eminentia thalami (Emt) and the anterior entopeduncular area (AEP); the last two jointly form the so-called hemispheric stalk domain (telencephalic border). The Emt borders upon the pallial telencephalon (which includes the olfactory bulb, OB), whereas AEP borders upon the subpallial telencephalon. The neural plate rim rostral to the forebrain choroidal roof contains the prospective septal domain. The topologic arrangement of pallium and subpallium in the neural plate shows that the pallium is primarily caudal to the subpallium. Abbreviations used: Acust, cochlear column; AEP, anterior entopeduncular area; Cb, cerebellum; CH, caudal hypothalamus; DT, dorsal thalamus; Emt, eminentia thalami; Eth, epithalamus; III, oculomotor nucleus; iorg, isthmic organizer; IV, trochlear nucleus; lt, lamina terminalis; Mammammillary area; Mes, mesencephalon; NH, neurohypophysis; Nigral Tegm, nigral tegmentum; OB, olfactory bulb; och, optic chiasma; p1–p3, prosomeres 1–3; Ped. area, peduncular (supraoptoparaventricular) area; Ped. pon., pedunculopontine region; Pin, pineal gland (epiphysis); Pontobulb, pontobulbar region; r1–r6, rhombomeres; r7, pseudorhombomere 7; rch, retrochiasmatic area; RH, rostral hypothalamus; Rhomb, rhombencephalon; RM, retromammillary area; Sco, subcommissural organ; TEL, telencephalon; Trig, trigeminal column; Vest, vestibular column; VT, ventral thalamus; VTA, ventral tegmental area; ZLI, zona limitans intrathalamica.
(Rubenstein et al., 1998) (see Fig. 2). The neural tube wall placed between the floor and the roof plates is divided into basal and alar primary longitudinal zones, distinguished initially by a characteristic neurogenetic heterochrony already recognized by His (1904), such that the basal plate differentiates precociously (Fig. 1; see also Puelles et al., 1987). Molecular specification data
and experimental causal analysis have consistently corroborated this basic DV distinction (an equilibrium state between opposed “ventralized” and “dorsalized” patterning effects), incidentally showing the inconstant sulcus limitans of His to be, even in favorable cases, just a mere approximation of the molecular boundary (see below). However, we still lack a precise and
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complete molecular definition of the alar–basal boundary at different stages, or of the secondary subdivisions formed within the primary longitudinal zones, in correlation with locally emergent anatomical structure. Nevertheless, this issue recently has seen considerable progress in the spinal cord (see review in Muhr et al., 2001) and is conventionally assisted by some degree of differential histological appearance (Fig. 3; see also Shimamura et al., 1995; Puelles, 1995). At the rostral end of the neural tube, the bilateral basal and alar plates converge respectively together at the midline, in the space existing between the neurohypophysis and the anterior commissure. The alar–basal boundary crosses the rostral midline between the optic chiasm (an alar structure, like the evaginated eyes) and the anterobasal (retrochiasmatic) nucleus (Figs. 1 and 2) (Shimamura et al., 1995, Puelles, 1995, 2001a; Marcus et al., 1999). The anlage of the anterobasal (retrochiasmatic) nucleus builds with the hypothalamic tuberal area the rostral end of the basal plate, whereas the suprachiasmatic, supraoptic, and preoptic areas represent the rostral end of the alar plate and converge rostromedially upon the optic chiasm and the lamina terminalis (Figs. 1 and 2). Further DV patterning within the basal and alar plates shows differential characteristics at different AP levels. In general, each part of the neural tube develops its own pattern of DV subdivisions. These are best understood in the hindbrain, where they form longitudinal sensory and motor columns (and other associated formations) related to cranial nerve nuclei
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(Fig. 2). DV patterning becomes quite complex in the forebrain, where the evaginated eyes and telencephalon, as well as various diencephalic centers, develop (Figs. 2 and 3). AP divisions of the neural tube are bounded early on by molecular limits orthogonal to the longitudinal DV zones; such boundaries already start to become established at neural plate stages (Figs. 4A–4C), and their number subsequently increases by gradual AP subdivision of the early primary regions, partly under the control of so-called “secondary organizers” or via retinoic acid-mediated caudalization and further neighborhood interactions. Differential growth generated by the region-characteristic molecular specification states soon leads to “vesiculation” and “segmentation” of the neural tube primordium. Vesicles are localized outpouchings created by proliferative singularities largely restricted to one of the longitudinal zones; they typically have a boundary (stalk) that is not orthogonal to the brain length axis—consider, i.e., the eye vesicles, the midbrain tectum, the cerebellum, or the telencephalon. Segments (neuromeres), in contrast, are serial transverse outpouchings whose limits are orthogonal to the complete set of DV neural zones; the transverse intersegmental boundaries generally become quiescent proliferatively, though there are exceptions (i.e., at the isthmus). Note that the term “vesicle” in the past was applied indiscriminately to vesicles and segments. Early segments are also known as proneuromeres, following a usage that restricts the term “neuromere” to the definitive set of smaller transverse subdivisions
FIGURE 3 Sagittal section through the brain of an E14.5 mouse embryo, immunoreacted for calbindin to illustrate some of the major anatomic subdivisions in the forebrain. Abbreviations used: cb, cerebellum; cth, caudal (dorsal) thalamus; emt, eminentia thalami; hb, hindbrain; ist, isthmus; mam mammillary area; mes, mesencephalon; mteg, midbrain tegmentum; ob, olfactory bulb; oem, ootoeminential domain; pall, pallium; poa, preoptic area; pt, pretectum; rm, retromammillary area; rth, rostral (ventral) thalamus; se, septum; spv, supraoptoparaventricular (peduncular) area; tm, tuberomammillary area; tu, tuberal area; ZLI, zona limitans intrathalamica.
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FIGURE 4 In situ hibridized mice embryos at late neural plate stages (A–C; whole mounts) and early neural tube stages (D–F; halved neural tubes flat-mounted for organotypic culture) (single- or double-color reactions). The characteristic expression domains of diverse genes are displayed; their names are color-coded depending on the respective arbitrary red versus blue reaction product. Approximate position of the postulated prosomeric domains is indicated in D relative to the Irx3 expression pattern. Note that the eye vesicle lies in a different plane than the rest of the forebrain and is seen superposed.
found in the closed neural tube. In our concept of neuromeres, the serially iterated fundamental morphologic constitution that warrants treating neuromeres as serial homologs or “metameres” is provided by their sharing a complete set of fundamental DV zones and consequently a generally comparable causal history of DV patterning. Note we do not expect that interneuromeric boundary properties, such as clonal restriction, which are themselves secondary to AP patterning, and may vary along the length axis (see Wilkinson, 2001), define the metamery of the neural segments, as is currently postulated by other authors. Our conception has the advantage that the full extent of the neural tube is “segmented,” providing an all-encompassing morphological framework for causal understanding and anatomical reference. In contrast, definition of neural metamery on the basis of boundary properties—i.e., clonal restriction—actually portrays neural segmentation as a transient oddity of a minor part of the neural tube (Larsen et al., 2001). A related concept is that of “tagma,” which refers to a series of adjacent segments sharing special regional characteristics. The caudal epichordal diencephalic segments (prosomeres 1 and 2) possibly build, jointly with the midbrain, a caudal forebrain tagma (i.e., as suggested by common early expression of the Irx3 gene; Bosse et al., 1997; see our Fig. 4D). The midbrain by itself seems segmentally undivided, in contradiction to various classical or recent accounts describing two mesomeres, though it certainly differentiates differentially along
the AP axis; some earlier authors were unaware of the differential growth process caused at the isthmomesencephalic junction by the isthmic organizer (reviews in Puelles et al., 1996; Martínez, 2001; Figs. 4A–4E). Some aspects of midbrain molecular specification (Figs. 3–6), structure and connectivity (i.e., development of dopaminergic cell populations), strongly support its inclusion in the caudal forebrain tagma, though in other aspects the midbrain resembles the hindbrain (i.e., having a motor nucleus). Prosomere 3 and the secondary prosencephalon (SP; we have come recently to consider this a rostral unsegmented proneuromere; Puelles and Rubenstein, 2003) can be grouped in a rostral forebrain tagma encompassing all forebrain elements rostral to the zona limitans intrathalamica (i.e., the domain unified by alar expression of Dlx and Arx genes and basal expression of Nkx2.1; Bulfone et al., 1993; Kitamura et al., 1997). These rostral and caudal forebrain tagmata might as well be joined into a forebrain protagma—SP, p1–p3, plus midbrain— defined by the early overall domain of Otx2 expression (Simeone et al., 1992b). The hindbrain tagma is represented by a set of 12 overt or hidden transverse units (rhombomere 0—the isthmus, classic rhombomeres 1–7, and pseudorhombomeres 8–11; see Cambronero and Puelles, 2000, on the concept of pseudorhombomeres). The spinal cord may be considered a spinal tagma as well, encompassing the full set of cervical, thoracic, lumbar, and sacral myelomeres (spinal neuromeres or pseudoneuromeres).
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FIGURE 5 In situ hibridized mice embryos at late neural tube stages (whole mounts; eye vesicles cut out, leaving eye stalk openings). The characteristic expression domains of diverse genes are displayed; their names are color-coded depending on the respective arbitrary red (in red) versus blue reaction product (in white). Description in the text. Note the outgrowth of the telencephalic vesicles inside the alar plate. Compare in D, E, and F the increasing size of the ZLI core, labeled with Shh.
The fundamental longitudinal, transverse, and vesicular subregions of the neural tube may become variously deformed or hidden during subsequent morphogenesis, but there clearly remain significant molecular traces of them, manifested in differential cytoarchitectony, chemoarchitectony, and adult gene expression. As mentioned above, the ventricular sulci abundantly used in earlier periods of neuroanatomy are tertiary results of brain development and therefore represent imprecise approximations to the relevant causal molecular boundaries. Patterns of neural differentiation, including cyto-, myelo-, and chemoarchitecture, result directly from the diversified histogenetic patterns in the neural wall, secondary to the early molecular specification states. They therefore represent the most reliable guides to the functionally relevant divisions in the mature brain wall.
THE NEURAL PLATE SUBDIVISIONS Molecular regions traceable already at neural plate stages underline the concept sketched above of DV longitudinal zones curving rostrally around a fixed floor plate endpoint, as opposed to wedge-shaped AP transverse regions (Figs. 1, 2, and 4). A good number of mouse genes are expressed early on along restricted DV longitudinal zones, either across the whole or a
large AP extent of the neural plate (i.e., SCF, Matsui et al., 1990; HNF3␣/, Sasaki and Hogan, 1993; BF-1, Hatini et al., 1994; Nkx2.2, Shimamura et al., 1995; PLZF, Avantaggiato et al., 1995; Grg4/3, Koop et al., 1996; Zic1, Nagai et al., 1997; ENC-1, Hernandez et al., 1997; Nkx2.9, Pabst et al., 1998; sFRP1, Leimeister et al., 1998). Other genes also are expressed longitudinally, but in shorter AP portions of the neural plate (Evx1, Bastian and Gruss, 1990; Wnt7b/3a/1, Parr et al., 1993; Nkx2.1, Shimamura et al., 1995; Ebk, Ellis et al., 1995; Sim2, Fan et al., 1996; Otlx2, Mucchieli et al., 1996; Fgf3, Mahmood et al., 1996; AP2/AP2.2, Chazaud et al., 1996; Nkx2.1, Pax6, BF-1, Fgf8, BMP7, Shimamura and Rubenstein, 1997; BMPs, Furuta et al., 1997; TCF4, Cho and Dressler, 1998; Dac, Caubit et al., 1999; Six6, Jean et al., 1999; Emx2, Suda et al., 2001). In contrast, various genes appear expressed in wedge-shaped transverse domains of the neural plate, encompassing all DV zones at different AP locations (i.e., Boc, Mulieri et al., 2002; Irx3, Bosse et al., 1997; Six3, Oliver et al., 1995; Six6, Toy and Sundin, 1999; Jean et al., 1999; Lhx5, Sheng et al., 1996; BF-1, Lai et al., 1990, 1991; Shimamura and Rubenstein, 1997; Krox20, Lobe, 1997; Hes1/3, Lobe 1997; En1, Lobe, 1997; Mf3, Labosky et al., 1997; Sax1, Schubert et al., 1995; Gsh1, Valerius et al., 1995; Gbx2, Wassarman et al., 1997; Hesx1, Dattani et al., 1998; Martinez-Barbera et al., 2000; Martinez-Barbera and Beddington, 2001; Ras/Rx,
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FIGURE 6 Microphotographic and schematic illustration of gene expression patterns characteristic of either the alar or the basal plate domains of the neural tube. (A,B) In situ hibridized mice embryos at E11.5 (A; single ISH) and E12.5 (B; double ISH) (whole mounts). The characteristic expression domains of three genes are displayed; their names are color-coded depending on the respective arbitrary red versus blue reaction product. Note in A the rostral thalamic Dlx2 expression stopping at the ZLI core, whereas Nkx2.2 labels the ZLI shell area around the core. Abbreviations are as in Fig. 3. (C,D) Schematic representation of the prosomeric model, showing the main postulated longitudinal and transversal subdivisions, superposed with some characteristic molecular genetic markers. See text for description. The mode in which extratelencephalic boundaries might continue into the telencephalon, with or without connection with the palliosubpallial boundary, remains tentative.
Dattani et al., 1998; Pax2/5/6, Schwarz et al., 1999; Otx2, Simeone et al., 1992a; Shimamura et al., 1995; sFRP2, Leimeister et al., 1998; Ptc, Gli, and Shh, Platt et al., 1997). This nonexhaustive list of examples reveals that a remarkable degree of differential molecular specification and regionalization at neural plate stages is already known, displaying patterns consistent with the proposed model of DV and AP axial dimensions and available fate maps (Figs. 1, 2, and 4) (Rubenstein et al., 1998; Inoue et al., 2000; Cobos et al., 2001). It should be noted that there arises a singularity, due to the radial symmetry found at the rostral midline of the neural primordium: the apparent AP dimension along the median neuroepithelium extending from the anterior commissure locus (rostral neuropore or end of
the roof plate) to the locus of the prospective neurohypophysis (rostral end of floor plate) is coded genetically consistently with its content of a full set of DV longitudinal zones (compare with Fig. 1). More laterally, this topological singularity partially affects as well the prospective telencephalon and eye fields (Figs. 1 and 2). Patterning of this median and paramedian rostral domain of the forebrain notably depends on blockage of BMP and Wnt signaling mechanisms, both of which represent “dorsalizing” signals (Wilson and Rubenstein, 2000). Thus, paradoxically, the topographically “anterior” end of the neural plate shows “dorsal” molecular characteristics. This part of the neural tube is also peculiar in being prechordal (overlying the prechordal plate and rostral mesendoderm) while the
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rest of the neuraxis is epichordal (overlies the notochord). This implies vertical inducing effects different from those of the local axial mesoderm and exclusive rostral patterning influences from the anterior visceral endoderm (Rubenstein et al., 1998; Wilson and Rubenstein, 2000). These important differences probably underlie the morphological singularities of the rostral forebrain.
THE CLOSED NEURAL TUBE The incipient bending of the length axis already observed at late neural plate stages increases considerably after neurulation, leading to the well-known cephalic and cervical (ventral) flexures of the neural tube, as well as to the oppositely oriented pontine flexure (Figs. 3–5). Observations of gene marker expression and fate mapping in different vertebrates consistently support the notion that molecularly distinct regions of the early neural tube bend coherently with it, implying that relative specification of DV and AP position along the neural wall is not affected by this macroscopic morphogenetic process. Precise reference to brain AP and DV “relative molecular” positions thus will henceforth need topological terms referred to the bent length axis (Fig. 3) (Puelles and Rubenstein, 1993; Puelles, 1995, 2001b), against current usage (compare, e.g., the BMPs expressed dorsally all along the neural tube roof in Furuta et al., 1997). It is important to realize that during the rebirth of neuroanatomy after the 2nd World War, topographic references for the brain became founded upon the now obsolete convention of a brain length axis lacking a cephalic flexure and ending rostrally inside the telencephalic vesicle—the bent axis was erroneously supposed to be transient during development (see recent use of this convention in Swanson, 1992, his Figs. 3–5). That assumption is clearly irreconcilable with the concept presented here and poses various terminological sources of confusion, due to its widespread usage. The possible confusion resulting from partial or complete adherence to such a brain model affects notably two brain areas: (a) the isthmic and pedunculopontine hindbrain regions frequently are misinterpreted as midbrain derivatives (the midbrain entirely lies rostral to them), and (b) some diencephalic areas are also wrongly attributed to the midbrain (i.e., the pretectum and the prerubral tegmentum extending into retromammillary areas). The classical rendering of the main diencephalon (in Herrick’s model) as consisting of superposed longitudinal areas (i.e., dorsal and ventral thalami, hypothalamus) is exactly 90º wrong when we refer to the observed bent axis of the forebrain (Figs. 3–5), since these diencephalic areas actually are transverse domains orthogonal to the causally
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determinant axial elements in the floor of the neural tube and in the underlying mesoderm (Puelles and Rubenstein, 1993; Rubenstein et al., 1994, 1998; Shimamura et al., 1995; Puelles, 1995, 2001b). Note these two problematic brain regions caudal and rostral to the midbrain precisely encompass the stretch of neural tube bent at the cephalic flexure. A further common cause of morphologic confusion lies in regarding the telencephalon, an entirely dorsal derivative of the rostral forebrain, as an area where palliosubpallial regionalization can be described as “dorsoventral” patterning (see pallium and subpallium in Figs. 2–6), implicitly assuming a phantom length-axis bifurcated inside each of these paired vesicles; see Puelles and Rubenstein, 1993). Fate mapping at neural plate stages has shown conclusively that the subpallium is rostral relative to the pallium (Inoue et al., 2000; Cobos et al., 2001) (see Fig. 2). A number of genes show domains of expression that cover the whole DV extent of the neural tube wall, with transverse boundaries at diverse AP locations. The prosomeric model identifies a number of morphologic boundaries that correlate with these molecular subdivisions (Figs. 4D, 5C–5E, 6C, and 6D) (Puelles and Rubenstein, 1993; Puelles, 1995, 2001a; Rubenstein et al., 1994, 1998; see Echevarria et al., 2001, for neural tube flat-mount culture). This model initially postulated six prosomeres in the forebrain (counted caudorostrally from the mes–diencephalic border in the order of appearance) and one mesomere. In a recent update of the model, we acknowledged that no strong evidence has accumulated for the postulated prosomeres 4–6 within the secondary prosencephalon, and we are now proposing that the secondary prosencephalon as a whole should be regarded as an unsegmented proneuromere, which is further patterned by singular mechanisms into specific telencephalic and hypothalamic subdivisions nonanalogous to either DV or AP divisions found more caudally in the neural tube (Puelles and Rubenstein, 2003). The rest of the forebrain, the caudal diencephalon or diencephalon proper, subdivides into prosomeres 1–3, for which there is strong evidence. Note we regard the prosomeric model as an advanced and empirically potent construct, which nevertheless remains essentially nonfinished. It already has been modified in recent years in light of accruing evidence (tracing of some boundaries or identity of neural derivatives of given areas) and will probably continue to evolve in the quest of greater consistency and usefulness. At closed neural tube stages, Six3 first appears restricted to the entire rostromedian DV domain originally postulated by us as p6 (Oliver et al., 1995) (compare Figs. 4D and 4E); this region later gives rise to the
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rostralmost forebrain, including the telencephalic septum, the optic vesicles, and the hypothalamus (some secondary domains appear elsewhere later). Interestingly, elimination of Six3 activity leads to severe stunting of the forebrain, amounting to complete loss of the entire secondary prosencephalon (Lagutin et al., 2003). Otx2 expression first appears in the whole forebrain tagma, down to the caudal limit of the midbrain (Fig. 4A). This boundary remains constant, while some rostral forebrain areas secondarily downregulate Otx2 (Simeone et al., 1992b). The Irx1/2/3 genes, present in the brainstem and midbrain, jointly show a rostral transverse boundary coinciding with the zona limitans intrathalamica in the diencephalon (ZLI ; p2/p3 limit; Bosse et al., 1997) (Figs. 3, 4D, and 5E). The genes En1 and En2 define overlapping transverse domains across the isthmic boundary, but their signal reaches, at least initially, the rostral midbrain limit. Gbx2 is widely expressed in the spinal cord and hindbrain and stops rostrally at the isthmomesencephalic boundary, abutting the caudal boundary of Otx2 and a transverse ring of Wnt1 expression in the caudal midbrain (Figs. 4A and 4B).
BASAL PLATE REGIONS Gene expression patterns illustrating longitudinal zones in the closed neural tube are well known. For instance, the basal plate domain in the extended forebrain (including midbrain) is defined at the ventricular lining by continued expression of the Shh gene, coding for a secreted protein largely responsible for early ventralizing patterning effects (Figs. 4F, 5A, 5D–5F). Though initially also expressed in the forebrain floor plate, Shh later becomes downregulated in the hypothalamic floor region. This forebrain–midbrain pattern contrasts with the hindbrain and spinal cord expression of Shh, where it remains restricted to the floor plate. Other genes contribute to the regional specification of the basal plate, with various AP restrictions. In the secondary prosencephalon, the basal plate zone of the hypothalamus characteristically expresses the transcription factors Nkx2.1 and Nkx5.1/Nkx5.2, overlapping the local Shh signal (Figs. 5B and 6B) (Shimamura et al., 1995; Rinkwitz-Brandt et al., 1995). Fkh-4 and Fkh-5/Mf3 signals are restricted to the mammillary region (Kaestner et al., 1996; Wehr et al., 1997). Hypocretin (orexin) also seems restricted to the posterior hypothalamic basal plate, above and behind the mammillary complex (Peyron et al., 1996). Dbx seems to be expressed selectively in the basal plate of p3 (Fujii et al., 1994). Emx1 characterizes the basal plate of p2 (Simeone et al., 1991; Puelles, unpublished observations), whereas Mf2
appears restricted to the basal domain of p1 and, separately, to the secondary prosencephalon (Sareina et al., 1998). The basal domain of Lim1 initially coincides just with p1 and the midbrain, though it later expands rostrally (Mastick et al., 1997). In the caudal forebrain (p1–p3, mes), as well as in the hindbrain and spinal cord, the medial part of the basal plate (where motoneurons are produced) expresses the Sax1 and Nkx6.1 genes (Schubert et al., 1995; Qiu et al., 1998). The Nkx6.1-positive column of basal neurons unifies the hindbrain, midbrain, and forebrain medial tegmentum up to the retromammillary area, irrespective of the change in expression pattern of Shh and several other genes at the isthmus (Fig. 6D) (Qiu et al., 1998). Rostral to the midbrain oculomotor nucleus, this neuronal band forms a recently characterized compact “periventricular tegmental area” where LHRH neurons are formed (Puelles et al., 2001); classical literature refers somewhat vaguely to this formation as the “nucleus of Darkschewitsch.” Isl-1 appears in all postmitotic motoneurons, as well as in other basal and alar derivatives in the forebrain (Ericson et al., 1995). The lateral part of the forebrain and midbrain basal plate, adjacent to the alar–basal boundary, expresses the genes Nkx2.2, Nkx2.9, and Ptc (Fig. 6B; all three continue in the hindbrain and spinal cord in a thin band, found adjacent to the floor plate expression of Shh; Shimamura et al., 1995; Platt et al., 1997; Pabst et al., 1998). Wnt7a and Wnt5a are expressed along much—if not all—of the epichordal basal plate (Parr et al., 1993). A band of Gli-1 and Ptc expression apparently parallels the alar–basal boundary at the alar side in the midbrain and diencephalon, apparently just outside the Shh expression in the basal plate (Hynes et al., 1997; Platt et al., 1997). It has not been determined yet whether the neighboring band of Nkx2.2 and Nkx2.9 expression, which seems to abut on this boundary from the basal side, overlaps partially with the Gli-1 and Ptx bands. Most genes expressed in the forebrain basal plate— i.e., Shh, Sim1, Sim2, Sax-1, Six3, Otlx2, Brx1, Nkx2.2, Nkx2.9, Ptc, Plp, DM20, Emx1, and PLZF—are deflected transversally into the core (i.e., Shh in Fig. 5F) or shell regions (i.e., Nkx2.2 in Fig. 6B) of the ZLI (this encloses the p2/p3 limit) at the transverse boundary between the classical ventral and dorsal thalamic regions (thalamus and prethalamus in our present terminology; TH and PTh in Figs. 3–6). Comparative data in zebrafish and chick embryos suggest that this paradoxical transverse ZLI spike of the longitudinal basal markers does not exist at early stages, when the longitudinal zones are first established, but is formed secondarily (Barth and Wilson, 1995; Hauptmann and Gerster, 2000; Larsen et al., 2001). Formation of the ZLI spike in zebrafish accompanies dorsal expansion of the rostral-most
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expression of the gene axial, the homolog of the mammalian HNF-3 gene, another basal plate marker (Sasaki and Hogan, 1993; Barth and Wilson, 1995). It seems that the transverse dorsalward deflection of longitudinal ventral markers at the ZLI (followed by other genes controlled by them, such as Nkx2.2; Shimamura et al., 1995; see also Platt et al., 1997) results from homeogenetic induction of “basal” genes in primitively alar cells, followed by consequent changes in the neighboring cell populations (S. Martínez, unpublished observations). Curiously enough, some roof plate gene expressions also become deflected ventrally into the ZLI during early development (e.g., Fgf8, Bmp4, and Wnt3a; see Crossley et al., 2001). The expression of diverse genes coding for diffusible morphogens at the ZLI (SHH, WNTs) underlies the current hypothesis that the ZLI may represent a diencephalic (thalamic) organizer. Rostrally to their deflection into the ZLI, most basal plate gene domains in the diencephalon curve into the floor at retromammillary or mammillary levels, after passing longitudinally ventral to the prethalamus (p3). It is not yet clear why this occurs. It is attractive to speculate that this phenomenon relates to the transition between epichordal and prechordal parts of the neural tube and portrays the end of epichordal induction effects. Genes such as HNF3 might depend directly or indirectly on signals diffusing exclusively from the notochord (whose rostral tip lies close behind the mammillary pouch) and thus are not present more rostrally, next to the prechordal plate. Several classical neuroanatomists postulated the mammillary or retromammillary regions to be at the rostral end of the basal plate (see reviews in Shimamura et al., 1995, and Puelles, 1995). Floor plate markers and local differentiation patterns comparable to those in the midbrain tegmentum extend for a distance rostral to the midbrain. This is consistent with the idea that the ventral neural tube directly exposed to chordal influence ends at the retromammillary region (the latter actually lies in the secondary prosencephalon, closely behind the mammillary complex; note that literature often refers to this area as the “supramammillary region,” a less apt term that implicitly assumes a non-bent longitudinal axis at the cephalic flexure). Due to the dogmatic perdurance of His’ (1904) tentative definition of the meso–diencephalic border (extending from the posterior commissure to the mammillary pouch), the retromammillary and prerubral tegmentum have traditionally been assigned to the midbrain tegmentum. This has obscured our understanding of this entire brain region, which turns out to contain distinct parts belonging to mes, p1–p3, and the caudal-most part of the secondary prosencephalon (hypothalamus);
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molecular specification patterns described above reveal both shared gene expressions (reflecting the general character of the epichordal forebrain basal plate) and differentially expressed genes, which provide specific identities to the diverse AP sectors. For instance, as a reflection of a shared causal pattern, dopaminergic neuronal populations of the mammalian ventral tegmental area have their origin throughout the paramedian floor continuum extending from the isthmus to the retromammillary region (Verney et al., 2001). The mammillary region itself apparently lies under the crossed inductive influences of the tip of the notochord and the caudal end of the prechordal plate, which possibly leads to its molecular, anatomical, and functional singularities. The rest of the ventral forebrain (tuberomammillary and tuberal hypothalamus) would be selectively influenced by prechordal mesodermal signals. Prechordal Nodal signaling upon the secondary prosencephalon is needed to impede cyclopia and holoprosencephaly; accordingly, a particular mechanism mediates the bilateral formation of the eyes and the telencephalic vesicles. Thus, while Shh and Isl-1 are expressed along the whole forebrain and midbrain basal plate, defining the generic ventralized character of this longitudinal zone, other basal plate genes show either prechordal or epichordal expression domains, apparently divided at the mammilloretromammillary boundary. The literature is extremely confusing about whether or not the rostrally convex curve of the epichordal basal genes encloses the mammillary bodies. Recently we have discovered this ambiguity to be related to the fact that the mammillary primordium is morphologically inconspicuous at early stages, and only becomes clearly identifiable as a distinct bulging pouch approximately after E14–15 in the mouse. At earlier stages there exists in this area of the forebrain floor a similar ventral bulge that actually corresponds to the prospective retromammillary area; this is later overshadowed by the more prominent mammillary protrusion. The precocious retromammillary pouch apparently has been frequently misinterpreted in developmental and gene mapping studies (including our own ones; i.e., Bulfone et al., 1993) as the mammillary pouch. The mouse gene Otlx2, for instance, described as mapping to the mammillary and retromammillary basal areas, clearly ends restrictedly at the retromammillary area (and also labels its laterally displaced derivative, the subthalamic nucleus), while the incipient mammillary pouch in front of it is distinctly devoid of this signal (Mucchielli et al., 1996; their Fig. 5B showing an E13.5 mouse embryo). A similar reinterpretation may be needed for Brx1 (Kitamura et al., 1997) and Ebf1/Ebf2/Ebf3 (Garel et al., 1997), among other genes. On the other hand, the Sim1
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and Sim2 genes, depicted early on as expressed along a basal band that surrounds the mammillary pouch, actually map precisely upon the mammillary primordium in the terminal arc where their respective bands approach the forebrain midline floor (Fan et al., 1996; their Fig. 6). Moreover, the final mammillary curve of the Sim1/2 basal domains coincides with expression of the Otx1, Otp, and PLZF genes (Avantaggiato et al., 1995), as well as with the genes Mf3 (Labosky et al., 1997) and Fkh-4 (Kaestner et al., 1996), and is delineated as well by the caudal boundary of some genes expressed in the tuberal or tuberomammillary hypothalamus, including the Dlx family genes (Avantaggiato et al., 1995; Puelles, unpublished observations) and Arx (Miura et al., 1997). Finally, the similarly arc-shaped posterior boundary of the Nkx2.1 expression domain in the basal hypothalamus, which initially one tends to believe respects the mammillary pouch (see Fig. 5B), actually contours the retromammillary region, as becomes clear later on (see Figs. 6B and 6D), when the mammillary pouch proper and all its derivatives stand out as strongly Nkx2.1-positive. Realization of this cause of confusion has led us in recent publications to, first, “move” the mammillary primordium from p4 to p5 (Puelles, 2001b), and, most recently, to simply consider it a specialized part of the unsegmented hypothalamic basal plate (Puelles and Rubenstein, 2003). The retromammillary tegmental region, jointly with the so-called “posterior hypothalamus,” represents the basal plate and floor domains at the epichordal–prechordal transition (Figs. 2, 3, and 6). There occurs also a more detailed, microzonal DV patterning inside the basal plate itself, driven by signals from the midline cells (Ruiz I Altaba and Jessell, 1993) and leading to a detailed neuroepithelial DV zonal specification where each microzone produces different subtypes of neurons. This process has been best studied in the mouse spinal cord and hindbrain (Osumi et al., 1997; Ericson et al., 1997; Briscoe et al., 1999; Sander et al., 2000; McMahon, 2000; Stone and Rosenthal, 2000).
ALAR PLATE REGIONS There are genes expressed in the closed neural tube whose signal extends selectively throughout the alar plate from end to end. Such is the case of the Zic genes (Zic1-3; Nagai et al., 1997). Other genes, like Pax7 and Pax3 (Stoykova and Gruss, 1994), are found in the alar plate of the spinal cord, the hindbrain, the midbrain, and part of the caudal diencephalon (p1; Fig. 6C). Pax2 and Pax8 also have extensive alar domains of expression, stopping rostrally at the isthmus; Pax5 is expressed only in a smaller domain centered upon the isthmo-
mesencephalic boundary (Stoykova and Gruss, 1994). Interestingly, another Pax gene—Pax6—is expressed initially throughout all alar forebrain domains, stopping caudally at the p1–mes boundary (Figs. 5C and 6C), though it is secondarily partly downregulated both rostral and caudal to the ZLI (incipient at the stage illustrated in Fig. 5C). At later stages this gene becomes largely restricted to the rostral half of the prethalamus in p3, the epithalamus in p2, and the caudal (commissural) pretectum in p1 (Fig. 8D) (Stoykova and Gruss, 1994; Mastick et al., 1997). The definitive Pax6 alar domain also extends through the eminentia thalami into the adjacent pallial part of the telencephalon (Figs. 5C, 6D, and 8B–8H; the eminentia thalami is a topologically dorsal area of p3 (see Figs. 2, 3, and 6), whose ventricular surface bulges at the back of the interventricular foramen, forming sulcus terminalis with the basal ganglia at the bottom of the caudal lateral ventricle—see EMT in Fig. 8; it represents the bed of the stria medullaris tract, rostral to the epithalamus). Wnt7b, similar to Pax6, is expressed in the eminentia thalami and expands rostrally into the telencephalic pallium in p5 (Parr et al., 1993). Other genes showing a connection of eminentia thalami expression with caudal (amygdaloid) telencephalic pallium signal are Dbx (Lu et al., 1994, 1996) and Otp (Wang and Lufkin, 2000). Finally, both the gene Lhx5 and the gene coding for R-cadherin appear expressed in the whole extratelencephalic alar plate rostral to the ZLI (Sheng et al., 1997; Redies and Takeichi, 1996). Other gene patterns in the alar plate are less extensive along the AP axis, but still respect some postulated interneuromeric boundaries. The forkhead gene BF-2 appears in the forebrain alar plate rostral to the ZLI (p2/p3) limit, but is excluded from the telencephalon, where a complementary pattern of BF-1 is found (Tao and Lai, 1992; Hatini et al., 1994; Xuan et al., 1995). The gene Arx (Miura et al., 1997) appears in the entire alar extent of p3 (prethalamus and the overlying eminentia thalami); this pattern displays most clearly the p3–SP boundary across the alar plate (for prethalamic molecular subdivisions, see Kitamura et al., 1997, and Nakagawa and O’Leary, 2001). Arx also shows a longitudinal thin alar band of expression along the alar–basal boundary of the secondary prosencephalon (SP), which ends in the suprachiasmatic area of the hypothalamus. It may be useful to call this the “chiasmatic band” (Figs. 6C and 6D). The Dlx family genes overlap the Arx-positive domain in the prethalamus, excluding the eminentia thalami, and in the chiasmatic band (Fig. 6), but their signal also appear additionally in the tuberomammillary and arquate hypothalamic areas (Bulfone et al., 1993). The Arx- and Dlx-negative alar region immediately dorsal to the
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chiasmatic band is known as the “optoeminential domain” (due to its end at the optic stalk; see oem in Fig. 3). Here typically the genes Brn2, Otp, and Sim1, are expressed, though there are suggestions that they do not completely overlap, possibly defining subdivisions within the optoeminential domain (Fig. 6C) (Simeone et al., 1994; Nakai et al., 1995; Fan et al., 1996; Michaud et al., 1998; Acampora et al., 1999). This area is the locus where the magnocellular and some parvocellular hypophysiotropic neuronal populations of the paraventricular, anterior periventricular, and supraoptic nuclei are formed, jointly with part of the entopeduncular nucleus (another part of the latter arises in the caudal part of the chiasmatic band). The gene Six6 is present early on, jointly with other genes, in the optic field and optic vesicles (Toy and Sundin, 1999; Crossley et al., 2001). Wnt3 defines the entire alar plate of p2 (thalamus plus epithalamus), whereas Gbx2 appears restricted therein to the dorsal thalamus area (Fig. 6C) (Bulfone et al., 1993; see later thalamic subdivisions in Nakagawa and O’Leary, 2001, and Gonzalez et al., 2001). The gene TCF-4 labels jointly the alar plate of p1 (pretectum) and p2 (thalamus and epithalamus; Fig. 5D) (Cho and Dressler, 1998), whereas the entire alar p1 expresses the gene Lim1 (Fujii et al., 1994). The Ebf family genes characterize the rostral (precommissural) pretectum (p1), as well the optoeminential and eminentia thalami domains mentioned above (Garel et al., 1997). On the other hand, Sax1 is expressed in caudal alar p1 (Schubert et al., 1995), a domain similarly marked by the gene AP-2 (Chazaud et al., 1996) and the gene Lmbx1 (Gogoi et al., 2002; Broccoli et al., 2002), all of which also extend into the adjoining midbrain. The rostral pretectum shows signals of the genes Dbx1 and Dbx2 (extending into p2; Shoji et al., 1996), as well as of PLZF (the latter also present in the epithalamus; Avantaggiato et al., 1995). As an example of a more heterogeneous pattern, Gsh-1 is expressed distinctly not only in alar p1, but also in the alar midbrain, the caudal bank of the ZLI in p2, alar p3, alar SP, and the subpallium (Valerius et al., 1995). Some gene expression patterns subdivide the alar midbrain into anterior and posterior parts corresponding to the superior and inferior colliculi. For instance, Hes3 appears in the caudal midbrain (inferior colliculus; Lobe, 1997), whereas Otlx2 appears in the alar rostral midbrain (superior colliculus; Mucchielli et al., 1996).
TELENCEPHALIC PATTERNS The evaginated telencephalic vesicle is divided basically into subpallial and pallial molecular domains
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(Figs. 6A–6D and 9) (Puelles et al., 2000). We presently conceive these two telencephalic primary domains as differential dorsal alar derivatives of the secondary prosencephalon, though they possibly do not represent straightforwardly either DV or AP subdivisions (Puelles and Rubenstein, 2003). It is doubtful that the palliosubpallial boundary, as defined for instance by abutting domains of Dlx and Tbr1 expression in all vertebrates examined so far (Figs. 6A, 6C, 7, 8, and 9), is strictly continuous with an extratelencephalic transversal boundary in the neural tube wall. It forms a curve that encloses the basal ganglia and the subpallial amygdala, a large part of the septum, the anterior entopeduncular area (at the telencephalic stalk), and the preoptic area (Figs. 6C–6D). The prospective pallidal subdomain marked by expression of Nkx2.1 is limited by another curve, enclosed by the larger one (Figs. 5B and 6A–6D); moreover, the smaller anterior entopeduncular area selectively expressing Shh also appears enclosed within the Dlx+Nkx2.1-positive domain, in a Russian-doll-like arrangement. None of these domains reach caudally the rostral border of p3 (represented here by the eminentia thalami, Emt), from which they are separated by intratelencephalic spikes of the gene expression territories of the optoeminential domain, which extend in front of the rostral border of p3 into the caudal telencephalic pole (amygdala; Figs. 6C and 6D). These spikes form part of the stria terminalis band, while other parts of this complex, representing as well the extended amygdala, develop within the striatal and pallidal subdomains (Bst). All this complexity suggests that several special patterning effects are superposed upon any fundamental prosomeric topology of the SP, possibly initiated by the action of a rostral organizer at the anterior neural ridge of the neural plate (ANR in Fig. 1; see Crossley et al., 2001), which acts upon nearby areas of the SP. The optoeminential domain at the transition between the telencephalic subpallium and the hypothalamus seems to be an alar pattern that just escapes the rostral organizer influence and probably relates causally to the eye field patterning mechanisms (Wilson and Rubenstein, 2000). The entire telencephalon falls within the expression domain of BF-1, coinciding already at neural plate stages with fate-map data (TEL; Fig. 2) (Shimamura et al., 1995) and bulging out as distinct paired vesicles shortly after neural tube closure (Tao and Lai, 1992; Hatini et al., 1994; Xuan et al., 1995). Curiously, the BF-1 expression domain extends outside the evaginated vesicles into the preoptic area and nasal portion of the optic vesicles (this, together with the preoptic sharing of some subpallial markers—Fig. 6—gives some molecular support to the old morphological conception of an
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FIGURE 7 Autoradiographic in situ hibridizations of parallel section series through an E13.5 mouse brain, cut in a plane horizontal to the forebrain axis. The upper range of photographs illustrates subpallial and prethalamic expression of Dlx2. The range at the bottom shows pallial expression of Emx1 in adjacent sections. Note the facing boundaries of these two patterns do not touch, leaving a thin negative space, conceived to represent the ventral pallium region (Puelles et al., 2000; see Fig. 9).
FIGURE 8 Autoradiographic in situ hibridizations of parallel section series through an E13.5 mouse brain, cut in a plane horizontal to the forebrain axis (same brain as in Fig. 7). The upper range of photographs (a,c,e,g) illustrates expression of Tbr1 throughout the pallial mantle zone and in derivatives of the eminentia thalami (EMT). The range at the bottom (b,d,f,h) shows in adjacent sections expression of Pax-6 in the pallial ventricular zone, extending into the EMT ventricular zone, and in parts of the prethalamus and commissural pretectum. Note in panels (d) and (f) a stream of Pax-6-positive neurons migrating radially inside the outer striatal subpallium and accumulating in the olfactory tuberculum and anterior amygdala (ms; TO; AA; compare with Fig. 9).
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impar telencephalic portion, associated essentially with the preoptic area. Attribution of the latter to the hypothalamus never was more than a convention, which seems increasingly obsolete; see Keyser, 1972). Shortly after the evagination of the telencephalic vesicle, the molecular palliosubpallial boundary becomes established (it coincides with the highest expression of tenascin-C in the neuroepithelium; Stoykova et al., 1997). The subpallium sensu lato (subpallium proper plus telencephalon impar) starts to express the Dlx genes (Dlx1, Dlx2, Dlx5, Dlx6; Bulfone et al., 1993; Liu et al., 1997) (Fig. 7), as well as Mash1 (Porteus et al., 1994; Tuttle et al., 1999), Isl-1 (Bulchand et al., 2001), netrin (Métin et al, 1997; Tuttle et al., 1999), Olig2 (Takebayashi et al., 2000), and Gsh2 (Yun et al., 2001), among other general subpallial markers. The basal ganglia primordia and centromedial part of the amygdala formed within this field soon bulge into the ventricular cavity. Both the striatal and pallidal domains of the basal ganglia extend rostromedially into the septum (Figs. 3 and 9) (Puelles et al., 2000). First there appears the medial ganglionic eminence (MGE), the pallidal primordium, which expresses, in addition to the Dlx genes, the Nkx2.1 and Lhx6 genes (Grigoriou et al., 1998; Sussel et al., 1999; Lavdas et al., 1999; Tuttle et al., 1999; Figs. 5B and 6B). The Nkx2.1 domain also covers the anterior entopeduncular area and the anterior preoptic area (AEP, POA). Coexpression of other Nkx genes—Nkx5.1 and Nkx5.2—distinguishes selectively the POA (Rinkwitz-Brandt et al., 1995),
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while the AEP selectively combines the expression of Shh in its ventricular zone (Figs. 5A and 5D–5F) (Sussel et al., 1999; Bulchand et al., 2001) and displays also selectively DM20 signal, associated with the local appearance of a source of oligodendrocyte precursors (Timsit et al., 1995). The telencephalic magnocellular cholinergic neurons possibly originate also from the AEP, colonizing thereafter the basal nucleus of Meynert, the diagonal band, and the septum; smaller cholinergic neurons invade the striatum (Marín and Rubenstein, 2001). Note that the boundaries between diverse subpallial regions in the mantle zone are less clear than those in the ventricular zone, because of the complex tangential cell migrations into adjacent histogenetic domains. The septum, on its part, strongly coexpresses steel as a distinctive molecular character (Bulchand et al., 2001). The lateral ganglionic eminence (LGE), representing the striatal primordium, bulges slightly later into the lateral vetricle, lateral and rostral to the MGE; both eminences fuse caudally at the amygdaloid caudal ganglionic eminence (Figs. 6B–6D). Apart from Dlx and other general subpallial marker genes, the striatal domain also displays some selective markers, such as Ebf1, SCIP, RAR␣, CRABP-1, and mCad8 (Garel et al., 1999) or Pax6 and Six3 (Puelles et al., 2000; Yun et al., 2001). Selective expression of striatin was described in the rat striatum (Fig. 6C) (Salin et al., 1998). On the other hand, the pallial domain of the telencephalon is generally delineated by a number of marker genes, showing strong neuroepithelial expression of
FIGURE 9 Comparison of characteristic molecular subdivisions in sauropsidian and mammalian telencephali to illustrate conservation of topology of molecular domains and differential morphogenesis/histogenesis, consistent with the respective postulated “field homologies” for both the pallium and the subpallium. Septum is shown unlabeled. DP, dorsal pallium; LP, lateral pallium; MP, medial pallium; mz, mantle zone; PA, pallidum; ST, striatum; VP, ventral pallium; vz, ventricular zone. Asterisk, radial migration of Pax6 cells; double asterisk, tangential migration of pallial cells. Note that the massive tangential migration of GABAergic interneurons from the subpallium into the pallial mantle is not represented.
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Pax6 (Figs. 5C and 8b–8h), R-cadherin, Ngn1/2 (Stoykova and Gruss, 1994; Stoykova et al., 1997, 2000; Wilson and Rubenstein, 2000; Yun et al., 2001), and many other genes, e.g., AP2.2 (Chazaud et al., 1996) and vzg-1 (Hecht et al., 1996). Curiously, a lower signal of Pax6 also appears in the striatal ventricular zone, accompanied by migration of Pax6-positive neurons in the local mantle, but the pallium itself is completely devoid of Pax6-expressing mantle cells (Figs. 5C, 8d, 8f, 8h, and 9) (Puelles et al., 2000). The pallial mantle shows initially general expression of Tbr1 (Figs. 8a, 8c, 8e, 8g, and 9) (Bulfone et al., 1995). We proposed a subdivision of the pallium into four molecularly distinct parts, named medial, dorsal, lateral, and ventral pallial portions (MP, DP,LP, VP; Fig. 9) (Puelles et al., 2000; see also Stoykova et al., 2000; Yun et al., 2001; Puelles, 2001a,b). The medial pallium largely includes hippocampal and parahippocampal cortex, while the dorsal pallium corresponds to the isocortex. On the other hand, the lateral and ventral pallial portions separately contribute to olfactory piriform cortex and the underlying claustral, endopiriform, and basolateral amygdaloid nuclei (Puelles et al., 2000). The Wnt7a gene characterizes the MP and DP. Emx1 is expressed in MP, DP, and LP, but is excluded from VP (Fig. 7; note VP does show a stream of possibly tangentially migrated superficial cells). Lhx2 is more strongly expressed in MP and DP than in LP and VP, though one of the derivatives of these, the claustrum, selectively expresses Lhx2 (Rétaux et al., 1999;Yun et al., 2001; Bulchand et al., 2001). Claustrum and endopiriform nuclei are also selectively positive for latexin (Arimatsu and Ishida, 1998). A good number of genes have been reported recently that are expressed regionally or gradientally in various ways in the mouse, rat, or human cortex. The reader is referred here to some relevant sources (Bulfone et al., 1995; Suzuki et al., 1997; Inoue et al., 1998; Grove et al., 1998; Rubenstein et al., 1999; Miyashita-Lin et al., 1999; Rétaux et al., 1999; Donoghue and Rakic, 1999; Bertuzzi et al., 1999; Nakagawa et al., 1999; Wilson and Rubenstein, 2000; Yun et al., 2001, 2003).
ABOUT MECHANISMS One may ask what is the rationale for the consistent formation of topologically conserved gene expression domains and resulting distinct brain wall regions. The conservativeness of the invariant Bauplan topology against random mutational effects that hypothetically should promote its variation (and consequent evolution) bespeaks of strong internal constraints, which maintain constant the number and relative spatial arrangement
of the primary histogenetic units, irrespective of their individual variations in secondary histogenetic aspects and tertiary morphogenesis and function. Present-day thoughts about how morphogenies achieve partial morphostasis (lack of change) during millions of years of evolution underline the role of causal nets of changebuffering activities of many transcription factor genes. These are arranged in retroactively and horizontally interconnected causal cascades, which build superposed and multiply redundant layers of regulated regulators within causal “attractor fields,” also known as “morphogenetic fields” (Thomson, 1988; Arthur, 1998; Striedter, 1998; Puelles and Medina, 2002). Such complex multi-stable causal entities represent basins in the organismic epigenetic landscape (Waddington, 1957), which tend to produce particular developmental outcomes despite considerable variations in the individual molecules or in the number and type of cellular elements enacting the “field effect.” Such collections of regulatory genetic loops and the resulting morphogenetic fields are held to be of ancient evolutionary origin, possibly coincident with the establishment of the fundamental animal morphotypes. Subsequent evolution indeed seems to have deepened considerably, rather than diminished, the regulatory capacity of the “attractor” mechanisms (their developmental “buffering” potential, or the depth of the morphogenetic basin). Evolution obviously diversified simultaneously the levels and types of emergent novelty that can be viably made consistent with these attractors. This may explain the coexistence of evolving phenotypes, eventually with emergent morphological and functional novelty, and a conserved Bauplan.
RELEVANT GENETIC MECHANISMS In the DNA sequence, specific “enhancer” or “repressor” motifs within gene promoters regulate the expression of each gene in particular brain (or body) locations and eventually also under particular functional conditions. These regulatory sites are the binding targets of particular transcription factors (frequently with associated regulating proteins), which thus combinatorially direct gene expression. As development proceeds, the region-specific constellations of expressed transcription factors interact in the nucleoplasm with the gene enhancers and suppressors. This process translates the positional aspects of the previous specification state (the spatially nonhomogeneous distribution of transcription factors and other molecules) into the next stage of regionalization, which results from the new combination of genes activated and resulting specification changes. Some genes reactivate themselves,
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or pairs (sets) of genes activate each other mutually, leading to extended temporal maintenance of some fundamental molecular aspects of the specification states. This phenomenon leads to progressive recruitment of a defined regional identity, as more such “permanent” genes are upregulated in the course of development. During evolution, some enhancer or suppressor sequences of one gene may have been duplicated and/or translocated by recombination into other genes. This phenomenon can explain the typical situation where different genes (notably redundant genes of the same family, formed by partial or complete chromosomal duplication) show identical, or very similar, expression domains (i.e., the neurally expressed Dlx1,2,5,6 or Irx1,2,3 genes). The resulting congruent expression control via comparable enhancers contributes to the developmental fixation of Bauplan elements. Viable promoter configurations are highly resistant to change and contribute by potential interaction of multiple and redundant transcription factors to the buffering of aleatory changes introduced by mutation in a single gene of the constellation. Simultaneously, the nature of these mechanisms allows for novel genes to be added to preexisting constellations (a relatively rare event) and, more importantly, allows deviant genes no longer performing an essential role within the constellation to vary further (a more frequent event), exploring novel functional possibilities, so to speak, and potentially leading to phenotypic variation and brain evolutionary change.
Acknowledgments We thank Oxford University Press, Wiley–Liss, Inc., and Christoph Redies for permission to use previously printed microphotographic or graphic materials.
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C H A P T E R
2 Development of the Telencephalon: Neural Stem Cells, Neurogenesis, and Neuronal Migration SHIRLEY A. BAYER and JOSEPH ALTMAN Laboratory of Developmental Neurobiology, Indiana University–Purdue University Indianapolis, Indiana, USA
Neural stem cell research is an intensely studied topic today. Most of the work is either on gene expression studies in vivo or biochemical characterizations in vitro. The research that is presented here is histological and cytological. Spatiotemporal changes in developing brain morphology (normal histology) and cell proliferation dynamics ([3H]thymidine autoradiography) are used to map stem cell heterogeneity in the neuroepithelium of the telencephalon and in the secondary germinal matrices derived from the telencephalic neuroepithelium from embryonic day (E) 11 to E22. The maps shown here often correlate with recently published gene expression maps of the telencephalon (Stoykova et al., 2000; Zappone et al., 2000; Bulchand et al., 2001; Schuurmans and Guillemot, 2002). Migration patterns throughout the telencephalon are briefly reviewed and the development of three migratory streams, the lateral, rostral, and dentate, is documented in greater detail. Because both the rostral and dentate migratory streams contain neural stem cells that persist in adult rodents, a brief review of adult neurogenesis is also included. Finally, we summarize the population dynamics of neural stem cells during normal development. The most important data used to generate the mosaic maps of the neuroepithelium and secondary germinal matrices are the timetables of neurogenesis of telencephalic neurons. These timetables were quantitatively determined in adult rats that were exposed on 2 to 4 consecutive days to [3H]thymidine during development (long-survival autoradiography). Figures 1
The Rat Nervous System, Third Edition
through 6 summarize telencephalic neurogenetic timetables. These data reveal when a group of neural stem cells is actively producing neurons, either in the expanding and receding parts of the primary neuroepithelium or in the expanding and receding secondary germinal matrices derived from the primary neuroepithelium. The actual location of a germinal zone and proliferation dynamics are based on observations in embryonic and fetal rats that survived 2 h after single [3H]thymidine injections (short-survival autoradiography). Sojourn and migration patterns are based on observations in embryonic and fetal rats that survived for successive 24-h intervals after single [3H]thymidine injections (sequential-survival autoradiography). When all of these methods are used together, and the observations are correlated between specimens, the fundamental processes of brain morphogenesis can be understood. For a detailed description of all three methods of [3H]thymidine autoradiography and their uses, see Bayer and Altman (1974, 1987, 1991a). The maps themselves are presented in two sets of sections from normal rat embryos and fetuses that were not exposed to [3H]thymidine. These are plates chosen from the Atlas of Prenatal Rat Brain Development (Altman and Bayer, 1995). The first set (Figs. 7 through 14) shows coronal (frontal) sections through the telencephalon that are slightly anterior to or just grazing the most anterior extent of the preoptic area of the diencephalon. The second set (Figs. 15 through 24) shows sagittal sections through the part of the anterior telencephalon that evaginates into the olfactory bulb.
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Copyright 2004, Elsevier (USA). All rights reserved.
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SHIRLEY A. BAYER and JOSEPH ALTMAN
These two cutting planes contain the neuroepithelia that will generate most telencephalic structures, including the hippocampus, the medial limbic cortex, the neocortex, the lateral limbic cortex, the primary olfactory cortex, the striatum, portions of the basal telencephalon, portions of the globus pallidus, the nucleus accumbens, the septum, portions of the amygdala, and the olfactory bulb.
NEUROGENETIC TIMETABLES IN THE TELENCEPHALON Pallidum The pallidum contains a diffuse collection of large neurons, many of which are cholinergic, scattered throughout the basal telencephalon: the entopeduncular nucleus, the globus pallidus, the substantia innominata, the horizontal limb of the diagonal band of Broca, and the large polymorph neurons in the olfactory tubercle. The magnocellular neurons get their major input from
either the caudate/putamen complex (striatum) or the ventral striatum (olfactory tubercle and the nucleus accumbens), and they project topographically to the cerebral cortex. The degeneration of pallidal axons may be associated with senile dementia of Alzheimer’s type (reviewed in Bayer, 1985b). In rats, the entopeduncular nucleus is embedded in the posteroventral part of the internal capsule and is the homolog of the internal segment of the primate globus pallidus. It contains the oldest neurons in the pallidum (graph 1, Fig. 1) that originate mainly between E12 and E14 in a sandwich gradient where neurons in the core are older than those in either the anterior or the posterior poles (Bayer, 1985b). The globus pallidus is a body of large neurons sandwiched between the lateral border of the internal capsule and the ventromedial border of the striatum. Most neurons originate between E13 and E16 (graph 2, Fig. 1) in a complex three-way neurogenetic gradient: posterior, ventral, and lateral (older) to anterior, dorsal, and medial (younger). The oldest neurons (birthdays on E13) are located in the posteroventral
FIGURE 1 Timetables of neurogenesis for major neuronal populations in dorsal and ventral pallidum (graphs 1–5) and the striatum (graphs 6–9). From Bayer and Altman (1995).
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globus pallidus; the youngest neurons (birthdays on E16) are located anteromedially (Bayer, 1985b). The substantia innominata contains medium- to largesized neurons lying beneath the striatum (see below) and the globus pallidus. These neurons are generated from E13 to E17 (graph 3, Fig. 1) in a two-way posterior and lateral (older) to anterior and medial (younger) neurogenetic gradient (Bayer, 1985b). The magnocellular preoptic nucleus or the nucleus of the horizontal limb of the diagonal band of Broca (MPO-HDB) in rats is identical to the basal nucleus of Meynert in primates (reviewed in Bayer, 1985b). In rats, this nucleus contains large neurons that sweep forward through the anteromedial and anterolateral basal telencephalon to blend in with the large polymorph neurons scattered in layer III of the olfactory tubercle. Anteromedially, the horizontal limb of the diagonal band is continuous with the vertical limb of the diagonal band of Broca. Neurons in the MPO-HDB are generated mainly from E13 to E16 (graph 4, Fig. 1) in a two-way posterior and lateral (older) to anterior and medial (younger) neurogenetic gradient (Bayer, 1985b). The large polymorph neurons in the olfactory tubercle are the most anterior pallidal neurons and resemble those in the globus pallidus, the substantia innominata, and the horizontal limb of the diagonal band. These neurons are generated mainly from E14 to E16 (graph 5, Fig. 1) in a lateral (older) to medial (younger) neurogenetic gradient (Bayer, 1985a).
1981). The fiber bundles of the internal capsule do not traverse the nucleus accumbens; rather, the anterior commissure passes through its medial part. Nucleus accumbens neurons are generated over a protracted period, from E15 through P3 (graph 7, Fig. 1). Neurogenetic gradients within the nucleus are similar to those in the caudoputamen complex; lateral and ventral neurons are older than medial and dorsal neurons. The small neurons in the olfactory tubercle are similar in size and dendritic structure to the medium spiny neurons in the caudoputamen complex and have a similarly long period of neurogenesis, from E14 to E20 (graph 8, Fig. 1). A few (3%) are generated from postnatal day (P) 0 to P3. These neurons settle in a lateral (older) to medial (younger) gradient (Bayer, 1985a), in a similar pattern but at an earlier time than those in the caudoputamen complex (compare graphs 6 and 8 in Fig. 1). The islands of Calleja are dense clusters of small granule cells in the olfactory tubercle and bordering the nucleus accumbens. Neurons are generated in the islands from E16 to E22 (graph 9, Fig. 1) in a two-way neurogenetic gradient (Bayer, 1985a); ventral and lateral neurons are older than dorsal and medial neurons. In the large island on the medial border of the nucleus accumbens, anterior neurons are older than posterior neurons.
Striatum
The anterior amygdaloid area is a diffuse collection of variably sized neurons lying lateral to the preoptic area and deep to the nucleus of the lateral olfactory tract and the anterior cortical nucleus. Anteromedially, there are scattered large cells resembling those in the horizontal limb of the diagonal band. Neurogenesis occurs mainly from E13 to E15 (graph 1, Fig. 2), but a few neurons originate as early as E12, and some are not generated until E21 (Bayer, 1980c). The long time span is due to the overlapping production of several distinct neuronal populations. Medium-sized neurons are generated mainly between E13 and E15, with a peak on E14; large neurons are generated on E14 and E15, with a peak on E14; small neurons are generated from E18 to E21. The nucleus of the lateral olfactory tract is a distinct spherical cluster of densely packed medium-sized neurons in the anteromedial amygdala. Its neurons are generated mainly on E14 and E15 (graph 2, Fig. 2) and settle in a medial (older) to lateral (younger) order. The nucleus of the accessory olfactory tract contains diffusely packed smaller cells posteromedial to the nucleus of the lateral olfactory tract. Its neurons are generated in a biphasic pattern, most on E12 and E13, and a few on E15 (graph 3, Fig. 2).
The medium-spiny neurons in the caudoputamen complex are generated mainly from E16 to E21–E22 (graph 6, Fig. 1). There are several neurogenetic gradients between these neurons (Bayer, 1984). The most prominent gradient is that ventrolateral neurons are older than dorsomedial neurons. But there are divergent neurogenetic gradients between anterior and posterior parts of the striatum. In the anterior part, older neurons are in superficial and posterior positions; younger neurons are deep and anterior. In the posterior part, the reverse is true; older neurons are in deep and anterior positions, and younger neurons are superficial and posterior. There is also a neurogenetic gradient between patch neurons (older) and matrix neurons (younger) throughout the striatum (Bayer, unpublished observations). The nucleus accumbens surrounds the inferior horn of the lateral ventricle and extends forward to the anterior olfactory nucleus; it blends posteriorly with the anterior part of the bed nucleus of the stria terminalis. The nucleus accumbens has been included in the septal region, but the structure of its neurons and its developmental patterns place it within the striatum (Bayer,
Amygdala
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FIGURE 2 Timetables of neurogenesis for major neuronal populations in the amygdala (graphs 1–14). From Bayer and Altman (1995).
The central nucleus lies in the dorsal part of the amygdala, just beneath the striatum and medial to nuclei in the basolateral group. Its neurons are generated from E13 to E18 (graph 4, Fig. 2) and settle in an anteromedial (older) to posterolateral (younger) order (Bayer, 1980c). The amygdalo–hippocampal area in rats is a small region in the posteromedial amygdala where the medial nucleus blends with the ventral hippocampus. Some of the youngest neurons in the amygdala are located here; neurogenesis occurs from E16 through
E19 (graph 5, Fig. 2) and the cells settle in a superficial (older) to deep (younger) gradient (Bayer, 1980c). The intercalated masses are clumps of densely packed small cells interspersed between other nuclei in the amygdala. Anteriorly, they are clustered around the temporal limb of the anterior commissure; posteriorly, they are clustered among the fibers in the core of the amygdala between nuclei in the corticomedial and basolateral groups. These neurons are generated late (E15 to E19; graph 6, Fig. 2) and settle in an anterior (older) to posterior (younger) order (Bayer, 1980c).
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The medial nucleus forms the medial wall of the amygdala from the anterior amygdaloid area to the ventral tip of the hippocampus. These neurons are generated from E13 to E16 (graph 7, Fig. 2) in an anteroventral (older) to posterodorsal (younger) neurogenetic gradient (Bayer, 1980c). The cortical nuclei are subdivided into anterior and posterior parts that have a strong anterior (older) to posterior (younger) neurogenetic gradient between them (graphs 8 and 9, Fig. 2). Both nuclei have superficial (older) to deep (younger) neurogenetic gradients, and the posterior nucleus has a medial (older) to lateral (younger) gradient (Bayer, 1980c). The basomedial nucleus lies in the core of the amygdala throughout much of its rostrocaudal extent, while the basolateral and lateral nuclei form a pyramidlike structure apposed to the white matter that borders the piriform cortex. Neurons in the basomedial and basolateral nuclei are generated from E14 through E17, while the lateral nucleus has younger neurons, with some arising as late as E19 and E20 (graphs 10–12, Fig. 2). All nuclei have anterior (older) to posterior (younger) neurogenetic gradients (Bayer, 1980c). In addition, the basolateral nucleus has a lateral (older) to medial (younger) gradient, while the lateral nucleus has a dorsal (older) to ventral (younger) gradient. The stria terminalis is a major fiber tract that leaves the amygdala and reaches various targets in the basal forebrain. Neurons that are scattered within this fiber tract collectively form the bed nucleus of the stria termi-
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nalis. The anterior part of the nucleus encircles the interbulbar part of the anterior commissure, extending from the posterior nucleus accumbens to the decussation of the anterior commissure. Neurons in the anterior part are generated from E13 to E20 with an overall peak on E15–E16 (graph 13, Fig. 2) and settle in a posterior (older) to anterior (younger) gradient (Bayer, 1979a, 1987). In addition, ventromedial neurons are generated earlier than dorsolateral ones. The preoptic continuation extends ventromedially into the posterior preoptic area. These neurons are generated mainly from E13 through E16, also with an overall peak on E15–E16 (graph 14, Fig. 2) and settle in a ventrolateral (older) to dorsomedial (younger) order (Bayer, 1987).
Septum The septum forms the subcallosal anteromedial wall of the telencephalon and is a prominent structure in the rat basal forebrain. The triangular and medial septal nuclei are in the midline. The anterior medial septal nucleus blends in with the vertical limb of the diagonal band of Broca just lateral to the midline. A large lateral septal nucleus, situated on either side of the midline nuclei, extends throughout the entire anteroposterior extent. The tiny bed nucleus of the anterior commissure resembles cells in the triangular nucleus and forms a compact cluster of small neurons where the columns of the fornix descend behind the decussation of the anterior commissure (Fig. 24).
FIGURE 3 Timetables of neurogenesis for major neuronal populations in the septum (graphs 1–5). From Bayer and Altman (1995).
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Beginning with the midline septal nuclei, neurons in the triangular nucleus (graph 1, Fig. 3) are generated from E13 to E17, with a peak on E15; those in the lateral part are generated slightly earlier than those in the midline (Bayer, 1979a). Neurons in the medial septal nucleus are generated from E13 to E17 (graph 2, Fig. 3) and settle in a posterior (older) to anterior (younger) order. Indeed, the oldest neurons in the septal complex lie in the medial septal nucleus above the decussation of the anterior commissure (Bayer, 1979a). Neurons in the nucleus of the diagonal band of Broca (vertical limb) are also generated from E13–E17 (graph 3, Fig. 3) and settle in a posterior (older) to anterior (younger) order, continuing the gradient in the medial septal nucleus. Neurons in the lateral septal nucleus are generated from E14 to E19 (graph 4, Fig. 3) and settle in a medial (older) to lateral (younger) order. The youngest neurons in the septal complex lie in this nucleus adjacent to the ependymal lining of the lateral ventricle. Neurons in the bed nucleus of the anterior commissure are generated from E14 to E17 and settle mainly on E15 and E16 (graph 5, Fig. 3) following a timetable similar to that of neurons in the triangular septal nucleus (Bayer, 1979a).
Cerebral Cortex The cerebral cortex is the largest structure in the rat telencephalon. It can be subdivided into the neocortex, the limbic cortex, the piriform (primary olfactory) cortex, and the hippocampal region. Neocortex and Limbic Cortex The neocortex has five cell-dense layers (II–VI), large Cajal–Retzius neurons sparsely distributed in layer I, and scattered neurons in the deep white matter (layer VII or the subplate). In rats, the superficial layers (II–IV) are thinner than those in the human neocortex but layers VI and V are thick (Bayer and Altman, 1991a). In the limbic neocortex, five cell-dense layers are also present. Generally, layers V and VI are easily distinguished from each other, but they tend to be thinner than the same layers in the neocortex. The superficial layers (IV–II) are quite reduced and are often grouped together in a single layer. Most neocortical and limbic cortical neurons are generated between E14 and E20 (graphs 1–5, Fig. 4) and settle in strict gradients to form the layers of the mature cortex. That settling can be separated into three major epochs (Bayer and Altman, 1991a). During the first epoch, the sequentially generated Cajal–Retzius neurons in layer I and subplate neurons (layer VII) settle in a superficial (older) to deep (younger) gradient. The peak time of origin of Cajal–Retzius neurons is on E14 (graph 1, Fig. 4), while subplate neurons are generated
on E14 and E15 (graphs 5, Fig. 4). Taken together, these two populations form the top and bottom “crust” of older neurons around a “sandwich” of younger neurons in layers VI–II. Neurons in layers VI–II are generated during the second and third epochs and settle in a deep (older) to superficial (younger) radial gradient, one of the most prominent neurogenetic gradients in the entire brain (reviewed in Bayer and Altman, 1991a). Layers VI–V are sequentially generated from E15 to E17 (second epoch, graphs 3 and 4, Fig. 4); layers IV–II are sequentially generated from E17 to E20 (third epoch graph 2, Fig. 4). Only a few of the most superficial neurons in layer II are generated on E21, the last day of cortical neurogenesis. Besides the radial gradient between layers VI and II, there are two additional neurogenetic gradients within these layers. First, a transverse gradient that runs parallel to the plane of coronal sections: neurons situated ventrolaterally (those closer to the rhinal sulcus) tend to be older than neurons situated dorsomedially (those closer to the cingulate cortex). Second, a longitudinal gradient that runs parallel to sagittal sections near the midline: neurons situated anteriorly (those closer to the frontal pole) tend to be older than neurons situated posteriorly (those closer to the occipital pole). The deep layers (VI–V) have strong transverse and longitudinal gradients, irrespective of any boundaries between cortical areas. However, the primary sensory areas of the rat cortex always contain neurons in layers II and III younger than the neurons in the same layers of the secondary sensory areas, even if the primary area is lateral to a secondary area. For example, the primary somatosensory and the primary visual areas contain superficial neurons younger than those in their medially situated secondary areas. The limbic cortex surrounds the neocortex. Although there is the same stacking of older to younger cells in the radial dimension, the medial limbic cortex (cingulate and retrosplenial areas) reverse the neocortical transverse gradient and the lateral limbic cortex (insular area) has a longitudinal gradient different than the one in the neocortex (Bayer and Altman, 1991a). These findings lend support to the argument that the limbic and neocortical parts of the cerebrum have different phylogenetic roots; the limbic neocortex may be partially linked to neurogenetic gradients in the paleocortex (Bayer and Altman, 1991a). Piriform (Primary Olfactory) Cortex The piriform cortex is located below the rhinal sulcus and forms the ventrolateral portion of the cerebral hemispheres. It extends nearly 7.4 mm in the rostrocaudal direction, from the anterior olfactory nucleus
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FIGURE 4 Timetables of neurogenesis for major neuronal populations in the neocortex and limbic cortex (graphs 1–5) and in the piriform or primary olfactory cortex (graphs 6–9). From Bayer and Altman (1995).
to the lateral entorhinal cortex. Comparative neuroanatomists consider the piriform cortex to be “paleocortex” because, unlike the neocortex, it is represented in the forebrains of fish, amphibians, and reptiles. Another characteristic that distinguishes the piriform cortex from the neocortex is that it receives monosynaptic input from the main olfactory bulb throughout its entire length and breadth (Bayer, 1986b), while all sensory input to the neocortex is through a relay in the thalamus. Most anatomists consider the piriform cortex to have three cell layers in addition to the cell-sparse external plexiform layer (I). Layer II contains densely packed small pyramidal cells, layer III sparsely packed medium-sized pyramidal cells, and layer IV very sparse large-sized pyramidal cells and polymorph cells. Neurogenesis in the piriform cortex proceeds in two gradients: deep neurons are older than superficial neurons, and posterior neurons are older than anterior neurons (graphs 6–9, Fig. 4). Deep neurons in layers III and IV are generated mainly from E13 to E16, 80% of
the posterior deep neurons on or before E15, and over 30% of the anterior deep neurons on or after E16. The superficial neurons are generated mainly from E15 through E18, 75% of the posterior ones on or before E16, and 37% of the anterior ones on or after E17. In the anterior piriform cortex, layer II is quite thick, and the small pyramidal cells are stacked two to three deep rather than in a monolayer. Here, the superficial neurons are generated slightly earlier than the deep ones (see Fig. 6 in Bayer, 1986b). These data indicate that the piriform cortex does not have the same type of radial gradient as the neocortex where younger neurons are always superficial to older deep neurons. The Hippocampal Region The hippocampal region is a prominent component of the rat cerebral cortex, containing five contiguous structures. The entorhinal cortex, the presubiculum, the parasubiculum, and the subiculum take up most of the ventroposterior cortical wall; the hippocampus proper extends forward beneath the corpus callosum and the
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deep white matter of the neocortex and the lateral limbic cortex. The hippocampus proper is one of the best known neuroanatomical structures due to intense study with a variety of descriptive and experimental anatomical methods (reviewed in Bayer, 1980a). Our studies in the rat include quantitative determinations of the timetables of neurogenesis (Altman, 1966; Bayer and Altman, 1974; Bayer, 1980a, 1982; Bayer et al., 1982), cell migration and settling (Bayer, 1980b; Altman and Bayer, 1990a,b,c), and vulnerability to X-irradiation (Bayer and Altman, 1975a,b).
sized pyramidal cells. Layer IV is a cell-sparse zone (lamina dessicans) with a few scattered large pyramidal cells. Layer V–VI contains relatively densely packed medium- and small-sized neurons. The neurogenetic timetables (graphs 1–4, Fig. 5) indicate a modified deep (older) to superficial (younger) neurogenetic gradient. Neurons in layer V–VI are generated mainly on E15, those in layers II and IV mainly on E15 and E16, and the youngest neurons in layer III mainly on E17. All layers have lateral (older) to medial (younger) neurogenetic gradients (Bayer, 1980a).
Entorhinal cortex The entorhinal cortex contains five layers that, with the exception of layer I, are substantially different from those found in the neocortex. Layer II contains the cell bodies of large stellate cells, grouped into islands laterally and separated from layer III by a cell-sparse zone. Layer III contains medium-
Subicular region The structures between the medial edge of the entorhinal cortex and the hippocampus are the parasubiculum, the presubiculum, and the subiculum proper. The parasubiculum and the presubiculum form a wedge in the posteromedial angle of the cortical wall; these parts of the subiculum are best seen
FIGURE 5 Timetables of neurogenesis for major neuronal populations in the entorhinal cortex (graphs 1–4), the subiculum (graphs 5–9), and the hippocampus (graphs 10–13). From Bayer and Altman (1995).
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in horizontal sections and are therefore not labeled in any of the photographs in Figs. 7–24. They share a triangular-shaped core of deep neurons that are generated from E15 to E17 (graph 7, Fig. 5), later than the deep neurons in the laterally situated entorhinal cortex. There is a lateral (older) to medial (younger) neurogenetic gradient in the superficial cells of the parasubiculum and the presubiculum. Those in the parasubiculum are generated earlier (mainly on E17 and E18) than the small superficial neurons in the presubiculum (compare graphs 5 and 6, Fig. 5). The pyramidal layer in the subiculum proper appears to be an extension of the deep neurons of the parasubiculum and the presubiculum. Within the layer, deep neurons are generated earlier (peak on E16) than superficial neurons (peak on E17, compare graphs 8 and 9, Fig. 5). When taken as a whole, neurons in the subiculum proper are generated later than the deep neurons in the parasubiculum and the presubiculum. These patterns indicate that the lateral (older) to medial (younger) neurogenetic gradient that begins in the entorhinal cortex continues throughout the subiculum (Bayer, 1980a). Hippocampus The hippocampus contains two interlocked C-shaped layers of cortex, dominated by the pyramidal cells of Ammon’s horn (fields CA1–3) and the granule cells in the dentate gyrus. In Ammon’s horn of the rat, the oldest pyramidal cells are in field CA3ab (peak on E17, graph 11, Fig. 5) and younger pyramidal cells flank them in fields CA1 (closer to the subiculum, graph 10, Fig. 5) and CA3c (in the hilus of the dentate gyrus, graph 12, Fig. 5). It is remarkable that the lateral (older) to medial (younger) neurogenetic gradient seen throughout the entorhinal cortex and the subiculum is broken by the sandwich gradient seen in the pyramidal cells of Ammon’s horn (Bayer, 1980a). The granule cells in the dentate gyrus are noted for their exceptionally late time of origin (reviewed in Bayer and Altman, 1974; Bayer, 1980a). Approximately 85% of these neurons are generated after birth in rats, mainly during the first postnatal week (graph 13, Fig. 5). Neurogenesis gradually tapers off during the second and third postnatal weeks, so that the dentate gyrus appears mature by the time of weaning (21 days). Most of the dentate granular neurons settle in a superficial (older) to deep (younger) gradient, opposite to the gradients between and within the layers of the neocortex (Bayer, 1980a). The dentate granular layer is also unusual because there are always a few neurons that can be labeled after [3H]thymidine injections are given to juvenile and adult rats (Altman, 1963; Altman and Das, 1965; Bayer, 1982; Bayer et al., 1982). It has
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been established that the neurons produced in adults add to the total population of dentate granule cells. One-year-old rats have significantly more neurons than 1-month-old rats (Bayer, 1982; Bayer et al., 1982).
Olfactory Bulb and Peduncle The Olfactory Bulb The olfactory bulb is a prominent component of the rat forebrain. Olfactory nerve fibers that originate from the olfactory epithelium in the upper part of the nasal cavity penetrate small foramina in the cribriform plate and terminate in the superficial glomerular layer of the olfactory bulb. In the glomerular layer, olfactory nerve axons synapse with the primary dendritic branches of mitral and tufted neurons. Axons of the mitral and tufted cells leave the olfactory bulb to terminate in various parts of the olfactory peduncle and in the primary olfactory cortex. There are three populations of short-axon interneurons: a large population of granule cells that forms a thick layer beneath the layer of mitral cells, small neurons scattered diffusely in the external plexiform layer, and small neurons dispersed between the glomeruli. The external plexiform layer lies between the glomerular and the mitral cell layers; it is a region where the secondary branches of mitral cell and tufted cell dendrites interact with input from granule cells and the external plexiform interneurons; it also contains the scattered cell bodies of the tufted output neurons (for details of olfactory bulb anatomy, see Bayer, 1983). Neurogenetic timetables in the olfactory bulb (graphs 1–7, Fig. 6) show a highly sequential pattern of generation between different neuronal populations (Bayer, 1983). The oldest neurons are the mitral cells that originate mainly on E14–E16. The internal, external, and interstitial tufted cells follow, with peaks on E16–E17, E18–E19, and E20–E22, respectively. The interneurons in the glomerular, external plexiform, and granular layers are generated mainly after birth (graphs 5–7, Fig. 6). Nearly all of the external plexiform cells and the periglomerular cells are generated by the end of the first postnatal week, but the large population of granule cells continues to be generated up to and beyond P19 (graph 7, Fig. 6). Granule cells in the olfactory bulb continue to be generated during the adult period since a few are always labeled within a few weeks after [3H]thymidine injections are given to adult rats (reviewed in Bayer, 1983). The Olfactory Peduncle The anterior olfactory nucleus is located posterior to the olfactory bulb in the olfactory peduncle. It is one of the major olfactory processing centers; the olfactory
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bulb is its major afferent input and is also the principal target of its axons. The anterior olfactory nucleus can be divided into a pars externa, an ectopic group of neurons in the anterior dorsolateral part of the peduncle, and the anterior olfactory nucleus proper, which contains the pars dorsalis, pars lateralis, pars ventralis, and pars medialis. The posterior parts of the anterior olfactory nucleus proper form transition areas to the primary olfactory cortex in the piriform lobe. A posterior (older) to anterior (younger) neurogenetic gradient is found both within and between components of the olfactory peduncle (Bayer, 1986a). Neurons in the pars externa are generated mainly between E16 and E19 (graph 8, Fig. 6), those in the anterior olfactory nucleus proper from E15 to E20 (graph 9, data in Fig. 6 are combined for all subdivisions), and those in the posterior transition areas from E14 to E19 (data are not shown in Fig. 6, see Bayer, 1986a). Only 3–4% of the neurons in the most anterior pars lateralis and pars dorsalis originate after birth. All parts of the anterior olfactory nucleus proper have a strong superficial (older) to deep (younger) neurogenetic gradient, while many of the transitional areas
have a gradient in the opposite direction, deep (older) to superficial (younger). These data suggest that characteristic patterns of neurogenesis, namely, the “insideout” versus the “outside-in” gradients, distinguish nuclear and cortical components of the olfactory brain. There is evidence that the pattern in which the anterior olfactory nucleus sends axons into the olfactory bulb is related to time of neuron origin: posterior parts project to the bulb first, anterior parts project later (reviewed in Bayer, 1986a).
MAPS OF STEM CELL MOSAICS IN THE TELENCEPHALIC NEUROEPITHELIUM The maps are presented in Figs. 7 through 24 from E11 to E22 in both the coronal (Figs. 7–14) and the sagittal planes (Figs. 15–24). In both sets of figures, the maturing components of the brain contained within the sections are identified as soon as they become recognizable. The maps are best viewed together, so they are placed near the end of Part IV of this chapter.
FIGURE 6 Timetables of neurogenesis for major neuronal populations in the olfactory bulb (graphs 1–7) and the anterior olfactory nucleus (graphs 8–9). From Bayer and Altman (1995).
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The Two Sources of Neurons: The Neuroepithelium and the Secondary Germinal Matrices The Neuroepithelium The primary source of cells specific to the nervous system (neurons, glia, choroid plexus, and ependyma) is a proliferative germinal matrix that is variably referred to as (1) the primitive ependymal layer, (2) the ventricular zone, or (3) the neuroepithelium (Langman et al., 1966). The latter term is now widely used. During gastrulation, the neuroepithelium differentiates from a sheet of columnar proliferative cells on the dorsal surface of the embryo, the neural plate. The neural plate subsequently forms a neural tube with a central fluidfilled lumen. The neural tube extends throughout the entire neuraxis. Its caudal part becomes the spinal cord, which retains its tubular appearance throughout life. Its rostral parts form three primary brain vesicles, the rhombencephalon (hindbrain), the mesencephalon (midbrain), and the prosencephalon (forebrain). Figures 7, 15, and 16 show high-magnification photographs of the prosencephalic neuroepithelium at an early stage after neural tube closure. Continuing cell proliferation in specific loci greatly expands the primary brain vesicles. The rhombencephalon subdivides into the myelencephalon (medulla) and the metencephalon (cerebellum and pons). The mesencephalon subdivides into the tectum (superior and inferior colliculi) and the tegmentum. The prosencephalon subdivides into the diencephalon (thalamus and hypothalamus) and the paired telencephalic vesicles (cerebral cortex and basal ganglia). Midbrain and hindbrain structures are shown in the thumbnail photographs of sagittal sections in Figs. 15–24. There is growing evidence that, notwithstanding its apparently homogeneous cellular composition, the neuroepithelium contains a heterogeneous population of neural stem cells that constitute the blueprint (Bauplan) of the mature central nervous system. In the following discussion we concentrate on the spatiotemporal neuroepithelial mosaic in the telencephalon where committed neural stem cells generate specific neurons according to strict timetables. The most probable germinal sources of telencephalic neurons are presented with comments about the initial radial migratory paths many of these neurons take as they settle in the maturing brain. Complex and stepwise migration patterns in the neocortex and major migratory streams in the telencephalon are summarized in Part IV. The Subventricular Zone Cells leaving the neuroepithelium have three fates: (1) they become postmitotic and differentiate as neurons, (2) they become glia or glial precursors, and
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(3) they retain their proliferative capacity and form secondary germinal matrices. The best-known secondary germinal matrix is the external germinal layer (egl) of the cerebellum. The egl forms a discreet layer over the surface of the developing cerebellum and produces granule cells, basket cells, and stellate cells in the cerebellar cortex (Altman and Bayer, 1996). The secondary germinal matrices of the telencephalon form other types of aggregates. In the developing cerebral cortex and basal ganglia, the secondary germinal matrix forms a subventricular zone adjacent to the primary neuroepithelium. In the developing olfactory bulb, proliferating cells migrate in a rostral migratory stream from the subventricular zones of the septum, accumbens, and cortex (Altman, 1969). In the developing hippocampus, the dentate migratory stream (Altman and Bayer, 1990a,b,c) contains the progenitors of granule cells in the dentate gyrus.
Germinal Sources of Telencephalic Neurons Neuroepithelium of the Ventral Telencephalon This neuroepithelium generates the pallidum, striatum, olfactory tubercle, nucleus accumbens, amygdala, septum, and part of the primary olfactory cortex. Its medial border extends to the point above the septal neuroepithelium (region 5 in the maps) where the neuroepithelium thins in the medial telencephalic wall (region 1B in the maps) and invaginates into the lateral ventricle as the choroid plexus. There are two prominent swellings of this neuroepithelium, a lateral ganglionic eminence (region 4A in the maps) and a medial ganglionic eminence (region 4B in the maps). The neuroepithelium in the corticopallidal angle is designated as region 3/4 in the maps because it generates neurons in cortical as well as ganglionic structures. Genetic expression studies (Stoykova et al., 2000; reviewed in Schuurmans and Guillemot, 2002) indicate that the neuroepithelium in regions 5, 4A, and medial 4B express genes Nkx2.1, several Dlx genes, Vax1, and Mash1. The neuroepithelium in lateral region 4B expresses Pax6, a gene expressed in the cortical neuroepithelium. Region 3/4 neuroepithelium expresses many of the same genes expressed in the cortical neuroepithelium including Pax6, Ngn1/2, Emx1/2 (Stoykova et al., 2000; Schuurmans and Guillemot, 2002), and Sox2 (Zappone et al., 2000). Pallidum The entopeduncular nucleus neurons originate in a strip of neuroepithelium that bridges the ventral telencephalic/diencephalic border (Altman and Bayer, 1986). That germinal source is part of the neuroepithelium that generates the zona incerta and (Text continues on p. 62)
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FIGURE 7 Nissl-stained 10-μm parrafin sections of the rat anterior coronal forebrain on E11 (A) and E12 (B). A is modified from E11 coronal plate 2; B is modified from E12 coronal plate 3 in Altman and Bayer (1995).
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FIGURE 8 Nissl-stained 10-μm parrafin section of the rat anterior coronal forebrain on E13; modified from E13 coronal plate 3 in Altman and Bayer (1995). The right half of the photograph is at low contrast so that labels are more visible. Arows indicate cells exiting the ganglionic and septal parts of the neuroepithelium. The incorporated table lists the compartments in the neuroepithelium and the major events taking place, based on timetables of neurogenesis in Figs. 1–6.
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FIGURE 9 As in Fig. 8 for the rat anterior coronal forebrain on E14; modified from E14 coronal plate 3 in Altman and Bayer (1995).
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FIGURE 10 As in Fig. 8 for the rat anterior coronal forebrain on E15; modified from E15 coronal plate 5 in Altman and Bayer (1995).
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FIGURE 11 As in Fig. 8 for the rat anterior coronal forebrain on E16; modified from E16 coronal plate 6 in Altman and Bayer (1995).
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FIGURE 12 As in Fig. 8 for the rat anterior coronal forebrain on E17; modified from E17 coronal plate 7 in Altman and Bayer (1995).
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FIGURE 13 As in Fig. 8 for the rat anterior coronal forebrain on E18; modified from E18 coronal plate 5 in Altman and Bayer (1995).
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FIGURE 14 As in Fig. 8 for the rat anterior coronal forebrain on E20; modified from E20 coronal plate 7 in Altman and Bayer (1995).
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FIGURE 15 Nissl-stained 10-μm parrafin sagittal section of the rat brain on E11; modified from E11 sagittal plate 2 in Altman and Bayer (1995). A shows the entire section with a box indicating the limits of the enlarged photograph in B.
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FIGURE 16 Nissl-stained 10-μm parrafin sagittal section of the rat brain on E12; modified from E12 sagittal plate 4 in Altman and Bayer (1995). A shows the entire section with a box indicating the limits of the enlarged photograph in B.
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FIGURE 17 Nissl-stained 10-μm parrafin sagittal section of the rat brain on E13; modified from E13 sagittal plate 3 in Altman and Bayer (1995). A shows the entire section with a box indicating the limits of the enlarged photograph in B.
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FIGURE 18 Nissl-stained 10-μm parrafin sagittal section of the rat brain on E14; modified from E14 sagittal plate 3 in Altman and Bayer (1995). A shows the entire section with a box indicating the limits of the enlarged photograph in B.
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FIGURE 19 Nissl-stained 10-μm paraffin sagittal section of the rat brain on E15; modified from E15 sagittal plate 3 in Altman and Bayer (1995). A shows the entire section with a box indicating the limits of the enlarged full-contrast photograph in B. C on the facing page shows a low-contrast copy of B with labels and an explanatory table.
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FIGURE 19, cont’d
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FIGURE 20 As in Fig. 19 for the sagittally sectioned rat brain on E16; modified from E16 sagittal plate 4 in Altman and Bayer (1995).
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FIGURE 20, cont’d
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FIGURE 21 As in Fig. 19 for the sagittally sectioned rat brain on E17; modified from E17 sagittal plate 3 in Altman and Bayer (1995).
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FIGURE 21, cont’d
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FIGURE 22 As in Fig. 19 for the sagittally sectioned rat brain on E18; modified from E18 sagittal plate 4 in Altman and Bayer (1995).
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FIGURE 22, cont’d
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FIGURE 23 As in Fig. 19 for the sagittally sectioned rat brain on E20; modified from E20 sagittal plate 3 in Altman and Bayer (1995).
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FIGURE 23, cont’d
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FIGURE 24 As in Fig. 19 for the sagittally sectioned rat brain on E22; modified from E22 sagittal plate 3 in Altman and Bayer (1995).
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FIGURE 24, cont’d
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the lateral hypothalamus, and it is not represented in any of the sections shown in the maps. Neurons migrate rapidly away from this site soon after their generation, and the entopeduncular nucleus is recognizable as early as E13, presumably containing neurons that were generated on E12 (Altman and Bayer, 1986). With the exception of the entopeduncular nucleus, all of the other pallidal neuronal populations have linked neurogenetic gradients that suggests these nuclei represent a single large system of magnocellular neurons populating the basal telencephalon (graphs 2–5, Fig. 1; Bayer, 1985b). It further implies that these neurons are generated sequentially in an anterior– posterior (longitudinal) ridge of neuroepithelium. The most likely source is the medial eminence of basal ganglia neuroepithelium (region 4B, Figs. 8–11 and 16–20). A few pallidal neurons migrate out of the basal ganglia neuroepithelium on E13 (Fig. 8) and many more migrate between E14 and E16 (Figs. 9–11). Posterior and ventral globus pallidus neurons settle within 2 days after their generation (see Figs. 29 and 30 in Altman and Bayer, 1986), and other pallidal neurons probably migrate predominantly radially from the medial eminence to settle throughout the ventral telencephalon. Striatum and small olfactory tubercle neurons Striatal medium spiny neurons and small neurons in the olfactory tubercle are probably generated in two steps by the basal ganglia neuroepithelium. (1) The primary neuroepithelium produces secondary neural stem cells that move into the subventricular zone and continue to proliferate; this takes place from E16 to E18 (Figs. 11–13). (2) Secondary neural stem cells in the subventricular zone produce medium spiny striatal neurons. Some of the oldest striatal neurons in the ventrolateral striatum are generated directly by primary neural stem cells in the lateral ganglionic eminence neuroepithelium (region 4A in the maps), because presumptive striatal neurons are already outside of the striatal subventricular zone on E16 (Fig. 11). At the time when striatal neurons start to be produced in large numbers (E18–19, graph 6, Fig. 1) there is only one eminence in the basal ganglia neuroepithelium and a single large subventricular zone (region 4, Fig. 13). Prior to that both eminences are present, each with a large subventricular zone. Nucleus accumbens The nucleus accumbens is another structure where most neurons are generated in a two-step process. Secondary neural stem cells committed to produce nucleus accumbens neurons move into the subventricular zone immediately surrounding the neuroepithelium in the inferior horn of the lateral ventricle (region 6 in the maps). As early as E17 (Figs. 12
and 21), a band of differentiating cells, presumably the oldest nucleus accumbens neurons, surrounds the subventricular zone in the inferior horn. Younger neurons settle consecutively inside surrounding rings of older neurons. Peak proliferative activity in the nucleus accumbens subventricular zone coincides with the peak period of neurogenesis. Low-level exposures to X-irradiation massively kill cells in the subventricular zone during the peak time of neurogenesis, while the neuroepithelium itself is less affected, indicating that the neuroepithelium is probably producing the ependyma (Bayer, 1979b). It is important to note that the subventricular zone producing the nucleus accumbens is also one source of secondary neural stem cells in the rostral migratory stream. Amygdala Early generated medium-sized and large-sized neurons in the anterior amygdaloid area are probably produced by primary neural stem cells in both eminences of the basal ganglia neuroepithelium (regions 4A and 4B in the maps); later generated small neurons may originate from secondary neural stem cells in the large basal ganglia subventricular zone (outside region 4 in the maps). Large- to medium-sized anterior amygdaloid neurons settle among neurons of the ventral pallidum just outside the basal ganglia neuroepithelium as early as E14. The anterior parts of the central nucleus and the basolateral group most likely are generated in the lateral eminence of the basal ganglia neuroepithelium (region 4A). Some modified pyramidal-like cells in the basolateral amygdala may be generated either in the cortical neuroepithelium (region 3) or in the corticopallidal angle (region 3/4) and may be the migrating neurons expressing Pax6 shown by Stoykova et al. (2000). Younger neurons in the posterior central nucleus appear to be part of the striatum and may be generated in the striatal subventricular zone. Neurons in the intercalated masses may be generated in the cortical neuroepithelium (region 3), migrate in the lateral migratory stream to the reservoir of the stream, and then leave to disperse between various amygdaloid nuclei. Neurons in the nuclei of the lateral and accessory olfactory tracts are not visible in the amygdala until relatively late. Possibly, these neurons are generated in a neuroepithelium that produces olfactory bulb mitral cells in the anterior basomedial floor of the ventral telencephalon (anterior region 6/posterior region 7 in the E15 map, Fig. 19). The late appearance of these nuclei suggests that they are generated in a distant source, then migrate posteriorly to settle in the amygdala. Morphogenetic studies of the bed nucleus of the stria terminalis indicate two distinct neuroepithelial sources (Bayer, 1987). The anterior bed nucleus is generated by
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the primary neuroepithelium in the inferior horn of the lateral ventricle posterior to the nucleus accumbens neuroepithelium (region 6A in the maps). Neurons migrate radially from that source so that older neurons settle ventromedially, and younger neurons settle dorsolaterally, closest to the inferior horn. The preoptic continuation of the strial bed nucleus is generated in the neuroepithelium at the base of the posterior part of the medial horn of the lateral ventricle, lateral to the area of fusion with the anterior thalamic neuroepithelium (region 4C in the maps). This is also part of the basal ganglia neuroepithelium (Figs. 19–21). Neurons migrate radially from that source and settle in a downward medial-curving pattern that extends toward the sexually dimorphic nucleus in the medial preoptic area. Younger neurons accumulate adjacent to the older lateral neurons. Throughout the anterior and posterior bed nucleus, neurons begin to migrate within 1 day after their generation and usually settle 1 or 2 days later (Bayer, 1987). Septum The source of most neurons in the septal complex is the neuroepithelium lining the ventromedial wall of the lateral ventricle (region 5, Figs. 7–14 and 19–24; Bayer, 1979b). Already by E15 in rat embryos, a thick band of young neurons has accumulated outside of that neuroepithelium (see it best in the coronal section, Fig. 10). The young neurons are presumably those that will form the medial septal and diagonal band nuclei. By E17, the neuroepithelium is less prominent, and more young neurons, presumably those of the lateral septal nucleus, accumulate just outside it, and the vertical limb of the diagonal band is recognizable (Fig. 12). More neurons accumulate on E18 (Fig 13) and E19. The septal neuroepithelium is thin by E20 (Fig. 14) and is changing to the primitive ependyma, while the zone of differentiating cells continues to enlarge. Neuroepithelium of the Dorsal Telencephalon This part of the neuroepithelium contains two major parts, the cortical (region 3) and the hippocampal (regions 2A, 2B, and 2C). The cortical neuroepithelium forms the roof of the telencephalon and is the source of Cajal–Retzius neurons, subplate neurons, and pyramidal cells throughout all layers in the limbic cortex and neocortex. Along with the neuroepithelium in the corticopallidal angle (region 3/4), the cortical neuroepithelium probably generates layer II neurons in the primary olfactory cortex and some neurons in the amygdala. The hippocampal neuroepithelium forms the medial hem of the cortex and is the source of neurons in the subiculum, Ammon’s horn of the hippocampus, and the dentate gyrus; it also contains a
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glial matrix for the fimbria and contributes cells to the invaginating choroid plexus. Neuroepithelial cells in regions 3 and 2A express Pax6, Ngn1/2, Emx1/2 (Stoykova et al., 2000; Schuurmans and Guillemot, 2002), Otx1 (Tarabykin et al., 2001), Sox2 (Zappone et al., 2000), and Lhx2 (Bulchand et al., 2001). The Bulchand et al. (2001) study provides a detailed map of additional genes expressed in the hippocampal neuroepithelium that correlate with its unique progeny in the cortex. Region 2A expresses EphB1; regions 2B and 2C have highly segregated expression of several Wnt genes, including Wnt2b, Wnt3a, and Wnt5a; regions 2A/B and the choroid plexus (region 1B) express Bmp4 and Bmp7; and the choroid plexus expresses Msx1. Neocortex and limbic cortex Using short- and sequential-survival [3H]thymidine autoradiography and exposures to low-level X-irradiation, timedependent successive transformations in the cortical neuroepithelium can be detected and linked to the three epochs of cortical neurogenesis (see Chapters 4 and 10 in Bayer and Altman, 1991a). During the first epoch (E13–E15), the cortical neuroepithelium is composed mainly of primary neural stem cells and radial glial cells. There are sparse founder cells of secondary neural stem cells that will move into the subventricular zone, glial stem cells, and ependymal stem cells. A single exposure to 200-R X-rays kills most cells in the neuroepithelium and the dying cells drop down into the ventricular lumen. [3H]Thymidine autoradiography indicates that most neuroepithelial cells undergo interkinetic neuronal migration. In that process the nucleus migrates within the cytoplasm during every cell cycle. DNA is duplicated when the nucleus is in the basal part of the cell, and mitosis occurs at the cell apex near the ventricular lumen. Two-hour-survival [3H]thymidine autoradiography shows a band containing many heavily labeled nuclei (the synthetic zone) at the base of the neuroepithelium and few labeled nuclei near the ventricular lumen (the mitotic zone). Cajal–Retzius and subplate neurons are the chief progeny of the primary neural stem cells during the first epoch. These neurons form clumps of heavily labeled cells in the basal part of the neuroepithelium 24 h after a single [3H]thymidine injection; 48 h after the injection, heavily labeled Cajal–Retzius and subplate neurons are outside all parts of the cortical neuroepithelium and may represent the Tbr1expressing cells shown by Stoykova et al. (2000). Also during this time, the cortical neuroepithelium is increasing in size (compare the size changes in Figs. 10–12) because it contains a large population of selfreplicating primary neural stem cells that will produce neurons later.
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During the second epoch (E16–E17), primary neuronal precursors undergoing interkinetic nuclear migration still predominate in the cortical neuroepithelium. Two hours after a [3H]thymidine exposure, nuclei are heavily labeled in a distinct synthetic zone but the number of heavily labeled nuclei in the mitotic zone is also increasing. Although low-level X-ray still kills most cells in the neuroepithelium, many cells survive. The shedding of dead cells into the ventricle declines on E16 and nearly stops on E17 (see Chapter 10 in Bayer and Altman, 1991a). The surviving cells are probably ependymal stem cells at the ventricular lumen and glial precursors; both cells are more radioresistant than neural stem cells. Despite the fact that primary neural stem cells are declining on a relative basis, the cortical neuroepithelium is still expanding on an absolute basis, and it reaches its greatest volume on E17. The chief progeny of the primary neural stem cells during this epoch are pyramidal cells that will settle in layers VI and V. These neurons rapidly move out of the neuroepithelium after they are generated and sojourn in layer-specific bands in the intermediate zone. Secondary neural stem cells also leave the neuroepithelium during this time to continue proliferating in the cortical subventricular zone, where they will generate some of the upper layer neurons in layers IV–II (Smart and McSherry, 1982; Tarabykin et al., 2001). During the third epoch (E18–E21), primary neuronal precursors undergoing interkinetic nuclear migration decline and disappear in the cortical neuroepithelium. Two hours after a [3H]thymidine exposure, heavily labeled nuclei are randomly distributed in the neuroepithelium; the distinction between the synthetic and the mitotic zones disappears. Low-level X-ray kills fewer cells in the neuroepithelium, indicating that ependymal stem cells form an intact layer at the ventricular lumen. It is during this third epoch that the volume of the cortical neuroepithelium shrinks both relatively and absolutely. By E20, the cortical neuroepithelium is already a primitive ependyma. The chief progeny of the neural stem cells during this epoch are in neurons in layers IV–II (Bayer and Altman, 1991a). The heterogeneous array of neurons in these layers probably originate from primary neural stem cells in the cortical neuroepithelium (regions 3 and 3/4) and secondary neural stem cells in the cortical subventricular zone. The neurons generated in the cortical neuroepithelium sojourn in a prominent band in the lower subventricular zone before migrating to the cortical plate (see Chapter 7, Figs. 7–3 to 7–8 in Bayer and Altman, 1991a). Secondary neural stem cells and their progeny in the subventricular zone express Svet1 during the peak times of layer IV–II neurogenesis.
Svet1 cells migrate through the intermediate zone, through the lower cortical plate, and settle in the upper cortical plate (Tarabykin et al., 2001). It is possible that the layer IV–II neurons generated in the cortical neuroepithelium also begin to express Svet1 during their sojourn in the lower subventricular zone, making that zone critical in determining an upper layer fate (Tarabykin et al., 2001) A new hypothesis is that most neocortical interneurons are generated in the medial eminence of the basal ganglia neuroepithelium (region 4B) and migrate into the cortex (Anderson et al., 1997, 2001; Denaxa et al., 2001). The dorsal and ventral parts of the telencephalic neuroepithelium and subventricular zone are continuous at the cortical–pallidal angle (region 3/4, Figs. 9–14), and cells could migrate through that region from the basal ganglia to the cortex (De Carlos et al., 1996). Piriform (primary olfactory) cortex Neurons in layers III–IV are generated in the corticopallidal angle (region 3/4) and in the lateral part of region 4A (Figs. 8–10; Bayer and Altman, 1991b; De Carlos et al., 1996). Neurons in layer II are probably generated in the cortical neuroepithelium (regions 3 and 3/4) and migrate laterally and ventrally for several days before settling above the layer III–IV neurons (Figs. 10–12; Bayer and Altman, 1991a). The layer II neurons in the piriform cortex appear late as a thin ventrolateral extension of the lateral limbic cortical plate. The posterior part of the piriform cortex matures earlier than the anterior part, in accordance with the posterior to anterior neurogenetic gradient (reviewed in Bayer, 1986b). Hippocampal region The neuroepithelium in the posterolateral cortical primordium is the presumed source of neurons in the entorhinal cortex (Bayer, 1980b). That neuroepithelial area is not in any of the sections shown, so a brief verbal summary of events follows. In rat embryos on E16, the entorhinal neuroepithelium is thick and a zone of young neurons migrate outward from its lateral part. The entorhinal neuroepithelium is still prominent on E17, and there are layers resembling the cortical intermediate zone and a cortical plate; both of these are thicker laterally than medially, reflecting the prominent lateral (older) to medial (younger) neurogenetic gradient that is found throughout the entorhinal cortex. By E18, the entorhinal neuroepithelium thins, coinciding with reduced neurogenesis, while the cortical plate becomes thicker, again more so laterally than medially. Also on E18, a cell-sparse region develops beneath the cortical plate in the entorhinal region that is similar to the upper intermediate zone in the neocortex. On E19, a
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split appears in the entorhinal cortical plate, possibly representing the lamina dessicans in layer IV. That morphological feature distinguishes the entorhinal area from the limbic and neocortical areas, where the cortical plate has no cell-sparse zones. The splitting of the cortical plate proceeds from a lateral to a medial direction up to E20. Although the lamination of the entorhinal cortex is obvious by E22, there are still a few spindle-shaped radially oriented cells in the intermediate zone, indicating that entorhinal neurons are still migrating. The presumed source of the subiculum (Bayer, 1980b) is the part of the hippocampal neuroepithelium (region 2A, Figs. 8–11 and 19–22) that is continuous with the cortical neuroepithelium. Between E18 (Fig 22) and E20 (Fig 23) the cortical plate extends into the differentiating zones outside the subicular/ammonic part of the hippocampal neuroepithelium. In horizontal sections of rat embryos, the bifurcation of the entorhinal cortical plate ceases to progress medially by E20, and the adjacent wedge-shaped nonbifurcated cortex can be more accurately delineated as the parasubiculum and the presubiculum. The neurons in this part of the cortical plate arrive there from E18 through E20 and probably represent deep neurons in the parasubiculum, the presubiculum, and the subiculum proper. The parasubiculum cannot be distinguished from the presubiculum until E22 because the migration of small neurons to the superficial layers of the presubiculum is exceptionally late (Bayer, 1980b). [3H]Thymidine autoradiographic studies indicate that the “bulge” in the neuroepithelium of the hippocampus has three components (Altman and Bayer, 1990a,b,c). One (region 2A) gives rise to the pyramidal cells of Ammon’s horn, a second (region 2B) gives rise to the granule cells in the dentate gyrus, and a third (region 2C) gives rise to glia that will populate the fimbria and probably part of the choroid plexus. Region 2A appears on E14 in rat embryos (Figs. 9 and 18). That neuroepithelium shows a high level of proliferative activity up to E18 (Figs. 9–12 and 18–22); relatively few pyramidal neurons are generated on E20 and the neuroepithelium declines (not shown). After a single [3H]thymidine injection on E18, the migratory routes of the pyramidal cells were tracked by killing animals at daily intervals after the injection (Altman and Bayer, 1990b). All of the pyramidal cells move out of the neuroepithelium 1 day after their generation and form a band of heavily labeled cells just outside it. On subsequent days, the pyramidal cells leave this band and migrate into the pyramidal layer. CA1 neurons migrate radially and take 4 days to reach their destina-
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tions. Although the CA3 neurons are generated earlier than the CA1 neurons, they take longer to migrate to the pyramidal layer because part of their migratory trajectory is a curved path around the edge of the accumulating CA1 neurons. Possibly the earlier time of origin of CA3 neurons is related to their longer pathway of migration. At the time of birth in rats, many CA3 pyramidal cells are still migrating into the lengthening pyramidal layer. The granule cells of the dentate gyrus are ultimately derived from the dentate neuroepithelium that indents slightly at the edge of the Ammonic neuroepithelium, a region called the “dentate notch” (region 2C, Figs. 11, 12, and 19–21; Altman and Bayer, 1990a,b,c), but the secondary neural stem cells that give rise to granule cells migrate from the notch in the dentate migratory stream before producing granule cells (see Part IV, Figs. 21–24). Olfactory Bulb and Peduncle Olfactory nerve fibers reach the telencephalon on E14 (Fig. 18) and define the part of the telencephalic neuroepithelium that begins to evaginate into an olfactory bulb on E15 (region 7, Fig. 19). However, [3H]thymidine autoradiography indicates that the mitral neurons of the olfactory bulb are generated in the septal/accumbal neuroepithelium (regions 5 and 6) and migrate into the olfactory bulb (Figs. 19–21; Bayer, unpublished observations). On E15 (Fig. 19), mitral neurons accumulate at the base of the brain behind the olfactory nerve fibers and their axons start to form the lateral olfactory tract. On E16 (Fig. 20), some earlygenerated mitral cells reach the evaginating olfactory bulb. On E17 (Fig. 21) and E18 (Fig. 22), more mitral neurons migrate into the bulb from a ventral direction and curve around it dorsally. The mitral cell layer appears on E17 (Fig. 21) and becomes more definite from E18 to E22 (Figs. 22–24). The neuroepithelium in the olfactory bulb itself may give rise to accessory olfactory bulb mitral cells and tufted cells that migrate radially to settle in the external plexiform layer outside the mitral cell layer (Figs. 23 and 24). Interneurons and granule cells are produced by secondary neural stem cells that migrate in the rostral migratory stream from the subventricular zones of the cortex and ventral telencephalon (Figs. 21–24). The anterior olfactory nucleus in the olfactory peduncle is generated just after the mitral neurons in the main olfactory bulb. It is likely that these neurons are produced by either the same neuroepithelium as mitral neurons (regions 5 and 6) or by the most posterior and ventral part of the evaginating olfactory neuroepithelium (region 7, Figs. 21–23).
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DEVELOPMENT OF THE LATERAL, ROSTRAL, AND DENTATE MIGRATORY STREAMS Lateral Migratory Stream and Cell Migration in the Cerebral Cortex The lateral migratory stream is a prominent band of horizontally oriented cells adjacent to the cortical subventricular zone in the lower intermediate zone that extends from the dorsomedial to the ventrolateral extent of the cortex. It is best seen in coronal sections (Figs. 12–14). In sagittal sections, only a thin part of the stream is visible (Figs. 21–24). This is the most complex migratory stream in the telencephalon for three reasons. First, only some neocortical neurons migrate in the stream. The Cajal–Retzius and subplate neurons migrate and settle without using the lateral migratory stream. Neurons settling in the dorsal neocortex probably do not use the stream. Second, the neocortical neurons in the stream are in the second stage of their migration after they have sojourned for approximately 24 h in layer-specific bands either in the intermediate zone or in the subventricular zone (Bayer and Altman, 1991a). Third, the cortical neuroepithelium produces neurons that migrate in the stream to destinations outside the neocortex before, during, and after neocortical neurons migrate in the stream. Migration of Cajal–Retzius and Subplate Neurons The Cajal–Retzius and subplate neurons are sequestered in the neuroepithelium after they are generated and migrate out radially within 1 day (Bayer and Altman, 1991a) to immediately settle in the primordial plexiform layer without entering the lateral migratory stream. The Cajal–Retzius cells assume a horizontal orientation, settle beneath the pial membrane among a subpial system of extracellular channels, and rapidly begin to differentiate. These channels are soon filled with early-arriving axons that synapse with Cajal– Retzius dendrites. The subplate neurons take several days before settling permanently in a morphologically distinct subplate. First, they accumulate beneath the Cajal–Retzius neurons in the primordial plexiform layer. Second, the subplate neurons become radially oriented and form a cortical plate (see it ventrolaterally on E16, Fig. 11). The thin cortical plate that extends to the dorsomedial cortex on E17 is composed mainly of subplate neurons (Fig. 12). As the cortical plate expands from ventrolateral to dorsomedial on E16 and E17, a deep set of extracellular channels appears (prominent white bands beneath the ventrolateral cortical plate on the left half of the photographs in Figs. 11 and 12). Third, subplate neurons delaminate from the cortical plate in a
ventrolateral to dorsomedial direction to settle permanently among the deep extracellular channels on E18 (Fig. 13). By E20 (Fig. 14) the subplate is a distinct layer below the cortical plate. The subplate neurons rapidly differentiate and form synaptic contacts with axons that grow into the deep channel system. It is postulated that these early migratory patterns of the Cajal–Retzius and subplate neurons are necessary prerequisites for the normal development of layers VI–II (reviewed in Bayer and Altman, 1991a). Migration of Layer VI–II Neurons Stage 1: Sojourn in layer-specific bands The neurons destined to settle in layers VI–V and many neurons in layers IV–II move out of the cortical neuroepithelium within 1 day after their generation and first sojourn in narrow layer-specific bands in the subventricular and intermediate zones (Bayer and Altman, 1991a). These bands can only be seen in autoradiographic sections 24 h after an exposure to [3H]thymidine. To save space, the pictures are not reproduced here, but see Chapter 7 in Bayer and Altman (1991a) for a detailed description of the layer-specific sojourn hypothesis. By correlating the timetables of neurogenesis with their sequential appearance, each band can be linked to a specific population of cortical neurons. The neurons destined to settle in layer VI sojourn in the upper intermediate zone very close to the base of the cortical plate; this is called the first superior band (sb1). The sb1 is in the rat cortex on E16 and E17, 1 day after [3H]thymidine injections on E15 and E16, and during the time that maximum numbers of layer VI neurons should be located outside of the neuroepithelium. Neurons bound for layer V sojourn in the second superior band (sb2) at a lower level in the intermediate zone. The sb2 is in the rat cortex on E17 and E18, just at the time when large numbers of layer V neurons should be outside of the neuroepithelium. Neurons bound for layers IV–II sojourn in the first inferior band (ib1) in the lower subventricular zone. The ib1 appears on E18, correlating with the first peak of neurogenesis of layer IV neurons, and remains until E21 when the youngest neurons bound for layers III and II are generated in the cortical subventricular zone. Many neurons in the ib1 are postulated to express Svet1 during their sojourn (Tarabykin et al., 2001) Stage 2: Predominantly radial migration to the cortical plate Layer VI–II cortical neurons continue their migration to the cortical plate after their sojourn. Those bound for layers VI–II in the dorsal neocortex migrate in the radial direction and settle on the next day; the entire sequence from birth to settling takes only 2 days. Layer VI and V neurons that settle in the
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dorsolateral neocortex (those generated on E15) also migrate predominantly radially and settle in 2–3 days because the cortical neuroepithelium is either immediately below or only slightly medial to the lateral cortical plate when they are migrating on E16 (Fig. 11) and E17 (Fig. 12). Stage 2: Predominantly lateral migration Layer V–II neurons generated on or after E17 that settle in the ventrolateral cortical plate cannot follow a radial migratory path. These neurons are generated approximately 0.5 to 1.0 mm medial to the points where they will penetrate the cortical plate because growth of the basal ganglia displaces the cortical neuroepithelium and the subventricular zone. After sojourning in the intermediate and the subventricular zones for 1 day, these neurons orient tangentially and enter the lateral migratory stream 2 days after their generation and migrate along the outside edge of the external capsule. The ventrolateral extension of the lateral migratory stream is first seen on E18 (Fig 13). One day later neurons leave the stream, turn, migrate radially through the upper intermediate zone, and finally enter the ventrolateral cortical plate around E20 4 days after their generation. Neurons bound for the far ventrolateral neocortex, such as the insular area, migrate laterally for 3 days and take 5 or more days to reach their destinations in the cortical plate. The later time of arrival of neurons in the ventrolateral and farventrolateral parts of the cortical plate is documented with [3H]thymidine autoradiograms in Chapter 9 in Bayer and Altman (1991a). Primary Olfactory Cortex Neurons and Others in the Basal Telencephalon The cortical neuroepithelium also gives rise to neurons that are destined to settle in the primary olfactory cortex and other sites in the basal telencephalon, such as the basolateral complex of the amygdala and the intercalated masses of the amygdala. Sequentialsurvival [3H]thymidine autoradiography after an injection on E15 can track heavily labeled cells moving from the neocortical lower intermediate zone into layer II of the primary olfactory cortex (Altman, unpublished observations). Layer II does not appear until E17 in the primary olfactory cortex as a thin ventrolateral extension of the neocortical plate (Fig. 12). In accordance with a ventral (older) to dorsal (younger) neurogenetic gradient, layer II continues to lengthen in the ventral direction as younger neurons are added dorsally on E18 (Fig. 13), E20 (Fig. 14), and beyond. Contrary to the neocortex, the layer III–IV neurons in the primary olfactory cortex do not form part of the cortical plate,
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possibly because they are generated by part of the basal ganglia neuroepithelium. Sequential-survival [3H]thymidine autoradiography after an injection on E15 can also track heavily labeled cells moving into deep parts of the ventral telencephalon, wrapping around and under the external capsule (Altman, unpublished observations). These neurons may be settling in the basolateral group of amygdaloid nuclei where some neurons resemble pyramidal cells in the cortex. Observations after later injections indicate that labeled cells migrate to and accumulate in a reservoir at the base of the lateral migratory stream (see Fig. 14). Cells move out of the reservoir and appear to migrate into the intercalated masses of the amygdala (Bayer, unpublished observations).
Rostral Migratory Stream and Adult Neurogenesis in the Olfactory Bulb The rostral migratory stream (Altman, 1969) is a large subventricular zone in the anterior forebrain that starts in the region of the septum and nucleus accumbens, curves around the olfactory neuroepithelium itself, and ends at the anterior border of the cortical subventricular zone. It appears on E17 both above and below the olfactory bulb neuroepithelium (rms, Fig. 21). From E18 on, the rostral migratory stream is continuous around the most anterior extent of the olfactory bulb neuroepithelium (Figs. 22–24). It is not known which part of the primary neuroepithelium contributes to the secondary neural stem cells that move into the rostral migratory stream, but it is likely that contributions come from cortical, septal, and nucleus accumbens neuroepithelia. Once inside the stream, secondary neural stem cells proliferate as well as migrate forward. Some secondary neural stem cells produce postmitotic neurons (olfactory granule cells, periglomerular granule cells, and other olfactory interneurons) far back in the stream and their progeny continues to migrate into the olfactory bulb; others may go all the way into the bulb before producing neurons (Altman, 1969; Kaplan and Hinds, 1977; Peretto et al., 1999). Once the cells reach the olfactory bulb, postmitotic neurons leave the stream and move into the granular layer. The outpouring of young neurons is especially prominent in the E22 brain (Fig. 24). The rostral migratory stream persists into adulthood and is a source of new olfactory bulb interneurons throughout adult life (Fig. 25A). Morphologic studies reveal that the adult rostral migratory stream contains bipolar undifferentiated cells (presumably neural stem cells) surrounded by astrocytes that form elongated tubes extending toward the olfactory bulb (Peretto et al., 1999). Quantitative studies (Roselli-Austin and Altman, 1979; Kaplan et al.,
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1985) have shown that the number of granule cells in the olfactory bulb increases in adults, a feature they share with granule cells in the dentate gyrus. [3H]Thymidine autoradiographic data indicate that many adult-generated neurons die and are replaced by the constant supply of new adult-generated neurons (Bayer, 1983; Kaplan et al., 1985); the subset of new adult neurons that show turnover may be related to turnover of the primary olfactory sensory neurons in the olfactory epithelium (Graziadei and Graziadei, 1979).
increases during adult life (Bayer et al., 1982; Bayer, 1982). In contrast to the granule cells of the olfactory bulb, there is little evidence of cell death in the granule cells of the dentate gyrus (Bayer, 1985c), and the functional importance of granule cell neurons may increase in the adult hippocampus.
Dentate Migratory Stream and Adult Neurogenesis in the Dentate Gyrus
Figure 26 summarizes the hypothetical changes that take place in neural and glial stem cell lines between E15 and E20 in the dorsomedial cortex. The diagram distinguishes two stages in cortical germinal zones. On E15 (Fig. 26A) and E16 (Fig. 26B) there is still only one germinal zone, the cortical neuroepithelium, which may be specified as early as E11 (Figs. 7A and 15). From E17 on (Figs. 26C–26F) there are two germinal zones, the primary cortical neuroepithelium and the secondary subventricular zone created by glial stem cells and neural stem cells exiting from the neuroepithelium. As cortical development proceeds, the primary germinal zone shrinks while the secondary germinal zone expands to reflect the continually changing number and types of neural, glial, and ependymal stem cell populations. The diagram in Fig. 26 shows neural stem cells and glial stem cells existing as separate populations in the early neuroepithelium (Figs. 26A and 26B), mainly for simplicity because the emphasis of our analysis is on the proliferation dynamics of stem cells, not on the time of commitment. Probably unique populations of stem cells arise sequentially in the cortical neuroepithelium through restriction of pluripotent stem cell lines; similar to “model B” in the Kalyani and Rao (1998) review of stem cell lineages in the spinal cord and peripheral nervous system. Retroviral cell lineage studies in the cortex (Grove et al., 1993; Krushel et al., 1993; McCarthy et al., 2001) support the initial heterogeneity of some stem cells (clones generate neurons and glia) and the sequential commitment and heterogeneity of others (clones restricted to specific types of neurons or specific types of glia).
The dentate/fimbrial neuroepithelium can be distinguished as a slight medial curve or “notch” at the base of the Ammon’s horn neuroepithelium on E15 (region 2B/C, Figs. 10 and 19) and E16 (Figs. 11 and 20). Region 2C of that neuroepithelium is the source of secondary neural stem cells that migrate into the dentate primordium and establish a secondary germinal matrix in the subgranular layer of the dentate gyrus. Beginning on E17, cells move out of the dentate neuroepithelium along the pia at the very edge of the cortex (dms, Fig. 21) and accumulate in a rounded area, the dentate primordium. The migrating cells on E17 are mostly postmitotic neurons (basket cells and large neurons in the molecular layer of the dentate gyrus) because short-survival [3H]thymidine autoradiography indicates no label uptake (Altman and Bayer, 1990c). By E18 (Fig. 22) many of the migrating cells are proliferating, indicating that secondary neural stem cells are in the stream (Altman and Bayer, 1990c). Up to E20 (Fig. 23), secondary neural stem cells continue to migrate into the dentate gyrus, following a curved path across the fimbria and around the expanding edge of Ammon’s horn. By E22 (Fig. 24), the migratory path is less distinct, and the subgranular layer of the dentate gyrus contains many secondary neural stem cells generating granule cell neurons. The external (or ectal) limb of the granular layer is already visible. During the first postnatal week, most of the granule neurons are generated and accumulate in a thick layer with older neurons stacked above younger neurons. Secondary neural stem cells thin out during the second and third postnatal weeks but many remain in a distinct subgranular layer (Fig. 25B). Secondary neural stem cells in the subgranular layer continue to produce granule neurons during juvenile and adult life. These new neurons move into the lower third of the granule cell layer (Altman, 1962; Altman and Das, 1965; Kaplan and Hinds, 1977; Bayer et al., 1982; Bayer, 1982; Kaplan and Bell, 1984). Quantitative studies indicate that the number of granule cells significantly
STEM CELL DYNAMICS IN CORTICAL GERMINAL ZONES
Neural Stem Cells Two different types of neural stem cells populate the cortical germinal zones. Primary neural stem cells (PNS, red and yellow ellipses, Fig. 26) are presumed to be columnar cells that go through the mitotic phase of the cell cycle at the ventricular lumen and generate neurons in the neuroepithelium. Secondary neural stem cells (SNS, orange ovals, Fig. 26) are initially in the neuroepithelium, move out, and generate neurons in the sub-
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FIGURE 25 A diagram summarizing adult neurogenesis in the olfactory bulb (A) and in the dentate gyrus of the hippocampus (B) based on the findings of Altman and Bayer and their coworkers in publications that appeared between 20 and 40 years ago (Altman, 1962, 1969; Altman and Das, 1965; Roselli-Austin and Altman, 1979; Bayer et al., 1982; Bayer, 1982, 1985c). Neural stem cells are represented as green circles in A and B; adult generated neurons are yellow-green ellipses in A and yellow-green ovals in B; neurons generated during the late-fetal, early postnatal period are magenta ellipses in A and magenta ovals in B. The large arrow in A indicates the direction taken by migrating secondary neural stem cells. The small arrows in A and B indicate the directions taken by migrating new adult neurons. The fact that olfactory sensory neurons are continually being renewed in the mammalian olfactory sensory epithelium has been extensively studied by Graziadei and Graziadei (1979).
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FIGURE 26 Summary diagram of the postulated changes in stem cell type and density from E15 (A) through E20 (F) in the germinal zones of the dorsomedial neocortex that produce motor cortex and somatosensory cortex. Primary neural stem cells (yellow and red ellipses) generate neurons in the neuroepithelium, secondary neural stem cells (orange ovals) generate neurons in the subventricular zone, glial stem cells (blue ovals) generate glia in both germinal zones, ependymal stem cells (violet squares) proliferate in the neuroepithelium, and ependymal cells completely replace the primary germinal matrix by E20 (F). The density changes and proportions of self-replicating and final neurogenetic divisions in both types of neural stem cells are based on timetables of neurogenesis in the motor cortex and the somatosensory cortex (Bayer and Altman, 1991a).
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ventricular zone. While in the neuroepithelium, SNS are presumed to be randomly distributed and go through the mitotic phase of the cell cycle at various distances from the ventricular lumen. Mitotic figures at some distance from the ventricular lumen are in the cortical neuroepithelium before the subventricular zone emerges, continually increase as the neuroepithelium declines, and are randomly distributed throughout the subventricular zone (Bayer and Altman, 1991a). One major contribution of comprehensive [3H]thymidine labeling is finding that throughout the central nervous system neurons in specific nuclei and laminae are generated over short time periods. The timetables of neurogenesis for layer VI–II cortical neurons (graphs 2–4, Fig. 4) show broader time spans because neurogenetic timetables are combined for all cortical areas, including the medial and lateral limbic cortices. But in the dorsomedial motor neocortex for example, peak neurogenesis of specific layers occurs on 2 days: 80% of layer VI neurons originate on E15 and E16, 78% of layer V neurons on E16 and E17, 88% of layer IV and lower layer III neurons on E17 and E18, and 77% of upper layer III and layer II neurons on E18 and E19 (see Fig. 14–4 in Bayer and Altman, 1991a). How can so many neurons be generated in such a short time? It is postulated that layer-specific neural stem cells take several days to prepare for a short burst of neurogenesis by continually renewing themselves at an exponential growth rate; all progeny remain in the cortical germinal zones and increase the number of layer-specific neural stem cells (self-replicating division). As neurogenesis begins, a few stem cell divisions produce either one or two postmitotic neurons (neurogenetic division). During peak neurogenesis, nearly all layer-specific neural stem cells produce only postmitotic neurons. Neurogenesis ends when the last layerspecific stem cells disappear from the neuroepithelium or the subventricular zone as they go through their final neurogenetic divisions to generate the youngest neurons in a given layer. The density and type of neural stem cells change hourly in the cortical germinal zones as neurogenesis takes place; some hypothetical changes are illustrated in Fig. 26 for the neuroepithelium and subventricular zone generating neurons in the dorsomedial neocortex. The proportions listed in Fig. 26 of neural stem cells in self-replicating and final neurogenetic divisions are based on the actual data of neuron origin using longsurvival [3H]thymidine autoradiography. Layer VI–V PNS predominate on E15 and reach peak density on E16; numbers decline on E17, and the last day any layer VI–V PNS exist in the neuroepithelium is E18 (red ellipses, Figs. 26A–26D). Stem cells generating neurons in layers IV–II have more complex changes because
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some are in the neuroepithelium (PNS, yellow ellipses, Fig. 26) and others are in the subventricular zone (SNS, orange ovals, Fig. 26). Another complication is that dorsomedial germinal zones in the neocortex are generating layer IV–II neurons not only for the motor cortex directly above but also for the ventrolaterally placed somatosensory cortex, where there are robust numbers of layer IV–II neurons. It is postulated that layer IV–II PNS generate a subset of older neurons in the superficial layers that have peak time of origin on E17 when the subventricular zone is still small (Fig. 26C); these stem cells have self-renewal exponential growth on E15 and E16, reach peak density on E17, decline sharply on E18, and generate their last neurons on E19. We also postulate that layer IV–II SNS (the Svet1 proliferating cells discovered by Tarabykin et al., 2001) generate a subset of younger neurons that has a peak time of origin on E19, when the subventricular zone is larger than the neuroepithelium (Fig. 26E); these stem cells show mainly self-duplicating division up to E18, reach peak density on E19 when most are either in neurogenetic division or in final neurogenetic division, and start to decline on E20. A few layer IV–II PNS generate the youngest neurons in layer II on E21 (not shown). It is possible that a very small fraction of layer IV–II PNS are retained in adults because layer IV neurogenesis can take place in the mature rat cortex (Kaplan, 1981).
Glial and Ependymal Stem Cells Glial and ependymal stem cells are different from neural stem cells because they are present in the developing brain and are still common in adult brains. The density of glial (blue ovals) and ependymal stem cells (violet squares) is lower than that of neural stem cells in cortical germinal zones up through E17 (Figs. 26A– 26C); by E19 and E20, they are the predominant stem cells (Figs. 26E and 26F). Ependymal stem cells always multiply in the neuroepithelium at the ventricular lumen. They are sparse on E15 and E16 and increase considerably on E17, but still do not form a continuous layer (Figs. 26A–26C). X-irradiation exposures result in dead cell debris shedding into the ventricular lumen. A continuous layer exists on E18 (Fig. 26D) because dead cell debris no longer sheds into the ventricular lumen after X-irradiation (see Chapter 10 in Bayer and Altman, 1991a). The ependymal layer continues to become more dense throughout the rest of development; neural stem cells are absent by E20, when the proliferating cells at the ventricle form the primitive ependyma (Figs. 26E and 26F). Glial stem cells multiply at random locations within the neuroepithelium on E15 and E16 (Figs. 26A and 26B). On E17 and E18 many glial stem cells move into
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the adjacent subventricular zone and they continue to proliferate in both germinal zones (Figs. 26C and 26D). Glial stem cells are mainly in the subventricular zone on E19 and are located outside of the primitive ependyma on E20 (Figs. 26E and 26F). The density of glial precursors continually increases in the subventricular zone; it is still large on E22 (Fig. 24) and populated with glial precursors because few to no neurons are being generated in the cortex (Bayer and Altman, 1991a). These stem cells generate both astrocytes and oligodendrocytes. The astrocyte precursors disperse out of the subventricular zone on E20 and E21 to locally multiply in the intermediate zone and cortical plate (Bayer and Altman, 1991a). Tekki-Kessaris et al. (2001) postulate that, similar to the spinal cord, the ventral forebrain has a focus of oligodendroglial stem cells in the neuroepithelium that eventually populate the dorsal forebrain, including the cortex. They show indirect evidence that oligodendroglial precursors migrate into the ventrolateral rat cortical subventricular zone from a source in the ventromedial neuroepithelium of the medial ganglionic eminence. The subventricular zones of the cortex and basal ganglia are continuous around the corticopallidal angle, and cells could migrate between telencephalic regions. Possibly, these pioneer oligodendroglial stem cells function to restrict uncommitted glial precursors to an oligodendroglial fate (Tekki-Kessaris et al., 2001).
References Altman, J. (1962). Are neurons formed in the brains of adult mammals? Science 135, 1127–1128. Altman, J. (1963). Autoradiographic study of cell proliferation in the brains of rats and cats. Anat. Rec. 145, 573–591. Altman, J. (1966). Autoradiographic and histological studies of postnatal neurogenesis. II. A longitudinal investigation of the kinetics, migration and transformation of cells incorporating tritiated thymidine in infant rats, with special reference to postnatal neurogenesis in some brain regions. J. Comp. Neurol. 128, 431–474. Altman, J. (1969). Autoradiographic and histological studies of postnatal neurogenesis. IV. Cell proliferation and migration in the anterior forebrain, with special reference to persisting neurogenesis in the olfactory bulb. J. Comp. Neurol. 137, 433–457. Altman, J., and Bayer, S. A. (1986). The development of the rat hypothalamus. Adv. Anat. Embryol Cell Biol. 100. Altman, J., and Bayer, S. A. (1990a). Mosaic organization of the hippocampal neuroepithelium and the multiple germinal sources of dentate granule cells. J. Comp. Neurol. 301, 325–342. Altman, J., and Bayer, S. A. (1990b). Prolonged sojourn of developing pyramidal cells in the intermediate zone of the hippocampus and their settling in the stratum pyramidale. J. Comp. Neurol. 301, 343–364. Altman, J., and Bayer, S. A. (1990c). Migration and distribution of two populations of hippocampal granule cell precursors during the perinatal and postnatal periods. J. Comp. Neurol. 301, 365–381. Altman, J., and Bayer, S. A. (1995). “Atlas of Prenatal Rat Brain Development.” CRC Press, Boca Raton, FL.
Altman, J., and Bayer, S. A. (1996). “Development of the Cerebellar System in Relation to Its Evolution, Structure, and Functions.” CRC Press, Boca Raton, FL. Altman, J., and Das, G. D. (1965). Autoradiographic and histologic evidence of postnatal neurogenesis in rats. J. Comp. Neurol. 124, 319–335. Anderson, S. A., Eisenstat, D. D., Shi, L., and Rubenstein, J. L. (1997). Interneuron migration from basal forebrain to neocortex: Dependence on Dlx genes. Science 278, 474–476. Anderson, S. A., Marin, O., Horn, C., Jennings, K., and Rubenstein, J. L. (2001). Distinct cortical migrations from the medial and lateral ganglionic eminences. Development 128, 353–363. Bayer, S. A. (1979a). The development of the septal region in the rat. I. Neurogenesis examined with [3H]thymidine autoradiography. J. Comp. Neurol. 183, 89–106. Bayer, S. A. (1979b). The development of the septal region in the rat. II. Morphogenesis in normal and X-irradiated embryos. J. Comp. Neurol. 183, 107–120. Bayer, S. A. (1980a). Development of the hippocampal region in the rat. I. Neurogenesis examined with [3H]thymidine autoradiography. J. Comp. Neurol. 190, 87–114. Bayer, S. A. (1980b). Development of the hippocampal region in the rat. II. Morphogenesis during embryonic and early postnatal life. J. Comp. Neurol. 190, 115–134. Bayer, S. A. (1980c). Quantitative [3H]thymidine radiographic analyses of neurogenesis in the rat amygdala. J. Comp. Neurol. 194, 845–875. Bayer, S. A. (1981). A correlated study of neurogenesis, morphogenesis and cytodifferentiation in the rat nucleus accumbens. In “The Neurobiology of the Nucleus Accumbens” (Chronister, R. B., and De France, J. F., Eds.), pp. 173–197. Haer Institute, Brunswick, ME. Bayer, S. A. (1982). Changes in the total number of dentate granule cells in juvenile and adult rats: A correlated volumetric and [3H]thymidine autoradiographic study. Exp. Brain Res. 46, 315–323. Bayer, S. A. (1983). [3H]Thymidine-radiographic studies of neurogenesis in the rat olfactory bulb. Exp. Brain Res. 50, 329–340. Bayer, S. A. (1984). Neurogenesis in the rat neostriatum. Int. J. Dev. Neurosci. 2, 163–175. Bayer, S. A. (1985a). Neurogenesis in the olfactory tubercle and islands of Calleja in the rat. Int. J. Dev. Neurosci. 3, 135–147. Bayer, S. A. (1985b). Neurogenesis of the magnocellular basal telencephalic nuclei in the rat. Int. J. Dev. Neurosci. 3, 229–243. Bayer, S. A. (1985c). Neuron production in the hippocampus and olfactory bulb of the adult rat brain: Addition or replacement? Ann. N. Y. Acad. Sci. 457, 163–172. Bayer, S. A. (1986a). Neurogenesis in the anterior olfactory nucleus and its associated transition areas in the rat brain. Int. J. Dev. Neurosci. 4, 225–249. Bayer, S. A. (1986b). Neurogenesis in the rat primary olfactory cortex. Int. J. Dev. Neurosci. 4, 251–271. Bayer, S. A. (1987). Neurogenetic and morphogenetic heterogeneity in the bed nucleus of the stria terminalis. J. Comp. Neurol. 265, 47–64. Bayer, S. A., and Altman, J. (1974). Hippocampal development in the rat: Cytogenesis and morphogenesis examined with autoradiography and low-level x-irradiation. J. Comp. Neurol. 158, 55–80. Bayer, S. A., and Altman, J. (1975a). Radiation-induced interference with postnatal hippocampal cytogenesis in rats and its long-term effects on the acquisition of neurons and glia. J. Comp. Neurol. 163, 1–20. Bayer, S. A., and Altman, J. (1975b). The effects of x-irradiation on the postnatally forming granule cell populations in the olfactory bulb, hippocampus, and cerebellum of the rat. Exp. Neurol. 48, 167–174.
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Bayer, S. A., and Altman, J. (1987). Directions in neurogenetic gradients and patterns of anatomical connections in the telencephalon. Prog. Neurobiol. 29, 57–106. Bayer, S. A., and Altman, J. (1991a). “Neocortical Development.” Raven Press, New York. Bayer, S. A., and Altman, J. (1991b). Development of the endopiriform nucleus and the claustrum in the rat brain. Neuroscience 45, 391–412. Bayer, S. A., and Altman, J. (1995). Neurogenesis and neuronal migration. In “The Rat Nervous System.” (Paxinos, G., Ed.), 2nd ed., pp. 1041–1077. Academic Press, San Diego. Bayer, S. A., Yackel, J. W., and Puri, P. S. (1982). Neurons in the rat dentate gyrus granular layer substantially increase during juvenile and adult life. Science 216, 890–892. Bulchand, S., Grove, E. A., Porter, F. D., and Tole, S. (2001). LIMhomeodomain gene Lhx2 regulates the formation of the cortical hem. Mech. Dev. 100, 165–175. De Carlos, J. A., López-Mascaraque, L., and Valverde, F. (1996). Dynamics of cell migration from the lateral ganglionic eminence in the rat. J. Neurosci. 16, 6146–6156. Denaxa, M., Chan,C.-H., Schachner, M., Parnevelas, J. G., and Karagogeos, D. (2001). The adhesion molecule TAG-1 mediates the migration of cortical interneurons from the ganglionic eminence along the corticofugal fiber system. Development 128, 4635–4644. Graziadei, P. P., and Graziadei, G. A. (1979). Neurogenesis and neuron regeneration in the olfactory system of mammals. I. Morphological aspects of differentiation and structural organization of the olfactory sensory neurons. J. Neurocytol. 8, 1–18. Grove, E. A., Williams, B. P., Li, D-Q.,Hajihosseini, M., Friedrich, A., and Price, J. (1993). Multiple restricted lineages in the embryonic rat cerebral cortex. Development 117, 553–561. Kalyani, A. J., and Rao, M. S. (1998). Cell lineage in the developing neural tube. Biochem. Cell Biol. 76, 1051–1068. Kaplan, M. S. (1981). Neurogenesis in the 3-month-old rat visual cortex. J. Comp. Neurol. 195, 323–338. Kaplan, M. S., and Bell, D. H. (1984). Mitotic neuroblasts in the 9-day-old and 11-month-old rodent hippocampus. J. Neurosci. 4, 1429–1441. Kaplan, M. S., and Hinds, J. W. (1977). Neurogenesis in the adult rat: Electron microscopic analysis of light radioautographs. Science 197, 1092–1094.
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Kaplan, M. S., McNelly, N. A., and Hinds, J. W. (1985). Population dynamics of adult-formed granule neurons of the rat olfactory bulb. J. Comp. Neurol. 239, 117–125. Krushel, L. A., Johnston, J. G., Fishell, G., Tibshirani, R., and van der Kooy, D. (1993). Spatially localized neuronal cell lineages in the developing mammalian forebrain. Neuroscience 53, 1035–1047. Langman, J., Guerrant, R. L., and Freeman, B. G. (1966). Behavior of neuroepithelial cells during closure of the neural tube. J. Comp. Neurol. 131, 15–26. McCarthy, M., Turnbull, D. H., Walsh, C. A., and Fishell, G. (2001). Telencephalic neural progenitors appear to be restricted to regional and glial fates before the onset of neurogenesis. J. Neurosci. 21, 6772–6781. Peretto, P., Merighi, A., Fasolo, A., and Bonfanti, L. (1999). The subependymal layer in rodents: A site of structural plasticity and cell migration in the adult mammalian brain. Brain Res. Bull. 49, 221–243. Roselli-Austin, L., and Altman, J. (1979). The postnatal development of the main olfactory bulb of the rat. J. Dev. Physiol. 1, 295–313. Schuurmans, C., and Guillemot, F. (2002). Molecular mechanisms underlying cell fate specification in the developing telencephalon. Curr. Opin. Neurobiol. 12, 26–34. Smart, I. H., and McSherry, G. M. (1982). Growth patterns in the lateral wall of the mouse telencephalon. II. Histological changes during and subsequent to the period of isocortical neuron production. J. Anat. 134, 415–442. Stoykova, A., Treichel, D., Hallonet, M., and Gruss, P. (2000). Pax6 modulates the dorsoventral patterning of the mammalian telencephalon. J. Neurosci. 20, 8042–8050. Tarabykin, V., Stoykova, A., Usman, N., and Gruss, P. (2001). Cortical upper layer neurons derive from the subventricular zone as indicated by Svet1 gene expression. Development 128, 1983–1993. Tekki-Kessaris, N., Woodruff, R., Hall, A. C., Gaffield, W., Kimura, S., Stiles, C. D., Rowitch, D. H., and Richardson, W. E. (2001). Hedgehog-dependent oligodendrocyte lineage specification in the telencephalon. Development 128, 2545–2554. Zappone, M. V., Galli, R., Catena, R., Meani, N., De Biasi, S., Mattei, E., Tiveron, C., Vescovi, A. L., Lovell-Badge, R., and Ottolenghi, S. (2000). Sox2 regulatory sequences direct expression of a β-geo transgene to telencephalic neural stem cells and precursors of the mouse embryo, revealing regionalization of gene expression in CNS stem cells. Development 127, 2367–2382.
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3 Autonomic Nervous System GIORGIO GABELLA Affiliation
body and the glands and the afferent (sensory) neurons that support the reflexes and the sensations from visceral organs. Many autonomic ganglia can be recognized with the naked eye as swelling or protrusions along nerve trunks or as knots within a mesh of nerves. Certain ganglia are connected in a sequence or ganglionated chain (the paravertebral sympathetic chain), while others are connected by a mesh of nerve trunks with which they form a plexus (the abdominal plexus or the pelvic plexus). Countless other microscopic ganglia are buried within a nerve or in the wall of viscera, and there are many single neurons along nerve trunks. In contrast. the sensory component consists mainly of neurons located in dorsal root ganglia (and in the nodose ganglion of the vagus nerve); in addition, afferent neurons are present within enteric ganglia. The autonomic nervous system is organized in groups of ganglia, which can be schematically subdivided into four groups, namely, paravertebral, prevertebral, paravisceral, and intramural (Fig. 1). Other ganglia are located in the head and provide motor innervation to salivary glands, cranial blood vessels, and the eye. The paravertebral ganglia are connected to each other and form two chains or ganglionated nerves, the sympathetic chains, which lie on either side of the vertebral column and are connected to the spinal nerves (hence to the spinal cord) by short nerve trunks, the “white” rami communicantes. The prevertebral ganglia are connected to each other and form a plexus (the abdominal plexus, which includes the celiac and the superior mesenteric ganglia) by the abdominal
LOCALIZATION OF AUTONOMIC GANGLIA General Organization The nerve cells and the nerves of the autonomic nervous system supply heart and blood vessels and intestinal, airway, urinary, and genital organs. The nerves regulate and coordinate bodily functions based on secretory activity of glands, on contraction and relaxation of smooth muscles and cardiac muscle, and on sensation arising from deep viscera. Muscles in the eye and skin and parts of the striated musculature of the esophagus and urethra are also innervated by autonomic nerves. While the central component of the autonomic nervous system consists of a few neuronal columns in the spinal cord and nuclei in the brain stem and the hypothalamus (see the relevant sections in other chapters), the peripheral part is scattered throughout the body. The peripheral autonomic nervous system of the rat, like that of other mammals, is of an extensive array of nerves and ganglia, connected to the CNS (spinal cord and brain stem) on one side and the viscera on the other. Viscera include the organs of the thoracic, abdominal, and pelvic cavities, the blood vessels, the organs of the head and neck, and the components of the skin. The autonomic nervous system has a common structural plan in all mammals, the rat being a species that has been studied extensively in this respect. The system comprises the efferent (motor) neurons that innervate the entire smooth musculature of the
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FIGURE 1 Highly schematic representation of the main groups of autonomic ganglia. The numbers indicate the topographical positions of the main autonomic nerves and of some individual ganglia: 1, superior cervical ganglion; 2, stellate ganglion; 3, lumber sympathetic ganglia; 4, intermediolateral column in thoracolumbar spinal cord; 5, rami communicantes; 6, thoracic splanchnic nerves; 7, lumbar splanchnic nerves; 8, mesenteric nerves; 9, hypogastric nerve; 10, perivascular nerves to blood vessels; 11, ciliary, otic, and sphenopalatine ganglia; 12, vagus nerve; 13, pelvic nerves; 14, cardiac ganglia; 15, pelvic ganglion; 16, prevertebral ganglia.
aorta. The paravisceral ganglia lie in the proximity of some viscera; the main groups are in the cardiac plexus and in the pelvic plexus, and other smaller ganglia are in a plexus close to the trachea and bronchi. Last, the intramural ganglia, which are too small to be seen with the naked eye, are situated within the wall of the gastrointestinal tract and biliary pathways.
Paravertebral and prevertebral ganglia are the main elements of the sympathetic outflow or the sympathetic pathway (referred to by many authors as the “sympathetic system”), which originates in the thoracic and lumbar segments of the spinal cord. The autonomic ganglia of the head are the cranial component of the parasympathetic pathway, which includes also the
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vagus nerve, all rooted in nuclei of the brain stem. The sacral component of the parasympathetic system originates from sacral segments of the spinal cord and consists chiefly of the main pelvic ganglion and a web of nerves known as the pelvic plexus. Tracheal, cardiac, and pelvic ganglia are situated along parasympathetic pathways; the pelvic ganglia, however, receive also a large input of sympathetic nerves. The intramural ganglia of the gut are neither sympathetic nor parasympathetic, although they are connected to both pathways; they constitute the enteric nervous system (Langley, 1921), a relatively autonomous component of the autonomic nervous system. The viscera have an abundant afferent (sensory) innervation, and if these fibers are regarded as part of the autonomic nervous system, as it seems they should be, they cannot be included in either the sympathetic or the parasympathetic pathway.
Sympathetic Chains The sympathetic chain is a bilaterally symmetric structure extending from the base of the skull to the sacrum. In the neck, the cervical sympathetic chain lies dorsal to the vagus nerve and the common carotid artery and ventral to the transverse processes of vertebrae and the prevertebral muscles. The chain has at this level two prominent ganglia, the superior cervical ganglion, and the inferior cervical ganglion (or stellate ganglion, which includes the uppermost thoracic sympathetic ganglia); a small intermediate cervical ganglion is sometimes found (Baljet and Drukker, 1979; Hedger and Webber, 1976) (Fig. 2). The superior cervical ganglion is spindle shaped, some 5 mm in length (often with a constriction in the middle), and lies dorsal to the bifurcation of the carotid artery. Among its (postganglionic) nerves, a carotid branch leaves the cranial pole of the ganglion and follows the internal carotid artery, and other smaller branches form a plexus around the external carotid artery. Other constant branches (rami) can be traced to the carotid body, to cranial nerves 9–12, and to cervical nerves 1–4 (Hedger and Webber, 1976). The stellate ganglion, consisting of the inferior cervical ganglion and the first two or three thoracic ganglia fused together, is located at the level of the first two thoracic vertebrae, on the right side being medial to the innominate artery (Hedger and Webber, 1976) (Fig. 2). Branches from the stellate ganglion join the lowermost cranial and the uppermost thoracic spinal nerves. Other branches connect with a plexus around the vertebral artery and with a plexus on the ventral side of the arch of the aorta (Hedger and Webber, 1976). In the thorax, the sympathetic chains lie ventral to the head of the ribs and dorsal to the parietal pleura
FIGURE 2 The cervical sympathetic trunk and its branches in the rat. A, aorta; B, brachiocephalic trunk; C, left common carotid artery; CN, carotid nerve; CT, costocervical trunk; C1, first cervical spinal nerve; I, internal carotid artery; LS, left subclavian artery; S, stellate ganglion; SC, superior cervical ganglion; ST, sympathetic trunk; V, vertebral artery; VN, vertebral nerve; E, external carotid artery; M, middle (intermediate) cervical ganglion; RS, right subclavian artery; T1, first thoracic spinal nerve. It should be noted that the cervical sympathetic trunk and superior cervical ganglion are located dorsal to the carotid artery (reproduced with permission from Hedger and Webber, 1976).
(Fig. 3). Each chain is made up of some 10 ganglia (including those usually fused with one another and with the inferior cervical ganglion). The lowermost ganglion lies opposite the 10th intercostal space. Small horizontal nerve trunks connect the two chains across the midline (Baljet and Drukker, 1979). In addition to the branches to the spinal nerves (rami communicantes) and small branches to the blood vessels, the thoracic sympathetic chains issue the splanchnic nerves (see below). In the abdomen the sympathetic chain is retroperitoneal and is embedded in the psoas muscle. There are five or six pairs of ganglia with rami communicantes to the spinal nerves, branches to blood vessels, and
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FIGURE 3 Lower cervical and thoracic sympathetic trunks of the rat (reproduced with permission from De Lemos and Pick, 1966).
small branches to the abdominal plexus (lumbar splanchnic nerves).
Rami Communicantes Rami communicantes are short nerve trunks connecting the ganglia of the sympathetic chain to the spinal nerves. The rami are particularly short in the rat
(De Lemos and Pick, 1966), and even when they are multiple and separated into two or more bundles they cannot be distinguished as white and gray rami. Preganglionic and postganglionic fibers are, therefore, mixed within each ramus, and because they have no distinctive structural features to indicate their orientation and nature, their identification can be made only after experiments of selective nerve sections.
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Splanchnic Nerves
Prevertebral Ganglia
Descending branches from the thoracic sympathetic ganglia give rise to the greater (major) splanchnic nerve, and occasionally to a lesser splanchnic nerve. Its apparent origin is usually from the 9th and the 10th ganglia (Baljet and Drukker, 1979). Both right and left greater splanchnic nerves enter the abdominal cavity, by piercing the diaphragm, between the medial and the lateral crus, and end in the abdominal plexus. The nerve, about 25 mm long, contains 190,000 nerve fibers, both afferent and efferent, the latter type pre- and postganglionic, and approximately 25,000 neurons (Isomura et al., 1985). There is often a paraaortic nerve, which originates in the lowermost thoracic sympathetic ganglia, enters the abdominal cavity, along the aorta, and terminates in the abdominal plexus. The lumbar splanchnic nerves are variable in number (usually four or five), size, and origin, and they extend from the lumbar sympathetic ganglia to the prevertebral plexus (Baljet and Drukker, 1979).
The prevertebral ganglia constitute the abdominal plexus, a large assembly of ganglia and nerve trunks lying close to the abdominal aorta and its main branches (Fig. 4). Blood vessels are the chief guide to the identification of prevertebral ganglia. Two sets of vessels stem from the abdominal aorta (Greene, 1935): parietal arteries (inferior phrenic arteries, lumbar arteries, ileolumbar arteries, middle caudal artery and terminal trunk, and common iliac artery) and visceral arteries (celiac artery, superior mesenteric artery, inferior mesenteric artery, renal arteries, and ovarian/ testicular arteries). The inferior mesenteric artery is often a branch of the right common iliac artery (Baljet and Drukker, 1979). Two major components can be distinguished in the abdominal plexus, the ciliac plexus [Paxinos et al., 1991 (Fig.4)], and the inferior mesenteric plexus, an intermesenteric plexus being interposed between them. The celiac plexus is situated around and between the
FIGURE 4 A left lateral representation (A) and a right lateral representation (B) of the celiac–superior mesenteric ganglion complex of the rat, as derived from serial sections. aa, abdominal aorta; ag, aorticorenal ganglion; ca, celiac artery; cg, celiac ganglion; cn, celiac nerve; ima, inferior mesenteric artery; ipa, inferior phrenic artery; ipv, inferior phrenic vein; isv, inferior suprarenal vein; k, kidney; msn, major splanchnic nerve; oa, ovarian artery; ra, renal artery; sg, suprarenal ganglion; sma, superior mesenteric artery; smg, superior mesenteric ganglion; srg, suprarenal gland; st, splanchnic trunk (reproduced by permission from Hammer and Santer, 1981).
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celiac artery and the superior mesenteric artery and extends dorsally between the adrenal glands and the cranial half of the kidneys. The left celiac ganglion is crescent shaped and lies on the lateral side of the celiac and superior mesenteric artery; the right celiac ganglion is triangular, smaller than the left one, and lies on the opposite side of the same arteries, dorsal to the inferior vena cava. Both celiac ganglia extend caudally, without distinct boundaries, into the superior mesenteric ganglia. A dorsal extension of the celiac ganglion forms the aorticorenal ganglion (Hammer and Santer, 1981) or ganglia, also more developed on the left than on the right side (Baljet and Drukker, 1979). Along the terminal part of the major splanchnic nerve, shortly before the celiac ganglion, there is a small ganglion called the suprarenal ganglion (Baljet and Drukker, 1979). Innumerable nerve trunks contribute to, and issue from, the celiac plexus. In addition to the thoracic and abdominal splanchnic nerves, there are nerve trunks (which include smaller or microscopic ganglia) within the plexus itself, including many nerves lying across the midline both ventral and dorsal to the aorta. Nerve trunks emerging from the celiac plexus and directed to abdominal organs reach the suprarenal arteries, the celiac artery, the superior mesenteric artery, the renal arteries, and the inferior phrenic arteries. Caudally, the celiac plexus continues into the intermesenteric plexus, an array of nerve trunks and very small ganglia lying on the ventral and lateral aspects of the aorta. The inferior mesenteric plexus of the two sides are extensively interconnected and lie around the initial segment of the inferior mesenteric artery. The inferior mesenteric ganglion, also called the hypogastric ganglion (Langworthy, 1965), is a spindle-shaped expansion along the main nerve trunk of the plexus. Caudally, the continuation of the inferior mesenteric ganglion is the hypogastric nerve, a bilaterally symmetric nerve that reaches the pelvic plexus. Nerve branches from the intermesenteric plexus can be followed to the kidneys, the ovaries, and the uterus or the testis. The main branches from the inferior mesenteric plexus, apart from the hypogastric nerve, are directed to the periphery along the inferior mesenteric artery.
Pelvic Plexus The pelvic plexus is a large and elaborate crossroads of nerves and ganglia supplying the rectum, the lower urinary tract, and the genital tract. The anatomy of this plexus, which is somewhat less complex in the rat than in other species, was investigated by Langworthy (1965), who used microdissection after vital staining with methylene blue and by Purinton et al. (1973) and Hulsebosch and Coggeshall (1982).
In the male rat, the main component of the plexus is a single, large, bilaterally symmetric ganglion, the right and left pelvic ganglia, sometimes referred as the hypogastric ganglion (Bentley, 1972; Sjöstrand, 1965) (Fig. 5). The ganglion is diamond-shaped, measuring about 2×4 mm, and lies on the side of the prostate, closely apposed to its fascia, ventral to the rectum, and caudal to the ureter and vas deferens. It shows lobulations that protrude in the direction of the surrounding organs. The ganglion is accompanied by a few, small, accessory ganglia, mainly related to the seminal vesicles and the vas deferens.
FIGURE 5 Pelvic ganglion stained in situ and in toto for acetylcholinesterase in an adult male rat. The right major pelvic ganglion (the dark triangular mass immediately left of center, with a perforation near its top which in vivo gives passage to a large artery for the bladder) is connected to the pelvic nerves (to the left), to the genital nerve (caudalward or downward, and to the left), to the hypogastric nerve (cranialward or upward), and to numerous nerves for the pelvic organs (to the right). Part of the bladder and its neck are visible near the right edge and in the right bottom corner. The right seminal vesicle, with a bulbous profile, appears vertically through the middle of the field; the left seminal vesicle is next to it and the ductus deferens (dark and cylindrical) is further to the right; all three are crossed by the right ureter (light, cylindrical, and widening near the point of entry into the bladder). To the far left is part of the rectum, displaying its myenteric plexus. Accessory ganglia are seen along the nerves to the ductus deferens and the urethra and along the hypogastric nerve.
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The main incoming nerve trunks to the ganglion are the hypogastric and the pelvic nerves. The hypogastric nerve, carrying the bulk of the sympathetic input, originates as the caudal continuation of the inferior mesenteric ganglion and reaches the cranial pole of the pelvic ganglion. It is retroperitoneal, medial to the external iliac artery, and passes behind the ureter, where it branches into the main and accessory hypogastric nerves. The terminal portion of the latter is slightly expanded as it contains the minute hypogastric ganglion (the hypogastric ganglion proper). The nerve contains about 1600 fibers, including sympathetic pre- and postganglionic fibers and sensory fibers (Hulsebosch and Coggeshall, 1982). The pelvic nerve, carrying the parasympathetic input to the pelvic ganglion, originates from the last lumbar (L6) and first sacral (S1) spinal nerves (Purinton et al., 1973). It consists of five to seven fascicles (Hulsebosch and Coggeshall, 1982), traveling mainly ventrally and reaching the dorsolateral aspect of the ganglion. The nerve contains about 5000 axons, mainly the preganglionic parasympathetic fibers for the pelvic neurons, but also afferent fibers and sympathetic postganglionic fibers (from paravertebral ganglion neurons). Numerous small efferent nerve trunks arise from the ganglion and reach the rectum, the ureter the vas deferens, the seminal vesicles, the prostate, the bladder, and the urethra. The largest trunk is the one that supplies the urethra and then proceeds to innervate the penis; this main penile nerve, or genital nerve, also contains hundreds of ganglion neurons (Dail et al., 1989). Eight or more small nerves are directed to the bladder; they divide into two groups, passing in front and behind the ureter and reaching the ventral and dorsal surface of the bladder. Minute ganglia can be seen along these nerves and those supplying the vas deferens and seminal vesicles. The largest of these accessory ganglia contains about 400 neurons, and the hypogastric ganglion has about 250 (Hondeau et al., 1995). In the female rat, the pelvic ganglion, also referred to as the paracervical or Frankenhauser ganglion (Kanerva, 1972; Marshall, 1970), is smaller and more difficult to expose than that in the male (Purinton et al., 1973). It is flat and lies firmly adherent on the side of the uterine cervix. Its largest branch, arising from the caudal portion of the ganglion, innervates the clitoris after giving branches to the urethra, vagina, and rectum. Other fine nerves issuing from the ganglion run to the bladder, cervix of the uterus, and upper portions of the vagina. A few small accessory ganglia can be found, usually on the ventral wall of the vagina near the bladder neck (Purinton et al., 1973). Extensive decussation of fibers on the midline occurs over the ventral surface of the cervix.
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In addition to topographical differences, the pelvic ganglion shows structural differences between male and female rats. The most prominent of them is that there are more than twice as many neurons in the male (about 14,000) than in the female (about 6000) (Greenwood et al., 1985), a difference in neuron numbers that becomes established postnatally. In the rat bladder intramural nerve ganglia are absent or very few in number.
Parasympathetic Nerves and Ganglia of the Head These ganglia are very small or microscopic, and they are associated with branches of certain cranial nerves. The ciliary ganglion lies lateral to the optic nerve and is attached to the initial part of the branch of the oculomotor nerve for the medial rectus muscle. Malmfors and Nilsson (1966) have described the exact position of the ganglion and the surgical approach for its excision [Paxinos et al., 1991 (Figs. 26–28)]. The ganglion is made up of about 200 ganglion neurons (Wigston, 1983). The optic ganglion of the rat [Paxinos et al., 1991 (Figs. 17, 43–45, and 103–106)] has no direct connections with the glossopharyngeal nerve, as is the case in man and other mammals (Al-Hadhithi and Mitchell, 1987), and the preganglionic fibers reach the ganglion via a connection with the facial nerve. The sphenopalatine ganglion is associated with the facial nerve [Paxinos et al., 1991 (Figs. 5, 6, 25–39, 75–80, and 82–87)]; its postganglionic nerves reach the lacrimal gland and the nasal mucosa. Otic and sphenopalatine ganglia are also major contributors of vasomotor fibers to cerebral vessels (Suzuki et al., 1988; Suzuki and Hardebo, 1991). The submandibular ganglion is a collection of minute ganglia located around the excretory ducts of the submandibular and the sublingual glands, in the connective tissue between these ducts and the lingual nerve, and within the submandibular gland itself (Ng et al., 1992). Two large aggregates of ganglion neurons, close to each other and located at the confluence of the internal carotid nerve and the greater superficial petrosal nerve, are known as the internal carotid ganglion (Mitchell, 1953; Suzuki et al., 1988). On the basis of the histochemical features of its neurons, the ganglion is considered an aberrant sympathetic ganglion or a rostral expansion of the superior cervical ganglion (Hardebo et al., 1992). The vagus nerve emerges from the cranial cavity through the jugular foramen. A prominent swelling of the nerve immediately after its emergence is known as the nodose ganglion [Paxinos et al., 1991 (Fig. 6, 59–61, 63, 67, 137–139, and 141)]; the ganglion issues two branches, the cranial, or pharyngeal, branch, forming a plexus with branches from the glossopharyngeal
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nerve, and the caudal branch, giving rise to the superior laryngeal nerve (Greene, 1935). There are about 6000 neurons in the nodose ganglion of the rat, and the full complement of ganglion neurons is already present at birth (Cooper, 1984). Neuronal mitoses in this ganglion are completed by the end of the second week in utero (Altman and Bayer, 1982). From the nodose ganglion, the trunk of the vagus nerve runs caudally into the neck. The main cervical branches are the cardiac branches and the recurrent nerve, which terminates as the inferior laryngeal nerve; from the thoracic vagus originate esophageal and pulmonary branches. The nerve reaches the abdominal cavity and terminates, spreading over the anterior (left vagus) and the posterior (right vagus) surface of the stomach. Details of the fine composition and distribution of the abdominal part of the vagis nerve are given by Prechtl and Powley (1990) and Berthoud et al. (1991, 1992).
STRUCTURE OF AUTONOMIC GANGLIA AND NERVES Preganglionic Neurons The parasympathetic preganglionic neurons are located in the spinal cord between the cervical 8 and the lumbar 2 levels (C8 and L2) [Paxinos and Watson, 1986 (Fig. 116, 118, and 119)]. The distribution and the morphology of preganglionic neurons have been studied to great advantage with the horseradish peroxidase (HRP) technique (retrograde filling). This has produced results that are more reliable than those obtained by degeneration methods and silver impregnation methods. The majority of the preganglionic neurons are in a column called the intermediolateral nucleus. A similar column in two or three sacral levels of the spinal cord contains the preganglionic neurons of the sacral parasympathetic outflow. The preganglionic neurons innervating the superior cervical ganglion of the rat are located in segments C8–T5 (90% of them in thoracic segments T1–T3). Seventy-five percent of the total of 1600 neurons retrogradely filled from the cervical sympathetic trunk of one side of the animal are in the intermediolateral nucleus, 23% are in the lateral funiculus, and the remainder is in the other central autonomic area and in the intercalated region (Rando et al., 1981). Injected neurons are exclusively homolateral to the injected cervical trunk (Rando et al., 1981). In contrast, Navaratnam and Lewis (1970) found chromatolytic neurons on both sides of the spinal cord after unilateral section of the pelvic nerves. An additional column of preganglionic neurons, termed the dorsal commissural nucleus, projecting into
the hypogastric nerve has been identified in the spinal cord levels L1-L2 (Hancock and Peveto, 1979). Schramm and collaborators (1975) reported labelling of preganglionic neurons at all the levels between T1 and L1 after injection of horseradish peroxidase into the adrenal medulla. Approximately 1000 neurons were labeled after injection into one gland (Schramm et al., 1976). They also reported that the neurons have a marked longitudinal orientation, as has been observed in other species, with the dendrites grouped into two bundles directed cranially and caudally. This high polarization of the dendrites arises rather late in development; it is absent in 3-week-old rats and is still far from complete in 7-week-old rats (Schramm et al., 1976). Preganglionic neurons in the rat spinal cord display an intense acetylcholinesterase activity [Navaratnam and Lewis, 1970; Paxinos and Watson, 1986 (Fig. 116)]. Nerve endings containing noradrenaline or serotonin are present around the cell bodies (Dahström and Fuxe, 1965).
Preganglionic Fibers Sympathetic preganglionic axons issue from neurons located mainly in the intermediolateral column of the thoracic and lumbar levels of the spinal cord. The fibers emerge from the cord within the ventral roots (T1–L2) bundled with the somatic motor fibers. From the ventral nerves the preganglionic fibers pass to the sympathetic chain via very short connections (rami communicantes). The latter also contain postganglionic fibers that travel to the periphery within somatic nerves. Depending on the level of origin, preganglionic fibers travel some distance up or down the sympathetic chain, forming synaptic contacts with neurons in more than one ganglion. In the lumbar segment of the chain, the preganglionic fibers are mainly descending (caudally directed). The length of the preganglionic fibers, therefore, can be considerable. In the upper thoracic segment they are mainly ascending (cranially directed) and in the cervical sympathetic trunk all the preganglionic fibers are directed cranially. In this trunk, however, there are also caudally directed postganglionic fibers, originating in the superior cervical ganglion, and cranially directed postganglionic fibers, originating in the middle and lower cervical ganglia (Bowers and Zigmond, 1981). Other sympathetic preganglionic fibers, having reached the paravertebral chain, pass into a splanchnic nerve and travel to prevertebral ganglia in the abdominal cavity and, in a smaller number, as far as the pelvic ganglion. In the rat, unlike other species, such as humans and cats, the great majority of preganglionic fibers are unmyelinated. For example, less than 1% of the axons
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in the cervical sympathetic trunk are myelinated (Brooks-Fournier and Coggeshall, 1981; Dyck and Hopkins, 1972; Hedger and Webber, 1976). The terminal branches of preganglionic fibers have varicosities and terminal boutons that synapse on ganglion neurons. In the ganglionic relay there is divergence; that is, each preganglionic fiber innervates several ganglion neurons. The numeric ratio between preganglionic and postganglionic neurons, as calculated by different investigators, varies from 1:5 to 1:20. The total number of neurons in the spinal cord that are retrogradely filled with horseradish peroxidase from the cervical sympathetic trunk is about 1600 (Rando et al., 1981), a value that should be compared with the number of neurons they innervate, that is, the neurons in the superior cervical ganglion (see Table 1). The divergence accounts for the fact that all ganglion neurons are innervated by preganglionic fibers, despite the smaller number of these fibers. In addition, each ganglion neuron receives synapses from more than one preganglionic neuron; that is, there is convergence of synaptic inputs onto each neuron. The latter process is ideally analyzed with electrophysiological techniques. Typical values obtained in rabbits (Wallis and North, 1978), hamsters (Lichtman and Purves, 1980), and guinea pigs (Njå and Purves, 1977) range between 7 and 11 preganglionic fibers per ganglion neuron; moreover, each ganglion neuron receives an input from several levels of the spinal cord (Njå and Purves, 1977). With the same technique, Purves et al. (1986) have obtained a figure of about 1000 preganglionic neurons for the superior cervical ganglion of the rat (against about 26,000 ganglion neurons), each preganglionic neuron innervating on average 240 ganglion neurons
TABLE 1
Number of Ganglion Neurons in the Superior Cervical Ganglion of the Rat
Mean number of neurons ± standard deviation (number of cases)
Study
45,000 ± 600
Davies, 1978
35,000 ± 600
Davies, 1978
39,000 ± 500 (4)
Klingman, 1972
37,000–38,000 (2)
Hedger and Webber, 1976
36,000
Ostberg et al., 1976
32,000 (1)
Levi-Montalcini and Booker, 1960
26,000–32,000 (6)
Eränkö and Soinila, 1981
25,000 ± 1940 (3)
Johnson et al., 1980
21,500 ± 3400 (3)
Santer, 1991
15,600 ± 6100 (17)
Brooks-Fournier and Coggeshall, 1981
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and each ganglion neuron being innervated by 9 preganglionic neurons, on average (Purves et al., 1986). Parasympathetic preganglionic fibers of the cervical region originate in nuclei of brain stem (nucleus of Edinger-Westphal, salivatory nuclei, dorsal vagal nucleus) and project onto the autonomic ganglia of the head. Sacral parasympathetic fibers originate from neurons in a short column at levels L6–S1 of the spinal cord (Tanaka and Zukeran, 1981) and project to the pelvic main and accessory ganglia. These preganglionic fibers are unmyelinated (Mallory et al., 1989), but their conduction velocity is faster than that of the corresponding unmyelinated postganglionic fibers. The degree of divergence and convergence in parasympathetic ganglia is considerably less than that in the sympathetic chain, as discussed below.
Sympathetic Ganglia The sympathetic ganglia are scattered along the sympathetic chain (paravertebral ganglia) and in the abdominal plexus (prevertebral ganglia). The best known of them is the superior cervical ganglion (Fig. 2). Because of its large size, its accessibility, its vascular supply, and the layout of its preganglionic and postganglionic nerves, it has been investigated more extensively than any other ganglion, the rat being one of the species of choice. Many of the structural features of the superior cervical ganglion are reproduced in the other sympathetic ganglia, although important differences are being found with more detailed studies, especially between prevertebral and paravertebral ganglia. In addition to ganglion nerve cells (principal ganglion neurons) (Fig. 6), sympathetic ganglia contain several other cell types. These include small granular cells (or small intensely fluorescent cells), cells of the glial type (Schwann cells and satellite cells), vascular cells (mainly endothelial cells), mast cells, and fibroblasts (in thin septa of connective tissue and in the capsule). The capsule, which is in continuation with the sheath of incoming and outgoing nerves, is relatively thick and offers a strong barrier to the diffusion of substances (Arvidson, 1979). However, substances (for example, horseradish peroxidase) injected systemically can diffuse into the ganglion from fenestrated capillaries (Jacobs, 1977) (see below). Injected tracers diffuse around the cells but do not penetrate the narrow space between a neuron and its satellite glial cells (Ten Tuscher et al., 1989). The satellite cells form a tight, continuous sheath around each ganglion neuron, blocking any diffusion of extracellular fluids, in contrast to the situation in sensory ganglia, in which satellite cells are loosely arranged and a tracer such as
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horseradish peroxidase freely reaches the cell membrane of the ganglion neurons (Ten Tuscher et al., 1989). Tight junctions are only occasionally found between satellite cells in rat sympathetic ganglia (Ten Tuscher et al., 1989), whereas there are numerous gap junctions [as Elfvin and Forsman (1978) have documented in the guinea pig]. By contrast, there is no extravasation of a systemically injected tracer in sympathetic nerve trunks, and it has been suggested that at this level (but not within ganglia) there is a blood– brain barrier to proteins (Jacobs, 1977). While the capillaries running between ganglion neurons are of the continuous type, have tight junctions, and are impermeable to injected tracers, those running close to the small intensely fluorescent cells are fenestrated and let tracers diffuse in the interstitial space of the ganglion (Chau and Lu, 1996). Most of the incoming fibers in paravertebral sympathetic ganglia, and virtually all the synaptic endings, originate from preganglionic neurons. Postganglionic fibers and fibers en passage, either pre- or postganglionic, are present within ganglia. Last, there are afferent fibers, probably en passage. For example, tracers injected in the superior cervical ganglion label a small number of dorsal root ganglion neurons in T1–T3 (Yamamoto et al., 1989).
Principal Ganglion Neurons The total population of sympathetic neurons in the rat probably numbers a few hundred thousand, but accurate counts are available only for the superior cervical ganglion (Table 1). The wide range in the values published by different authors is probably accounted for by a certain amount of experimental error (Hendry, 1976), but also by some variability between individual animals and possibly also between strains of rats. The variability in the number of neurons in the superior cervical ganglion in mammalian species in general is wide, ranging from about 4200 in a bat (Webber and Kallen, 1968) to nearly a million in a human (Ebbeson, 1968). The final number of neurons is established during fetal life, with few mitoses occurring in ganglion neurons of the rat after birth (Eränkö, 1972). From the first week after birth the number of principal cells remains unchanged (Davies, 1978) or shows a slight decrease (Eränkö and Soinila, 1981; Henry and Campbell, 1976). Brooks-Fournier and Coggeshall (1981) have obtained the lowest counts (15,000 on average, in 17 ganglia) and have also reported large differences in neuron number (up to 80%) between right and left ganglions. Santer (1991) has shown that there is no loss of neurons in the superior cervical ganglion of senescent rats (24 months old).
Principal ganglion neurons of the rat are multipolar neurons measuring up to 50 μm in diameter, mostly 25–40 μm (Tamarind and Quilliam, 1971). By comparison with other animal species, especially those of large body size, the dendritic arborization of sympathetic neurons in the rat is not extensive and the relative volume of neuropil is small (Fig. 6). There is little or no evidence of substantial structural differences within the population of ganglion neurons. Cajal (1911) suggested that the number and pattern of dendrites characterize neuronal ganglionic subpopulations; however, it has proven difficult to demonstrate, by silver methods, the dendrites in sympathetic ganglia, especially in the rat. Recently, a combination of electrophysiology and intracellular injection of HRP has allowed Kiraly et al. (1989) to see, in considerable detail, the dendritic trees in the superior cervical ganglion of the rat. On the basis of the dendritic patterns, neurons were classified as radiate (poorly branching dendrites arising all around the cell), tufted (extensively branching dendrites arising, clustered, from one area of the cell or from two opposite areas and running in opposite directions), and intermediate (Kiraly et al., 1989). The size and extension of dendrites in the superior cervical ganglion are correlated during development with the size of the animal (Voyvodic, 1987); experimentally induced changes in the size of the target (e.g., the submandibular gland) influence the size of dendritic trees (Voyvodic, 1989). There is marked expansion of the dendritic trees during postnatal development (Purves et al., 1986). In aged rats this process is reversed (at least in the superior cervical ganglion) and there is reduction in soma size, total dendritic length, number of branch points, and total area of dendritic arborization (Andrews et al., 1994). Ganglion neurons are individually ensheathed by satellite cells. This glial sheath is continuous over the neuronal soma; in some areas it is reduced to a very thin cytoplasmic process interposed between the neuron on one side and the basal lamina and connective tissue on the other. A glial sheath extends over the dendrites. Here, however, there are areas where the neuronal cell membrane is uncovered and lies directly apposed to the basal lamina and connective tissue (Fig. 7B). In these dendritic regions, there are large clusters of vesicles and, occasionally, membrane specializations similar to dense projections. Similar clusters of vesicles can also be found in the more superficial parts of the cytoplasm of the cell body and along the dendrites (Fig. 7A). Each neuron has an axon, which can be clearly recognized in silver-impregnated preparations; the axon travels within the ganglion, often along a tortuous path but without dividing or giving off branches. Under the electron microscope, the axon can be recognized only at some distance from the cell body, and
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FIGURE 6 Superior cervical ganglion of a rat. Araldite section stained with toluidine blue, showing ganglion neuron profiles (some nucleated) and the surrounding neuropil. The latter include satellite cells, neurites, blood vessels, and connective tissue (from Gabella, 1976). (800×)
its exact point of origin is therefore not usually seen. Dendrites from different cells are often in membraneto-membrane contact with each other (dendrodendritic contacts), or they form dendrosomatic contacts (Kiraly et al., 1989). These commonly occurring contacts, which do not have synaptic features, have been interpreted as evidence of intraganglionic connectivity, enabling the neurons to modulate or regulate each other’s activity (Kiraly et al., 1989). Only a limited topographic subdivision of ganglion neurons into groups is apparent in sympathetic ganglia. The question of the localization of these neurons in relation to the organ they innervate has been investigated through the retrograde reaction of axotomized neurons (Matthews and Raisman, 1972), the retrograde transport of nerve growth factor (Hendry et al., 1974) and HRP (Bowers and Zigmond, 1979), and the increased utilization of glucose in stimulated neurons (Yarowski et al., 1979). Neurons tend to be located in the part of the ganglion near the site of emergence of their (postganglionic) fibers (Matthews and Raisman, 1972), but this localization is ill defined, and in practice neurons projecting to a particular organ may be found in any part of the ganglion (Hendry et al., 1974). However, the neurons whose axons extend in the
internal carotid artery are located mainly in the cranial part of the superior cervical ganglion; those projecting in the external carotid nerve are mainly located in the caudal portion of the ganglion, where there are also neurons sending their axons in the cervical trunk (Bowers and Zigmond, 1979).
Small Intensely Fluorescent Cells Small intensely fluorescent (SIF) cells are identified by their small size, their distribution in small clusters, and their very intense formaldehyde-induced fluorescence (Eränkö and Harkonen, 1965; Norberg et al., 1966). Under the electron microscope their cytoplasm appears rich in large, dense-cored vesicles, hence the term small-granule-containing cells (Matthews and Raisman, 1972) (Fig. 8). These cells are strikingly heterogeneous in distribution, morphology, and chemical composition and are part of a large group of chromaffin and chromaffin-like cells (see review in Taxi, 1979), which includes cells of the paraganglia and the adrenal medulla and cells scattered in many tissues outside the nervous system. They all originate from the neural crest, probably from a common progenitor (Anderson, 1989). In the rat embryo, SIF cells appear
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FIGURE 7 Superior cervical ganglion of rat. (A) Electron micrograph of a ganglion fixed by immersion in glutaraldehyde. A preganglionic nerve ending (center) synapses on a cell process (dendrite) containing a mitochondrion, ribosomes, neurofilaments, and a large cluster of electronlucent vesicles. An ill-defined band of electron-dense material lies beneath the postsynaptic membrane (56,000×). (B) Electron micrograph of a dendrite with a large number of vesicles lying directly underneath its surface. The cell membrane has some dense projections attached to it and is here devoid of a satellite cell sheath (38,000×). (C) Fluorescence micrograph (by Dr. Lars Olson) (Falck–Hillarp method for catecholamines). The nerve cell bodies and some of their processes show specific fluorescence of varying intensity (270×).
later than principal ganglion neurons, and, therefore, at least in the superior cervical ganglion, they cannot be regarded as precursors of ganglion neurons (Hall and Landis, 1991). In vitro, however, SIF cells from the rat superior cervical ganglion develop long processes and convert into nerve cells, if the corticosteroids
necessary for their differentiation are withdrawn from the incubation medium and replaced with nerve growth factor (NGF) (Doupe et al., 1985). The number of SIF cells is variable even in the same ganglion. In the rat superior cervical ganglion, up to 1000 (Santer et al., 1975) or 370 (Williams et al., 1977)
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FIGURE 8 Rat pelvic ganglion. The electron micrograph shows a small granular cell (SIF cell) packed with dense-cored vesicles. The cytoplasm also displays mitochondria, microtubules, and the endoplasmic reticulum; at the right is part of the nucleus. The cell is surrounded by a continuous capsule of satellite cells (14,000×).
SIF cells have been counted. Eränkö and Soinila (1981) found an average of about 450 SIF cells per ganglion and observed a twofold increase in the number of SIF cells during the first 3 weeks of postnatal life. However, there seems to be a subsequent decrease in the number of SIF cells during development (Lempinen, 1964). The trend can be counteracted by glucocorticoid injection: treatment of rats with hydrocortisone at birth induces an increase of up to 10 times the number of SIF cells (Eränkö and Eränkö, 1972). The SIF cells of rat sympathetic ganglia measure 10–15 μm in diameter, and many of them are grouped into tight clusters, sheathed by satellite glial cells, and have extensive membrane-to-membrane contact between adjacent SIF cells. There are occasional discontinuities in the thin glial sheath and at these points the surface of a SIF cell lies bare and is usually directly opposite a fenestrated capillary. The cytoplasm contains a large number of dense-cored vesicles, rather variable in size, electron density, and shape; on the basis of these features of the vesicles, two or three types of SIF cells have been identified (Taxi, 1979): Type I SIF cells have granular vesicles measuring 80–100 nm (versus
40–50 nm for synaptic vesicles), whereas type II SIF cells have vesicles of 150–300 nm in diameter, similar to those of adrenal medullary cells. The SIF cells contain and probably release a biogenic amine; the type of amine varies from species to species and even between different ganglia of the same species. In the rat superior cervical ganglion the SIF cells, which are predominantly of type I, contain mainly dopamine (Björklund et al., 1970), but it has subsequently been reported that in this ganglion there are separate groups of SIF cells, containing dopamine or containing noradrenaline or serotonin (5-HT) (Konig, 1979; Verhofstad et al., 1981). Some SIF cells display two or more processes; a few are tens of micrometers in length, are ultrastructurally similar to the cell body, and have a varicose outline. Other cells, especially those in large clusters, have no processes. The SIF cells receive synapses from preganglioninc fibers, predominantly on the cell body. A few SIF cells (and notably some in the superior cervical ganglion) form specialized contacts with principal ganglion neurons, which are described as efferent synapses (Matthews and Raisman, 1969); these are usually somadendritic,
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and large granular vesicles are grouped around dense projections on the presynaptic membrane. Those SIF cells that have afferent and efferent synapses can be regarded as interneurons (Williams, 1967). Many, and possibly the majority of SIF cells, have no efferent synapses, and these, if not all SIF cells, are considered to be endowed with an endocrine role, releasing substances (amines) in the interstitial space or in the local circulation of a ganglion. The stimuli can be of central nervous system origin (via preganglionic fibers) or local (via chemoreceptors) A chemoreceptive role is suggested by the structural similarity of certain SIF cells to cells of the carotid body and the aortic glomus (Kondo, 1977). It is noteworthy that, according to Grillo (1978), about 10% of the synapses onto SIF cells in the superior cervical ganglion of the rat are not affected by preganglionic denervation; moreover, some efferent synapses of the SIF cells are not on ganglion neurons, but on large axons originating from the glossopharyngeal nerve, and are probably afferent.
Nerve endings, Synapses, and Other Cell Junctions There are abundant nerve endings synapsing onto principal neurons of sympathetic ganglia (Fig. 7A). The synapses are usually on dendrites or on dendritic spine-like processes and only rarely on the cell soma; in contrast, axosomatic synapses are common in ganglia of immature rats (Smolen and Raisman, 1980). The ultrastructural features of ganglionic synapses in rat sympathetic ganglia have been thoroughly investigated (see review by Matthews, 1983). Most of the intraganglionic endings are packed with small agranular vesicles (49–60 nm in diameter), in addition to a few mitochondria, endoplasmic reticulum, and microtubules; large granular vesicles, although representing no more than a small proportion of the vesicle population, are usually well in evidence. In the superior cervical ganglion, virtually all synaptic endings disappear after decentralization of the ganglion, and this confirms that they are of preganglionic origin. The synaptic cleft is rich in acetylcholinesterase (Somogyi and Chubb, 1976), acetylcholine is released (in quantal form) upon stimulation, and decentralization reduces acetylcholine levels by nearly 60% (Klingman and Klingman, 1969). Transmission across the ganglion is achieved by cholinergic synapses mainly operating through nicotinic receptors (see review by Skok, 1983). There are also synapses from preganglionic fibers onto SIF cells and occasionally from SIF cells onto a ganglion neuron. Numerous junctions of the adherens type (presumably of mechanical significance) occur between
neurons and satellite cells and between neuronal elements. Dendrodendritic contacts are numerous (Kiraly et al., 1989), but the suggestion of Kondo et al. (1980) that they are synaptic has not been confirmed.
Neurotransmitters and Related Substances The great majority of neurons in sympathetic ganglia are adrenergic (Fig. 7C). Catecholamines are stored in the cell body, in dendrites, in the axon, and, in a much higher concentration, in the varicosities of the terminal portion of the axon. The catecholamine content of the cell bodies, as detected histochemically by fluorescence microscopy, is variable from neuron to neuron and tends to decrease with age (Santer, 1979). Ultrastructurally, the biogenic amines are localized in large dense-cored vesicles, in small dense-cored vesicles clustered beneath the cell membrane, and in tubules of endoplasmic reticulum (Richards and Tranzer, 1975). A small percentage of sympathetic ganglion neurons (about 4% in the superior cervical ganglion; Yamauchi and Lever, 1971) are intensely positive for acetylcholinesterase and are negative for monoaminoxidase and catecholamines. These neurons, which also contain vasointestinal peptide (Landis and Fredieu, 1986), supply vasodilator cholinergic fibers to some blood vessels and secretomotor fibers to the eccrine sweat glands (Langley, 1922; Wechsler and Fisher, 1968). However, there is firm evidence that in the rat there is no cholinergic sympathetic innervation to the limb muscle blood vessels (Guidry and Landis, 2000). Sympathetic neurons (from the superior cervical ganglion) obtained from newborn rats and grown in vitro under certain conditions (which include the presence of nonneuronal cells; Patterson and Chung, 1977) undergo a transition from adrenergic to cholinergic (Furshpan et al., 1976, 1982; Johnson et al., 1976). A similar transition seems to occur in vivo: the ganglion neurons that innervate sweat glands are adrenergic in very young rats, and only adrenergic fibers are found around the developing glands. By the end of the third week of age, however, the same neurons have become cholinergic and only cholinergic fibers are found within the glands (Landis and Keefe, 1983). However, these nerve fibers, which are, both functionally and histochemically, cholinergic, maintain a limited ability to take up and store catecholamines, and some of them remain able to synthesize small amounts of catecholamines (Landis and Keefe, 1983). Neuropeptides are found within the rat sympathetic ganglia, although their amounts, as assessed by immunofluorescence, are lower than those in other species, for example, the guinea pig. A few single fibers immunoreactive for substance P are found in the stellate
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and the superior cervical ganglion (Hökfelt et al., 1977a), and a small number of fibers weakly immunoreactive for vasoactive intestinal polypeptide (VIP) occur in the superior cervical ganglion (Hökfelt et al., 1977b). There are no positive cell bodies for either peptide. There are also a few fibers immunoreactive for enkephalin and somatostatin (Hökfelt et al., 1977c); after colchicine treatment a positive reaction can be detected in some cell bodies. Many neurons in rat sympathetic ganglia (paravertebral, prevertebral, and pelvic) have intense NADPH-diaphorase activity (Santer and Symons, 1993): this enzyme is a cofactor of nitric oxide synthase (Hope et al., 1991), and these neurons are therefore capable of producing and presumably releasing nitric oxide, as suggested by pharmacological studies (Gillespie et al., 1989).
Prevertebral Ganglia The prevertebral ganglia are in many respects structurally similar to the ganglia of the sympathetic chain. An important difference, established mainly in the guinea pig (Crowcroft and Szurszewski, 1971), is that the ganglion neurons receive inputs not only from the spinal cord via the splanchnic nerves but also from neurons located in the wall of the gut and from neurons located in adjacent ganglia of the abdominal plexus. Several neuropeptides are localized in nerve fibers in prevertebral ganglia, including substance P, VIP, and enkephalin, although their occurrence is sparser in the rat than in the guinea pig (Schultzberg, 1983). Of particular interest is the localization of substance P fibers in some nerve endings abutting on ganglion neurons in the guinea pig. These are afferent fibers from dorsal root ganglion cells and they innervate the viscera; however, while in transit through the prevertebral ganglia, they issue collateral branches that synapse on ganglion neurons (Matthews and Cuello, 1982). This arrangement allows a reflex involving direct spread of stimuli (for example, nociceptive stimuli) from afferent axons to efferent neurons. Leranth and Ungvary (1980) have described the presence of several ultrastructural types of axons and have commented on the complexity of the synaptic connections in rat prevertebral ganglia.
Pelvic Ganglia The main components of the ganglion are the principal neurons, measuring 20–40 μm in diameter, sheathed by satellite cells (Fig. 9). Both cell types are similar in appearance to those found in the abdominal ganglia (Dail et al., 1975; Kanerva and Teräväinen, 1972). The neurons, however, visualized by intracellular injection of Lucifer yellow, have only one to four processes,
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one of which is the axon, and are therefore in this respect simpler than paravertebral and prevertebral ganglion neurons (Tabatabai et al., 1986). The dendrites are not only few in number but are also short, thin, and unbranched. Several neurons have no dendrites. The number of preganglionic inputs per neuron is on average only two, indicating that only two preganglionic fibers converge on each ganglion neuron. In addition there are ganglion neurons with large vacuoles (vacuolated neurons) (Fig. 9B). The vacuoles, measuring up to 20 μm in diameter, greatly enlarge the cell and displace the other components of the neuron, which is otherwise similar in structure and synaptic connections to the principal ganglion neurons. The significance of the vacuoles is obscure. The vacuolated neurons are about 0.8% of the neuronal population in the pelvic ganglion of pregnant rats and less than 0.2% in rats that are not pregnant (Lehmann and Stange, 1953). Vacuolated neurons are found also in the pelvic ganglion of male rats (Dail et al., 1975) in the range of 0.8–1.2% (Partanen et al., 1979); they make their appearance around the 7th week of life, but they disappear in castrated animals (Partanen et al., 1979). Small intensely fluorescent cells form a complete wrapping around ganglion neurons; the glial capsule of some neurons is formed by concentric layers of glial cell processes, surrounded by a basal lamina, and layers of collagen fibrils, so that a characteristic onion-like appearance that is not found in other ganglia is generated (Fig. 10). Small intensely fluorescent cells are also consistently found, in large numbers, usually in clusters. Under the electron microscope, they are recognized by their size and by the large dense-cored vesicles (Fig. 8). Most or all of them are of type II (Dail et al., 1975). Cholinergic and adrenergic neurons are both found in the pelvic ganglion. The adrenergic neurons (identified by formaldehyde-induced fluorescence) are about one-third of the neuronal population in the pelvic ganglion of the female rat (Kanerva et al., 1972) whereas they constitute the majority of neurons in the male (Dail et al., 1975). Cholinergic neurons (whose identification, based on an intense reaction for acetylcholinesterase, is less certain) are about one-fifth of all neurons. In the female rat, cholinergic neurons are among the largest in the ganglion (Kanerva, 1972); in the male they are small (15–25 μm in diameter) and are mainly found near the entrance of the pelvic nerve into the ganglion (Dail et al., 1975). A large proportion of the small neurons contain VIP; the axons of these neurons (VIP-ergic fibers) are plentiful in the smooth musculature of the penis, in the helicine arteries (Dail et al., 1983), and in the myometrium (Gu et al., 1984). It has been shown, in some autonomic neurons of the cat, that VIP neurons are often acetylcholinesterase positive (Lundberg, 1981).
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FIGURE 9 Pelvic ganglion of adult female rats (from Gabella et al., 1992). (A) The micrograph illustrates various types of cells: e, endothelial cell; f, fibroblast; g, nucleus of satellite glial cell; h, Schwann cell nuclei; m, mast cell; n, principal ganglion neurons; p, pericyte; and s, small granule cells or small intensely fluorescent (SIF) cells. (B) Vacuolated neuron. (C) Binucleate neuron. (D) The micrograph illustrates the laminar appearance of the glial capsule around some neurons (arrows). The scale bar represents 30 μm.
Most of the ganglion neurons (including the vacuolated cells) receive synapses, of the cholinergic type, from preganglionic fibers: unlike the situation in paravertebral ganglia, the nerve endings mainly abut the soma or somatic spines (Kanerva and Teräväinen, 1972a, 1972b). Some endings are found tunneling deep inside a perikaryon. Other synapsing nerve endings are not readily identified as cholinergic in that they contain a vast number of larger granular vesicles (Kanerva and Teräväinen, 1972a, 1972b). Some of the cholinergic neurons are surrounded by adrenergic terminals (as seen in fluorescence microscopy), which are regarded as collaterals of adrenergic neurons in the same ganglion (Dail et al., 1975). Adrenergic varicosities abutting the adrenergic neurons
have also been observed by means of fluorescence microscopy (Dail et al., 1975). The origin of these structures remains uncertain: they could be collaterals from other ganglion neurons, processes of SIF cells, or short dendritic processes from the same ganglion cell. Ultrastructural evidence of adrenergic endings synapsing on pelvic ganglion neurons has been found in the guinea pig (Watanabe, 1971); it is possible that the same situation occurs in the rat. Substance P-containing fibers form baskets around 10–20% of rat pelvic ganglion neurons. Most of the fibers disappear after section of the pelvic nerve and probably originate from dorsal root ganglia; the rest originate from SIF cells, which also stain for substance P (Dail and Dziurzynsky, 1985). Several peptides are found in pelvic ganglion
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FIGURE 10 Pelvic ganglion of an adult female rat. The electron micrograph shows a neuron, with nucleus and nucleolus. Its glial capsule is made of several layers of satellite processes and collagen (6400×).
neurons (neuropeptide Y and VIP), in nerve terminals (somatostatin, substance P, and enkephalin), or in both (Keast, 1991). There is good physiological evidence of reflex activity mediated through the pelvic ganglion in rats of either sex, without relay in the dorsal root ganglia (Purinton et al., 1971). This has led to the suggestion that there are peripheral afferent neurons (“sensory perikarya”), and selective denervation experiments have shown that these neurons are located distal to the pelvic and the hypogastric nerves and are probably situated in the pelvic ganglion itself (Purinton et al., 1971). The pelvic ganglion has two separate preganglionic inputs: sympathetic fibers originating from the lumbar levels of the spinal cord (and reaching the ganglion via rami communicantes, lumbar splanchnic nerves, and the hypogastric nerve) and parasympathetic cholinergic fibers originating in the spinal cord at L6 and S1 levels (and reaching the ganglion via the pelvic nerve). This traditional notion is confirmed by the electron microscopy study of Hulsebosch and Coggeshall (1982),
which, however, has shown an unexpected complexity in the nerve pathways connected to the pelvic ganglion. Thus, of the 1600 axons in the hypogastric nerve 58% are sympathetic postganglionic, 34% are sympathetic preganglionic, and 8% are sensory. Of the nearly 5000 axons of the pelvic nerve 34% are sensory and 49% are parasympathetic preganglionic; the remaining 17% are sympathetic postganglionic axons. Sympathetic fibers (preganglionic and postganglionic) are present also in the pudendal nerve, a nerve that is mainly a somatic sensory nerve (Hulsebosch and Coggeshall, 1982). Only 12% of all the preganglionic fibers to the pelvic ganglion are myelinated. A small proportion of postganglionic fibers are also myelinated. The two types of preganglionic fibers do not mix or converge, but they instead project onto separate neurons (Tabatabai et al., 1986). This property, together with the paucity of dendrites (Tabatabai et al., 1986), suggests that the integrative role of the pelvic ganglion is markedly smaller than that in other autonomic ganglia, for example, the superior cervical ganglion (Brown and McAfee, 1981).
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The cells of origin of the preganglionic fibers, identified with HRP after retrograde transport from the hypogastric nerve, are localized in the spinal segments L1 and L2, but not in the intermediolateral nucleus. Most of the neurons form a column along the midline in the dorsal gray commissure [dorsal commisural nucleus (DNC); Hancock and Peveto (1979)].
Cardiac and Tracheal Ganglia The cardiac plexus is made by many minute ganglia located beneath the epicardium and at the base of the aorta and pulmonary artery [King and Coakley, 1958; Paxinos et al., 1991 (Fig. 2), 1994 (Fig. 8); Pauza et al., 2002]. There is no bilateral symmetry, of course, and the total number of neurons is about 4000 (Pardini et al., 1987). About half the neurons are located near the superior border of the interatrial septum; other groups lie posterior to the right atrium (23.5%), and between superior vena cava and aorta (2.5%) (Pardini et al., 1987). The neuronal population consists of cholinergic neurons; these also contain various peptides and some of them display aspects of the adrenergic phenotype, such as immunoreactivity for dopamine β-hydroxylase. There are also a few SIF cells, some adrenergic fibers in transit, probably originating from the stellate ganglion and sensory fibers. In the rat the adrenergic fibers are only in transit and do not appear to form pericellular synaptic nests around ganglion neurons. The ultrastructure of the rat cardiac ganglia, in many respects similar to that of other autonomic ganglia, is described by Ellison and Hibbs (1976). The incoming synapses are mainly axosomatic and most of the synapsing nerve endings appear to be cholinergic; other endings contain mainly flat and lucent vesicles, whereas axons with dense-cored vesicles do not make contacts with ganglion neurons in this species. On the dorsal aspect of the trachea, overlying the tracheal muscle, a few scores of small nerve ganglia and connecting strands constitute the tracheal plexus, linked mainly with nerve trunks from the vagus nerve and made of postganglionic parasympathetic neurons. A few ganglia of this plexus are found near the primary bronchi and nerves extend to reach glands and smooth musculature in the lung.
Parasympathetic Ganglia of the Head Three quarters of the 250 neurons of the rat submandibular ganglion are each one innervated by a single preganglionic fiber, the remaining ones being innervated by two or three fibers (Lichtman, 1977). The arrangement whereby most ganglion neurons are driven by a single preganglionic neuron arises during
postnatal development. At birth most ganglion neurons are innervated by four to six preganglionic fibers. During the first 6 to 7 weeks of postnatal life, there is a progressive reduction in the number of preganglionic fibers converging on each neuron until the majority of neurons have a single input. At the same time, however, the total number of synaptic endings on each neuron increases (Lichtman, 1977). In the adult rat the neurons are usually devoid of large dendrites, but they have numerous minute cytoplasmic projections from the cell body and from the initial portion of the axon. Synaptic boutons are mainly associated with these projections. In preparations stained with zinc-iodide osmium, an average of 44 boutons per neuron was counted (Lichtman, 1977). Two distinct populations of neurons are recognized electrophysiologically (Kawa and Roper, 1984): the neurons innervating the submandibular gland and those innervating the sublingual gland. About one-third of the former (and none of the latter) are electrically coupled (however, gap junctions have not been found; Lichtman, 1977). After decentralization, intrinsic synapses (that is, synapses arising from other ganglion neurons) are found in 72% of the submandibular neurons and in only 12% of the sublingual neurons (Kawa and Roper, 1984). The extent to which interneuronal connections among submandibular neurons are present in the absence of decentralization remains to be established. In the submandibular ganglion of another species, the mouse, all synapses disappear after decentralization, a clear sign of the absence of interneurons or interneuronal synaptic connections (Yamakado and Yohro, 1977). The general ultrastructure of the submandibular ganglion of the rat is described by Ng et al. (1992) Of the 200 or so ganglion neurons in the rat ciliary ganglion, some are without dendrites, some have few long dendrites, and some have several long dendrites (Wigston, 1983). Each neuron is innervated by one to four preganglionic axons (on average 2.2), which are cholinergic and form synapses on perikarya and dendrites (Wigston, 1983).
Intramural Ganglia of the Gut A myriad of small intramural ganglia, joined by connecting strands, are gathered into two ganglionated plexuses, the myenteric and the submucosal plexus. The myenteric plexus is intramuscular, being located between the circular and longitudinal muscle layers; it extends without interruption from the esophagus (including the portion where the musculature is striated rather than smooth), through the stomach and small and large intestine, to the anal canal. In the stomach, myenteric ganglia are larger and more numerous near
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the lesser curvature. In the small intestine of the rat (unlike other mammalian species) myenteric neurons are distributed in cords parallel to the circular musculature, rather than discrete ganglia. By contrast, the myenteric ganglia of the large intestine are larger and have a better defined outline. Myenteric ganglia are found throughout the full length of the anal canal. In the small intestine there are about 9400 myenteric neurons per square centimeter of serosal surface. The submucosal plexus is found in the submucosa of the small and large intestines, usually close to the inner aspect of the circular muscle layer. Its neurons are about half as numerous as those in the myenteric plexus, and they are also, on average, smaller in size. Submucosal neurons are not found in the stomach. The intrinsic neurons of the gut form a complex and varied population (Fig. 11). Several types of neurons have been distinguished on the basis of the number of cell processes (as visualized by intracellular injection or by methylene blue staining, affinity for silver salts, and cell size (see a review in Gabella, 1979). Most of the more recent studies have been carried out on the guinea pig: fewer data are available for the rat. For the guinea pig myenteric plexus several investigators have put forward classifications based on ultrastructural features (Cook and Burnstock, 1976), on distribution of
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neuropeptides (Furness and Costa, 1980), and on electrophysiological properties (Wood, 1981). The myenteric ganglia (but not the submucosal ones) also contain neurons, well documented in the rat, projecting centripetally to the celiac and superior mesenteric ganglia (Furness et al., 2000). In the rat the terminal portion of the rectum contains a substantial number of neurons projecting to the spinal cord via the dorsal roots (Dörffler-Melly and Neuhuber, 1988). The enteric ganglia have a compact structure with tightly packed cells and cell processes (Fig. 12). The shape and thickness of myenteric ganglia change greatly with the contraction of the adjacent muscle layers. Collagen fibrils, fibroblasts, interstitial cells, and capillaries do not penetrate the ganglia but lie around them without forming a proper capsule. A single basal lamina is spread over the surface of the whole ganglion. Tracers injected intravenously in high concentrations diffuse from perigangliar capillaries and penetrate the interstices of the enteric ganglia of the rat (Jacobs, 1977). The cell types found within the ganglia are neurons and glial cells, the latter outnumbering the former by about three to one. The processes of glial cells and the neuronal processes (partly of intrinsic and partly of extrinsic origin) constitute the neuropil. The ganglion neurons, when examined under the electron microscope,
FIGURE 11 Whole-mount preparation of the muscle coat of the rat cecum, showing some neurons of the myenteric plexus. The faint staining in the background is due to the muscle cells of the circular layer (160×).
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FIGURE 12 Electron micrograph (montage) of a ganglion of the myenteric plexus of the rat small intestine. To the right is the longitudinal musculature; to the left is the circular musculature (in transverse section). The ganglion displays a neuronal cell body of complex shape, with its nucleus, and a large number of neuronal and glial processes (13,000×).
have a complex and irregular shape. Characteristically, parts of the neuronal perikarya reach the surface of the ganglion, and their membrane is in direct contact with the basal lamina and the connective tissue surrounding
the ganglion. Axosomatic and axodendritic synapses are numerous. The great majority of them survive an extrinsic denervation of the gut and are therefore of intrinsic origin. Tentative classifications of the vesicle-containing
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nerve endings of the enteric ganglia have been proposed for species other than the rat. The distribution of neuropeptides in the enteric ganglia of the rat has been studied in detail by Schultzberg and collaborators (1980). More than 50% of the neurons in the submucosal plexus of the ileum display immunofluorescence for VIP, about 20% for substance P, and 19% for somatostatin neurons (Schultzberg et al., 1980). There are no adrenergic ganglion neurons. Adrenergic fibers are seen within the muscle layers, around the intramural blood vessels, and within the ganglia (Van Driel and Drukker, 1973). The enteric glial cells pervade all the spaces within the ganglia, lying over parts of the surface of neurons and between nerve processes. Glial processes reach the surface of the ganglia and are the more conspicuous features of these glial cells. The gliofilaments (intermediate filaments) are inserted in dense plaques anchored to the cell membrane at the surface of the ganglion (Gabella, 1981). They are immunologically identical to the gliofilaments found in astrocytes (Jessen and Mirsky, 1980). There are many specialized contacts between vesicle-containing nerve endings and enteric glial cells (Gabella, 1981).
Neuromuscular Junctions Most of the axons issued by ganglion neurons, the so-called postganglionic fibers, terminate on muscle cells or on gland cells. The terminal portion of each branch of a fiber has a beaded structure, made of expansions, or varicosities, and intervaricose segments. The branching of preterminal autonomic axons and the presence of varicosities allow an extremely large number of endings (the term is used here to include varicosities) to be deployed by each axon. The number of varicosities per neuron can be two orders of magnitude larger than the number of endings made by a somatic motoneuron. Because of the sequential distribution of varicosities, each varicosity is both a point of transmission of an action potential along the axon and a potential point of transmitter release. In some smooth muscles, notably those of the intestine, axons are grouped in progressively smaller bundles and they tend to remain grouped together even in their terminal or varicose portions. Other muscles, such as those of the iris, bladder, and ductus deferens, in contrast, contain arborizations of nerve bundles that lead to individual axons with little or no Schwann cell wrapping in their terminal portions. Varicosities are very variable in length, diameter, and spatial frequency even within the same fiber. The separation between nerve varicosity and muscle cell, as well as the extent of the glial wrapping, is also
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variable. Varicosites are usually packed with axonal vesicles, but they also contain mitochondria, microtubules, and a few elements of smooth endoplasmic reticulum. Axonal vesicles may be clustered against the membrane of the varicosity. Structural specializations that characterize interneuronal synapses or neuromuscular junctions of skeletal muscles are absent or very faint at the nerve endings in smooth and cardiac muscles (Canale et al., 1986). As regards the innervation of blood vessels, detailed studies have shown that sympathetic nerve endings have structural relations with muscle cells that range from close contacts, with less than 20 nm of separation and fusion of the two basal laminae, to loose contacts, with a separation of 100 nm or more; the range is continuous, although at least two types of varicosities are distinguished (Luff and McLachlan, 1989). In small arterioles the majority of the endings have features indicating that they form neuromuscular junctions (Luff et al., 1991). In visceral muscles, various patterns of termination of the efferent fibers are observed. It may be useful to present two different arrangements of the intramuscular termination of autonomic motor nerves—as exemplified in the intestine and the bladder, although it is not clear whether they represent two exclusive patterns, or whether they are two patterns over a continuum of varying structural arrangements. In the intestine the intramuscular terminal nerves form a plexus rather than a tree-like terminal distribution. Isolated axons are rare and short. Most of the axons, including the majority of varicosities, are found within nerve bundles, and the varicose portion of an axon is usually located near the surface of the bundle, beneath its basal lamina. All the axons are tightly packed together with extensive membrane-to-membrane contact, even in large nerve trunks, and the Schwann cell component of the nerves is relatively small. The vesicle-containing varicosities thus face the extracellular space at large: the nearest cellular structures, apart from other axons and Schwann cells, are muscle cells and interstitial cells of Cajal. There is anatomical evidence of juxtaposition of vesicle-containing varicosities and muscle cells, strongly suggesting sites of transmission from nerve to muscle. Whether these juxtapositions represent true neuromuscular junctions is a mute point, because the structural configurations are very variable and often indistinct and rarely intimate. The possibility of nerve transmission to interstitial cells is much discussed (Sanders, 1996). In contrast, the intramuscular nerves of the bladder have a tree-like terminal pattern and the branching of the nerve bundles continues until each axon runs singly between muscle cells (Fig. 13). The varicosities are large and become progressively larger along the
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FIGURE 13 Muscle layer of the rat bladder. The electron micrograph shows three smooth muscle cells, approximately in transverse section. Between them is a nerve ending (varicosity) packed with axonal vesicles. The neuromuscular gap is approximately 40 nm and is occupied by an amorphous material that probably corresponds to two fused basal laminae. The ending is completely bare; that is, there is no Schwann cell sheath (35,000×)
terminal segment of the axon; they are variable in size but markedly larger than the varicosities of the intramuscular nerves of the gut. The intramuscular axons are individually wrapped by a Schwann cell (unlike those of intestinal nerves) and make no contact with each other, both in the nerves proper (Fig. 14) and in the nerve trunks that penetrate the wall of the organ; early varicosities have part of their surface uncovered by Schwann cell and abutting on the basal lamina (an arrangement refered to as a “window”); further down the axon the varicosities, fully loaded with vesicles, lose progressively their Schwann cell sheath and the last two or three of them are devoid of Schwann cell sheath, the axon extending some micrometers further than the Schwann cell (Fig. 15). The structure of terminal varicosities and the individual point of termination of an axon can be identified by serial sections (Gabella, 1995) (Fig. 16). The varicosities are packed with vesicles and lie mostly close to the surface of a muscle cell; sometimes they abut on two or three muscle cells, or lie in a groove of a muscle cell. The distance between the two membranes is often reduced to 30–50 nm. It seems correct in these situations to talk of autonomic neuromuscular junctions and to assume that these are
the discrete points of transmission from nerves to muscle. Although the structural configurations remain very variable, these neuromuscular junctions are characterized by the axon expanding into a varicosity and losing (completely or over a window) its Schwann cell cover, the separation from the muscle cells being reduced to a few tens of nanometers (the gap, or junctional cleft, being occupied or not by a basal lamina, but not by collagen or other structures extracellular materials) (Fig. 17). Subjunctional specializations are not observed on the muscle cell membranes lying beneath autonomic varicosities, even when the latter form identified neuromusuclar junctions; there are no postjunctional membrane densities or folds or specific subjunctional structures. However, clustering of postjunctional ATPreceptors has been documented in the muscle cells of the rat detrusor; the receptors are gathered into patches, about 1 μm across, that lie beneath the nerve varicosities (Hansen et al., 1998). The vesicles packing the varicosities in the bladder detrusor muscle are of uniform type although both acetylcholine and ATP are released from these nerve terminals. The high density of ATP-receptors (P2X-receptors) on muscle cells of the
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FIGURE 14 Electron micrograph of an intramural nerve of a rat bladder, showing several axon–glial bundles with unmyelinated axons. Nuclei of Schwann cells are visible. Many collagen fibrils, here mainly in transverse section, occupy the spaces between the axon–glial bundles. The axons display mitochondria, neurofilaments, some microtubules, and, occasionally, a cluster of small lucent vesicles.
bladder detrusor and the intensity of the atropineresistant excitatory input are characteristic of the rat.
Sensory fibers The sensory component of the autonomic nervous system consists mainly of neurons in dorsal root ganglia. Their central projections to the dorsal horn of the
spinal cord intermingle in part with somatic afferent projections, thus providing the anatomical basis of referred pain. The central projection synapses on interneurons that project onto preganglionic autonomic neurons, providing the basis for polysynaptic reflexes, or directly onto the preganglionic neurons (monosynaptic reflexes). The peripheral projections of these sensory neurons reach the adventitia of blood vessels
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FIGURE 15 Electron micrographs from serial sections of a rat detrusor muscle showing an axon coursing between muscle cells, all in transverse section. The axon is devoid of Schwann cells over the entire length studied (10 μm). The varicosity at the start of the series contracts into an intervaricose segment of 0.15 μm in diameter, then expands into a varicosity of about 0.7 μm in diameter, then contracts again into an intervaricose segment, and then expands again into a varicosity. The intervaricose segment in (xv) measures 0.05 μm and is occupied by a single microtubule. There are four microtubules in (i–v), six in (vi–xi), two in (xii), and one in the remaining ones. The roughly triangular space outlined by the three muscle cells and occupied by the axon is larger at the level of the varicosity, e.g., in (vi), than at the level of the intervaricose portion (xiv–xviii) (from Gabella, 1995).
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FIGURE 16 Electron micrographs from serial sections of a rat detrusor muscle showing an axon coursing between muscle cells, all in transverse section. In this series, an axon, accompanied by a slender Schwann cell process, terminating in (vi), expands into a varicosity, which is the terminal one since the axon ends in (x). This terminal varicosity is not lying particularly close to the surrounding muscle cells (from Gabella, 1995).
and the wall of most viscera. These afferent fibers reach the viscera traveling within splanchnic nerves and in postganglionic nerves; afferent and efferent fibers are thoroughly mixed within these nerves, and without seeing their origin or the terminal portion they cannot be distinguished anatomically from one another (Fig. 14). Afferent fibers for blood vessels in the body wall and limbs travel initially within somatic nerves.
The density of distribution of sensory endings is very high in certain structures, for example, the mucosa of the bladder, while it is sparse in others, for example, the intestinal mucosa. It has been calculated that the rat bladder is innervated by about 16,000 ganglion neurons approximately half of which are efferent (motor) and half sensory (Gabella, 1999). The terminal portions of the sensory fibers in the bladder are found in the mucosa,
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FIGURE 17 Electron micrographs from serial sections of a rat detrusor muscle showing an axon coursing between muscle cells, all in transverse section. This series illustrates the formation of an autonomic neuromuscular junction in the bladder musculature The 18 micrographs are taken from a set of serial sections covering a thickness of 10 μm. In the top left micrograph an intervaricose portion of the axon is fully wrapped by a Schwann cell process. The Schwann cell wrapping then retracts and a “window” appears where the axonal membrane is in contact with the basal lamina. The axon grows, increasing over 35-fold in the cross-sectional area, the bundle of microtubules is displaced to one side, and many axonal vesicles appear and pack the varicosity. The “window” expands and the distance between axolemma and smooth muscle cell membrane is reduced to about 20 nm over a wide area. The postjunctional membrane shows no typical structural specializations (from Gabella, 1995).
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mostly lying very close to the deep aspect of the urothelium. These fibers (readily identified by histochemical methods because of their high content of the neuropeptides substance P and, especially in the rat, CGRP) form a tight mesh which is particularly well developed in the caudal part of the bladder near the neck (Figure 18, top) and is sparse in the equatorial region and almost absent in the cranial region of the bladder. The last few hundreds of micrometers of a sensory fiber are distinctly varicose; these varicosities are smaller in size than those of efferent axons, they contain some vesicles but not as densely packed as in efferent axons, and they do not appear to be associated with specialized cellular structures or special components of the extracellular materials. Some fibers extend into the epithelium reaching very close to the luminal surface (Fig. 19, bottom). The mechanism of transduction at these sensory endings (which are regarded as “free” endings in that they are not associated with a corpuscular receptor) is not clear. Release of neurochemicals from the afferent nerve ending itself is probably part of the process. Recent evidence from the bladder (of mice and rabbits) shows that ATP is produced by the epithelial cells and is released upon mechanical stimulation Ferguson et al., 1997), and it can then act on the P2X-receptors present in subepithelial afferent nerve fibers (Evans and Surprenant, 1996) and trigger an afferent impulse (Cockayne et al., 2000). The release of neurochemical from afferent nerve endings (which can occur upon chemical or mechanical stimulation or by antidromic nerve impulses) is a crucial mechanism in the process of neurogenic inflammation which is known to occur, in rodents, in some viscera, including bladder and trachea.
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FIGURE 18 Whole-mount preparation of the bladder mucosa stained with CGRP antibody. A dense plexus of immunoreactive fibers lies parallel to the lumenal surface and very close to the epithelium. These fibers originate from dorsal root ganglia and provide the main sensory innervation to the bladder (from Gabella and Davis, 1998).
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FIGURE 19 (Top) Whole-mount preparation of the bladder mucosa of a rat, stained for CGRP, showing terminal and branching points of sensory axons, sequence and range of varicosities, and an axonal loop from a single axon, all spreading in a very flat plane immediately below the epithelium. (Bottom) Varicose terminal portion of sensory fiber, stained for CGRP, situated within the epithelium of the rat bladder mucosa (from Gabella and Davis, 1998, modified).
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C H A P T E R
4 Primary Afferent Projections to the Spinal Cord GUNNAR GRANT and BRITA ROBERTSON Department of Neuroscience, Karolinska Institutet Stockholm, Sweden
The primary afferent fibers projecting to the rat spinal cord enter via the dorsal roots. It has been suggested, however, that also ventral roots contribute afferents. It appears from studies conducted on the cat that the ventral roots may contain afferents at sacral levels and that these fibers terminate in the spinal gray matter (Mawe et al., 1984). Unmyelinated afferent fibers have been demonstrated in the L7 ventral root in the cat. Instead of penetrating into the central nervous system, these fibers either make U-turns or enter the pia mater (Risling and Hildebrand, 1982; Risling et al., 1984). Physiological studies suggest the occurrence of an additional category of sensory axons in feline sacral ventral roots. Blindly ending sensory axons with small, circumscribed spot-like receptive fields in ventral roots can be activated by chemical or mechanical stimuli such as a slight stretch of the roots (Jänig and Koltzenberg, 1991). Such “nervi nervorum” seem indeed to represent the dominating sensory component in the S2 ventral roots of the cat (Häbler et al., 1990). Electrophysiological data suggest that the ventral root afferents in the cat finally enter the central nervous system via the dorsal root rather than directly through the ventral root. Hence, dorsal root axons and neurons in the spinal gray matter can be activated from the distal but not the proximal stump of a divided ventral root (Chung et al., 1983, 1985; Kim et al., 1988; Shin et al., 1985, 1986). Unmyelinated ventral root afferents have also been found in the rat, but they appear to be significantly less numerous than their feline and human counterparts (Coggeshall et al., 1977). Further, there is evidence for the existence of myelinated
The Rat Nervous System, Third Edition
sensory axons making U-turns in rat ventral roots (Baik-Han et al., 1989; Bostock, 1981). The dorsal roots in the rat are grouped in pairs of 8 cervical, 13 thoracic, 6 lumbar, 4 sacral, and 3 caudal (coccygeal; for example, Waibl, 1973). The number of dorsal root ganglion cells in single pairs may vary considerably between the two sides (Ygge et al., 1981). A similar variation can therefore be expected to exist also in the number of dorsal root axons. Their actual number, however, may be larger than the number of ganglion cells (Chung and Coggeshall, 1984; Langford and Coggeshall, 1979). In the monkey, small caliber dorsal root axons are segregated into a lateral bundle as the dorsal rootlets enter the spinal cord (Snyder, 1977). This is not the case in the cat and does not appear to be prominent in the rat either (Willis and Coggeshall, 1991). After entering the spinal cord, the dorsal root afferents are distributed differently depending upon size. Coarse calibered fibers run medially into the dorsal funiculus, whereas fine fibers approach the dorsal horn via the dorsolateral fasciculus (Lissauer’s tract). More than two-thirds of the axons in the dorsolateral fasciculus at lumbosacral and midthoracic levels in the rat have been demonstrated to be of primary afferent origin (Chung et al., 1979). Anatomical studies on primary afferent projections to the spinal cord have been conducted mainly in cat and rat. Data from these studies, taken together, suggest that the primary afferent terminations in the spinal gray matter largely follow two principles of organization. First, fine calibered fibers are distributed preferentially
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in superficial laminae of the dorsal horn, whereas coarse fibers project more ventrally (for references see below). Second, somatic primary afferents terminate somatotopically along a mediolateral axis in the dorsal horn (Smith, 1983; Ygge and Grant, 1983; Cervero and Connell, 1984b; Molander and Grant, 1985, 1986; Swett and Woolf, 1985; Woolf and Fitzgerald, 1986; Ueyama et al., 1987; Shortland et al., 1989; Rivero-Melián and Grant, 1990, 1991; Shortland and Woolf, 1993; RiveroMelián, 1996; see also Willis et al., Chapter 27). With regard to visceral primary afferents, such afferents do not seem to have been studied specifically with regard to somatotopic organization. If present, such an organization may be difficult to reveal, due to the more widespread distribution of the afferents (e.g. Morgan et al., 1981; Kuo et al., 1983; Nadelhaft and Booth, 1984; Neuhuber et al., 1986; Sugiura et al., 1989; Sugiura and Tonosaki, 1995; Wang et al., 1998). In the sections below, we first describe the distribution of primary afferents to different laminae and some specific nuclei. Thereafter, their somatotopic arrangement is considered.1
PROJECTION OF PRIMARY AFFERENT FIBERS TO DIFFERENT LAMINAE AND SOME SPINAL CORD NUCLEI As in the cat and monkey (LaMotte, 1977; Réthelyi, 1977; Light and Perl, 1979a; Beal and Bicknell, 1981; Gobel et al., 1981), both lamina I (the marginal layer) and lamina II (substantia gelatinosa) of the rat spinal cord are reported to receive unmyelinated as well as fine myelinated primary afferent fibers (e.g., Light and Perl, 1979a; Janscó and Király, 1980; Nagy and Hunt, 1983; McMahon and Wall, 1985; Cruz et al., 1987; Fitzgerald, 1989; LaMotte et al., 1991). In the guinea pig, physiologically characterized, horseradish peroxidase (HRP)-labeled cutaneous and visceral C fiber afferents have been shown to terminate in both lamina I and lamina II (Sugiura et al., 1986, 1989, 1993; see also Willis et al., Chapter 27).
Lamina I The major primary afferent input appears to be provided by Aδ fibers, although there is also a cutaneous unmyelinated C fiber input (Sugiura et al., 1986; see 1 The distribution of different kinds of neurotransmitters/ neuromodulators and their receptors is not dealt with here. The reader is referred to the chapters dealing specifically with neurotransmitters; see also Ribeiro-da-Silva, Chapter 6; Weihe, 1990; Willis and Coggeshall, 1991; Hunt et al., 1992; Lawson, 1992.
also Gobel et al., 1981). In the primate, LaMotte (1977) found that afferent endings in lamina I degenerated slower than those in lamina II and suggested that Aδ primary afferents gave rise to a lamina I input. This was supported by evidence from physiological studies on cat and monkey (Kumazawa and Perl, 1978; Mense and Prabhakar, 1986). Direct evidence for a termination of Aδ fibers in lamina I in these two species was shown by Light and Perl (1979b) and further supported by morphological work on the monkey (Ralston and Ralston, 1979). With respect to muscle afferents, the number of afferents projecting to lamina I seems sparse and appears to vary not only between different muscle groups but also between species. Some studies on the cat show a clear terminal projection to lamina I (Craig and Mense, 1983; Nyberg and Blomqvist, 1985; Mense and Prabhakar, 1986; Mense and Craig, 1988), whereas others report essentially no or only sparse labeling following application of tracer in cats and rats (Mysicka and Zenker, 1981; Ammann et al., 1983; Abrahams et al., 1984; Bakker et al., 1984; Molander and Grant, 1987; Rivero-Melián, 1996). Projections of articular afferents have been the subject of a study in the cat (Craig et al., 1988). In addition to a projection to lamina I, the deep dorsal horn was found to receive afferents, similar to the situation for muscle (see below). As the authors point out, their data therefore support the existence of a common pattern for the central distribution of deep somatic afferents. They also found it reasonable to suggest that the articular afferent input to lamina I would comprise small diameter myelinated and unmyelinated (Group III and IV) fibers and may be primarily nociceptive. Apart from a somatic primary afferent input to lamina I, projections of visceral afferents have also been reported in monkey, cat, guinea pig, and rat (DeGroat et al., 1978; Morgan et al., 1981, 1986; Neuhuber, 1982; Ciriello and Calaresu, 1983; Kuo et al., 1983; Nadelhaft et al., 1983; Cervero and Connell, 1984a, 1984b; Neuhuber et al., 1986; Sugiura et al., 1989; Wang et al., 1998). In a quantitative analysis of unmyelinated C fiber afferents in guinea pig, more than 60% of the central synaptic enlargements of the visceral afferents were found to be localized superficially in lamina I, and the adjacent area (Sugiura et al., 1993). This seemed to be the main region of termination. Ten to twenty percent of the boutons appeared in deeper layers.
Lamina II Unmyelinated C fiber afferents have been found to provide the main primary afferent input in monkey, cat, guinea pig, and rat (Light and Perl, 1979a; Sugiura et al.,
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1986, 1989, 1993; Cruz et al., 1991). Such fibers are reported to have their main termination site in the same transverse band where fluoride-resistant acid phosphatase (FRAP)-positive terminals have been found (Coimbra et al., 1974; see also Ribeiro-da-Silva and Coimbra, 1982; Nagy and Hunt, 1983; and Ribeiro-daSilva, Chapter 6). Some fine myelinated afferent fibers, supposedly Aδ fibers subserving high-threshold mechanoreceptors, appear to terminate preferentially in the superficial parts (lamina IIo; Nagy and Hunt, 1983; lamina IIA of Ribeiro-da-Silva, Chapter 6). This has also been reported in the cat and monkey (Beal and Bicknell, 1981; LaMotte, 1977). Additionally, some fine myelinated fibers, presumably Aδ D-hair, and cutaneous mechanoreceptive Aβ afferents reach the deepest part of lamina II from the more ventrally situated lamina III in the rat (Cruz et al., 1987, 1991; Woolf, 1987; Beal et al., 1988; Shortland et al., 1989; Shortland and Woolf, 1993). Although lamina II appears to receive mainly unmyelinated cutaneous afferents, a small number of unmyelinated visceral afferents have been shown to terminate in this lamina in the guinea pig (Sugiura et al., 1989, 1993). Furthermore, presumed preterminal axons and/or terminals of visceral afferents have been found in the superficial part of lamina II in the rat, both from the inferior mesenteric plexus and hypogastric nerve (Neuhuber, 1982) and from the greater splanchnic nerve (Neuhuber et al., 1986). In the cat, the arborizations of unmyelinated afferents entering from the superficial part of the dorsal horn have been found distributed in narrow (150 μm wide) zones, and their terminals in still narrower (16–28 μm thick) sagittal sheets (Réthelyi, 1977). A zonal organization can also be seen for primary afferents in lamina II in the rat (Ygge and Grant, 1983; Molander and Grant, 1985, 1986; Tong et al., 1999). Recently, a group of itch-specific, mechanically insensitive dorsal horn neurons connected to very slowly conducting primary afferents (C fibers) were identified in monkey (Andrew and Craig, 2001). Primary afferents with similar properties have been found in humans (Schmelz et al., 1997). In the rat, histamine-responsive dorsal horn neurons have been described, but these respond also to mechanical stimuli and, thus, do not appear to be itch-specific (Jinks and Carstens, 2000).
The Lateral Spinal Nucleus In the dorsolateral funiculus, just lateral to the superficial dorsal horn, the rat spinal cord contains an aggregation of neurons called the lateral spinal nucleus (LSp); (see Grant and Koerber, Chapter 5). This has been described to receive visceral primary afferent fibers (Neuhuber, 1982; Neuhuber et al., 1986) and to respond
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to subcutaneous and/or deep structures (Menétrey et al., 1980). Willis et al. (Chapter 28) consider a possible role of the lateral spinal nucleus in nociception.
Laminae III–VI The primary afferent fibers projecting to the deep parts of the dorsal horn, including laminae III–V, and in the enlargements also lamina VI, are in general of a caliber coarser than those projecting to the superficial laminae. One exception to this is certain types of muscle and visceral afferents, terminating in lamina V, which have been identified in the cat (Light and Perl, 1979b; Craig and Mense, 1983; Kuo et al., 1983; Cervero and Connell, 1984a, 1984b; Morgan et al., 1986). Studies in the rat suggest that fine fibers, derived from muscle and viscera, also project to lamina V in this species (Ciriello and Calaresu, 1983; Neuhuber et al., 1986; Molander and Grant, 1987; Wang et al., 1998). The large-diameter afferent fibers enter the dorsal horn from the dorsal funiculus. For the cat, the course and termination of these fibers have been studied extensively, using different methods, including intraaxonal application of HRP to physiologically identified units. The results of these studies have been reviewed in a monograph on organization in the spinal cord (A. G. Brown, 1981; see also Maxwell and Bannatyne, 1983; Semba et al., 1983; Fyffe, 1984; Ralston et al., 1984; Willis and Coggeshall, 1991). With regard to largediameter primary afferent fibers in the rat, only a few studies have been published. The most extensive of these are the studies by Woolf (1987), Shortland et al. (1989), and Shortland and Woolf (1993), in which the method of intraaxonal application of HRP was used for an analysis of three types of low-threshold cutaneous mechanoreceptors. The general pattern of the terminal arborizations was one of mediolaterally compressed, rostrocaudally oriented sheets. The terminal arborizations of the hair follicle afferents had a distinctive morphology, identical to the “flame-shaped arbors” of Scheibel and Scheibel (1968). They had a recurrent course, distributing arborizations with synaptic boutons from lamina IV ventrally to inner lamina II dorsally. The two other types of units arborized within laminae III–V: rapidly adapting glabrous skin mechanoreceptors, which also may have some arbors projecting dorsally into lamina II, and slowly adapting type I afferent fibers, which in general have their terminal arbors somewhat deeper, in laminae IV, V, and even VI. Cutaneous afferent projections to the deep dorsal horn have also been demonstrated by transganglionic tracing in the rat (LaMotte et al., 1991; Maslany et al., 1992; RiveroMelián and Grant, 1991; Woolf and Fitzgerald, 1986). This method has also revealed muscle and visceral
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afferent projections, presumably of fine calibered fibers, to lamina V, as was commented on above. In addition, muscle afferent fiber projections to lamina VI, as well as to more ventral laminae, have been found (Molander and Grant, 1987; Rivero-Melián, 1996).
Lamina VII The intermediate gray, lamina VII, has been shown to receive a projection from muscle nerves in the rat (Mesulam and Brushart, 1979; Smith, 1983; Molander and Grant, 1987; Rivero-Melián, 1996). Muscle nerve projections to the dorsal nucleus (D; Clarke’s column) have also been demonstrated (Brushart and Mesulam, 1980; Molander and Grant, 1987; Rivero-Melián, 1996). In addition, cutaneous primary afferents project to part of this nucleus (Rivero-Melián and Grant, 1991). In the cat, articular nerves also contribute afferents to the dorsal nucleus (Craig et al., 1988). In the rat, neck muscle afferents project to the central cervical nucleus (CeC) which is located in the upper cervical segments of the spinal cord. This has been demonstrated both by tracing (Mysicka and Zenker, 1981; Ammann et al., 1983; Örnung et al., 1995) and in electrophysiological studies (Popova et al., 1995). Furthermore, there is evidence that the sacral parasympathetic nucleus, which is found at the dorsolateral border of lamina VII at L6 and S1 levels in the rat, also receives a primary afferent projection, although of visceral origin (Nadelhaft and Booth, 1984; Wang et al., 1998).
Area X Area X and the dorsal gray commissure have been shown in several studies to receive visceral afferents in the rat. These have been derived both from renal (Ciriello and Calaresu, 1983) and pelvic (Nadelhaft and Booth, 1984; Neuhuber, 1982; Wang et al., 1998) nerves, as well as from the greater splanchnic nerve (Neuhuber et al., 1986). The area has also been shown to receive somatic afferents, both in rat (Neuhuber et al., 1986) and cat (Cervero and Connell, 1984b; Honda, 1985). Furthermore, Honda (1985) found that cells in this area in the sacral spinal cord in the cat received primary afferent inputs converging from a wide range of receptor types in somatic and visceral structures. A possible involvement of cells in this area in the transmission of visceral nociception has recently been discussed (Wang et al., 1999; see also Willis et al., Chapter 27).
The Ventral Horn The organization of primary afferent projections to the ventral horn has been studied in detail by tracing
in the rat. Smith (1983) investigated the development and postnatal organization of primary afferents to the thoracic cord, using unconjugated HRP. She found significant labeling, however, only in animals less than 17 days of age. Other investigators have studied the projections of muscle afferents in the adult animal at lumbar levels (Mesulam and Brushart, 1979; RiveroMelián and Grant, 1990; Rivero-Melián, 1996) and in the upper cervical cord (Mysicka and Zenker, 1981; see also Örnung et al., 1995). Very prominent labeling was achieved by using HRP conjugated to the B-fragment of cholera toxin (Rivero-Melián and Grant, 1990; RiveroMelián, 1996). This seems superior for the labeling of somatic myelinated afferents. The results achieved by Smith confirmed that there are connections between afferents and motoneurons with axons in the same nerve and showed that the afferent boutons were distributed widely across the dendritic arbors of the motoneurons. At lumbar levels the densest primary afferent projection from each injected muscle nerve was found in the homonymous group of motoneurons (Rivero-Melián, 1996). It is obvious that the principle of organization of spinal cord primary afferent fibers, that fine-calibered fibers terminate in superficial laminae of the dorsal horn and coarse-calibered fibers more ventrally in the gray matter, is not an absolute one. Fine-calibered primary afferents are found in lamina V and visceral, presumed fine fibers terminate both in lamina VII, at the sacral level, and in area X and the dorsal gray commissural region. Indeed, a highly specialized central projection of primary afferent endings related to sensory function and not to fiber diameter was proposed by Light and Perl (1979b). Furthermore, afferent fibers from different types of peripheral targets, such as skin, muscle, and viscera have different, characteristic termination sites (Fig. 1). The finding of a partial overlap of some types of afferent fibers, such as visceral and cutaneous fibers, as in lamina I, and somatic and visceral in the area around the central canal, would have to be expected if convergence of different types of afferent fibers is to be made possible.
SOMATOTOPIC ORGANIZATION OF PRIMARY AFFERENT PROJECTIONS Early physiological studies on the cat demonstrated a somatotopic organization of cells in the dorsal horn activated by low-threshold cutaneous afferent fibers, suggesting a similar organization for the incoming afferents (Koerber and Brown, 1982). Physiological studies have confirmed such an organization (see A.G. Brown, 1981; P.B. Brown et al., 1991, 1992). There was
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FIGURE 1 Schematic drawings of transverse sections of the spinal cord gray matter on one side of one lower lumbar (left) segment and one lower thoracic (right) segment in the rat, showing principal termination sites for afferent fibers from skin and muscle (left) and viscera (right).
also anatomical support for a somatotopic arrangement of the incoming afferents (see Grant and Ygge, 1981; Ygge and Grant, 1983). As will be described below, the HRP tracing method has confirmed such an arrangement and extended our knowledge as to the intricacy of the organization. The thoracic level, where the segmental pattern of the body is clearly preserved, should be well suited for studies of the general principles of organization of primary afferent projections in the spinal gray matter. In such studies conducted on the rat, it was found that the dorsal and ventral rami, the two main components of the spinal nerve, have their projections restricted to the lateral and medial parts of the dorsal horn, respectively (Smith, 1983; Ygge and Grant, 1983). Furthermore, the projections of the two main branches of the ventral ramus were found to be somatotopically organized, within the projection compartment of their parent nerve (Ygge and Grant, 1983) (Fig. 2). This principle of organization was confirmed in a later study of projections of cutaneous afferent fibers from different dorsoventral sectors of the cat’s tail, using single-unit labeling of physiologically identified primary afferent fibers (Ritz et al., 1989). The analysis of the rostrocaudal extension of the projections showed that the mediolateral compartments extended into neighboring segments, resulting in an overlap between compartments from corresponding rami of adjacent spinal nerves (Ygge and Grant, 1983). The central branches of hindlimb and forelimb nerves and lumbar dorsal root ganglia, as well as afferents
from cutaneous regions of the paws (see Fig. 2), have also no been shown to be organized somatotopically in mediolateral compartments in the dorsal horn similar to those of the thoracic spinal nerve (Molander and Grant, 1985, 1986; Nyberg and Blomqvist, 1985; Swett and Woolf, 1985; Woolf and Fitzgerald, 1986; Shortland et al., 1989; Rivero-Melián and Grant, 1990, 1991; Maslany et al., 1992; Shortland and Woolf, 1993; Rivero-Melián, 1996). Furthermore, central branches of the pudendal nerve in rat are similarly organized (Ueyama et al., 1987). Studies by Mirnics and Koerber (1995) indicate that the somatotopic organization of the incoming afferents is established very early in development and requires little refinement to match that seen in the adult. The somatotopic arrangement does not exclude the possibility that afferent fibers also project outside their predicted termination sites. An example of this, although not from the dorsal horn, is the projection from the rat sciatic nerve not only to the gracile but also to the cuneate nucleus in the rat (Grant et al., 1979). Such “exterior” projections might conceivably serve interactions between different peripheral sources, necessary for proper sensory function.
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FIGURE 2 (Left) Schematic drawing of transverse section of the spinal cord gray matter on one side of the 10th thoracic segment in the rat, showing somatotopically arranged termination of nerves from dorsal, lateral, and ventral sectors of the trunk. (Right) Schematic dorsal view map of lamina II, depicting density centers of projections from various parts of the rat’s hindpaw skin (bottom) and the somatotopic termination of nerve branches from different sectors of the trunk (top) (compare with the drawing on the left, which was modified from Fig. 5 in Molander and Grant, 1990). Ammann, B. M., Gottschall, J., and Zenker, W. (1983). Afferent projections from the rat longus capitis muscle studied by transganglionic transport of HRP. Anat. Embryol. 166, 275–289. Andrew, D., and Craig, A. D. (2001). Spinothalamic lamina I neurons selectively sensitive to histamine: A central neural pathway for itch. Nat. Neurosci. 4, 72–77. Baik-Han, E. J., Kim, K. J., and Chung, J. M. (1989). Electrophysiological evidence for the presence of looping myelinated afferent fibers in the rat ventral root. Neurosci. Lett. 104, 65–70.
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Schmelz, M., Schmidt, R., Bickel, A., Handwerker, H. O., and Torebjörk, H. E. (1997). Specific C-receptors for itch in human skin. J. Neurosci. 15, 8003–8008. Semba, K., Masarachia, P., Malamed, S., Jacquin, M., Harris, S., Yang, G., and Egger, M. D. (1983). An electron microscopic study of primary afferent terminals from slowly adapting Type I receptors in the cat. J. Comp. Neurol. 221, 466–481. Shin, H. K., Kim, J., and Chung, J. M. (1985). Flexion reflex elicited by ventral root afferents in the cat. Neurosci. Lett. 62, 353–358. Shin, H. K., Kim, J., Nam, S. C., Paik, K. S., and Chung, J. M. (1986). Spinal entry route for ventral root afferent fibers in the cat. Exp. Neurol. 94, 714–725. Shortland, P., and Woolf, C. J. (1993). Morphology and somatotopy of the central arborizations of rapidly adapting glabrous skin afferents in the rat lumbar spinal cord. J. Comp. Neurol. 329, 491–511. Shortland, P., Woolf, C. J., and Fitzgerald, M. (1989). Morphology and somatotopic organization of the central terminals of hindlimb hair follicle afferents in the rat lumbar spinal cord. J. Comp. Neurol. 289, 416–433. Smith, C. L. (1983). The development and postnatal organization of primary afferent projections to the rat thoracic spinal cord. J. Comp. Neurol. 220, 29–43. Snyder, R. (1977). The organization of the dorsal root entry zone in cats and monkeys. J. Comp. Neurol. 174, 47–70. Sugiura, Y., Lee, C. L., and Perl, E. R. (1986). Central projections of identified, unmyelinated (C) afferent fibers innervating mammalian skin. Science 234, 358–361. Sugiura, Y., Terui, N., and Hosoya, Y. (1989). Differences in distribution of central terminals between visceral and somatic unmyelinated (C) primary afferent fibers. J. Neurophysiol. 62, 834–840. Sugiura, Y., Terui, N., Hosoya, Y., Tonosaki, Y., Nishiyama, K., and Honda, T. (1993). Quantitative analysis of central terminal projections of visceral and somatic unmyelinated (C) primary afferent fibers in the guinea pig. J. Comp. Neurol. 15, 315–325. Sugiura, Y., and Tonosaki, Y. (1995). Spinal organization of unmyelinated visceral afferent fibers in comparison with somatic afferent fibers. In “Visceral Pain” (Gebhart, D. F., Ed.), pp. 41–59. IASP Press, Seattle. Swett, J. E., and Woolf, C. J. (1985). The somatotopic organization of primary afferent terminals in the superficial laminae of the dorsal horn of the rat spinal cord. J. Comp. Neurol. 231, 66–77.
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Tong, Y.-G., Wang, H. F., Ju, G., Grant, G., Hökfelt, T., and Zhang, X. (1999). Increased uptake and transport of cholera toxin B-subunit in dorsal root ganglion neurons after peripheral axotomy: Possible implication for sensory sprouting. J. Comp. Neurol. 404, 143–158. Ueyama, T., Arakawa, H., and Mizuno, N. (1987). Central distribution of efferent and afferent components of the pudental nerve in the rat. Anat. Embryol. 177, 37–49. Waibl, H. (1973). Zur Topographie der Medulla Spinalis der Albinoratte (Rattus norvegicus). Adv. Anat. Embryol. Cell Biol. 47(fasc. 6), 1–42. Wang, C.-C., Willis, W. D., and Westlund, K. N. (1999). Ascending projections from the area around the spinal cord central canal: A Phaseolus vulgaris leucoagglutinin study in rats. J. Comp. Neurol. 415, 341–367. Wang, H. F., Shortland, P., Park, M. J., and Grant, G. (1998). Retrograde and transganglionic transport of horseradish peroxidase conjugated cholera toxin B subunit, wheat germ agglutinin and isolectin B4 from Griffonia simplicifolia I in primary afferent neurons innervating the rat urinary bladder. Neuroscience 87, 275–288. Weihe, E. (1990). Neuropeptides in primary afferent neurons. In “The Primary Afferent Neuron: A Survey of Recent MorphoFunctional Aspects” (W. Zenker and W. L. Neuhuber, Eds.), pp. 161–172. Plenum, New York. Willis, W. D., and Coggeshall, R. E. (1991). “Sensory Mechanisms of the Spinal Cord,” 2nd ed. Plenum, New York. Woolf, C. J. (1987). Central termination of cutaneous mechanoreceptive afferents in the rat lumbar spinal cord. J. Comp. Neurol. 261, 105–119. Woolf, C. J., and Fitzgerald, M. (1986). Somatotopic organization of cutaneous afferent terminals and dorsal horn neuronal receptive fields in the superficial and deep laminae of the rat lumbar spinal cord. J. Comp. Neurol. 251, 517–531. Ygge, J., Aldskogius, H., and Grant, G. (1981). Asymmetries and symmetries in the number of thoracic dorsal root ganglion cells. J. Comp. Neurol. 202, 365–372. Ygge, J., and Grant, G. (1983). The organization of the thoracic spinal nerve projection in the rat dorsal horn demonstrated with transganglionic transport of horseradish peroxidase. J. Comp. Neurol. 216, 1–9.
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C H A P T E R
5 Spinal Cord Cytoarchitecture GUNNAR GRANT Department of Neuroscience, Karolinska Institutet Stockholm, Sweden
H. RICHARD KOERBER Department of Neurobiology, The University of Pittsburgh School of Medicine Pittsburgh, USA
The cytoarchitectonic scheme presented for the cat spinal cord by Rexed (1952, 1954) has gained wide acceptance in the neuroscience literature. It is based on the morphology and arrangement of Nissl-stained cell bodies in transverse sections, providing a framework to which localized features, anatomical, physiological, or histochemical, may be related. The gray matter is divided into 10 cytoarchitectonic regions, laminae I–IX and an area around the central canal (area X). As emphasized Rexed (1952), the borders between the different laminae may be indistinct and should be recognized as zones of transition rather than as strict borderlines. Although originally presented for the cat, Rexed’s scheme has, with some alterations, been found to be applicable also to the rat spinal cord (Fukuyama, 1955; Steiner and Turner, 1972; McClung and Castro, 1976; Molander et al., 1984, 1989; Paxinos and Watson, 1986). The following description of the rat spinal cord cytoarchitecture represents an updated version of that of the chapter by Molander and Grant in the 2nd edition of The Rat Nervous System, which was based primarily on previously published observations by Molander et al. (1984, 1989).
Lima and Coimbra (1986) described fusiform, multipolar, flattened, and pyramidal cell types, most of which have their major dendrites within lamina I or in the adjacent white matter. Some send dendrites ventrally as far as lamina V (Beal et al., 1989). The flattened and pyramidal neurons correspond to the marginal cells described in the classical literature (Rexed, 1952; Lima and Coimbra, 1986). A large proportion of the cells with perikarya in lamina I or the adjacent white matter seem to be wide dynamic range neurons activated by both low- and high-intensity stimulation (Menétrey et al., 1977; McMahon and Wall, 1983; Woolf and Fitzgerald, 1983). Other neurons seem to respond primarily to either low- or high-threshold stimulation (McMahon and Wall, 1983; Woolf and Fitzgerald, 1983). Furthermore, there is evidence that neurons in lamina I, as well as in lamina II, respond to both pruritic and algesic chemical stimuli and thus might participate in transmitting sensations of itch and/or chemogenic pain (Jinks and Carstens, 2000; cf. Grant and Robertson, Chapter 4). Subpopulations of neurons in lamina I project to the brain stem, including among other structures the nucleus of the solitary tract, the parabrachial nucleus, and the periaqueductal gray (Menétrey et al., 1982; Chaouch et al., 1983; Cechetto et al., 1985; Lima and Coimbra, 1989, 1990; Esteves et al. 1993; Tavares et al., 1993; Feil and Herbert, 1995; Kayalioglu et al., 1999; Bester et al., 2000), to hypothalamus (Burstein et al., 1987, 1990a; Kayalioglu et al., 1999), and to thalamus (Granum, 1986; Kemplay and Webster, 1986; Lima and Coimbra, 1988; Hylden et al., 1989; Burstein et al., 1990b; Kobayashi, 1998; Kayalioglu et al., 1999). The type of
LAMINA I Lamina I (marginal zone) forms a thin rim along the dorsal and dorsolateral edges of the dorsal horn. Most of the cells are small but a few mediolaterally elongated large cells can usually be seen in each section. The neuropil is oriented tangentially to the lamina. Using three-dimensional reconstructions from Golgi sections,
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dendritic pattern seems to be correlated to projection target (Beal et al., 1989; Lima and Coimbra, 1990). Earlier studies in rat suggested a lack of correlation between cell morphology and functional properties of lamina I cells (Woolf and Fitzgerald, 1983). More recently, however, Han et al. (1998) showed a strong correlation between morphological type and functional characteristics in cat. They report that cells responding specifically to nociceptive stimuli were identified as different varieties of fusiform cells. Those responding to innocuous cold were pyramidal and those classified as polymodal nociceptive were morphologically identified as multipolar (also see Light and Willcockson, 1999).
neurons in lamina II are relatively few, but some have been found to project to the caudal ventrolateral reticular formation of the medulla oblongata (Lima and Coimbra, 1991) and a few cells in a region approximately corresponding to lamina II have been found to project to the lateral cervical nucleus and the brain stem (Giesler et al., 1978) and thalamus (Burstein et al., 1990b). There appear to be morphological differences in dendritic tree shape between projection neurons and locally projecting neurons (Beal et al., 1989), but no clear correlation has been found between morphology and functional types [Light et al., 1979 (cat); Woolf and Fitzgerald, 1983; Light and Willcockson, 1999 (rat)].
LAMINA II
LAMINA III
Lamina II (substantia gelatinosa) is subjacent and parallel to lamina I. It is wider than lamina I and is characterized in Nissl-stained material by its dominance of small round cell bodies with sparse Nissl substance. At the levels of the enlargement lamina II diverges from the usual parallel arrangement with lamina I. At these level lamina II is depressed ventrally away from lamina I (Woodbury et al., 2000). Interspersed between lamina I and lamina II is a distinct hemi-lamina that differs from lamina I as it lacks myelinated fiber inputs and large marginal layer neurons. This area does not receive input from fibers that bind the IB4 isolectin (Wang et al., 1994; Woodbury et al., 2000) but does receive a rich peptidergic innervation (e.g., Silverman and Kruger, 1988, 1990). At the lumbar level, the location of this dip in lamina II somatotopically corresponds to the glabrous skin of the feet (Woodbury et al., 2000). Lamina II has an intensely stained outer zone (IIo; named IIA by Ribeiro-da-Silva, Chapter 6) with densely packed cells and a less compact inner zone (IIi; named IIB by Ribeiro-da-Silva, Chapter 6). Myelinated fibers are spars except for bundles of myelinated fibers that cross the lamina, particularly in its medial part. Neurons in lamina IIo are most often characterized as nociceptive, responding best to high-intensity stimulation. Most neurons in IIi respond maximally to brush stimuli and are classified as non-nociceptive (Woolf and Fitzgerald, 1983; Light, 1992; Light and Willcockson, 1999). These results are consistent with the demonstration of extensive input from low-threshold mechanoreceptors in IIi (Woodbury et al., 2000). A description of rat lamina II neurons, which was based on Golgi and retrograde tract tracing techniques, was published by Beal et al. (1989). On the basis of dendritic morphology, the cells were classified into limiting, central, islet, stalked, inverted stalk, arboreal, spiny, vertical, and star-shaped cells. Tract
Lamina III runs just ventral and parallel to lamina II. It has a cytoarchitectonic appearance similar to that of lamina II but shows a slightly wider range of cell sizes and is less compact. The border between lamina II and lamina III is difficult to recognize from cell morphology, but it can often be distinguished by a clearly visible transition from the homogeneous neuropil characteristic of IIi to a more heterogeneous neuropil in lamina III. If a myelin stain is used, the almost myelin-free lamina IIi stands out clearly against lamina III, which contains numerous fine myelinated fibers. The dendritic fields of many lamina III neurons are oriented rostrocaudally [Scheibel and Scheibel, 1968 (cat and rat); Beal et al., 1988 (rat)]. Many cells in lamina III respond only to weak mechanical stimuli (Cervero et al., 1988). Cells in a region corresponding approximately to lamina III have been shown to project to other regions within the same segment of the spinal cord [Light and Kavookjian, 1988 (cat and monkey)], the dorsal column nuclei [Giesler et al., 1984 (rat)], the lateral cervical nucleus [Baker and Giesler, 1984 (rat)], and the thalamus [Burstein et al., 1990b (rat)]. Brown (1981) noted that postsynaptic dorsal column neurons in the cat have wide-spread dendrites, some reaching laminae I and IIo, whereas the dendrites of spinocervical tract cells are oriented more rostrocaudally and do not reach laminae I and IIo. Whether this is true also in the rat is as yet unknown.
LAMINA IV Lamina IV forms the base of the head of the dorsal horn and curves ventrally along its medial border. It becomes continuous with the contralateral lamina IV in the dorsal commissure at lumbar and sacral levels and ends at area X (see below) at thoracic and cervical levels.
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The cells in lamina IV appear more loosely arranged than those in lamina III, and some of them are multipolar and considerably larger. In the thoracic and upper lumbar region, lamina IV becomes interrupted by the elongated cells in Clarke’s column at the base of the dorsal horn. Cells in this nucleus have their dendrites oriented rostrocaudally [Scheibel and Scheibel, 1968 (cat and rat); Loewy, 1970 (cat)], respond to proprioceptive and cutaneous stimuli [Oscarsson, 1973 (cat)], and project to the cerebellum (Matsushita and Hosoya, 1979; RiveroMelián and Grant, 1990). A small group of spinocerebellar neurons have also been found in the dorsal column white matter just dorsal to Clarke’s column at levels T13 through L2 (Beal et al., 1990; Rivero-Melián and Grant, 1990). This group of neurons is, however, not the same as the network of neurons located along the midline of the dorsal column white matter described by Abbadie et al. (1999). The cells in lamina IV have widespread dendritic fields [Scheibel and Scheibel, 1968 (cat and rat)]. Many of the neurons seem to have their major dendritic orientation toward superficial laminae, so called “antenna-like neurons” [Szentágothai, 1964 (cat); Scheibel and Scheibel, 1968 (cat and rat); Schoenen, 1982 (man)]. As in lamina III, many cells in lamina IV respond only to light mechanical stimuli, although nociceptivespecific and wide dynamic range neurons are present as well (cf. Cervero et al., 1988). Furthermore, as in lamina III, subpopulations of cells in a region corresponding approximately to lamina IV project locally within the spinal cord [Mannen, 1975 (cat)] to the lateral cervical nucleus (Baker and Giesler, 1984), to the dorsal column nuclei (Giesler et al., 1984), and to the thalamus (Burstein et al., 1990b; Kayalioglu et al., 1999).
tract neurons in the lamina V region are the lateral cervical nucleus (Baker and Giesler, 1984), the dorsal column nuclei (Giesler et al., 1984), the brain stem reticular formation (Chaouch et al., 1983), the midbrain (Menétrey et al., 1982), the cerebellum (Matsushita and Hosoya, 1979; Rivero-Melián and Grant, 1990), the thalamus (Burstein et al., 1990b; Kayalioglu et al., 1999), and the amygdala (Burstein and Potrebic, 1993). Some neurons project to other parts of the spinal cord [Mannen, 1975 (cat)].
LAMINA VI Lamina VI forms the base of the dorsal horn. It consists of a narrow band of darkly stained compactly arranged neurons and is present mainly in the enlargements. The borders with the neighboring laminae V and VII are ambiguous. The dendritic fields of the cells in this layer are similar to those described above for lamina V, although they may be more extensive [Brown, 1981 (cat)]. Cells in this layer have been described to respond to cutaneous and proprioceptive inputs (Wall, 1967). Some respond primarily to noxious stimuli, others are of the wide dynamic range type (Cervero et al., 1988). A subpopulation of the cells in this layer seems to project to ventral horn motoneurons [Hongo et al., 1989 (cat)]. Cells in the medial part of lamina VI in the upper cervical segments give rise to axons projecting to the cerebellum (Matsushita and Xiong, 2001).
LAMINA VII LAMINA V Lamina V forms the neck of the dorsal horn and is the widest layer situated here. The wide lateral part of this layer can easily be recognized by its reticulated appearance; the medial nonreticulated part narrows as it approaches the midline dorsal to the central canal. The neurons in lamina V appear more heterogeneous in shape and size than those in lamina IV, but the border between lamina IV and V is difficult to distinguish, particularly medially. The dendritic fields of the cells in this layer radiate primarily in the transverse plane and to a lesser extent rostrocaudally [Scheibel and Scheibel, 1968 (cat and rat); Mannen, 1975 (cat); Brown, 1981 (cat)]. Correlating morphology with function, Ritz and Greenspan [1985 (cat)]. noted that cells responding to both noxious and light mechanical stimuli were larger than those responding only to noxious or only to light mechanical stimuli. The projection targets of
Lamina VII corresponds to the intermediate zone of the gray matter and to parts of the ventral horn not occupied by laminae VIII and IX. It has a lighter and more homogeneous appearance in Nissl-stained sections than the adjacent laminae. Lamina VII contains the intermediolateral nucleus in segments T1–L3 (preganglionic sympathetic neurons) and L6–S1 (preganglionic parasympathetic neurons) and the intermediomedial nucleus at all levels. The central cervical nucleus can be seen in segments C1–3. Cells in this nucleus, as well as some of the other cells in lamina VII, are known to project to the cerebellum (Matsushita and Hosoya, 1979; Rivero-Melián and Grant, 1990; Matsushita, 1991; Matsushita et al., 1991; Matsushita and Yaginuma, 1995), as well as to the vestibular nuclei (Matsushita et al., 1995; Sato et al.,1997). There are also cells in lamina VII that project to other parts of the spinal cord [Mannen, 1975 (cat)], to the brain stem reticular formation (Chaouch et al., 1983; Shokunbi
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et al., 1985), and to the thalamus (Chaouch et al., 1983; Burstein et al., 1990b).
LAMINA VIII Lamina VIII, located in the ventral or ventromedial part of the ventral horn, has a more heterogeneous appearance and generally slightly larger cells than lamina VII. This lamina contains commissural cells. As with lamina VII, some cells in this region project to the brain stem reticular formation (Chaouch et al., 1983; Schokunbi et al., 1985) and to the thalamus (Burstein et al., 1990b).
LAMINA IX Lamina IX consists of collections of cell groups bordering the lateral and ventral edges of the ventral horn. Many of the darkly stained large cells in these groups are motoneurons projecting through the ventral roots. The groups can often be ascribed to particular muscles or groups of muscles (cf. Swett et al., 1986; RiveroMelián, 1996). The range of soma sizes shows a bimodal pattern, presumably representing larger α-motoneurons and smaller γ-motoneurons (Swett et al., 1986). The dendrites of these neurons have a wide distribution, occasionally extending as far dorsally as lamina III (Cook and Woolf, 1985).
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FIGURE 1, cont’d Schematic drawings of transverse sections from different levels of the spinal cord. Outlines from Figs. 77 and 78 in The Rat Brain in Stereotaxic Coordinates (George Paxinos and Charles Watson, Eds.), Academic Press, San Diego. I–IX, cytoarchitectonic laminae; X, area X; dl, dorsolateral fasciculus; CeCv, central cervical nucleus; D, dorsal nucleus (Clarke); IML, intermediolateral nucleus; IMM, intermediomedial nucleus; LSp, lateral spinal nucleus; LatC, lateral cervical nucleus; py, pyramidal tract.
AREA X Area X is the area surrounding the central canal. It borders the white matter ventrally and dorsally, except for the lumbosacral levels, where it borders dorsally dorsal horn layers crossing the midline. The cells are generally smaller and more densely packed than those
in the adjacent lamina VII. They are pyramidal, stellate, and fusiform, and many of the cells respond to noxious stimuli (Nahin et al., 1983). Cells in the area have been found to project to the brain stem (Menétrey et al., 1982; Nahin et al., 1983; Wang et al., 1999), amygdala (Burstein and Potrebic, 1993), the hypothalamus (Burstein et al., 1987), and the thalamus (Burstein et al.,
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1990b). At lumbosacral levels, a rostrocaudally arranged column of cells has been found to be immunoreactive to different opioids (Nicholas et al., 1999). Subpopulations of these contribute to ascending pathways to the reticular formation of the medulla oblongata (Nahin and Micevych, 1986) and to the thalamus (Ju et al., 1987). A possible involvement of cells in area X in the transmission of visceral nociception has recently been discussed (Wang et al., 1999; see also Willis et al., Chapter 27).
LATERAL SPINAL NUCLEUS The lateral spinal nucleus consists of multipolar neurons in the white matter ventrolateral to the lateral edge of the dorsal horn and is present at all levels of the spinal cord. Cells in this nucleus generally respond only to stimulation of subcutaneous and/or deep structures (Menétrey et al., 1980). They have been shown to project bilaterally to the midbrain (Menétrey et al., 1982; Kayalioglu et al., 1999), hypothalamus (Burstein et al., 1987; Kayalioglu et al., 1999) and the thalamus (Burstein et al., 1990b; Kayalioglu et al., 1999). In addition, neurons in the lateral spinal nucleus as well as the lateral funiculus in the upper cervical spinal cord have been shown to project directly to the sympathetic preganglionic neurons (Jansen and Loewy, 1997).
LATERAL CERVICAL NUCLEUS The lateral cervical nucleus consists of mainly rounded neurons and is found just lateral to the lateral spinal nucleus in the C1–3 segments. All cells in this nucleus respond to hair movement and some to noxious stimulation (Giesler et al., 1979). They project mainly contralaterally to the midbrain (Giesler et al., 1988) and the thalamus (Granum, 1986; Kemplay and Webster, 1986; Burstein et al., 1990b).
References Abbadie, C., Skinner, K., Mitrovic, I., and Basbaum, A. I. (1999). Neurons in the dorsal column white matter of the spinal cord: Complex neuropil in an unexpected location. Proc. Natl. Acad. Sci. USA 98, 9836–9841. Baker, M. L., and Giesler, G. J. (1984). Anatomical studies of the spinocervical tract of the rat. Somatosens. Mot. Res. 2, 1–18. Beal, J. A., Knight, D. S., and Nandi, K. N. (1990). Nerve cell bodies in the dorsal funiculus of the rat spinal cord. Exp. Brain Res. 81, 372–376. Beal, J. A., Nandi, K. N., and Knight, D. S. (1989). Characterization of long ascending tract projection neurons and nontract neurons in the superficial dorsal horn (SDH). In “Processing of Sensory Information in the Spinal Cord” (Cervero, F., Bennett, G. J., and Headly, H. M., Eds.), pp. 181–197. Plenum, New York.
Beal, J. A., Russel, C. T., and Knight, D. S. (1988). Morphological and developmental characterization of local-circuit neurons in lamina III of rat spinal cord. Neurosci. Lett. 86, 1–5. Bester, H., Chapman, V., Besson, J. M., and Bernard, J. F. (2000). Physiological properties of the lamina I spinobrachial neurons in the rat. J. Neurophysiol. 83, 2239–2259. Brown, A. G. (1981). “Organization in the Spinal Cord: The Anatomy and Physiology of Identified Neurons.” Springer-Verlag, Berlin. Burstein, R., Cliffer, K. D., and Giesler, G. J., Jr. (1987). Direct somatosensory projections from the spinal cord to the hypothalamus and telencephalon. J. Neurosci. 7, 4159–4164. Burstein, R., Cliffer, K. D., and Giesler, G. J., Jr. (1990a). Cells of origin of the spinothalamic tract in the rat. J. Comp. Neurol. 291, 329–344. Burstein, R., Dado, R. J., and Giesler, G. J., Jr. (1990b). The cells of origin of the spinothalamic tract of the rat: A quantitative reexamination. Brain Res. 511, 329–337. Burstein, R., and Potrebic, S. (1993). Retrograde labeling of neurons in the spinal cord that project directly to the amygdala or the orbital cortex in the rat. J. Comp. Neurol. 335, 469–485. Cechetto, D. F., Standaert, D. G., and Saper, C. B. (1985). Spinal and trigeminal dorsal horn projections to the parabrachial nucleus in the rat. J. Comp. Neurol. 240, 153–160. Cervero, F., Handwerker, H. O., and Laird, J. M. A. (1988). Prolonged noxious mechanical stimulation of the rat’s tail: Responses and encoding properties of dorsal horn neurones. J. Physiol. (London) 404, 419–436. Chaouch, A., Menétrey, D., Binder, D., and Besson, J. M. (1983). Neurons at the origin of the medial component of the bulbopontine spinoreticular tract in the rat: An anatomical study using horseradish peroxidase retrograde transport. J. Comp. Neurol. 214, 309–320. Cook, A. J., and Woolf, C. J. (1985). Cutaneous receptive field and morphological properties of hamstring flexor α-motoneurones in the rat. J. Physiol. (London) 364, 249–263. Esteves, F., Lima, D., and Coimbra, A. (1993). Structural types of spinal cord marginal (lamina-I) neurons projecting to the nucleus of the tractus solitarius in the rat. Somatosens. Mot. Res. 10, 203–216. Feil, K., and Herbert, H. (1995). Topographic organization of spinal and trigeminal somatosensory pathways to the rat parabrachial and Kolliker–Fuse nuclei. J. Comp. Neurol. 353, 506–528. Fukuyama, U. (1955). On cytoarchitectural lamination of the spinal cord in the albino rat. Anat. Rec. 121, 396. Giesler, G. J., Björkeland, M., Xu, Q., and Grant, G. (1988). Organization of the spinocervicothalamic pathway in the rat. J. Comp. Neurol. 268, 223–233. Giesler, G. J., Cannon, J. T., Urca, G., and Liebeskind, J. C. (1978). Long ascending projections from substantia gelatinosa Rolandi and the subjacent dorsal horn in the rat. Science 202, 984–986. Giesler, G. J., Nahin, R. L., and Madsen, A. M. (1984). Postsynaptic dorsal column pathway of the rat. I. Anatomical studies. J. Neurophysiol. 51, 276–291. Giesler, G. J., Urca, G., Cannon, J. T., and Liebeskind, J. C. (1979). Response properties of neurons of the lateral cervical nucleus in the rat. J. Comp. Neurol. 186, 65–78. Granum, S. L. (1986). The spinothalamic system of the rat. I. Locations of cells of origin. J. Comp. Neurol. 247, 159–180. Han, Z. S., Zhang, E. T., and Craig, A. D. (1998). Nociceptive and thermoreceptive lamina I neurons are anatomically distinct. Nat. Neurosci. 1, 177–178. Hongo, T., Kitazawa, S., Ohki, Y., Sasaki, M., and Xi, M. C. (1989). A physiological and morphological study of premotor interneurones in the cutaneous reflex pathways in cats. Brain Res. 505, 163–166. Hylden, J. L., Anton, F., and Nahin, R. L. (1989). Spinal lamina I projection neurons in the rat: Collateral innervation of parabrachial area and thalamus. Neuroscience 28, 27–37.
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Jansen, A. S., and Loewy, A. D. (1997). Neurons lying in the white matter of the upper cervical spinal cord project to the intermediolateral cell column. Neuroscience 77, 889–898. Jinks, S. L., and Carstens, E. (2000). Superficial dorsal horn neurons identified by intracutaneous histamine: Chemonociceptive responses and modulation by morphine. J. Neurophysiol. 84, 616–627. Ju, G., Melander, T., Ceccatelli, S., Hokfelt, T., and Frey, P. (1987). Immunohistochemical evidence for a spinothalamic pathway cocontaining cholecystokinin- and galanin-like immunoreactivities in the rat. Neuroscience 20, 439–456. Kayalioglu, G., Robertson, B., Kristensson, K., and Grant, G. (1999). Nitric oxide synthase and interferon-γ receptor immunoreactivities in relation to ascending spinal pathways to thalamus, hypothalamus and the periaqueductal grey in the rat. Somatosens. Mot. Res. 16, 280–290. Kemplay, S. K., and Webster, K. E. (1986). A qualitative and quantitative analysis of the distributions of cells in the spinal cord and spinomedullary junction projecting to the thalamus of the rat. Neuroscience 17, 769–789. Kobayashi, Y. (1998). Distribution and morphology of spinothalamic tract neurons in the rat. Anat. Embryol. 197, 51–67. Light, A. R. (1992). The initial processing of pain and its descending control: Spinal and trigeminal systems. In “Pain and headache” (Gildenberg, P. L., Ed.), Vol. 12. Karger, Basel. Light, A. R., and Kavookjian, A. M. (1988). Morphology and ultrastructure of physiologically identified substantia gelatinosa (lamina II) neurons with axons that terminate in deeper dorsal horn laminae (III–V). J. Comp. Neurol. 267, 172–189. Light, A. R., Trevino, D. L., and Perl, E. R. (1979). Morphological features of functionally defined neurons in the marginal zone and substantial gelatinosa of the spinal dorsal horn. J. Comp. Neurol. 186, 151–172. Light, A. R., and Willcockson, H. H. (1999). Spinal laminae I–II neurons in rat recorded in vivo in whole cell, tight seal configuration: Properties and opioid responses. J. Neurophysiol. 82, 3316–3326. Lima, D., and Coimbra, A. (1986). A Golgi study of the neuronal population of the marginal zone (lamina I) of the rat spinal cord. J. Comp. Neurol. 244, 53–71. Lima, D., and Coimbra, A. (1988). The spinothalamic system of the rat: Structural types of retrogradely labelled neurons in the marginal zone (lamina I). Neurosci. Lett. 27, 215–230. Lima, D., and Coimbra, A. (1989). Morphological types of spinomesencephalic neurons in the marginal zone (lamina I) of the rat spinal cord, as shown after retrograde labeling with cholera toxin subunit B. J. Comp. Neurol. 279, 327–339. [Erratum: J. Comp. Neurol. (1989) 286, 542] Lima, D., and Coimbra, A. (1990). Structural types of marginal (lamina I) neurons projecting to the dorsal reticular nucleus of the medulla oblongata. Neuroscience 34, 591–606. Lima, D., and Coimbra, A. (1991). Neurons in the substantia gelatinosa Rolandi (lamina II) project to the caudal ventrolateral reticular formation of the medulla oblongata in the rat. Neurosci. Lett. 132, 16–18. Loewy, A. D. (1970). A study of neuronal types in Clarke’s column in the adult cat. J. Comp. Neurol. 139, 53–80. Mannen, H. (1975). Reconstruction of axonal trajectory of individual neurons in the spinal cord using Golgi-stained serial sections. J. Comp. Neurol. 159, 357–374. Matsushita, M. (1991). Cerebellar projections of the central cervical nucleus in the rat: An anterograde tracing study. Neurosci. Res. 12, 201–216. Matsushita, M., Gao, X., and Yaginuma, H. (1995). Spinovestibular projections in the rat, with particular reference to projections from the central cervical nucleus to the lateral vesticular nucleus. J. Comp. Nuerol. 361, 334–344.
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Matsushita, M., and Hosoya, Y. (1979). Cells or origin of the spinocerebellar tract in the rat, studied with the method of retrograde transport of horseradish peroxidase. Brain Res. 173, 185–200. Matsushita, M., Ragnarson, B., and Grant, G. (1991). Topographic relationship between sagittal Purkinje cell bands revealed by a monoclonal antibody to zebrin I and spinocerebellar projections arising from the central cervical nucleus in the rat. Exp. Brain Res. 84, 133–141. Matsushita, M., and Xiong, G. (2001). Uncrossed and crossed projections from the upper cervical spinal cord to the cerebellar nuclei in the rat, studied by anterograde tracing. J. Comp. Neurol. 432, 101–118. Matsushita, M., and Yaginuma, H. (1995). Projections from the central cervical nucleus to the cerebellar nuclei in the rat, studied by anterograde axonal tracing. J. Comp. Neurol. 353, 234–246. McClung, J. R., and Castro, A. J. (1976). Neuronal organization in the spinal cord of the rat: An analysis of the nine lamina scheme of Rexed. Anat. Rec. 184, p. 474. McMahon, S. B., and Wall, P. D. (1983). A system of rat spinal cord lamina I cells projecting through the contralateral dorsolateral funiculus. J. Comp. Neurol. 214, 217–223. Menétrey, D., Chaouch, A., and Besson, J. M. (1980). Location and properties of dorsal horn neurons at origin of spinoreticular tract in the lumbar enlargement of the rat. J. Neurophysiol. 44, 862–877. Menétrey, D., Chaouch, A., Binder, D., and Besson, J. M. (1982). The origin of the spinomesencephalic tract in the rat: An anatomical study using the retrograde transport of horseradish peroxidase. J. Comp. Neurol. 206, 862–867. Menétrey, D., Giesler, G. J., and Besson, J. M. (1977). An analysis of response properties of spinal cord dorsal horn neurones to nonnoxious and noxious stimuli in the spinal rat. Exp. Brain Res. 27, 15–33. Molander, C., Xu, Q., and Grant, G. (1984). The cytoarchitectonic organization of the spinal cord in the rat. I. The lower thoracic and lumbosacral cord. J. Comp. Neurol. 230, 133–141. Molander, C., Xu, Q., Rivero-Melián, C., and Grant, G. (1989). Cytoarchitectonic organization of the spinal cord in the rat. II. The cervical and upper thoracic cord. J. Comp. Neurol. 289, 375–385. Nahin, R. L., Madsen, A. M., and Giesler, G. J. (1983). Anatomical and physiological studies of the gray matter surrounding the central canal. J. Comp. Neurol. 220, 321–335. Nahin, R. L., and Micevych, P. E. (1986). A long ascending pathway of enkephalin-like immunoreactive spinoreticular neurons in the rat. Neurosci. Lett. 65, 271–276. Nicholas, A. P., Zhang, X., and Hökfelt, T. (1999). An histochemical investigation of the opioid cell column in lamina X of the male rat lumbosacral spinal cord. Neurosci. Lett. 270, 9–12. Oscarsson, O. (1973). Functional organization spinocerebellar paths. In “Handbook of Sensory Physiology” (Iggo, A., Ed.), Vol. 2, pp. 340–380. Springer-Verlag, Berlin. Paxinos, G., and Watson, C. (1986). “The Rat Brain in Stereotaxic Coordinates.” Academic Press, Sydney. Rexed, B. (1952). The cytoarchitectonic organization of the spinal cord in the cat. J. Comp. Neurol. 96, 415–496. Rexed, B. (1954). A cytoarchitectonic atlas of the spinal cord in the cat. J. Comp. Neurol. 100, 297–379. Ritz, L. A., and Greenspan, J. D. (1985). Morphological features of lamina V neurons receiving nociceptive input in cat sacrocaudal spinal cord. J. Comp. Neurol. 238, 440–452. Rivero-Melián, C. (1996). Organization of hindlimb nerve projections to the rat spinal cord: A choleragenoid horseradish peroxidase study. J. Comp. Neurol. 364, 651–663. Rivero-Melián, C., and Grant, G. (1990). Lumbar dorsal root projections to spinocerebellar cell groups in the rat spinal cord: A double labeling study. Exp. Brain Res. 81, 85–94.
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Sato, H., Ohkawa, T., Uchino, Y., and Wilson, V. (1997). Excitatory connections between neurons of the central cervical nucleus and vesticular neurons in the cat. Exp. Brain Res. 115, 381–386. Scheibel, M. E., and Scheibel, A. B. (1968). Terminal axon patterns in cat spinal cord. II. The dorsal horn. Brain Res. 9, 32–58. Schoenen, J. (1982). The dendritic organization of the human spinal cord: The dorsal horn. Neuroscience 7, 2057–2087. Schokunbi, M. T., Hrycyshyn, A. W., and Flumerfelt, B. A. (1985). Spinal projections to the lateral reticular nucleus in the rat: A retrograde labelling study using horseradish peroxidase. J. Comp. Neurol. 239, 216–226. Silverman, J. D., and Kruger, L. (1988). Lectin and neuropeptide labeling of separate populations of dorsal root ganglion neurons and associated “nociceptor” thin axons in rat testis and cornea whole-mount preparations. Somatosens. Res. 5, 259–267. Silverman, J. D., and Kruger, L. (1990). Selective neuronal glycoconjugate expression in sensory and autonomic ganglia: Relation of lectin reactivity to peptide and enzyme markers. J. Neurocytol. 19, 789–801. Steiner, T. J., and Turner, L. M. (1972). Cytoarchitecture of the rat spinal cord. J. Physiol. (London) 222, 123–125. Swett, J. E., Wikholm, R. P., Blanks, R. H. I., Swett, A. L., and Conley, L. C. (1986). Motoneurons of the rat sciatic nerve. Exp. Neurol. 93, 227–252.
Szentágothai, J. (1964). Neuronal and synaptic arrangement in the substantia gelatinosa Rolandi. J. Comp. Neurol. 122, 219–239. Tavares, I., Lima, D., and Coimbra, A. (1993). Neurons in the superficial dorsal horn of the rat spinal cord projecting to the medullary ventrolateral reticular formation express c-fos after noxious stimulation of the skin. Brain Res. 623, 278–286. Wall, P. D. (1967). The laminar organization of dorsal horn and effects of descending impulses. Physiol. (London) 1888, 403–423. Wang, H., Rivero-Melián, C., Robertson, B., and Grant, G. (1994). Transganglionic transport and binding of the isolectin B4 from Griffonia simplicifolia I in rat primary sensory neurons. Neuroscience 62, 539–551. Wang, C.-C., Willis, W. D., and Westlund, K. N. (1999). Ascending projections from the area around the spinal cord central canal: A Phaseolus vulgaris leucoagglutinin study in rats. J. Comp. Neurol. 415, 341–367. Woodbury, C. J., Ritter, A. M., and Koerber, H. R. (2000). On the problem of lamination in the superficial dorsal horn of mammals: A reappraisal of the substantia gelatinosa in postnatal life. J. Comp. Neurol. 417, 88–102. Woolf, C. J., and Fitzgerald, M. (1983). The properties of neurones recorded in the superficial dorsal horn of the rat spinal cord. J. Comp. Neurol. 221, 313–328.
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C H A P T E R
6 Substantia Gelatinosa of the Spinal Cord ALFREDO RIBEIRO-DA-SILVA Departments of Pharmacology & Therapeutics and Anatomy & Cell Biology McGill University, Montréal, Québec, Canada
The superficial layers of the dorsal horn of the spinal cord and of the trigeminal subnucleus caudalis, particularly the substantia gelatinosa (or lamina II of Rexed), are the areas that have been traditionally associated with the modulation of nociceptive information since the classical clinical studies of Ranson (1914). Considerable attention to this area was triggered in the 1960s and 1970s by the publication of physiologically based pain theories (Cervero and Iggo, 1978; Melzack and Wall, 1965), which postulated the existence of synaptic circuits involving interneurons and afferent fibers conveying distinct inputs. These theories introduced the basic concept that nociceptive transmission can be modified by the concomitant activation of other fiber systems. In recent years, there has been considerable progress in understanding the anatomical and neurochemical characteristics of the relevant cells and systems. However, our knowledge of this area is still far from complete, and, unfortunately, too many oversimplified schemes can be found in textbooks and even in reviews. In this chapter, I provide an overview of the substantia gelatinosa of the spinal cord in the rat, with emphasis on its anatomical, ultrastructural, and immunocytochemical aspects. Although I will focus on lamina II, or the substantia gelatinosa proper, I will also describe briefly lamina I (marginal layer) and lamina III (superficial part of the nucleus proprius) because of their close interrelations and physiological relevance. Certain issues are discussed elsewhere in this volume and will be described here only very briefly. For an overview of the spinal cord cytoarchitecture see Grant and Koerber, Chapter 5. Readers interested in primary
The Rat Nervous System, Third Edition
sensory fibers should consult Grant and Robertson, Chapter. The ascending projections of the spinal cord are discussed briefly here. Readers interested in the ascending and descending pathways in the spinal cord are advised to consult the chapter by Tracey (see Chapter 7). An integrated view of pain mechanisms is presented in the chapter by Willis and collaborators (see Chapter 27).
DEFINITION The substantia gelatinosa of the spinal cord was given its name by Rolando in 1824 (quoted by Ramón y Cajal, 1909), based on the translucent and gelatinous appearance it possesses when examined in fresh tissue. In the cat, Rexed (1952) utilized 100-μm-thick freezing microtome sections stained for Nissl substance to subdivide the spinal cord into several horizontal laminae, based on cell density and size and the morphology of the Nissl bodies. Lamina II had a particularly high cellular density, because of the occurrence of many small neurons. Rexed made lamina II correspond to the substantia gelatinosa, which he divided into dorsal (more cellular) and ventral (less cellular and thicker) parts. More recent studies usually subdivide lamina II into outer lamina II (or lamina IIo) and inner lamina II (or lamina IIi). Rexed’s cytoarchitectonic classification has been adapted to the rat (see Grant and Koerber, Chapter 5) and to other species, such as the monkey (Ralston, III, 1979). The laminar pattern can also be recognized in samples examined with dark
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field (e.g., cryostat sections processed for receptor binding studies), stained with fiber stains (e.g., the Mahon method), or osmicated and Epon-embedded (see Light, 1992, for details). Using Epon-embedded 1or 2-μm-thick semi-thin sections, lamina I can be separated from outer lamina II by the abundant small myelinated fibers in the former; these are less abundant in outer lamina II and are almost entirely absent from inner lamina II. The lamina II–III border is easy to identify on semi-thin sections because of the numerous small myelinated fibers that occur in lamina III. At the light microscopic level, the subdivisions of the superficial laminae in the rat are therefore very similar to those observed in other mammals such as the cat and monkey. Unfortunately, the ultrastructural observation of the rat dorsal horn creates unexpected problems. In fact, in contrast with the dorsal horn of the monkey and cat (Ralston, III, 1968, 1979; Ribeiro-da-Silva and Coimbra, 1982), outer lamina II in the rat is virtually devoid of synaptic glomeruli (see below for details) (Ribeiro-da-Silva and Coimbra, 1982). Inner lamina II has a narrow dorsal band which is rich in synaptic glomeruli of type I (with an electron-dense central varicosity) and has very few of type II (which possess a light and large central varicosity) (Ribeiro-da-Silva and Coimbra, 1982). The more extensive ventralmost part of lamina II is rich in synaptic glomeruli of type II and has very few glomeruli of type I (Ribeiro-da-Silva and Coimbra, 1982). In contrast, in the cat and monkey, the glomeruli of the dense type prevail in lamina IIo (Knyihár-Csillik et al., 1982b; Maxwell et al., 1990). This difference in the distribution of synaptic glomeruli is very likely the result of interspecies differences in the distribution of primary sensory fibers. Therefore, while the cytoarchitectonically defined outer lamina II looks similar in rat, cat, and monkey, there are probably differences among species in primary afferent input. It is as if outer lamina II in the rat had certain features of lamina I. As a result of these interspecies differences in the distribution of synaptic glomeruli, I usually prefer to use an alternative nomenclature when dealing with rat dorsal horn: lamina IIA (instead of lamina IIo) and lamina IIB (instead of lamina IIi). Further, I subdivide lamina IIB into two sublaminae: sublamina IIBd (corresponding to the dorsalmost part of inner lamina II) and sublamina IIBv (corresponding to most of inner lamina II). In cross sections of the cervical dorsal horn (C4–C5 level) of young adult rats (200–250 g in weight), lamina I is approximately 20 μm thick, lamina IIA and sublamina IIBd are 20 μm each, and Sublamina IIBv is 40 to 60 μm-thick (Ribeiro-da-Silva and Coimbra, 1982). A diagram of these laminar subdivisions is shown in Fig. 1. At lumbar levels, which are frequently used for studies on animal models of chronic pain, the major
difference is that the thickness of the most superficial laminae is less in the lateral than in the intermediate and medial parts. However, at midlumbar levels, Todd et al. (1998) propose a lamina I in the middle much thicker than that in the lateral and medial parts of the dorsal horn. This view is based on the distribution of projection neurons and pattern of immunostaining for substance P receptors and does not follow the standard cytoarchitectonic criteria. Todd et al. (1998) compare this region of possibly thicker lamina I to the “dorsal cap” described in the cat by Snyder (1982). In my opinion, when defining the limits of the main laminae, it is important to stick to the parameters defined in studies using classical cytoarchitectonic methods, as outlined in the chapter by Grant and Koerber (see Chapter 5). Unfortunately, this is not often followed. As a consequence of the use of poorly defined criteria when delimiting dorsal horn laminae, many published micrographs and diagrams show a lamina I that is too thick and includes part of lamina II. One approach to define the laminae on sections processed for immunocytochemistry is to stain an adjacent section using a Nissl method. The Rexed lamination can be easily marked on a micrograph of the Nisslstained section and a transparency with the lamination overlaid on images from the sections that were immunostained. An example of the use of this approach is shown in Fig. 2.
CHARACTERISTICS OF NEURONS OF THE SUPERFICIAL LAMINAE OF THE SPINAL CORD Lamina I Lima and Coimbra (1986) have described four morphological types of neurons in the rat using the Golgi method, a classification still followed by most researchers. Fusiform neurons are elongated rostrocaudally and are more abundant in the lateral part of the lamina. Multipolar neurons have characteristically radiating dendritic trees and prevail in the medial part of the lamina. Pyramidal neurons have cell bodies of triangular shape and occur throughout the entire mediolateral extension of lamina I, always at the edge of the white matter. Flattened cells have dendritic trees that spread in the mediolateral and rostrocaudal axes. Cells of each of the four types are occasionally (6% of the total) two to three times the regular size (Lima and Coimbra, 1986). The larger versions of the pyramidal and flattened cells probably represent the classical Waldeyer cells (Lima and Coimbra, 1988; Puskar et al., 2001). Lamina I is considered an important
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FIGURE 1 Rexed’s laminae of the rat spinal cord at C4 level and details of subdivisions of lamina II. (A) On top, drawing of the limits of Rexed’s laminae. The framed area (enlarged underneath) represents the part that is equidistant from both the medial and the lateral edges of the dorsal horn. The equivalence of the two possible ways of subdividing lamina II is shown in the enlarged area. I have suggested a different nomenclature for the rat from that used for the cat, on the basis of ultrastructure and termination of sensory fibers. Panels B and C are shown at the same magnification as that of the lower part of panel A to facilitate the correlation of the lamination in Epon-embedded semi-thin section (B) and Nissl preparation (C). (B) Micrograph obtained from a 5-μm-thick plastic section of material incubated for the demonstration of acid phosphatase (FRAP) activity (arrows). Note that the FRAP-reactive band corresponds very closely to the limits of sublamina IIBd. (C) Micrograph originated from a 50-μm-thick section stained for Nissl. It shows the characteristic aggregation of neurons in lamina IIA. DC, dorsal columns. Scale bar (for both micrographs) = 20 μm.
projection area to higher structures. Main projection sites from lamina I are the thalamus (for reviews see Lima and Coimbra, 1988; Todd et al., 2000) and certain areas of the brain stem, particularly the lateral reticular nucleus, the parabrachial nucleus, and the periaqueductal gray matter (for reviews see Lima, 1997; Todd et al., 2000). Although it has been proposed, based on some experimental evidence, that the morphological types of lamina I neuron differ in their neurotransmitter/modulator content and supraspinal projection pattern (Lima, 1997), this issue remains controversial. In fact, evidence is accumulating that favors a correlation between the morphological and physiological properties of neurons in lamina I (Prescott and De Koninck, 2002).
Lamina II Despite several studies, our understanding of lamina II neurons in the rat is less than it is in the cat. In the latter species, lamina II cells have been extensively studied using anatomical and physiological approaches. Cells of lamina II have been classified since the work of Ramón y Cajal (1909) into two main morphological types: the central cell, which is widespread throughout the lamina, and the limiting cell, which occurs in an outer band close to the laminae I–II border. These types were identified by Gobel (1975, 1978) in the cat and named islet cells and stalked cells, respectively. In the rat, Todd and Lewis (1986) using the Golgi method confirmed the occurrence of
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FIGURE 2 Laminar distribution of CGRP and IB4 in the rat lumbar dorsal horn, as an example of the application of Rexed’s lamination to confocal microscope images. A section, adjacent to the one that was processed for immunocytochemistry, was stained with a Nissl method and the laminar limits were marked on a transparent sheet. This was placed over the images at the same magnification as that obtained with the confocal microscope. The limit of lamina IIBd was defined based on our previous work that shows that its thickness is approximately the same as that of lamina IIA. Both panels A and B were derived from the same confocal micrograph, corresponding to an optical section about 1 μm in thickness, after elimination in the confocal microscope software of the display corresponding to the other channel. In A, corresponding to immunostaining for CGRP, note that the fiber terminal density is high in laminae I–IIBd and low in lamina IIBv. In B, corresponding to lection IB4 binding, note that the highest density of fiber terminals is in the middle third of lamina II.
both stalked and islet cells in lamina II. The stalked cells corresponded to half of the stained cells in the outer part of lamina II, whereas islet cells were found throughout the entire lamina and corresponded to about one third of the entire stained neuronal population. However, Todd and Lewis (1986) also reported that about half of the cells in lamina IIBv could not be classified as either stalked or islet cells, although they could be subdivided into groups based on their dendritic arborization. The axons of these cells either passed to lamina III or remained in lamina II. Some of these cells may correspond to the stellate and LII–III border cells previously described in other species (Todd and Lewis, 1986). In the cat, both islet and stalked cells were electrophysiologically characterized, filled with horseradish peroxidase (HRP), and studied at the light and electron microscopic levels by Bennett, Gobel, and collaborators (Bennett et al., 1980; Gobel et al., 1980). At least some stalked cells, with an axonal arborization in lamina I, seem to relay excitatory impulses to lamina I cells and, therefore, represent feed-forward excitatory interneurons. The main electrophysiological findings have been that the physiological properties of islet cells differed according to their localization, as those situated in deep lamina II did not respond to noxious stimuli while those in outer lamina II responded specifically to these stimuli. This agrees with previous studies in the cat by Light and collaborators (1979) who found that the cells in the outer half of lamina II responded to noxious cutaneous stimuli while those in the inner half
of lamina II only responded to innocuous stimuli. Also in the cat, when examining lamina II cells, the type of response elicited seemed to have little correlation with their morphology (light et al., 1979) but depended more on the localization of the dendritic arborization. As dendrites receive most of the information from incoming fibers, the fibers which terminate deeply in lamina II seemed not to transmit nociceptive information in the cat (Light and Perl, 1979). However, this is not likely the case in the rat because of the differences in the termination pattern of sensory fibers. In fact, as explained below, the nonpeptidergic subpopulation of small-diameter sensory fibers in rodents terminates mostly in the outermost part of inner lamina II (sublamina IIBd), and the available evidence indicates that these fibers are nociceptive (Alvarez and Fyffe, 2000; Snider and McMahon, 1998). In agreement with this, studies in C fibers which combine intracellular recording with intracellular injection with a marker revealed a considerable termination of unmyelinated polymodal nociceptive fibers in a certain region of ventral lamina II in the guinea pig (Sugiura et al., 1986). The available evidence indicates that in animals such as the guinea pig and the rat, unmyelinated fibers terminate deeper in lamina II than they do in cats and monkeys. Originally, lamina II was considered to be a closed system (Szentágothai, 1964), receiving afferents but not projecting to any area of the brain. However, there is now evidence that a small number of lamina II neurons project to the brain (thalamus, lateral cervical
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nucleus, or pontine–medullary junction) (for review see Willis and Coggeshall, 1991). One study claims that a considerable number of islet cells project to the reticular formation of the medulla (Lima and Coimbra, 1991).
Lamina III In the cat, neurons of lamina III have been described as a heterogeneous population of nonnociceptive cells (Maxwell et al., 1983), based on intracellular injections of physiologically characterized neurons. However, the concept that the cells are all nonnociceptive needs revision at least for the rat, based on the detection in laminae III and IV of neurons that express the substance P receptor and possess dorsally oriented dendrites that branch in laminae I and II (Brown et al., 1995; Littlewood et al., 1995; Liu et al., 1994a; Naim et al., 1997). Most of these neurons project to supraspinal levels (Todd et al., 2000). Little is known concerning the other lamina III neuronal populations in rat.
ULTRASTRUCTURE OF THE SPINAL DORSAL HORN The features that allow the characterization of each lamina and sublamina under the electron microscope are the density of small myelinated fibers and the distribution of synaptic glomeruli (see above). Readers interested in a detailed description of the general ultrastructural characteristics of each lamina and sublamina should consult Ribeiro-da-Silva and Coimbra (1982). In this chapter, we focus on synaptic glomeruli.
Synaptic Glomeruli The ultrastructure of the spinal and medullary dorsal horn has been studied in detail in the rat (Coimbra et al., 1974; Ribeiro-da-Silva et al., 1985; Ribeiro-da-Silva and Coimbra, 1982). The most striking ultrastructural feature of the dorsal horn is the presence of synaptic glomeruli, which are complex synaptic arrangements in which a “central” (core) axonal bouton is surrounded by several dendrites and axonal boutons (surrounding boutons). The core (C) axonal bouton is of primary sensory origin, as demonstrated by studies showing their degeneration after multiple dorsal root transections or labeling after the injection of tracers (Coimbra et al., 1984; Cruz et al., 1987). The C bouton interacts with the dendrites of spinal cord interneurons (Gobel et al., 1980) or projection neurons (Maxwell et al., 1985). Some of these dendrites contain synaptic vesicles (presynaptic dendrites) and are presynaptic to the C bouton and/or to other dendrites (Gobel, 1976;
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Ribeiro-da-Silva et al., 1985). Surrounding glomerular axonal boutons, most likely originating from neurons intrinsic to the dorsal horn (see below under Neurochemistry of the Dorsal Horn), are presynaptic to the glomerular C boutons and to glomerular dendrites. Synaptic glomeruli are thought to play an important role in sensory mechanisms because they constitute a significant part of the synaptic population of the superficial dorsal horn (Duncan and Morales, 1978; Murray and Goldberger, 1986) and display complex synaptic arrangements (Gobel, 1976; Knyihár-Csillik et al., 1982a; Ribeiro-da-Silva et al., 1985). See Fig. 3 for details of the ultrastructure of a synaptic glomerulus. The literature does not have a consistent definition of what should be considered a synaptic glomerulus. However, a proper definition is essential, as glomeruli can be excellent markers to identify the termination of sensory fibers at the ultrastructural level. Terminals of fibers originating from the brain stem or from neurons intrinsic to the spinal cord (identified by antigenic markers such as serotonin and GABA) are sometimes the core element of synaptic arrangements that are simpler than synaptic glomeruli. On an isolated electron micrograph, a complex synaptic arrangement can be classified as a synaptic glomerulus if it meets all of the following criteria: (a) it must have a C bouton possessing agranular round synaptic vesicles, (b) the C bouton must be in apposition to at least four “surrounding” dendritic profiles (one or more can be replaced by axonal boutons and presynaptic dendrites), and (c) two or more synaptic specializations must be found between C and surrounding profiles. Types of surrounding profiles are: (1) dendrites devoid of synaptic vesicles (“plain” or “common” dendrites – D), (2) vesicle-containing or presynaptic dendrites (V1), and (3) surrounding axonal boutons (V2). In the rat (but not in the cat or monkey), lamina I has very few synaptic glomeruli. Glomeruli become abundant only in lamina IIB, particularly in sublamina IIBd. Glomeruli are rather frequently encountered in lamina III.
Types of Synaptic Glomeruli Two main types of synaptic glomeruli have been described in the rat (Ribeiro-da-Silva and Coimbra, 1982). Type I glomeruli possess a relatively small C bouton of scalloped contour, with closely packed synaptic vesicles and very few mitochondria (Fig. 3). Two varieties can be described. Glomeruli of type Ia (or type I “nonpeptidergic”) have a particularly electrondense C bouton, with vesicles displaying a very wide variation in diameters, and have on average one V 1 and one V2 terminal per glomerulus. Glomeruli of type Ib (or type I “peptidergic”) possess more than three
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FIGURE 3 Diagrammatic representation of a synaptic glomerulus. The drawing was based on an electron micrograph of a type Ia glomerulus and shows the morphological features and the synaptic circuits involving the core and surrounding profiles. C, central or core bouton; D, “regular” dendrite; V1, presynaptic dendrite; V2, peripheral axonal bouton; G, glial profile.
dense-core vesicles in the C bouton, are immunoreactive for sensory peptides, and have simplified synaptic architecture (virtually all surrounding profiles are dendrites postsynaptic to the central bouton). Type II glomeruli have a larger C bouton, of less scalloped contour, which is lighter and richer in mitochondria than their type I counterparts. Furthermore, type II glomeruli are richer in surrounding axonal boutons (V2) than type I glomeruli. Two varieties of type II glomeruli can be recognized (Fig. 4): type IIa (devoid of neurofilament bundles in the C bouton) and type IIb (with neurofilament bundles in the C bouton). Type IIb glomeruli are particularly rich in V2 boutons. For a more detailed description of glomerular types the reader should consult Ribeiro-da-Silva et al. (1985, 1989). Figure 4 displays diagrammatically the glomerular types in lamina II and gives the relative frequency in which they occur at cervical levels C4–C5 in rat.
Functional Role of Synaptic Glomeruli The functional role of glomeruli is far from known. Most varicosities in primary sensory fibers are unrelated to glomeruli (see e.g., Coimbra et al., 1984). However, the available evidence strongly indicates that glomeruli are “multiplier systems,” i.e., devices via which primary
sensory information is transmitted to several dorsal horn neurons by means of a single axonal bouton. In turn, synaptic glomeruli are important integrators, being often postsynaptic to other neuronal profiles. Therefore, synaptic glomeruli are very important elements in sensory transmission. Most likely, the C boutons of type I glomeruli (CI) represent unmyelinated nociceptive fibers, because they correspond to the termination of fibers that are capsaicin-sensitive (Ribeiroda-Silva and Coimbra, 1984). However, capsaicin also damages the smaller Aδ fibers; therefore some CI boutons may represent the termination of Aδ fibers. It is tempting to state that all C boutons of type I glomeruli represent the termination of nociceptive sensory fibers. If this is the case, then type I glomeruli are of the utmost importance for the transmission of pain-related information. Most peptidergic small-diameter primary afferents are nonglomerular. However, about 20% of type I glomeruli are of the peptidergic type. These peptidergic (or Type Ib) glomeruli are most likely only multiplier systems, because their peptide-containing core boutons share an important characteristic with nonglomerular endings of the same fiber population: the fact that they are virtually never postsynaptic to other neuronal profiles. This is in complete contrast with the arrangement of type I glomeruli of the
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FIGURE 4 Diagrammatic representation of the morphological properties and relative incidence of the several types of synaptic glomeruli in lamina II.
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Results of the colocalization of substance P and CGRP were based on a double-labeling study involving a combination of an anti-substance P internally radiolabeled monoclonal antibody with anti-CGRP antibody (Ribeiro-da-Silva, 1994); results of the colocalization of CGRP and somatostatin were based on a study combining preembedding (somatostatin) and postembedding (CGRP) immunocytochemistry (Ribeiro-da-Silva, 1994). As recent studies have shown that boutons colocalizing SOM and CGRP also bind IB4 (see, e.g., Alvarez and Fyffe, 2000), a dashed arrow was added to the figure to illustrate that very likely the subdivision between peptidergic and nonpeptidergic type I glomeruli is not absolute. D, “regular” dendrite; V1, presynaptic dendrite; V2, peripheral axonal bouton; G, glial profile; neurofil., neurofilaments; glom., glomerular; FRAP, fluoride-resistant acid phosphatase; SOM, somatostatin; CGRP, calcitonin gene-related peptide; SP, substance P.
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nonpeptidergic type (type Ia) in which both presynaptic dendrites and peripheral axons are presynaptic to the core bouton and therefore are likely also very important integrating devices. These nonpeptidergic terminals correspond to the fibers that express the P2X3 receptor and bind the lectin IB4. In relation to type II glomeruli, we can extrapolate from ultrastructural studies of physiologically characterized fibers in the cat which show glomerular morphology very similar to that of the C boutons of Type II glomeruli (CII) (for review see Maxwell and Réthelyi, 1987). Therefore, the C boutons of type IIa glomeruli probably represent the termination of Aδ D-hair fibers, and those of type IIb (with neurofilaments) the termination of thicker fibers. In the rat, both varieties of type II glomeruli display rather complex synaptic arrangements, involving both presynaptic dendrites (V1) and surrounding axonal boutons (V2 in type IIa or V2 in type IIb).
Electron Microscopic Properties of Lamina II Neurons Stalked and islet cells were studied at the ultrastructural level by Todd (1988), using the Golgi method. As previously demonstrated in the cat, stalked cells did not give origin to presynaptic dendrites, in contrast with islet cells. Both cell types participated in synaptic glomeruli through their dendritic processes.
NEUROCHEMISTRY OF THE DORSAL HORN Since the publication of the previous edition of this book, significant advances have been made in our understanding of the chemical substances that occur in the superficial laminae of the dorsal horn. Unfortunately, there are no recent reviews on the topic. What follows is a brief integrated overview of the most studied neurochemicals in the region and, when applicable, of their respective receptors.
nated or thinly myelinated sensory fibers that terminate mainly in laminae I and II (Cuello and Kanazawa, 1978; Hökfelt et al., 1975). Immunoreactivity for substance P is particularly intense in lamina I and outer lamina II, but decreases substantially in inner lamina II (Ribeiro-daSilva et al., 1989). In lamina III, SP immunoreactivity is reduced even further and represents mostly fibers crossing toward deeper laminae. In laminae IV–V, there are clusters of substance P-immunoreactive (IR) fibers and boutons separated by areas with sparse immunoreactivity (Ruda et al., 1986). It should be clearly stated that, contrary to common belief, not all substance P immunoreactivity in the superficial dorsal horn is of primary sensory origin as multiple dorsal rhizotomies and capsaicin treatment are unable to fully deplete substance P immunoreactivity. Furthermore, substance P-containing cell bodies have been identified in spinal laminae I and II, both with immunocytochemistry (Ljungdahl et al., 1978; Ribeiro-da-Silva et al., 1991) and in situ hybridization (Warden and Young, 1988). Also, although most substance P-containing systems descending from the brain stem terminate in the ventral horn (Gilbert et al., 1982; Hökfelt et al., 1978), some may terminate in the superficial laminae of the dorsal horn. It is interesting to note that most, if not all, substance P-IR cell bodies in the spinal dorsal horn colocalize enkephalin immunoreactivity (Ribeiro-da-Silva et al., 1991). At the ultrastructural level, substance P immunoreactivity in the central boutons of synaptic glomeruli is particularly meaningful, because such profiles are of known sensory origin (Coimbra et al., 1984; Murray and Goldberger, 1986). Substance P immunoreactivity has also been detected in glomerular C boutons in several animal species, including the rat (Ribeiro-daSilva et al., 1989; Ribeiro-da-Silva and Cuello, 1987). In the rat, substance P immunoreactivity has been detected in 10% of the C boutons of synaptic glomeruli in lamina II (Figs. 4 and 5A). All these glomerular boutons had large dense-core vesicles (characteristic of glomeruli of the type Ib variety).
Other Neurokinins Neurokinins The three main mammalian neurokinins are substance P, neurokinin A, and neurokinin B. They all occur in the superficial laminae of the dorsal horn. Substance P There is now unquestionable evidence of the involvement of the neurokinin substance P in the processing of sensory information in the region of the first sensory synapse (for reviews see Cuello, 1987; Henry, 1982; Otsuka and Yanagisawa, 1990). Immunocytochemically, substance P has been shown to occur in either unmyeli-
Virtually all substance P-containing neurons in the rat express precursors that produce both substance P and neurokinin A (Carter and Krause, 1990) which means that their distribution is essentially the same. However, neurokinin B derives from a different precursor and, in contrast to substance P, it does not occur in primary sensory neurons (Ogawa et al., 1985). A recent light and electron microscopic immunocytochemical study of neurokinin B in the dorsal horn of the spinal cord revealed that, in the superficial laminae, its signal was detected in axon terminals in laminae I–II, with a peak in lamina IIB, as well as in cell bodies and dendrites
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mostly in lamina IIB (McLeod et al., 2000). Lamina III showed much less immunolabeling. So, in contrast to substance P, immunoreactivity for neurokinin B increased from lamina I to lamina IIB. Interestingly, neurokinin B immunoreactivity occurred in dendrites of type I glomeruli, suggesting a participation in the modulation of nociception (McLeod et al., 2000). Neurokinin Receptors The original descriptions of substance P receptor (neurokinin-1 receptor) immunoreactivity in the dorsal horn reported that it was present in neurons with cell bodies located in lamina I and in deeper layers (laminae III–IV) (Liu et al., 1994a; Nakaya et al., 1994). According to these reports, the substantia gelatinosa proper did not have any cell bodies immunoreactive for the neurokinin-1 receptor (NK-1r) and possessed much less immunoreactivity than lamina I, as this was restricted to cell processes mostly from neurons in deeper laminae. However, more recent studies reported immunoreactivity for the NK-1r in cell bodies in both lamina I and outer lamina II (LIIA) (McLeod et al., 1998; Ribeiro-daSilva et al., 2000). It should be pointed out that most of these NK-1r-IR neurons project to higher levels: the thalamus (Marshall et al., 1996), the parabrachial nucleus (Ding et al., 1995; Todd et al., 2000), the lateral reticular nucleus, the dorsal part of caudal medulla, and, to a minor extent, the periaqueductal gray (Todd et al., 2000). In contrast with the NK-1r, the receptor for neurokinin A (neurokinin-2 receptor) hardly occurs in the CNS (for review see Ribeiro-da-Silva et al., 2000), indicating that either neurokinin A acts through another receptor in the CNS or it acts mainly in the periphery. In the superficial laminae of the dorsal horn, some immunoreactivity for the neurokinin-2 receptor was detected in a narrow band in the lateral part of lamina I, but seemed to be located in glial cells (Zerari et al., 1998). Concerning the preferential receptor for neurokinin B, the neurokinin-3 receptor, it occurs in cell bodies located in laminae I and, mostly, in lamina II of the spinal cord (Ding et al., 1996; Mileusnic et al., 1999; Zerari et al., 1997).
Calcitonin Gene-Related Peptide (CGRP) ‘Immunoreactivity for CGRP has been shown to occur in dorsal root ganglia and in primary sensory fibers which project mainly to the superficial laminae of the spinal cord (Ju et al., 1987; Wiesenfeld-Hallin et al., 1984). In the dorsal horn, CGRP-IR boutons occur mostly in laminae I, IIA, and IIBd (Fig. 2), as well in patches in lamina V. One of the interesting features of CGRP immunoreactivity in sensory systems is its colocalization with substance P (Ju et al., 1987; Wiesenfeld-Hallin et al., 1984). In reality, substance P immunoreactivity is almost invariably colocalized with CGRP in dorsal root
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ganglion cells, although CGRP immunoreactivity occurs in a considerably higher percentage of these cells than substance P (Ju et al., 1987). Another interesting feature of CGRP immunoreactivity in the dorsal horn is its almost complete disappearance after dorsal rhizotomy (Chung et al., 1988; Traub et al., 1989). This finding suggests that all CGRP immunoreactivity in the dorsal horn originates from primary sensory fibers, a finding that is confirmed by in situ hybridization studies which do not reveal any dorsal horn neurons synthesizing the peptide (Réthelyi et al., 1989). Therefore, it seems legitimate to use the colocalization of CGRP and substance P in the same terminal as a marker of primary sensory origin. At the ultrastructural level, CGRP occurs mostly in nonglomerular varicosities in the dorsal horn of the rat spinal cord, although a few varicosities are of the glomerular type (Merighi et al., 1989, 1991; Ribeiro-daSilva and Cuello, 1991). Most CGRP immunoreactivity in the dorsal horn is colocalized with either substance P (Fig. 5A) or somatostatin immunoreactivities (Fig. 5B) (Ribeiro-da-Silva, 1994). The distribution of CGRP receptors in the spinal cord has been studied with ligand binding approaches. They occur in high densities in lamina I and in deeper laminae but occur in low densities in lamina II (Yashpal et al., 1992). However, following peripheral denervation, considerable CGRP binding was detected in lamina II, indicating that the neurons have the capacity to produce the receptor (Kar et al., 1994)
Somatostatin Somatostatin-like immunoreactivity occurs both in primary sensory fibers and in neurons of the spinal cord (Alvarez and Priestley, 1990a; Hökfelt et al., 1976; Ribeiro-da-Silva and Cuello, 1990b). In the superficial laminae, somatostatin-IR neurons occur mainly in lamina II (Alvarez and Priestley, 1990a; Ribeiro-daSilva and Cuello, 1990b). Somatostatin receptors form a family of five receptors (sst1 to sst5), all belonging to the G protein-coupled receptor superfamily (Dournaud et al., 2000). Immunoreactivity for receptor subtypes has been detected in cell bodies and processes in the superficial laminae of the dorsal horn (Schulz et al., 1998; Von Banchet et al., 1999).
Opioid Peptides Enkephalin Since their discovery, endogenous opioid peptides have been considered important candidates for presynaptic interactions in the dorsal horn of the spinal cord. The opioid peptides met- and leu-enkephalin occur in high concentrations in lamina I and II of the spinal
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FIGURE 5 Examples of neurochemicals and their colocalizations in synaptic glomeruli as detected by immunocytochemistry. A Core (C) bouton of a type Ib synaptic glomerulus colocalizing CGRP (immunogold particles) and substance P (dense precipitate). Note the immunogold-labeled dense-core vesicles (arrowheads) in the C bouton (CIb). The C bouton was never found postsynaptic to surrounding profiles in this peptidergic glomerulus. Sublamina IIBd. (B) Core (C) bouton of a type Ib synaptic glomerulus colocalizing CGRP (immunogold particles) and somatostatin (dense precipitate). Note the immunogold-labeled dense-core vesicles (arrowheads) in the C bouton (C Ib). As in A, the C bouton was never found postsynaptic to surrounding profiles in this peptidergic glomerulus. Sublamina IIBd. (C) Immunocytochemistry of GABA as demonstrated by means of an anti-GABA polyclonal antibody revealed by an anti-rabbit IgG conjugated to 10-nm gold particles (postembedding protocol). Two type I glomeruli of the nonpeptidergic subtype are shown. Note the intrinsic electron-dense core boutons (CIa) typical of this glomerular variety. Some of the glomerular surrounding profiles show GABA immunoreactivity (gold particles). D, “regular” dendrite; V1, presynaptic dendrite; V2, surrounding axonal bouton. GABA+, profiles possessing GABA immunoreactivity. Sublamina IIBd. Scale bars (in both micrographs) = 1 μm.
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cord (Höfelt et al., 1977; Hunt et al., 1981) and have been demonstrated in nerve cell bodies in laminae I–III (Del Fiacco and Cuello, 1980; Hunt et al., 1981; Miller and Seybold, 1989). Double-labeling studies combining radioimmunocytochemistry and DAB-based immunocytochemistry have demonstrated that sometimes enkephalin and substance P-IR varicosities establish separate synapses on a common dendrite and that substance P-IR C glomerular boutons are presynaptic to enkephalin-IR dendrites in the rat (Cuello, 1983; Ribeiro-da-Silva et al., 1991). Enkephalin-IR boutons were never presynaptic to substance P-IR boutons (Ribeiro-da-Silva et al., 1991). Such results demonstrate (together with data indicated below) that substance Pcontaining glomerular C boutons excite dendrites of enkephalinergic interneurons in the substantia gelatinosa and that the axons of such neurons inhibit the dendrites of neurons that have been excited by substance P. The discovery of substance P and enkephalin colocalization in a considerable number of neurons and axonal varicosities in both rat and cat (Ribeiro-daSilva et al., 1991; Senba et al., 1988; Tashiro et al., 1987) added a new dimension to the problem. In reality, almost all substance P-IR neurons in the rat dorsal horn colocalize enkephalin and approximately 50% of enkephalin-IR cells colocalize substance P (Ribeiro-daSilva et al., 1991; Senba et al., 1988). It seems likely that most of the enkephalin immunoreactivity comes from neurons intrinsic to the dorsal horn. Enkephalin has been localized in serotonergic neurons of the raphe nuclei that project to the spinal cord, but most such fibers terminate in the ventral horn (Menétrey and Basbaum, 1987; Tashiro et al., 1988). Also, some enkephalin immunoreactivity may originate from primary sensory fibers. However, enkephalin has never been detected in a significant number of neurons in the dorsal root ganglia. Based on the above, it is clear that the colocalization with enkephalin can be used as a marker for substance P immunoreactivity in nerve terminals of dorsal horn origin. In the cat, enkephalin-IR boutons have been shown to synapse on spinothalamic neurons (Ruda et al., 1984) and on neurons of the dorsal column postsynaptic pathway (Nishikawa et al., 1983). Dynorphins Dynorphin immunoreactivity has been detected in neurons of laminae I and II (Miller and Seybold, 1987). Endormorphins Of the two endomorphins, endomorphin-2 is the most abundant in the superficial laminae of the dorsal horn, where it occurs in laminae I and IIA with a distribution similar to that of substance P, with which it is colocalized in sensory fibers (Martin-Schild et al., 1997,
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1998, 1999). In contrast, endomorphin-1 is intrinsic to the CNS and occurs in fibers in laminae I and II (MartinSchild et al., 1999). Opioid Receptors As dorsal rhizotomy leads to a reduction of both μand δ-opioid receptor binding (Fields et al., 1980), it has been postulated that such receptors should be, at least in part, localized in primary sensory fibers. In situ hybridization cytochemistry has confirmed the occurrence of opioid receptors in dorsal root ganglia neurons and in dorsal horn neurons (Minami and Satoh, 1995). Combined light and electron microscopic studies utilizing antibodies against the δ-opioid receptor have shown conflicting results. One group claims that the receptors occur both on cell bodies and dendrites of dorsal horn neurons and in axon terminals (Cheng et al., 1995, 1997). Surprisingly, another group has found the δ-opioid receptor associated mainly with densecore vesicles on sensory fibers and not with the plasma membrane, as expected for a G-protein-coupled receptor (Zhang et al., 1998). The receptor has been shown to be colocalized in terminals with enkephalin (Cheng et al., 1995) and in sensory fibers with substance P (Zhang et al., 1998). In contrast, the κ receptor has been localized mostly postsynaptically (Arvidsson et al., 1995), whereas μ receptor immunoreactivity occurs mostly in lamina II (Honda and Arvidsson, 1995; Kemp et al., 1996), in axon terminals, in dendritic profiles, and in cell bodies of dorsal horn neurons (Cheng et al., 1996, 1997). Interestingly, the great majority of cell bodies immunoreactive for the μ-opioid receptor, which were mostly located in lamina II, did not contain either GABA or glycine immunoreactivities, suggesting that the neurons that express the μ receptor might be mostly excitatory interneurons (Kemp et al., 1996).
Glutamate It has been shown by immunocytochemistry that glutamate is localized in virtually all sensory fibers and that at the ultrastructural level it occurs in virtually all the central varicosities of glomeruli, supporting the hypothesis that glutamate is the fast excitatory transmitter of primary sensory fibers (Battaglia and Rustioni, 1988; De Biasi and Rustioni, 1988). Glutamate and substance P have been shown to be colocalized in a considerable number of dorsal root ganglia cells (Battaglia and Rustioni, 3 1988) and terminals in the dorsal horn (De Biasi and Rustioni, 1988). Aspartate is colocalized with glutamate in some of these sensory fibers, particularly in those of small diameter (Tracey et al., 1991). Glutamate receptors have been studied in the dorsal horn by applying receptor binding and in situ hybridization
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(Henley et al., 1993), as well as immunocytochemistry. The latter studies have shown that AMPA receptors have a widespread distribution in cells of the dorsal root ganglia and dorsal horn (Tachibana et al., 1994). One study has shown that Ca2+-permeable AMPA receptors were localized mostly in GABAergic inhibitory interneurons and NK-1r-IR neurons (Albuquerque et al., 1999). Interestingly, NMDA receptors have been shown to occur also in sensory fibers using light and electron microscopy (Liu et al., 1994b), a localization that has also been described for glutamate metabotropic receptors (Ohishi et al., 1995).
Inhibitory Amino Acids GABA and Glycine It has been shown that some neurons are immunoreactive for GABA or GAD or take up [3H]GABA and are assumed to be GABAergic (Barber et al., 1982; Hunt et al., 1981; Ribeiro-da-Silva and Coimbra, 1980; Todd and McKenzie, 1989), while others specifically incorporate [3H]glycine or are immunoreactive with antibodies against glycine and are considered to be glycinergic (Ribeiro-da-Silva and Coimbra, 1980; Todd and Sullivan, 1990). By combining immunocytochemistry with Wallerian degeneration in the rat (Barber et al., 1978) or with the intracellular filling of identified sensory fibers in the cat (Maxwell and Noble, 1987), GABAergic neurons have been shown to be presynaptic to primary sensory boutons (Fig. 5C). The available evidence indicates that GABA, like enkephalin, is present mostly in local circuit neurons, and a colocalization of both neurochemicals has been demonstrated at the light microscopic level in the superficial dorsal horn (Todd et al., 1992). We have confirmed this finding at the ultrastructural level (see Fig. 6). Furthermore, it has been suggested that virtually all glycinergic neurons in laminae I–III are also GABAergic (Todd, 1991; Todd and Sullivan, 1990). However, only about half of the GABAergic cells colocalize glycine (Todd, 1991; Todd and Sullivan, 1990). Recent evidence also indicates the costorage of GABA and glycine within the same vesicles at synapses in the superficial dorsal horn (Chéry and De Koninck, 1999). Glycinergic varicosities, like the GABAergic ones, can be presynaptic to primary sensory fibers in glomeruli (Todd, 1996). GABA and Glycine Receptors GABAA receptors have been described by in situ hybridization methods in cells of both the dorsal root ganglia and the spinal cord (Persohn et al., 1991), supporting the morphological finding that GABA-IR fibers are frequently presynaptic to sensory fibers (see above). Using immunocytochemistry, GABAA receptor sub-
units were shown to occur in laminae I–III (Alvarez et al., 1996; Bohlhalter et al., 1996). An ultrastructural study with an antibody generated against the GABAA receptor subunits β2–β3 revealed that most of the immunostaining was localized to dendrites and cell bodies, although some central elements of glomeruli were also labeled, confirming that the receptor also occurs in primary sensory neurons (Alvarez et al., 1996). The light microscopy distribution of GABAB receptor immunoreactivity has recently been described in the spinal cord and was highest in laminae I and II, where it occurred both in cell bodies and in the neuropil (Margeta-Mitrovic et al., 1999). In contrast to GABA receptors, glycine receptors are restricted to dorsal horn neurons. Gephyrin (a glycine receptor-associated protein) has been found postsynaptic to boutons immunopositive for GABA (Mitchell et al., 1993), a finding that was to be expected as many neurons colocalize GABA and glycine immunoreactivities (see above). The specificity of the mixed GABA/glycine synapses in the superficial dorsal horn appears to be determined by the expression, properties, and subsynaptic localization of the target GABAA, GABAB, and glycine receptors (Chéry and De Koninck, 1999, 2000) and to change during development (Keller et al., 2001).
Other Classical Transmitters and Other Neuropeptides Cell bodies immunoreactive for choline acetyltransferase (ChAT) have also been described in this area of the central nervous system (CNS) (Barber et al., 1984; Kimura et al., 1981; Todd, 1991). Such cholinergic neurons occur mainly in laminae III–IV and are presynaptic to primary sensory fibers in synaptic glomeruli and to cells of the dorsal horn (Ribeiro-da-Silva and Cuello, 1990a). A study from my laboratory has demonstrated that most of these ChAT-IR neuronal cell bodies (Fig. 7A) and boutons (Figs. 7B–7D) colocalize GABA immunoreactivity. Serotonin originates from cell bodies located in the brain stem (for review see Ruda et al., 1986). In the cat, retrograde tracing has shown that serotonin-IR profiles have direct contacts with projection neurons (Ruda, 1986). Despite two ultrastructural studies, very little is known concerning the synaptic contacts of noradrenergic fibers in the dorsal horn, except that they are presynaptic to dorsal horn neurons (Doyle and Maxwell, 1991; Hagihira et al., 1990). However, the light microscopic distribution of noradrenergic fibers in the dorsal horn and their origin in the brain stem are well known (Fritschy and Grzanna, 1990; Westlund et al., 1983). Neurotensin immunoreactivity occurs in neurons in laminae I and II (Hunt et al., 1981; Seybold and Elde, 1982).
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FIGURE 6 Examples of colocalization of GABA and enkephalin (ENK) in laminae II–III as detected by immunocytochemistry. (A) ENK/GABA colocalization in a presynaptic dendrite (V1) of a type Ia synaptic glomerulus; note another presynaptic dendrite possessing exclusively GABA immunoreactivity (V1 GABA+). (B) ENK/GABA colocalization in a peripheral axon (V2 profile) of a type Ia glomerulus; note a presynaptic dendrite (V1 GABA +) which is immunoreactive for GABA only. (C, D) Colocalization of ENK and GABA immunoreactivities in V2 profiles of type II glomeruli. D, “regular” dendrite; V1, glomerular presynaptic dendrite; V2, glomerular peripheral axon; CIa, central varicosity of type Ia glomerulus; CIIa, central varicosity of type IIa glomerulus; CIIb, central varicosity of type IIB glomerulus. Scale bars = 0.5 μm.
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FIGURE 7 Examples of colocalization of ChAT and GABA immunoreactivities in laminae II–III, as detected by immunocytochemistry. (A,B) In nonglomerular profiles, (C,D) in synaptic glomeruli. (A) Nerve cell body (CB) in lamina III colocalizing ChAT (immunoprecipitate) and GABA (gold particles) immunoreactivities. (B) ChAT/GABA colocalization in an axonal bouton (arrow) in lamina IIA. (C) GABA+ChAT colocalization in a peripheral axon (V2 profile) of a type I synaptic glomerulus; note a presynaptic dendrite (V1) which is immunoreactive exclusively for GABA. (D) Two V2 profiles in a type II glomerulus colocalizing ChAT/GABA immunoreactivities; a third V2 profile possesses exclusively GABA immunoreactivity. (D), dendrite; V1, glomerular presynaptic dendrite; V2, glomerular peripheral axon; CIa, central varicosity of type Ia glomerulus; CIIb, central varicosity of type IIb synaptic glomerulus. Scale bars = 0.5 μm.
Markers of Nonpeptidergic Primary Sensory Fibers Since a seminal article by Hunt and Rossi in 1985 (Hunt and Rossi, 1985), the concept of the occurrence of two populations of sensory fibers conveying nociceptive information, the peptidergic and the nonpeptidergic, has emerged. The first express sensory neuropeptides (in particular substance P), and the second display fluoride-resistant acid phosphatase (FRAP)
activity. This concept was largely neglected for a decade while investigators focused mostly on the terminations of fibers expressing sensory neuropeptides, in particular substance P. However, interest in the concept has been revived in recent years. It was clarified that the population that expressed FRAP activity, originally described a few years earlier by two groups independently (Coimbra et al., 1970, 1974; Knyihár, 1971; Knyihár and Gerebtzoff, 1973), could specifically bind the isolectin IB4 and be recognized by the monoclonal antibody
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LA4 (Alvarez et al., 1989a,b; Dodd and Jessell, 1985; Jessell and Dodd, 1985, 1989). However, the real interest in the nonpeptidergic population emerged following the discovery that the two populations differed in neurotrophic support in the adult. In fact, during development, both populations require nerve growth factor (NGF) for survival, but shortly after birth only the peptidergic type continue to respond to NGF, whereas the nonpeptidergic population starts to respond instead to glial cell line-derived neurotrophic factor (GDNF) (Bennett et al., 1998). Accordingly, the peptidergic population expresses the NGF high-affinity receptor trkA, whereas the nonpeptidergic expresses GDNF receptors. It was shown that the latter population also expressed the purinergic receptor P2X3 (Bradbury et al., 1998; Snider and McMahon, 1998) and the capsaicin VR1 receptor (Guo et al., 1999). Although the distinction between two populations of primary sensory fibers, peptidergic and nonpeptidergic, seems attractive, it is not completely accurate as a small proportion of sensory fibers that colocalize CGRP and somatostatin do not respond to NGF in the adult and bind the lectin IB4 (Alvarez and Fyffe, 2000). It should also be noted that, in all of the above putative nociceptive fibers, the “classical” synaptic transmitter is very likely glutamate (Battaglia and Rustioni, 1988; De Biasi and Rustioni, 1988; Merighi et al., 1991), or both glutamate and aspartate (Merighi et al., 1991; Tracey et al., 1991). Of the markers of nonpeptidergic nociceptive sensory fibers described above, the one that has been best studied is FRAP. At the light microscope level, FRAP activity is localized in a band in the middle third of lamina II, corresponding to sublamina IIBd (Ribeiroda-Silva et al., 1986) (see also Fig. 1). At the ultrastructural level, FRAP occurs in the C boutons of synaptic glomeruli of type I but not type II (Ribeiro-da-Silva et al., 1986). The physiological role of this enzymatic activity is still unknown, but it is useful as a marker of a subset of small-diameter sensory fibers. In most recent studies, the binding of IB4 has been used as the marker of the nonpeptidergic nociceptive fiber population (see Fig. 2).
Neurochemistry of Synaptic Glomeruli The C boutons of synaptic glomeruli are likely all immunoreactive for glutamate and possibly for aspartate (De Biasi and Rustioni, 1988; Tracey et al., 1991). Of the neuropeptides in the C boutons of glomeruli, CGRP is the most abundant, as it occurs in virtually all the C boutons of type Ib (i.e., with dense-core vesicles – see Figs. 4, and 5A, and 5B). Substance P immunoreactivity occurs in a subpopulation of those CGRP-IR C boutons of type I glomeruli (Ribeiro-da-Silva et al., 1989; Ribeiro-da-Silva and Cuello, 1991) (Figure 5A).
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Somatostatin also occurs in the C boutons of glomeruli (Alvarez and Priestley, 1990b; Ribeiro-da-Silva and Cuello, 1990b), where it is colocalized with CGRP (Ribeiro-da-Silva, 1994). Relative to surrounding glomerular profiles, several neurochemicals have been detected in “regular” glomerular dendrites (D): substance P (Ribeiro-da-Silva et al., 1989), neurokinin B (McLeod et al., 2000), enkephalin (Ribeiro-da-Silva et al., 1991), somatostatin (Ribeiro-da-Silva and Cuello, 1990b), GABA (Fig. 5C), glycine (Todd, 1990), and ChAT (Ribeiro-da-Silva and Cuello, 1990a). In presynaptic dendrites (V 1), the following antigenic sites have been detected, among others: somatostatin (Ribeiro-daSilva and Cuello, 1990b), enkephalin, GABA (Todd and Lochhead, 1990) (Fig. 5C), and glycine (Todd, 1990). In glomerular peripheral axons (V2), the following were detected: GABA (Barber et al., 1978; Todd and Lochhead, 1990), glycine (Todd, 1990), ChAT (Ribeiroda-Silva and Cuello, 1990a), and enkephalin (Ribeiroda-Silva et al., 1991). Certain colocalizations have been found in the surrounding profiles of glomeruli: GABA+ChAT (Figs. 7C and 7D) in V2 profiles and dendrites (D); GABA + enkephalin in V1, D, and V2 profiles; (Fig. 6) and enkephalin +substance P in D profiles (Ribeiro-da-Silva et al., 1991). GABA+glycine colocalization has been demonstrated in cell bodies (Todd and Sullivan, 1990) at the light microscopic level. Subsequently, Todd (1996) has provided evidence of GABA+glycine colocalization in V2 profiles and some V1 profiles in type II, but not in type I, glomeruli. The occurrence of GABA+glycine colocalization in presynaptic dendrites (V1 profiles) of type II glomeruli is not surprising as Spike and Todd (1992) had detected such colocalization in islet cells. However, it should be pointed out that GABA, and not glycine receptors, has been detected on primary sensory fibers. Therefore, it is likely only GABA that acts on the C boutons, whereas glycine targets other glomerular profiles.
FINAL REMARKS In conclusion, since the influential theoretical paper of Melzack and Wall (1965) introducing the spinal gate control theory, many complex synaptic arrangements have been postulated in the rat superficial dorsal horn, fitting or contradicting their main hypothesis. Despite the recent progress, the fact is that there is still insufficient direct evidence integrating the circuitry of the dorsal horn, the physiological characteristics of neurons, and the chemical nature and type of synapses involved. In the rat, it seems that the outer two-thirds of lamina II play a major role in the modulation of nociception. However, the details of modulatory mechanisms and neurochemicals involved are still not well known.
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Acknowledgments I dedicate this book chapter to Professor António Coimbra (Porto, Portugal), who was my thesis supervisor and to whom I owe a significant part of my scientific training. Many of the results reported here on the classification of synaptic glomeruli derive from my long-term collaboration with him. The author is particularly grateful to Drs. Andrew J. Todd (Glasgow, UK) and Yves De Koninck (U. Laval, Québec, Canada) for critical reading of the manuscript. I am also grateful to Mrs. Marie Ballak and Ms. Johanne Ouelette for expertise in electron microscopy, to Mr. Sid Parkinson for editorial assistance, to Mr. Alan Forster for photographic expertise, and to Mrs. Manon St. Louis for help with immunocytochemistry. The original data on transmitter colocalization given in this chapter are the result of research supported by the Canadian Institutes of Health Research (CIHR).
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C H A P T E R
7 Ascending and Descending Pathways in the Spinal Cord DAVID TRACEY School of Medical Sciences, University of New South Wales Sydney, New South Wales, Australia
by the axons of spinal neurons projecting to other segments of the spinal cord, to the dorsal column nuclei, the sensory trigeminal nuclei, and the reticular formation. The dorsal columns also contain axons descending from the dorsal column nuclei. In the rat, most of the fibers of the corticospinal tract descend in the basal part of the dorsal columns. The classic view of the dorsal columns is that they are composed of the myelinated axons of mechanoreceptors and transmit sensory information from these receptors in skin, muscles, and joints. Recent work shows that the dorsal columns also transmit information from visceral nociceptors (Feng et al., 1998; Willis et al., 1999).
Ascending pathways in the spinal cord conduct information from sensory receptors and interneurons to the brain, while descending pathways transmit motor commands as well as signals which modulate the transmission of sensory information from the spinal cord to supraspinal levels. This chapter provides an overview of the neuroanatomy of these pathways, with some reference to functional aspects. The chapter is arranged according to the level of origin or termination of the pathways (medulla, pons, midbrain, and telencephalon). Some attention is given to the neurochemistry and extent of collateralization of the neurons involved. References are to studies carried out on the rat unless another species is mentioned.
Direct dorsal column pathway The axons are ascending collaterals of sensory neurons with cell bodies in the dorsal root ganglia. These axons are somatotopically organized so that fibers from the tail run close to the midline, while fibers from the hindlimb, trunk, and forelimb are added to the lateral border of the column at progressively more rostral levels. Primary afferents entering the cervical and upper thoracic segments of the spinal cord have collaterals which terminate in the cuneate and external cuneate nuclei, while those entering the cord at lower thoracic and lumbosacral levels terminate in the gracile nucleus. These terminations have a complex somatotopic organization, which is discussed in the chapter on the somatosensory system (Tracey, Chapter 25). Lumbar afferents also have dense projections to spinocerebellar tract cells in the dorsal nucleus (Ganchrow and Bernstein, 1981; RiveroMelián and Grant, 1990) with minor projections to other
ASCENDING PATHWAYS Pathways from the Spinal Cord to the Medulla The best known of these is the dorsal column pathway, but there are also ascending pathways from the spinal cord to the sensory trigeminal nuclei, the lateral cervical nucleus, the vestibular nuclei, nuclei X and Z, the nucleus of the solitary tract, the reticular formation, and the inferior olivary nucleus. Dorsal Column Pathways The dorsal columns contain two groups of ascending fibers. The first group is made up of the ascending collaterals of primary afferents and constitutes the direct dorsal column pathway. The second group is formed
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brain stem nuclei (Ganchrow and Bernstein, 1981) including nucleus Z (Leong and Tan, 1987). However, few of the fibers which enter the dorsal columns reach the dorsal column nuclei. Only 15% of fibers entering the cord at lumbar levels reach the cervical dorsal columns, so that most leave the dorsal columns within two to three segments of their level of entry (Smith and Bennett, 1987). Some of these fibers terminate on neurons giving rise to other ascending tracts, such as the dorsal spinocerebellar tract (RiveroMelián and Grant, 1990), while about 25% of the axons in the dorsal column are propriospinal fibers, i.e., fibers originating and terminating in the spinal cord (Chung et al., 1987). Primary afferents also have collateral branches which descend in the dorsal columns, but only 3% reach as far as two segments from the site of entry (Smith and Bennett, 1987). The dorsal columns are often thought to be composed of the myelinated axons of mechanoreceptors. However, about 25% of primary afferents in the dorsal columns are unmyelinated (Chung et al., 1987). In the gracile fasciculus, many of these axons are collaterals of primary afferents which ascend at least as far as C3 and might reach the gracile nucleus (Patterson et al., 1992, 1990, 1989). However, injection of retrograde tracers into the dorsal column nuclei labeled only large cell bodies in the dorsal root ganglia. Small cell bodies, which give rise to unmyelinated axons, were not labeled (Giuffrida and Rustioni, 1992), suggesting that unmyelinated fibers in the dorsal columns do not terminate in the dorsal column nuclei. They may terminate instead on postsynaptic dorsal column neurons or on spinothalamic neurons—many of which are located at high cervical levels (see section on spinothalamic tract). Postsynaptic dorsal column pathway A substantial number of primary afferent fibers do not project directly to the dorsal column nuclei, but terminate on spinal neurons whose axons then project to the gracile and cuneate nuclei. In the rat, as in other animals, these postsynaptic dorsal column (PSDC) neurons are located primarily in lamina 4 (de Pommery et al., 1984) or central gray (Al-Chaer et al., 1996; Wang et al., 1999) and constitute about 30–40% of neurons projecting to the dorsal column nuclei (Giesler et al., 1984). There is a somatotopic arrangement of PSDC cells, such that those at lumbar levels of the cord project to the gracile nucleus, while those in the cervical enlargement project to the cuneate nucleus (Giesler et al., 1984). The axons of PSDC neurons terminate at all rostrocaudal levels of the gracile and cuneate nuclei and also terminate in the external cuneate nucleus; they make apparent synaptic contacts with lemniscal neurons projecting to the ventrobasal thalamus (Cliffer and Giesler, 1989). Post-
synaptic dorsal column neurons appear to provide the most important ascending pathway for nociceptive signals from the pelvic viscera (Al-Chaer et al., 1996; Willis et al., 1999). See also Willis et al., Chapter 27. Spinoreticular Tracts There are three main groups of spinoreticular neurons: (1) those projecting to the lateral reticular nucleus (LRt); (2) a group projecting to the medial nuclei of the pontomedullary reticular formation, including the gigantocellular reticular nucleus (Gi), the paragigantocellular nucleus (PGi), and the caudal part of the pontine reticular nucleus (PnC); and (3) neurons that innervate the dorsal reticular nucleus of the medulla (MdD). Each group receives a projection from the area around the central canal (Wang et al., 1999). Spinal neurons projecting to the LRt originate in the intermediate gray, ventral horn, and lateral spinal nucleus (Menétrey et al., 1983). The axons ascend in the ventrolateral funiculus (Zemlan et al., 1978) and terminate in a topographically organized manner in the caudal three-quarters of the nucleus (Rajakumar et al., 1992). However, these neurons appear to be heterogeneous in function. One subgroup responds to innocuous changes in joint position (Menétrey et al., 1984a) and may be implicated in motor control (Magnuson et al., 1998). This role is consistent with the cerebellar projection of LRt. A second subgroup of spinal neurons projecting to LRt responds only to noxious inputs (Menétrey et al., 1984a) and is more likely to be involved in nociception. This is consistent with the finding that a region of the LRt receives visceral and cutaneous nociceptive inputs (Ness et al., 1998) and is an important site of pain modulation (Janss and Gebhart, 1988). Neurons projecting to the medial pontomedullary reticular formation are located mainly in contralateral laminae 5, 7, and 8 (Chaouch et al., 1983; Van Bockstaele et al., 1989), where their distribution overlaps with that of spinothalamic neurons (q.v.). In fact about 8% of spinoreticular neurons send collaterals to the thalamus (Kevetter and Willis, 1983). Many spinoreticular axons terminating in the Gi ascend in the ventrolateral funiculus (Zemlan et al., 1978). Electrophysiological experiments in the cat and monkey found that a surprisingly large proportion of spinal neurons projecting to the medial pontomedullary reticular formation were not activated by peripheral stimuli, although a few were activated by low- and/or high-threshold cutaneous afferents (Haber et al., 1982; Sahara et al., 1990). It is possible that some of the unresponsive spinoreticular neurons are sensitized and activated under conditions of chronic pain (Pezet et al., 1999). A third group of spinoreticular neurons can be distinguished, which projects to the MdD. Neurons in the MdD are
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activated by noxious stimuli (Villanueva et al., 1989) and may form an important link in the transmission of signals from the spinal cord to the medial thalamic nuclei (Villanueva et al., 1998). The cells of origin of spinal neurons projecting to the MdD are mostly ipsilateral and located at all levels of the spinal cord (Lima, 1990; Villanueva et al., 1991); they are particularly dense in laminae 5–7 of the cervical enlargement (Raboisson et al., 1996). Physiological evidence suggests that the axons of these spinoreticular neurons (like those projecting to other parts of the reticular formation) run in the ventrolateral funiculus (Bing et al., 1990). Spinocervical Tract The spinocervical tract consists of axons ascending in the dorsolateral fasciculus to the lateral cervical nucleus in the upper cervical cord (see Grant and Koerber, Chapter 5). Cells of origin are concentrated in layers 3–5 at all levels of the cord, but are far fewer in number in the rat than in the cat (Baker and Giesler, 1984). The lateral cervical nucleus of the rat is small relative to that in the cat and shows no evidence of somatotopic organization (Giesler et al., 1988). In the cat, most spinocervical tract neurons are excited by hair deflection, although there is evidence for input from other modalities as well (Brown, 1981). Other Ascending Pathways to the Medulla In addition to the pathways described above, there are ascending spinal pathways to the nucleus of the solitary tract, trigeminal nuclei, vestibular nuclei, and nuclei, X and Z. The caudal part of the nucleus of the solitary tract receives afferent fibers from the spinal cord (Torvik, 1956) and from the spinal trigeminal nucleus. The cells of origin are located in laminae 1, 5, and 10 and in the lateral spinal nucleus (Guan et al., 1998; Menétrey and Basbaum, 1987; Wang et al., 1999) and overlap with neurons giving rise to the spinomesencephalic and spinoreticular tracts. Spinosolitary fibers transmit sensory data from the viscera (Hubscher and Berkley, 1995) and may be involved in integrating somatic and visceral information from the trunk (Guan et al., 1998; Menétrey and Basbaum, 1987). The sensory trigeminal complex receives afferent fibers from the spinal cord (Phelan and Falls, 1991; Torvik, 1956; Xiong and Matsushita, 2000). These axons ascend in the dorsal columns and the lateral funiculus (Phelan and Falls, 1991) and end in a narrow band just deep to the spinal trigeminal tract. They are likely to be important in reflex control of head and neck orientation. Projections from the spinal cord to the vestibular nuclei terminate primarily in the medial, spinal, and lateral vestibular nuclei (MVe, SpVe, and LVe), with particularly strong projections from the C2 and C3
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segments containing the central cervical nucleus (Matsushita et al., 1995). Retrograde labeling studies suggest that the superior vestibular nucleus also receives terminations from the spinal cord (Vincent and Rubertone, 1984). A significant part of the spinovestibular projection appears to relay sensory information from the neck. Sensory data from the neck need to be integrated with vestibular information to generate appropriate postural reflexes. See also Vidal and Sans, Chapter 30. Nuclei X, Y, and Z were originally described as accessory vestibular nuclei. Nucleus Z receives ascending collaterals of the dorsal spinocerebellar tract (Low et al., 1986) and projects in turn to the ventrobasal thalamus. This pathway transmits proprioceptive information from the hindlimb to the somatosensory cortex in the cat (McIntyre et al., 1985) and other mammals. Nucleus Z also receives sparse terminations from ascending collaterals of primary afferents from the hindlimb (Leong and Tan, 1987); fibers ascending in the lateral funiculus also project to nucleus X. Spinal inputs to the inferior olivary nucleus are discussed below with the spinocerebellar pathways.
Pathways from the Spinal Cord to the Pons These include projections to the parabrachial and Kölliker–Fuse nuclei, pontomedullary reticular formation, and basilar pontine nuclei. Parabrachial Nucleus The parabrachial nucleus is located around the superior cerebellar peduncle at the junction of the pons and midbrain. Parabrachial neurons are implicated in autonomic processing and nociception; they receive terminations from laminae 1 and 2 and the lateral spinal nucleus (Feil and Herbert, 1995), from laminae 5 and 7 (Kitamura et al., 1993), and from lamina 10 (Wang et al., 1999). The majority of spinoparabrachial neurons are excited only by noxious stimuli and the pathway is thought to be involved in autonomic and emotional or aversive reactions to painful stimuli (Bester et al., 2000). The Kölliker–Fuse nucleus is a subnucleus of the parabrachial nucleus. Its neurons are involved in respiratory and cardiac regulation and receive terminations from lamina 1 (Cechetto et al., 1985), from the lateral spinal nucleus of upper cervical segments (Feil and Herbert, 1995), and from lamina 10 (Wang et al., 1999). Other Projections from Spinal Cord to Pons A region of the dorsolateral pontine tegmentum corresponds to the micturition reflex center of Barrington. This region receives projections from the
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parasympathetic nuclei of the lumbosacral cord (Ding et al., 1997; Hamilton et al., 1995). Caudal regions of the basilar pontine nuclei receive a sparse projection from neurons located in the intermediate basilar nucleus of C1–C2 and in laminae 6–7 of the lumbar cord (Mihailoff et al., 1989; Swenson et al., 1984; Yamada et al., 1985). The locus coeruleus and the subcoerulear region receive terminals from neurons in lamina 10 (Wang et al., 1999). Spinoreticular projections to the pons are discussed previously together with those to the medulla under Spinoreticular Tracts.
Pathways from the Spinal Cord to the Cerebellum Pathways from the spinal cord to the cerebellum include two, the dorsal and the ventral spinocerebellar tracts, which transmit information from mechanoreceptors in the hindlimb, while several pathways transmit information from receptors in the forelimb and neck. Spinocerebellar axons terminate in lobules 1–5 of the anterior lobe and lobule 8 of the posterior lobe (Berretta et al., 1991; Tolbert et al., 1993) and in the deep cerebellar nuclei (Matsushita, 1999). In the granular layer of the cerebellar cortex, these axons terminate as mossy fiber terminals, arranged in longitudinal aggregates subjacent to sagittal bands of Purkinje cells (Ji and Hawkes, 1994). The general pattern of organization of the spinocerebellar tracts in the rat is the same as that in the cat and other animals. Dorsal and Ventral Spinocerebellar Tracts The cells of origin of the dorsal spinocerebellar tract are located in Clarke’s column (dorsal nucleus) from about T1 to L3 (Matsushita and Hosoya, 1979). The axons enter the lateral funiculus where they ascend (Zemlan et al., 1978). The axons overlap with those of the ventral spinocerebellar tract in the lateral funiculus and enter the cerebellum via the inferior cerebellar peduncle (Yamada et al., 1991). They signal information about position and movement of the hindlimb in the cat (Bosco et al., 2000). Neurons which give rise to the ventral spinocerebellar tract include groups of large cells in laminae 7 and 9 of the lumbar spinal cord, referred to as spinal border cells. Most of these cells have axons that cross the cord in the anterior commissure; they ascend in the lateral funiculus and enter the cerebellum via the superior cerebellar peduncle (Yamada et al., 1991) and then decussate a second time to terminate ipsilateral to their cells of origin.
lamina 6 and the other in central lamina 7 (Matsushita and Hosoya, 1979). These neurons project in the superior cerebellar peduncle to the ipsilateral cerebellum (Matsushita and Hosoya, 1979; Yamada et al., 1991). Neurons in the external cuneate nucleus and the rostral cuneate nucleus contribute to the cuneocerebellar tract (Tolbert and Gutting, 1997) and receive proprioceptive inputs from primary afferent fibers in the dorsal columns. This tract is in some ways a forelimb analog of the dorsal spinocerebellar tract and carries information about the position and movement of the forelimb. The central cervical nucleus is located just lateral to the central canal from C1 to C3, and projects to the cerebellar cortex and nuclei in the inferior and superior cerebellar peduncles (Matsushita and Yaginuma, 1995). It transmits information from receptors in the neck and labyrinths. Spinoolivary Tract and Other Indirect Spinocerebellar Pathways There is an indirect projection from the spinal cord to the cerebellum via the inferior olivary nucleus, whose climbing fibers terminate exclusively in the cerebellum (see Voogd, Chapter 9). Spinoolivary neurons terminate in the medial and dorsal accessory olivary nuclei (Azizi and Woodward, 1987; Swenson and Castro, 1983b); their cells of origin are located in the medial aspect of the nucleus proprius and in the central cervical nucleus (Swenson and Castro, 1983a). Other polysynaptic pathways from the spinal cord to the cerebellum include the projection from the spinal cord to the lateral reticular nucleus (see above) and the projection from the dorsal column and trigeminal nuclei to the inferior olivary nucleus (Molinari et al., 1996).
Pathways from the Spinal Cord to the Midbrain Spinomesencephalic neurons are located mainly in the cervical cord (Yezierski and Mendez, 1991) and project to three main regions of the midbrain: the superior colliculus, the central gray, and the midbrain reticular formation. All three regions receive nociceptive inputs and form part of the neural circuitry involved in the localization or descending control of pain (see Willis et al., Chapter 27). There are also terminations in the anterior and posterior pretectal nuclei, the red nucleus, the Edinger–Westphal nucleus, and the interstitial nucleus of Cajal (Menétrey et al., 1982; Willis and Westlund, 1997; Yezierski, 1988).
Other Spinocerebellar Pathways
Superior Colliculus
In the cervical enlargement, there are two distinct groups of spinocerebellar neurons—one in medial
Most spinotectal neurons are located contralaterally in laminae 3 to 5 and in laminae 7 to 8 (Morrell and Pfaff,
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1983). Spinotectal neurons are also found in lamina 1 and in the lateral spinal nucleus (Menétrey et al., 1982). The axons run in the lateral funiculus and terminate in the deep and intermediate layers of the superior colliculus (Antonetty and Webster, 1975) as well as the intercollicular nucleus (Zemlan et al., 1978) and pretectal nuclei (Yezierski, 1988). The tract provides somatic input to the superior colliculus, where it is integrated with visual and auditory information to play a role in head orientation. Central Gray Spinal neurons project to the caudal part of the central gray via the ventrolateral funiculus (Bernard et al., 1995; Bianchi et al., 1990). Functionally distinct columns have been recognized in the periaqueductal gray, with nociceptive input from deep somatic and visceral structures activating neurons in the ventrolateral column and nociceptive input from the skin activating the lateral column (Clement et al., 2000). Cells of origin are located mainly in the upper cervical and sacral spinal cord, and those projecting to the lateral column are organized in a manner somewhat similar to that of the spinoparabrachial projection (Keay et al., 1997). There is a strong projection from lamina 10 (Wang et al., 1999). See also Keay and Bandler, Chapter 10. Midbrain Reticular Formation Anterograde labeling of spinomesencephalic neurons in the lumbosacral cord showed that they have relatively dense terminations in the cuneiform nucleus in the caudal part of the midbrain and sparser terminations in the rostral part of the midbrain, including the deep mesencephalic nucleus (Veazey and Severin, 1982; Yezierski, 1988). The cells of origin are similar in location to those projecting to the superior colliculus and central gray (Menétrey et al., 1982). They include lamina 1 cells with axons in the contralateral dorsolateral fasciculus and collateral branches to the cuneiform nucleus (McMahon and Wall, 1985) and neurons in lamina 10 (Wang et al., 1999).
Pathways from the Spinal Cord to the Diencephalon The major projection from the spinal cord to the diencephalon is the spinothalamic tract (Fig. 1). Spinal neurons also project to the hypothalamus and to parts of the subthalamus and epithalamus (Cliffer et al., 1991). Spinothalamic Tract The spinothalamic tract (STT) is the main pathway for information from receptors signaling pain and temperature (Willis and Westlund, 1997). Several groups of STT neurons can be distinguished, including cells in
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medial laminae 4–6 and lateral laminae 7–9 (Granum, 1986; Kemplay and Webster, 1986; Kobayashi, 1998). In the rat, at least 50% of STT neurons are located in the first four cervical segments, and about 90% of STT neurons have axonal terminations contralateral to their cell bodies. The axons generally cross the midline within a few segments of the cells of origin (Granum, 1986; Kemplay and Webster, 1986) and ascend in the ventral or ventrolateral funiculus (Giesler et al., 1981). The spinothalamic tract terminates in three main regions—the ventroposterolateral nucleus (Peschanski et al., 1983); the intralaminar nuclei, primarily the central lateral nucleus (Ma et al., 1987); and the posterior complex (Dado et al., 1994a; Ledoux et al., 1987). STT axon terminals are also found in the nucleus gelatinosus (submedius) (Craig and Burton, 1981), but they are sparse (Cliffer et al., 1991). A study of STT neurons in the cervical enlargement of the rat found that about 50% responded to both noxious and innocuous stimuli (wide dynamic range) while 44% responded only to noxious stimuli (high threshold) and 6% responded preferentially to innocuous stimuli (Dado et al., 1994b). These data are consistent with those from STT neurons in the lumbar enlargement of monkeys (Willis and Coggeshall, 1991; Willis and Westlund, 1997). However, lumbar STT neurons of the rat differ from those of primates in that only a small percentage of the rat’s complement of STT neurons are located in the lumbar enlargement, and most of these respond primarily to innocuous stimuli (Dado et al., 1994b; Menétrey et al., 1984b). In the sacral spinal cord of the rat, a significant proportion of STT neurons responded to noxious visceral inputs such as distension of the colon, rectum, and vagina (Katter et al., 1996). Spinothalamic neurons send collaterals to several regions of the CNS (Lu and Willis, 1999), including the medullary reticular formation (Kevetter and Willis, 1983), the periaqueductal gray (Harmann et al., 1988; Liu, 1986), and the parabrachial area (Hylden et al., 1989). Spinal Projections to Other Parts of the Diencephalon There is a substantial projection from the spinal cord to the hypothalamus. Spinohypothalamic neurons are located bilaterally, mostly in the deeper laminae of the dorsal horn and the lateral spinal nucleus (Burstein et al., 1990). They terminate in several regions of the hypothalamus, including the lateral, posterior, and dorsal hypothalamic areas (Cliffer et al., 1991; Wang et al., 1999). Their response properties are similar to those of spinothalamic neurons (Burstein et al., 1991; Dado et al., 1994b; Katter et al., 1996). There is also a projection from the spinal cord to the zona incerta, mainly from the dorsal horn and intermediate gray of the cervical
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A
PO VPL CL
CM
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FIGURE 1 Spinothalamic tract (STT). (A) Sites of termination in the centrolateral thalamic nucleus (CL), the posterior thalamic nuclear group (PO), and the ventral posterolateral thalamic nucleus (VPL). Note the patchy distribution of spinothalamic terminals (Cliffer et al., 1991). (B) Course of spinothalamic axons (Giesler et al., 1981; Hylden et al., 1989). (C) Cells of origin (Kemplay and Webster, 1986).
and lumbar cord (Shaw and Mitrofanis, 2001; Wang et al., 1999).
Pathways from the Spinal Cord to the Telencephalon There is a direct projection from neurons in the spinal cord to some regions of the telencephalon, including the basal ganglia, amygdala, and infralimbic and medial orbital cortex (Cliffer et al., 1991; Newman et al., 1996; Wang et al., 1999). Spinal neurons projecting to these regions are found bilaterally in the deeper layers of the dorsal horn, lamina 10, and the lateral spinal nucleus
(Burstein and Potrebic, 1993; Wang et al., 1999). These projections provide a direct pathway for somatosensory information from the spinal cord to the limbic system and basal ganglia.
DESCENDING PATHWAYS Pathways from the Telencephalon to the Spinal Cord The vast majority of neurons in the telencephalon which project to the spinal cord are in the cerebral cortex.
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Corticospinal Tract
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et al., 1990). Corticospinal neurons are not restricted to primary motor and sensory cortex, but are found in a number of other cortical regions. In frontal cortex, corticospinal neurons are found in an area corresponding with the supplementary motor area (Fr2) and in the prefrontal cortex (Li et al., 1990; Miller, 1987). In parietal cortex they are found in the second somatosensory area (Par2) and in the posterior parietal cortex (part of Par1); corticospinal neurons are also located in the visual association cortex, the anterior cingulate cortex (Miller, 1987), and the infralimbic cortex (Hurley et al., 1991).
Most corticospinal neurons are located in the primary motor cortex, equivalent to Fr1 + Fr3, and in the forelimb and hindlimb parts of the primary sensory cortex, equivalent to FL and HL (Fig. 2). In primary motor cortex, corticospinal neurons are located throughout layer 5, whereas in primary sensory cortex they are restricted to layer 5b (Miller, 1987). Neurons in the forelimb area of motor and sensory cortex project to the cervical enlargement, while those in the hindlimb area project to the lumbar enlargement (Li
A RSG
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FIGURE 2 Corticospinal tract. (A) Cells of origin (Miller, 1987). The dorsal aspect of the cortex is shown, with nomenclature after Zilles (Palomero-Gallagher and Zilles, Chapter 23). Par1+FL+HL together constitute the first somatosensory area, often referred to as SI; while Par2 is equivalent to the second somatosensory area, SII. Fr1+Fr3 together make up the motor cortex, while Fr2 corresponds to the supplementary motor area. (B) Course of corticospinal axons. Note the bundle of uncrossed axons in the ventral funiculus, vfu (Casale et al., 1988). (C) Terminations in the spinal cord (Casale et al., 1988).
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The corticospinal tract of the rat decussates in the caudal medulla and runs in the base of the dorsal columns (Armand, 1982) but there is also a ventral uncrossed tract in the ventral funiculus (Brösamle and Schwab, 1997), as well as other minor components (Liang et al., 1991). In the rat, corticospinal neurons send collaterals to the midbrain and trigeminal nuclei (Catsman-Berrevoets and Kuypers, 1981; Killackey et al., 1989). A few corticospinal axons send collaterals to the pontine nuclei and the red nucleus (Akintunde and Buxton, 1992). Corticospinal axons terminate in all spinal laminae contralateral to the cells of origin (Fig. 2), with dense terminations in laminae 3–7 of the dorsal horn and less dense terminations in laminae 1 and 2 and the ventral horn (Casale et al., 1988; Liang et al., 1991). Corticospinal axons make synaptic contacts with motoneurons in the rat (Liang et al., 1991), as they do in primates. The corticospinal tract plays a role in the control of movement through its terminations in the intermediate gray and ventral horn, which include direct terminations on motoneurons (Liang et al., 1991). However, the corticospinal tract is not essential for the control of skilled limb movements such as reaching for and grasping food (Whishaw et al., 1998). Diencephalic Projections to the Spinal Cord There is a major projection from the hypothalamus to the spinal cord, terminating primarily in lamina 1 of the dorsal horn and in the preganglionic sympathetic and parasympathetic cell columns. The cells of origin are located in several distinct groups—the paraventricular, arcuate, and perifornical nuclei and the lateral hypothalamus. These neurons use peptides such as oxytocin and vasopressin as neurotransmitters and terminate bilaterally in the spinal cord (Cechetto and Saper, 1988; Palkovits, 1999). There is also a dopaminergic projection from the All group, located in the posterior and dorsal hypothalamic areas and in the caudal thalamus (Skagerberg and Lindvall, 1985). Paraventricular neurons containing vasopressin terminate directly on preganglionic sympathetic neurons and are involved in the response to stressful stimuli (Motawei et al., 1999). The spinal terminations of neurons in the perifornical nuclei and lateral hypothalamic area contribute to the control of blood pressure (Allen and Cechetto, 1992), while the projections of arcuate and retrochiasmatic neurons to the thoracic cord are implicated in production of melatonin and regulation of energy balance (Elias et al., 1998; Ribeiro-Barbosa et al., 1999). Cells in the medial part of the zona incerta project to the cervical and lumbar regions of the cord, with most terminations in laminae 4, 5, and 10 (Schwanzel-Fukuda et al., 1984; Shaw and Mitrofanis, 2001; Watanabe and
Kawana, 1982). There is a sparse projection to the ventral horn of the cervical cord from the parafascicular nucleus of the thalamus (Marini et al., 1999).
Pathways from the Midbrain to the Spinal Cord There are projections to the spinal cord from the red nucleus and from those parts of the midbrain which receive spinal inputs, i.e., the superior colliculus, the central gray, and the midbrain reticular formation. Rubrospinal Tract Neurons in both the parvicellular and magnocellular parts of the red nucleus project to the spinal cord. There is a somatotopic organization of the nucleus such that the ventrolateral part projects to the lumbar cord, while dorsomedial parts project to the cervical cord (Daniel et al., 1987; Strominger et al., 1987). This organization reflects the sequence of descent of rubrospinal fibers during development (Lakke and Marani, 1991). Most rubrospinal axons terminate in contralateral laminae 5–7 where they establish contact with excitatory and inhibitory interneurons (Antal et al., 1992). Lesions of the red nucleus impair locomotion and skilled reaching movements in the rat (Muir and Whishaw, 2000; Whishaw et al., 1998). Other Projections from the Midbrain to the Spinal Cord Tectospinal axons originate in the deep and intermediate layers of the superior colliculus and project to the cervical cord, mainly to contralateral lamina 5, 7, and 8 (Murray and Coulter, 1982; Yasui et al., 1998). They are implicated in the control of head movements. There are also projections to the spinal cord from the periaqueductal gray (Masson et al., 1991), the midbrain reticular formation (Satoh, 1979; Veazey and Severin, 1980a, 1980b; Waldron and Gwyn, 1969), and the dorsal raphe (Bowker et al., 1981; Kazakov et al., 1993; Skagerberg and Björklund, 1985) and from accessory oculomotor nuclei such as the Edinger–Westphal nucleus, the nucleus of Darkschewitsch, and the nucleus of the posterior commissure (Leong et al., 1984).
Pathways from the Pons to the Spinal Cord The pons contains several groups of neurons that project to the spinal cord. These include neurons in the pedunculopontine tegmental nucleus and the pontine reticular formation (Rye et al., 1988; Sirkin and Feng, 1987; Spann and Grofova, 1989). The parabrachial nucleus (including the Kölliker– Fuse nucleus) is involved in the modulation of nocicep-
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tion (Blomqvist et al., 1994) and autonomic functions. Its neurons project to the dorsal horn and intermediolateral cell column (Fulwiler and Saper, 1984; Yoshida et al., 1997). Several groups of noradrenergic neurons project to the spinal cord. These are the A5 group in the ventrolateral brain stem, the locus coeruleus (A6), and the A7 group which overlaps with the Kölliker–Fuse nucleus and the subcoeruleus nucleus (Kwiat and Basbaum, 1992). Their descending axons have been implicated in the control of autonomic functions, modulating the perception of pain (Jones, 1991) and modifying motor behavior such as locomotion. The course and terminations of axons descending from these noradrenergic neurons depend on the substrain of rat. In Sprague– Dawley rats supplied by Harlan, most locus coeruleus neurons projected to the dorsal horn. In contrast, in Sprague–Dawley rats supplied by Sasco, most locus coeruleus neurons projected to the ventral horn (Sluka and Westlund, 1992). Such differences in spinal projections have also been shown for A5 and A7 groups, although the A5 group appears to have consistent terminations in the intermediolateral cell column (Clark and Proudfit, 1991, 1993; Fritschy and Grzanna, 1990; Sluka and Westlund, 1992). The intermediolateral cell column also receives axon terminals from enkephalincontaining neurons in these “noradrenergic” groups (Romagnano et al., 1991). In the dorsolateral pontine tegmental region there is a group of neurons which corresponds to the micturition reflex center of Barrington. Neurons in this region project to the spinal parasympathetic nucleus and to pudendal motoneurons (Ding et al., 1995). Barrington’s nucleus may also influence the activity of sympathetic neurons in the spinal cord (Cano et al., 2000).
Pathways from the Cerebellum to the Spinal Cord Neurons in the deep cerebellar nuclei project to the cervical spinal cord (Bentivoglio, 1982; Leong et al., 1984). Some of these neurons send collaterals to the diencephalon or superior colliculus (Bentivoglio and Kuypers, 1982).
Pathways from the Medulla to the Spinal Cord These include projections from the trigeminal and dorsal column nuclei, the medullary reticular formation, and the raphe nuclei, as well as the vestibular complex. Trigeminal and Dorsal Column Nuclei Neurons in all three subnuclei of the spinal trigeminal nucleus (Sp5C, Sp5I, and Sp5O) send axons as far as
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the thoracic cord (Lakke, 1997) or further (Ruggiero et al., 1981). Trigeminospinal neurons are also found in the principal sensory nucleus (Phelan and Falls, 1991) and the mesencephalic trigeminal nucleus (Leong et al., 1984). Descending projections from the gracile and cuneate nuclei are present in the rat (Burton and Loewy, 1977; Villanueva et al., 1995); there is also a spinal projection from the external cuneate nucleus (Leong et al., 1984; Zemlan et al., 1979). The gracile nucleus seems to project to the lumbar cord and sacral cord, while neurons in the cuneate nucleus project mainly to the cervical cord (laminae 1, 4 & 5). Cuneospinal neurons are concentrated in the ventral parts of the nucleus (Leong et al., 1984; Masson et al., 1991). Reticular Formation Thirteen groups of reticulospinal neurons have been described in the medulla (Newman, 1985), including the raphe nuclei (see below). The gigantocellular complex (Gi) has several components which project to the spinal cord. Their axons course bilaterally in the ventral and lateral funiculi and terminate in all laminae, including laminae 1 and 2, the intermediolateral cell column, and the sacral parasympathetic nucleus (Martin et al., 1985). Terminations of Gi reticulospinal axons have been implicated in the modulation of blood pressure (Aicher et al., 2000) and the control of axial musculature (Robbins et al., 1992; Sasaki, 1999). The ventrolateral part of the intermediate reticular nucleus contains a cell column which includes the ventral respiratory group and its rostral pole, the Bötzinger complex. These groups form part of the medullary respiratory network and project to the phrenic nucleus in the cervical cord (Ellenberger, 1999). Adjacent to the ventral respiratory group is the rostral ventrolateral medulla, a functionally distinct group whose descending axons modulate the activity of preganglionic sympathetic neurons (Aicher et al., 2000; Lipski et al., 1996). Reticulospinal neurons are also found in the dorsal and ventral medullary nuclei (MdD and MdV) (Tavares and Lima, 1994; Villanueva et al., 1995). Those in the dorsal reticular nucleus are involved in pain modulation (Villanueva et al., 1996). The retroambiguus nucleus projects to sympathetic and spinal motoneurons and is implicated in respiration, vocalization, and copulation (Hardy et al., 1998; Holstege et al., 1997). Raphe Nuclei The medullary raphe nuclei are the raphe magnus (RMg), the raphe obscurus (ROb), and the raphe pallidus (RPa); all of these have projections to the spinal cord (Bowker et al., 1982) and up to 85% of raphe–spinal neurons contain 5-HT (Bowker and Abbott, 1990).
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Neurons in the raphe magnus and the adjacent ventral part of the gigantocellular reticular formation project to the spinal cord in the dorsolateral funiculus (Fig. 3) (Bowker et al., 1982; Skagerberg and Björklund, 1985). Their axons terminate mainly in the dorsal horn, with sparse projections to the ventral horn as well (Jones
A
ROb GiV
RMg RPn
and Light, 1990). This pathway plays an important role in the descending control of pain (Mason, 1999; Wei et al., 1999). Neurons in the raphe obscurus and raphe pallidus nuclei project in the ventrolateral white matter (Fig. 3) (Skagerberg and Björklund, 1985) and many terminate on motoneurons in the ventral horn (Hermann et al., 1998; Holstege and Kuypers, 1987a, 1987b). Most of these raphe–spinal neurons have multiple neurotransmitters, including serotonin, glutamate, GABA, and neuropeptides such as substance P and thyrotropinreleasing hormone (Hökfelt et al., 2000). Sympathetic preganglionic neurons in the intermediolateral cell column receive synaptic contacts from axons originating in both the raphe pallidus and the raphe magnus (Bacon et al., 1990). The function of the medullary raphe nuclei has been described in general terms as a system for integration and gain control in autonomic and somatomotor systems (Lovick, 1997). Vestibular Nuclei
B
Vestibulospinal projections arise from all four divisions of the vestibular nuclear complex: the lateral, medial, spinal, and superior vestibular nuclei. Neurons in all four nuclei send axons as far as the lumbosacral cord, but most spinally projecting neurons are located in the lateral vestibular nucleus (Leong et al., 1984; Masson et al., 1991). The medial vestibular nucleus projects predominantly to the dorsal horn of the upper cervical spinal cord (Bankoul and Neuhuber, 1992). Some vestibulospinal neurons send collateral projections to the oculomotor nuclei (Tracey and Wenderoth, 1992).
dlfu
vlfu
C gr
2
Propriospinal Connections
1
3
10
CC 9
4 LSp 5 IML 7 8 9
VMnF
FIGURE 3 Serotoninergic pathways to the spinal cord. (A) Cells of origin. (B) Course of serotoninergic axons. (C) Terminations of serotoninergic axons. Neurons can be divided into two groups: A ventral group (cross hatch) includes the raphe magnus nucleus (RMg) and the ventral part of the gigantocellular reticular nucleus (GiV) and has axons which course mainly in the dorsal part of the lateral funiculus (dlfu) and terminate primarily in the dorsal horn. The second group (stipple) includes the raphe obscurus nucleus (ROb) and the raphe pallidus nucleus (RPa) and has axons which course mainly in the ventral part of the lateral funiculus (vlfu) and terminate primarily in the ventral horn. There is overlap between the projections of the two groups (Bowker et al., 1982; Jones and Light, 1990; Skagerberg and Björklund, 1985).
Propriospinal neurons connect one part of the spinal cord with another. They have been implicated in the control of movement (Cowley and Schmidt, 1997) and in nociception (Sandkuhler et al., 1993). Propriospinal axons constitute approximately 33% of axons in the white matter of the sacral cord (Chung and Coggeshall, 1983; Chung et al., 1987). Their cell bodies are located in all laminae except lamina 9 (Bice and Beal, 1997; Menétrey et al., 1985; Verburgh et al., 1990) and project to the ipsilateral dorsal and ventral horns and lamina 10, as well as to the contralateral cord (Matsushita, 1998; Petko and Antal, 2000). However, Petko and Antal argue that there are significant differences between the medial and lateral parts of the dorsal horn, with the lateral part of the superficial dorsal horn receiving most C-fiber terminations and giving rise to most of the ascending pathways dealing with nociception. Propriospinal neurons in the lateral dorsal horn differ from those in the medial dorsal horn in that they have reciprocal connections with the whole rostrocaudal extent of the
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cord, have commissural connections with the contralateral dorsal horn, and are the main source of projections to the ventral horn and supraspinal centers (Petko and Antal, 2000). These differences in connectivity suggest that it is the propriospinal neurons in the lateral part of the dorsal horn which play a significant role in nociception.
Acknowledgments I thank Professor M. Matsushita, Dr. J. Mitrofanis, and Dr. R.B Simerly for constructive comments and Ms. Alicia Fritchle for assistance with illustrations. I also thank Professor Peter Grafe for providing the facilities for the preparation of the manuscript.
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8 Precerebellar Nuclei and Red Nucleus TOM J. H. RUIGROK Department of Neuroscience, Erasmus MC Rotterdam The Netherlands
The cerebellum receives afferents from many sources in the brain stem and spinal cord that are collectively known as the precerebellar nuclei. Clearly, these precerebellar nuclei cannot be regarded as a single group, but should be differentiated into various functionally and morphologically distinct clusters. The largest group consists of neurons that terminate as the so-called mossy fibers in the granular cell layer of the cerebellar cortex (Ramón y Cajal, 1888, 1911). Well-known and quantitatively important sources of mossy fibers are the spinal cord (see Tracey, Chapter 7), the pontine nuclei, the vestibular nuclei (see Vidal and Sans, Chapter 31), the lateral reticular nucleus, the dorsal column nuclei, the trigeminal nuclei, and a score of reticular nuclei. A second group supplying afferents to the cerebellum consists of only a single nucleus. The inferior olivary complex gives rise to all climbing fibers, terminating upon the dendritic tree of the cerebellar Purkinje cells (Ramón y Cajal, 1888, 1911; Szentágothai and Rajkovits, 1959; Desclin, 1974). Finally, a third group of precerebellar nuclei provide monoaminergic inputs to the cerebellum and are most likely involved in modulatory functions (André et al., 1991, 1993; Strahlendorf et al., 1991). Serotonergic afferents are found in diffusely beaded terminals within the granular cell layer as well as in the cerebellar nuclei (Bishop and Ho, 1985). Noradrenergic terminals mainly originate within the locus coeruleus and are found within all layers of the cerebellar cortex and cerebellar nuclei (Hökfelt and Fuxe, 1969; Olson and Fuxe, 1971; Chan-Palay, 1977). This chapter deals with two of the main sources of mossy fibers, the basal pontine nuclei (including the
The Rat Nervous System, Third Edition
reticulotegmental nucleus) and the lateral reticular nucleus, as well as with the source of the climbing fibers, the inferior olivary complex. In addition, this chapter reviews and discusses the role of the red nucleus in cerebellar functioning. This prominent center in the midbrain, which gives rise to the rubrospinal tract, is intimately related to cerebellar function since it receives a major input from the cerebellar nuclei. It, furthermore, supplies afferents to some important precerebellar centers such as the lateral reticular nucleus and the inferior olive, but also sends input to the cerebellum directly.
PONTINE NUCLEI The basilar pontine nuclei (Pn) consist of a large cluster of rather densely grouped small to mediumsized neurons that are located near the ventral surface of the metencephalon. These nuclei receive a massive input from the cerebral cortex, but also from a number of subcortical brain areas. Their neurons project to the cerebellum by way of the middle cerebellar peduncle and terminate as mossy fiber terminals within the granular cell layer of large areas of the cerebellar cortex. The nucleus reticularis tegmenti pontis or reticulotegmental nucleus, located directly dorsal to the Pn and also providing a major mossy fiber projection to the cerebellum, has several features in common with the pontine nuclei (Schwarz and Thier, 1996) and both are often considered simultaneously. Other authors, however, regard the RtTg as a specialized nucleus of
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the pontine reticular formation (Newman and Ginsberg, 1992) since it differs both in ontogeny (Altman and Bayer, 1987) and in pattern of connectivity (see below) from the Pn. Therefore, it is described in a separate subsection.
Cytoarchitecture The rat Pn cover almost 2 mm in the rostrocaudal direction and are found between the level of the interpeduncular nucleus and that of the trapezoid body. They are surrounded and traversed by a number of large fiber bundles. Laterally, the middle cerebellar peduncle emerges from the Pn. It carries the pontine efferent fibers that course to the cerebellum. Most efferent fibers of the pontine neurons cross the midline at the ventral surface, before entering the middle cerebellar peduncle. Descending fibers of the cerebral peduncle take up a position as the longitudinal fibers of the pons (lfp) in the dorsal part of the Pn but also as scattered bundles throughout the Pn. Ascending fibers of the medial lemniscus are located dorsal to the lfp and the Pn. Four main subdivisions are generally recognized with respect to their position relative to the lfp (Mihailoff et al., 1981b) (Fig. 1). The medial, ventral, and lateral subdivisions consist of rather tightly packed and homogeneously distributed neurons, and the peduncular nuclei immediately surround the lfp. A number of smaller subnuclei may also be identified. However, borders are not easy to delineate between the various subdivisions.
FIGURE 1 Schematized diagram of the pontine nuclei (modified from Mihailoff et al., 1981b). Abbreviations used: dL, dorsolateral pontine area; dM, dorsomedial pontine area; dPd, dorsal peduncular area; L, Lateral nucleus; lfp, longitudinal fascicle of the pons; M, medial nucleus; mcp, medial cerebellar peduncle; ml, medial lemniscus; RtTgC, central part of the reticulotegmental nucleus of the pons; RtTgP, pericentral part of the reticulotegmental nucleus; V, ventral nucleus; vM, ventromedial area; vPd, ventral peduncular area.
Neurons in the Pn have been shown to demonstrate a rather variable morphology. The projection neurons in the dorsal and medial regions of the Pn are generally somewhat larger and possess more dendrites compared to the neurons in the ventral Pn areas. Cluster analysis indicated that these differences are due to a dorsoventral gradient rather than reflecting different cell types (Schwarz and Thier, 1996). Mihailoff and collaborators (1981b), studying Golgi material, suggested that a small population of small neurons displaying local axon collaterals, could indicate an inhibitory feedback mechanism. However, although some of these neurons indeed may be GABAergic, the impact of an intrinsic GABAergic source at best is very limited (Border and Mihailoff, 1985; Aas and Brodal, 1990), or may even be nonexistent (Mock et al., 1999).
Afferents to the Basilar Pontine Nuclei Cerebral Cortex In the rat, most afferents to the Pn arise from layer V neurons located throughout the entire ipsilateral cortex (Legg et al., 1989). However, there are clear regional differences in the relative contribution of each cortical area to the corticopontine system. Most fibers originate from the sensory motor and visual cortices. In addition, the primary auditory (rostral temporal cortex) as well the cingulate, the retrosplenial, and the agranular insular cortices provide an appreciable corticopontine projection also. Relatively small contributions are derived from the caudal temporal cortex and from the perirhinal cortex (Burne et al., 1978; Mihailoff et al., 1978; Wiesendanger and Wiesendanger, 1982a, 1982b; Mihailoff et al., 1985; Legg et al., 1989). The corticopontine fibers usually also send fibers to other subcortical structures (O’Leary and Stanfield, 1985; Ugolini and Kuypers, 1986; Leergaard et al., 1995). Within the corticopontine projections a topographical pattern has been frequently reported. Projections from the motor cortex predominantly terminate in the medial subdivision of the Pn, whereas the somatosensory and visual cerebral cortices project to more central and lateral areas, respectively (Wiesendanger and Wiesendanger, 1982b; Mihailoff et al., 1985). These earlier studies reported that cortical areas containing hindlimb and face representation terminate in one or several clusters that show an essentially longitudinal orientation (also see Panto et al., 1995). However, recent studies using three-dimensional analysis of serial sections indicated that these clusters are not distributed primarily in rostrocaudal columns but in curved and elongated lamellar clusters, displaying an internal-to-external somatotopic arrangement (Leergaard et al., 2000b). As such the
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projections from the peri-oral regions of the head are found in the center of the Pn whereas the projections from extremities and trunk are located in multiple shelllike and complementary regions more externally in the Pn (Figs. 2A and 2B). Hence, within the distribution of corticopontine terminals, the spatial relationships from the major cortical body representations appear to be preserved (Panto et al., 1995; Leergaard et al., 2000b). The establishment of this specific pattern of terminations may be related to the differences in maturation of the cerebral cortex in conjunction with the ontogeny within the Pn as has been hypothized by Leergaard and collaborators (Fig. 2A: Leergaard et al., 1995, 2000b). Also, at even more detailed levels, such as the pontine projection from individual cortical barrel fields, the shell-like, multiple, and essentially inside-out representation of the terminal fields holds true (Fig. 2C) (Leergaard et al., 2000a). The terminal fields of the cortical barrel fields representing whiskers of the same row were found to be located in different shells (anterior whisker represented more centrally, compared to the more posterior whisker), whereas barrels across rows (i.e., located in columns) resulted in terminal fields in the same shell. Despite the fact that the somatotopic pattern of the corticopontine projections is largely preserved in a complementary (i.e., nonoverlapping) way, some overlap (up to 20%) was reported in the pontine projections from the individual barrel fields (Panto et al., 1995; Leergaard et al., 2000a). As yet, the visual corticopontine input has not been investigated in similar detail but was earlier found to terminate predominantly within the lateral third of the basal Pn with exception of its lateral-most part. In addition, small patches of labeling are found rostromedially (Wiesendanger and Wiesendanger, 1982b). Auditory projections arising from the primary temporal cortex are rather weak and terminate ventrally within the lateral third of the nuclei. Anatomical and physiological studies (Ruegg et al., 1977; Potter et al., 1978; Wiesendanger and Wiesendanger, 1982b) have suggested that there are major zones of convergence from widely differing cortical regions. Mihailoff et al. (1981b) attributed this convergence not only to overlap of the corticopontine termination clusters, but also to the tendency of the dendritic trees of the pontine neurons to invade neighboring corticopontine termination zones. However, a detailed morphological study by Schwarz and Thier (1995) showed that the dendritic fields of most pontine projection neurons respect the borders of cortical afferent fields. Cerebellar Nuclei A second major input system to the Pn originates in the cerebellar nuclei (Watt and Mihailoff, 1983a, 1983b; Angaut et al., 1985b; Lee and Mihailoff, 1990; Teune et al.,
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2000; also see Voogd, Chapter 9). Although considerable overlap with the corticopontine projection is evident, the level of specificity between the corticopontine and the cerebellopontine projections remains to be investigated (Leergaard et al., 2000a). The cerebellopontine projection is predominantly contralateral and reaches the Pn via the crossed descending limb of the superior cerebellar peduncle. Fascicles of cerebellopontine fibers leave the main bundle of the descending limb throughout the rostrocaudal extent of the Pn and pass around or through the medial lemniscus and the cerebral peduncle to terminate in the pontine gray. The cerebellopontine system is composed of collateral branches of cerebellar efferent fibers that project to either the thalamus or the inferior olive (Lee et al., 1989) and was claimed to consist, at least in part, of glutamatergic and GABAergic fibers (Border et al., 1986; Border and Mihailoff, 1987). This finding is consistent with an electrophysiological study that reports both excitatory as well as inhibitory monosynaptic responses of Pn neurons as the result of electrical stimulation of the lateral cerebellar nucleus (Lat) (Berretta et al., 1991). However, an ultrastructrural double-labeling study has clearly concluded that the cerebellopontine projection is nonGABAergic (Schwarz and Schmitz, 1997). Also, it was recently shown that electrical stimulation of the Lat is capable of inducing enhanced expression of the immediate early gene c-Fos suggesting that the activity of the cerebellar nuclei may significantly influence activity patterns in the Pn presumably by way of the direct cerebellar nucleopontine projections (Bosco et al., 2000). Although all divisions of the cerebellar nuclei provide input to the Pn, the largest number of cerebellopontine fibers, as well as the largest Pn domain covered by terminal arborizations, are derived from the Lat. Basically, the Lat projections are distributed to three longitudinal columns, one in each major subdivision of the Pn. An inverted topographical pattern in this projection, so that caudal parts of the Lat tend to project to more rostral Pn regions than do the rostral Lat areas, has been described by Angaut and colleagues (1985b). Projections from the interposed nuclei to the Pn appear to be restricted to the ventral peduncular nucleus at more caudal levels of the pontine gray matter. However, according to Watt and Mihailoff (1983a), the interpositus projection may also extend into the ventral pontine subnucleus, where it overlaps with projections from the Lat. The medial cerebellar nucleus provides only few projections to the Pn that are mainly found in the dorsomedial area, where they may partly overlap with projections from the Lat, but also with input from the mammilary nucleus and the cingulate cortex (Wiesendanger and Wiesendanger, 1982b; Watt and Mihailoff, 1983b).
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FIGURE 2 Topographic organization of corticopontine projections in the rat. (A) Diagram of the hypothesis explaining the establishment of the general topographic organization in the rat corticopontine system. Temporal gradients of development, from early to later, are illustrated by dark, medium, and light shading. Early arriving corticopontine fibers (red) innervate the early established central core of the pontine nuclei, whereas later arriving fibers (yellow and blue) innervate progressively more external volumes. Modified from Leergaard et al. (2000b) with permission; see also Leergaard et al. (1995). (B) Three-dimensional surface model of the projections from major SI body representations to the pontine nuclei. (B1) Diagram of the right cerebral hemisphere indicating the position of the SI body map. The different areas of the body map are color coded. (B2) Three-dimensional reconstruction of the corresponding clustered pontine projection regions seen in a ventral view of the brain stem. Note that the clusters together form concentric layers with an overall inside-out organization. Modified from Leergaard et al. (2000a,2000b). (C) Reconstruction showing the topography of pontine terminal fields arising in the rat SI whisker barrel field (modified from Leergaard and Bjaalie, 2002, with permission; see also Leergaard, 2003). (C) (Left) The anterograde tracers biotinylated dextran amine (BDA, blue) and fluororuby (FR, red) were injected into electrophysiologically defined individual whisker representations in SI (upper left inset) and the distribution of labeling was computer reconstructed in three dimensions (lower left inset). (Middle) Computer-generated dot map showing the distribution of BDA-labeled (blue) and FR-labeled (red) fibers within the ipsilateral pontine nuclei. The clusters of red dots surround the clusters of blue dots externally. (Right) The outer boundaries of labeled clusters are demonstrated by solid surfaces. The labeled clusters arising from the same row of SI barrels are located in dual lamellae that are shifted from internal to external.
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Tectum Another important input station to the Pn is provided by the tectum. Especially the superior colliculus sends a major, ipsilateral projection to the peduncular and lateral regions of the caudal Pn. The latter projection appears to be topographically organized: the medial part of the superior colliculus projects primarily to peduncular regions whereas its lateral part rather terminates in the ventrolateral pontine gray. A contralateral projection to the dorsomedial and medial parts of the peduncular subnuclei has also been described (Burne et al., 1981). In the rabbit, it was established (Wells et al., 1989) that the projection is limited to the dorsolateral Pn when the injection was restricted to the superficial laminae of the superior colliculus. Pretectal areas also project to the lateral-most pontine areas but at somewhat more rostral levels. The inferior colliculus appears to provide a rather sparse projection to the lateral Pn areas caudal to the termination fields of the superior colliculus (Burne et al., 1981). Additional visually related input to the Pn is derived from the ventral lateral geniculate nucleus (Ribak and Peters, 1975; Wells et al., 1989). Hypothalamus The hypothalamus, in particular the mammilary nuclei, provides another well-known projection to, primarily, the medial and dorsomedial parts of the pontine gray (Cruce, 1977; Hosoya and Matsushita, 1981; Aas and Brodal, 1988; Mihailoff et al., 1989; Allen and Hopkins, 1990; Liu and Mihailoff, 1999). These projections show convergence with projections from the prefrontal cortex implying that some form of integration of limbic and/or autonomic processes may take place within the Pn (Allen and Hopkins, 1998). Other Sources Apart from the major projections mentioned above, a study by Mihailoff et al. (1989) revealed that the Pn receive afferents from a score of other spinal and brain stem centers, which are very briefly mentioned here. Most of these projections have been confirmed in the cat (Aas, 1989). A spinopontine projection arises from marginal regions of the dorsal nucleus (Clarke’s nucleus: see also Yamada et al., 1985) and terminates predominantly in the caudal Pn. A corresponding projection from the external cuneate nucleus to the caudal Pn has also been identified (Kosinski et al., 1986). In addition, a pontine projection also originates from the dorsal column nuclei and includes an area directly ventrolateral to the cuneate nucleus. This projection mainly arises as collaterals of medial lemniscus fibers that project to the ventral posterolateral nucleus of the
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thalamus (Kosinski et al., 1988b) and was already identified by Ramón y Cajal (1911). Additional somatosensory projections to the Pn arise from the interpolar subdivision of the spinal trigeminal nucleus (Swenson et al., 1984). Spinal, trigeminal, and dorsal column nuclear projections to the Pn provide a pathway for peripheral sensory information to be transmitted rather directly to the Pn, thus contrasting to incoming sensory information from the somatosensory cortex (Azizi et al., 1986; Kosinski et al., 1988a). A vestibulopontine projection originates specifically from the spinal vestibular nucleus and adjacent nucleus X. Reticulopontine projections are described as rather sparse and originate mainly from the ventral reticular, gigantocellular pars alpha and the paragigantocellular nuclei. At least some of these projections appear to be GABAergic (Border et al., 1986). In the cat, it has been shown that a cholinergic pontine input may originate from the dorsolateral pontine tegmentum (Aas et al., 1990). The accessory optic system, such as the medial and lateral terminal nuclei, but also certain accessory oculomotor nuclei such as the nucleus of Darkschewitsch and the Edinger–Westphal nucleus, also provide input to the Pn. Noteworthy, a relatively large, and partially GABAergic (Border et al., 1986), pontine projection arises from the region near the lateral and ventral borders of the red nucleus as well as from the adjacent deep mesencephalic nucleus. A scant projection to the Pn finds its origin from neurons located within the peripeduncular nucleus and adjacent portions of the substantia nigra and from ventral and lateral regions of the periaquaductal gray. Besides the already mentioned diencephalic projection from the ventral lateral geniculate nucleus to the Pn, a notable and predominantly ipsilateral projection arises from the zona incerta (Mihailoff, 1995). Finally, pontine input from the locus coeruleus and from the raphe nuclei suggests noradrenergic and serotonergic projections, respectively. When considering all the subcortical afferent sources to the Pn, it is noted that some of these areas (i.e., dorsal column nuclei, vestibular nuclei, reticular formation) also send mossy fibers to the cerebellum, and, thus, besides establishing a rather direct connection with the cerebellum also may provide an indirect cerebellar pathway via the Pn (Mihailoff et al., 1989). As yet, it is not known if these projections arise as collaterals of the projection to the Pn and so the functional significance of this particular circuitry must await further analysis.
Efferents of the Basilar Pontine Nuclei The Pn project to the cerebellum mostly via the contralateral middle cerebellar peduncle. A sparse to
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moderate projection to the cerebellar nuclei, in particular to the lateral cerebellar nucleus, has been demonstrated with physiological (Shinoda et al., 1992) and anatomical techniques (Eller and Chan-Palay, 1976; Mihailoff, 1993, 1994) but could not be substantiated anatomically in the cat (Dietrichs and Walberg, 1987). The relative sparsity of the, presumably collateral, projection to the cerebellar nuclei from the Pn contrasts the clear-cut and rather dense collateral projection which arises from the reticulotegmental nucleus of the pons (Gerrits and Voogd, 1987; Mihailoff, 1993). Pontocerebellar fibers terminate as mossy fibers in the granular cell layer where they are distributed widely in the hemispheres, including the paraflocculus, and to the vermal lobules VI to IX. The vestibulocerebellar parts (nodulus and flocculus) as well as the anterior lobe do not appear to receive a pontocerebellar innervation, although Gerrits (1985) demonstrated a major pontine projection to especially the intermediate and hemispheral parts of the contralateral anterior lobe in the cat. Some evidence suggests that pontocerebellar mossy fibers use glutamate as the major transmitter (Beitz et al., 1986; Border and Mihailoff, 1991). It is generally believed that the pontocerebellar projection is precisely organized and characterized by complex patterns of convergence as well as divergence; that is, it has been demonstrated that single pontine neurons can project to two different lobules within the same hemisphere or even to both hemispheres (Mihailoff, 1983; Rosina and Provini, 1984). Convergence is readily apparent in retrograde transport studies where relatively small cortical injections may label different areas within the Pn (Azizi et al., 1981; Eisenman, 1981; Mihailoff et al., 1981a). Nevertheless, in the cat, it has been suggested that the projections to paraflocculus are mostly governed by topographical patterns. Layers of pontine neurons project to different parafloccular folia as was demonstrated in this anatomical study employing multiple fluorescent tracers (Nikundiwe et al., 1994). The number of double labeled pontine neurons as well as the position of lamellar-like layers of labeled pontine neurons was strongly dependent on the interfoliar distance of the injection sites. In a recent anterograde study in the rat, it was shown that labeling of relatively small groups of pontine neurons results in mossy fiber projections to multiple, parasagittally organized, strips of cerebellar cortex, which were observed bilaterally but with a contralateral preponderance (Serapide et al., 2001). The strips with mossy fiber terminals were well-defined and frequently sharply bordered. Even the smallest injections still resulted in the labeling of multiple strips, whereas larger injections failed to show a zonal-like pattern of termination. The authors conclude that the pontocerebellar projection is
organized in multiple pathways that project to specific sets of strips of cerebellar cortex. Since the corticonuclear projection also follows a zonal pattern, with each output to a different part of the cerebellar nuclei, which in turn are suggested to subserve different functional purposes, it would be interesting to study the potential relation between the corticonuclear and pontocortical zonal organization. Mostly due to the converging and diverging termination characteristics, it is still difficult to describe the precise anatomical relations between the Pn and the cerebellum. Using retrograde tracer techniques, it has been possible to state that the posterior vermis mainly receives pontine-relayed afferences from visual, auditory, and somatosensory regions of the cerebral cortex. In addition, certain areas of lobules VI and VII also receive mossy fibers from pontine regions that are under tectal influence (Azizi et al., 1981). In line with the anterograde study of Serapide et al. (2001), a parasagittal organization of pontocerebellar projections was also established for lobule VIII (Eisenman, 1981). A medial zone receives mossy fibers from medial and ventrolateral regions of the caudal part of the pontine gray; an intermediate zone from the intermediate pontine region; and a lateral zone from medial, ventrolateral, and dorsal areas of the pons. Pontocerebellar projections to the hemispheres, originate from many regions in the Pn (Mihailoff, 1993). It was noted that the projections to the lobulus simplex are organized rather differently from those to the other hemispheral components because most of its mossy fibers originate from neurons located ipsilaterally within the ventral part of the rostal pontine gray. Crus I receives most mossy fibers from neurons distributed along the medial, ventral, and lateral regions of the contralateral pontine gray, whereas more central pontine areas project to the Crus II. The paramedian lobule is supplied by mossy fibers emanating from the central region of the contralateral pons. The peduncular subnuclei also supply mossy fibers to the cerebellar hemispheres. The paraflocculus receives a projection from a medial and a lateral column of cells as well as from scattered neurons within the peduncular subnuclei, which may convey both auditory and visual signals (Azizi et al., 1985; Glickstein and Stein, 1991). Different pontine projections are directed to the dorsal and ventral paraflocculus (Eisenman, 1980), which may well reflect the difference in function of these two parafloccular regions (Gerrits and Voogd, 1982; Gerrits et al., 1984; Azizi et al., 1985).
Functional Considerations The Pn tie the cerebral and the cerebellar cortices via two conspicuously large fiber bundles, i.e., the cerebral
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peduncle and the medial cerebellar peduncle. However, it has become evident that the Pn itself is not a mere link between both cortices but can also be seen as a major integrating center. Not only because different cerebral cortical areas may converge upon individual pontine neurons (Ruegg et al., 1977; Potter et al., 1978; Leergaard et al., 2000a, 2000b), but also since many diverse brain stem centers as well as the spinal cord also provide an input to the Pn (Mihailoff et al., 1989). It is interesting that many of these centers also provide a direct mossy fiber input to the cerebellum. Finally, cerebellar output feeds back into the Pn mostly by nonGABAergic pathways. As such, the Pn cannot be interpreted as a mere station of passage of the information flow from cerebrum to cerebellum, but should be regarded as a highly integrative center, capable of updating the cerebellum with integrated information on ongoing somatosensorimotor, visual, auditory, and autonomic and affective processes. Glickstein and Stein (1991), have suggested that the visual and somatosensory input to the Pn and their relay to the cerebellum may present an important pathway for the control of visually guided movements. Schwarz and Thier have recently argued that the Pn are specifically adapted to form a necessary interface enabling cerebellar processing of cerebral information. The necessity of such an interface would transpire from the greatly different computational principles that govern the cerebral cortex and the cerebellum (Schwarz and Thier, 1999).
Reticulotegmental Nucleus of the Pons The reticulotegmental nucleus of the pons (RtTg) is located dorsal to the medial lemniscus, along the midline. It appears to be continuous with the dorsomedial aspect of the pontine gray, especially at rostral levels. Whether or not the neurons located within the medial lemniscus should be regarded as part of the RtTg or of the Pn remains a matter of conjecture (Mihailoff et al., 1988; Schwarz and Thier, 1996). Torigoe et al. (1986b) describe two cytoarchitectonically distinct portions of the RtTg. A central part (RtTgC) consists of rather tightly packed cells, whereas a pericentral part (RtTgP) is composed of loosely packed small neurons. The RtTgC is located dorsal to the medial lemniscus over the caudal two thirds of the Pn. At some points it is continuous with the dorsomedial Pn area (Mihailoff et al., 1981b). Caudal to the Pn, the RtTg extends caudodorsally until it dissipates just rostral and ventral to the abducens nucleus. The pericentral part is found at the dorsolateral margins of the RtTgC rostrally, but is positioned ventral to its caudal part (Fig. 1). Schwarz and Thier (1996), based on a morphological study of intracellularly injected projection neurons in both Pn
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and RtTg, claim that differences in size and dendritic pattern of these cells can be explained by a dorsoventral gradient that basically ignores the border between both nuclei. RtTg afferents originate from the cerebellar nuclei, the cerebral cortex, and a number of brain stem centers. Excitatory cerebellar afferents are mainly derived from the Lat and, to a lesser degree, from the interposed nuclei (Angaut et al., 1985a; Torigoe et al., 1986a; Schwarz and Schmitz, 1997; Verveer et al., 1997; Buisseret-Delmas et al., 1998; Teune et al., 2000). Afferents from the cerebral cortex stem from layer V neurons. The cingular cortex, thought to be homologous with the frontal eye fields of the cat and primates, projects to the RtTgC, whereas the pericentral RtTg receives afferents from the somatomotor cortex, in particular (Torigoe et al., 1986b). Brain stem projections arise from various visuomotor areas such as the nucleus of the optic tract, the contralateral superior colliculus, the medial terminal nucleus, the ventral lateral geniculate nucleus, the ventral tegmental relay zone, the anterior and posterior pretectal nuclei, and the supraoculomotor periaquaductal gray. Moreover, a number of areas that may subserve a wider variety of motor behaviors also supply afferents to the RtTg, such as the zona incerta, the fields of Forel, the interstitial nucleus of the mlf, the vestibular nuclei, and the reticular formation (Burne et al., 1981; Torigoe et al., 1986a; Redgrave et al., 1987; Gayer and Faull, 1988; Matsuzaki and Kyuhou, 1997). A limbic input is furthermore supplied via afferents from the mammilary nuclei, the lateral hypothalamic area, the habenula, the preoptic nuclei and the diagonal band of Broca (Cruce, 1977; Terasawa et al., 1979; Hosoya and Matsushita, 1981; Torigoe et al., 1986a; Allen and Hopkins, 1990). The RtTg sends mossy fibers to most lobules of the cerebellar cortex with a slight contralateral preponderance. In the cat only the nodulus is reported to be devoid of RtTg afferents (Gerrits and Voogd, 1986). Strong RtTg input has been described to terminate within the flocculus and ventral paraflocculus and the oculomotor vermal areas of lobules VI, VII and VIII (Blanks et al., 1983; Cazin et al., 1984; Yamada and Noda, 1987; Gayer and Faull, 1988; Päällysaho et al., 1991). Mossy fiber input to the flocculus arises from caudal regions in the RtTg whereas projections to the paraflocculus originate from more rostral parts (Osanai et al., 1999). Collaterals of the RtTg mossy fibers terminate within the Lat and, to a lesser degree, in the interposed nuclei (Brodal et al., 1986; Gerrits and Voogd, 1987; Schwarz and Schmitz, 1997; Verveer et al., 1997). Furthermore, RtTG efferents have been described to terminate within the medial vestibular nucleus of the rabbit (Balaban, 1983), the nucleus prepositus hypoglossi of the rat (Cazin et al., 1984; Korp et al., 1989), and even the visual cortex of
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the mouse (Castaneyra-Perdomo, 1984). It is not known if the same neurons also provide input to the cerebellum. Due to the input of many visuomotor centers to the RtTg and its projection to the oculomotor vermis and flocculus, it is obvious that this precerebellar nucleus functions as an important relay center for optokinetic processes and various visuovestibular interactions (Averbuch-Heller and Leigh, 1996; Buttner-Ennever and Horn, 1997). However, lesion, behavioral, and electrophysiological studies have implied that many neurons of the RtTg may be involved in the execution of movements and locomotion as well (Chesire et al., 1983, 1984; Brudzynski and Mogenson, 1984; Matsunami, 1987; Hammer and Klingberg, 1991). Whether or not this behavioral involvement of the RtTg is in any way related to the visuomotor input and/or to the limbic inputs of the RtTg remains to be determined.
LATERAL RETICULAR NUCLEUS The lateral reticular nucleus (LRt) is situated ventrally in the medulla oblongata, dorsolateral to the inferior olivary complex and ventromedial to the spinal tract of the trigeminal nerve. Its caudal pole first appears slightly caudal to the inferior olive and it extends to the level of the rostral quarter of the inferior olive. As a major source of mossy fiber projections to the cerebellar cortex, the LRt plays an important role in the control of motor activity and coordination, especially when related to the realization of fine and target-reaching movements of the forelimb (Oscarsson, 1958; Clendenin et al., 1974b; Illert et al., 1977; Arshavsky et al., 1978; Alstermark et al., 1987b; Ekerot, 1990a). More recently, involvement of the LRt in nociceptive processes has received increasing attention (Murphy and Behbehani, 1993; Ness et al., 1998). In particular neurons with descending projections to the dorsal horn of the spinal cord are thought to play a role in these processes (Gebhart and Ossipov, 1986; Liu et al., 1989, 1990). However, although precerebellar neurons within the LRt have been implicated, especially in visceral nociceptive processing (Ness et al., 1998), as yet, it is not known to what extent precerebellar LRt neurons are involved in these processes (Lee and Mihailoff, 1999). Here, we discuss the LRt only as a structure that mainly consists of precerebellar neurons.
Cytoarchitecture As a “reticular” nucleus in the very general sense of the word, the boundaries of the LRt cannot always be precisely defined. Only at caudal levels can its contours be clearly delineated, while at rostral levels the nucleus becomes more diffuse and sometimes poorly discernible
from the surrounding reticular formation. The caudorostral extension of the LRt is about 2800 μm, while mediolaterally and dorsoventrally its greatest dimensions are about 1400 and 800 μm, respectively. Kapogianis et al. (1982a) estimated the caudorostral length of the LRt to be about 1000 μm shorter. This discrepancy is due to the fact that the rostral pole of the LRt has been redefined. Using immunohistochemical techniques, Kaneko et al. (1989) first suggested that Paxinos and Watson’s (1986) linear nucleus of the medulla should be included in the LRt, a hypothesis that was confirmed by a retrograde tracing study of Newman and Ginsberg (1992) and by cytologic, enzyme histochemical, and anterograde and retrograde transport studies of Cella et al. (1992). In most mammals studied, it is possible to recognize a parvicellular, a magnocellular, and a subtrigeminal part within the LRt (Brodal, 1943; Walberg, 1952; Valverde, 1961; Ramón-Moliner and Nauta, 1966; Kitai et al., 1972; Hrycyshyn and Flumerfelt, 1981a; Hrycyshyn et al., 1982; Kapogianis et al., 1982a). However, in each subdivision, cells of a predominant average diameter are intermingled with cells of other sizes (Kapogianis et al., 1982b). The subtrigeminal part is characterized by predominantly medium-sized cells, but comprises many large cells as well. Moreover, the only distinct subdivision is represented by the subtrigeminal part, while the magnocellular and the parvicellular subdivisions partially overlap, particularly at midrostral levels. Their boundaries, therefore, remain arbitrary (Menétrey et al., 1983; Shokunbi et al., 1986). Caudally, in transverse sections, the LRt first appears at about 200 μm below the caudal pole of the inferior olive as a cluster of cells which rapidly develops into a principal, dorsomedially oriented, ovoid part and a more superficially located cell strip which is connected to the principal division by thin bridges of neuropil. Through this caudal extension of the LRt, it is possible to approximately delineate its magnocellular part first dorsomedially (stippled area in Fig. 3, levels 1–3) and then dorsomedially and dorsolaterally (Fig. 3, levels 4 and 5), while its parvicellular part corresponds to the ventral region of the principal LRt and to the strip of cells running along its ventrolateral boundary. At about 800 μm of the LRt length, the medial portion of this strip begins to fuse with the principal division, while the thin connecting bridges become progressively larger until no separation is left between the medial twothirds of the strip and the principal LRt. The lateral third of the strip virtually disappears. The very lateral part of the LRt now begins to develop in what more rostrally will become the subtrigeminal division (Fig. 3, levels 6–8). At the same levels, the ventral displacement of the caudo- and rostroventrolateral reticular nucleus (CVL and RVL) (Paxinos and Watson, 1986), joined a
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FIGURE 3 Diagrammatic representation of the rat inferior olivary complex and lateral reticular nucleus (LRt), based on transverse sections, spaced 160 μm. Caudal is at the bottom left (level 1); rostral is at the top right (level 21). The various olivary subdivisions are indentified by different hatching patterns. Abbreviations used: Amb, nucleus ambiguus; IOD, dorsal accessory olive; dfIOD, dorsal fold of IOD; DC, dorsal cap of Kooy; DM, dorsomedial group; DMCC, dorsomedial cell column; CVL, caudoventrolateral reticular nucleus; β, nucleus β; Li, linear nucleus of the medulla; LRtm, magnocellular part of the LRt; LRtp, parvicellular part of the LRt; LRts5, subtrigeminal part of the LRt; PO, principal olive; RVL, rostroventrolateral reticular nucleus; VLO, ventrolateral outgrowth; IOM, medial accessory olive. Bar equals 1 mm.
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little more rostrally by the nucleus ambiguus, causes a flattening and indentation of the dorsal boundary of the LRt. Ultimately this leads to the division of the LRt into a medial and a lateral (subtrigeminal) subdivision (LRtS5, Fig. 3, levels 7–10). Along with these developments in the morphology of the LRt, a rearrangement of the internal cytoarchitecture also takes place: the magnocellular part now has shifted ventromedially, but many large cells are also located within the surrounding parvicellular areas. Of the two divisions in which the LRt has been split by the CVL/RVL, the medial one is rather well-defined in its ventral aspect, while its dorsal part is more diffuse with two cell-poor extensions toward the medial reticular formation (Fig. 3, levels 10–14). The lateral division, on the other hand, has wellcircumscribed boundaries throughout its extent and represents the most rostral subdivision of this nucleus. Roughly triangular in shape at more caudal levels, it becomes progressively narrower in its mediolateral diameter while extending dorsally to adapt the form of a diagonal bar (nucleus linearis, Li). This part of the LRt consists of a long arm, directed dorsomedially, and of a short arm, directed more medially. The medial extremity of this short arm shows a tendency to bend steeply ventrally, but the boundaries at this point are less distinct than those at the lateral side. Finally, the two arms of the nucleus progressively shorten until their joining point remains as the rostral-most part of the LRt (Fig. 3, level 18).
Afferents to the Lateral Reticular Nucleus Data available from investigations in different mammals indicate that the main afferent input to the LRt is a bilateral, topographically organized projection from the spinal cord (Brodal, 1943; Morin et al., 1966; Kunzle, 1973; Mizuno and Nakamura, 1973; Corvaja et al., 1977; Martin et al., 1977; Corvaja and d’Ascanio, 1981; Hrycyshyn and Flumerfelt, 1981b; Flumerfelt et al., 1982; Menétrey et al., 1983; Shokunbi et al., 1985; Westman et al., 1986; Cella et al., 1991; Rajakumar et al., 1992). Moreover, the LRt receives afferents from several supraspinal centers, such as the contralateral red nucleus, the medial cerebellar nucleus, the cerebral cortex, the vestibular nuclei, and, as demonstrated in the cat, the superior colliculi and the hypothalamus (Kuypers, 1958; Walberg, 1958a; Walberg, 1958b; Hinman and Carpenter, 1959; Walberg and Pompeiano, 1960; Kawamura et al., 1974; Künzle and Wiesendanger, 1974; Corvaja et al., 1977; Hrycyshyn and Flumerfelt, 1981b; Qvist et al., 1984; Dietrichs et al., 1985; Shokunbi et al., 1986; Rajakumar et al., 1992). Current knowledge about the organization of the massive spinal input to the LRt has been mainly derived
from electrophysiological studies in the cat, which have revealed the existence of at least three distinct afferent tracts, all ascending in the lateral funiculus of the spinal cord, namely, the bilateral ventral flexor reflex tract (bVFRT), the ipsilateral forelimb tract (IFT) and a group of propriospinal neurons located in the third and fourth cervical segments (Holmqvist et al., 1960; Lundberg and Oscarsson, 1962; Rosén and Scheid, 1973a, 1973b; Clendenin et al., 1974b; Clendenin et al., 1974c; Illert et al., 1978; Alstermark et al., 1981a, 1984; Ekerot, 1990a, 1990b, 1990c). Apart from the three tracts in the lateral funiculus, one ascending tract in the dorsal funiculi has been distinguished (Clendenin et al., 1975; Ekerot, 1990a), but not yet completely characterized. The spinal projections to the LRt have been shown to result in both monosynaptic excitatory and inhibitory responses. No comparable experiments, however, have been performed in the rat and no conclusive data yet exist about the anatomical equivalent of the physiologically identified spinal pathways. The following data on the spinal afferents to the LRt only refer to retrograde and anterograde tracer studies performed in the rat and demonstrate the projecting spinal cells and their termination area within the LRt. As a result of the retrograde labeling following HRP injections in the LRt, Menétrey et al. (1983) found that labeled neurons were present at all spinal levels and in particularly large numbers in the cervical and lumbar enlargements. Labeled cells were located, with contralateral predominance, in all segments of the spinal cord, within laminae VII, VIII, and X, in the reticular expansion of the dorsal horn, in the superficial layers of the dorsal horn, and in the nucleus of the dorsolateral funiculus. Next to this labeling pattern common to all spinal segments, a specific pattern was shown to be exclusively present in the cervical and lumbar enlargements, which contained additional labeled neurons in the ipsilateral lamina VII and in the contralateral laminae III and IV, respectively. These results were only partly confirmed by Shokunbi et al. (1985), who, using the same technique, showed that discrete HRP placements in the caudomedial part of the LRt resulted, in the cervical segments, in labeled cells mainly in laminae V and VII and, less heavily, in laminae III and IV ipsilaterally, in laminae VII and VIII contralaterally, and in lamina X. At thoracic levels, few cells were labeled bilaterally in lamina VII, while the lumbar segments showed a certain amount of labeled neurons in the contralateral lamina VIII and adjacent lamina VII. Injections of HRP in the caudolateral part of the LRt, instead, resulted in retrograde labeling of a few ipsilateral cervical neurons located in lamina VII and a prominent labeling of the contralateral lumbar segments, where the HRP-containing cells were mainly located in
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laminae IV and V. No labeled neurons were encountered within the superficial-most laminae of the dorsal horn. This last conclusion was in accordance with a retrograde and anterograde transport study by Cella et al. (1991) who noticed that small injections of WGA–HRP in the dorsal LRt regions mainly resulted in retrogradely labeled cells within the ipsilateral cervical cord. Injections placed in the ventral LRt predominantly labeled neurons located bilaterally within the lumbar spinal cord. Subtrigeminal injections are characterized by a combination of bilateral cervical and lumbar labeling. The anterograde labeling in the LRt subsequent to injections with Phaseolus vulgaris-Leucoagglutinin (PHA-L) in the spinal cord resulted in four different labeling patterns, depending on the segmental level and laminae where the injection had been placed. Injections in the cervical enlargement demonstrated, when placed in the dorsal horn, an essentially ipsilateral projection to the LRt, in the caudal dorsolateral magnocellular area of the nucleus and, when placed in ventral horn, a bilateral projection to the LRt, in a more dorsomedial magnocellular area. Instead, injections in the lumbar enlargement demonstrated a bilateral projection to the LRt in more ventral, parvicellular areas. Termination patterns varied only slightly with injections placed in either dorsal or ventral horn. Labeled terminals were occasionally found in the rostromedial and rostrolateral regions of the LRt, which fits the attribution of these two areas to the LRt. These results are somewhat at variance with those obtained by Rajakumar et al. (1992), who, using anterograde transport of WGA–HRP, failed to note an ipsilateral spinoreticular projection arising from lumbar levels. Furthermore, they were unable to differentiate between dorsal and ventral horn projections. Common to these different studies is the finding that the largest amount of spinal neurons projecting to the LRt is found within the cervical and lumbar enlargements and that a specific ipsilateral pathway takes its origin from the cervical cord. It is attractive to speculate that these two different projecting patterns to the LRt could represent anatomical equivalents of the physiologically demonstrated iFT and bVFRT of the cat, respectively. Apart from these considerations most retrograde and anterograde tracer studies basically resulted in bilateral labeling patterns in the spinal cord and LRt, respectively. However, a retrograde double labeling study by Koekkoek and Ruigrok (1995) demonstrated that individual spinoreticular neurons located throughout the spinal cord project to either the ipsilateral or the contralateral LRt, but only seldom to both regions simultaneously. In conclusion, it is obvious that the anatomical projections of the spinal cord to the LRt, related to the establishment of multiple, physiologically distinguishable, spinoreticular tracts, suggest a highly
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complex functional organization of the spinoreticulocerebellar pathway. In the cat, physiological evidence was found that part of the spinoreticular projection may arise as collaterals of the spinocerebellar pathway (Alstermark et al., 1990). However, for the rat no systematic study seems to be available on the degree of collateralization of the spinoreticular, spinocerebellar, and spinoolivary projections. With respect to the nonspinal afferents to the LRt the rubral projection appears to be the most extensive. It arises from neurons in the caudal two-thirds of the contralateral red nucleus. In a retrograde tracer study employing HRP, Shokunbi et al. (1986) showed that terminals of neurons located ventrally and ventrolaterally in the red nucleus distributed terminals to the rostrolateral part of the LRt, while neurons located dorsally and dorsomedially projected to the rostromedial LRt. In a subsequent anterograde study using WGA–HRP (Rajakumar et al., 1992), only a small projection from the contralateral red nucleus to the lateral part of the rostral half of the LRt was found. It is generally believed that the rubral projection to the LRt consists of collateralizing rubrospinal tract fibers. A cerebellar input to the LRt mostly arises from the medial cerebellar nucleus (Shokunbi et al., 1986; Rajakumar et al., 1992; Teune et al., 2000). According to Shokunbi and colleagues (1986), this projection is bilateral with ipsilateral preponderance and distributes diffusely throughout the LRt, particularly to its ventral and medial parts, whereas Rajakumar et al. (1992) found that medial afferents only terminated in the contralateral LRt, mainly in the dorsomedial aspect of the rostral twothirds of the magnocellular division. It was noticed by Rajakumar et al. (1992) that these different results might be due to the use of different tracers and the possible uptake of HRP by passing fibers. The input from the cerebral cortex is scant in the rat. Shokunbi et al. (1986) as well as Rajakumar et al. (1992) agree by reporting that it arises from neurons located in layer V of the contralateral frontoparietal sensorimotor cortex and which project to the rostromedial part of the LRt. Projections from the anterior pretectal nucleus to the ventrolateral regions of the caudal medulla oblongata also incorporate the LRt and have been suggested to be related to the nociceptive functions of this region (Zagon et al., 1995). It can be concluded that, while spinal projections to the LRt have already been rather extensively investigated, much less is known about supraspinal afferents to the LRt. Most authors agree in attributing to the caudal one-half of the nucleus the function of integrating the various spinal signals, while the middle third of the nucleus, where rubral, cerebellar, and spinal terminals appear to overlap, would subserve the function of integrating spinal and supraspinal impulses to the
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cerebellum. The rostral part of the LRt could take part in a separate corticocerebellar pathway. On the afferents to the newly defined LRt areas (i.e., the rostromedial and linear parts) no specific experimental data appear to be available.
Efferents of the Lateral Reticular Nucleus The LRt represents one of the most important sources of mossy fibers to the cerebellar cortex, also reaching, by way of collaterals, the cerebellar and lateral vestibular nuclei (Brodal, 1975; Künzle, 1975; Bishop et al., 1976; Matsushita and Ikeda, 1976; Chan-Palay, 1977; Martin et al., 1977; McCrea et al., 1977; Dietrichs and Walberg, 1979; Eisenman, 1982; Hrycyshyn et al., 1982; Dietrichs, 1983; Payne, 1987; van der Want et al., 1987; Qvist, 1989b; Päällysaho et al., 1991; Ruigrok et al., 1995; Parenti et al., 1996; Wu et al., 1999). A few authors also report a minor efferent path to the inferior olive, suggesting a possible role of the LRt within the spinoolivocerebellar system (Brown et al., 1977; Swenson and Castro, 1983a). The LRt projection to the cerebellar cortex passes through the ipsilateral inferior cerebellar peduncle and terminates as mossy fibers in the granular cell layer. Although the pathway is mainly uncrossed, a single nucleus projects to both sides of the cerebellum, except for the input to the lobulus paramedianus, which is exclusively ipsilateral. The mossy fiber terminal arborizations within the cortex are arranged, at least partly, in parasagittal bands (Eisenman, 1982; Hrycyshyn et al., 1982; Wu et al., 1999), possibly interdigitating with the mossy fibers arriving by way of the cuneocerebellar tract (Voogd et al., 1969). Studies using electrophysiologic techniques in the cat, retrograde fluorescent double-labeling techniques in the rat, and a single fiber anterograde study in the rat have demonstrated that individual LRt neurons may innervate both left and right sides of the cerebellar hemispheres, both within and between parasagittal zones (Clendenin et al., 1974a; Payne, 1983; Ghazi et al., 1987; Payne, 1987; Wu et al., 1999). In the rat as well as in the cat, the LRt mossy fibers project to lobules I through V of the anterior lobe, to the rostral part of lobule VI, to the most caudal part of lobule VII, to lobule VIII, to the medial part of the ansiforme lobule, and to the simple and paramedian lobules. Minor projections have also been demonstrated to the caudal part of lobule VI, to the rostral part of lobule VII, to the lateral part of the ansiforme lobule, to the paraflocculus, and to the flocculonodular lobe (Brodal, 1943; Clendenin et al., 1974a; Künzle, 1975; Kimoto et al., 1978; Dietrichs and Walberg, 1979; Eisenman, 1982; Hrycyshyn et al., 1982; Payne, 1987; Qvist, 1989a; Päällysaho et al., 1991).
There is agreement among different authors that within the anterior lobe, lobules II and III, the classic hindlimb-related area, receive input mainly from the ventral, parvicellular LRt, which in turn receives mainly terminals from lumbosacral neurons (see above). Lobules IV and V, which constitute the forelimb area, receive input mainly from the magnocellular LRt, which is the predominant relay station for the cervical cord. Moreover, the pyramis (lobule VIII) is supplied exclusively by the parvicellular LRt and the copula pyramidis by the subtrigeminal part. The simple, ansiform and paramedian lobules mainly receive projections from the magnocellular LRt (Eisenman, 1982; Hrycyshyn et al., 1982). However, a considerable overlap characterizes the projections from different LRt regions to the various subdivisions of the cerebellum, suggesting a rather diffuse organization of the LRt– cerebellar system. Both in the cat and the rat, the LRt projection to the vermis is much denser than the projections to the hemispheres, but in the rat, unlike in the cat, the projection to the anterior part of the cerebellar hemispheres notably exceeds the one to the lobulus paramedianus. In the rat, as well as in the opossum, it is suggested that the LRt projection also reaches nonspinal areas of of the cerebellum, like the simple and ansiforme lobules (Künzle, 1975; Martin et al., 1977). Moreover, the topographic arrangement in the projection of the LRt found in the cat, has been denied (Eisenman, 1982) or could be only partly confirmed (Hrycyshyn et al., 1982) for the rat. Very little is known about the cerebellar projections arising from the rostromedial and rostrolateral regions of the LRt, but there is agreement between the results of Newman and Ginsberg (1992) and of Cella et al. (1992) in showing that these two areas participate in the ascending pathway to the cerebellum. The cerebellar nuclei as well as the lateral vestibular nucleus also receive predominantly ipsilateral projections from the LRt (Ruigrok et al., 1995; Parenti et al., 1996; Wu et al., 1999). According to the detailed retrograde study by Parenti et al. (1996), the lateral cerebellar nucleus receives its terminals mostly from the rostral dorsomedial LRt, whereas the interposed nuclei are targeted by efferents from its dorsolateral and central parts. Finally, the caudal regions of the intermedioventral region would seem to prefer to project to the medial cerebellar nucleus. However, Wu et al. (1999) showed that individual neurons can provide collaterals to multiple nuclei simultaneously. Neurons within the boundaries of the LRt have been reported to project to the spinal cord (e.g., Janss and Gebhart, 1988; Liu et al., 1989). Some of these cells may possess collaterals to the periaquaductal central gray (Lee and Mihailoff, 1999). However, as yet it is not
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known if and, if so, to what extent these cells project to the cerebellum.
Functional Considerations From the afferent projections to the LRt it will be obvious that this center is predominantly concerned with the regulation of somatic sensorimotor events. Spinal and supraspinal impulses necessary for the control of movements of the ipsilateral forelimb are integrated and possibly related or coordinated with motor activity in other parts of the body. The outcome of LRt integrative properties is relayed to the cerebellum where additional integrative processes result in an adequate cerebellar output (Parenti et al., 1996; Ezure and Tanaka, 1997). Of the three characterized spinal pathways, the bVFRT, the iFT, and the C3–C4 propriospinal neurons, the first is thought to participate in a more global motor control while the latter two appear to be specifically related to the movements of the ipsilateral forelimb (Clendenin et al., 1974b, 1974c; Alstermark et al., 1981b; Ekerot, 1990c). These two general functions to which the LRt contributes very probably correspond to different regions of the nucleus, although some overlap may exist. Not only do they receive inputs from different levels of the spinal cord but they also send afferents to different regions of the cerebellum. In the regulation of sensorimotor control, the bVFRT has the specific characteristic of being activated by cutaneous afferents as well as by group II and III muscle afferents that participate in limb flexor reflexes (Eccles and Lundberg, 1959). Moreover, the integration and transfer of information concerning peripheral motor behavior is also influenced by descending motor pathways, since the bVFRT is monosynaptically activated by stimulation of the lateral vestibulospinal tract (Holmqvist et al., 1960; Clendenin et al., 1974b). This integration of input is indicative for the role of the bVFRT in postural control and coordination of movements and it has suggested that the bVFRT carries information about activity in spinal motor centers influenced by segmental afferents and descending motor paths (Clendenin et al., 1974b; Arshavsky et al., 1978). Besides the inhibitory and excitatory inputs mediated by the bVFRT, single LRt units responding to peripheral stimuli have also been shown to receive inhibitory or excitatory input from the cerebral cortex (Agree and Kitai, 1967). Indeed, a direct route from the cerebral cortex reaches the LRt through the pyramidal tract, while an indirect cortical influence is probably mediated by the red nucleus (Allen and Tsukahara, 1974). The combination of both excitatory and inhibitory cortical control of the LRt may serve as a mechanism
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for fine regulation of the tonic excitatory drive from the LRt to the cerebellar granule cells and cerebellar nuclei (Shokunbi et al., 1986). With regard to the motor control of the ipsilateral forelimb, the C3–C4 propriospinal neurons play an important role in target-reaching movements (Alstermark et al., 1981b). These neurons are activated by the corticospinal, rubrospinal, and tectospinal tracts but also, though weakly, by afferents of the ipsilateral forelimb (Illert et al., 1977; Alstermark et al., 1987a, 1987b, 1987c; Ekerot, 1990a, 1990b). In the rat, it is not known if the neurons in the central cervical nucleus (Verburgh et al., 1989) have similar characteristics. The iFT controls fine movements of the forelimb, such as grasping movements following the target-reaching movement. It is strongly activated from peripheral receptive fields of the ipsilateral forelimb. Both the bVFRT and the iFT consist of an inhibitory and an excitatory component (I-iF and E-iF) (Ekerot, 1990b). The large number of LRt neurons with a convergent input from the bVFRT and the I-iF tract suggests that the two functional parts of the LRt represent different aspects of a common physiologic system (Ekerot, 1990a, 1990b, 1990c). It has been suggested that the LRt is involved not only with sensorimotor activity but also with pain mechanisms, because electrical stimulation of brain stem sites, including the LRt, has been shown to modulate or suppress nociceptive reflexes (Sessle and Hu, 1981; Dostrovsky et al., 1982; Gebhart and Ossipov, 1986; Tanaka and Toda, 1986; Liu et al., 1990; Sotgiu and Bellinzona, 1991; Mineta et al., 1995). Moreover, a retrograde tracer technique study concerning spinal afferents to the LRt (Menétrey et al., 1983) has shown that the lateral portion of the nucleus may receive a projection from laminae I and II of the dorsal horn. These two laminae of the dorsal horn are known to receive terminals from thin afferent (Aδ and C) fibers. However, the location of these neurons within the boundaries of the LRt as well as their participation as a precerebellar source is doubted (e.g., see Shokunbi et al., 1986; Cella et al., 1991; Tavares and Lima, 1994; Lee and Mihailoff, 1999). Neuroanatomical and electrophysiologic studies have implicated the LRt in controlling autonomic cardiovascular activity. Some authors consider the LRt as a part of the system of neuron populations known in the cat as the ventrolateral medulla (VLM) (Henry and Calaresu, 1974; Loewy and McKellar, 1981; Spyer, 1981; Reis et al., 1984; Ciriello et al., 1986; Duffin and Aweida, 1990). However, as yet, the relation, if any, between the LRt and the VLM is far from clear. Furthermore, it must be noted that the involvement of the LRt in cardiorespiratory events may be also related to its functions in motor control, since the mechanic respiratory movements also depend on pure somatic motricity (Cella
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et al., 1991). Indeed, a convergence of information on respiratory and locomotor rhythms on the same neurons within the LRt has recently been demonstrated (Ezure and Tanaka, 1997). The role of the linear and rostromedial parts of the LRt also remains to be elucidated. Therefore, at the moment, it is premature to attempt a more global explanation of the way the various functional properties of the LRt complete or influence each other or to try to define which of its regions are specifically involved in a particular function.
INFERIOR OLIVARY NUCLEUS The inferior olivary nuclear complex is a prominent bilateral aggregation of neuronal cells located ventromedially in the caudal part of the medulla oblongata. It receives afferent connections from many different sources in the brain stem and spinal cord. Its efferent fibers are the sole source of cerebellar climbing fibers (Desclin, 1974) and, as such, this nucleus has a marked effect on cerebellar functioning.
Cytoarchitecture As in most mammals, the inferior olivary complex of the rat consists of three main subdivisions, supplemented by several smaller neuronal subnuclei (Fig. 3). In the rat, the medial accessory olive (IOM) is the largest of the three subdivisions. Its caudal-most border is found just rostral to the pyramidal decussation (approximately 1500 μm caudal to the obex) and extends over approximately 2600 μm to terminate about 200 μm caudal to the rostral-most pole of the olivary complex. The dorsal accessory olivary nucleus (IOD) is, at caudal levels, initially found directly dorsolateral to the IOM (Fig. 3) (levels 10 and 11). At more rostral levels, the principal olive (IOPr) becomes interpolated between IOD and IOM. Further rostrally, the IOD and IOPr merge and this aggregate forms the rostral pole of the olivary complex. Opinions differ somewhat as to the number and name of the various smaller subdivisions and cell groupings as is outlined below. The IOM is usually divided into a caudal and a rostral half or lamella. Azizi and Woodward (1987) further divided the caudal half into a horizontal and a vertical lamella. Within the caudal part of the IOM (levels 7–9, Fig. 3), three subgroupings are generally recognized and referred to as cell groups a, (IOA), b (IOB), and c (IOC) from lateral to medial (Gwyn et al., 1977). Dorsomedially, the nucleus β (IOBe) adjoins IOC. In agreement with Bernard (1987), Nelson and Mugnaini (1988), Ruigrok and Voogd (1990, 2000), and BuisseretDelmas and Angaut (1993), we include the caudal part
of IOC in IOBe (Fig. 3, levels 7 and 8; see also Ruigrok, 1997). IOBe gradually moves dorsally, thus making way for the more rostral part of IOC (Fig. 3, levels 8–10). It terminates about 1250 μm rostral to its caudal pole. A small cell cluster separates from the dorsomedial margin of the IOBe. This cell cluster enlarges somewhat and, after merging with its contralateral counterpart, terminates after approximatly 300 μm (level 16). In analogy with the situation in the cat, this cell group was identified as the dorsomedial cell column (IODMCC) by Azizi and Woodward (1987), Bernard (1987), Nelson and Mugnaini (1988) and Ruigrok and Voogd (1990, 2000). In the cat, however, the IODMCC is associated with the ventral lamella of the IOPr at more caudal levels and merges rostrally with the IOM, thus showing no relation to the IOBe (Brodal and Kawamura, 1980). Some authors, therefore, refer to a conspicuous enlargement on the medial end of the ventral lamella of the IOPr as the IODMCC (Gwyn et al., 1977; Furber and Watson, 1983; Sotelo et al., 1986; Apps, 1990). However, this olivary region has been shown to be linked with the dorsolateral hump (IntDL) of the rat cerebellar nuclei (Ruigrok and Voogd, 1990; Buisseret-Delmas and Angaut, 1993), and, most probably, is not homologous to the IODMCC of the cat. The term dorsomedial group (IODM), therefore, is applied to this specific IOPr region. In a study of the inferior olive using immunostaining for glutamic acid decarboxylase (Nelson and Mugnaini, 1988), the IODMCC and IODM were found to be linked at caudal levels. Since the IODMCC of both sides are intimately linked in the midline (Fig. 3, levels 15 and 16), the related regions of IODM and IODMCC have been referred to as the transition area (T-area, Fig. 4) Nelson and Mugnaini, 1988; De Zeeuw et al., 1996). Directly dorsal to the caudal aspect of IOBe (level 7 of Fig. 3) a small cell cluster appears which is generally referred to as the dorsal cap of Kooy (IOK). The IOK extends rostrally for about 800 μm. Approximately 600 μm rostral to its caudal tip a small cell grouping detaches itself ventrolaterally from the IOK and becomes adjacent to the lateral border of IOBe. This is the ventrolateral outgrowth (IOVL), which eventually merges rather suddenly with the ventral lamella of the IOPr (level 14, Fig. 3; see also Nelson and Mugnaini, 1988). The caudal pole of the IOPr is first recognized about 1300 μm rostral to caudal pole of the IOM. Its dorsolateral part is associated with the ventromedial part of the caudal IOD. As this point of fusion of the two subdivisions progressively moves dorsomedially in succesively more rostral areas, it becomes obvious that (1) the IOPr divides into a dorsal and a ventral lamella which are connected laterally and (2) the IOD also appears as a folded structure (Fig. 3, levels 12 and 13; Fig. 4). At more rostral
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levels the dorsal IOPr lamella fuses with its ventral counterpart and finally also with the IOD. The IOD is first recognized approximately 200 μm caudal to the caudal pole of the IOPr as a small cell cluster lateral to the IOBe at level 10 (Fig. 3). More rostrally, this so-called dorsal fold of the IOD (IODdf) (Azizi and Woodward, 1987) expands ventrolaterally, until it reaches the ventral surface, where it curves medialward. This medial extension becomes adjacent to the dorsal lamella of the IOPr and enlarges dorsomedially to become the ventral fold of the IOD or the IOD proper. For most of its rostrocaudal length the medial IOD is continuous with the dorsal fold of the IOPr, making the demarcation of both divisions difficult. Careful examination of sections incubated for acetylcholine esterase or cytochrome oxidase and of the afferent and efferent connections indicates that the medial tip of the dorsal lamella of the IOPr should be included with the IOD. As such the IOD becomes immediately adjacent to the IODM group of the ventral lamella of the IOPr (Fig. 3, level 15; Fig. 4) (Ruigrok and Voogd, 1990). Rat IO neurons are small (soma diameter range, 12–25 μm) (Gwyn et al., 1977) and possess four to seven primary dendrites. In many mammalian species olivary
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cells can be divided into a type with dendrites that recurve toward the soma, giving the dendritic tree a rather globular appearance. A second, simpler, type possesses dendrites that radiate away from the soma. In the rat, these two cell types are found throughout the olivary complex. Golgi impregnations of young animals sometimes show axons with recurrent collaterals (King, 1980) for review); however, these collaterals are not encountered in intracellularly HRP-injected olivary neurons in adult cats (Ruigrok et al., 1990). The dendritic tree of olivary cells is occupied by simple as well as rather complex dendritic appendages. In cat it has been demonstrated that appendages of a number of different cells are entwined and surrounded by GABAergic as well as nonGABAergic terminals with an excitatory appearance (De Zeeuw et al., 1989b, 1990a, 1990b). The whole, packed in a glial sheath, constitutes a glomerulus and is characteristic of the olivary neuropil (King, 1976). Another characteristic feature of olivary neurons is their electrotonic coupling by gap juntions. These gap junctions are frequently found between the spiny appendages (Llinás et al., 1974; Sotelo et al., 1974; De Zeeuw et al., 1989a, 1990a, 1990b). Within the rostralmost part of the IOM and within the IODdf, small
FIGURE 4 Reconstructed dorsal view of the inferior olivary complex of the rat. Different (sub-)nuclei are indicated with different shadings. Note the transition area (T-area) where the neuropil of the various regions seem to intertwine and are also in contact with the contralateral side (modified after De Zeeuw et al., 1996).
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neuronal somata that stain positive for glutamic acid decarboxylase have been noted, suggesting that in these areas GABAergic local interneurons may be present (Fredette et al., 1992).
Afferents to the Inferior Olivary Nucleus The inferior olive receives afferent connections from large parts of the central nervous system. However, the origin of the afferent projections to any particular subdivision appears to be rather restricted and coincides with the modular organization of the efferent climbing fiber projection. It follows that the various subdivisions of the inferior olive are incorporated in an impressive range of cerebellar functions. It has been convincingly demonstrated that the IOD is the recipient of pathways from somatosensory nuclei that relay cutaneous tactile and nociceptive information (Gellman et al., 1983; Molinari et al., 1990; Garwicz et al., 1992, 1996, 1997). These pathways arise from the spinal cord, the spinal trigeminal nucleus, and the dorsal column nuclei (Boesten and Voogd, 1975; Swenson and Castro, 1983a, 1983b; Apps, 1998). Lumbosacral fibers terminate laterally within the dorsal and ventral folds of the IOD, whereas cervical levels project to more medial areas. Projections from the interpolar part of the trigeminal nucleus are found in the rostromedial part of the IOD (Huerta et al., 1983, 1985; Van Ham and Yeo, 1992, 1996). Terminal arborizations from the gracile and cuneate nuclei tend to overlap with projections from the lumbosacral and cervical spinal cord, respectively (Boesten and Voogd, 1975; Berkley and Hand, 1978). Using electrophysiological techniques (mapping of responsive fields; Gellman et al., 1983), and with the aid of detailed anterograde tracer techniques (Molinari et al., 1991; Matsushita et al., 1992), it has been demonstrated in the cat that a detailed somatotopical map can be found within the rostral half of the IOD. An additional, but more crude, somatotopical representation appears to be present within the caudal half of the cat IOD, which most probably is homologous with the rat dorsal fold. The IOD, furthermore, receives input from the lateral mesencephalic nucleus, the pretectal area, and the reticular formation (Swenson and Castro, 1983a, 1983b; Bull et al., 1990). It is of interest that these areas are also the recipients of cerebellar input as has been demonstrated in the cat (Bull and Berkley, 1991). In the rat it has been shown that the anterior interposed nucleus (IntA) of the cerebellum provides a GABAergic projection to the caudolateral, hindlimb-related, and rostromedial, facerelated, parts of the IOD. A similar GABAergic projection from the lateral vestibular nucleus has been demonstrated to terminate in the IODdf (Ruigrok and Voogd,
1990; Fredette and Mugnaini, 1991). GABAergic projections to the intermediate, presumably forelimb-related, part of the IOD have been suggested to arise from the cuneate area (Nelson and Mugnaini, 1989). However, in the cat it has been reported that the forelimb recipient zones of the IOD also receive a GABAergic cerebellar projection (Molinari, 1992). The caudal part of the IOM (horizontal lamella, groups A and B) also processes somatosensory information since it also receives input from the spinal cord, dorsal column nuclei, and spinal part of the trigeminal nucleus. However, contrary to the situation in the IOD, a somatotopical representation is less obvious (Gellman et al., 1983; Huerta et al., 1985). Moreover, input from the vestibular nuclei may overlap with the somatosensory information (Swenson and Castro, 1983a, 1983b). Teleceptive information arising from the deep layers of the superior colliculus predominantly terminates within the C group (Fig. 5) (Hess, 1982; Kyuhou and Matsuzaki, 1991; Akaike, 1992). The rostral periaquaductal gray and the interstitial nucleus of the medial longitudinal fascicle (Fig. 5) also provide extensive projections to the caudal half of the IOM including IOBe. A prominent input to the IOBe is also derived from the vestibular nuclei (Brown et al., 1977; Swenson and Castro, 1983a, 1983b; Kaufman et al., 1991, 1996). Part of this projection, at least, has been shown to be GABAergic (Nelson and Mugnaini, 1989). A sparse, but definite, and presumably GABAergic projection to the lateral and medial parts of the caudal IOM, as well as to the IOBe and IODMCC, has been shown to arise from the medial cerebellar nucleus (Med) (Ruigrok and Voogd, 1990). However, these connections cannot account for the massive GABAergic projection also found in the caudal IOM. An additional GABAergic projection to the IOMC has been shown to arise from the ipsilateral parasolitary region (Nelson and Mugnaini, 1989; De Zeeuw et al., 1993). The origin of a major GABAergic pathway to the IOMA and IOMB groups has yet to be identified. The IOK and IOVL both play an important role in the control of compensatory eye movements as has been amply demonstrated in the rabbit (Leonard et al., 1988). It receives its main input from the nucleus of the optic tract (OT, to the IOK) and the accessory optic nuclei such as the medial terminal nucleus (MT, to the IOVL). Additional IOVL projections stem from the periaquaductal central gray and the visual tegmental relay zone (VTRZ) (Giolli et al., 1984, 1985). A dopaminergic projection to the IOVL has been shown to be derived from neurons in the medial mesodiencephalic junction (Toonen et al., 1998). A projection from the medial cerebellar nucleus to the IOVL, described by Angaut and Cicirata (1982) and Swenson and Castro (1983b), could not be verified by Ruigrok and Voogd (1990) who,
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FIGURE 5 Sources of inferior olivary afferents in the midbrain. (A–D) Microphotographs of consecutively more caudal levels of the midbrain. Some nuclei and tracts have been plotted as have been cells that were retrogradely labeled from the injection in the inferior olivary complex shown in panel E. Examples of the retrogradely labeled neurons are shown in the inset in panel E (arrows). Note that most labeled cells were found surrounding the fasciculus retroflexus and that virtually none were located within the confines of the red nucleus. Also see Fig. 6. Plots were constructed using Neurolucida (Microbrightfield, Inc.) software (Ruigrok, unpublished results).
instead, mention a IOVL projection from a small area in the parvicellular part of the lateral cerebellar nucleus (see also Nelson and Mugnaini, 1989; Ruigrok et al., 1992). The IOK and IOVL both receive a GABAergic as well as a nonGABAergic projection from the prepositus hypoglossal nucleus (De Zeeuw et al., 1993). The rostral lamella of the IOM and the IOPr receive afferents from areas located at the mesodiencephalic junction. A continuum of neurons surrounding the fasciculus retroflexus, defined as area parafascicularis prerubralis by Carlton et al. (1982), encompassing the rostral part of the nucleus of Darkschewitsch, the medial accessory oculomotor nucleus (MA3), the rostral interstitial nucleus of the mlf, and the prerubral field can be found to project to the inferior olive (Figs. 5, and 6) (Brown et al., 1977; Swenson and Castro, 1983a; Swenson and
Castro, 1983b; Bentivoglio and Molinari, 1984; De Zeeuw et al., 1990a). In the cat, it has been demonstrated that presumably homologous areas project in a topographical fashion to the rostral half of the IOM, to the ventral lamella of the IOPr, and to its dorsal lamella, respectively (Saint-Cyr and Courville, 1982; Onodera, 1984; Holstege and Tan, 1988). Moreover, specific projections from the sensorimotor and parietal association cortices have been attributed to these regions in various animal species. As to the much debated olivary projections arising from the red nucleus, the reader is referred to the section dealing with this nucleus (also see Figs. 5 and 6). Prominent GABAergic projections from the posterior interposed nucleus (IntP) of the cerebellar nuclei to the rostral lamella of the IOM and from the Lat to the IOPr have been amply demonstrated (Angaut
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et al., 1987; Angaut and Sotelo, 1989; Ruigrok and Voogd, 1990; Fredette and Mugnaini, 1991). The IODM group of the ventral lamella of the IOPr receives a specific innervation from the dorsolateral hump (IntDL) of the rat cerebellar nuclei, in addition to projections stemming from the spinal trigeminal nucleus and the adjacent reticular formation (Huerta et al., 1983; Swenson and Castro, 1983a; Ruigrok and Voogd, 1990). A schematic summary of the cerebellar nucleoolivary projection is given in Fig. 7. Here, the IO and the
cerebellar nuclei are represented as more or less continuous sheets of cells, folded in their subnuclei. In this scheme there is a rather simple topographical relation between both cell masses, especially when the IntP is regarded as a caudal projection originating from the Med and Lat, and its target nucleus, the rostral lamella of the IOM, as a rostral expansion of the vertical lamella of the IOM. Likewise, one can consider the IntDL as an enlargement intercalated between the dorsal Lat and the lateral IntA that projects to the IODM group of the inferior olive which can be interpreted as a medial bulge between the medial IOD and the dorsal lamella of the IOPr, which, thus, becomes located adjacent the ventral lamella of the IOPr (Ruigrok and Voogd, 1990). Indoleaminergic as well as catecholaminergic projections to specific subdivisions of the rat inferior olivary complex have been described (Wiklund et al., 1977; Bishop and Ho, 1984, 1986; Toonen et al., 1998). The neuropeptides enkephalin, substance P, cholecystokinin, and corticotropin-releasing factor have also been encountered in olivary afferent profiles (King et al., 1989). In summary, the specific subdivisions of the IO all receive a major GABAergic as well as a nonGABAergic projection. The GABAergic projection is derived from the cerebellar nuclei, but, for some subdivisions, may also originate from the vestibular nuclei, from the prepositus hypoglossal nucleus, or from parasolitary and cuneate regions. In certain regions GABAergic boutons may arise from locally found interneurons. The nonGABAergic afferent projections to the caudal IOM and IOD may be subdivided into those that relay, more or less directly, sensory information and those that relay more highly integrated information including cerebellar output. The rostral IOM and IOPr, on the other hand, appear to process integrated information from both the cerebellum and the cerebral cortex. Modulatory influences from various aminergic and peptidergic systems may influence this information processing (van der Steen and Tan, 1997).
Efferents of the Inferior Olive
FIGURE 6 Three-dimensional reconstruction of mesodiencephalic junction of the same experiment shown in Fig. 5. However, the junction is now shown as a three-dimensional reconstruction (Neurolucida, Microbrightfield, Inc.) based on serial plots of sixteen 40-μm sections (1 of 4 sections was plotted). (A) Caudal view, (B) rostral view. Note that within the confines of the red nucleus (R) as well as of the nucleus of Darkschewitsch (Dk) only a few labeled cells were found. Most labeled neurons were located surrounding the fasciculus retroflexus. Also, note the vast quantities of labeled cells in the deep mesencephalic nucleus, pretectum, central gray, and zona incerta (cf. Fig. 5; Ruigrok, unpublished results).
The inferior olive is the sole source of climbing fibers to the cerebellum (Desclin, 1974). They terminate extensively on the dendritic tree of Purkinje cells (Szentágothai and Rajkovits, 1959; Eccles et al., 1966b) and provide a collateral projection to the cerebellar nuclei (Kitai et al., 1977; van der Want et al., 1989; Ruigrok, 1997; Ruigrok and Voogd, 2000). The climbing fiber projections from the various subdivisions of the IO are topographically organized into a number of sagittally oriented strips that are characterized by the projection of the Purkinje cells in those strips to the cerebellar and vestibular nuclei. The correlation between
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FIGURE 7 Schematized cerebellar nucleoolivary relationships. The cerebellar nuclei and olivary nuclear complex are visualized as unfolded continuous sheets of cells. Projections from the olivary sheet to the cerebellar nuclei are excitatory (Audinat et al., 1992) and are indicated with arrowheads. The reciprocal projection from the cerebellar sheet to the inferior olive is GABAergic (Fredette and Mugnaini, 1991) and is indicated with filled circles. Folds in both sheets are indicated by open arrows (modified after Ruigrok and Cella, 1995, also see Ruigrok and Voogd, 2000). See text for further explanation.
the olivocerebellar and the corticonuclear projection bear similar characteristics in the rat, cat, and monkey. The collateral projection of the climbing fibers to the cerebellar nuclei as well as the GABAergic nucleoolivary projection appears to be aligned with the olivocorticonuclear projection. Indeed, the formation of a number of parallel circuits linking the inferior olive and the cerebellum appears to constitute the essence of cerebellar functioning. The reader is referred to Chapter 9 by Voogd for a comprehensive review on the olivocerebellar projection in the rat (see also Buisseret-Delmas and Angaut, 1993). Initial studies have suggested that the climbing fiber system may use aspartate as a neurotransmitter (Wiklund et al., 1982, 1984; Kimura et al., 1985), but more recent reports claim that glutamate (Vollenweider et al., 1990; Zhang and Ottersen, 1993; Grandes et al., 1994; Dzubay and Jahr, 1999; Laake et al., 1999; Wadiche and Jahr, 2001) is the most likely neurotransmitter candidate of the climbing fibers. N-Acetylaspartylglutamate, in addition, has also been suggested to be involved as a neurotransmitter/neuron modulator in at least a subset of climbing fibers (Sekiguchi et al., 1989; Renno
et al., 1997). Corticotropin-releasing factor, enkephalin, and cholecystokinin have also been reported as neuropeptides present in particular subsets of climbing fibers (King et al., 1986; Young et al., 1986; Palkovits et al., 1987; van den Dungen et al., 1988; Bishop, 1990; King and Bishop, 1990; King et al., 1992).
Functional Considerations The role of the inferior olive in the operation of the cerebellum remains rather enigmatic. Indeed, the function(s) of the cerebellum itself are not entirely understood. Although its role in motor functions has been amply documented (e.g., see Holmes, 1939; Ito, 1984; Arshavsky et al., 1986), later studies have suggested that the cerebellum, and the IO, also may be involved in visceral functions and affective behavior (Bradley et al., 1987; Nisimaru et al., 1991; Waldrop and Iwamoto, 1991), and even in certain mental activities (Ito, 1990; Schmahmann, 1991; Fiez et al., 1992, 1996; Leiner et al., 1993; Schmahmann and Sherman, 1998). Furthermore, it has been shown that the IO plays a role in classical conditioning (Voneida et al., 1990; Sears and Steinmetz,
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1991; Yeo and Hesslow, 1998). It is obvious that the function of the IO will be reflected in its sources of afferent information, in its integrating capabilities, and in the effect of its efferent impulses. IO afferents are known to transmit a wide variety of sensory modalities that may be integrated at various levels with cerebral input, cerebellar input, or both (e.g., Kistler et al., 2000; Schwarz and Welsh, 2001). These characteristics of the IO afferent systems have prompted the suggestion that the IO may function as a detector of events and/or errors of a variety of physiological processes (Oscarsson, 1980; Ito, 1984; De Zeeuw et al., 1998b; Ito, 1998). Indeed, climbing fiber responses mediated via a number of direct or indirect spinoolivocerebellar pathways have been implicated to signal specific somatosensory conditions (Garwicz et al., 1992; Ekerot et al., 1997). Recently, it has become clear that the excitability of these pathways may be subject to gating processes, purportedly in order to minimize or eliminate propagation of expected signals (Apps et al., 1997; Apps and Lee, 1999; Apps, 2000). When considering the integrative capabilities of olivary neurons, the rather peculiar conductances of olivary neurons should be taken into account together with the fact that olivary cells are electrotonically coupled to each other (Llinás and Yarom, 1981a, 1981b; 1986; Benardo and Foster, 1986; Yarom, 1991). These features, in conjunction with the intricate network of interwoven dendrites with their many long and frequently complex spiny appendages (Sotelo et al., 1974; Gwyn et al., 1977; Ruigrok et al., 1990), would appear to warrant rather complex input–output relationships for this nucleus (De Zeeuw et al., 1998b). The observation that these spiny appendages of olivary neurons form the core of the olivary glomeruli (King, 1976) and are surrounded by excitatory as well as GABAergic synapses can be interpretated as representing a structural correlate of a device that may be very well suited to detect, and respond to, changes and/or differences in the temporal resolution of the various inputs (Segev and Rall, 1988, 1998; De Zeeuw et al., 1990a; 1998b; Ruigrok et al., 1990; Segev and Rall, 1998; Lang, 2001). Climbing fiber impulses result in a powerful excitation of the innervated Purkinje cells, which respond with a characteristic “complex spike.” The complex spike consists of a series of characteristic dendritic calcium spikes, which may induce somatic firing (Llinás and Sugimori, 1980). As the result of a complex spike, up to six action potentials with a frequency of about 500 Hz may be conducted along the Purkinje cell axon (Eccles et al., 1966a; Ito and Simpson, 1971). Nevertheless, at a first inspection, the rather low firing frequency of olivary neurons (1–2/s) would appear to preclude an important contribution of the IO to the overall firing
rate of the Purkinje cells. However, cooling and lesioning of the IO has demonstrated quite the reverse. In effect, behavioral and physiological studies suggest that lesions of the IO, especially in its initial stages, resemble lesions of the whole cerebellum (Llinás et al., 1975; Colin et al., 1980; Batini and Billard, 1985; Demer et al., 1985). This effect is, most likely, due to the interaction of the IO climbing fiber and mossy fiber–parallel fiber input at the Purkinje cell level. The climbing fiberinduced complex spike (CS) gives rise to a temporal depression of the mossy fiber–parallel fiber activated simple spikes (SSs) of the Purkinje cells. Conversely, a reduction in frequency or a complete abolition of CSs enhances the frequency of SSs. Due to the GABAergic action of the Purkinje cell terminals on their target (Ito and Yoshida, 1966; Ito, 1984), this will result in a massive inhibition of the cerebellar nuclei. Apart from the tonic effects of CSs on the frequency of SS firing (Strata, 1984) more subtle and long-term effects between CS and SS responsiveness have also been demonstrated. Particularly, it has been noted that repeated stimulation of climbing fibers depresses the synaptic efficacy of near-simultaneously firing parallel fibers. This long-term depression (LTD) has been hypothesized to enable the climbing fibers, acting as an error signal, to adapt the output of the Purkinje cells semipermanently to new or specific requirements in motor function (Marr, 1969; Albus, 1971; Ito, 1984, 1994, 2001). Indeed, it was recently shown that genetically modified mice (in which protein kinase C had been blocked in Purkinje cells only) not only failed to show LTD but also failed to show adaptation of the vestibuloocular reflex (De Zeeuw et al., 1998a) Another school suggests that the IO acts as a real afferent system. As such it would not serve as a modulator of the SS responsiveness at the Purkinje cell level, but it is suggested that the climbing fiber-induced CS may bring about specific responses in Purkinje cell target areas that are necessary to adjust to a particular situation (Llinás and Mühlethaler, 1988; Llinás, 1991; Welsh et al., 1995). The tremorogenic action of the indolamine harmaline, which results in rhythmic firing of the inferior olive and in related bursting of neurons in the cerebellar nuclei and brain stem, has been put forward as evidence of direct impact of the inferior olive on motor programming (De Montigny and Lamarre, 1973; Llinás and Volkind, 1973; Llinás and Sasaki, 1989). Timing and synchrony of the olivary activations are key elements in this theory. Indeed, it has been demonstrated that the electrotonic coupling by gap junctions may be modulated by GABAergic synapses (De Zeeuw et al., 1989b, 1990a; Llinás and Sasaki, 1989; Lang et al., 1996). In theory, this would enable the IO to respond with different aggregates of
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coupled cells to a specific input in different situations. The relevance of the timing of events may be related to the intrinsic oscillation of the membrane potential found in the coupled olivary cells (Benardo and Foster, 1986; Llinás and Yarom, 1986; Yarom, 1991). Rhythmic firing of groups of olivary cells related to ongoing oscillatory movements such as locomotion have recently been noted in freely moving animals (Smith, 1998) and also resulted in increased Fos labeling in related regions of the inferior olive and the cerebellar nuclei (Ruigrok et al., 1996). Some evidence obtained in Lurcher mice that lack Purkinje cells would indeed suggest that the collaterals of climbing fibers may participate in inducing Fos in the cerebellar nuclei (Oldenbeuving et al., 1999). A somewhat undervalued aspect of cerebellar functioning in general and of olivary functioning in particular may be found in the likelihood that activity patterns may be reverberating and thus be maintained within the various circuits between brain stem and cerebellum. The interaction between intrinsic subthreshold oscillations of the membrane potential of inferior olivary neurons (Lampl and Yarom, 1993) and the activity pattern in olivocerebelloolivary and olivocerebello– midbrain–olivary circuits may be specifically revelant for cerebellar functioning (Ruigrok and Voogd, 1995; Kistler and van Hemmen, 1999; Kistler et al., 2000).
RED NUCLEUS The red nucleus, which gets its name thanks to the pinkish color of the large rounded structure found in fresh human tissue, is a conspicuous nucleus located on either side of the midbrain tegmentum of limb-using vertebrates (ten Donkelaar, 1988). It subserves a premotor function and is closely related to the cerebellum since it not only receives a prominent input from the cerebellar nuclei but also acts as a source of information for various precerebellar nuclei. In most mammals studied, a magnocellular part is distinguished from a more rostrally placed parvicellular part. In primates this subdivision is easy to recognize (Paxinos et al., 2000), although the magnocellular part is only poorly developed in anthropoids and, especially, in man. It follows that the human red nucleus essentially consists of the parvicellular division of the nucleus (Nathan and Smith, 1982; Paxinos and Huang, 1995). In most mammals, however, the parvicellular part is not so well defined. Caudally, it appears to overlap with the magnocellular part, whereas its rostral boundaries are difficult to establish. The two subdivisions are generally believed to serve a different function, but their connections, as reported in the literature are subject to many controversies. The next paragraph attempts to
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elucidate some of these issues in the cytoarchitecture and connectivity pattern of especially the rat red nucleus.
Cytoarchitecture The red nucleus of the rat is roughly ovoid in shape and located bilaterally in the midbrain tegmentum. Its caudal tip is found approximately 2.5 mm rostral to the interaural line (Paxinos and Watson, 1986), where it emerges as a prominent cell group within the crossed superior cerebellar peduncle. Its rostral boundary is more difficult to establish but, by convention (Reid et al., 1975b), is defined just caudal to the level of the fasciculus retroflexus, at approximately 3.7 mm rostral to the interaural plane. Rostral to this level the prerubral field is more or less continuous with the red nucleus. The superior cerebellar peduncle envelops and traverses the red nucleus at all rostrocaudal levels. Outgoing fibers of the oculomotor nucleus pass medially from and through its caudal aspect. The medial lemniscus (ml) is found adjacent to the ventrolateral border of the rostral half of the nucleus. The dorsal tegmental decussation, the medial longitudinal fasciculus, and the medial tegmental tract border the red nucleus on its dorsomedial side. Clearly, different cell types are found within the confines of the red nucleus of the rat. In a first, detailed, study by Reid et al. (1975a, 1975b), four types were recognized, primarily based on soma size. Giant (soma diameter, >40 μm) and large (26–40 μm) neurons, which possess similar structural characteristics, predominated in the caudal third of the nucleus. Medium neurons (20–25 μm) displayed a lower cytoplasmic to nuclear ratio and contained fewer and poorly organized Nissl bodies. Small neurons (<20 μm) were usually achromatic and were frequently seen in association with neuroglial cells. Medium and small cells made up most of the rostral two thirds (i.e., the parvicellular part). Strominger et al. (1987) only recognized three neuronal populations: neurons with coarse Nissl bodies, neurons with a fine granular Nissl substance, and achromatic neurons. The soma sizes of neurons with coarse and fine Nissl substance overlap considerably, whereas the achromatic neurons are clearly smaller than the other two cell types. “Coarse” neurons were found exclusively in the caudal tip, while the rostral tip harbored predominantly “fine” neurons. In the intermediate red nucleus both cell groups were found. The small neurons were found throughout the nucleus. Finally, studies by Tucker et al. (1989) differentiated between neurons with a relatively small, oval, and eccentrically placed nucleus and displaying a large cytoplasmic–nuclear ratio (magnocellular neurons) and neurons with a relatively large rounded and a centrally placed nucleus displaying a
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small cytoplasmic to nuclear ratio (parvicellular neurons). Approximately 3000 magnocellular neurons were counted which could be divided into a largesized (>25 μm) and a small-sized (<25 μm) population and which dominated the caudal and ventral part of the nucleus. Parvicellular neurons (±20,000) were classified as large-sized (30–45 μm), medium-sized (15–30 μm), or small-sized (>15 μm) cells and may all be found throughout the nucleus. Although there is no consensus between different authors, it is agreed that the caudal pole harbors the largest neurons. Between 250 and 400 μm from the caudal pole, this large-celled part can be subdivided into a rather compact ventrolateral part and a more loosely arranged dorsomedial part (Reid et al., 1975b; see also Figs. 8A and 8B). The ventrolateral part is continuous with the so-called lateral horn of the rat red nucleus (Reid et al., 1975b) and is somewhat separated from the dorsomedial part, which appears to divide into a dorsal and a dorsomedial grouping of neurons. Rostral to this level no subdivisions are apparent. At least a part of the small neuronal population may represent local GABAergic interneurons, which have been demonstrated in turtle, cat, and monkey (VuillonCacciuttolo et al., 1984; Keifer et al., 1992; Ralston, 1994). Large neurons in the caudal two-thirds of the rat red nucleus frequently stain positive for calbinding D28k, whereas medium to large neurons in the rostral two-thirds frequently contain parvalbumin. Both populations, however, were strongly intermingled and double-labeled cells were only seldomly encountered (Hontanilla et al., 1995). The nucleus minimus deserves some comment. This aggregation of small cells lateral to the parvicellular part of the red nucleus was first described by Von Monakov (1909) in the rabbit and later identified in the cat by others (Brodal and Gogstad, 1954; Taber, 1961). In the rat, data are controversial. Reid et al. (1975b) did not find a nucleus minimus. However, they described the lateral horn as a subdivision of the red nucleus and as consisting of predominantly small- and mediumsized neurons. Faull and Carman (1978), who based their opinion on the pattern of terminal degeneration after superior cerebellar peduncle lesions, concluded that a nucleus minimus complying to Von Monakov’s description may be found intercalated between fascicles of the medial lemniscus. However, the position of this nucleus is rather similar to that of the lateral horn of Reid. Finally, Paxinos and Watson’s atlas of the rat brain (1986), based on Faull and Carman’s paper, delineates a nucleus minimus lateral to the dorsal part of the red nucleus, where it appears to be dorsal or dorsolateral from the lateral horn of Reid et al. Based on our own material of cerebellar nuclear projections to this area
(see below), we propose that the term nucleus minimus should be abandoned. Rather, we would advocate the term pararubral area, which forms an integral part of the parvicellular part of the red nucleus rostrally but becomes discernible as a more or less separated cluster of neurons located dorsolateral to its magnocellular part (Figs. 8H and 9: also see Fig. 6 of Ruigrok and Cella, 1995). As such, the pararubral area is located within the medial part of the nucleus reticularis subcuneiformis of Newman (1985). As mentioned earlier, the rostral boundary of the parvicellular red nucleus is difficult to establish. Based on the efferent connections of this area, it has been suggested by Kennedy (1987; Tucker et al., 1989) that the area directly surrounding the fasciculus retroflexus should be considered a part of the red nucleus. In rat, the area dorsomedial to this fiber bundle is recognized as (the rostral part of) the nucleus of Darkschewitsch and its ventrocaudal continuation as the nucleus accessorius medialis of Bechterew (?edial accessory oculomotor nucleus, MA3, of Paxinos and Watson, 1986). The rostral interstitial nucleus of the medial longitudinal fascicle and the prerubral field are situated ventral and ventrolateral to the fasciculus retroflexus, respectively (Paxinos and Watson, 1986). Carlton et al. (1982) designated the whole area surrounding the retroflex bundle as the nucleus parafascicularis prerubralis on the basis of its efferent connections. In this respect, it is noteworthy that in primates the parvicellular red nucleus is indented rostromedially by the retroflex bundle and extends rostrally to it. In human, the fasciculus retroflexus even traverses the parvicellular red nucleus completely (Paxinos and Huang, 1995), thus separating a dorsomedial part, which may be homologous to (part of) the nucleus parafascicularis prerubralis of the rat. It will be evident that extensive and detailed studies on the afferent as well as the efferent connections of these areas in the various animals are needed in order to establish whether areas with similar names indeed subserve similar functions.
Afferents to the Red Nucleus The red nucleus receives input from the cerebellar nuclei as well as from the cerebral cortex. Projections arising from the posterior thalamic nucleus (Roger and Cadusseau, 1987), zona incerta (Ricardo, 1981), hypothalamic areas, central pontine gray, nuclei raphe dorsalis and magnus, gigantoreticular nucleus, parvicellular reticular nucleus, parabrachial nuclei, and locus coeruleus (Bernays et al., 1988) have also been described. In cat, projections from the dorsal column nuclei and the spinal cord have been demonstrated to reach and terminate within the red nucleus (Boivie, 1988).
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FIGURE 8 Relation between the origin of the rubrospinal tract and the cerebellar nucleorubral connections. (A) Retrograde labeling of rubral neurons after WGA–HRP injection into the contralateral cervical spinal cord. (B) Retrograde labeling after WGA–HRP injection into the contralateral lumbar spinal cord. Note that the labeled cells are positioned ventral to those labeled in panel A. (C,E,G) Injection sites of the anterograde tracer PHA-L into the lateral part of the IntA, the medial part of the IntA, and the ventral, parvicellular part of the Lat, respectively. (D,F,H) Corresponding terminal labeling in the contralateral red nucleus. Note the the resultant labeling after a medial IntA injection (D) overlaps with the location of rubrospinal neurons that project to the lumbar cord, whereas the lateral IntA projects to the dorsal red nucleus (F) where the rubrocervical neurons are found. The parvicellular Lat gives rise to a conspicuous terminal labeling in the pararubral area (small arrows in panel H, also noted labeled, nonterminal, fibers within confines of the red nucleus). Open arrow in panels A, B, D, F, and H, idicates the lateral horn. Bar equals 200 μm (Ruigrok, unpublished results).
Various studies employing degeneration (Caughell and Flumerfelt, 1977) and retrograde and/or anterograde techniques (Daniel et al., 1987; Angaut and Cicirata, 1988) have recognized that the projections from the contralateral cerebellar nuclei to the red nucleus in the rat are organized in a somatotopical fashion. Our
material of small injections into the cerebellar nuclei with the anterograde tracer PHA-L (Ruigrok and Voogd, 1990) confirms and extends these observations (Figs. 8C–8H). Massive projections arise from the anterior interposed nucleus (IntA); its lateral part projects to the dorsomedial part of the magnocellular
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red nucleus, whereas its medial part provides heavy terminal arborizations in its ventrolateral part and lateral horn. The projection from the IntA stems from coarse axons and terminates on somata and proximal dendrites of the magnocellular neurons (Flumerfelt, 1978, 1980; Dekker, 1981). The Lat provides a major input to especially the parvicellular part of the nucleus. Here, a topographical organization also can be recognized. The rostral part of the Lat projects rather ventromedially, whereas more dorsolateral areas of the parvicellular part are supplied by the caudal part of the Lat (Angaut and Cicirata, 1988). A conspicuous projection to the cell aggregate located lateral to the magnocellular red nucleus (pararubral area) was found to arise specifically from the parvicellular subdivision of the Lat (Ruigrok et al., 1993; Teune et al., 2000: see also Figs. 8G and 8H). Red nuclear projections from the posterior interposed nucleus are sparse and are found along its dorsomedial aspect. This cerebellar nucleus distributes terminals mainly to the medial accessory oculomotor nucleus and to the medial part of the nucleus parafascicularis prerubralis (Teune et al., 2000, however, cf. Daniel et al., 1987). A small but definite projection is found from the medial cerebellar nucleus to the medial part of the base of the lateral horn. It should be recognized that the projections from the medial, posterior interposed as well as from the lateral cerebellar nuclei consist of rather fine caliber fibers that terminate on intermediate and distal dendrites and are not as massive when compared to the projections from the anterior interposed nucleus (Caughell and Flumerfelt, 1977; see also Figs. 8C and 8F). It is suggested that all rubral projections from the cerebellum are collaterals from ongoing fibers that eventually terminate in the thalamus (Shinoda et al., 1988) and are excitatory (Toyama et al., 1970; Oka, 1988). Most likely they make use of an excitatory amino acid as neurotransmitter (Bernays et al., 1988; Giuffrida et al., 1993; Schwarz and Schmitz, 1997). In the cat, using physiological techniques, it was found that at least some of the nucleoolivary projection neurons (thought to be all GABAergic: De Zeeuw et al., 1989b, Fredette and Mugnaini, 1991) collateralize to the red nucleus and/or thalamus (McCrea et al., 1978; Andersson and Hesslow, 1987). However, so far this notion could not be corroborated by anatomical studies (Teune et al., 1994; Schwarz and Schmitz, 1997). The projections from the rat sensorimotor cortex are not as well documented as those arising from the cerebellar nuclei. Gwyn et al. (1974) using degeneration techniques, reported that the sensorimotor cortex provides projections to the parvicellular part of the red nucleus only. This was confirmed by Brown (1974a) who also noticed that the prerubral field and an area dorsolateral
to the red nucleus (i.e., the pararubral area) receive a particularly heavy cortical input (cf. projections from the sensorimotor cortex to the subcuneiform reticular nucleus, Newman et al., 1989). Physiological studies by Giuffrida et al. (1988a, 1988b), however, claim that both magno- and parvicellular parts of the red nucleus of the rat are controlled by cerebral as well as cerebellar influences. This agrees well with a study using retrograde transport of small injections of lectin coupled to colloidal gold in different parts of the red nucleus in the guinea pig (Giuffrida et al., 1991). Retrogradely labeled neurons in layer V of the agranular frontal cortex were found after injections into the parvi- and into the magnocellular part of the red nucleus. In a study employing the use of selective retrogradely transported tracers, Bernays et al. (1988) suggested that the cerebral afferents to the red nucleus make use of an excitatory amino acid as transmitter (also see Giuffrida et al., 1993). Cadusseau and Roger (1987, 1988) have described a conspicuous and essentially reciprocal projection from the posterior thalamic nucleus to the parvicellular part of the red nucleus in the rat. The posterior thalamic nucleus is positioned within the sub-pretectal area at the mesodiencephalic junction and appears to be involved in the assimilation of somatosensory and/or nociceptive information. In this regard it is interesting that the zona incerta, considered to be a highly integrative somatosensory center, also provides input to both the posterior thalamic nucleus and the parvicellular red nucleus (Ricardo, 1981; Watanabe and Kawana, 1982; Roger and Cadusseau, 1985; Roger and Cadusseau, 1987). A somatosensory input from the spinal cord to the red nucleus that bypasses the cerebellum and cerebral cortex has been reported in the cat (Wiberg and Blomqvist, 1984a, 1984b; Padel et al., 1986; Boivie, 1988; Rathelot and Padel, 1997; Steffens et al., 2000) and in the monkey (Wiberg et al., 1987; Kerr and Bishop, 1991). In the rat, evidence has been obtained that direct reciprocal connections between the red nucleus and the trigeminal complex may function in a potentially similar way (Godefroy et al., 1998). Finally, a serotonergic projection arising from the raphe magnus and the raphe dorsalis nuclei to the red nucleus as well as a noradrenergic projection has been demonstrated in rat and cat (Bosler et al., 1983; André et al., 1987; Bernays et al., 1988) and has been shown to exert a powerful modulatory action on the activity of rubral neurons (Schmied et al., 1991; Ciranna et al., 1996; Faherty et al., 1997; Licata et al., 1998, 2001).
Efferents of the Red Nucleus When examining the efferent connections of the red nucleus a distinction should be made in the efferents
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of its parvicellular part and in those of its magnocellular part. However, it has been pointed out that, contrary to the situation in primates, in the rat this distinction is not easily made. Various authors have pointed out that large neurons may be found well into the parvicellular region. Yet, in monkeys, available evidence indicates that a rather strict separation of the efferent connections of both subdivisions of the red nucleus exists. The magnocellular part gives rise to the crossed rubrospinal and rubrobulbar projection, whereas the parvicellular part gives rise to the central tegmental tract which descends to the ipsilateral inferior olivary complex. In the cat, a similar organization has been suggested, although here, as in the rat, a division of the red nucleus in a parvi- and magnocellular part is less clear. Obviously, the efferent connections of the rat red nucleus may give insight into its subdivisions. However, data on the projections arising from the red nucleus are confusing. Originally, only the caudal third of the nucleus with its giant- and large-sized neurons was thought to give rise to the rubrospinal tract (Gwyn, 1971; Flumerfelt and Gwyn, 1974; Murray and Gurule, 1979). Its dorsomedial part was found to project to the cervical enlargement, whereas its ventrolateral part connected with the lumbosacral cord (Figs. 8A and 8B). However, it has become clear that at least some parvicellular neurons also project to the spinal cord (Huisman et al., 1981, 1983; Shieh et al., 1983; Tucker et al., 1989; Kennedy, 1990). The rubrospinal tract descends dorsally within the contralateral lateral funiculus where it is separated from the substantia gelatinosa by a small spinocervical tract. It terminates at the base of the dorsal horn and intermediate regions of the ventral horn (Brown, 1974b). Rubrospinal terminals may synapse with both excitatory and inhibitory interneurons and a considerable number of fibers may send projections to the ipsilateral side of the cord (Antal et al., 1992). Rubrospinal projections are considered to be excitatory and most likely make use of either glutamate or aspartate as neurotransmitter (Benson et al., 1991) The parvicellular red nucleus is generally thought to provide a projection to the inferior olive. In the rat, using anterograde as well as retrograde techniques, such a projection has been described by Swenson and Castro (1983a, 1983b). However, Rutherford et al. (1984) and Carlton et al. (1982) specifically denied this projection and claimed that most olivary projections stem from the area surrounding the fasciculus retroflexus (i.e., their nucleus parafascicularis prerubralis: also see Figs. 5, 6, and and 9). Finally, Kennedy (1987), using a modified HRP visualization technique, claimed that many neurons not only in the parvicellular part but also in magnocellular part were (faintly) retrogradely
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labeled after inferior olivary injections. Initial studies by Kennedy (Tucker et al., 1989; Kennedy, 1990; Tucker and Kennedy, 1990), employing double retrograde labeling techniques with fluorescent tracers, suggested that the rubroolivary pathway, at least in part, may exist of collaterals of the rubrospinal pathway but these ideas could not be corroborated in more recent years. In analogy with the situation in monkey, Kennedy furthermore proposed that the nucleus parafascicularis prerubralis should be redefined as being a part of the parvicellular red nucleus. Although we can agree with Kennedy on this point, it should be appreciated that (A) the retrograde labeling as the result of inferior olive injections is considerably more abundant and intense in the area parafascicularis prerubralis as compared to the labeling of cells in the parvicellular part of the red nucleus, suggesting the origin of a dense projection to the inferior olive from the former area, and (B) the pararubral area, with its input from the ventral part of the Lat, should also be incorparated in the rubral complex (Figs. 8 and 9). No specific data on the efferent projections of this area have been published as yet. Although Newman (1985) claims that the subcuneiform reticular nucleus projects to the spinal cord, it can be seen from Fig. 8 that the large, retrogradely labeled cells located dorsolateral to the red nucleus do not seem to correspond to the area of anterogradely labeled fibers derived from the parvicellular part of the lateral cerebellar nucleus (compare Figs. 8A and 8B with Fig. 8H). In addition to the rubrospinal and rubroolivary pathways, the red nucleus also provides a crossed rubrobulbar projection, presumably via collaterals of the rubrospinal pathway, which terminate in various brain stem centers like the lateral part of the facial nuclei, the parvicellular reticular formation, the rostral part of the lateral reticular nucleus, the oral part of the spinal trigeminal nucleus, and the principal sensory trigeminal nucleus, the descending vestibular nucleus, and the dorsal column nuclei (Flumerfelt and Gwyn, 1974; Hinrichsen and Watson, 1983; Godefroy et al., 1998). As a fourth major terminal source, the red nucleus has been shown to give rise to a rubrocerebellar pathway (Huisman et al., 1983; Yarom et al., 1991). Presently no information is available on the special characteristics of the rubronuclear and/or rubrocortical projection patterns in the rat, but in the cat these projections have been reported to specifically target the IntA (Nakamura et al., 1987). Finally, rubrothalamic projections, in particular arising from the parvicellular part of the nucleus, have been described to terminate in the posterior thalamic nucleus (Roger and Cadusseau, 1987) and, in the cat, in the ventrolateral thalamic nucleus (Condé and Condé, 1980).
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Functional Considerations Obviously, many questions still remain unanswered concerning the function of the red nucleus. The, previously made, distinction between magno- and parvicellular subdivisions that serve different functions, may still be useful, but appears to be rather naive. Present knowledge suggests that the red nuclear area may comprise at least three populations of neurons. A caudally located, predominantly large-celled, group participates in the execution of motor behavior, it receives its main input from the anterior interposed nucleus of the cerebellum and gives rise to the rubrospinal tract. A more rostrally located cell group consisting of slightly smaller cells, possibly assisted by a group of small cells located lateral to the magnocellular subdivision, receives its main input from the cerebellar dentate, the sensorimotor cortex, and the posterior thalamic nucleus. In the rat, many of these parvicellular neurons appear to project to the spinal cord but may also project to the inferior olive. Finally, a rostrally located group of small neurons surrounding the fasciculus retroflexus (area
parafascicularis prerubralis) receives a massive input from the sensorimotor cortex, but also from the dentate and the posterior interposed nuclei and appears to project mainly to the inferior olive. Interestingly, this region has also been shown to project to the nucleus raphe magnus (Carlton et al., 1982) and has been implied to play a role in antinociceptive functions (Peschanski and Mantyh, 1983). In this respect it should be noted that electrical stimulation of the red nucleus area has been shown to inhibit the tail flick response to noxious heat (Prado and Roberts, 1985; Kumar et al., 1995). Some of the various (suggested) divisions and efferents of the whole rubral complex are schematized in Fig. 9. In monkey, the rubrospinal tract has been implicated to be involved in controlling limb movements and more specifically of that of the hand and fingers (Lawrence and Kuypers, 1968a, 1968b; Gibson et al., 1985a, 1985b; van Kan and McCurdy, 2001). Indeed, recently, it was noted that in rat also activity of the red nucleus could be clearly related to skilled movements of the forelimb (Whishaw et al., 1998; Jarratt and Hyland, 1999). However, a rubrospinal impact on more general limb actions, such as
FIGURE 9 Diagrammatic representation of some of the efferent connections of the rubral area. Hatched lines represent minor pathways. Rubroolivary fibers are found in the central (ctt) and in the medial (mtt) tegmental tracts and arise from the prerubral field (PR), from the accessory oculomotor nucleus (MA3), and, in particular, from the area surrounding the fasciculus retroflexus (fr). Rubrospinal fibers (rst) originate mainly from the caudal, magnocellular, part of the red nucleus (RMC) but also from more rostral parts (RPC). The projections specifically originating from the pararubral area (paraR) have not yet been investigated.
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scratching or locomotion, has also been firmly established (Arshavsky et al., 1986; Muir and Whishaw, 2000). Although it has been convincingly demonstrated that this rubral complex functions as an important premotor center, at present it is not clear exactly what signals are conveyed and how its function relates to the function of the corticospinal system. Many physiologic similarities appear to exist between both systems, although some differences have also been noticed (Massion, 1988; Kennedy, 1990; Cheney et al., 1991). Either system may, at least partly, compensate for lesions in the other system (Lawrence and Kuypers, 1968b; Whishaw et al., 1998). Also, it has been suggested that the red nucleus may provide a tonic framework against which the motor cortex can produce more precise movements (Whishaw and Gorny, 1996). The red nucleus has also been implicated in mediating conditioned responses (Chapman et al., 1990; Pananceau et al., 1996; Ryou et al., 1998; Voneida, 1999). On the role of the parvicellular part of the red nucleus, i.e., in the rat those parts that project to the inferior olive (prerubral and parafascicular parts), even less is known. The role of the dentatorubroolivocerebellar circuit would appear to gain in importance in higher evolved species as this coincides with a dramatic expansion of the lateral cerebellar nucleus, the parvicellular red nucleus, the central tegmental tract, the principal olive, and the cerebellar hemisphere. This circuit may reverberate signals and match them with either descending cerebral input or ascending spinal input or both and with the intrinsic oscillations of the inferior olivary neurons (Oscarsson, 1980; De Zeeuw et al., 1998b; Kistler and van Hemmen, 1999). Kennedy (1990) has proposed that the parvicellular part of the red nucleus may be functioning as a switching device designed for automatization of learned movements. Once movements are learned by the motorcortex, its connections to the parvicellular red nucleus serve, by way of the rubroolivocerebellar pathway, to automize or condition the rubrospinal pathway. Indeed, lesion studies seem to be in accordance with such a notion (Kennedy and Humphrey, 1987; Fanardjian et al., 1999). However, although this attractive hypothesis has its merits, clearly many questions remain unanswered, one of them being that it does not explain why the rubrospinal pathway is virtually nonexistent in humans (Nathan and Smith, 1982; Massion, 1988; Paxinos et al., 1990), whereas an impressive range of automated movements are an essential element of our everyday life.
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9 Cerebellum JAN VOOGD Department of Neuroscience, Erasmus MC Rotterdam The Netherlands
(Larsell, 1948) and the cerebellum of the rat. Consequently he subdivided the cerebellum of both species into 10 lobules, numbered 1 to 10 from rostral to caudal (Fig. 1e). The deep primary fissure separates the anterior lobe from the posterior lobe. The primary and preculminate fissures, which subdivide the anterior lobe in the lobules 1 to 3 and 4 to 5, are foliated on their anterior and posterior walls and reach the lateral margin of the cerebellum. The other interlobular fissures of the anterior lobe do not reach as far laterally (Fig. 1c). Shallow indentations in the surface of lobules 4 and 5 indicate the border between the vermis and the hemispheres. These indentations are more distinct in lobule 6 (Bolk’s [1906] lobulus simplex), caudal to the primary fissure. A deep paramedian sulcus is present lateral to lobule 7, but absent in lobule 8 (the pyramis). The cortex of the pyramis continues uninterruptedly into the hemisphere as the copula pyramidis. None of the interlobular fissures in the segment of the posterior lobe, located between the primary and prepyramidal fissures, is completely continuous between the vermis and the hemisphere (Fig. 1b). At the junction of lobules 6c, lobule 7, and the hemisphere, the cerebellar cortex is interrupted and the white matter comes to the surface (Figs. 1b, 6f, 6h, and 6j). Three fissures come together at this point: the vermal segment of the posterior superior fissure, located between lobules 6 and 7; the hemispheral segment of the posterior superior fissure, which separates the simple lobule from the crus 1 of the ansiform lobule; and the intercrural fissure of the ansiform lobule. The ansoparamedian fissure, located
The cerebellum of the rat is used extensively in neurobiologic research, but no systematic description of its morphology is available. This chapter deals with the anatomy of the lobes and lobules, their afferent and efferent connections, the zonal distribution of Purkinje cells, and the structure of the cerebellar nuclei of the rat. The precerebellar nuclei and their cerebellar projections are reviewed in this volume by Ruigrok (Chapter 8). This chapter does not include a review of the histology of the cerebellar cortex of the rodent. For information on this subject the reader is referred to Ramon y Cajal’s (1911) original studies, to the monograph of Palay and Chan-Palay (1974), and to the recent surveys of Dino et al. (1999, 2000). The chemical neuroanatomy of the cerebellum, including the “diffuse” catecholaminergic and cholinergic afferent systems, was reviewed by Voogd et al. (1996b). A short reviews of the structure and connections of the cerebellum was published by Voogd and Glickstin (1998).
THE GROSS ANATOMY OF THE CEREBELLUM Early references to the gross anatomy of the cerebellum of the rat can be found in the papers of Bradley (1904), Bolk (1906), Ingvar (1919), Riley (1928), and Açiron (1951). The development and the adult configuration of the lobes and lobules of the cerebellum of the rat were described by Larsell (1952) and Larsell and Jansen (1970). Larsell was struck by the close similarity between midsagittal sections of the avian cerebellum
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FIGURE 1 The cerebellum of the rat: graphic reconstructions from serial sections. The anterior lobe has been removed on the right side of the figures to show the simple lobule in the caudal bank of the primary fissure. Interruptions of the cortex are hatched. (a) Caudal aspect. (b) Dorsal aspect. (c) Rostral aspect. (d) Ventral aspect. (e) Midsagittal section. (f) Diagram of the cortical loop of the paraflocculus and the flocculus. Abbreviations for this and subsequent figures: 1–10, lobules of the cerebellum; A, cerebellar zone A; ANT, anterior lobe; ApmF, ansoparamedian fissure; B, cerebellar zone B; C1, crus 1 of the ansiform lobule; C1–C3, CX, cerebellar zone C1–C3 or CX; c2, cervical segment 2; C2, crus 2 of the ansiform lobule; CeC, cerebellar commissure; CL, central lateral nucleus; CO, cochlear nucleus; COP, copula pyramidis; D1, D2, D0, cerebellar zones D1, D2, D0; DA, dorsomedial subnucleus of the POv; DAOv, d, dorsal or ventral fold of the dorsal accessory olive; DCo, dorsal cochlear nucleus; DLH, dorsolateral hump (central cerebellar nuclei); DLP, dorsolateral protuberance; DMC, dorsomedial crest (central cerebellar nuclei); dmcc, dorsomedial cell column; FB, fast blue; FL, flocculus; FLped, floccular peduncle; GABA, γ-aminobutyric acid; GI, gigantocellular nucleus; Glu, glutamate; ic, internal capsule; IC, interstitial cell groups; IcF, intercrural fissure; icp, inferior cerebellar peduncle; Inf, infracerebellar nucleus; Int, interposed cerebellar nucleus; IntA, anterior interposed nucleus; IntP, posterior interposed nucleus; IntPpc, parvocellular part of the posterior interposed nucleus; IO, inferior olive; IPfls, intraparafloccular sulcus; jrb, juxtarestiform body; Lat, lateral cerebellar nucleus; Latpc, parvocellular part of the lateral cerebellar nucleus; LD, laterodorsal nucleus (thalamus); LVe, lateral vestibular nucleus; MAO, medial accessory olive; MAOc, r, caudal or rostral part of the medial accessiory olive; mcp, middle cerebellar peduncle; MD, mediodorsal nucleus of the thalamus; Med, medial cerebellar nucleus; MedCM, caudomedial subdivision of the medial cerebellar nucleus; MedDLP, dorsolateral protuberance of the medial cerebellar nucleus; MedM, middle subdivision of the medial cerebellar nucleus; MedMpc, parvocellular part of the middle subdivision of the medial cerebellar nucleus; MV, medial vestibular nucleus; NI, interposed cerebellar nucleus; NL, lateral cerebellar nucleus; NM, medial cerebellar nucleus; NY, nuclear yellow; ocf, olivocerebellar fibers; PCrt, parvocellular reticular formation; PFL, paraflocculus; PflS, parafloccular sulcus; PIF, posterolateral fissure; PM, paramedian lobule; PmS, paramedian sulcus; Pod, v, dorsal or ventral lamina of the principal olive; PpF, prepyramidal fissure; Pr, nucleus prepositus hypoglossi; PreculF, preculminate fissure; PrF, primary fissure; PsF, posterior superior fissure; SC, superior colliculus; scp, superior cerebellar peduncle; SecF, secondary fissure; Sim, simple lobule; smv, superior medullary velum; spS, spinal trigeminal nucleus; SpVE, spinal vestibular nucleus; SuVe, superior vestibular nucleus; unc, uncinate tract; Vco, ventral cochlear nucleus; VL, ventrolateral nucleus (thalamus); VM, ventromedial nucleus (thalamus); vsc, ventral spinocerebellar tract; X, zone X; Y, group Y of the vestibular nuclei.
between the caudal folium of crus 2 of the ansiform lobule and the rostral folium of the paramedian lobule, ends in the paramedian sulcus lateral to lobule 7. The relation between the vermis and the hemispheres clearly differs for different segments of the cerebellar cortex. Functionally, the mediolateral continuity of the cortex depends on the presence of parallel fibers, that is, of a molecular layer (Marani and Voogd, 1979; Voogd, 1975). In the anterior lobe, the simple lobule, and lobule 8, the cortex of the vermis continues uninterruptedly into the hemispheres. In between lobules 6b and 6c and 7, and the ansiform and paramedian lobules, however, the cortex bridging the paramedian sulcus is greatly constricted or even completely absent. In Bolk’s (1906) terms, the folial chains of vermis and hemisphere of this part of the posterior lobe are completely independent of each other. The cortex of lobules 9 (the uvula) and 10 (the nodule) and the secondary and posterolateral fissures ends in a deep paramedian sulcus which separates these lobules from the copula pyramidis (Fig. 1d). Laterally the copula continues into the paraflocculus. The cortex of the paraflocculus constitutes a laterally directed loop, which is continuous with the cortex of the flocculus at the bottom of the hemispheral segment of the posterolateral fissure (Fig. 1f). The cortex of the paraflocculus is interrupted in the center of the loop in the so-called intraparafloccular sulcus. These areas, where the central white matter comes to the surface,
are found at the caudoventral and rostral aspects of the paraflocculus. For descriptive purposes the dorsal and ventral limbs of the loop are distinguished as the dorsal and ventral paraflocculus, but this distinction is secondary to the essential continuity of the folial chain of the hemisphere. The paraflocculus of the rat is located in the fossa subarcuata, a bony cavity on the posterior surface of the petrosal bone. Larsell (1952) has stated that a lateral extension of the secondary fissure separates the dorsal from the ventral paraflocculus. No such continuity exists in the rat. The fissures of this part of the cerebellum develop independently in the cortex of the caudal vermis and in the hemisphere and end at the white matter in the paramedian and interparafloccular sulci, which separates the caudal vermis from the paraflocculus and the flocculus. The taenia of the roof of the fourth ventricle is attached to the margin of the nodule, the copula pyramidis, and the flocculus. A posterior medullary velum is not present, although the areas devoid of cortex, bordering the tenia in the paramedian sulcus and the ventral aspect of the paraflocculus, could be considered as such. The superior medullary velum is continuous with the cerebellar commissures in the central white matter of the cerebellum. The morphology of the cerebellum of the rat conforms to the general mammalian pattern as described by Bolk (1906), Riley (1928), and Voogd et al. (1998). The
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cortex of the vermis and hemispheres is continuous in the anterior lobe and the simple lobule and in a restricted portion of the posterior lobe between the prepyramidal and secondary fissures. In the intermediate and caudal segments of the posterior lobe, the vermis and hemispheres behave as independent folial chains, and mediolateral connections between them are absent or greatly attenuated. In most respects, this description of the cerebellum of the rat closely corresponds to the observations of Larsell (1952) and to the description of the mouse cerebellum by Marani and Voogd (1979), to which the reader is referred for further details. Interruptions of the cerebellar cortex between the ansiform lobule and the vermis, and in the center of the parafloccular loop, were also found to be present in the mouse and in most other mammalian species investigated (Voogd et al., 1998). Larsell’s account remains indispensible as the basis for the nomenclature of the rat cerebellum. It should be noted that the vermal segment of the lobulus simplex is denoted as lobule 6a, and the vermal segment of the crus I as the lobules 6b and c. This differs from the usage in other mammals, where the vermis of the lobulus simplex constitutes the entire lobule 6, and the vermal segment which is in continuity with the crus I corresponds to the rostral segment of lobule 7 (lobule 7A). Lobules 6 and 7, therefore, should not be considered as homologs of the lobules bearing the same numbers in other mammalian species. In recent years studies of deviations from the normal folial pattern in mice mutants or transgenic mice have appeared. Combined with an analysis of modifications of longitudinal zonal patterns in the expression of Purkinje cell-specific substances, it was proposed that the cerebellum is subdivided into five transverse zones characterized by independent variations in their transverse and longitudial patterns (Ozol et al., 1999).
THE CEREBELLAR NUCLEI AND THEIR EFFERENT PATHWAYS The Subdivision of the Cerebellar Nuclei The cerebellar nuclei usually are subdivided according to Weidenreich (1899). His scheme was applied to pinnipedia and cetacea by Ogawa (1935) and extended by Ohkawa (1957), whose comparative anatomic studies included rodents. These authors divided the cerebellar nuclei into two groups of interconnected nuclei. The caudal group consists of the medial cerebellar or fastigial nucleus and the posterior interposed nucleus; the rostral group consists of the anterior interposed nucleus and the lateral cerebellar or dentate nucleus (Fig. 2). Myelinated fibers occupy the space between the two nuclear groups;
the border between the two nuclei within a group often is more difficult to define. Korneliussen (1968) applied this subdivision to the cerebellar nuclei of the rat. His description takes account of the presence of certain subnuclei which are peculiar to the rat and which were first described by Goodman et al. (1963). His description was adopted in most experimental studies of the connections of the nuclei. It also served as the starting point for the detailed Golgi and morphometric studies of the dentate nucleus (Chan-Palay, 1977) and the medial cerebellar nucleus (Beitz and Chan-Palay, 1979a, 1979b) of the rat. Additional cerebellar nuclei which should be considered as separate structures are the “interstital cell groups,” located between the caudal medial and the posterior interposed nucleus (Buisseret-Delmas et al., 1993) and the basal interstitial nucleus (Langer, 1985). The latter is a group of small, acetylcholinesterase-positive neurons, which extends from the white matter of the flocculus, in the roof of the fourth ventricle, next to the cerebellar nuclei, to the white matter of the nodulus. It exists in the rat, but has not been studied in great detail (Komei et al., 1983). Neurons of the cerebellar nuclei constitute a mixed population of cells of all shapes and sizes. Several authors noticed a binominal distribution for cell size in the cerebellar nuclei (Courville and Cooper, 1970; ChanPalay, 1977, monkey; Palkovits et al., 1977, cat). This distribution can be explained by the presence of a population of small, inhibitory, GABAergic neurons and a population of excitatory, presumably glutaminergic neurons of different sizes, as reported by Batini et al. (1992) for the rat cerebellar nuclei (Fig. 3). The excitatory neurons give rise to highly branching axons, with collaterals which may descend to the spinal cord and ascend to the thalamus (Fig. 7) (Bentivoglio and Kuypers, 1982; Bentivoglio and Molinari, 1986; Gonzalo-Ruiz and Leichnetz, 1987; Lee et al., 1989; Teune et al., 1995; Teune, 1999). The small GABAergic neurons project preferentially to the inferior olive (see Ruigrok, this volume, Chapter 8, for particulars). GABAergic nuclear cells with projections to the cerebellar cortex have been found by several authors (Chan-Palay et al., 1979; Angaut et al., 1988; Batini et al., 1989). However, most nucleocortical fibers take their origin as collaterals from the putative glutaminergic relay cells of the cerebellar nuclei and terminate as mossy fibers in the cerebellar cortex (McCrea et al., 1978; Hámori and Takács, 1989; Hámori et al., 1990; see also Tolbert et al., 1980). Consequently the sizes of nucleocortical cells in the cat follow the same distribution as neurons which could be retrogradely labeled from the thalamus (Tolbert et al., 1978). The nucleocortical projection in the rat was studied by Buisseret-Delmas and Angaut (1988, 1989b).
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FIGURE 2 The cerebellar nuclei of the rat. Transverse section 1 is the most caudal one. The three-dimensional diagram is a dorsal view of the nuclei. Redrawn from Voogd et al. (1996a). Abbreviations as in Fig. 1
A population of small glycinergic interneurons of the cerebellar nuclei, some of which colocalize GABA, was found by Chen and Hillman (1993b) in the rat. Their content of glycine distinguishes these cells from the GABAergic neurons which project to the olive, because these cells never colocalize glycine (de Zeeuw, personal communicaton). According to Gruesser-Kornehls and Bäurle (2001), the appearance of parvalbuminexpressing neurons in the cerebellar nuclei of certain mouse mutants is due to the activity of glycinergic and GABAergic interneurons which exert an increased inhibition of the nuclear neurons and which compensate for the loss of inhibition by the Purkinje cells. The organization of the cerebellar nuclear efferents generally supports the distinction of the two groups of nuclei. Voogd (1964) and Verhaart (1970) described a
subdivision of the superior cerebellar peduncle, which contains the ascending fibers of several nuclei, into a smaller medial part and a larger lateral portion, in most mammals studied. The medial third of the superior cerebellar peduncle of the cat contains fibers from the medial cerebellar and posterior interposed nuclei. The lateral two-thirds of the peduncle contain efferents from the anterior interposed and lateral cerebellar nuclei. This localization was confirmed by Haroian et al. (1981) for the rat (Fig. 4). The small caliber, GABAergic nucleoolivary tract connects the lateral and interposed nuclei with the contralateral inferior olive. These fibers collect in the lateral angle of the fourth ventricle and ascend in a bundle located ventral to the superior cerebellar peduncle to their decussation (Chan-Palay, 1977, monkey; Legendre and Courville, 1987, cat; Cholley et al., 1989, rat).
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FIGURE 4 The fiber composition of the superior cerebellar peduncle in the rat. Relabeled and reproduced from Haroian et al. (1981). Abbreviations are as in Fig. 1.
FIGURE 3 Cell-diameter distributions in the nucleus medialis (Fsg), the nucleus interpositus (Int), and the nucleus lateralis (Lat) of GABAergic and glutaminergic neurons in rat cerebellar nuclei. The populations of GABA-immunoreactive neurons are tabulated under panel A, and glutamate-immunoreactive neurons under panel B. In panel C, the spectra from the three nuclei are averaged for both populations and plotted together. The size range of the GABA and Glu overlap is the same as for cells positively identified as colocalizing GABA and Glu. Abscissae: diameter of the neurons in micrometers (class interval, 2.5 μm). Ordinates: percentage of neurons in each diameter class. From Batini et al. (1992).
The Medial (Fastigial) Cerebellar Nucleus The medial cerebellar nucleus of the rat is characterized by the prominent dorsolateral protuberance of Goodman et al. (1963), a group of large neurons extending far dorsally into the white matter of the posterior lobe (Figs. 2 and 6). Korneliussen (1968) further subdivided the medial nucleus into middle and caudomedial portions. The caudomedial subdivision is the most distinct one. Most of its cells are small (Beitz and Chan-Palay, 1979a; Beitz, 1982). The caudomedial subdivision of the medial nucleus is located at the base of the nodule and the uvula. Dorsally, it remains separated from the rest of the nucleus by myelinated fibers;
ventrally, where it lines the roof of the fourth ventricle, it merges with the middle portion of the medial nucleus. The middle subdivision is distinguished by its high content of myelinated fibers which belong to two groups. The uncinate tract emerges from and traverses the nucleus on its way to the cerebellar commissure. Smaller, so-called “perforating fibers,” traverse its caudal part, medial to the dorsolateral protuberance, on their way to the vestibular nuclei. These fibers originate from Purkinje cells of the anterior vermis (Voogd et al., 1991). The unique shape of the dorsolateral protuberance and its afferent corticonuclear connections from the hemisphere of the posterior lobe (Goodman et al., 1963; Buisseret-Delmas, 1988a; Buisseret-Delmas and Angaut, 1993; Armstrong and Schild, 1978a, 1978b) set it apart from the rest of the medial nucleus, which receives its corticonuclear projection from the vermis, and preclude its identification with any of the subdivisions of the medial cerebellar nucleus of other species such as the cat and monkey. The uncinate tract takes its origin from the entire medial nucleus, including the dorsolateral protuberance. It crosses the midline in the caudal part of the cerebellar commissure (Fig. 5), rostral to the gliotic, interfastigial area, in small bundles dorsal and caudal to this area, and in the superior medullary velum. Contralaterally, uncinate fibers pass rostral to and through the hilus of the medial nucleus (Fig. 6). The tract arches dorsal to the superior cerebellar peduncle, immediately rostral to the anterior interposed nucleus, to join the inferior cerebellar peduncle in its course lateral to the vestibular nuclei. Some of the fibers of the uncinate tract join the medial part of the superior peduncle as the crossed ascending limb of the uncinate tract (Haroian et al., 1981) (Fig. 4). Over most of their intracerebellar course, the efferent fibers of the uncinate and the superior cerebellar peduncle remain separated from the spino- and reticulocerebellar fibers
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or uncinate tract fibers passing through the nucleus, or did not pay attention to the intracerebellar course of the system. The main projections of the rostromedial portion of the nucleus are bilateral and include the vestibular nuclei (mainly the magnocellular portion and more caudal ventral and lateral regions of the medial vestibular nucleus, the spinal vestibular nucleus, and the parasolitary nucleus) and the bulbar reticular formation. Rostrally this projection extends into the ipsilateral pontine reticular formation, with minor targets in the mesencephalon and the diencephalon. The dorsolateral protuberance gives rise to a major projection to the contralateral bulbar medial reticular formation, extending into the pons in a region bordering on the trigeminal nuclei and including the parabrachial nuclei. In the mesesencephalon terminations include the deep mesencephalic nucleus and the adjoining central gray. Collateralization to the bulbar reticular formation and the thalamus has been observed (Fig. 7) (Bentivoglio and Kuypers, 1982). Efferents of the caudomedial medial nucleus focus on the contralateral paramedian pontine reticular formation, with strong projections to the pararubral area, the deep mesencephalic nucleus, the central gray, deep layers of the superior colliculus, and regions adjoining the oculomotor nuclei and the fasciculus retroflexus. Thalamic targets include the parafascicular, ventromedial and ventrolateral nuclei. Collaterals of the same neuron may terminate in the spinal cord, the bulbar reticular formation, the tectum, and the thalamus (Fig. 7). Nucleoolivary fibers from the medial nucleus are considered by Ruigrok (this volume, Chapter 8). FIGURE 5 (Top) Midsagittal section through the cerebellum of the rat. For symbols see Fig. 6. (Bottom) Drawing of Häggqvist-stained section through the cerebellar commissure, with contributions from the uncinate tract and the inferior and middle cerebellar peduncles. Abbreviations are as in Fig. 1.
of the inferior cerebellar peduncle by a layer of thin, olivocerebellar fibers. Uncrossed fastigiobulbar fibers take their origin from the middle and caudomedial subdivisions of the fastigial nucleus, but a contribution of the dorsolateral protuberance seems to be small or absent (Voogd et al., 1985). The few experimental studies on the efferents of the medial cerebellar nucleus of the rat (Achenbach and Goodman, 1968; Angaut and Cicirata, 1982; Ruigrok and Voogd, 1990; Watt and Mihailoff, 1983; Teune, 1999; Teune et al., 2000) either used silver impregnation methods for degenerated axons after lesions of the medial nucleus, which always interrupt the corticofugal
The Posterior Interposed Nucleus and the Interstitial Cell Groups The posterior interposed nucleus is the smallest of the central nuclei of the rat, but it has a very high cell density (Figs. 6c–6i). It contains rather large cells; small cells are more numerous ventrally. A cell group located between the posterior interposed nucleus and the fastigial nucleus, which formerly was included with the posterior interposed, was considered as an independant cerebellar nucleus by Buisseret-Delmas et al. (1993), because it it serves as the target nucleus for one of the corticonuclear projection zones of the anterior lobe (the X zone, see also Trott and Armstrong, 1987b). It is known as the interstitial cell group (Figs. 2 and 10C). The efferent connections of the posterior interposed nucleus of the rat have been studied by Haroian et al. (1981), Daniel et al. (1987), and Teune et al. (2000). They cross in the dorsal part of the decussation of the superior cerebellar peduncle and terminate along the
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FIGURE 6 (A–F) Sagittal sections through the cerebellum of the rat. (a, c, h, g, and i) Nissl-stained sections through the medial part of the cerebellar nuclei. (b, d, f, h, j, and k) Drawings of parallel Häggqvist-stained sections. Coarse fibers of the restiform body are indicated with open circles; olivocerebellar fibers are in black. Pontocerebellar fibers are stippled; the efferent fibers in the superior cerebellar peduncle are hatched. Calibration (bar, 1 mm) refers to Nissl-stained sections. Abbreviations are as in Fig. 1.
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FIGURE 6, cont’d (A–F) Sagittal sections through the cerebellum of the rat. (a, c, h, g, and i) Nissl-stained sections through the medial part of the cerebellar nuclei. (b, d, f, h, j, and k) Drawings of parallel Häggqvist-stained sections. Coarse fibers of the restiform body are indicated with open circles; olivocerebellar fibers are in black. Pontocerebellar fibers are stippled; the efferent fibers in the superior cerebellar peduncle are hatched. Calibration (bar, 1 mm) refers to Nissl-stained sections. Abbreviations are as in Fig. 1.
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FIGURE 7 (a–c) Double-labeling of cells of the cerebellar nuclei of the rat after combinations of injections of fluorescent tracers in the thalamus, the superior colliculus, the medial bulbar reticular formation, and the spinal cord. Relabeled and reproduced from Bentivoglio and Kuypers (1982). (d) Retrograde labeling of cells of the dorsolateral hump after injections of fast blue (FB) in the lateral, parvocellular reticular formation and double labeling of cells in more ventral parts of the interposed nucleus after combined injections of nuclear yellow (NY) in the thalamus. From Bentivoglio and Molinari (1986). Abbreviations are as in Fig. 1.
medial margin of the red nucleus, the central gray, the deep mesencephalic nucleus, the deep layers of the superior colliculus, the nucleus of Darkschewitsch, the subparafascicular nucleus, and the zona incerta. Their thalamic targets include the ventromedial, ventrolateral, and the intralaminar nuclei. The contribution of the posterior interposed nucleus to the crossed descending limb of the superior cerebellar peduncle is small. In the
rat, the posterior interposed nucleus does not contribute fibers to the pontine nuclei (Watt and Mihailoff, 1983). Small caliber fibers descend dorsolateral to the pyramidal tract to the level of the inferior olive, where they terminate on the rostral part of the medial accessory olive and the ventral lamella of the principal olive (Swenson and Castro, 1983a, 1983b; Daniel et al., 1987; Ruigrok and Voogd, 1990; Ruigrok, this volume,
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Chapter 8). The retrograde labeling studies of Bentivoglio and Kuypers (1982) in the rat did not distinguish between the anterior and posterior interposed nuclei. Cells projecting to the spinal cord appeared to be most numerous in the region of the interstitial cell group (Fig. 9C). They collateralize to the superior colliculus, the thalamus, and the medial reticular formation (Bentivoglio and Kuypers, 1982) (Fig. 7). Other connections of the interstitial cell groups were detailed by Buisseret-Delmas et al. (1998).
The Anterior Interposed (Interpositus) Cerebellar Nucleus, the Dorsomedial Crest, and the Dorsolateral Hump The dorsomedial crest and the dorsolateral hump were described by Goodman et al. (1963) as lateral and dorsal protrusions of the undivided interposed nucleus. The cells of the dorsomedial crest and the adjoining medial part of the anterior interposed nucleus are smaller than the cells of the lateral part of this nucleus. A distinct border is present between the small cells of the dorsomedial crest and the larger cells of the posterior interposed nucleus. The dorsolateral hump is a ridge of small cells on the rostrolateral and dorsal surface of the anterior interposed nucleus. Korneliussen (1968) included the lateral fourth of the anterior interposed nucleus in the hump. When the hump is defined
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in this way, it includes the large cells of the caudal pole of the anterior interposed nucleus, which lie intercalated between the posterior interposed and the lateral nucleus. Hump and caudal pole can also be distinguished as separate bulges in the surface relief of the nuclei. (Fig. 2). According to Woodson and Angaut (1984), the dorsolateral hump is the main origin of the uncrossed descending branch of the superior cerebellar peduncle. According to Ruigrok and Voogd (1990) it also includes the portion of the anterior interposed nucleus ventromedial to the hump. Originally, this system was described by Ramon y Cajal (1903, 1911) with the Golgi method (Fig. 8). Mehler (1967, 1969) retraced it with the Nauta method in rats and guinea pigs. Its fibers enter the brain stem between the motor and principal sensory nuclei of the trigeminal nerve (Fig. 10B) and descend in the lateral reticular formation to terminate here or in deep layers of the principal and spinal trigeminal nuclei. Some fibers descend as far as the spinal cord (Achenbach and Goodman, 1968; Faull, 1978; Woodson and Angaut, 1984). The origin of the uncrossed descending branch of the superior peduncle was illustrated by Bentivoglio and Molinari (1986) (Fig. 7). Efferents of the anterior interposed nucleus, including those of its dorsolateral hump, travel in the middle part of the superior cerebellar peduncle (Fig. 4). The anterior interposed nucleus contributes to the crossed ascending
FIGURE 8 Sagittal section showing the origin of the uncrossed descending branch of the superior cerebellar peduncle of the mouse using the Golgi method. Reproduced from Ramon Y Cajal (1911). Original labeling: A, rootfibers of the trigeminal nerve; B, bifurcation of the vestibular nerve; C, superior cerebellar peduncle; D, uncrossed descending branch of the superior cerebellar peduncle; E, inferior cerebellar peduncle; G, middle cerebellar peduncle; H, trapezoid body; O, lateral cerebellar nucleus; a, ascending branch of the trigeminal root; b and d, spinal tract of the trigeminal nerve.
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and descending branches of the superior cerebellar peduncle. The terminations of the ascending branch in the magnocellular part of the red nucleus and the ventrolateral complex of the thalamus, of the descending branch in the basilar pons and the reticulotegmental nucleus, and of the nucleoolivary fibers in the dorsal accessory olive are discussed by Ruigrok (this volume, Chapter 8). Cells projecting to the ventrolateral complex of the contralateral thalamus and the contralateral medial bulbar reticular formation, including the inferior olive, are found over the entire anterior interposed nucleus. Cells with collateral projections to the thalamus and superior colliculus are located in the lateral part of the nucleus; cells with double projections to the thalamus and the medial bulbar reticular formation extend more laterally into the dorsolateral hump. Fibers of the anterior interposed nucleus do not descend into the spinal cord. These features are illustrated in Fig. 7.
The Lateral (Dentate) Cerebellar Nucleus, Group Y, and the Basal Interstitial Nucleus of Langer The lateral cerebellar nucleus of the rat consists of a dorsolateral magnocellular portion and a ventromedial parvocellular portion (Korneliussen, 1968). The cytoarchitecture of the lateral nucleus was analyzed by ChanPalay (1977). Fusiform cells, belonging to the infracerebellar nucleus of Gacek (1977, 1979), corresponding to the dorsal group Y of Highstein and Reisine (1979) in the cat and/or the basal interstitial nucleus of Langer (1985), are located ventral to the lateral nucleus, within the floccular peduncle. Cells of the ventral group Y are located as a compact subnucleus ventromedial to the floccular peduncle, capping the inferior cerebellar peduncle (Fig. 6). The efferent connections of the lateral nucleus are contained in the ventral and lateral parts of the superior cerebellar peduncle (Haroian et al., 1981) (Fig. 4). Some of the afferents of the group Y probably take the same route. The ventral group Y neurons give rise to commissural and cerebellar connections; the infracerebellar nucleus (dorsal group Y) projects to the oculomotor complex (Highstein and Reisine, 1979). The lateral nucleus contributes to the crossed ascending and descending branches of the superior cerebellar peduncle. The terminations of the crossed ascending fibers in the parvocellular red nucleus and in the thalamus and of the crossed descending fibers in the pontine nuclei and the reticulotegmental nucleus and the nucleoolivary projection to the principal olive were reviewed by Teune et al. (2000) and Ruigrok (this volume, Chapter 8).
The double-labeling study of Bentivoglio and Kuypers (1982) confirmed the projection of the lateral, magnocellular part of the lateral nucleus to the thalamus. Collateral projections to the superior colliculus and the spinal cord and the medial bulbar reticular formation arise from different cell groups (Fig. 7).
LONGITUDINAL, ZONAL ORGANIZATION OF PURKINJE CELLS IN THE CEREBELLAR CORTEX: CHEMOARCHITECTURE AND CONNECTIONS Corticonuclear Projection Zones Although the paradigm of the essential similarity in the longitudinal organization of the corticonuclear and olivocerebellar projections was established in anatomical and electrophysiological studies in the cat (Voogd, 1964, 1969; Voogd and Bigaré, 1980; Armstrong et al., 1974; Trott and Armstrong, 1987a, 1987b; Oscarsson, 1969, 1973), the relation between this longitudinal pattern and the chemoarchitecture of the cerebellar cortex only can be studied in rodents, with a clear, zonally distributed chemical heterogeneity of the Purkinje cells (Scott, 1964; Hawkes et al., 1985). In this section I review studies on the corticonuclear and olivocerebellar projections in the rat, culminating in Buisseret-Delmas’ (1988a, 1988b) demonstration of their organization in similar zonal patterns, the evidence of the chemical heterogeneity of the Purkinje cells and their astroglial satellites, the Bergmann glia, and the still fragmentary evidence of the relationship of the connections of the Purkinje cells to their histochemical identity. It has been known since the Marchi studies of Klimoff (1899) in the rabbit that the corticonuclear projection is strictly uncrossed and that the cerebellar vermis is connected with the medial cerebellar nucleus and the hemisphere with the interposed and lateral cerebellar nuclei. Corticovestibular fibers originate from the vermis and the flocculus. Since Klimoff’s time, an impressive amount of detail has been assembled, mainly in the cat and the rabbit, on the projection of different lobules to different combinations of the cerebellar and vestibular nuclei. Most of these older studies, which were reviewed by Voogd (1964), Larsell and Jansen (1972), and Haines et al. (1982), used large lesions and employed arbitrary criteria to define the borders between the vermis and the hemisphere and between the different central cerebellar nuclei. Information on the lobular organization of the corticonuclear projection in the rat is fairly substantial, but, as pointed out by Armstrong and Schild (1978a), the localization in the corticonuclear
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projection is sharper in a mediolateral direction than in a rostrocaudal direction. Attention, therefore, must be focused on the existence in the cerebellar cortex of longitudinal zones with a specific projection to the central cerebellar or vestibular nuclei. A subdivision of the cerebellar cortex into medial (vermal), intermediate, and lateral zones projecting to the medial, interposed, and lateral cerebellar nuclei, respectively, was introduced by Jansen and Brodal (1940, 1942) and applied to the rat cerebellum by Goodman et al. (1963). The position of the borders between these three cortical zones depended on the position of the arbitrary borders between the medial, interposed, and lateral nuclei, and not on specific landmarks in the cortex itself. This also holds for the border between the vermis and the hemisphere in the rat, which is distinct only for the lobules 6b, 6c, 7, 9, and 10. An important deviation from Jansen and Brodal’s three-zone concept was the observation of Goodman et al. (1963) that the medial hemisphere of the rat cerebellum projects to the dorsolateral protuberance of the fastigial nucleus. This unique projection, which is not present in carnivores and primates, later was confirmed in the studies of Armstrong and Schild (1978a, 1978b) and Haines and Koletar (1979). Umetani et al. (1986) established that it originates from the region located between the primary and prepyramidal fissures. Historically ideas on the longitudinal organization in the corticonuclear projection are based on the observation that Purkinje cell axons use morphologically distinct, parasagittal compartments in the cerebellar white matter to reach their target nuclei. Myelins stains, like the Häggqvist method, which allow the distinction of the fairly coarse, myelinated axons of the Purkinje cells from other constituants of the white matter (Voogd, 1964, 1969), or acetylcholinesterase staining, which accentuates the borders between the white matter compartments (Hess and Voogd, 1986), has been used to define the architecture of the white matter compartments in carnivores, primates, and the rabbit. These methods have never been systematically and successfully applied to the cerebellum of the rat. In other species, knowledge of the compartmentalized architecture of the white matter, in combination with studies using antegrade or retrograde axonal tracing techniques, resulted in the designation of a fairly stereotyped zonal pattern in the corticonuclear projection. This pattern is characterized by the projection of one or more longitudinal Purkinje cell zones to a single cerebellar or vestibular target nucleus (Voogd and Bigaré, 1980). A major advance in our knowledge of the longitudinal organization of the cerebellar cortex was made when it became clear that the organization of the olivocerebellar and the corticonuclear projections is very similar (Voogd,
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1969; Courville et al., 1974; Groenewegen and Voogd, 1977; Groenewegen et al., 1979). More recently, BuisseretDelmas and her collaborators were able to confirm the principles and the longitudinal pattern in the corticonuclear and olivocerebellar projection in the rat, in a systematic analysis of small injections of WGA–HRP in the cerebellar cortex of this species (Buisseret-Delmas, 1988a, 1988b; Buisseret-Delmas and Angaut, 1989a, 1993; Buisseret-Delmas et al., 1993; Yatim et al., 1995). According to Buisseret-Delmas (Fig. 9) three corticonuclear projection zones—A, X, and B—can be distinguished in the vermis. The medial A zone extends over the entire vermis and projects to the middle and caudomedial subdivisions of the fastigial nucleus (see also Päällysaho et al., 1990; Umetani, 1989; Tabuchi et al., 1989; Voogd and Ruigrok, 1997). The X zone is present in the anterior lobe, probably extends into lobule 6a, and, according to Yatim et al. (1995), is also represented in lateral lobules 9 and 10 (Fig. 10). It projects to the interstitial cell groups. The B zone occupies the lateral vermis of the anterior lobe and lobule 6a and projects to the lateral vestibular nucleus (Voogd et al., 1991). In the cerebellar hemisphere the A2 zone, three C zones, and three D zones were distinguished. The A2 zone (the lateral extension of the A zone of BuisseretDelmas, 1988a) projects to the dorsolateral protuberance of the fastigial nucleus. A2 is represented in the lobulus simplex, the crura of the ansiform lobule, and the paramedian lobule (Fig. 11I). According to BuisseretDelmas (1988a) A2 is continuous with the vermal A zone; in our experience the B zone separates A from A2 in the lobulus simplex. Lateral to A2 the C2 zone, with the flanking C1 and C3 zones, is located. In carnivores C1 and C3 were found to project to the anterior interposed nucleus and C2 to the posterior interposed nucleus. A different projection was advocated by BuisseretDelmas (1988b) in the rat: C1 is connected with medial and C2 with more lateral portions of both interposed nuclei and C3 only projects to the anterior interposed nucleus (e.g., Pardoe and Apps, 2002). In a recent study we confirmed the original target nuclei, as established for carnivores, in the rat (Fig. 19) (Voogd et al., 2003). C1 and C3 are confined to the anterior lobe, the lobulus simplex, the crus II, and the paramedian lobule. C1 proceeds into the copula pyramidis. C1 and C3 are absent from the crus I, the paraflocculus, and the flocculus. C2 extends over the entire cerebellum, including the paraflocculus and the flocculus. Three D zones, projecting to the lateral cerebellar nucleus, were distinguished by Buisseret-Delmas and Angaut (1989a). D0 projects to the dorsolateral protuberance, D1 to the ventral and caudal portions of the lateral nucleus, and D2 to its dorsal and rostral portions. D0 is confined to the anterior lobe, the lobulus simplex, crus
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FIGURE 10 Diagrams of the connections of the X and Cx zones in the cerebellum of the rat. (A) Localization of the anterior and posterior X and the Cx zones. Compare with Fig. 9 for their position relative to the B and C1–C3 zones. (B) Horizontal projection of the medial accessory olive, indicating the origin of the projection to the rostral X and Cx zones as an oblique band at the border of the rostral and caudal subdivisions of the medial accessory olive (vertical hatching) and to the caudal X zone from the dorsomedial cell column (dots). Compare with Fig. 13 for the climbing fiber projection of the dorsomedial cell column to lobules 9 and 10. (c) Termination of Purkinje cell axons within the interstitial cell groups. Panels A and B were modified from Buisseret-Delmas et al. (1993), panel C was redrawn from Buisseret-Delmas and Angaut (1993). Abbreviations: I–X, lobules I–X; β, subnucleus beta; CX, CX zone; dmcc, dorsomedial cell column; IC, interstitial cell groups; MAO, medial accessory olive; NI, interposed nucleus; NM, medial cerebellar nucleus; X, X zone. FIGURE 9 Topographical arrangement of the olivo- and corticonuclear connections of the cerebellum in the albino rat. (A) The subdivisions of the inferior olive; (1) is the most caudal transverse section. (B) Diagram of the zonal organization of the rat cerebellar cortex. (C) The cerebellar nuclei; (1) is the most caudal transverse section. Redrawn, and modified by addition of the connections of the dorsolateral hump (DLH; Buisseret and Angaut, 1989a) from BuisseretDelmas and Angaut (1993). Compare with Fig. 1g, for differences in the projection of the C1, C2, and C3 zones to the anterior and posterior interposed nucleus, of the D1 and D2 zones in their connections with the lateral cerebellar nucleus and the inferior olive, and in the sequence of the D0, D1, and D2 zones. Abbreviations are as in Fig. 1.
II, and the paramedian lobule. D1 and D2 extend over all lobules. The conclusion that each cerebellar zone projects to a single cerebellar target nucleus was challenged by Panto et al. (2001), who found a systematic distribution of corticonuclear terminals in other cerebellar nuclei. It is argued in the last section of the chapter that these additional foci of terminal labeling may represent
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mossy fiber collaterals, labeled from the cortical injection sites.
Climbing Fibers: The Olivocerebellar Projection
FIGURE 11 (I) Lateral extension of zone A (or A2 zone) in the posterior lobe with its projection to the dorsolateral protuberance (dlp) of the fastigial nucleus in the rat. The cumulative results of eight injections of WGA–HRP in the posterior lobe are illustrated. The injection sites are represented as gray areas in panel B and the corresponding afferent and efferent connections are represented in black in panels A and C, respectively. Dots indicate single labeled neurons in panel A and few sparsely labeled terminals in panel C. The lateral extension of the A zone receives a projection from the medial subnucleus C of the caudal medial accessory olive (MAO) Buisseret-Delmas (1988a). (II) Tectorecipient zones of Akaike (1992) in the medial part of the simple lobule (SI) and the crus 2 (CII). This zone is interrupted in the crus 1 and it is absent from the anterior lobe and the copula. The tectorecipient zone in lobule 7 is separated from the corresponding zone in the crus 2 by a strip with other, nonspecified, olivocerebellar connections. The tectal response zone in the hemisphere differs from the lateral extension of the A zone of Buisseret-Delmas (1988a) because it is absent from the crus 1 and from the rostral folia of the paramedian lobule. From Akaike (1992). Abbreviations: ANT, anterior lobe; COP, copula pyramidis; CrI, II, crus 1,2 of the ansiform lobule; PMD, paramedian lobule; SI, simple lobule; IV–IX, lobules IV–IX of Larsell.
The olivocerebellar projection to the cerebellar cortex and the cerebellar nuclei is topically organized. This was already known (Brodal, 1940) before it was realized that the inferior olive is the main source of climbing fibers in the rat (Desclin, 1974). Brodal (1940) investigated the projection of the inferior olive with the retrograde cell degeneration method in young cats and rabbits and concluded that specific lobules received olivocerebellar fibers from specific subdivisions of the contralateral olivary nucleus. Voogd (1969) and Oscarsson (1969) showed that each subdivision of the inferior olive projects to a particular longitudinal strip of cortex, which can be traced through a number of successive lobules. According to Voogd (1969), the olivocerebellar fibers reach the Purkinje cells of these strips through the same myeloarchitectonic compartments which contain the projection of these Purkinje cells to the central cerebellar nuclei. He concluded that the organization of the olivocerebellar projection and organization of the corticonuclear projection are essentially similar. The concept of the longitudinal zonal organization of the olivocerebellar projection was further developed in the anterograde axonal transport studies of Courville et al. (1974), Groenewegen and Voogd (1977), Groenewegen et al. (1979), and Gerrits and Voogd (1982) in the cat and applied in the retrograde transport studies, summarized in the monograph of Brodal and Kawamura (1980). Direct evidence for a longitudinal organization of the olivocerebellar projection in the rat was provided by Chan-Palay et al. (1977) using autoradiography of 35 S-labeled methionine to demonstrate the sagittal organization of the olivocerebellar projection in the rat. According to their findings, the projection is bilateral, and banded areas that receive labeled climbing fibers alternate with areas that receive climbing fibers from extraolivary sources. Convincing evidence that the injections of the inferior olive in this study must have been incomplete and that, instead, the entire cortex of the cerebellum is provided with climbing fibers from the inferior olive was obtained by Armstrong et al. (1982) and Campbell and Armstrong (1983a). These authors were unable to confirm the presence of an uncrossed component in the olivocerebellar projection of the rat. A zonal arrangement was recognized by Sotelo et al. (1984) in their autoradiographic studies in neonatal rats. Sugihara et al. (1999, 2001) reconstructed the entire trajectory of individual olivocerebellar fibers, from small injections of biotinylated destran amine (BDH) in the
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inferior olive of the rat. Figure 14 from Sugihara et al. (2001), illustrates the two or three climbing wide strip, innervated from a small focus in the caudal medial acessory olive (MAO), which extends over more than 15 mm over the cerebellar surface. The subdivision and the afferent connections of the inferior olive of the rat were discussed by Ruigrok (this volume, Chapter 8). An important contribution to the morphology of the inferior olive of the rat was made by Azizi and Woodward (1987). They subdivided the MAO into a horizontal lamella (corresponding to the subnuclei A and B of the caudal MAO), a vertical lamella (including the subnucleus C, the group beta, the dorsal cap (DC), and the ventrolateral outgrowth (VLO) and a rostral lamella (corresponding to the rostral MAO and the dorsomedial cell column (DMCC). They distinguished a dorsal fold of the caudal dorsal accessory olive (DAO), which is joined laterally to the rest of the DAO, which they indicated as the ventral fold. They distinguished the enlarged, medial extension of the ventral lamina of the principal olive (PO) from the DMCC as the dorsomedial subnucleus (DM) (Fig. 12). The zonal projections of subnuclei of the inferior olive to the Purkinje cells of the cerebelllar cortex, their collateral projections to the cerebellar nuclei, the reciprocally organized nucleoolivary connections, and the corticonuclear projections all are in perfect register (Buisseret-Delmas and Angaut, 1993; Ruigrok and Voogd, 1990, 2000; Ruigrok, this volume, Chapter 8). The zonal pattern in the olivocerebellar projection, proposed by Buisseret-Delmas (Fig. 9) (BuisseretDelmas, 1988a, 1988b; Buisseret-Delmas and Angaut, 1989a, 1993; Buisseret-Delmas et al., 1993) differs in some respects from Azizi and Woodward’s (1987) scheme of the projection of the different lamellae and folds of the rat inferior olive (Fig. 12). Both recognized a medial vermal A zone, innervated by the caudal MAO (zones 3 and 4 of Azizi and Woodward, 1987), and a lateral B zone (zone 1), innervated by the dorsal fold of the DAO. The X zone, which receives climbing fibers from an oblique strip at the border of the caudal and rostral halves of the MAO (Fig. 10), was not recognized by Azizi and Woodward (1987). The C2 zone (zone 5), flanked by the C1 (zone 2) and C3 zones, innervated by the rostral MAO and the rostral DAO, respectively, was recognized by Buisseret-Delmas (1988b) in the hemisphere, but an equivalent of the C3 zone is lacking in Azizi and Woodward’s scheme. Two zones in the intermediate part of the hemisphere which were not accounted for by Azizi and Woodward (1987) are the A2 zone (the “lateral extension of the A zone” of Buisseret-Delmas, 1988a) located in the medial hemisphere of lobules 6 and 7 and the Cx zone (Fig. 11A). The A2 zone corresponds to the lateral “tectal response
FIGURE 12 Diagram of lamellar and zonal distribution of olivary afferents and efferents in the rat. The two lamellae (folds) of the dorsal accessory olIve (DAO, 1 and 2) and the horizontal lamella of the medial accessory olive (MAO, 3) appear to receive afferents mainly from the spinal cord and dorsal column nuclei while projecting to the anterior vermis and parts of the intermediate cerebellum. The medial MAO (vertical lamella, 4) receives from the vestibular and visual areas and projects to the posterior vermis as well as the flocculus. The rostral lamella of the MAO and both lamellae of the principal olive (PO) receive projections from higher centers and sends fibers to the lateral hemispheres. In the lower part of the figure, three drawings of the inferior olive demonstrate the lamellae corresponding to their sagittal zones of projection in the cerebellum. From Azizi and Woodward (1987).
zone” of Akaike (1986a, 1986b, 1987, 1989, 1992). The medial “tectal response zone” is located in the medial half of lobule 7. They contain the climbing fiber-evoked potentials on stimulation of the ipsilateral superior colliculus (Fig. 11II). They receive their climbing fibers from two separate, but overlapping, populations of neurons in the rostral subnucleus C (the tectorecipient zone of the MAO. The CX zone, originally, was described in electrophysiological studies of climbing fiber branching in the cat (Ekerot and Larson, 1982). It was found to receive branches from the same climbing fibers terminating in the X zone. It is located in the hemisphere, immediately medial to C1, but its peripheral response properties were found to be indistinguishable from those of the C1 zone (Trott and Armstrong, 1987a).
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Contrary to C1, it receives its climbing fibers from the MAO (Campbell and Armstrong, 1985). In the rat a CX zone, receiving climbing fibers from the DMCC, was distinguished by Buisseret et al. (1993). Its presence in the posterior lobe also was advocated by Atkins and Apps (1997) and Pardoe and Apps (2002). In the lateral hemisphere both Buisseret-Delmas and Angaut (1989a) and Azizi and Woodward (1987) distinguished medial D1 (zone 6) and lateral D2 (zone 7) zones, which receive projections from the dorsal and the ventral lamina of the PO, respectively. An additional D0 zone, innervated by the dorsomedial subnucleus of Azizi and Woodward (1987), was distinguished by Buisseret-Delmas and Angaut (1989a). The projection from the caudal MAO to the vermis is not a uniform one. Subzones, receiving their climbing fibers from different subnuclei of the caudal MAO and the group beta, have been reported for several lobules. In the anterior lobe a lateral strip of Purkinje cells may receive its climbing fibers from the subnucleus B, which receives a projection from the vestibular nuclei. These Purkinje cells have been shown to project to both the fastigial and the vestibular nuclei (Voogd and Ruigrok, 1997). Two zones have been distinguished in lobule 7. The medial zone corresponds to the medial tectorecipient zone of Akaike (1992, cf. Hess, 1982; Sugita et al., 1989). The lateral zone may receive its climbing fibers from the group beta (Furber and Watson, 1983). The olivocerebellar projection to lobules 8 and 9 was defined by Eisenman (1981a, 1984) and Apps (1990) for the rat. Alternating strips, innervated by the caudal MAO and the group beta, were present in lobule 8 (Fig. 22). The complicated innervation pattern of lobules 9 and 10 is illustrated in Fig. 13 (Voogd and Ruigrok, 1997). Branching of olivocerebellar fibers, which terminate in different sites of the cortex, has been reported in many studies. Estimates of the number of climbing fiber collaterals issued by a single neuron, based upon a comparison of the total numbers of Purkinje cells and cells of the inferior olive (Schild, 1970, about 7) and on direct observations of individual olivocerebellar fibers (Sugihara et al., 1999, 8.5 ±3.7; Sugihara et al., 2001, 7 climbing fibers on average), both in the rat, are in good accordance. The presence and the typical distribution of collaterals of single olivocerebellar fibers in the cat was first described in the electrophysiological studies of Armstrong et al. (1973), Oscarsson and Sjölund (1977a, 1977b), and Ekerot and Larson (1982). Two types of collateralization were distinguished: sagittal and transverse. In sagittal collateralization the climbing fibers were distributed over different anterior and posterior segments of the same zone or set of zones. Transverse branching of olivocerebellar fibers occurred between zones innervated by the same olivary subnucleus, i.e.,
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FIGURE 13 Diagram comparing the olivocerebellar projection zones of the uvula and the nodulus of the rat (left side) to the zebrin pattern (right side). Zebrin-positive areas are shaded; zebrin positive bands P1+ – P4+ are indicated with the numbers 1–4. Olivary subnuclei in the horizontal projections of the principal olive (PO) and the medial accessory olive (MAO) and their projections zones are indicated in with the same symbols. Note that P2+ and P3+ are bisected by climbing fiber bands from the rostral and caudal group Beta and the dorsomedial cell column (DMCC). Zebrin-negative bands P2- and P3- are innervated by the caudal MAO and the dorsomedial group (DM). DC, dorsal cap; VLO, ventrolateral outgrowth. Reproduced from Voogd et al. (1996a).
between the X and the CX zones, and between C1 and C3 (Ekerot and Larson, 1982). Most of the anatomical studies on climbing fiber branching used double retrograde labeling methods and confirmed the presence of sagittal branching patterns in cat and rat (Brodal et al., 1980; Rosina and Provini, 1983; Hrycyshyn et al., 1989; Wharton and Payne, 1985; Eisenman, 1981a; Eisenman and Goracci, 1983; Lawes and Payne, 1986; Payne et al., 1985). Transverse branching between the X and lateral CX zones was studied by Apps et al. (1991) in the cat. Direct observations of climbing fiber branching have been made by Wiklund et al. (1984) with D-aspartate tracing, by Sugihara et al. (1999, 2001) with labeling of single olivocerebellar axons (Fig. 14), and by Chen and
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Aston-Jones (1998) and Voogd et al. (2003) using cortical injections of cholera toxin B unit (CTb). Voogd et al. (2003) found collateral labeling of climbing fibers after injections of the C1, Cx, and C2 zones of the copula in the anterior lobe and after injections of A2, C1, C2, C3, and D1 zones of the paramedian lobule in corresponding
zones of the lobulus simplex. Evidence of transverse branching was found for the C1 and C3 zones of the posterior lobe, which collateralize to both the anterior C1 and C3 zone, and for the CX zone of the copula which shares collaterals with the X and CX zones of the anterior lobe.
FIGURE 14 Climbing fibers originating from small areas in the inferior olive distribute within narrow longitudinal bands in the cerebellar cortex. (a) Forty-two climbing fibers arising from six axons. The color-coding of the individual axons in the original figure has been omitted. (Inset) Lateral view of the entire axonal trajectories from the biotinylated dextran amine (BDA) injection site in the centromedial portion of the medial accesory olive. (b) The distribution of the climbing fibers plotted on the unfolded vermal cortex from the midline to the left by 1.3 mm. Blank and dotted areas in the unfolded scheme represent the cerebellar cortex exposed in the cerebellar surface and hidden in the sulci, respectively. Dotted line indicates the contour of the distribution area. (Inset) The area for the unfolded display. Reproduced from Sugihara et al. (2001).
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Zonal Organization of the Vestibulocerebellum and the Paraflocculus The vestibulocerebellum includes the nodulus (lobule 10), the flocculus, and adjacent portions of lobule 9 and the paraflocculus. Lobule 10 receives climbing fibers from a combination of vestibular-innervated (group beta, DMCC) and optokinetic olivary subnuclei (DC and VLO; Fig. 13). Climbing fibers to the flocculus mainly stem from the optokinetic subnuclei of the olive (Blanks et al., 1983; Bernard, 1987). A large proportion of the climbing fibers from the the DC and the VLO are branches from climbing fibers which also terminate in the nodulus (Takeda et al., 1989a, 1989b; and b; Maekawa et al., 1989). The corticonuclear and vestibular projectons of lobules 9 and 10 of the rat have been reported by Bernard (1987), but a complete analysis of its zonal organization (compare Wylie et al., 1994, in the rabbit) is not yet available. Ruigrok et al. (1992) analyzed the zonal organization of the olivocerebellar projection to the flocculus and the adjacent paraflocculus in the rat. Two pairs of interdigitating zones, innervated by the DC and the VLO, respectively, and a lateral C2 zone could be distinguished in the rat (Fig. 15). The distal segments of these zones crossed the posterolateral fissure and were found to receive climbing fibers from more rostromedial levels of the DC (for the FE/FE´ zones) and the ventral leaf of the PO (for the FD/FD´ zones). The projections from the DC to lobule 10 and the flocculus earlier were traced with parvalbumin immunohistochemistry in rat pups by Wassef et al. (1992b). Corticonuclear projections of the flocculus of the rat include the caudoventral parts of the lateral and interposed nuclei, the group Y, and certain vestibular nuclei (Umetani, 1992). Balaban et al. (2000) used retrograde transport from the vestibular nuclei to define its zonal organization. The zonal pattern in the dorsal flocculus and the adjacent paraflocculus closely corresponds to the spatial organization of the olivocerebellar projection as published by Ruigrok et al. (1992). Zones FD/FD´ project to the superior vestibular nucleus, and zones FE/FE´ project to the medial vestibular and rostral lateral vestibular nuclei. In the ventral flocculus the pattern is less clear (Fig. 16). These observations are in accordance with the situation in other species (Voogd et al., 1996a). Nothing is known about a posssible zonal organization in the olivocerebellar projection to the paraflocculus of the rat. According to Furber and Watson (1983), Azizi and Woodward (1987), and Buisseret-Delmas and Angaut (1993) it receives climbing fibers from the rostral MAO and the PO. Its corticonuclear projection is directed at the ventral parvocellular part of the lateral
FIGURE 15 Diagram of the projection from the inferior olive to the flocculus and the ventral paraflocculus in the rat. The medial accessory olive (MAO) and the principal (PO) are drawn as diagrams of the unfolded inferior olive; the cortex of the flocculus and the ventral paraflocculus are unfolded. The symbols in the olive flocculus and the ventral paraflocculus correspond to each other. Compare with Fig. 16. Abbreviations: C2, C2 zone; caud, caudal; dc, dorsal cap; FD, FD´, FD and FD´ zones, (projections of vlo and PO); FE, FE´, FE and FE´ zones, (projections of dc); FLOd and v, dorsal and ventral surface of the flocculus; MAO, medial accessory olive; PO, principal olive; rost, rostral; vlo, ventrolateral outgrowth; VPFL, ventral paraflocculus. From Ruigrok et al. (1992).
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FIGURE 16 The corticovestibular projection of the flocculus and the adjacent paraflocculus in the rat. Summary diagram showing the localization of retrogradely labeled Purkinje cells on the ventral and dorsal surface of the flocculus and the adjacent ventral paraflocculus, based on a series of experiments with injections of the different vestibular target nuclei. The outlines of the olivocerebellar projection zones FE(´), FD(´), and C2 based on Ruigrok et al. (1992, Fig. 15) are indicated in each diagram. (A) Injections of the caudal medial vestibular nucleus (MVe), inferior vestibular nucleus (SpVe), and nucleus prepositus hypoglossi. (B) Injections of the superior vestibular nucleus (SuVe). (C) Injections of the rostral MVe. (D) Injections of the ventral lateral vestibular nucleus (SuVe). Caudal and rostral MVe and ventral LVe receive Purkinje cell axons from different strips within the projection of the FE and FE’zones. SVN receives its main projection from the FD and FD´ zones. Redrawn from Balaban et al. (2000).
cerebellar nucleus and the lateral pole of the posterior interposed nucleus (Armstrong and Schild, 1978a, 1978b; Buisseret-Delmas and Angaut, 1993).
Longitudinal Zones: Chemoarchitecture The relative lack of information on the organization of the corticonuclear and olivocerebellar projections in rats, in the period before Buisseret-Delmas started to contribute to this topic, constrasts strongly with the abundance of information on the histochemical differentiation of longitudinal zones in the cerebellar cortex of rodents. The enzyme histochemical studies of Scott (1964, 1965) and Marani (1982, 1986) already showed the presence of alternating longitudinal zones of high and low 5´-nucleotidase (5´-N) activity in the cerebellar cortex of the vermis and the hemispheres in mice and rats. The pattern of 5´-N-positive and -negative zones is complete in the sense that it is present in all lobules of the vermis and the hemisphere and unequivocal
because, in the mouse at least, the bands are clearly delineated. The pattern is less distinct in the rat because a high background activity is present all over the molecular layer. The cellular localization of this enzyme is still disputed. Marani (1982, 1986) favored a primarily neural localization in the Purkinje cells. Others advocate a Bergmann glial plasma membrane localization (Kreutzberg et al., 1978; Schoen et al., 1987, 1988). A Purkinje cell-dependent, presumed Bergmann glial localization of 5´-N was demonstrated by Hess and Hess (1986) in Purkinje cell-deficient mutant mice. A midline band, flanked by six, symmetrically disposed, 5´-N-positive bands can be recognized in mice. The bands in the anterior and posterior lobes are not necessarily continuous. The 5´-N-positive bands are narrow in the ventral part of the anterior lobe. They increase in width in the dorsal parts of the anterior lobe and the simple lobule and even more in the rest of the posterior lobe, where the 5´-N-negative zones are reduced to narrow slits.
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An identical, “zebrin” pattern was discovered by Hawkes et al. (1985). The epitope recognized by the Hawkes family of monoclonal antibodies, known as the “anti-zebrins,” is exclusively localized in Purkinje cells. The first of the zebrins (mabQ113, zebrin I) was documented by Hawkes et al. (1985) and Hawkes and Leclerc (1987) as a monoclonal which recognized a 120-Kda protein in a subset of Purkinje cells of the rat. The epitope is present in dendrites, soma, axons, and axon terminals of these Purkinje cells and these cells are arranged in longitudinal zones alternating with strips of nonimmunoreactive Purkinje cells (Fig. 17). A second antibody (anti-zebrin II), which reacts with tissue of nonmammalian and mammalian species, was produced by Brochu et al. (1990). The epitope of zebrin II is associated with a 36-kDa polypeptide, identified as aldolase C (Hawkes, 1992; Ahn et al., 1992). The zonal distribution of zebrin I- and zebrin II-immunoreactive Purkinje cells is identical (Hawkes and Leclerc, 1987; Brochu et al., 1990). The congruence of the 5´nucleotidase and the zebrin pattern was shown in mice by Eisenman and Hawkes in 1989. The zonal pattern in the distribution of zebrinimmunoreactive and nonimmunoreactive Purkinje cells is identical or very similar to that of nerve growth factor receptor protein (Koh et al., 1989; Sotelo and Wassef, 1991; Dusart et al., 1994), to the monoclonal antibody B30 of Stainier and Gilbert (1989), which recognizes two minor gangliosides, to protein kinase C delta (Chen and Hilman, 1993a), to the glutamate transporter EAAT4 (Dehnes et al., 1998), and to the GABAB slice variant GB1b (Fritschy et al., 1999). A reversed pattern, i.e., colocalization with zebrin-negative Purkinje cells, has been found for P-path-immunoreactive
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Purkinje cells in the cerebellum of the mouse (Edwards et al., 1989) and for the anti-BW66 antibody, against the microtule-associated protein MAP 1a (Touri et al., 1996). Colocalization of zebrin II and P-path immunoreactivity only occurs in restricted regions (Leclerc et al., 1992). A distribution which partially complements the zebrin pattern was found for mouse Purkinje cells displaying HNK immunoreactivity (Hawkes, 1992; Eisenman and Hawkes, 1993) and for the constitutive expression of the 25-kDa heat-shock protein Hsp25 (Armstrong and Hawkes, 2000; Armstrong et al., 2001). Hsp25 is not expressed by Purkinje cells of rat cerebellum (Plumier et al., 1997; Armstrong et al., 2001). Bergmann glial fibers, immunoreactive for an antibody against FAL (3-fucosyl-N-acetyl-lactasamine), are arranged in a zonal pattern in adult mice. This pattern also appears to be complementary to the distribution of zebrin-immunoreactive Purkinje cells (Bartsch and Mai, 1991; Marani and Mai, 1992). Zebrin-positive and -negative Purkinje cells display a selective vulnerability to different noxes: in the Nervous mutation in mice the zebrin-negative Purkinje cells are most resistant (Wassef et al., 1987; Edwards et al., 1994), however, in a transgenic mouse model for Niemann– Pick’s disease the zebrin-negative Purkinje cells are the first to disappear (Sarna et al., 2001). A transient, zebrin-like pattern in the expression of L7 in mouse Purkinje cells was shown to be under genetic control (Oberdick et al., 1993; Oberdick, 1994). The zonal distributions of other Purkinje cell markers mentioned in the literature are not necessarily similar to the zebrin pattern (Ingram et al., 1985; Chan-Palay et al., 1981, 1982a, 1982b; Nilaver et al., 1982; Nunzi et al., 1999; Fusco et al., 2001).
FIGURE 17 The reconstruction of parasagittal bands of mabQ113+ (zebrin I-immunoreactive) Purkinje cells in the adult rat cerebellar cortex as seen anteriorly (a) and posteriorly (b). The band pattern is based upon the serial reconstruction of nine complete and five partial cerebellums from sections cut in the horizontal plane and four complete reconstructions from sections cut coronally. Bands P1+ through P7+ are labeled. From Hawkes and Leclerc (1987).
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The zebrin pattern, therefore, is the common denominator in the distribution of a number of different, seemingly unrelated substances and properties of Purkinje cells and their Bergmann glial covering. A unifying theory, explaining this distribution is still lacking, and no information is available on the possible differences in electrophysiological parameters of zebrin-positive and negative Purkinje cells. The nomenclature used for the bands of zebrinpositive and -negative Purkinje cells was introduced by Hawkes and Leclerc (1987). It is based on the staining of Purkinje cell dendrites in the molecular layer. The axons of zebrin-positive Purkinje cells can be traced into the white matter, where they appear more or less as distinct bundles. Hawkes and Leclerc (1987) grouped the zebrin I-positive Purkinje cells in a midline band (P1+) and seven, symmetrically disposed, parasagittal bands (P2+–P8+, Figs. 17 and 18). The midline band consists of the fused median zebrin I-immunoreactive Purkinje cells of both sides: the axons of these cells collect in distinct bundles on both sides of the midline. The intercalated zebrin-negative areas were indicated with the same number as the next medial zebrin Ipositive band (i.e., P1− is located between P1+ and P2+). The diagram of Hawkes and Leclerc (1987) (Fig. 17) suggests that all zebrin-positive bands, with the exception of P8+, continue uninterruptedly from the posterior lobe into the anterior lobe. In the anterior lobe six zebrin-positive bands, numbered P1+ to P6+ were distinguished. With the exception of the P3+ band, the zebrin-positive bands are distinct and clearly delineated. Staining of Purkinje cells in P3+ is less complete and its borders are fuzzy. The P1+ and P2+ bands increase in width in the dorsal part of the anterior lobe and in dorsal lobule V one or two satellite bands are usually present between them. Bands P3+, P4+, and P5+ cannot be precisely identified in the ventral lobules of the anterior lobe (lobules 1–3), while the lateral P6+ band is often divided into a narrow medial portion and a wide lateral portion. The pattern of zebrin banding in the lobulus simplex (the hemispheral expansion of lobule 6a) is continuous with and very similar to that of the anterior lobe. Apart from P3+, several narrow satellite bands are present in the region between P2+ and P4+. Bands P4+ and P5+ can be followed over the surface of the two sublobules of the lobulus simplex and continue on the rostral surface of crus I of the ansiform lobule. In the ansiform lobule (the hemispheral region lateral to lobules 6b and 6c) the bands coalesce into a uniform, zebrin-positive area. The band pattern reappears in crus II where the two narrow P4b+ and P5a+ bands and the more lateral and wider P5+, P6+, and P7+ bands can be distinguished. In the paramedian lobule the pattern shifts
laterally relative to crus II, and the P6+ and 7+ bands are often fused. Bands P4b+ and P5a+ generally fuse in the ventral part of the paramedian lobule. The pyramis (lobule 8) is characterized by the distinct zebrin-positive bands P1+ to P4+. Its hemisphere, the copula pyramidis, contains a zebrin-positive patch on the apex of the lobule. Laterally, the P5+/P7+ bands fuse into a zebrin-positive area, which is shifted further laterally with respect to the corresponding bands in the paramedian lobule. Laterally this zebrin-positive area continues into the paraflocculus and the flocculus. Wide, zebrin-positive separated by zebrin-negative slits are present in lobule 9. Most Purkinje cells of lobule 10 are zebrin-positive, although zonally distributed regions with higher and lower immunoreactivity can be recognized in the bottom of the posterolateral fissure and in lobule 10.
Correlations of the Corticonuclear and Olivocerebellar Projections with the Zebrin Pattern Gravel et al. (1987) and Wassef et al. (1992a) demonstrated that the position of antegradely labeled longitudinal strips of climbing fibers correlates with the zebrin pattern, but were unable to show a precise correspondance of specific zebrin-positive or -negative zones with the olivocerebellar projection of the individual subnuclei of the olive. For some regions of the cerebellum this object was achieved in our studies using antegrade axonal tracing from small injection sites restricted to individual olivary subnuclei, mapping of retrogradely labeled Purkinje cells from injections confined to particular cerebellar or vestibular nuclei, and/or the tracing of climbing fiber collaterals from injections of CTb of electrophysiologically and anatomically identified single zones in the posterior lobe of rat cerebellum (Fig. 19) (Voogd et al., 1993, 1996a; Voogd and Ruigrok, 1997; Voogd et al., 2003). The DAO, intermediate regions of the MAO, and and the DM were found to project to zebrin-negative territory. Rostral MAO with the DMCC, the PO with the VLO, and the DC and the group beta innervated zebrin-positive Purkinje cells. The projections from the caudal MAO include both zebrin-positive and zebrin-negative regions, but could not be studied in sufficient detail. The situation in the hemisphere of the rat cerebellum is fairly clear. The C2 zone, innervated by the rostral MAO, occupies the zebrin-positive P4+ band in the anterior lobe and the lobulus simplex and the P5+ band in the crus II, the paramedian lobule, and the copula pyramidis. The C1 and C3 zones, innervated by the rostral pole (ventral fold) of the DAO, correspond to the zebrin-negative bands, located at either side of
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FIGURE 18 Reconstruction of the localization of zebrin-immunoreactive Purkinje cell zones in the cerebellum of the rat. Numbers indicate the zebrin-positive Purkinje cell zones P1–P7 of Hawkes and Leclerc (1987). Abbreviations: 1–7. Zebrin-positive bands 1–7; COP, copula pyramidis; CrI and CrII, crus I and II of the ansiform lobule; PMD, paramedian lobule; SI, simple lobule; I–X, lobules I–X.
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FIGURE 19 Diagram comparing the pattern of zebrin-positive and-negative bands in the anterior cerebellum (anterior lobe and lobulus simplex) and the posterior cerebellum (lobules 7 and 8, crus II, paramedian lobule, and copula) with the olivocerebellar and corticonuclear projection zones in the rat. The zebrin-postive bands are numbered and hatched. For each projection zone the source of the climbing fiber projection in the inferior olive (stippled) and the cerebellar target nucleus is indicated. The topographical relations between connections and the P1+/P4a+ bands in the posterior cerebellum have not yet been verified. The projections of the C1–C3, D1, and D2 zones to single cerebellar target nuclei and the relative position of the D0 zone differ from those in the diagram of Buisseret-Delmas and Angaut (1993; Fig. 9). The A2 zone is not indicated in the anterior cerebellum because its relation to the zebrin pattern is incompletely known. Data are from Voogd et al. (1993; in preparation). Abbreviations: 1–7, zebrin-positive zones P1+ / P7+; A–D2, corticonuclear and olivocerebellar projection zones A–D2; Dd, dorsal fold of the dorsal accessory olive; Dh, dorsolateral hump; DM, dorsomedial group of the ventral lamina of the PO; DP, dorsolateral protuberance of the medial cerebellar nucleus; Dv, ventral fold of the dorsal accessory olive; IA, anterior interposed nuxleus; IC, interstitial cell groups; IP, posterior interposed nucleus; Lc, caudal part of the lateral cerebellar nucleus; Lr, rostral part of the lateral cerebellar nucleus; LV, lateral vestibular nucleus; Mc, caudal medial accessory olive; Mi, intermediate medial accessory olive; Mm, middle subnucleus of medial cerebellar nucleus; Mr, rostral medial accessory olive; Pd, dorsal lamina of the principal olive; Pv, ventral lamina of the principal olive.
P4+ in the anterior lobe and the lobulus simplex and of P5+ in the posterior lobe. The B zone, which receives its climbing fibers from the caudal pole (dorsal fold) of the DAO, similarly, occupies the medial part of the zebrin-negative P2− band in the anterior cerebellum. Climbing fibers from intermediate levels of the MAO were found to branch to zebrin-negative strips, medially to P4+ and laterally to P2+, corresponding to the X and CX zones, respectively. In the lateral hemisphere, the PO-innervated D1 and D2 zones correspond with the zebrin-positive P5+ and P6+ bands in the anterior lobe and with P6+ and P7+ in the posterior lobe, respectively. The DM-innervated D0 zone is located in the zebrin-negative strip, located between P5+ and P6+ in the anterior cerebellum and between P6+ and P7+ in the posterior lobe. This D1–D0–D2 sequence is at variance with the D0–D1–D2 sequence, as originally reported by Buisseret-Delmas and Angaut (1989a) (compare Figs. 9 and 19). The A2 zone corresponds with a medial region in the crus II and the paramedian lobule, containing the zebrin-positive P4b+ and P5a+ bands and with a similar region in the medial lobulus simplex. The uniform, zebrin-positive appearance of the crus I and the paraflocculus is in accordance with the lack of projections of the DAO and the DM to zebrin-negative territory in these lobules. Similarly, the fusion of the
P5+, P6+, and P7+ bands in the paramedian lobule and the copula pyramidis, corresponds with the absence of zebrin-negative C3 and D 0 zones in these lobules. The question as to whether the zebrin-negative P4b− and the zebrin-postive P4b+ and P5a+ bands of the A2 zone are innervated by different groups of olivary neurons in the caudal MAO cannot, as yet, be answered. The shift in the numbering of zebrin bands, corresponding to particular climbing fiber zones, between the anterior and posterior cerebellum (compare Figs. 17, 18, and 19), can be explained by the absence of zebrin-negative DAO and DM-innervated zones in crus I. The uniform zebrinpositive appearance of crus I prevented Hawkes and Leclerc (1987) from establishing their continuity. The correspondance of the climbing fiber zones with the zebrin-postive and negative bands in lobules 9 and 10 is illustrated in Fig. 13. It should be noted that the zebrin-positive bands P2+ and P3+ are bisected by branching projections from caudal group beta to P1+ and medial P2+, from rostral group beta to lateral P2+ and medial P3+, and from the DMCC to lateral P3+. Moreover, the DM and the caudal MAO project to the narrow, zebrin-negative strips P2− and P3−, respectively (Voogd et al., 1996a; Voogd and Ruigrok, 1997). Overall, the zebrin pattern of the rat cerebellar hemisphere can be considered, therefore, to be the result of zebrin-negative zones innervated by DAO, DM, and
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intermediate MAO, interdigitating with zebrin-positive zones innervated by rostral MAO and PO and the vestibular and optokinetic subnuclei of the olive (group beta, DMCC, DC, VLO). In crus I, the flocculus and the paraflocculus, where zebrin-negative zones are not represented, the Purkinje cells are uniformly zebrinpositive. It remains to be determined whether this distinction between zebrin-negative and -positive zones is linked to the fact that subnuclei of the olive innervating the former all receive a somatotopically organized input from the periphery (Molinari et al., 1996; Yatim et al., 1996), whereas olivary subnuclei innervating the latter are dominated by afferent connections from higher levels of the brain stem.
AFFERENT MOSSY FIBER SYSTEMS The origin and the termination of the main afferent mossy fiber systems of the cerebellum are reviewed by Ruigrok (this volume, Chapter 8). Here we address the question of the topographic distribution of some of these tracts. Mossy fiber systems enter the cerebellum through the inferior and middle cerebellar peduncles. The ventral spinocerebellar tract, which courses rostral to the entrance of the trigeminal nerve, reaches the cerebellum dorsal to the superior cerebellar peduncle, where it rejoins the fibers of the inferior cerebellar peduncle. Within the cerebellum they remain separated from the cerebellar nuclei by a layer of olivocerebellar fibers. Mossy fibers cross in a separate portion of the cerebellar commissure, rostral and dorsal to the fibers of the uncinate tract (Fig. 6). The common features in the distribution of mossy fibers are well-illustrated in the recent paper of Wu et al. (1999) on the course and termination of individual mossy fibers from the lateral reticular nucleus of the rat (Fig. 20). The parent fibers enter the cerebellum laterally and sweep medially, as semicircular fibers, located rostral and dorsal to the cerebellar nuclei. They usually cross in the rostral and dorsal portion of the cerebellar commissure and, therefore, distribute bilaterally. The parent fibers emit collaterals at certain preferential positions, which enter the white matter of the folia and terminate as ill-defined, longitudinal stripes of mossy fiber rosettes in the granular layer (see also Scheibel, 1977). Some mossy fiber systems also send collaterals to the cerebellar nuclei. The primary orientation of the “parent” mossy fibers, therefore, is a transverse one, contrasting with the strictly longitudinal (parasagittal) orientation of the olivocerebellar and corticonuclear projections. The termination of a mossy fiber system usually is restricted
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to a particular combination of lobules or folia. This type of distribution of mossy fiber systems has been used to subdivide the cerebellum into functional regions, such as its spinal, vestibular, visual, and cerebropontine territories. Within these territories mossy fibers terminate as ill-defined longitudinal stripes of mossy fiber rosettes, separated by empty areas, as shown for the mossy fiber system of the lateral reticular nucleus (Fig. 20) and several other mossy fiber pathways, including the pontocerebellar projection. The termination in multiple longitudinal aggregates raises important questions on (1) the spatial organization of overlap and segregation of different mossy fiber systems, (2) the paradox that possible effects of such a termination in segregated longitudinal aggregates of mossy fiber terminals would be erased by the transverse orientation in the next link of the pathway consisting of the axons of the granule cells, the parallel fibers, and (3) the relation of the longitudinal aggregates of mossy fiber terminals to the compartmental organization of the corticonuclear and olivocerebellar projections. The question of the overlap and the segregation of mossy fiber systems is considered in the next sections on specific mossy fiber pathways. The effect of the transverse orientation of the parallel fibers on the patterns in the termination of mossy fibers has been mitigated by the observation that granule cells preferentially influence Purkinje cells located immediately superficial to them, by multiple syanapses on their ascending branches (Llinas, 1982; Bower and Woolston, 1983). Any pattern in the termination of the mossy fibers, therefore, will be reproduced at the level of the Purkinje cells. The transverse branches of the parallel fibers extend over large distances; over the entire width of the lobules of the vermis and the hemisphere in the rat. As a consequence, mossy fibers exert a strong influence on certain arrays of Purkinje cells and a weaker influence on the Purkinje cells in between. A correspondance in the distribution of climbing fiber and mossy fiber evoked potentials has been shown by Eccles et al. (1968a, 1968b, 1971, 1972) for ill-defined patches of the cat cerebellar cortex, which received both mossy and climbing fiber input from the same receptive area on the limbs. Ekerot and Larson (1973, 1980) found a similar spatial correspondance for the effects of stimulation of different limb nerves mediated by climbing fibers terminating in the C1, C2, and C3 zones of the anterior lobe of the cat and the slightly wider zones of termination of the exteroceptive component of the cuneocerebellar tract. This correspondance was extended to the level of the microzones by Garwicz et al. (1998). Recent studies of tactile projections to crus II of the rat cerebellum (Brown and Bower, 2001) revealed a similarity in the peripheral receptive field organization
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FIGURE 20 Course and termination of single mossy fibers in the cerebellum of the rat. (A) Frontal view of a completely reconstructed, biotinylated dextran amine-labeled, single mossy fiber from the lateral reticular nucleus. The fiber entered the cerebellum through the ipsilateral restiform body, projected bilaterally to the cortex and the cerebellar nuclei, and formed a multiple, longitudinal zonal projection pattern by its cortical arborescent collaterals. Scale bars, 0.5 mm. (B) Mapping of mossy fiber rosettes in the cerebellar cortex after biotinylated dextran amine injection in the left lateral reticular nucleus, showing bilateral projction with ipsilateral predominance and zone-like terminal distribution in the cerebellar cortex (a–f, rostral to caudal). Scale bar, 1 mm. From Wu et al. (1999). Abbreviations: COPab, copula pyramidis, lobules a and b; D, dorsal; DN, lateral cerebellar nucleus; FN, fastigial nucleus; icp, inferior cerebellar peduncle; IP, posterior interposed nucleus; LRNm, magnocellular part of the lateral reticular nucleus; Lt, left; LVN, lateral vestibular nucleus; PM, paramedian lobule; Rt, right; Sima, Simb, lobulus simplex, lobules a and b; V, ventral.
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of Purkinje cell complex spikes (generated by activity in climbing fibers) and the immediately subjacent granule cells (which receive their principal input from mossy fibers). These observations are in accordance with our anatomical observations on the distribution of mossy fiber collaterals, namely, that collaterals of mossy fibers terminating in a particular locus always terminate subjacent to the strips of climbing fiber collaterals arising from olivocerebellar fibers terminating in the same cortical locus (Voogd et al., 2003). When the similarity in receptive field organization of the Purkinje cells and the subjacent granule cells applies to the entire cerebellum, this may have important consequences for our understanding of the organization of the Purkinje cells in longitudinal zones and microzones. Questions on overlap and segregation in the termination of different mossy fiber systems in a particular zone, on somatotopical localization and the relation of Welker’s (1987) maps of a discontinuous (fractured) localization to the multiple representations of the body in the microzones, and on the nature of the mossy fiber input of zones and regions that lack a somatopical organization now have become relevant issues. One feature of the termination of mossy fiber systems which has not been discussed is their termination in the cerebellar nuclei. It has been attempted to investigate this type of termination using injections of retrograde tracers into the cerebellar nuclei. However, the proximity of the afferent tracts to the central nuclei may easily lead to false positive results. The experiments of Eller and Chan-Palay (1976) with injections of HRP into the lateral cerebellar nucleus of the rat showed a multitude of extracerebellar afferents to this nucleus. Of these sources, the pontine nuclei and the nucleus reticularis tegmenti pontis (Gerrits and Voogd, 1987; Shinoda et al., 1995; Mihailoff, 1993), the lateral reticular nucleus (Ruigrok et al., 1995; Wu et al., 1999), and the raphe nucleus (Chan-Palay, 1977) were confirmed with anterograde axonal tracing methods. The question of the projection of the basal and reticular pontine nuclei to the cerebellar nuclei recently was studied by Mihailoff (1993) with antegrade axonal transport of the more sensitive tracer Phaseolus vulgaris leucoagglutinin. Both the pontine nuclei and the tegmental pontine nuclei were found to send fibers to the cerebellar nuclei, but the density of the projection was greater for the reticular nucleus. Pontine nuclei were found to project to dorsal regions of the fastigial (to the dorsolateral protuberance), interposed, and lateral nuclei, the nucleus reticularis tegmenti pontis to ventral and caudal parts of the nuclei. The rostral and medial parts of the anterior interposed nucleus are spared. The lateral reticular nucleus, similarly, projects to all cerebellar nuclei, but the projection focuses on more or
less complementary regions of the nuclei, including the ventral and ventrolateral fastigial nucleus, the interstitial cell groups, medial parts of the interposed nuclei, and the lateral vestibular nucleus (Ruigrok et al., 1995; Wu et al., 1999) (Fig. 20). Projections to the same regions of the fastigial and interposed nuclei were traced from different levels of the spinal cord (Matsushita, 1999a, 1999b; Matsushita and Yaginuma, 1995; Matsushita and Xiong, 2001; Matsushita and Gao, 1997). All the collateral projections of the reticular nuclei and the cord are bilateral, with a predominance of the lipsilateral side. The pertinent negative results of Eller and ChanPalay (1976) with respect to possible collateral projections to the nuclei of the dorsal column nuclei were confirmed in the anterograde transport study of Gerrits et al. (1985) in the cat. Similar data are not available for the other precerebellar nuclei of the rat. The tentative conclusion is that not all mossy fiber systems distribute collaterals to the central nuclei. The reticular nuclei, including the reticulotegmental and lateral reticular nuclei, the spinal cord, and the monoaminergic systems seem to be the main sources of the extracerebellar nuclear afferents. The rubrocerebellar pathway (Brodal and Gogstad, 1954), a collateral pathway of the rubrospinal tract, was investigated with double-labeling techniques and shown to terminate in the anterior interposed nucleus in the rat (Huisman et al., 1983). It is the only pathway known to terminate in the cerebellar nuclei and not in the cortex. In our experiments on the collateralization of mossy fibers from small injection sites in the cerebellar cortex of the rat (Voogd et al., 2003) we often observed multple, bilateral patches of thin varicose axons in the cerebellar nuclei, apart from the coarse terminals of the Purkinje cell axons. We considered these fine plexuses as collateral projections of the mossy fibers. Panto et al. (2001), similarly, observed multiple foci of termination in the cerebellar nuclei after injections of the cortex. These authors did not mention the bilaterality of these projections and considered all of them as terminals from Purkinje cell axons.
TERMINATIONS OF MOSSY FIBER SYSTEMS IN DIFFERENT REGIONS OF THE CEREBELLUM Projections from the Spinal Cord, the Dorsal Column Nuclei, the Trigeminal Nuclei, and the Lateral Reticular Nucleus Regions dominated by spinocerebellar, cuneocerebellar, and trigeminocerebellar input correspond to the
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anterior lobe and the lobulus simplex, lobule 8, the crus II, the paramedian lobule, and the copula pyramidis. As pointed out in the previous section, this part of the cerebellum is characterized by the presence of X, B, C1, C3, and D0 zones, which receive somatosensory climbing fiber input from the intermediate MAO, the DAO, and the dorsomedial subnucleus. The output of these zones is directed at the spinal cord (X zone, through the interstitial cells group, B zone through the lateral vestibular nucleus), the lateral reticular formation and the trigeminal nuclei (D0 zone through the dorsolateral hump and the uncrossed descending limb of the brachium conjunctivum), and the red nucleus (C1 and C3 zones, through the anterior interposed nucleus). The lateral reticular nucleus, which projects to the same lobules, relays information from the spinal cord and the red nucleus to the cerebellum (Ruigrok, this volume, Chapter 8). Spinocerebellar tracts in the rat were traced by Anderson (1943) with the Marchi method and illustrated by Voogd (1967). These tracts are distributed bilaterally to the anterior lobe, with a preference for its ventral part, to the bottom of the primary fissure, the pyramis, and the dorsal part of the uvula and to the ventral part of the paramedian lobule and the copula pyramidis. Fibers of
the ventral spinocerebellar tract terminate more medially and do not reach lobule 1, the uvula, or the paramedian lobule. The termination of the individual spinocerebellar tracts has not been studied in the rat. The origin of the spinocerebellar fibers from the cord in the rat was studied by Snyder et al. (1978), Matsushita and Hosoya (1979), and Beretta et al. (1991a). Branching of spino and cuneocerebellar fibers to the anterior lobe and the posterior lobes of the cerebellum of the rat was demonstrated by Beretta et al. (1991a, 1991b). A zonal pattern has been demonstrated in the termination of the spinocerebellar, cuneocerebellar, and lateral reticular–cerebellar tracts. The mediolateral periodicity in the termination of the spinocerebellar tracts is already present at birth (Arsenio-Nunes and Sotelo, 1985). The semiquantitative plotting study of Tolbert et al. (1993) used a semiquantitative method to plot the spinocerebellar terminals. They showed that spinocerebellar projections from the thoracic and lumbar cord are often restricted to certain transverse bands often centered at the bottom of the interlobular fissures. These bands are fractured in multiple longitudinal aggregates of mossy fiber terminals (Fig. 21). These longitudinal aggregates, therefore, are often discontinuous, with interruptions usually located at the apex of the lobules.
FIGURE 21 Surface reconstruction of the lobules I–V of the anterior lobe of the rat, showing the position of spinocerebellar terminals (SpCb) from a bilateral injection of the lumbar and thoracic cords (grey figures) and an injection of the right cuneate nucleus (ICu/ECu; black figures). The anterior–posterior (AP) dimension of the cerebellar surface has been reduced, relative to its width (ML). In lobule V, three concentrations of spinocerebellar terminals are indicated (Lat-SpCb, Me-SpCb, and Mi-SpCb), which altermate with a patches of cuneocerebellar terminals (CuCb). From Alisky and Tolbert (1997).
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The zonation in the spinocerebellar projection also was shown by Gravel and Hawkes (1990) for the projection of the lumbar and thoracic cord to the lobules of the anterior lobe of the rat. Their mossy fiber terminal aggregates usually were more discrete than those illustrated in the paper of Tolbert et al. (1993), and they were able to correlate the positions of these aggregates with the zebrin bands in the overlying molecular layer (Fig. 22). In subsequent papers Tolbert and Gutting (1997), Alisky and Tolbert (1997), and Ji and Hawkes (1984) showed that the multiple zonal termination of the cuneocerebellar and the spinocerebellar fibers from the lumbar and thoracic levels of the cord remains segregated in the cerebellar cortex. The cuneocerebellar fibers terminate in a lateral strip in the anterior vermis and in patches in the hemisphere of lobule 5 (Fig. 21). Spinocerebellar fibers from the cervical cord overlap with the cuneocerebellar projection (Matsushita et al., 1991; Ji and Hawkes, 1994). The relationship between the zebrin bands and the projections of the external cuneate nucleus and the spinocerebellar tracts in lobules 2 and 3 is illustrated in Fig. 22, from the paper of Ji and Hawkes (1993). In the case of the rat lateral reticular nucleus (Fig.20) (Wu et al., 1999) the striped termination pattern is bilaterally symmetrical and occupies the dorsal part of the anterior lobe (lobules 4 and 5), the lobulus simplex (6), and the pyramis with the copula pyramidis (8). The topographical relations of this pattern with the
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spinocerebellar and the cuneocerebellar projections and the zebrin pattern have not been studied. Trigeminocerebellar mossy fiber projections have been studied in the rat by Shambes et al. (1978a, 1978b), Woolston et al. (1981), Huerta et al. (1983), Akaike (1989), Arends et al. (1991), and Phelan and Falls (1991). Systematic studies of this system in the rat, using antegrade axonal transport techniques, have not been published thus far. However, the electrophysiological studies of Welker and Shambes on the spatial organization of somatosensory projections to the granule layer of the rat cerebellar cortex (reviewed by Welker, 1987) are mostly confined to receptive fields on the face and, therefore, concern the trigeminocerebellar mossy fiber projection. These studies were restricted to the posterior lobe of the cerebellum. Receptive fields were mostly cutaneous, varied widely in size, and had differentially enlarged representations on specific folia for certain body parts. Somatosensory short-latency projections to the granular layer occupy all hemispheric folia (except for the copula) as well as dorsal lobule 9 in the posterior vermis. They are mainly ipsilateral, with a few bilateral projections. They are shaped as irregular patches, which vary in size between 0.3 and 0.3 mm3. Arrays of juxtaposed patches form mosaics. Receptive fields often have multiple representations on different folia. The somatotopical localization in the receptive mosaic is “fractured”; i.e., the original continuity of the receptive fields has become lost. Multiple patches
FIGURE 22 Lobules II and III of the rat anterior vermis: a schematic representation of the relationships between Zebrin-positive and -negative bands of Purkinje cells and the mossy fiber projections from the external cuneate nucleus, and lumabr, thoracic and cervical levels of the cord. There is one zebrin (P1+) compartment at the midline and two others (P2+, P3+) positioned laterally. Terminals of the cuneocerebellar tract (Cu1) are clustered under P1+ and within P2- (Cu2) and P2- (Cu3). Only the medial edge of Cu3 clearly corresponds to a zebrin+/− boundary. The lumbar and thoracic spinocerebellar terminals (Gravel and Hawkes, 1990) distribute complementary to the cuneocerebellar fields. The lumar L2 fields fade toward their medial edge. The mossy fiber terminals from the cervical cord are shown as spread uniformly across the vermis. From Ji and Hawkes (1994).
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sharing the same receptive field are innervated by branches from the same trigeminocerebellar mossy fibers. Projections from the somatosensory cortex (Bower et al., 1981) and the superior colliculus (Kassel, 1980), similarly, are organized in patches which exhibit homotopy with the patches activated from the periphery. These projections are confined to the hemisphere and, presumably, are relayed by the pontine nuclei. Unfortunately, this fractured somatotopical pattern has not been extended to the anterior regions of the rat cerebellum and has not been correlated with the longitudinal pattern in the olivocerebellar projection. A partial correspondance of the tactile map with the zebrin pattern has been reported by Hallem et al. (1999) for the crus II of the rat.
Pontocerebellar Mossy Fibers The projection from the basal and reticular tegmental nuclei of the pons was charted by Burne et al. (1978b), Azizi et al. (1981), and Mihailoff et al. (1981) using retrograde transport of HRP in the rat. The retrogradely labeled cells formed multiple foci or discontinuous lamellae, in medial, lateral, dorsal, and central regions of the contralateral, and in some cases the ipsilateral, pontine nuclei and in the nucleus reticularis tegmenti pontis. Most neurons projecting to vermal lobules 6a, 8, and 9 were located in caudal regions of the pons, with most neurons projecting to 6a located within the reticular nucleus, cells projecting to lobule 8 in medial and lateral patches in the pontine nuclei (Eisenman, 1981b), and cells projecting to lobule 9 in dorsal and medial patches in the caudal pons. Most of the neurons projecting to the copula, the paramedian lobule, and the crus II are found in central and medial patches in the caudal pons and in the reticular nucleus. Rostral regions of the pons project to the crus I. The pontocerebellar projections as they appear from these studies generally are not sharply focused. The anterior lobe of the rat never was included in these or similar studies. The tecto– and pretecto–pontine cerebellar pathways were traced by Burne et al. (1981). They were found to influence extensive regions in the hemisphere and the posterior vermis. No equivalent appears to exist for the focused olivocerebellar projection to the tectorecipient zone in lobule 7, reported by Hess (1982) and Akaike (1992). A localized projection was described for the pathways from the visual cortex, via medial and lateral patches in the rostral pons, to the contralateral paraflocculus (Burne et al., 1978a; Eisenman, 1980). A similar pathway seems to exist for the projection of the auditory cortex to the paraflocculus. Auditory pontocerebellar projections to the caudal vermis are relayed by the inferior colliculus (Azizi et al., 1985).
Serapide et al. (2001) recently reported on an often bilateral pattern of longitudinal stripes separated by “interstripes” in the projection of the pontine nuclei to all lobules of the cerebellum, with the exception of the anterior lobe. Stripes were present after small injections of antegrade tracers in different parts of the pontine nuclei; larger injections resulted in diffuse labeling. The stripes and the interstripes, therefore, are innervated by different, but adjacent, parts of the pontine nuclei. The precise, topical relations between the pontine nuclei and the stripes and the interstripes in a particular lobule cannot be established from their data. The topographical relations of these projections from the pontine nuclei to the zonal patterns in the termination of other mossy fiber systems and to the zebrin pattern presently are unknown.
Vestibular Projections: Mossy Fibers Terminating in Flocculus, Nodulus, and Adjacent Areas Vestibular root fibers enter the cerebellum from the superior vestibular nucleus, as part of the ascending branch of the vestibular root (Lorente de No, 1933; Mannen et al., 1982; Sato et al., 1989). The development of the primary vestibulocerebellar projections was studied in rat embryos, where the root fibers can be distinguished by their parvalbumin immunoreactivity (Morris et al., 1988). The literature on the projection of the vestibular nerve was reviewed in the recent study of Gerrits et al. (1989) on the primary vestibulocerebellar projection in the rabbit. The evidence on the origin and distribution of secondary vestibulocerebellar projections was reviewed for the rat by Rubertone et al. (1995). Both primary and secondary vestibulocerebellar fibers terminate in lobule 10 and ventral lobule 9, in lobules 1 and 2, and in the cortex in the depth of the vermal fissures. This projection is mostly ipsilateral for the fibers of the vestibular root and bilateral for the secondary vestibulocerebellar projection. The secondary vestibulocerebellar projection to the hemisphere is restricted to the flocculus and the adjacent cortex of the ventral paraflocculus. A primary vestibulocerebellar projection to the flocculus is absent in the rabbit (Gerrits et al., 1989) and probably in most other mammals including the rat. Vestibulocerebellar mossy fibers take their origin from neurons in all vestibular nuclei, with the exception of the Deiters’ nucleus and a sparse projection from the magnocellular medial vestibular nucleus. The distribution of neurons projecting to either flocculus or caudal vermis or to both is rather similar and is bilaterally symmetrical. Most neurons were found in the medial, superior, and descending vestibular nuclei in this order. Widespread projections of the prepositus hypoglossal
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nucleus and neighboring perihypoglossal nuclei terminate bilaterally with an ipsilateral predominance in the vermis, in the flocculus and the paraflocculus, and in the cerebellar nuclei (see McCrea and Baker, 1985, and Roste, 1989, for particulars). Some cerebellumprojecting neurons of the nucleus prepositus hypoglossi and the caudal parts of the vestibular nuclear complex contain acetylcholine and/or CRF. Choline acetyltransferase (ChAT)-immunoreactive mossy fibers recently were charted in lobules 9 and 10 of the caudal vermis and the flocculus in the rat and other mammalian species by Barmack et al. (1992a, 1992b). They were most numerous in the caudal vermis, the rosettes were large in lobule 10 and smaller in ventral lobule 10 and lobules 1–3 of the anterior lobe. The cholinergic mossy fiber innervation of the flocculus was restricted to the ventral folium and the ventral half of the dorsal folium of this lobule. A particularly dense plexus of thin, beaded fibers, which may detach from the mossy fibers, was present in the flocculus. The origin of these cholinergic mossy fibers was traced from the caudal medial vestibular nucleus, the vestibular efferent, and the nucleus prepositus hypoglossi, with double-labeling of retrogradely transported HRP from injections in the caudal vermis and the flocculus and ChAT immunohistochemistry. Single- and doublelabeled ChAT-immunoreactive neurons were absent from the superior nucleus. Single HRP-labeled cells were present in all vestibular nuclei with the exception of the lateral vestibular nucleus. In other brain stem nuclei only a few neurons in the lateral reticular nucleus were double-labeled for HRP and ChAT following injections in lobules 9 and 10 (Barmack et al., 1992b). The origin of mossy fiber projections to the nodulus, the uvula, and the flocculus of the cat were quantified by Akaogi et al. (1994). Major projections to the nodulus (>95%) and the ventral uvula (>70%) were derived from the vestibular nuclei. The dorsal uvula receives its main projection (>80%) from the pons, and the flocculus receives projections from the reticular formation and the raphe nuclei (>50%) and the nucleus prepositus hypoglossi (20%). A similar situation may be inferred from the studies of Blanks et al. (1983) and Osanai et al. (1999) for the flocculus of the rat.
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C H A P T E R
10 Periaqueductal Gray KEVIN A. KEAY and RICHARD BANDLER Department of Anatomy and Histology, and Pain Management Research Institute Royal North Shore Hospital, The University of Sydney Sydney, New South Wales, Australia
Darkschewitz, and the interstitial nucleus of Cajal), the dorsal raphe nucleus, the mesencephalic trigeminal nucleus, and the dorsal tegmental nuclei. Cytoarchitectural studies of the PAG (Beitz, 1985; Beitz and Shepard, 1985; Gioia et al., 1985; Hamilton, 1973a, 1973b; Liu and Hamilton, 1976, 1980; Meller and Dennis, 1990a, 1990b, 1993) have revealed that it contains predominantly small- to medium-sized (5–20 μm in diameter) fusiform-, triangular-, and stellate-shaped neurons, whose soma and axons are oriented usually in a rostral–caudal direction. It has not proved possible to subdivide the PAG into discrete subnuclei using cytoarchitectonic criteria such as soma size, pigmentation, or dendritic morphology and orientation. However, many investigators have commented on an increase in the size of neurons and their packing density, the greater the distance from the aqueduct (e.g., density: 10,780 mm3 (near aqueduct) to 21,950 mm3 (dorsolateral to aqueduct) (Beitz, 1985; Beitz and Shepard, 1985)). This has led to suggestions that the PAG is divisible radially into: (i) a relatively cell-sparse juxtaaqueductal zone, next to the aqueduct; (ii) an adjacent, inner or medial zone, containing a moderate density of small neurons; and (iii) an outer or lateral zone, with a higher density of small- to medium-sized neurons (Beitz, 1985; Gioia et al., 1985; Hamilton, 1973a, 1973b; Onstott et al., 1993; Ramon y Cajal, 1911). The conceptualization of the PAG as radially organized has yet to prove fruitful in the reinterpretation of existing anatomical and functional data or in the generation of new experimental approaches to the study of the PAG (although see (Ruiz-Torner et al., 2001; Vanderhorst et al., 2000)).
Early Cytoarchitectural Studies The periaqueductal gray (PAG), also known as the midbrain central gray, constitutes a cell-dense region, bordered laterally by the descending tectospinal fibers, which surrounds the midbrain aqueduct (cerebral aqueduct/aqueduct of Sylvius). In the rostral midbrain (at the level of posterior commissure) as the third ventricle narrows to become the midbrain aqueduct, the PAG forms an elongated, oval-shaped collection of neurons in continuity with the periventricular gray matter of the hypothalamus (Fig. 1A). More caudally (at the level of the superior colliculus) as the aqueduct shortens dorsoventrally, the dorsal two-thirds of the PAG expands laterally and the PAG becomes an inverted pear shape structure (Figs. 1B and 1C). More caudally still (at a midcollicular level) as the mediolateral diameter of the aqueduct increases and the dorsal raphe nucleus appears, the ventral third of the PAG expands and the PAG takes on a rhomboid shape (Fig. 1D). Finally at the caudal end of the midbrain, as the aqueduct expands to become the fourth ventricle, the dorsal two-thirds of the PAG progressively narrows in its mediolateral extent (Fig. 1E), eventually disappearing. The ventral third of the PAG becomes continuous, however, with the pontine gray matter which constitutes the floor of the fourth ventricle. The common usage of the term PAG usually excludes a number of nuclei which, although technically within its boundaries, are structurally and functionally distinct from the PAG. These include ocular-related nuclei (i.e., oculomotor and trochlear nuclei, the Edinger–Westphal nucleus, the nucleus of
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FIGURE 1 Serial coronal sections of the periaqueductal gray region spaced 1 mm apart showing the radial and columnar organization described in the text. (Sections are modified from the Stereotaxic Atlas of Paxinos and Watson, 1982.) Abbreviations used: III, oculomotor nucleus; EW, Edinger–Westphal nucleus; Dk, nucleus of Darkschewitz; dm, dorsomedial column of the PAG; dl, dorsolateral column of the PAG; lat, lateral column of the PAG; vl, ventrolateral column of the PAG; m, medial PAG; ja, juxtaaqueductal PAG; DR, dorsal raphe nucleus; Me5, mesencephalic nucleus of the trigeminal; LDTg, lateral dorsal tegmental nucleus; DTgP, dorsal tegmental nucleus.
Overall, the cytoarchitectonic organization of the PAG of the rabbit, cat, monkey, and human appears identical to that of the rat (Beitz, 1985; Beitz and Shepard, 1985; Hamilton, 1973a, 1973b; Liu and Hamilton, 1976, 1980; Mantyh, 1982; Meller and Dennis, 1990a, 1990b, 1993; Paxinos and Huang 1995; Paxinos et al., 2000; Ramon y Cajal, 1911).
PAG COLUMNAR ORGANIZATION Early Functional Studies Early functional studies reported that aversive or defensive reactions, hypertension, sexual behavior (lordosis), and analgesia were readily evoked by electrical stimulation within or immediately adjacent to the PAG (Depaulis et al., 1988; Fardin et al., 1984a, 1984b; Liebeskind et al., 1973; Morgan and Franklin, 1988; Morgan et al., 1989; Sakuma and Pfaff, 1979; Sandner et al., 1987; Schmitt and Karli, 1980; Yeung et al., 1977). Although, there were suggestions from these studies that defensive and sexual reactions were most easily evoked from the dorsal PAG, and analgesia was more readily evoked from the ventral PAG, the appreciation that PAG organization took the form of a series of rostrocaudally oriented, longitudinal neuronal columns emerged only later, from studies that utilized the technique of microinjection of excitatory amino acids (EAA). As summarized in Fig. 2, these studies revealed: (i) that EAA microinjections made within the dorsal PAG evoked active defensive reactions and (ii) that the particular
defensive strategy expressed reflected the rostrocaudal position of the injection cannula. Thus, stimulation, within the dorsal PAG, at rostral sites triggered a “confrontational defense reaction,” the animal facing and threatening the stimulus (e.g., experimenter, another animal), often with vocalization; whereas stimulation, within the dorsal PAG, at caudal sites triggered an escape or flight response, the animal turning and running away from, rather than confronting, the stimulus (Bandler and Carrive, 1988; Bandler et al., 1985, 1991; Bandler and Depaulis, 1988; Bandler and Shipley, 1994; Carrive et al., 1987, 1989; Depaulis et al., 1989, 1992; Depaulis and Vergnes, 1986; Morgan and Franklin, 1988; Morgan et al., 1998; Yardley and Hilton, 1987; Zhang et al., 1990). The different defense reactions were accompanied always by hypertension and tachycardia, although the two strategies, confrontational defense/ threat (rostrally) versus escape/flight (caudally), were each characterized by a distinct set of regional blood flow changes (see Fig. 2). In contrast to the active defensive strategies that characterized the effects of dorsal PAG excitation, microinjections of EAA within the ventrolateral part of the caudal PAG (vlPAG) evoked a passive coping reaction/disengagement from the environment, characterized by quiescence and immobility, decreased vigilance, hyporeactivity, hypotension, and bradycardia. It was found also that (i) that the passive coping reaction evoked by vlPAG stimulation was associated with an opioid-mediated analgesia, whereas (ii) the active defense reactions evoked by dorsal PAG stimulation were associated usually with a non-opioidmediated analgesia (Bandler et al., 1985, 1991; Depaulis
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active coping strategies evoked from the "dorsal" PAG confrontational defense / threat non-opioid mediated analgesia hypertension and tachycardia extracranial vasodilation hindlimb & renal vasoconstriction dm
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passive coping strategies evoked from the vlPAG FIGURE 2 Schematic illustration of the dorsal and ventrolateral neuronal columns within (from left to right) the rostral PAG, the intermediate PAG (two sections), and the caudal PAG. Injections of excitatory amino acids (EAA) within the dorsal (dark shading) vs ventrolateral (vlPAG) (light shading) columns evoke fundamentally opposite, active vs passive emotional coping strategies. EAA injections made within the rostral portions of the dorsal PAG evoke a confrontational defense/threat reaction, tachycardia, and hypertension (associated with decreased blood flow to limbs and viscera and increased blood flow to extracranial vascular beds). EAA injections made within the caudal portions of the dorsal PAG evoke escape/flight, tachycardia, and hypertension (associated with decreased blood flow to visceral and extracranial vascular beds and increased blood flow to limbs). In contrast, EAA injections made within the vlPAG evoke cessation of all spontaneous activity (quiescence), a decreased responsiveness to the environment (hyporeactivity), hypotension, and bradycardia. Non-opioid-mediated and opioid-mediated analgesia are evoked, respectively, from the dorsal and the vlPAG. (Modified from Fig. 1 of Keay and Bandler, 2001).
et al., 1992, 1994; Krieger and Graeff, 1985; Lovick, 1992, 1993, 1996; Morgan et al., 1998; Yaksh et al., 1976). To summarize, then, excitation of neurons within two longitudinally oriented columns of PAG neurons evokes fundamentally distinct, integrated patterns of somatic, autonomic, and antinociceptive adjustments. Overall, the dorsal PAG-evoked, active coping reactions correspond remarkably well to the natural strategies employed by an animal when threatened or attacked, whereas the ventrolateral PAG-evoked, passive coping reactions are strikingly similar to the reaction of an animal to serious traumatic injury (i.e., blood loss, deep pain) or chronic stress (e.g., repeated defeat in social encounters) (Bandler and Keay, 1996; Bandler et al., 2000a, 2000b; Keay et al., 2000; Lovick, 1993).
Neurochemical Studies Although the functional studies provided a basis to subdivide the PAG into dorsal and ventrolateral
longitudinal columns, neurochemically there are good grounds for further subdivision of the dorsal PAG. As illustrated in Fig. 3, within the dorsal PAG there lies a wedge-shaped, dorsolateral (dl) zone which stains intensely for specific neurochemicals, e.g., NADPH– diaphorase (Fig. 3), also nitric oxide synthase (NOS), cholecystokinin, acetylcholinesterase, and met– enkephalin (not illustrated), but not for other neurochemicals, e.g., glycine-2 transporter (Fig. 3) and cytochrome oxidase (not illustrated). Conversely, adjacent to the wedge-shaped dorsolateral zone lie dorsomedial (dm) and lateral (l) zones, which: (i) stain intensely for substances for which there is absence of staining in the dorsolateral zone, e.g., cytochrome oxidase and glycine 2 transporter; but (ii) stain weakly or not at all for those substances that intensely label the dorsolateral zone (e.g., NADPH–diaphorase). The restricted distributions of these neurochemical markers led to the suggestion (Bandler et al., 1991; Bandler and Keay, 1996; Bandler and Shipley, 1994) that the dorsal PAG was broadly
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FIGURE 3 (Top) Photomicrographs of the PAG stained for the presence NADPH–diaphorase-containing neurons. Note the dense labeling in the dorsolateral PAG column. (Middle) Photomicrographs of the PAG stained for the presence of a glycine 2 transporter (GLY2-T). Note the labeling predominantly in the dorsomedial, lateral, and ventrolateral PAG columns and the absence of label in the dorsolateral PAG column. (Bottom) Schematic subdivision of the dorsal PAG into three columns: dm, dorsomedial; dl, dorsolateral; l, lateral (also see Fig. 1). Note that active emotional coping reactions are evoked readily by EAA microinjections made within the dlPAG or the lPAG (see Fig. 2). Active emotional coping reactions have been reported also following electrical or chemical stimulation of the dmPAG/deep layers of the superior colliculus (see for example, Krieger and Graeff, 1985).
divisible into three longitudinal columns, usually designated dorsomedial (dmPAG), dorsolateral (dlPAG), and lateral (lPAG). The utility of this particular columnar scheme has been supported by anatomical and functional–anatomical studies that are considered below. Other patterns of distinct PAG immunohistochemical staining have been reported. For example, VIP and galanin staining is restricted to the juxtaaqueductal zone
(Melander et al., 1986a; 1986b; Moss and Basbaum, 1983; Moss et al., 1983); phenylethanolamine N-methyltransferase and calcitonin staining are particularly intense within parts of the vlPAG (Fabbri et al., 1985; Herbert and Saper, 1992); calbindin staining and to a large extent calretinin staining are most pronounced in the dlPAG, the vlPAG, and the ventral part of the lPAG, but are absent in the dorsal part of the lPAG and the dmPAG
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(Paxinos et al., 1999); neurofilament protein SMI-32 staining is present in the outer (lateral) zone of dmPAG, lPAG, and vlPAG, but is absent in the inner (medial) zone of these columns and in the dlPAG (Paxinos et al., 1999). In addition, the distribution within the PAG of low-abundance peptides, transmitter substances, and their receptors, have been studied using in situ hybridization (De Belleroche et al., 1990; Harlan et al., 1987; Jansen et al., 1998; Lanaud et al., 1989; Mansour et al., 1994, 1995; Rattray et al., 1992; Seroogy et al., 1989; Smith et al., 1994; Tolle et al., 1993) and receptor autoradiographic techniques (Gundlach, 1991; Williams and Beitz, 1989a, 1989b, 1990). These studies have revealed additional discrete inter- and intracolumnar patterns of substancespecific cellular label (mRNAs) and receptors (silver grain densities). These variations may well reflect important organizational properties of the PAG. However, before significance can be attached to any of these distinctive patterns, anatomical and functional studies focused on these more subtle differences are needed.
ANATOMICAL STUDIES Brain Stem Efferents The somatomotor, cardiovascular, and antinociceptive adjustments which characterize active and passive coping can be readily elicited naturally, or by PAG stimulation, in a precollicular decerebrate rat or cat (i.e., a preparation in which the brain stem has been disconnected from the forebrain, including the hypothalamus). Such findings suggest that projections to the lower brain stem (there is a relative paucity of direct PAG–spinal projections) provide the essential substrates for PAG-mediated active and passive coping. As illustrated schematically in Fig. 4 both the vlPAG and lPAG project extensively to ventromedial and ventrolateral medullary regions controlling cardiovascular, somatomotor, and antinociceptive functions (Bandler et al., 1991; Bernard and Bandler, 1998; Carrive et al., 1988; Ennis et al., 1991; Hamilton, 1973b; Hamilton and Skultety, 1970; Henderson et al., 1998; Lovick 1985, 1992b, 1996; Morgan et al., 1989; Van Bockstaele et al., 1991; Vanderhorst et al., 2000). Interestingly, the “functionally opposed” vlPAG and lPAG broadly target the same ventromedial and ventrolateral medullary regions, suggesting that the different sets of projections: (i) use different neurotransmitters or (ii) target different neural populations in each area. Consistent with either hypothesis there is good evidence that vlPAG and lPAG excitation have opposite physiological effects on RVLM and VMM neural activity (Lovick, 1985, 1992a, 1992b, 1993, 1996; Morgan, 1991; Morgan et al., 1998; Verberne
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and Guyenet, 1992; Verberne and Boudier, 1991). The dmPAG column, whose functions are less frequently studied, projects also to the ventromedial and ventrolateral medulla. The dlPAG column, however, has no direct projections to the medulla (Fig. 4). Instead, it strongly targets: (i) the cuneiform nucleus, a region which projects to the ventrolateral medulla and from which active defensive behaviors (freezing, flight, hypertension) are evoked (Mitchell et al., 1988a, 1988b; Redgrave et al., 1988), and (ii) the superolateral parabrachial nucleus, a region which strongly innervates retrochiasmatic and ventromedial (dorsomedial division) hypothalamic nuclei (Bernard and Bandler, 1998; Krout et al., 1998).
Diencephalic Efferents Distinct PAG columns project also to specific hypothalamic and midline and intralaminar thalamic regions (Floyd et al., 1996 ; Krout and Loewy, 2000). These PAG–diencephalic projections likely contribute to active and passive coping responses in the intact animal. The lateral hypothalamic area, a region from which hypotension and bradycardia are readily evoked by EAA microinjection (Allen and Cechetto, 1992; Gelsema et al., 1989; Spencer et al., 1990), is selectively targeted by the vlPAG, whereas dorsal and medial hypothalamic areas from which hypertension, tachycardia, and somatomotor activation are evoked by microinjection of EAAs or GABA antagonists (Allen and Cechetto, 1992; DeNovellis et al., 1995; Gelsema et al., 1989; Sun and Guyenet, 1986; Waldrop et al., 1988) receive inputs from the lPAG and the dlPAG (see Fig. 6). In addition, the vlPAG provides the heaviest input to the thalamus, specifically to centromedial, centrolateral, intermediodorsal, and paraventricular nuclei, and to a restricted, medial part of the caudal, ventromedial nucleus (VMc) (Floyd et al., 1996; Krout and Loewy, 2000). The lPAG provided a more moderate input to same regions, with the exception of the VMc. The dlPAG, in contrast, projects predominantly to the paraventricular thalamic nucleus (Krout and Loewy, 2000).
Spinal and Medullary Afferents In terms of “direct” sensory inputs, the PAG is dominated by afferents (somatic and visceral) arising from the spinal cord, the medullary dorsal horn (Sp5) and the nucleus of the solitary tract (Sol) (Bjorkeland and Boivie, 1984; Clement et al., 1998; Cowie and Holstege, 1992; Herbert and Saper, 1992; Keay and Bandler, 1992; Keay et al., 1997a, 1997b; Mantyh, 1982; Menetrey et al., 1982; Wiberg and Blomqvist, 1984; Yezierski, 1988; Yezierski and Mendez, 1991; Yezierski and Schwartz,
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CVLM FIGURE 4 Schematic illustration of somatic and visceral afferents to different PAG neuronal columns (top half of figure) and medullary projections arising from different PAG neuronal columns (bottom half of figure). It can be seen that the ventrolateral column of the PAG (vlPAG) receives afferents from the spinal cord and the nucleus of the solitary tract (Sol) and projects to both the rostral and caudal ventrolateral medulla (RVLM, CVLM) and the ventromedial medulla (VMM). The lateral column of the PAG (lPAG) receives afferents from spinal cord and the medullary dorsal horn (Sp5) and projects to the RVLM, CVLM, and VMM. The dorsolateral column of the PAG (dlPAG) has no significant somatic or visceral inputs arising from spinal cord, Sp5, or Sol. The dlPAG does not project directly to the medulla, but can influence the rostral ventrolateral and ventromedial medulla via a projection to the cuneiform nucleus (cnf). (Modified from Fig. 2 of Keay and Bandler, 2001).
1986; Yezierski et al., 1987). These inputs terminate almost exclusively in the vlPAG and lPAG columns; i.e., there is no anatomical evidence of significant, direct spinal, Sp5, or Sol projections to either the dlPAG or the dmPAG. The lPAG receives a somatotopically organized input (i.e., lumbar enlargement to caudal lPAG, cervical
enlargement and Sp5 to progressively more rostral parts of lPAG); whereas, afferents from Sol and spinal cord converge onto the vlPAG without any apparent topographical organisation (see Fig. 4). Interestingly, the Sol does not project directly to the lPAG, nor does the Sp5 directly innervate the vlPAG.
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The spinal projections to both lPAG and vlPAG arise predominantly from the superficial and deep dorsal horn, with two notable exceptions: (i) in the sacral cord, vlPAG- and lPAG-projecting neurons are located predominantly in the region of the sacral parasympathetic nucleus; and (ii) in the upper cervical cord (segments C1–C3), vlPAG projections arise predominantly from neurons in deep dorsal horn and the intermediate and ventral gray. It should be noted that approximately 30% of all spinal neurons that project to the vlPAG are located in the C1 spinal segment, with an additional 20% found in segments C2–C3. Approximately 50% of the spinal neurons that project to the lPAG are located also within the superficial and deep dorsal horn of the upper cervical cord (C1–C3). The functional significance of this extraordinarily large upper cervical input to the vlPAG and lPAG has yet to be investigated (although see Clement et al., 2000; Keay and Bandler, 2002; Keay et al., 1997b, 2000). In addition to Sol–vlPAG projections, there are extensive projections to the PAG arising from the ventrolateral, ventromedial, and dorsomedial medulla. The general principle underlying these projections is that ventromedial and dorsomedial medullary regions preferentially target the vlPAG (Herbert and Saper, 1992); whereas ventrolateral medullary neurons project to dmPAG, lPAG, and vlPAG (Beitz, 1982; Clement et al., 1998; Hamba et al., 1990; Herbert and Saper, 1992; Kwiat and Basbaum, 1990). The absence of any substantial medullary projection to the dlPAG is a particularly striking finding.
Forebrain Afferents The potential significance of prefrontal cortical (PFC) projections to specific PAG columns (although there were earlier reports of PFC–PAG projections (e.g., Hurley et al., 1991; Sesack et al., 1989) was appreciated only after the work of Shipley and colleagues (Shipley et al., 1991). Their study provided the first systematic evidence that projections arising from specific PFC fields had patterns of termination that respected PAG columnar boundaries. Recent studies in both rat and primate have confirmed and extended these observations. In the rat, projections to the PAG arise from the medial wall, dorsomedial convexity, and select orbital and insular PFC areas (Floyd et al., 2000). As summarized schematically in Fig. 5, discrete PFC subgroups can be identified on the basis of their projections to a specific PAG column(s). Thus, dorsolateral orbital (DLO), agranular insular (AId, AIp), and medial orbital (MO, VO, VLOm) cortical areas project almost exclusively to the vlPAG. As well, the rostroventral medial PFC wall (PL and IL, blue shaded) projects predominantly to the vlPAG. In contrast, strong projections to the dlPAG
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originate from the caudodorsal medial PFC wall (PL and IL, purple shaded) and the cortex of dorsomedial convexity (Acd and Acv, pink shaded) (Fig. 5). (Note: there are also projections to the lPAG (not illustrated in Fig. 5) that arise from PL, ACd, DLO, and AId; although each of these cortical areas has a stronger projection to either the vlPAG or the dlPAG (Floyd et al., 2000)). In the macaque, medial and select orbito-insular PFC areas are divisible also into subgroups which share projections to different PAG columns (see An et al., 1998). A striking feature of the primate brain is a dramatic growth in the size and complexity of the medial PFC (macaque PFC is predominantly dygranular and granular cortex, whereas rat PFC is exclusively agranular cortex) and an associated remarkable increase in the density of medial PFC projections to the dlPAG (An et al., 1998). The fact that the dlPAG receives no direct spinal or medullary afferents highlights the potential significance of its medial PFC input. Projections to the PAG from the amygdala and the hypothalamus also respect columnar boundaries. Amygdaloid projections to PAG arise principally from the central nucleus and terminate in all but the dlPAG column (Price and Amaral, 1981; Rizvi et al., 1991). With respect to the hypothalamus (see Fig. 6), the lateral hypothalamic area (LHA) projects selectively to the vlPAG. The vlPAG and lPAG also receive inputs from dorsal and medial hypothalamic regions (not illustrated). Hypothalamic projections to the dlPAG are more restricted, arising primarily from the dorsal (DHA), posterior (PHA), and anterior (AHA) hypothalamic areas, as well as from the dorsomedial subdivision of ventromedial hypothalamic nucleus (VMHdm) (Floyd et al., 2001; Veening et al., 1982, 1987, 1991).
THE PAG AND PARALLEL CIRCUITS FOR EMOTIONAL COPING Anatomical Overview In both the rat and the primate, it has been further revealed that the PFC subgroups which project preferentially to specific PAG columns project also to distinct regions of the hypothalamus (An et al., 1998; Bernard and Bandler, 1998; Floyd et al., 2000, 2001; Öngür et al., 1998). As illustrated schematically in Fig. 6: (i) the orbitoinsular and rostroventral medial PFC areas that project to the vlPAG project selectively to the LHA; (ii) the caudodorsal medial PFC areas that project to the dlPAG project selectively to DHA, PHA, and AHA; and (iii) the PAG columns and distinct hypothalamic regions that receive common PFC inputs, in turn, are reciprocally interconnected, i.e., vlPAG–LHA; dlPAG–DHA/
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AId
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FIGURE 5 Surface diagrams of lateral (left) and medial (right) views of the rat brain are drawn in the top row (modified from Krettek and Price, 1977) below which is a coronal drawing of the PAG with the location of dlPAG (pink) and vlPAG (blue) columns indicated. Blue shading (top panels) indicates the cortical regions that project to the vlPAG column. These include rostral PL, rostral IL, and MO on the medial wall (top row, right); and VO, VLOm, AIp, AId, and DLO on the orbital and lateral cortical surfaces (top row, left). Pink and purple shading (top panels) indicates the cortical regions that project exclusively (pink) or predominantly (purple) to the dlPAG column. These comprise caudal PL, caudal IL, ACd, and ACv on the medial wall and PRh cortical area on the lateral wall. Abbreviations used: ACd, dorsal anterior cingulate cortex; ACv, ventral anterior cingulate cortex; AId, dorsal agranular insular cortex; AIp, posterior agranular insular cortex; DLO, dorsolateral orbital cortex; IL, infralimbic cortex; MO, medial orbital cortex; PL, prelimbic cortex; PRh, perirhinal cortex; VLOm, ventrolateral orbital cortex, medial part; VO, ventral orbital cortex. (Modified from Fig. 17 of Flody et al. 2000)
PHA/AHA. These anatomical findings suggest that the dorsolateral and ventrolateral (to a lesser extent the lateral) PAG columns are embedded with distinct, but parallel, circuits that extend rostrally to include specific orbital and medial prefrontal cortical areas and specific hypothalamic regions (Fig. 6). To summarize, two PAG columns, the ventrolateral and lateral, are spinal-, Sp5-, and Sol-recipient (Fig. 4). That is, they are regions within which signals from physical stressors (e.g., cutaneous or deep pain, hemorrhage) gain access to neural substrates mediating distinct emotional coping reactions. In contrast, the dorsolateral PAG column (which mediates active coping) has neither direct spinal nor medullary afferents, but does receive strong medial PFC input (more so in the primate than in the rat). These anatomical connections suggest that active coping mediated by the dlPAG may be driven by stressors that have a predominantly psychological component (i.e., are dependent on PFC neural processing), whereas active coping mediated
by the lPAG is likely to driven by physical stressors. Passive emotional coping, whether the precipitating event is physical or psychological, should be mediated exclusively by the vlPAG.
Functional Studies (Immediate Early Gene Expression) Consistent with this anatomical analysis, studies which have utilized immediate early gene (c-fos) expression as a marker of neuronal activation indicate that PAG columns are selectively activated by specific classes of stress (Bellchambers et al., 1998; Canteras and Goto, 1999; Chieng et al., 1995; Clement et al., 1996; Keay and Bandler, 1993, 1998, 2002; Keay et al., 1994, 1997a, 2000, 2001; Tassorelli and Joseph, 1995). For example, three distinct “inescapable” physical stressors (muscle pain (intramuscular formalin), visceral pain (intravenous 5-HT), inescapable cutaneous pain (clip of neck)), each of which evoke passive coping as their
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Prefrontal Cortex DLO AId FPm
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FIGURE 6 Blue shading indicates the orbital and medial prefrontal cortical (PFC) areas that project to both the vlPAG and the lateral hypothalamus (LHA). Yellow shading indicates the orbital and medial PFC areas that project to the dlPAG and the medial hypothalamic regions (AHA, anterior hypothalamic area; DHA, dorsal hypothalamic area; PHA, posterior hypothalamic area). Note also that hypothalamic areas and PAG columns projected upon by common PFC areas are also interconnected. See Fig. 5 for cortical abbreviations.
primary response, selectively activate neurons in the vlPAG column (Fig. 7A). Other manipulations (not illustrated) which also evoke passive coping as their primary response (e.g., hypotensive haemorrhage (Keay et al., 1997a); noxious stimulation of cerebral vessels
(Keay and Bandler, 1998); systemic injection of nitroglycerin (Tassorelli and Joseph, 1995)) similarly elicit selective vlPAG Fos expression. In contrast, stressors which as their primary response evoke an active coping reaction elicit Fos expression in the lPAG and/or the
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FIGURE 7 Camera-lucida drawings of coronal sections through the PAG (5.8, 6.8, 7.8, and 8.8 mm caudal to bregma) showing patterns of neural activation following physical or psychological stressors which trigger as their primary reaction either active or passive coping. (A) Patterns of neural activation following three physical stressors which evoke passive coping as their primary response: (i) intramuscular injection of formalin (top row), (ii) intravenous injection of 5HT (middle row), and (iii) clip applied to the dorsal skin of the neck (bottom row). The shaded area indicates the ventrolateral PAG column. (B) Patterns of neural activation following two physical stressors which evoke active coping as their primary response: (i) opiate withdrawal (top row) and (ii) radiant heat applied to the skin of the neck (bottom row). The shaded area indicates the lateral PAG column. C Pattern of neural activation evoked by a “psychological stressor,” exposure of a rat to a cat (additional data generously provided by Professor Newton Canteras). The shaded area indicates the dorsolateral PAG column. (Modified from Fig. 5 of Keay and Bandler, 2001)
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dlPAG (Figs. 7B and 7C). Note, however, that when active coping is triggered by a physical stressor (e.g., opiate withdrawal, radiant heat) Fos expression is much stronger in the lPAG than in the dlPAG (Fig. 7B). In contrast, when a “psychological” stressor is used (e.g., the presence of a cat, but without physical contact) Fos expression in the dlPAG predominates (Fig. 7C). The presence of significant vlPAG Fos expression in Figs. 7B and 7C likely reflects the fact that a stress-triggered period of active coping may be followed by a delayed period of recovery and healing (i.e., passive coping/ recuperation), if the opportunity is available (Bandler et al., 2000a, 2000b).
CONCLUSIONS All mammals possess the capacity to affect appropriate responses to “escapable” or “inescapable” stressors and to facilitate recovery and healing once the stress passes. Different stressors possess, to varying degrees, physical and psychological components. A substantial body of evidence has been reviewed which supports the concept that the PAG is divisible into a number of distinct, longitudinal neuronal columns, each of which lies embedded within a circuit that extends rostrally to include specific PFC and hypothalamic areas. These PFC–PAG/hypothalamic circuits, in turn, project caudally to affect somatic and autonomic premotor neurons within the ventrolateral medulla and the ventromedial (raphe) and paramedian medullary neural pools. The evidence reviewed suggests that different PAG columns (and their distinctive forebrain and brain stem connections) play important roles in coordinating distinct emotional coping strategies for dealing with different classes of stress. Specifically, it has been proposed: (i) that the lPAG column (and its associated circuit) is activated preferentially by “escapable” physical stressors to which an active defensive reaction(s) is the primary response; (ii) that the dlPAG column (and its associated circuit) is activated preferentially by “escapable” psychological stressors to which an active defensive response is the primary response; and (iii) that the vlPAG column (and its associated circuit) is activated (a) by “inescapable” physical or psychological stressors for which passive coping behavior is the primary response or (b) as a delayed/secondary response, to promote recovery and healing following any stressor.
Acknowledgments The authors acknowledge the support of NHMRC (Australia) for their work described in this chapter.
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Functional, Anatomical and Neurochemical Organization.” (Depaulis, A., and Bandler, R., Eds.). pp. 417–448. Plenum Press, New York. Smith, G. S., Savery, D., Marsden, C., Lopez Costa, J. J., Averill, S., Priestley, J. V., and Rattray, M. (1994). Distribution of messenger RNAs encoding enkephalin, substance p, somatostatin, galanin, vasoactive intestinal polypeptide, neuropeptide Y, and calcitonin gene-related peptide in the midbrain periaqueductal grey in the rat. J. Comp. Neurol. 350, 23–40. Spencer, S. E., Sawyer, W. B., and Loewy, A. D. (1990). L-Glutamate mapping of cardioreactive areas in the rat posterior hypothalamus. Brain Res. 511, 149–157. Sun, M. K., and Guyenet, P. G. (1986). Hypothalamic glutamatergic input to medullary sympathoexcitatory neurons in rats. Am. J. Physiol. 251, R798–R810. Tassorelli, C., and Joseph, S. A. (1995). Systemic nitroglycerin induces fos immunoreactivity in brainstem and forebrain structures of the rat. Brain Res. 682, 167–181. Tolle, T. R., Berthele, A., Zieglgansberger, W., Seeburg, P. H., and Wisden, W. (1993). The differential expression of 16 NMDA and non-NMDA receptor subunits in the rat spinal cord and in periaqueductal gray. J. Neurosci. 13, 5009–5028. Van Bockstaele, E. J., Aston-Jones, G., Pieribone, V. A., Ennis, M., and Shipley, M. T. (1991). Subregions of the periaqueductal gray topographically innervate the rostral ventral medulla in the rat. J. Comp. Neurol. 309, 305–327. Vanderhorst, V. G., Terasawa, E., Ralston, H. J., III, and Holstege, G. (2000). Monosynaptic projections from the lateral periaqueductal gray to the nucleus retroambiguus in the rhesus monkey: Implications for vocalization and reproductive behavior. J. Comp. Neurol. 424, 251–268. Veening, J., Buma, P., Ter Horst, G. J., and Roeling, T. A. P. (1991). Hypothalamic projections to the pag in the rat: Topographical, immuno-electron microscopical and functional aspects. In “The Midbrain Periaqueductal Gray Matter: Functional, Anatomical, and Neurochemical Organization” (Depaulis, A., and Bandler, R., Eds.). Plenum Press, New York. Veening, J. G., Swanson, L. W., Cowan, W. M., Nieuwenhuys, R., and Geeraedts, L. M. (1982). The medial forebrain bundle of the rat. II. An autoradiographic study of the topography of the major descending and ascending components. J. Comp. Neurol. 206, 82–108. Veening, J. G., Te Lie, S., Posthuma, P., Geeraedts, L. M., and Nieuwenhuys, R. (1987). A topographical analysis of the origin of some efferent projections from the lateral hypothalamic area in the rat. Neuroscience 22, 537–551. Verberne, A., and Guyenet, P. (1992). Midbrain central gray: Influence on medullary sympathoexcitatory neurons and the baroreflex in rats. Am. J. Physiol. 263, R24–R33. Verberne, A. J., and Boudier, H. R. S. (1991). Midbrain central grey: Regional hemodynamic control and excitatory amino acidergic mechanisms. Brain Res. 550, 86–94. Waldrop, T. G., Bauer, R. M., and Iwamoto, G. A. (1988). Microinjection of GABA antagonists into the posterior hypothalamus elicits locomotor activity and a cardiorespiratory activation. Brain Res. 444, 84–94. Wiberg, M., and Blomqvist, A. (1984). The spinomesencephalic tract in the cat: Its cells of origin and termination pattern as demonstrated by the intraaxonal transport method. Brain Res. 291, 1–18. Williams, F. G., and Beitz, A. J. (1989a). Production and characterization of a novel monoclonal antibody against neurotensin: Immunohistochemical localization in the midbrain and hypothalamus. J. Histochem. Cytochem. 37, 831–841. Williams, F. G., and Beitz, A. J. (1989b). A quantitative ultrastructural analysis of neurotensin-like immunoreactive terminals in the
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C H A P T E R
11 Locus Coeruleus, A5 and A7 Noradrenergic Cell Groups GARY ASTON-JONES Laboratory of Neuromodulation and Behavior, Department of Psychiatry University of Pennsylvania School of Medicine, Philadelphia, USA
CYTOARCHITECTURE
Several significant advances in understanding the structure and function of the locus coeruleus (LC) system have taken place since the previous edition of this book. In particular, numerous studies have extended our understanding of neurotransmitter-defined inputs to the LC. Also, substantial progress has been made in identifying inputs to dendrites of LC neurons that lie outside of the LC nuclear core. The recent application of viral transsynaptic tract-tracing techniques has begun to extend our understanding of how these systems are regulated by circuits that feed into these norepinephrine (NE) cells, including second- and higher-order afferents. This chapter also extends the previous version by including advances in functional understanding of these NE systems, ranging from the role of the A5 and A7 systems in pain to the role of the LC system in attention and cognitive processing. The purpose of this chapter is twofold. One goal is to provide a succinct synopsis of the most salient anatomical features of the LC and other metencephalic NE neuronal systems in the rat. A second goal is to emphasize new anatomical results obtained since the previous editions of this book, so as to update readers with the most current information. Owing to length limitations, only a skeleton outline of the extensive anatomical knowledge that exists for these neurons can be provided. I have tried to include features most likely to be of interest to a large number of readers.
The Rat Nervous System, Third Edition
Cell Types and Subnuclei The A4 and subcoeruleus cell groups are considered here to be part of the LC. However, the A5 and A7 cell groups are considered to be separate from the subcoeruleus; the subcoeruleus is the ventral extension of the LC and does not encroach into the periolivary region of the A5 cells or into the periparabrachial area of the A7 cells. In the rat, the LC nucleus is readily recognized in Nissl-stained sections where it appears as a densely packed cluster of darkly stained cells in the rostral rhombencephalic tegmentum (Fig. 1). The nucleus stretches for 1.2 mm along the ventrolateral edge of the IVth ventricle, abutting the medial side of the mesencephalic nucleus of the trigeminal nerve. Caudally the nucleus extends to the genu of the facial nerve; rostrally it reaches into the periaqueductal gray (Grzanna and Molliver, 1980). The LC reaches its largest mediolateral extent at the level of the motor nucleus of the trigeminal nerve. Estimates of the number of neurons in the rat LC (unilaterally) range from about 1400 to 1800 (Descarries and Saucier, 1972; Goldman and Coleman, 1981; Loughlin et al., 1986; McBride et al., 1985; Swanson, 1976) depending on the staining method used to delineate the nucleus.
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FIGURE 1 Bright-field photomicrographs of two adjacent sections through the rat locus coeruleus. The section shown on the left was stained with cresyl violet. The section shown on the right was processed for dopamine β-hydroxylase immunohistochemistry to visualize noradrenergic neurons and extensive dendritic processes. The bar represents 100 μm. Dorsal is at the top and medial is at the left of each figure.
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Studies with the Golgi method have identified several different types of neurons in the rat LC. Swanson (1976) distinguished medium-sized fusiform cells and somewhat larger multipolar neurons in the rat LC. Other investigators distinguished a third class of ovoidshaped cells in the rat LC (Cintra et al., 1982; Pfister and Danner, 1980; Shimizu and Imamoto, 1970). The cell types differ not only in size and shape but also in the orientation of their dendrites. Small fusiform cells are obliquely positioned with the long axis extending mainly in the anterior–posterior directions and tilted in a dorsolateral to ventromedial orientation suggesting a dendritic arborization mainly in the sagittal and horizontal plane. In contrast, the dendritic arborization of multipolar LC neurons appears to be primarily in the frontal plane (Sievers et al., 1981). Loughlin et al. (1986) analyzed the appearance of retrogradely filled LC neurons following injections of horseradish peroxidase into selected terminal fields and were able to distinguish six different subpopulations of cells in the rat LC. A principal finding of this study was that morphologic subpopulations of LC neurons have different efferent targets. Despite differences in their morphology, nearly all neurons in the rat LC contain noradrenaline, and it has become customary to consider the presence of this transmitter and its biosynthetic enzymes the defining property of the rat LC. In addition to the morphological heterogeneity among its cells, the rat LC can be divided into subnuclei based upon the size of its cells and the orientation of its dendrites. Swanson (1976) distinguished a large dorsal portion of the LC comprised of small and tightly packed cells. This dorsal subdivision is readily distinguished from a somewhat smaller ventral subdivision in the caudal third of the nucleus consisting of larger, less densely packed cells. The number of cells in the ventral LC has been estimated to be 200 per nucleus. Extending laterally and dorsally is an outpost of subependymal NE neurons in the roof of the fourth ventricle referred to as the A4 group by Dahlstrom and Fuxe (1964). A distinct feature of these neurons is the set of processes that extend between ependymal cells toward the ventricular surface. A small subdivision of the LC is formed by a small group of large multipolar neurons scattered in the ventral portion of the periadqueductal gray (Grzanna and Molliver, 1980; Grzanna et al., 1980). These cells lie approximately 500 μm rostral to the compact portion of the LC and can only be distinguished from neighboring cells in the rostral periaqueductal gray (PAG) by their NE content and the presence of the corresponding biosynthetic enzymes. These cells have prominent dendrites that radiate in all directions within the ventrolateral portion of the periaqueductal gray.
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Delineation of the subcoeruleus in the rat has been inconsistent and no satisfactory nomenclature has yet emerged. Unlike the LC, the subcoeruleus is a biochemically heterogeneous cell group containing both NE and non-NE neurons. Following the introduction of the histofluorescence method there has been a tendency to focus on the NE cells of the subcoeruleus. Olson and Fuxe (1972) refer to a subcoeruleus area which contains NE cell bodies connecting the ventral part of the LC, the A5 and the A7 group. Amaral and Sinnamon (1977) suggested that the term subcoeruleus should apply only to the cluster of NE-containing cell bodies that lies immediately ventral to the LC. However, this cell cluster is continuous with a sheet of scattered NE neurons that extends ventrally toward the A5 group and rostrally toward the A7 group. Grzanna et al. (1987) delineated the NE-containing cells of the subcoeruleus and counted approximately 130 cells per nucleus. Based on retrograde transport studies, these scattered NE cells in the pontine tegmentum between the ventral portion of the LC proper and the A5 and A7 groups share projections with the ventral LC.
Neurotransmitters within Rat LC Neurons In the rat, the LC nucleus proper is a dense collection of noradrenergic neurons as evidenced by either catecholamine-induced fluorescence or immunohistochemistry for the synthetic enzymes tyrosine hydroxylase (TH) or dopamine β-hydroxylase (DBH; Fig. 1). Analyses with these stains indicated that all neurons within this nucleus are noradrenergic. However, more recent studies indicate the presence of a limited population of small, round neurons within the LC that stain with an antibody to GABA (Ijima et al., 1987; Ijima and Ohtomo, 1988). The functional significance of these small neurons is unknown. It is notable that the rostral pole of the LC in the rat is more neurochemically heterogeneous than the nucleus proper and contains many non-NE neurons intermixed with NE neurons. This characteristic of the rostral pole may yield properties not seen in more caudal LC areas (e.g., additional afferents, interneurons). Other putative neurotransmitter molecules in addition to NE can distinguish subsets of rat NE neurons. Most prominent among these is the neuropeptide galanin (Austin et al., 1990; Holets et al., 1988; Levin et al., 1987; Melander et al., 1986; Skofitsch and Jacobowitz, 1985; Sutin and Jacobowitz, 1988) which is present in most, though not all, LC NE neurons. Additional peptides present in a smaller percentage of noradrenergic LC neurons include neuropeptide Y (NPY) (Everitt et al., 1984; Sutin and Jacobowitz, 1988), vasopressin, neurophysin (Caffe et al., 1985, 1988), neurotensin, vasoactive
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intestinal peptide (VIP), and atrial natriuretic factor (Sutin and Jacobowitz, 1988). Coexistence of NE, vasopressin, and neurophysin has been reported in some subcoeruleus neurons (Caffe et al., 1985). The majority of the NPY-containing neurons were found in the dorsal LC, and very few noradrenergic neurons in the subcoeruleus were found to also contain either NPY or galanin (Holets et al., 1988). While enkephalin has been reported to exist within some NE neurons of cat LC (Charnay et al., 1982, 1984) as well as in some early reports in rat LC neurons (Finley et al., 1981; Khachaturian et al., 1983), more recent work by us and others has found no evidence for enkephalin–NE coexistence within the rat LC (Drolet et al., 1992; Fallon and Leslie, 1986; Murakami et al., 1987). Similarly, although it has been suggested that corticotropin-releasing hormone (CRH) may be contained within some LC NE neurons, we (Valentino et al., 1992) and others (Sutin and Jacobowitz, 1988) find no evidence for this in more recent studies. It has also been reported that a higher percentage of LC neurons that contain NPY or galanin project to the hypothalamus than to the spinal cord or cerebral cortex (Holets et al., 1988), indicating that LC neurons may have specialized targets corresponding to colocalized peptides. Non-peptide transmitter candidates have also been identified within a large percentage of LC NE neurons, including N-acetylaspartylglutamate (Forloni et al., 1987) and the putative marker of glutamatergic neurons glutaminase (Drolet and Aston-Jones, 1991; Kaneko et al., 1989, 1990). A recent study reported that some rat LC neurons express tryptophan hydroxylase mRNA as well as immunoreactivity for serotonin (Ijima and Sato, 1991). These results have yet to be confirmed by other studies. In addition, the functional significance of possible colocalization of other transmitter molecules within LC neurons is unclear. For example, it has been reported that neuropeptide Y and galanin (Moore and Gustafson, 1989), as well as vasopressin (Caffe et al., 1988), may not be transported to LC terminals in cortical areas, despite being located within LC somata that innervate these areas.
NE Transporters Recent studies have cloned the molecule responsible for reuptake of NE, termed the NE transporter (NET) (Barker and Blakely, 1995; Pacholczyk et al., 1991). Immunolocalization of NET in rat brain has shown that it is confined to NE neurons and processes and is not present within, e.g., DA or serotonin (5-HT) neurons (Schroeter et al., 2000). NET labeling exhibited a nonuniform pattern of expression along axons, reflecting a high degree of spatial organization of NE clearance. In
addition, ultrastructural analysis of NET in the prefrontal cortex revealed a prominent cytoplasmic localization in presynaptic terminals, indicating possible regulated trafficking of the transporter controlling NE clearance (Schroeter et al., 2000). There is evidence that NET may be phosphorylated in a protein kinase Cdependent manner, and it appears that transmitters, antagonists, and second messengers can modify the intrinsic activity and surface expression or protein levels of amine transporters including NET (Blakely and Bauman, 2000). Thus, it is likely that NET activity is a mechanism contributing to synaptic plasticity rather than a static determinant of transmitter clearance. NET has also been found in A5 and A7 NE neurons, as expected (Comer et al., 1998).
Electrotonic Coupling within the LC In neonatal rats Christie and colleagues have provided compelling evidence that LC neurons are electrotonically coupled (Christie and Jelinek, 1993; Christie et al., 1989). In rats less than about 1 week of age, these investigators found abundant dye coupling and electrotonic conduction between pairs of LC neurons. Although this evidence for electrotonic coupling among LC cells wanes as animals approach adulthood, recent evidence from Williams and colleagues reveals that coupling may persist into adulthood. They found that the reversal potential for opiates (Osborne and Williams, 1996; Travagli et al., 1995), the effects of locally applied neurotransmitters on LC neurons in the slice (Travagli et al., 1995), and synchronous activity among adult LC neurons (Ishimatsu and Williams, 1996; Travagli et al., 1995) could be explained by electrotonic coupling. The apparent coupling was reduced after application of the coupling blocker carbenoxolone. Coupling was also reduced by cutting slices of the LC in the coronal plane instead of the horizontal plane (Osborne and Williams, 1996; Travagli et al., 1996) or by isolating the cell body region of the LC in horizontal slices from the rostral and caudal dendritic zones (Ishimatsu and Williams, 1996). This indicates that coupling may predominantly occur between distal dendrites of LC neurons in the peri-LC region. More recent studies have also shown coupling between LC neurons and astrocytes in neonatal LC. This coupling was shown anatomically with dye coupling and with staining for connexin proteins and also found to be functional in that depolarization of astrocytes increased the firing rate of LC neurons (AlvarezMaubecin et al., 2000). Studies recording LC neurons in behaving monkeys have found that electrotonic coupling among LC neurons may have important behavioral consequences
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as well (Usher et al., 1999). Different modes of LC activity were simulated by changes in coupling among LC neurons, and these different modes were found to be capable of producing changes in attentiveness on a target detection task. Thus, coupling among cells in the LC could be an important mechanism regulating functions of this noradrenergic efferent network.
AFFERENTS TO THE NUCLEUS LOCUS COERULEUS Neurotransmitter Inputs to the LC and Peri-LC Area There are various lines of evidence that a wealth of neurotransmitters innervate the LC. Here, we briefly
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review neurochemically identified fibers that have been localized in the rat LC, as well as the receptor content and pharmacological sensitivity of these neurons. However, due to the very small size of the LC nucleus and the marked neurochemical topography in the LC region, studies employing punch or other tissue sampling of the LC for biochemical measures are unable to specifically ascribe results to the LC nucleus vs surrounding areas, and these studies are not included here. The recently discovered dense innervation of the LC nucleus by the novel neuropeptide hypocretin (also known as orexin) is particularly intriguing (Fig. 2) (Cutler et al., 1999; de Lecea et al., 1998; Hervieu et al., 2001; Horvath et al., 1999). This peptide is made only by neurons in the hypothalamus. Neuropharmacologic studies have shown that hypocretin strongly activates LC neurons by decreasing a resting potassium conductance
FIGURE 2 (A) Hypocretin (orexin) innervation of the LC. Bright-field photomicrograph of a frontal section through the rat LC stained with an antibody against hypocretin. Note dense innervation of the LC nucleus by fibers containing this peptide. Neutral red counterstain. Fourth ventricle is to the left (medial); dorsal is up. (B) Innervation of peri-LC zone from the medial prefrontal cortex. Dark-field photomicrograph showing fibers anterogradely labeled with Phaseolus vulgaris leucoagglutinin (PHA-L; gold color) after an injection in the medial prefrontal cortex of a rat. The LC nucleus appears as a dark cluster of neurons to the right of the gold-labeled PHA-L fibers. Note that the prefrontal fibers provide very little input to the LC nuclear core, but instead preferentially terminate in the ventromedial peri-LC area. This innervation is among LC extranuclear dendrites (compare to location of LC dendrites in Fig. 1). Stimulation of this area of the cortex activates LC neurons (see Fig. 5). The fourth ventricle is medial (at left); dorsal is up.
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FIGURE 3 Voltage-dependent depolarization of LC neurons by hypocretin (HCRT; orexin) in brain slice. (A1, A2) Two depolarizing responses to a puff application of HCRT. Both responses were recorded in the same cell, either at resting membrane potential (A1) or 10 min later when the cell was hyperpolarized to −85 mV (A2). Note a smaller depolarization in the latter. (B) Three puff applications of HCRT (as above, except 30-s application) to the same cell, at 10-min intervals and different membrane potentials as indicated. The first application evoked a clear depolarization at resting membrane potential (B1). The second application, after the membrane potential was shifted to 90 mV, produced no depolarization (B2). The third application again depolarized the cell when the membrane potential was returned to the previous resting level (B3). TTX (1 μM) and Co2+ (1 mM) were added to the bath 3 min before trace B1 was recorded and were continuously present during the following records. Note that Ca2+ spikes and associated membrane oscillations, but not the HCRT-induced depolarization, were blocked by Co2+. The dotted lines with the numbers below indicate the level of membrane potential in all records. (A, B) LC neurons from different slices. Taken from Ivanov and Aston-Jones, 2000.
(Fig. 3) (Hagan et al., 1999; Horvath et al., 1999; Ivanov and Aston-Jones, 2000). Hypocretin has attracted a great deal of attention due to its apparent role in feeding, as well as in regulation of sleep and waking (Willie et al., 2001). The former would be consistent with the recent demonstration of leptin receptors in the LC and A7 cell groups (Hay-Schmidt et al., 2001). However, the latter may also be particularly relevant for innervation of the LC, as the LC NE system has long been implicated in regulation of arousal (AstonJones and Bloom, 1981a).
As reviewed in Table 1, a host of immunohistochemically defined fibers have been localized within the LC or in the peri-LC region containing LC dendrites (discussed below) (Shipley et al., 1996). As seen in Table 1, most such observations have been consistently made by different investigators. Opiate receptors (Atweh and Kuhar, 1977; Van Bockstaele et al., 1996b, 1996c), α1 and α2 adrenoceptors (Jones et al., 1985; Lee et al., 1998a, 1998b; Young and Kuhar, 1980), calcitonin gene-related peptide binding sites (Skofitsch and Jacobowitz, 1985), and moderate levels of muscarinic cholinergic receptors (Rotter et al., 1979) have been reported in the LC. More recently, receptors for glutamate (Van Bockstaele and Colago, 1996), purines (Kanjhan et al., 1999; Yao et al., 2000), hypocretin/orexin (Sunter et al., 2001), neurokinins (Chen et al., 2000; Hahn and Bannon, 1999), and CRH (Morin et al., 1999) have been identified in the LC. There are limitations to the interpretation of these studies, however. For example, it is well documented (Herkenham, 1987) that receptor localization does not always correlate with anatomical inputs containing the appropriate corresponding neurotransmitters. In addition, receptor localization and immunohistochemical studies alone do not specify the sources or anatomic pathways responsible for the proposed chemically defined inputs. In neuropharmacologic studies, LC neurons are strongly influenced by a wide range of putative neurotransmitters. For example, LC cells are potently inhibited by α2-adrenergic agonists (Aghajanian et al., 1977; Cedarbaum and Aghajanian, 1976, 1977), GABA (Cedarbaum and Aghajanian, 1977; Guyenet and Aghajanian, 1979) and μ opiate agonists (Bird and Kuhar, 1977; Williams and North, 1984). These neurons are excited by substance P (Guyenet and Aghajanian, 1977), adrenocorticotropin hormone (Olpe and Jones, 1982; Valentino et al., 1983), CRH (CRH; Valentino et al., 1983), acetylcholine (ACh; Aston-Jones et al., 1991a, 1991b; Bird and Kuhar, 1977; Guyenet and Aghajanian, 1979), and glutamate (Aston-Jones et al., 1991a, 1991b; Cherubini et al., 1988); neurotensin and serotonin have yielded more complex results (Aston-Jones et al., 1991a, 1991b; Guyenet and Aghajanian, 1977; Young et al., 1978). It is difficult to draw conclusions about the sources of afferents to the LC from such studies, and it is possible these drugs could be acting on presynaptic terminals of afferents to the LC. In fact, a recent study found that 5-HT and opioid receptors are localized on non-NE terminals within the LC, as well as on LC NE processes (Van Bockstaele, 2000; van Bockstaele et al., 1997). This suggests that 5-HT and opioids may regulate other afferents to the LC presynaptically, as well as regulating LC neurons directly.
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TABLE 1 Fibers in peri-LC
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Neurotransmitters in LC and peri-LC
Transmitter
LC
References
ACh
−
+
Altschuler et al., 1984; Butcher and Woolf, 1984; Hartman et al., 1986; Kimura et al., 1984; Ruggiero et al., 1990; Sutin and Jacobowitz, 1988
Epinephrine
+
+
Astier et al., 1986, 1987; Berod et al., 1984; Haselton and Guyenet, 1987; Hokfelt et al., 1974, 1985; Pieribone and Aston-Jones, 1991; Pieribone et al., 1988
serotonin
+
+
Beitz, 1982; Bowker et al., 1981; Charnay et al., 1984; Hunt and Lovick, 1982; Pieribone et al., 1989; Steinbusch, 1984; Thor et al., 1988; Van Bockstaele, 2000
excitatory amino acids
+
+
Aston-Jones and Ennis, 1988; Ennis and Aston-Jones, 1986, 1988; Ottersen and StormMathisen, 1984a, 1984b
GABA
+
+
Aston-Jones et al., 1990, 1991c; Ennis and Aston-Jones, 1989a, 1989b; Mugnaini and Oertel, 1985; Ottersen and Storm-Mathisen, 1984a, 1984b; Shipley et al., 1988
Enkephalin
+
+
Cassini et al., 1989; Charnay et al., 1985; Conrath-Verrier et al., 1983; Drolet et al., 1992; Fallon and Leslie, 1986; Finley et al., 1981; Guthrie and Basbaum, 1984; Hokfelt et al., 1977, 1979; Hunt and Lovick, 1982; Khachaturian et al., 1983; Lynch et al., 1984; Miller and Pickel, 1980; Sar et al., 1978; Uhl et al., 1979; Van Bockstaele et al., 2000; Watson et al., 1980
Substance P
+
+
Cassini et al., 1989; Hokfelt et al., 1978; Ljungdahl et al., 1978; Nomura et al., 1982; Sutin and Jacobowitz, 1988; Triepel et al., 1985
Neurotensin
+
+
Beitz, 1982; Jennes et al., 1982; Minagawa et al., 1983; Papadopoulos et al., 1986; Triepel et al., 1984; Uhl et al., 1979
VIP
+
+
Eiden et al., 1982; Martin et al., 1987; Sutin and Jacobowitz, 1988; Wang and Aghajanian, 1989
Somatostatin
+
+
Johansson et al., 1984; Vincent et al., 1985
CRH
+
+
Bloom et al., 1982; Cummings et al., 1983; Merchenthaler, 1984; Merchenthaler et al., 1982; Olschowka et al., 1982; Sakanaka et al., 1987; Swanson et al., 1983; Valentino et al., 1992; Van Bockstaele et al., 1998a
Hypocretin/orexin
+
+
Cutler et al., 1999; de Lecea et al., 1998; Hervieu et al., 2001; Horvath et al., 1999
Galanin
+
+
Melander et al., 1986; Skofitsch and Jacobowitz, 1985; Sutin and Jacobowitz, 1988
Coexistence of Neurotransmitters in Afferents to LC Evidence indicates that the LC is heavily innervated by glutamate, GABA, and enkephalin inputs (see above). The high incidence of neurons in medullary afferents to the LC that stained for enkephalin (Drolet et al., 1992), combined with the strong GABA or glutamate-mediated effects of stimulating these same regions on LC activity (Ennis and Aston-Jones, 1988; Ennis and Aston-Jones, 1989a, 1989b), made it seem very likely that opiates would colocalize in GABAergic or glutamatergic LC inputs. Indeed, recent ultrastructural studies have revealed that enkephalin inputs to LC neurons can also contain either GABA (Van Bockstaele and Chan, 1997) or glutamate (Van Bockstaele et al., 2000). It seems likely that other examples of colocalized transmitters in afferents to the LC will be identified as well.
ventromedial and lateral hypothalamus (Saper et al., 1976, 1979), ventrolateral medulla (Loewy et al., 1981; McKellar and Loewy, 1982; Sawchenko and Swanson, 1982), and central nucleus of the amygdala (Cedarbaum and Aghajanian, 1978). Deutch et al. (1986) report anterograde transport of Phaseolus vulgaris leucoagglutinin (PHA-L) into LC from the ventral tegmental area in rat (unconfirmed in our studies, described below). There are some qualifications to these studies, however. First, amino acids may be transported transsynaptically, so that such labeling in LC must be viewed with caution. In addition, limited documentation in many previous amino acid studies leaves it unclear whether the labeling is actually within the LC (a relatively tiny nucleus) or in immediately adjacent structures. In other cases it is not clear whether the transported label is in terminals or in fibers passing through or nearby the LC.
Retrograde and Anterograde Tract Tracing Early Tract-Tracing Studies Using tritiated amino acids for anterograde transport, projections have been reported to the LC from the ventral tegmental area (Beckstead et al., 1979), median and dorsal raphe (Conrad et al., 1974; Pierce et al., 1976),
Major afferents Early experiments used retrograde transport of unconjugated horseradish peroxidase (HRP) revealed with diaminobenzidine (DAB) as the peroxidase substrate to examine inputs to the LC in rat (Cedarbaum and Aghajanian, 1978; Morgane and Jacobs, 1979; Clavier, 1979). All three of these studies reported
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similar findings: retrogradely labeled neurons in a complex array of structures in the brain and spinal cord. In the forebrain, major inputs were identified from the central nucleus of the amygdala, the bed nucleus of the stria terminalis, the medial preoptic area, and the dorsomedial and paraventricular nuclei of the hypothalamus. From the brain stem, prominent inputs were reported from the contralateral LC, midbrain central grey, vestibular nuclei, lateral reticular nucleus, and nucleus tractus solitarius (Sol). Substantial inputs were also reported from the fastigial nucleus of the cerebellum and from the marginal zone of the dorsal spinal horn. Although these studies revealed a number of possible regions that project to the LC, these early HRP techniques had several limitations. First, free HRP diffuses substantially, and it is possible that some labeled areas reflect inputs to peri-LC regions that may receive a different set of afferents than the LC nucleus proper (see below). In addition, HRP is avidly taken up by nonterminal fibers of passage, so that labeled neurons could project through, but not to, the LC. Finally, the HRP– DAB method is relatively insensitive, so that the full constellation of inputs to the LC may not have been detected. Others and we reinvestigated afferents to the LC using more sensitive and selective techniques. iontophoretic wheat germ–agglutinin-conjugated HRP (WGA–HRP), as revealed by the tetramethylbenzidine (TMB) reaction, produced injections restricted to the LC nucleus (AstonJones et al., 1986). Such deposits yielded retrogradely labeled neurons most consistently and strongly in two areas, both located in the rostral medulla: the nucleus paragigantocellularis lateralis (LPGi) and the area on the medial edge of the nucleus prepositus hypoglossi. This latter region, however, may not be a component of the prepositus hypoglossi but corresponds to an area subsequently defined in human tissue as a distinct structure, the epifasicular nucleus (EF) (Paxinos and Huang, 1995). The most prominent afferent to LC (in terms of number of densely labeled neurons) was the LPGi. This nucleus, described in rat by Andrezik et al. (1981), is located in the rostral ventrolateral medulla. Retrogradely labeled LPGi neurons were predominantly ipsilateral to the injection site. These cells were scattered in a region extending caudally from a zone just medial to the facial nucleus to the rostral pole of the lateral reticular nucleus; medially, these neurons extended to the inferior olive and, laterally, to the trigeminal sensory nuclei. The second major source of afferents to the LC was located in the dorsomedial rostral medulla, in the region corresponding to the EF. This group of neurons, located on the medial border of the prepositus hypoglossi and centered slightly rostrally to the LPGi-labeled cells, was densely aggregated along the dorsal-most border
of the medial longitudinal fasiculus where it meets the IVth ventricle; labeled cells were also scattered ventrally along the lateral aspects of, and occasionally within, this fasiculus. Retrograde labeling in EF was bilateral, but slightly greater contralaterally. Minor afferents In our initial studies with WGA– HRP (Aston-Jones et al., 1986), two additional areas consistently exhibited retrograde transport, but with only a few sparsely labeled cells. This labeling was found in the dorsal cap of the paraventricular hypothalamic nucleus (Pa) and in the intermediate zone of the spinal gray. For the Pa dorsal cap cells, labeling was bilateral but slightly greater ipsilaterally. Neurons in more central portions of the Pa were only labeled when injections substantially exceeded the boundaries of LC. Labeled neurons in the spinal cord were scattered in the intermediate zone near the central canal, predominantly contralaterally. Many of these cells were so weakly labeled as to be at the threshold of detection. The ventral tegmental area (VLTg), dorsal and median raphe nuclei, PAG, Sol, A5 area, and lateral as well rostral hypothalamus and preoptic area also contained a few labeled cells in some animals, but were unlabeled in other cases. Additional anterograde tracing studies indicated that the VLTg, dorsal spinal horn, and rostral Sol do not project to the core LC nucleus, but instead project to structures adjacent to the LC. Recent Tracing Studies Some studies employed focal LC injections of the more sensitive tracers WGA–HRP (inactivated) coupled to colloidal gold (WGA–apoHRP–Au) or cholera toxin b subunit (CTb). These experiments yielded more consistent retrograde labeling in the PAG (Ennis et al., 1991) and medial preoptic area (Rizvi et al., 1992), indicating that these areas send projections into the LC. My collaborators and I have confirmed with anterograde transport of PHA-L that the ventrolateral PAG and the lateral aspect of the medial preoptic area send sparse projections into the LC nucleus (Ennis et al., 1991). It is noteworthy that these areas send much more pronounced terminations into the immediately adjacent ventromedial and rostral peri-LC regions, areas that contain abundant LC dendrites (described below). The innervation of these dendrites by extrinsic inputs is being elucidated in part with ultrastructural analyses (see below). Retrograde labeling with WGA–apoHRP–Au or CTb from injections centered in the LC nucleus revealed labeled neurons in certain areas more consistently than seen with WGA–HRP tracing, including the Kölliker– Fuse nucleus (A7 area), A5 area, median raphe (B9 area), and caudal and lateral hypothalamus (Luppi et al., 1991). However, the extent of effective injection sites with
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these tracers has not been well studied, so that confirmation by anterograde tracing is needed to confirm such possible additional inputs to the LC. This is especially important as these nuclei send prominent projections to areas immediately surrounding the LC. Again, ultrastructural analysis is required to determine if any of these areas innervates extranuclear LC dendrites. Other conceivable sources of afferents to the LC were more difficult to examine with tracing methods because of their proximity to the LC. In particular, nearby areas including the LDT nucleus, Barrington’s nucleus, parts of the PAG, and other pericoerulear areas were usually contained within the halo of LC injections and were, therefore, very difficult to assess as possible LC afferents. However, recent anterograde studies confirmed inputs to the LC nucleus from Barrington’s nucleus (Valentino et al., 1996) and the ventrolateral PAG (Bajic and Proudfit, 1999). Cases with LC injections that were “off center” such that they impinged on neighboring structures such as the PB, vestibular, or LDT nuclei contained substantial retrograde labeling in areas (e.g., amygdala, spinal dorsal horn, Sol, insular cortex) previously reported to prominently project to the LC nucleus. These areas were unlabeled after injections restricted to the LC. Taken together, these results indicate that the LC receives major afferents from the rostral medulla, as well as from more limited sources of inputs. It appears that many of the previously inferred afferents to the LC terminate, in fact, in the PB and PAG nuclei which are directly adjacent to the LC; the extensive connections of these two areas were unknown when the earlier HRP–DAB studies of LC afferents were published. Recent Studies Using Anterograde Tracing Methods To confirm our retrograde labeling for specific afferentation of the LC, we examined anterograde labeling in the LC area from various nuclei previously reported to be prominent afferents to the LC. After WGA–HRP injections into the central nucleus of the amygdala, the principal LC nucleus was devoid of anterograde fiber labeling; only the rostral pole (where NE and non-NE neurons are interdigitated, as described previously) contained scattered terminals. Dense anterograde labeling was present in the adjacent PB nucleus. Recent studies employing PHA-L anterograde tracing have largely confirmed this result (Wallace et al., 1992). This region also contains LC extranuclear dendrites, and recent ultrastructural analyses indicates that amygdala projections may terminate in part on these LC processes (Van Bockstaele et al., 1996a, 1996e). Our injections of WGA–HRP or PHA-L into the dorsal horn of the thoracic spinal cord, VLTg, prefrontal cortex, or rostral Sol yielded similar results: no
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anterograde labeling in the core of the LC nucleus but robust labeling in the PB lateral to the LC (from Sol) or the PAG medial to the LC (from VLTg, cortex, and dorsal spinal horn) nuclei (Fig. 2B). In contrast to results in rat, recent results indicate that dorsal spinal horn neurons project into the LC in monkey (Westlund and Craig, 1996); this may represent an interesting species difference. Recent ultrastructural analysis reveals that the Sol innervates LC dendrites in the lateral peri-LC region (see below). Labeled fibers following PHA-L injections into the VLTg have been noted in the rostral pole (containing interdigitated NE and non-NE neurons), but not the main body, of the LC nucleus (Deutch et al., 1986). Injections into the caudal Sol (commissuralis region) yielded occasional scattered fibers in the LC (Blessing and Aston-Jones, unpublished observations); as LC injections did not consistently label neurons in the Sol, these fibers could be axons of passage projecting to the adjacent PB area. Overall, the results of these anterograde tracing experiments were consistent with our retrograde data indicating that many previously reported afferents to the LC actually terminate in neighboring structures. Earlier retrograde studies of afferents to the LC did not use anterograde tracing to confirm that candidate afferents actually terminated in the LC. Anterograde labeling was prominent in the LC following WGA–HRP injections into either the LPGi or the EF, confirming that these areas are major sources of inputs to the LC. Similar results have also been obtained using PHA-L (Guyenet and Young, 1987; Van Bockstaele and Aston-Jones, unpublished observations) or biotinylated dextran (BDA) anterograde tracing (Van Bockstaele et al., 1998). Our recent studies with PHA-L tracing have revealed three distinct pathways by which LPGi projections reach the LC (Van Bockstaele et al., 1989): (i) The medullary adrenergic bundle uses a dorsomedial pathway to reach the LC (reviewed below). (ii) PHA-L injections into the medial LPGi labeled fibers reaching the LC primarily by a ventromedial pathway. (iii) Finally, laterally placed injections of PHA-L in the LPGi revealed a lateral pathway which proceeds rostrally lateral to the superior olive and ascends through the lateral pontine tegmentum, through the ventral and dorsal parabrachial regions, to enter the LC from its lateral and rostral aspects. This pathway closely resembles that reported by others (Guyenet and Young, 1987). These results were recently confirmed with other tracers as well (Van Bockstaele et al., 1998b).
Microphysiology Studies of Afferents to the LC The above anatomic results indicate that major LC afferents arise from the LPGi and the EF. In additional experiments, single cell recordings and electrical stimu-
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lation substantiated these conclusions. Space constraints prevent a full description. In brief, no neurons were antidromically activated in the Sol or contralateral LC from LC stimulation, and only 2 of 44 neurons in the lateral reticular nucleus were driven antidromically from the LC (Ennis and Aston-Jones, 1989a, 1989b). One of these was located in the rostral pole of this nucleus, at the caudal border of the LPGi, and may be a member of this latter set of cells. By contrast, a high percentage of neurons in the LPGi (25%) and the EF (28%) were antidromically activated by LC stimulation. These studies revealed two physiologically distinct subpopulations of LPGi neurons projecting to LC. Other findings described below indicate that there are at least three different neurotransmitter systems in this pathway as well. Taken together, the results of these antidromic stimulation experiments are entirely consistent with our anatomic findings. As LC dendrites extend into a shell-like region surrounding the LC nucleus itself (reviewed below), it is possible that fibers innervating areas adjacent to the LC may contact dendrites of LC neurons. We (AstonJones et al., 1986) have investigated this possibility with physiological techniques. High intensity (2 mA) stimulation of the central nucleus of the amygdala elicited only weak and inconsistent synaptic activation in a few LC neurons. Five other LC neurons were antidromically activated, as expected from the fact that the LC projects to the central nucleus of the amygdala. In contrast to this lack of consistent response in the LC, central amygdala stimulation caused strong, short-latency synaptic activation in 19 of 30 neurons in the adjacent PB area. Similar results have been obtained for another area that heavily innervates the peri-LC region, the Sol (Ennis and Aston-Jones, 1989b). These electrophysiologic studies suggest that the central nucleus of the amygdala and Sol have strong inputs to the PB but not to the LC. In contrast, stimulation of a specific region of the medial prefrontal cortex that also sends projections to the peri-LC region (Zhu and Aston-Jones, 1996) produced consistent activation of LC neurons (Fig. 4) (Jodo and Aston-Jones, 1997; Jodo et al., 1998). It has also been reported that stimulation of a similar area in ketamine-anesthetized rats produced inhibition of LC neurons, indicating that excitatory and (presumably indirect) inhibitory influences from the medial prefrontal cortex on LC activity may exist (Sara and Herve-Minvielle, 1995).
Indirect Afferents to the LC—Defining Afferent Circuitry Knowledge of direct afferents is critical to understanding the function of a brain structure. However,
this is not sufficient, as each input could convey several different types of information depending upon the circuits that the input neurons are enmeshed within. To unravel this circuit-level question of afferent control of the LC, we have begun using the transynaptic retrograde tracer pseudorabies virus (PRV). PRV is a live organism that is transported selectively retrogradely and avidly crosses synaptic junctions to label second and higher order afferents to neurons at the site of the injection. We (Aston-Jones and Card, 2000; Chen et al., 1999) have characterized the use of this tracer with central injections and found that it is a reliable and powerful tool for circuit-level afferent analysis. Focal injection of PRV into the LC yielded labeling in the LPGi and the EF at short survival times, as expected given that these are major direct inputs. However, at longer survival periods (greater than 44 h), neurons were also labeled in (among other sites) the suprachiasmatic nucleus (SCh; Fig. 5) (Aston-Jones et al., 2001). This labeling was particularly intriguing because it suggested the first specific circuit for circadian regulation of sleep/waking and performance. We determined with double labeling that the dorsomedial nucleus of the hypothalamus (DM) is a likely relay from the SCh to the LC. As the DM does not strongly innervate the LC nucleus proper, these results imply that the DM may innervate LC processes in the peri-LC dendritic zone. The role of the DM as an SCh–LC relay was confirmed when lesions of the DM substantially reduced the PRV labeling in the SCh after injection in the LC (Aston-Jones et al., 2001). Additional studies showed that the LC exhibits a circadian rhythm in discharge activity and that this rhythm was eliminated with DM lesions (Aston-Jones et al., 2001). Therefore, the SCh– DM–LC circuit is functionally important for circadian regulation of LC activity and, by implication, also of arousal and cognitive performance. Additional studies are currently underway to test these ideas. These findings are but one result among many intriguing outcomes showing the importance of circuit-level afferent analysis and the utility of the PRV tool in carrying afferent anatomy to this next functionally important step.
Conclusions of Tract-Tracing and Microphysiology Studies Tract-tracing and microphysiology studies reveal that the LPGi and EF are major afferents to the LC. Minor afferents with consistent WGA–HRP retrograde labeling are the dorsal cap of the PA and the intermediate zone of the spinal cord. Additional afferents identified retrogradely with WGA–aopHRP–Au or CTB and confirmed with anterograde tracing include the medial preoptic area and the ventrolateral PAG. Additional areas have
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FIGURE 4 Activation of LC neurons by stimulation of the medial prefrontal cortex in rat. Electrical stimulation was given at three different depths below the surface of the brain (1, 2, and 3 mm) in the prefrontal cortex, corresponding approximately to superficial, middle, and deep locations in the dorsomedial prefrontal cortex along the same stimulation electrode tracks. In the left PSTHs single pulse stimulation is designated by arrows. In the right PSTHs train stimulation was given during the epoch designated by small dots. Bin width in each PSTH was 5 ms. This response may indicate the the prefrontal cortex innervates extranuclear LC dendrites in the peri-LC area (see Fig. 2B). Taken from Jodo et al., 1998.
been identified as afferents to the LC based upon the neurotransmitter contents of fibers, including the tuberomammillary nucleus and the posterior hypothalamus (described below). Many areas previously thought to project to the LC (including the central nucleus of the amygdala, Sol, prefrontal cortex, and dorsal horn of the cord among others) densely innervate pericoerulear regions, but not the LC nuclear core. Some of these (Ace, Sol) have been demonstrated to contact extranuclear LC dendrites. The prefrontal cortex may also innervate these processes as stimulation of this area causes consistent activation of LC neurons. Finally, tracing with transynaptic methods has revealed a circuit from the SCh to the LC. Additional functionally identified circuit
afferents will be defined with these techniques in the near future.
Neurochemical Identity of Afferents to the LC Table 1 lists immunocytochemical studies indicating that the LC is innervated by fibers that stain for a variety of neurochemical markers. It is noteworthy that many of these neurotransmitters proposed to innervate the LC are contained in LPGi and EF neurons. For example, immunocytochemical studies reveal that LPGi and EF neurons stain for markers of adrenaline (Hokfelt et al., 1974; Howe et al., 1980), acetylcholine (Butcher and Woolf, 1984; Kimura et al., 1984), excitatory amino
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FIGURE 5 (Left panels) Labeling of neurons in the suprachiasmatic nucleus (SCh) after injection of pseudorabies virus (PRV) in the LC. Brightfield photomicrographs of frontal sections taken through the SCh at different survival times after PRV injection in the LC, as indicated. The number of labeled neurons in the SCh increased from 44 h (A) to 66 h (C) of survival. Also, labeling was more prominent on the side ipsilateral to the LC injection site (right side in these photographs). Sections were counterstained with neutral red. 3V, third ventricle; ox, optic chiasm. Bar = 200 μm. (Right panels) Histograms showing the distributions of LC firing rates during different epochs of the circadian cycle. Three paired groups of rats were maintained in either 12-h/12-h dark/light (A and C) or 24-h darkness (B). One paired group received bilateral ibotenic acid lesions of the DM (C). Impulse activity was recorded in LC neurons during either the dark or light photoperiod (A and C) or the active or inactive epoch of the rat’s circadian cycle in 24-h darkness (B). There was a significant difference in LC firing rates in animals taken from their dark vs light periods (A) and from their active vs inactive periods when maintained in continuous darkness (B; P<0.0001, each). Lesions of the DM eliminated the difference in LC firing rates during the dark vs light photoperiods (C). The scale on the y axis only corresponds to the histogram bars. The solid lines on each of the graphs represent best-fit normal distribution curves for the histogram data. Taken from Aston-Jones et al., 2001.
acids (Forloni et al., 1987; Toomin et al., 1987), enkephalin (Hokfelt et al., 1977; Khachaturian et al., 1983), CRH (Swanson et al., 1983), substance P (Ljungdahl et al., 1978), 5HT (Steinbusch, 1984), and GABA (Mugnaini and Oertel, 1985). We have performed singlelabeling immunohistochemical screening studies for the locations of several of these neurotransmitter markers in the LPGi and the EF, and we find that neurons staining for phenylethanolamine N-methyltransferase (PNMT, a marker for adrenergic neurons), 5-HT, enkephalins, substance P, GABA/GAD, ChAT, and dynorphin are located in regions that also contain neurons labeled retrogradely from the LC in other studies. Thus, it is possible that multiple neurotransmitter systems arise from neurons in either or both of these areas. Indeed, studies discussed below provide direct evidence for adrenergic, glutamatergic, GABA, and CRH inputs from the LPGi. It should be borne in mind that at least some of the neurotransmitter diversity in the afferent innervation of the LC may stem from colo-
calization of neurotransmitters, e.g., neuropeptide Y is colocalized with adrenergic neurons of the C1 group in the LPGi (Blessing et al., 1986). Here we review evidence for neurotransmitter inputs to LC neurons based upon the neuropharmacology of responses of LC neurons to stimulation of afferent sources and upon double-labeling anatomical studies employing retrograde transport combined with immunohistochemistry of neurotransmitter markers. Pharmacology of Inputs to the LC Excitatory amino acid input from the LPGi Singlepulse electrical stimulation of the LPGi elicits predominantly short-latency phasic activation of LC neurons; a minority of LC neurons is inhibited by such stimulation (described below). Intracerebroventricular (icv) or local intracoerulear microinfusion of non-NMDA-type excitatory amino acid (EAA) antagonists strongly attenuated or completely blocked LPGi-induced excitation in all LC neurons tested (Ennis and Aston-Jones, 1986,
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1988). In addition to blocking LPGi responses, these EAA antagonists simultaneously attenuated footshock (sciatic nerve stimulation)-evoked excitation of LC neurons. Inhibitory adrenergic input from the LPGi As noted above, some LC neurons were inhibited by LPGi stimulation. To determine whether C1 adrenergic neurons located in the LPGi were involved in this inhibitory projection, we characterized the effects of the α2 adrenoceptor antagonist idazoxan (IDA) on inhibitory responses of LC neurons to LPGi stimulation (Aston-Jones et al., 1992). Intravenous administration of IDA attenuated LPGi-evoked inhibition and often revealed an underlying weak excitation. Intraventricular administration of EAA antagonists eliminated excitation from LPGi and disclosed an underlying inhibitory response in many LC neurons that were previously excited by LPGi stimulation. These results revealed that about 90% of LC neurons receive inhibition from the LPGi. Intravenous or intracoerulear IDA significantly reduced such LPGi-evoked inhibition, completely blocking this response in many LC cells tested. These results indicate that C1 adrenergic neurons in the LPGi provide a direct inhibitory input to the great majority of LC noradrenergic neurons. These findings are compatible with our anatomical results showing that the C1 neurons in the LPGi provide the bulk of adrenergic innervation of the LC (described below) and that most or perhaps all LC cells receive both EAA and adrenergic inputs from this area. Inhibitory GABA input from the EF In contrast to the predominant excitation of LC from LPGi, stimulation of the EF yielded nearly uniform inhibition of LC activity (Ennis and Aston-Jones, 1989a; Ennis and AstonJones, 1989b). The GABA antagonist picrotoxin significantly attenuated inhibition of the LC from the EF, completely blocking such inhibition in most cells. Iontophoretically applied or microinfused bicuculline (BIC) blocked EF-evoked inhibition in nearly all LC cells tested. Local application of this agent into the LC did not affect footshock-evoked excitation of LC neurons and had no overall effect on postactivation inhibition following such excitation. Interestingly, continuous iontophoretic application of BIC alone increased the mean spontaneous discharge rate of LC neurons, suggesting a tonic GABAergic input in vivo. In contrast to the effect of the GABA antagonists picrotoxin or BIC, iontophoretic application of the glycine antagonist strychnine hydrochloride did not effect EFevoked inhibition of LC discharge. Hypocretin/orexin input to the LC As noted above, recent anatomical studies revealed a dense innervation
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of LC by hypocretin/orexin fibers. The sole source of this peptide is in the lateral and dorsal hypothalamus (de Lecea et al., 1998; Sakurai et al., 1998). Our studies in brain slices have revealed that this peptide strongly excites LC neurons directly, so that excitation is observed in the absence of synaptic transmission in the slice preparation (Fig. 3) (Horvath et al., 1999). This response appears to be due to inhibition of a resting “leak” potassium conductance in LC cells (Ivanov and Aston-Jones, 2000). Double Labeling Anatomical Studies Glutaminase-positive afferents to the LC from the LPGi We (Drolet and Aston-Jones, 1991) combined WGA–apoHRP–Au retrograde tracing with immunohistochemistry for phosphate-activated glutaminase, a purported marker of glutamatergic neurons. Numerous glutaminase-immunoreactive cell bodies were observed in the LPGi. Double-labeling revealed that such glutaminase-positive neurons represent a substantial proportion of the LC-projecting neurons in the LPGi. This provides anatomical support of the above pharmacological evidence for a major EAA input to the LC from the LPGi. Adrenergic inputs to the LC from C1 cells in the LPGi The LC is densely innervated throughout with PNMT-immunoreactive fibers (Berod et al., 1984; Hokfelt et al., 1974; Milner et al., 1989; Pieribone and Aston-Jones, 1991; Pieribone et al., 1988). In fact, the LC appears to be the primary target in the pons for adrenergic fiber innervation. In ultrastructural studies, PNMT-immunoreactive varicosities are numerous and make conventional symmetric and asymmetric synapses onto dendrites of LC neurons (Milner et al., 1989). We combined retrograde transport with immunohistochemistry for PNMT to identify the source of adrenergic afferents to the LC (Pieribone and AstonJones, 1991; Pieribone et al., 1988). Double-labeled LC afferent neurons were located among both C1 and C3 adrenergic neurons in the LPGi and the EF, respectively. No afferent neurons were found in the vicinity of the C2 adrenergic cell group in the Sol or the dorsal motor nucleus of the vagus, confirming our previous results with WGA–HRP (Aston-Jones et al., 1986; described above) Overall, approximately 21% of LC afferent neurons in LPGi are PNMT-positive (C1 neurons), while only 4% of LC afferents in the EF (C3) are PNMT-positive (Pieribone and Aston-Jones, 1991). This study also identified two pathways for PNMTimmunoreactive fibers to innervate the LC. Fibers from neurons in both C1 and C3 were found to enter the medullary adrenergic bundle and to ascend within this bundle to innervate the LC. This is consistent with
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previous results that electrolytic lesions of this adrenergic bundle in the rostral medulla cause an almost total loss of adrenergic fiber innervation of the LC (Astier et al., 1987). Fibers from the C3 cell group were found to travel on the ventral surface of the IVth ventricle and then distribute laterally to innervate the LC and surrounding areas. Both in vivo iontophoretic studies and in vitro experiments (discussed above) conclude that adrenaline potently inhibits the spontaneous activity of LC neurons via α2 receptors (Cedarbaum and Aghajanian, 1976; Williams et al., 1985). Together with the above anatomic data, these studies indicate that adrenergic neurons, most prominently in the C1 cell group, exert an α2-mediated inhibitory effect on LC neurons. We confirmed that stimulation of the C1 area inhibits LC neurons via α2 receptor activation (Aston-Jones et al., 1992). Serotonergic inputs to the LC The LC receives a dense serotonin innervation as seen with autoradiography for serotonin uptake sites (Leger and Descarries, 1978), tryptophan hydroxylase immunoreactivity (Pickel et al., 1977), and serotonin immunoreactivity (Steinbusch, 1984). Ultrastructural examination of tryptophan hydroxylase immunoreactivity (Pickel et al., 1977), 5HT (Van Bockstaele, 2000) and serotonin uptake sites (Leger and Descarries, 1978), in LC indicated that many of these terminals may not form classical synapses within the LC. No obvious fiber pathway to the LC is evident in serotonin-stained material and the source of serotonin innervation to the LC has been controversial. Lesions of the dorsal raphe reduced biochemical markers and uptake sites for serotonin in micropunches containing the LC and surrounding areas, leading Pujol and coworkers to propose that such innervation derives from the dorsal raphe complex (MacRae-Degueure and Milon, 1983; Pujol et al., 1978). However, labeled cells were not consistently observed in the dorsal raphe or raphe magnus following WGA–HRP (Aston-Jones et al., 1986), Fluorogold (Pieribone and Aston-Jones, 1988), CTb (Luppi et al., 1991), or WGA–apoHRP–Au injections restricted to the nucleus LC (unpublished observations). Furthermore, in preliminary studies injections of WGA–HRP or PHA-L into the dorsal raphe have failed to produce anterograde transport into the LC. In addition, serotonergic fiber innervation of the LC remains apparently undiminished following electrolytic lesions of the dorsal raphe area (Pieribone et al., 1989). Thus, our results disclose no substantial serotonin input to the LC from the dorsal raphe. In other preliminary studies, serotonergic neurons in the lateral wings of the B9 area were retrogradely labeled with CTb from the LC (Luppi et al., 1991). However, as noted above, afferents revealed by this tracer require anterograde
labeling for confirmation, which has not yet been conducted for this possible pathway. Recent studies reveal that although serotonin has no consistent effect on spontaneous LC discharge, this agent dramatically reduces glutamatergic, but not cholinergic, activation of LC neurons (Aston-Jones et al., 1991a–1991c). GABAergic inputs to the LC Several studies (Berod et al., 1984; Ijima and Ohtomo, 1988; Ottersen and StormMathisen, 1984a, 1984b) have identified dense glutamic acid decarboxylase (GAD)- or GABA-immunoreactive fiber staining in the LC. We have confirmed such findings with both light and electron microscopy. There is strong physiologic and pharmacologic evidence that at least a part of the GABAergic innervation of the LC arises from GABA neurons in the EF (Ennis and AstonJones, 1989a, 1989b, reviewed above) and may be responsible for a short-latency synaptic potential recorded in vitro (Cherubini et al., 1988). Additionally, in unpublished anatomical studies we have found a restricted population of GABA-positive neurons in the EF region that is a major source of LC afferents. In studies using retrograde transport of WGA–apoHRP–Au or CTb from the LC combined with immunohistochemistry for GABA or GAD, we have found that many LC-projecting neurons in the EF are putatively GABAergic (unpublished observations). Paradoxically however, electrolytic lesions of the EF have failed to eliminate GAD-immunoreactive terminals in the LC (Shipley, Ennis, and Aston-Jones, unpublished). This raises the possibility that some GABA terminals present in the LC do not arise from the EF but rather from other sources. In this regard, it is noteworthy that GAD- and GABA-positive neurons are found in the LPGi area that also contains LC afferent neurons (Ruggiero et al., 1985; Mugnaini and Oertel, 1985; AstonJones, unpublished). In addition, there are numerous GABAergic neurons in the adjacent peri-LC region (Jones, 1991). We have recently determined that many such putatively GABAergic neurons become retrogradely labeled after injection of retrograde tracers into the LC (Aston-Jones et al., 2001). We have also confirmed previous reports (Ijima and Ohtomo, 1988) for a population of small GABA-staining neurons located within the LC nucleus proper. These results indicate that neurons within the LC or peri-LC region may also provide a substantial GABAergic innervation of the LC. As expected, GABA has a strong inhibitory effect on LC neurons (Shefner and Osmanovic, 1991; also see above). Luppi and colleagues recently found that bicuculline, an antagonist of GABA-A receptors, disinhibits LC neurons during sleep (Gervasoni et al., 1998). This confirms previous proposals that LC neurons are actively inhibited during sleep (Aston-Jones and Bloom, 1981a,
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1991b), and identifies at least one possible behavioral function of the strong GABA input to LC neurons. Enkephalin inputs to the LC There is abundant evidence for opioid inputs to the LC. Numerous fibers within the LC nucleus stain with an antibody raised against enkephalin. Enkephalinergic terminals are reported to make synapses upon neurons in the LC (Pickel et al., 1979), and opioid binding sites are dense in the LC (Pert et al., 1976). In addition, LC spontaneous activity is potently suppressed by directly applied opiates (Bird and Kuhar, 1977; Guyenet and Aghajanian, 1979; Williams and North, 1984); these effects are mediated primarily through μ receptors on LC neurons (Williams and North, 1984). Our studies using an antibody directed against the extended arg–gly–leu–met–enkephalin molecule (derived from the enkephalin precursor, proenkephalin A) have revealed that the enkephalin innervation of the LC is denser than previously appreciated (Drolet et al., 1992). Enkephalin-positive fibers are especially dense in the rostral and ventromedial pericoerulear regions containing extranuclear LC dendrites, raising the possibility that distal dendrites of LC neurons also receive enkephalin inputs. Our retrograde tracing with WGA–apoHRP–Au combined with enkephalin immunohistochemistry revealed that a substantial percentage (more than 50%) of LC-projecting neurons in the LPGi and EF contain enkephalin (Drolet et al., 1992). These findings have been confirmed and extended by recent work at the ultrastructural level. Van Bockstaele and colleagues found that met– or leu–enkephalinpositive terminals make synaptic contacts with THpositive dendrites in the LC (Van Bockstaele et al., 1995; Van Bockstaele and Chan, 1997); some of these LC neurons were identified as cortically projecting (van Bockstaele et al., 1996d). Additional studies have localized μ receptors on the dendrites of LC neurons, both outside of apparent synaptic contact (Van Bockstaele et al., 1996b), and in apposition to leu–enkephalinpositive terminals (Van Bockstaele et al., 1996c). This group also found δ opioid receptors on presynaptic axon terminals in the LC (van Bockstaele et al., 1997). Finally, there is evidence (as noted above) that enkephalin is colocalized in both GABAergic (Van Bockstaele and Chan, 1997) and glutamatergic inputs to LC neurons (Van Bockstaele et al., 2000). The significance of these opioid peptide projections to the LC is the subject of ongoing research. One recent study found that stress induces increased endogenous opioid inhibition of LC neurons (Curtis et al., 2001), consistent with previous work where endogenous opioid influences on LC neurons were only found under stressful conditions (Abercrombie and Jacobs, 1988).
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CRH inputs to the LC Using an antibody directed against rat/human CRH, Valentino et al. (1992) found numerous CRH-positive fibers in the LC and CRHpositive cells in areas that contain LC afferents. WGA– apoHRP–Gold retrograde tracing combined with immunohistochemistry revealed that a population of LC-projecting neurons in the LPGi stain for CRH. A few doubly labeled neurons were also found in the dorsal cap of the paraventricular hypothalamic nucleus. In addition, there are many CRH cells in the pericoerulear area, raising the possibility that local pericoerulear neurons contribute to the CRH innervation of the LC. Indeed, we found that Barrington’s nucleus, a peri-LC structure densely populated with CRH neurons, send many CRH inputs to the LC (Valentino et al., 1996). No LC NE neurons were observed to stain for CRH. Ultrastructural studies found that CRH fibers directly terminate on LC processes (Van Bockstaele et al., 1996a). Some of the CRH innervation of LC processes in the rostral peri-LC region originates from the central nucleus of the amygdala (Van Bockstaele et al., 1996a; Van Bockstaele et al., 1998a). Recent work has found direct evidence for CRH-1 receptor localization in NE neurons of the rodent LC (Sauvage and Steckler, 2001), confirming that CRH has direct effects on the activity of LC cells. Effects of CRH, and putative activation of CRH afferents, on LC activity are described elsewhere (Valentino, 1989; Valentino et al., 1991). Ultrastructural Studies of Inputs to LC Neurons Shimizu and Imamoto (Shimizu and Imamoto, 1970; Shimizu et al., 1979) and Groves and Wilson (Groves and Wilson, 1980a) provided the first systematic studies of the ultrastructure of the LC. LC neurons have abundant cytoplasmic organelles including a highly developed Golgi apparatus that extends into the dendrites. Most afferent terminations in the LC nucleus synapse on dendrites ranging between 0.5 and 2.5 μm in diameter and onto spine-like appendages on dendrites and cell bodies. The majority of these synapses fell into four categories: (i) synapses with small round, densely packed vesicles (41%); (ii) those with large rounded vesicles (20%); (iii) synapses with large flattened vesicles (23%); and (iv) those with numerous small flattened vesicles (11%). The remaining 5% had mixtures of these and/or contained dense-core vesicles. In a second study, Groves and Wilson (1980b) found that 5-hydroxydopamine labeled a small percentage of all these synaptic types; these results were taken as indirect evidence for monoaminergic synapses of various types. In early studies, Pickel and co-workers (Pickel et al., 1979) demonstrated substance P- and met–enkephalincontaining axons and terminals in the LC although they
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did not use double-labeling to confirm that these peptidergic inputs synapsed onto noradrenergic neurons. This could be important because numerous noncatecholaminergic dendrites are present within the LC nucleus; these dendrites presumably derive from pericoerulear neurons. Milner et al. (1989) demonstrated a high percentage of synapses in the LC that were immunoreactive for PNMT. This study supported previous light microscopic and neurophysiological evidence for an adrenergic projection to LC neurons from the ventrolateral medulla. More recent electron microscopic studies by Van Bockstaele and colleagues elucidate afferentation of LC neurons in greater detail. Several of these studies are reviewed previously under sections corresponding to specific transmitter inputs. In addition, analyses of anterograde transport of biotinylated dextran amine (BDA) from the LPGi found that this structure monosynaptically innervates NE processes in the LC and peri-LC region (Van Bockstaele et al., 1998), confirming previous tract-tracing studies (Aston-Jones et al., 1986). Ultrastructural studies have also revealed that the bed nucleus of the stria terminalis (BST) innervates extranuclear dendrites of LC neurons in the rostral peri-LC region (Van Bockstaele et al., 1999b). Similar experiments have also demonstrated projections from the NTS (Van Bockstaele et al., 1999a) and from the ventrolateral PAG to extranuclear LC dendrites in the periLC zone (Bajic et al., 2000). Other Putative Neurotransmitter Candidates Innervating the LC The inputs reviewed above represent the most thoroughly investigated neurochemical afferents to the LC. As indicated in Table 1, a variety of other neurotransmitter markers are found in fibers that innervate the LC, but the sources of these markers have not been identified.
Glia in the LC Recent studies have shown that the LC is richly endowed with glia and that astroglia in particular intimately comingle with NE neurons and processes within the LC (Alvarez-Maubecin et al., 2000). These studies also found that glia and neurons in the LC were functionally connected through electrotonic coupling. The additional finding that neurons and glia stained for the molecular substrate of electrotonic coupling, connexin proteins 26 and 32, supported this result. Although reported only for neonatal animals, these findings support prior observations for electrotonic coupling in the LC (described above) and extend those results to also include coupling between LC neurons and astroglia.
Conclusions The results concerning afferent regulation of the LC mandate the need to know more about the anatomy and physiology of the LPGi and EF, as well as other sources of inputs. The integrative functions of these areas are critical for understanding the functional role of the LC in brain and behavioral processes. The set of activities represented in the LPGi and EF are diverse, but cluster around functions involved in autonomic regulation, sensory processing, and behavioral orientation (reviewed in Aston-Jones et al., 1991c). This is particularly significant for understanding LC function since as reviewed above (Aston-Jones and Bloom, 1981a, 1981b) the most intense output of the LC reliably corresponds to sympathoexcitatory stimuli and behavioral orienting responses. In addition, it has become clear in the last few years that the extranuclear dendrites of LC neurons are also important to understand, as they receive afferents that do not directly innervate the LC nucleus proper. This “extranuclear LC” area is reviewed in more detail below.
THE PERICOERULEAR REGION: THE “EXTRANUCLEAR LC” Inputs to the Pericoerulear Region It has been commonly believed that the region surrounding the LC in the rat is largely composed of fiber tracts with few if any neurons. However, our work (Aston-Jones et al., 1986, 1991c; Shipley et al., 1996) along with that of other groups (e.g., Cechetto et al., 1985; Saper, 1982, 1987; Sesack et al., 1989; Wallace et al., 1989) has shown that several brain areas contribute dense terminal fields to the neuropil immediately adjacent to the cell bodies that make up the nucleus LC proper (see below). There are dense inputs to the PB area lateral to the LC from the Sol (Mantyh and Hunt, 1984; Ennis and Aston-Jones, 1989a, 1989b; Van Bockstaele et al., 1999a), the dorsal horn of the spinal cord (Cechetto et al., 1985; Standaert et al., 1986), and the central nucleus of the amygdala (Aston-Jones et al., 1986; Van Bockstaele et al., 1996a; Wallace et al., 1989) among others. The pontine gray rostral, medial, and ventral to the LC, on the other hand, receives inputs from the frontal cortex (Hurley et al., 1991; Sesack et al., 1989; Zhu and Aston-Jones, 1996), the dorsal raphe (Bobillier et al., 1979; Conrad et al., 1974; Pieribone et al., 1989), the central nucleus of the amygdala (Aston-Jones et al., 1986; Wallace et al., 1989), and the VLTg (Deutch et al., 1986). In addition, we have shown that there is a dense projection to the rostromedial peri-LC region from the medial preoptic area (MPA) (Rizvi et al., 1994). This
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MPA input also terminates heavily in the region between the medial edge of the LC and the ependymal layer of the IVth ventricle. A few fibers from the MPA enter the nuclear core of the LC but the preponderance of the fibers terminates among the extranuclear dendrites of LC neurons (see below). Our recent studies also demonstrate input to this rostromedial peri-LC region from the DM. Thus, injections of retrograde tracers into this area produce labeled neurons in the DM, whereas similar injections confined to the LC nuclear core produce little labeling in the DM. Our recent results indicate that this input is an important relay for circadian information reaching the LC (Aston-Jones et al., 2001) (summarized above). This same rostroventromedial pericoerulear region is heavily targeted by fibers containing several peptides and includes Barrington’s nucleus which is a dense cluster of CRH neurons. Many of these neurons project into the LC proper (Valentino et al., 1996).
Architecture of the Pericoerulear Region These findings cast doubt on the view that the pericoerulear area is a relatively cell-free area and prompted an analysis of the neuropil in the region surrounding the “nuclear core” of the LC. Several interesting observations have emerged. In addition to Barrington’s nucleus and the laterodorsal tegmental nucleus, already well documented by others, we have found that the pericoerulear area immediately rostral, ventral, and medial to the LC proper contains many neurons which vary in size, shape, and dendritic orientation; these neurons do not fall easily into the described boundaries of Barrington’s or the lateral dorsal tegmental nuclei. Thus, inputs to areas immediately adjacent to the LC, particularly those in this rostroventromedial pericoerulear area, could terminate on these unidentified neurons. On the other hand, additional studies of this pericoerulear region have revealed that it also contains a dense, focal plexus of “extranuclear” LC dendrites (Shipley et al., 1996). This extranuclear dendritic plexus, which may be targeted by some or all of the discrete terminal systems found in this rostroventromedial pericoerulear area, is discussed next.
Extranuclear Dendrites of LC Neurons Several reports have shown that processes of LC neurons extend for a few hundred micrometers outside of the nuclear core of the LC (Cintra et al., 1982; Grzanna and Molliver, 1980; Grzanna et al., 1980; Shimizu and Imamoto, 1970; Shimizu et al., 1978; Swanson, 1976). However, in most cases it has not been clear whether these extranuclear processes are dendrites, axons, or
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both. Moreover, it is not known whether these “extranuclear dendrites” arise mainly from those LC neurons situated at the periphery of the nucleus or if the majority of LC neurons have extranuclear dendrites. Using gold–silver intensification (Gallyas et al., 1982) of dopamine β-hydroxylase (DBH) immunohistochemically stained material, we found that extranuclear LC processes have a remarkable degree of spatial organization. The vast majority of these processes ramify in two distinct, focal pericoerulear zones—rostroventromedial to the LC and a narrow strip that extends from the caudal juxtaependymal boundary of the LC closely apposed to the ependymal cell layer of the IVth ventricle. At the light microscopic level, many of these processes appeared to be obvious dendrites; others, however, were very thin and beaded, and could be axons. To unambiguously identify the nature of these extranuclear processes, we analyzed DBH- and tyrosine hydroxylase (TH)-stained material at the EM level (Shipley et al., 1996). Of more than 500 labeled processes in the rostroventromedial and caudal juxtaependymal peri-LC zones, all but three labeled processes were dendrites. We also found that these extranuclear LC dendrites are heavily targeted by noncatecholaminergic afferent synapses. Thus, LC neurons have an appreciable postsynaptic surface that lies a considerable distance outside the confines of the nucleus proper. Moreover, this “receptive surface” is preferentially distributed in two discrete peri-LC zones. These studies could not resolve whether these extranuclear dendrites arise primarily from a subset of LC neurons (e.g., those located near the periphery of the nucleus) or whether extranuclear dendrites were a characteristic feature of most LC neurons. To address this issue, we studied the morphologies and dendritic domains of individual LC neurons filled with biocytin in in vitro tissue slices (Shipley et al., 1990). Filled LC neurons had remarkably similar morphologies, with four or five major dendrites extending from the soma in all directions and a single thin process (presumably the axon) often emanating from a proximal dendrite. As shown in Fig. 6, dendrites of individual LC neurons typically exited the nuclear core of LC at its medial, rostral, or caudal boundary and extended for up to 500 μm into the rostral, medial, or caudal pericoerulear region. Most commonly, dendrites that exited the lateral margin of the nucleus coursed for ≤100 μm and then made an abrupt turn to extend in a rostral or caudal direction. These extranuclear dendritic fields were characteristic of the majority of LC neurons independent of the location of their cell body in the nucleus. Thus, individual LC neurons typically have extranuclear dendrites that extend into one or both of the preferred extranuclear dendritic zones.
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FIGURE 6 Extranuclear dendrites of LC neurons. (A) Horizontal section through the LC, showing a reconstruction of a single biocytin-filled LC neuron. The majority of the dendrites of LC neurons extend outside the LC nucleus proper into two focal zones: the rostromedial and the caudomedial pericoerulear regions. The dendrites of the LC neuron shown here extend into the rostromedial pericoerulear area. Arrows indicate the axon of this cell. At the bottom right is a drawing of the horizontal section. Rostral is at the top; medial is at the left. (B) Electron micrograph of extranuclear LC dendrites (D) contacted by synapses containing presynaptic vesicles (pv). Arrowheads indicate symmetrical synapses; the arrow indicates an asymmetrical synapse. LC dendrites labeled here by antibodies to DBH are located in the rostromedial pericoerulear region.
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The fact that several brain areas (see above) project densely and selectively into the zones containing these extranuclear LC dendrites raises the interesting possibility that some of these inputs synapse with the extranuclear dendrites of LC neurons. Both the LPGi and the EF, the two major inputs to the nuclear core of the LC, also project to these two pericoerulear dendritic zones and, thus, may terminate both on proximal and more distal LC dendrites. However, the rostroventromedial peri-LC receives input from several brain areas (frontal, insular, and perirhinal cortices; amygdala; MPA; dorsal raphe; and VLTg) that do not appreciably innervate the nuclear core of the LC. Recent studies (reviewed above) reveal that some of these areas directly innervate extranuclear LC dendrites. Although inputs to the soma-rich LC nucleus might exert a greater influence on LC discharge than inputs to extranuclear dendrites, the later inputs could significantly regulate LC activity.
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grade tracer pseudorabies virus (PRV) into the LC proper (Aston-Jones et al., 2001). This tracer also has a very limited diffusion, due to the large size of the viral particles and the high affinity for extracellular neuronal membrane molecules, and produces no apparent halo around the LC injection site (Aston-Jones and Card, 2000; Chen et al., 1999). One important property of this tracer is that it is transported through the length of the dendrites of infected neurons and transsynaptically labels inputs to distal dendrites (Aston-Jones and Card, 2000; Card et al., 1993). Therefore, results with focal PRV injections in the LC nuclear core include neurons that innervate distal extranuclear LC dendrites. We hypothesize that at least some of the neurons labeled with PRV in these studies in the peri-LC region may serve as interneurons and innervate distal LC dendrites. Note that many of these peri-LC neurons that are labeled after LC injections of either WGA– apoHRP–gold or PRV stain for GABA or GAD (AstonJones et al., 2001).
Pericoerulear Inputs to LC? As noted above, there are many neurons in the pericoerulear area. However, it is not known if any of these neurons innervate the LC, i.e., if there are “local” afferents to the LC. Our previous studies using injections of retrograde tracers into the LC (Aston-Jones et al., 1986) could not adequately address this issue because the injected tracer, WGA–HRP, produced an injection “halo” in the pericoerulear area, particularly in the rostromedial pericoerulear zone. We were able to tentatively rule out inputs from the PB area, but possible inputs from rostromedial pericoerulear areas were not analyzed. Indeed, results using the tracers PHA-L and WGA–apoHRP–Gold suggest that pericoerulear neurons may innervate the LC. One region in which retrogradely labeled cells were often found within the injection halo of WGA–HRP cases was the caudal ventrolateral PAG, rostral to the LC. Anterograde transport of PHA-L from the caudal ventrolateral PAG revealed prominent innervation of the central gray ventromedial to LC and scattered light innervation of the LC as well (Ennis et al., 1991). Stimulation this PAG region strongly influences pericoerulear neurons adjacent to the LC and has a moderate influence on LC neurons (Ennis et al., 1991). Recently, we found that injections of WGA– apoHRP–Gold into the LC, which produce very focal injections lacking a “halo,” yielded retrograde labeling in this peri-LC dendritic zone, indicating that at least some cells in this area may project into the LC nucleus proper. In additional studies, we found that many small neurons in the peri-LC dendritic zone were labeled following injections of the transynaptic retro-
EFFERENT PROJECTIONS OF LC NEURONS Ascending Projections Olfactory Structures The olfactory bulb and olfactory cortex compose a major fraction of the telencephalon in rats and other macrosomatic animals. In a quantitative analysis of LC NE innervation of the olfactory bulb (Shipley et al., 1985), it was determined that at least 40% of all LC neurons project to the bulb. Actually, this number may be in error on the low side as counts of labeled LC neurons were limited to those cases where injections of the retrograde tracer WGA–HRP were restricted to the rostral half of the main olfactory bulb in order to rule out any cells labeled by tracer that might spread into the caudally adjacent accessory olfactory bulb or anterior olfactory nucleus. Retrograde labeling was not found in any other structures containing NE neurons, thus it was concluded that the LC is the sole source of NE innervation of the bulb. This conclusion was supported by a subsequent study using anterograde tracing methods and DBH immunocytochemistry which demonstrated that LC NE fibers provide a dense and remarkably specific innervation of both the main and accessory olfactory bulbs (McLean et al., 1989). LC NE axons and varicosities form a plexus that is especially dense in the granule cell and internal plexiform layers of the main olfactory bulb. A sparser plexus of fibers innervates the more superficial external plexiform layer but the most superficial cellular layer
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of the bulb—the glomerular layer—is essentially devoid of NE fibers. This highly selective innervation pattern is unusual for the LC NE system. However, as the identical LC NE innervation pattern was observed in the accessory olfactory bulb which, though architectonically similar to the main olfactory bulb, has entirely distinct afferent and efferent connections, it was concluded that the LC NE system provides a uniquely laminar-specific innervation of the main and accessory olfactory bulbs. As the laminar segregation of specific neuron types in the olfactory bulb is more specific than that in any other cortical structure in the rat, the observed selective termination of LC NE fibers in the granule cell, internal plexiform, and (to a lesser extent) external plexiform layers suggests that the most likely cellular target of LC NE fibers in both the main olfactory bulb and the accessory olfactory bulb is the granule cells. Recent neurophysiological evidence indicates that LC projections may also terminate on mitral cells in the bulb. These experiments in slices of the bulb revealed that NE fibers act directly on mitral cells at α1 adrenoceptors to increase an “up” state and enhance responses to weak inputs (Hayar et al., 2001). This suggests a mechanism whereby LC stimulation in vivo increases responses of mitral cells to low-level olfactory nerve inputs (Jiang et al., 1996). In contrast to the olfactory bulb, much less is known about LC NE innervation of the set of structures known collectively as the primary olfactory cortex, which is directly innervated by the main and accessory olfactory bulbs. While earlier studies using the histofluorescence method leave little doubt that the primary olfactory cortex is richly innervated by catecholaminergic fibers, far less is known about the specific contributions by LC and/or non-LC NE fibers or by DA inputs from the brain stem. NE fibers richly innervate the entire rostrocaudal extent of the primary olfactory cortex, which stretches from the caudal end of the olfactory bulb throughout all the piriform, periamygdaloid, and lateral entorhinal cortices. NE fibers show a moderate to strong degree of laminar selectivity in these temporal cortical fields, strongly innervating the superficial half of layer I (layer Ia) and the middle and deep parts of layer III. Layer Ib has the sparsest innervation and layer II and the superficial part of layer III are intermediate. This pattern of innervation gives fewer clues about the possible neuronal targets of LC NE targets in olfactory cortex than in the olfactory bulb. Neocortex and Hippocampus Neocortex Shortly following the demonstration of NE projections from the brain stem to the cerebral cortex (Fuxe et al., 1968), the LC was identified as the
sole source of this cortical afferent (Jones and Moore, 1977; Mason and Fibiger, 1979; Ungerstedt, 1971). Later studies revealed substantial projections of the rat LC to all areas and spanning all layers of the neocortex (Levitt and Moore, 1978; Morrison et al., 1978, 1979). In the rat the pattern of LC axon distribution in cortex varies little between different areas of cortex. The general features of the coeruleocortical projections in the rat are described by Morrison et al. (1978). Layer I is characterized by a dense grid-like pattern of axons running tangentially to the cortical surface. Layers II and III contain mostly radial fibers while layer IV contains short and somewhat tortuous axons. Layers V and VI contain numerous axons oriented predominantly in the anteroposterior direction. Retrograde transport studies established that the coeruleocortical projection in the rat is almost exclusively ipsilateral with only 5–10% of LC neurons projecting to the contralateral neocortex (Ader et al., 1980; Room et al., 1981; Simpson et al., 1997; Waterhouse et al., 1993). In agreement with the finding of Morrison et al. (1981) concerning the rostrocaudal course of LC axons within the cortex, Loughlin et al. (1982) showed that coeruleocortical axons collateralize most heavily in the anterior–posterior dimension within the cortex and only to a limited extent in the mediolateral dimension. A study by Sakaguchi and Nakamura (1990) found that over 61% of randomly sampled LC neurons were antidromically activated from neocortical sites. Intracortical trajectory of LC axons By using dopamine β-hydroxylase immunocytochemistry in combination with intracortical lesions, Morrison et al. (1981) analyzed the course of LC axons within rat cortex. Based upon their findings these authors proposed the existence of a tangential intracortical course of the coeruleocortical projection: LC axons that enter the cortex through the frontal pole travel caudally within the gray matter forming a sheet of fibers that extends tangentially across cytoarchitectural fields of cortex. Hippocampus LC projections account for the entire NE input to the hippocampal formation. LC neurons projecting to the hippocampus are found primarily in the dorsal one-third of the LC (Loughlin et al., 1986a, 1986b; Mason and Fibiger, 1979) and originate in fusiform cells. LC axons reach the hippocampal formation via three distinct routes: (i) the ventral amygdaloid pathway, (ii) the fornix, and (iii) the cingulum bundle. Some authors hold that the projection originates predominantly in the larger, multipolar LC neurons (Loughlin et al., 1986a, 1986b; Loy et al., 1980), although another study (Haring and Davis, 1983) found exclusively
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small fusiform neurons labeled in the dorsal LC after injections of retrograde tracers into the dorsal parts of the dentate gyrus. Fibers traveling in the ventral amygdalofugal bundle innervate the entire hippocampal gyrus and the midseptotemporal and ventral regions of the dentate gyrus (Haring and Davis, 1983); fibers entering via the fornix innervate the septal pole of the dentate gyrus; and fibers entering from the cingulum bundle innervate mainly the ventral dentate gyrus.
out as perhaps the only major brain region essentially devoid of NE fibers. However, recent studies reveal a considerable NE innervation in the ventral striatum, particularly in the caudal medial shell of the nucleus accumbens (Berridge et al., 1997; Delfs et al., 1998). It is notable that this NE innervation originates primarily from the A2 and A1 cell groups of the caudal medulla, with relatively little contribution from the LC or other NE cell groups (Delfs et al., 1998).
Thalamus
Most areas of the basal forebrain receive at least moderate NE innervation. For example, NE inputs ramify throughout the substantia inominata. These terminals are relatively large in diameter and make asymmetric endings primarily on dendrites (Chang, 1989). One basal forebrain system that has received considerable attention, particularly in conjunction with the increased interest in Alzheimer’s disease, is the magnocellular cholinergic system including the medial septum, the nucleus of the diagonal band and the nucleus basalis. All these structures receive a moderate to strong NE innervation (Zaborszky and Cullinan, 1996). Based on a variety of tract-tracing and immunocytochemical studies, it appears that the majority of these NE fibers may derive from the LC. This suggests that the LC NE system influences the magnocellular cholinergic basal forebrain system although it must be recognized that the cholinergic neurons of the basal forebrain system are embedded in structures that are complex and heterogeneous, containing multiple neurotransmitters/peptides other than ACh. Relatively few studies have examined specific LC NE influences on the cholinergic system. An exception to this is the work of Zaborszky and Cullinan (1996) who have provided biochemical and EM immunocytochemical evidence for a direct influence of NE terminals on identified basal forebrain cholinergic neurons. Specifically, 6-hydroxydopamine lesions of ascending catecholaminergic fibers cause a reduction in ChAT levels in basal forebrain areas containing cholinergic neurons. The LC NE system does not appear to selectively target cholinergic neurons, however, as the entire septal complex receives a moderate to strong NE innervation yet the cholinergic neurons are restricted to the medial septal nucleus. Indeed, the heaviest NE innervation of the septum appears to be in its ventral and ventrolateral parts of the septum, well outside of the known dendritic spread of the medial septal cholinergic neurons. There is also moderate to dense NE innervation of the BST. The BST has several distinct subdivisions, which receive distinct patterns of NE inputs. This basal telencephalic complex appears to be involved in a number of complex functions including sexual
There have been relatively few studies of the specific LC NE innervation of the thalamus with tract-tracing and/or immunocytochemical methods. The most comprehensive account of NE innervation of the thalamus is the glyoxylic fluorescence study of Lindvall et al. (1974). NE fibers, primarily from the LC, differentially innervate different thalamic nuclei. The most prominent innervation is to the anterior thalamic group; the anteroventral nucleus, particularly its lateral aspect, is one of the most heavily innervated structures in the brain. The dorsal lateral geniculate and the ventrobasal complex, sensory nuclei for the visual and somatosensory systems, respectively, receive moderate to dense innervation but the principal sensory relay in the auditory pathway, the medial geniculate, receives a relatively sparse innervation. The lateral dorsal and posterior nuclei also receive an innervation less robust than that of the dorsal lateral geniculate and ventrobasal complex. The ventroanterior and ventromedial nuclei receive moderate innervation. In general, the midline nuclei are sparsely innervated by NE fibers but the paraventricular nucleus receives a very dense innervation of presumed adrenergic fibers as this plexus is robustly stained by specific antibodies to PNMT. The lateral and medial habenular nuclei (epithalamus) have a moderate to dense innervation although the source of this input appears to derive mainly from noncoerulear fibers. The thalamic reticular nucleus, a key structure for coordinating thalamocortical activity, has a dense NE plexus that derives from the LC. A recent study by Simpson and colleagues (1997) found that LC neurons retrogradely labeled from ventrobasal or posterior thalamic nuclei are found throughout the rostrocaudal extent of the nucleus, but clustered somewhat caudally overall. In contrast to neurons that project to the cerebral cortex, they found that LC neurons projecting to these thalamic nuclei were located bilaterally, but with an ipsilateral predominance. Striatum NE innervation is very sparse or absent in most areas of the striatum. In fact, the dorsal striatum stands
Basal Forebrain
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behavior and autonomic function. Recent work has also implicated the BST in anxiety (Davis and Shi, 1999) and in the aversiveness of opiate withdrawal (Delfs et al., 2000). Overall, DBH fiber innervation in medial BST is greater than that in the lateral BST (Phelix et al., 1992). However, the ventral BST receives perhaps the densest NE innervation in the brain. In ultrastructural studies DBH terminals formed synapses with dendritic shafts and spines of BST neurons (Phelix et al., 1992). In addition, there are frequent contacts from DBH terminals onto CRH-positive neurons in the ventrolateral BST (Phelix et al., 1994). Recent tract-tracing studies in our lab (Delfs et al., 2000) demonstrated that the majority of NE in the ventral BST originates in the A2 and A1 neurons of the caudal medulla, and not in the LC as had been previously supposed. Amygdala The amygdala receives a topographically organized innervation by NE fibers throughout its various subnuclei (Fallon et al., 1978). There are several sources of this NE input, including projections from the LC, the A2 neurons in the Sol, and the A1 neurons in the caudal ventrolateral medulla (Clayton and Williams, 2000; Zardetto-Smith and Gray, 1990, 1995). We have observed that the LC preferentially innervates the medial subcomponent of the central nucleus of the amygdala, whereas the NE input to the lateral division of the central amygdala nucleus originates from nonLC sources (Aston-Jones et al., 1996). NE input to the amygdala has attracted considerable attention in studies of memory. McGaugh and colleagues, as well as others, have found that memory for emotionally salient events is enhanced as a consequence of elevated NE release in the basolateral amygdala (McGaugh, 2000). Interestingly, this memory-enhancing effect requires NE from the A2 group in the Sol (Williams and McGaugh, 1993), while other studies indicate that the LC is also involved (Clayton and Williams, 2000). Preoptic Area
innervated by NE fibers and receives direct input from the LC and the A1 and A2 NE cell groups in the caudal medulla (Chou et al., 2002). This has implications in regulation of sleep and waking, as the ventrolateral preoptic area has been found to critically regulate sleep (Lu et al., 2000), and the LC has long been implicated in arousal and waking (Aston-Jones et al., 1984). Hypothalamus and Midbrain The hypothalamus is densely innervated by NE axons. The majority of these axons originate in cells of the A1 and A2 cell groups of the medulla, with only a sparse contingent of LC axons. Mason and Fibiger (1979) observed retrogradely labeled neurons in the rostral pole of the LC following HRP injections into the hypothalamus, a finding later confirmed by Loughlin et al. (1986a, 1986b). The vast majority of LC axons traverse the lateral hypothalamus en route to telencephalic regions, and the possibility that some labeling after hypothalamic injections was due to uptake by passing fibers cannot be ruled out. Cunningham and Sawchenko (1988) traced fibers from the LC to the medial wall of the paraventricular nucleus of the hypothalamus, but did not find LC projections to the supraoptic nucleus. This is consistent with our observations for anterograde transport of WGA–HRP from the LC (unpublished observations). LC axon terminals in the midbrain are most prominent in the tectum. By using anterograde transport of the lectin PHA-L in combination with dopamine βhydroxylase immunocytochemistry, Fritschy and Grzanna (1990b) demonstrated a bilateral distribution of LC axons in the inferior and superior colliculus, the dorsal and lateral periaqueductal gray, and the interpeduncular nucleus. Numerous PHA-L-labeled LC axons were present in the dorsal bundle but only a few labeled fibers could be detected in the midbrain tegmentum.
Descending Projections
The medial preoptic area has moderate to strong catecholaminergic inputs that would appear to be composed primarily of NE- and epinephrine-containing fibers. There is retrograde labeling evidence for direct projections from the LC and from adrenergic neurons in the ventral medulla to the preoptic area, a sexually dimorphic structure that plays a pivotal role in sexual behaviors and the regulation of gonadal steroid function. The cells of origin of this complex catecholaminergic innervation and the relative importance of epinephrine and NE to these functions are largely unknown. However, recent studies by Saper and colleagues have found that the ventrolateral preoptic area is densely
Cerebellum The innervation of the cerebellum by LC NE fibers has been described in considerable detail. Early studies indicated that the NE innervation of the cerebellar cortex was derived entirely from the LC (Moore and Bloom, 1979; Olson and Fuxe, 1971). Light microscopic observations using formaldehyde- or glyoxylic acidinduced fluorescence in the cerebellum revealed widespread innervation of the cerebellar cortex by fluorescent (presumably noradrenergic) fibers. These fibers enter the cerebellum via the superior peduncle (Jacobowitz and Kostrezewa, 1971; Pickel et al., 1973)
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and pass from the underlying white matter through the granule cell layer without considerable branching or apparent terminations. NE fibers then ramify in the molecular layer with numerous branches and varicosities, particularly in the vicinity of the proximal dendrites of Purkinje cells (Bloom and Battenburg, 1976; Bloom et al., 1971, 1972; Moore and Bloom, 1979). In the outer molecular layer the fibers appear to bifurcate and run parallel to the folium surface. Detailed ultrastructural analyses of NE synapses in the cerebellar cortex were made by Bloom and colleagues using autoradiography of sites taking up 3NE or by localizing degenerating fibers induced by treatment with the selective catecholamine neurotoxin 6-hydroxydopamine. These studies revealed that the majority of the NE synapses were onto dendrites of Purkinje cells in the mid-to-outer molecular layer (Bloom et al., 1971, 1972). Occasionally presumed NE terminals were seen to contact Purkinje cell dendrites in the inner molecular layer. These fibers appeared to climb along Purkinje dendrites before giving off terminallike varicosities. The estimated percentage of total cerebellar terminals that are presumably noradrenergic was only about 1%, but it was concluded that sufficient arborization existed to allow NE innervation of each Purkinje dendritic field (Bloom et al., 1972). These anatomical studies formed the basis for a great deal of physiological and pharmacological work which provided the initial detailed characterization of NE functional effects on central neurons, using the LC– Purkinje cell synapse as a model system (Bloom et al., 1972). Pons and Medulla The entire brain stem is richly innervated by NE axons. Early studies of the projections of the LC to the pons and medulla concluded the existence of widespread distribution of the efferent network in the pons and medulla. However, studies employing bilateral LC lesions revealed a distinct pattern of organization for the NE innervation of the brain stem. According to the observations by Levitt and Moore (1979), the LC projects primarily to sensory and association nuclei of the brain stem with NE neurons from non-LC sources projecting to motor nuclei and autonomic centers. This latter view was supported by a study of LC axon distribution by Fritschy and Grzanna (1990b) who used anterograde transport of PHA-L to demonstrate a remarkably restricted distribution of LC axons primarily to the trigeminal complex, especially the trigeminal nucleus pars caudalis. Spinal Cord Despite the obvious conceptual interest in knowing the detailed distribution of LC axons in the spinal cord, this topic has remained a subject of considerable debate.
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Since the demonstration of LC projections to the spinal cord (Ader et al., 1980; Commissiong et al., 1978; Nygren and Olson, 1977; Westlund et al., 1983), several laboratories have attempted to characterize their distribution within the cord. Early studies suggested that the LC projects primarily to the ventral horn thus implicating this nucleus in the control of motor output of the spinal cord (Commissiong et al., 1978). Anterograde transport of PHA-L by Fritschy and Grzanna (1990a) traced LC axons to the superficial laminae of the dorsal horn, implicating the LC in the control of sensory inputs to the spinal cord. This distribution is in good agreement with the pattern of distribution described in the brain stem where LC axons are distributed primarily to sensory and association nuclei (Fritschy and Grzanna, 1990b; Levitt and Moore, 1979). Within the spinal cord LC axons appear to descend the length of the cord with the superficial laminae of the dorsal horn. However, an entirely different pattern of LC axon distribution was reported by Clark and Proudfit (1991). These authors traced LC axons to the ventral horn of the spinal cord and were unable to detect any LC axons in the superficial layers of the dorsal horn. However, these authors noted striking substrain differences when they compared the noradrenergic innervation of the spinal cord in Sprague–Dawley rats from Sasco, Inc., vs Harlan Sprague–Dawley, Inc. (Clark et al., 1991). Using discrete injections of the retrograde tracer fluoro-gold into the superficial dorsal horn of Harlan rats (the strain used by Fritschy and Grzanna, 1990a, 1990b), Clark et al. (1991) observed more retrogradely labeled neurons in the LC than in the A5 and A7 cell groups, a finding in agreement with the anterograde study of Fritschy and Grzanna (1990a).
General Properties of LC Projections The functional significance of the broad projections from the LC nucleus depends upon the degree to which individual LC neurons share in such a multitarget innervation strategy. It is possible that different LC neurons project to select target areas and convey functions specialized for their specific targets. On the other hand, it is possible that individual LC neurons innervate a number of different targets, so that their function is more general and integrative. Several recent studies have examined these issues and are reviewed below in two sections: (i) the collateralization of individual LC neurons, and (ii) the topography of neurons within the LC based upon the targets that they innervate. Efferent Collateralization of LC Neurons This issue has been addressed using both electrophysiological methods to antidromically activate LC
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neurons from multiple brain areas and anatomical methods to doubly retrogradely label LC neurons from multiple target regions. Together, these studies indicate that single LC neurons are highly branched with projections often leading to distant and functionally different target sites. Retrograde labeling of LC neurons from multiple sites Several studies have found that two retrograde tracers injected into different target areas doubly label individual LC neurons. Some LC neurons were doubly labeled after injections of fluorescent tracers into pairs of sites in different hemispheres, including cortex–cortex, hippocampus–cortex, thalamus–cortex, thalamus– hippocampus, and in a few cases hippocampus– hippocampus (Ader et al., 1980). These results are compatible with those of others (Room et al., 1981) that individual LC neurons could project to at least two of the following sites (either ipsilaterally or bilaterally): prefrontal cortex, thalamus, hippocampus, and spinal cord. Injections into the cortex, thalamus, and hippocampus revealed not only ipsilateral but also contralateral labeling of cells in the LC. In addition, injections of fluorescent tracers into any forebrain area combined with an injection into the spinal cord produced doubly labeled LC neurons. A study in mice found that over 50% of cerebellar cortical-projecting LC neurons were also retrogradely labeled from ipsilateral forebrain sites and that these doubly labeled neurons appeared to be scattered throughout the LC nucleus (Steindler, 1981). Similar results were found in rat where doubly labeled LC neurons occurred after injections of retrograde tracers into frontal cortex and either cerebellar cortex, occipital cortex, or spinal cord (Nagai et al., 1981). Single LC neurons are reported to innervate both dorsal and ventral aspects of the area dentata of the hippocampus (Haring and Davis, 1983). Branched projections from single LC and subcoeruleus neurons (presumed to be noradrenergic) to both amygdala and the cerebellum have also been reported using double retrograde tracing (Dietrichs, 1985). Detailed studies of the distribution of LC projections to rat cortical areas by Loughlin et al. (1982) revealed that while individual LC neurons often were labeled from two distinct cortical areas, double labeling was much more frequent following injections into cortical areas aligned in the rostrocaudal axis (e.g., frontal and parietal cortices) than with injections placed at different mediolateral positions in the cortex (e.g., cingulate and suprarhinal cortices). This result is consistent with results of Morrison et al. (1981) for rostrocaudally oriented NE fibers in rat cortex. Double labeling was especially frequent with injections placed in ventral and deep sites of the same cortical region.
Evidence of branched projections from subcoeruleus neurons to the medial preoptic area and cervical spinal cord (Leanza et al., 1989), or to the raphe pontis and hypothalamic zona incerta (Leanza et al., 1988), has also been reported using double-labeling techniques. However, it is unknown whether these branched neurons are noradrenergic. A recent study by Waterhouse and colleagues has revealed additional organization in LC projections of an intriguing nature (Simpson et al., 1997). These investigators used retrograde labeling to study the innervation of different nuclei within the somatosensory pathway by individual LC neurons. They found that LC neurons were more likely to be doubly retrogradely labeled in cases where the two injections were made into functionally related areas (e.g., barrel field cortex and the ipsilateral ventrobasal thalamus) than when cortical and thalamic injections were made into functionally unrelated areas (e.g., barrel field cortex and ipsilateral dorsolateral geniculate nucleus). These results present a novel and potentially functionally important topography and specificity in the anatomy of the “ubiquitous” set of LC efferents. As one possible functional upshot, given the proposed role of LC neurons in attention (Aston-Jones et al., 2000), such “functionally homologous” branching could support selective attention to one vs other modalities of sensory stimuli. This possibility remains to be tested. Antidromic activation of LC neurons from multiple sites The above results with double retrograde labeling are largely compatible with “electro-anatomy” experiments, where antidromic activation from electrical stimulation in different target sites has been used to chart branched LC projections. The earliest such study by Nakamura and Iwama (1975) revealed that individual LC neurons projected to frontal and visual cortices, hippocampus and frontal cortex, hippocampus and visual cortex, and from three sites in one cell, hippocampus and frontal and visual cortices. In addition, of 3 cells driven antidromically from the cerebellar cortex, 2 were similarly driven from the cerebral cortex. Faiers and Mogenson (1976) found that 7 of 21 LC neurons antidromically identified as projecting through the supracallosal bundle under the frontal cortex also projected to the olfactory bulb. More evidence of branched LC axons was obtained in a study by Takigawa and Mogenson (1977), who found individual LC neurons antidromically activated from olfactory bulb, supracollosal bundle, and bed nucleus of the stria terminalis. This same study revealed that many subcoeruleus neurons could also be antidromically activated from the supracollosal bundle. Single LC neurons were similarly antidromically activated
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from the olfactory bulb and the cingulate cortex (Aston-Jones et al., 1980). Finally, a study by Guyenet (1980) found that 4 of 8 spinally projecting LC neurons were also antidromically driven by stimulation of the midbrain dorsal noradrenergic bundle and that each of the 4 neurons driven antidromically from the cerebellum also projected rostrally through the dorsal noradrenergic bundle. Topography of LC Neurons with Specific Targets Possible topographical distinctions within the LC are relatively difficult to study due to the small volume and number of cells in the nucleus and the highly divergent nature of the overall projection. This situation seems compatible with the scenario that most cells project to more than one target area, so that strictly segregated subgroups of LC neurons distinguished by efferent targets may not be prevalent. Nonetheless, examples of topographic specificity for LC neurons with particular targets have been described. The clearest example of a subgroup of selectively projecting LC neurons is the set projecting to the spinal cord. Many studies have shown using a variety of techniques that spinally projecting LC neurons are highly preferentially located in the ventral caudal aspect of the nucleus (Loughlin et al., 1986a, 1986b; Room et al., 1981; Satoh et al., 1977; Westlund et al., 1981, 1983). Other studies indicate that most LC neurons identified by a particular target overlap spatially within the nucleus with other sets of LC neurons that project to different target areas. Nonetheless, there are subtle distinctions among such groupings, such that interdigitated cells defined by different targets exhibit topographically distinguishable gradients of localization within the nucleus. Loughlin et al. (1982, 1986a) found that LC cells retrogradely labeled from the hippocampus were clustered in the dorsal aspect of the nucleus, while those labeled from the hypothalamus clustered strongly in the rostral aspect of the LC. Cells projecting to the cerebral or cerebellar cortices, on the other hand, were more evenly distributed throughout the nucleus. Morphological distinctions were also found among groups of LC neurons with different targets, such that fusiform cells project to the cerebral cortex and hippocampus, large multipolar neurons in ventral LC innervate the spinal cord and cerebellum; and small round cells in the central and anterior LC, along with multipolar anterior cells, preferentially project to the hypothalamus (Loughlin et al., 1986b). Cells centrally located in the nucleus were numerously retrogradely labeled following injections into many different target areas. Room et al. (1981) found that medial cerebellar injections yielded retrogradely labeled neurons throughout the LC nucleus. Haring and Davis (1983)
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reported that LC neurons retrogradely labeled from the dorsal area dentata were preferentially located within the dorsal aspect of the LC nucleus, whereas cells labeled from ventral area dentata injections were more widely dispersed in the LC nucleus. Fusiform and multipolar cells were most commonly labeled in the LC from area dentata injections. These investigators also reported that the septal and ventral poles of the dentate gyrus are innervated by distinct fiber pathways from the LC, employing the fornix and cingulum, respectively (Haring and Davis, 1985). In a detailed study of cortically projecting LC neurons, Waterhouse et al. (1983) found that LC cells projecting to the cerebral cortex tended to be localized within the caudal three-fifths of the dorsal ipsilateral LC nucleus. Within this portion of the nucleus, groups of neurons identified as projecting to occipital, sensorimotor, or frontal cortices were observed to form a dorsal to ventral gradient, while occipital-projecting LC cells tended to be more caudally placed in the LC nucleus than those projecting to the sensorimotor or frontal cortices. Only the frontal cortex received innervation from LC neurons in both dorsal and ventral subdivisions of the nucleus. Overlapping sets of cells were labeled from cerebrocortex, caudate, hippocampus, and cerebellum. These findings differ in some regards with earlier conclusions that cortically projecting LC neurons in rat are randomly distributed throughout the nucleus except for its ventral division (Mason and Fibiger, 1979). It is noteworthy that the density of LC innervation varies considerably among different cortical or other target areas, as reviewed above. It is not known whether these distinct innervation patterns or densities are related to select populations of neurons that innervate different regions. Ultrastructural Characteristics of LC Terminals The terminals of LC neurons have been examined in EM studies in several brain areas. Early reports from Descarries and colleagues (Descarries and Beaudet, 1983; Descarries et al., 1977) using EM autoradiographic examination of NE terminals in the cerebral cortex concluded that most NE terminals did not make synaptic contacts but rather existed as nonsynaptically arranged terminals to provide NE in a paracrine fashion to a local cortical area. Similar results have been reported by this lab more recently using EM localization of cortical terminals stained with antibodies against NE (Seguela et al., 1990). However, quantitative studies by Koda et al. (1978) in the hippocampus found that NE terminals (identified by the presence of small granular vesicles following permanganate fixation) formed specialized synaptic junctions with other neurons as frequently as
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non-NE terminals. In addition, studies by Papadopoulos, Parnavelas and colleagues (Papadopoulos and Parnavelas, 1990; Papadopoulos et al., 1987) using serial EM reconstruction of noradrenergic synapses in cerebral cortex identified with DBH immunohistochemistry found that the great majority of NE terminals formed conventional synaptic contacts onto neuronal profiles. These results are consistent with those of similar studies by Olschowka et al. (1981) who found that most DBHpositive terminals in areas of the diencephalon, the cerebellum, and the limbic cortex formed axodendritic synapses characterized by specialized junctional appositions. Thus, although results from different labs vary as to the frequency with which LC terminals form synaptic contacts onto target neurons, considerable evidence exists to indicate that this system uses conventional synaptic transmission at many of its terminations. The possibility remains, of course, that both synaptic and paracrine modes of neurotransmission exist at the same or different NE terminals. More recent studies by Aoki (1992) have found that terminals in the cerebral cortex that stain for TH are often located in apposition to astrocytic processes that stain for an antibody raised against a β-adrenergic receptor. These observations are consistent with other studies of Stone and colleagues (Stone and John, 1991) for a glial localization of β-adrenergic receptors and open the possibility for additional modes of LC influence in target areas involving glial cell activities.
OTHER METENCEPHALIC NORADRENERGIC NEURONS (A5 AND A7 CELL GROUPS) The neuroanatomy of the A5 and A7 cell groups has been studied much less extensively than that of the LC. These two groups form what has been termed the pontine lateral tegmental noradrenergic cell groups (Moore and Bloom, 1979; Moore and Card, 1984). They are distinct from the more medially and dorsally placed LC neurons in cytology, location, and connections. As summarized below, the lateral tegmental noradrenergic neurons have much efferent connections much more restricted than those of the LC cells, innervating primarily brain stem and spinal structures. Noncoerulear NE neurons form a nearly continuous column of cells in the ventrolateral portion of the metencephalon extending from the rostral region of the motor nucleus of the facial nerve to the pontine– midbrain junction. Recognizing two distinct clusters of NE cells, Dahlstrom and Fuxe (1964) divided this cell column into a rostral and a caudal portion which they labeled the A7 and A5 groups, respectively. This sepa-
ration of NE cells in the ventrolateral metencephalon into two separate groups has been questioned. Other investigators (Moore and Bloom, 1979) consider these neurons the metencephalic portion of a column of NE neurons that is continuous with A1 cells in the ventrolateral medulla and refer to the entire cell complex as the lateral tegmental group. A5 and A7 cells differ from LC neurons in that they lack ascending projections to the forebrain. The significance of the A5 and A7 groups has remained controversial. Nevertheless, there is a considerable body of evidence that a distinction between A5 and A7 cells is justified on connectional grounds. Tracer studies indicate that the A5 and A7 groups have distinct projection fields. Grzanna et al. (1987) noticed different labeling patterns in the A5 and A7 groups following tracer injections into the motor nuclei of the trigeminal and facial nerves, respectively. In double-labeling experiments, Lyons and Grzanna (1988) demonstrated that A7 cells have divergent projections to the motor nucleus of the trigeminal nerve and the spinal cord, suggesting a role of A7 cells in the control of motor output. There is general agreement that A5 cells project to autonomic nuclei of the brain stem and spinal cord (Byrum and Guyenet, 1987). More recent studies have focused on A7 neurons and their role in nociception. Proudfit and colleagues have shown that spinally projecting A7 neurons, which are implicated in antinociception, receive a direct input from the ventrolateral PAG, indicating a possible route for PAG-induced NE-dependent antinociception (Bajic and Proudfit, 1999). In addition, these neurons contain receptors for substance P (Chen et al., 2000) and receive substance P inputs (Proudfit and Monsen, 1999). These investigators have also implicated GABA neurons that project to A7 cells in antinociception (Nuseir and Proudfit, 2000). Recent studies also found that A5 NE neurons serve as a relay between the caudal ventrolateral medulla and the spinal cord (Tavares et al., 1996). This may indicate a pathway by which the caudal ventrolateral medulla exerts effects on blood pressure and respiratory function (Koshiya and Guyenet, 1994).
CONCLUSIONS The LC NE system in rat remains the premier chemically characterized neural system in the brain. This system is notable because of it has very widespread and divergent projections, and it provides the bulk of the brain’s NE. Although extensive work has revealed that LC projections to many target areas form conventional synapses onto neurons, this does not rule out
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the possibility of additional, nonsynaptic release of the NE transmitter. LC neurons contain several peptides in addition to NE. This provides some of the clearest evidence for heterogeneity among LC neurons, which otherwise appear in many respects to resemble one another closely. At the level of the LC nucleus, detailed immunohistochemical studies have found that LC dendrites extend outside of the LC proper in a polarized fashion, creating dendritic zones surrounding the LC nucleus. Recent results show the potential importance of this peri-LC surround (dendritic zone) in the afferent regulation of LC neurons. Other recent findings show an important circuit from the SCh through the DM to the LC. This circuit may participate in the circadian regulation of arousal and cognitive performance. Major afferents to the LC nucleus proper include the rostral medullary nuclei LPGi and the EF. These findings reveal that the LC is closely linked with autonomic circuitry in the CNS, consistent with a host of previous results. These results are consistent with the view that the LC system serves as the cognitive limb of a global rapid response system, whereby LC and sympathetic systems are coactivated in parallel to yield rapid adaptive responses to urgent stimuli (AstonJones et al., 1991b; 1996). A broader view of LC function has recently emerged from recent studies of LC activity in behaving monkeys. This hypothesis states that the NE LC system regulates attention and behavioral flexibility, either promoting focused attention and responding to stimuli relevant to an existing task or facilitating the search for another task that is more adaptive in the current context (Aston-Jones et al., 2000). In addition to these results for the LC system, recent work has significantly extended our knowledge of the connections and possible functions of the A5 and A7 metencephalic cell groups. Examination of the anatomy of these metencephalic NE systems continues to reveal unexpected specificity with new and deeper functional implications. However, many additional studies at the circuit and ultrastructural levels are needed to fully benefit from the new findings.
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C H A P T E R
12 Oromotor Nuclei JOSEPH B. TRAVERS Department of Oral Biology,Ohio State University Columbus, Ohio, USA
This chapter will describe the intrinsic organization of the trigeminal (Mo5), facial (7), and hypoglossal (12) motor nuclei and identify the sources of central projections to them. Brain stem projections to these nuclei originate from both sensory and reticular formation structures and serve a wide range of oral behaviors that range from simple oral reflexes, e.g., the dysynaptic jaw-opening reflex, to complex oral functions such as swallowing, mastication, and respiration. Although swallowing, mastication, licking, and respiration are each thought to be organized by brain stem central pattern generators that provide a coordinated output to the appropriate oromotor pools (reviewed in Jean, 2001; Nakamura and Katakura, 1995; Rekling and Feldman, 1998; Travers et al., 1997), there is increasing evidence that oromotor nuclei are more than simple output neurons. In addition to receiving excitatory and inhibitory projections utilizing classic neurotransmitters, the oromotor nuclei also receive inputs that utilize a variety of neuromodulatory substances. The intrinsic membrane properties of motoneurons (Del Negro et al., 1999) as well as the colocalization of neuromodulators confer the potential to further shape patterned motor output. γ-Aminobutyric acid (Davidoff and Schulze, 1988), calcitonin gene-related peptide (Skofitsch and Jacobowitz, 1985), urotensin II (Dun et al., 2001), and urocortin (Bittencourt et al., 1999) have each been localized within oromotoneurons, and mRNA for cholecystokinin has been identified as well (Ingram et al., 1989; Sutin and Jacobowitz, 1990). Further adding to the complexity of the oromotor nuclei are interneurons within 12 (Boone and Aldes, 1984; Takasu and
The Rat Nervous System, Third Edition
Hashimoto, 1988), possible axon collaterals within Mo5 (Moore and Appenteng, 1989), and, in species other than rat, central projections originating from Mo5 and 7 (cat: Kotchabhakdi and Walberg, 1977; Roste, 1989; rabbit: Bukowska and Grottel, 1997). Although each of the oromotor nuclei have unique characteristics, the coordination between muscles innervated by Mo5, 7, and 12 during feeding, grooming, and respiration is perhaps the most compelling reason to discuss the neuroanatomy of these nuclei within one chapter.
MOTOR TRIGEMINAL NUCLEUS [REFER TO INT. 0.2 TO −0.8 MM] Intrinsic Organization Myotopic Organization The motor trigeminal nucleus of the rat is conventionally divided into a large dorsolateral division defining the rostrocaudal length of the nucleus and a smaller ventromedial division in the caudal two-thirds (Jacquin et al., 1983; Limwongse and DeSantis, 1977; Lynch, 1985; Mizuno et al., 1975; Rokx and van Willigen, 1985; Sasamoto, 1979). Although an accessory nucleus for Mo5 was designated using cobalt labeling of the peripheral nerve (Szekely and Matesz, 1982), these neurons almost certainly correspond to the ventromedial subdivision of the main nucleus rather than to motoneurons outside the main nucleus. Figure 1 depicts the myotopic organization of Mo5. The jaw closing muscles—the masseter (superficial,
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Ms; anterior deep, Ma), temporalis (T), and medial (external) pterygoid (Pm)—are innervated from the dorsolateral division (DL); the jaw opening muscles— the anterior digastric (AD) and mylohyoid (MY)—are innervated from the ventromedial division (VM). A third jaw opening muscle, the lateral (internal) pterygoid (Pl) is grouped with jaw closing motoneurons in the ventral aspect of the dorsolateral division. In the rat, the location of medial and lateral pterygoid motoneurons have not been located individually within the DL; however, medial pterygoid motoneurons are located either ventral (guinea pig: UemuraSumi et al., 1982) or lateral (rabbit: Matsuda et al., 1978) to lateral pterygoid motoneurons. A laminar organization further defines the distribution of motoneurons within the DL (Rokx et al., 1985). Motoneurons innervating the anterior deep masseter muscle are interposed between motoneurons innervating the superficial masseter muscles further laterally and the temporalis muscle dorsomedially. Different “compartments” (Weijs, 1996) or “anatomical partitions” (Saad et al., 1997) of the rabbit masseter muscle function with some degree of independence during mastication. The spatial separation of motoneurons innervating these different compartments potentially allows for the segregation of input as a source for differential activation. The degree of motoneuron separation, however, is unclear. Weijs (1996) found that superficial masseter motoneurons occupied a dorso-
lateral position within the dorsal subdivision compared to deep masseter motoneurons that were more medial. The overlap between these two populations of neurons was on the order of 50%. In contrast, after applying separate fluorescent tracers to different nerve branches, the overlap between deep and superficial masseter motoneurons was estimated at over 90% (Saad et al., 1997). Motoneurons innervating the transverse mandibular muscle have not been specifically located in the rat but are clustered together in the same region as motoneurons innervating the superficial masseter muscle in guinea pig (Segade, 1990). Within the ventromedial division of Mo5, anterior digastric motoneurons are dorsomedial to mylohyoid motoneurons. Innervation appears strictly ipsilateral. Evidence that a small number of Mo5 neurons innervate the contralateral AD (Kemplay and Cavanagh, 1983) was not confirmed (Rokx et al., 1985). The tensor palatini is also innervated by motoneurons in the ventromedial division (cat: Keller et al., 1983). In rat, the tensor tympani is innervated by trigeminal motoneurons located ventral to Mo5 and medial to exiting trigeminal rootlets and thus appears in approximately the same anatomical location as group k neurons (Spangler et al., 1982). Group k neurons are a cell column outside the cytoarchitectonic boundaries of Mo5 (rabbit: Meesen and Olszewski, 1949) and contains (additional) motoneurons innervating the masseter and anterior digastric muscles (rabbit: Donga
FIGURE 1 The myotopic organization of the motor trigeminal nucleus is depicted in three coronal sections. The larger dorsolateral (DL) subdivision extends over the rostrocaudal length of the nucleus, the smaller ventrolateral (VM) subdivision only over the caudal two-thirds (b & c). Motor pools innervating primarily jaw closure muscles in the DL are largely segregated: superficial masseter (Ms), anterior deep masseter (Ma), temporalis (T), medial pterygoid (Pm), and lateral pterygoid (Pl). Jaw openers in the VM include the anterior digastric (AD) and mylohyoid (MY).
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et al., 1992; Saad et al., 1997). Group k motoneurons are smaller than those in Mo5 and mirror the topology seen in the main nucleus, i.e., masseter motoneurons are dorsal to digastric motoneurons. However, there are few references to group k in rat (e.g., Li et al., 1995) and group k innervation of masseter and digastric muscles has not been reported. Cytoarchitectonics Each Mo5 contains approximately 2265 to 2979 cells (Limwongse and DeSantis, 1977), the majority of which innervate jaw closing muscles (Kemplay and Cavanagh, 1983; Szekely and Matesz, 1982). The dorsolateral division contains both small (8–14 μm) and large (28–42 μm) diameter multipolar cells, which correlates with a bimodal distribution of nerve fiber diameters (Limwongse and DeSantis, 1977). Muscle spindles in the jaw closing muscles of rats (Karlsen, 1965) may terminate on small (presumed) γ efferent motoneurons in dorsolateral Mo5. Two classes of multipolar cells in the ventromedial division are also evident, although the large cells (24–34 μm in diameter) are not as large as their dorsolateral counterparts and the small cells (16–20 μm in diameter) are not as small. An absence of very small neurons in the ventromedial division is consistent with the lack of muscle spindles in jaw opening muscles (Limwongse and DeSantis, 1977). Axosomatic synapses cover, on average, 78% of the soma of large multipolar Mo5 cells in contrast to the smaller multipolar or fusiform cells that have proportionally far fewer synapses (Card et al., 1986). In addition to somata size, intracranial axonal trajectory further differentiates between dorsolateral and ventromedial cells. Axons from the dorsolateral division exit the brain directly, forming a few large roots that pass just ventral to the principal trigeminal sensory nucleus (Pr5). Axons from the ventromedial division, however, first course dorsally to form a genu rostral to the more prominent facial nerve (7n) genu before turning ventrolaterally as a separate root, parallel to fibers from the dorsolateral division (Jacquin et al., 1983; Szekely and Matesz, 1982). Although classical descriptions of trigeminal motoneurons do not include axon collaterals (Ramon Y. Cajal, 1972), collaterals were observed for each of four Mo5 cells filled intracellularly with horseradish peroxidase (HRP) (Moore and Appenteng, 1989). For three of the four cells, the exiting motoneuron axon arborized within Mo5 and the fourth axon arborized in Pr5. Unfortunately, axon collaterals have not been reported in any other intracellular labeling studies (Lingenhohl and Friauf, 1991; cat: Shigenaga et al., 1988; Yabuta et al., 1996; Yoshida et al., 1987), leaving their existence in question.
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As with all the cranial motor nuclei, Mo5 is cholinergic. In addition, calcitonin gene-related peptide (CGRP) (Skofitsch and Jacobowitz, 1985), urotensin II (Dun et al., 2001), and urocortin (Bittencourt et al., 1999) have been localized in Mo5 cells. Messenger RNA for cholecystokinin (CCK) has also been widely reported (e.g., Ingram et al., 1989; Sutin and Jacobowitz, 1990); however, there is little evidence for immunohistochemical detection of the peptide. Dendritic Architecture Dendrites of neurons located centrally within Mo5 radiate symmetrically from the soma compared to more peripherally located cells with dendrites that radiate preferentially toward the interior of the nucleus or follow the contour of the nucleus (Fig. 2) (Card et al., 1986; Lingenhohl and Friauf, 1991). Dendrites are largely confined to the nucleus; however, a few dendrites of jaw closing motoneurons extend dorsally and laterally beyond the borders of Mo5 into the mesencephalic trigeminal nucleus (Me5), the principal trigeminal nucleus (Pr5), and the supra- and intertrigeminal regions or medially into the pontine reticular formation (Lingenhohl and Friauf, 1991; Mong et al., 1988), (cat: Yoshida et al., 1987). Dendrites of motoneurons that innervate non-oral musculature do not overlap the dendritic fields of orally related trigeminal motoneurons. Thus, dendrites of tensor tympani motoneurons do not overlap the dendritic or soma fields of nearby jaw closing or opening motoneurons but are in close proximity to the superior olive, providing a possible substrate for auditory reflex function (cat: Friauf and Baker, 1985). A quantitative ultrastructural analysis of synapses on masseter motoneurons indicated a differential distribution such that putative inhibitory synapses were preferentially distributed on proximal dendrites (cat: Bae et al., 1999). Interneurons A class of small fusiform-shaped neurons located primarily around the borders of Mo5 that receive few synaptic terminals may be interneurons (Card et al., 1986). Other, presumably nonmotoneuronal cells within Mo5 have central projections. Cells within Mo5 were retrogradely labeled from injections of HRP into the cerebellum (cat: Kotchabhakdi and Walberg, 1977; Roste, 1989) (rabbit: Bukowska and Grottel, 1997) and a projection from Mo5 to the hypoglossal nucleus has also been reported (Manaker et al., 1992). In addition, a small projection from neurons in the jaw closing region of Mo5 to the homologous region on the contralateral side could contribute to bilateral jaw closing (Juch et al., 1993; Ter Horst et al., 1990; cat: Mizuno et al., 1983; rabbit: Kolta et al., 2000).
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FIGURE 2 Intracellular fills of masseter motoneurons. (a) Motoneurons near the edge of the nucleus have dendrites that radiate toward the center of the nucleus and follow the nucleus contour. (b) Motoneurons in the center of the nucleus have dendrites that radiate symmetrically. In many cases, dendrites extend into the adjacent reticular formation. From Lingenhohl and Friauf, 1991.
Afferent Projections Forebrain Pathways Although there is little anatomical evidence for direct forebrain projections to Mo5 in rat based on retrograde (Travers and Norgren, 1983; Vornov and Sutin, 1983) or anterograde tracers (Zhang and Sasamoto, 1990), this view may be in need of modification. Recent work in cat (Fung et al., 2001) suggests direct hypothalamic projections of orexin-containing neurons to the motor trigeminal and hypoglossal nuclei, and mRNA for the receptor for melanin-concentrating hormone, another hypothalamic feeding-related peptide, is found in all of the rat oromotor nuclei including the motor trigeminal nucleus (Saito et al., 2001). Forebrain structures certainly have a direct influence on trigeminal motoneuron activity. Electrical stimulation of either the frontal cortex or the central nucleus of the amygdala can produce rhythmic jaw movements in a number of species including rat (Ohta, 1984; Sasamoto and Ohta, 1982). In addition, the relatively short-latency onset of EPSPs in jaw opening motoneurons and IPSPs in jaw closing motoneurons was suggestive of a monosynaptic pathway (Ohta, 1984). One brief report describes a few direct cortico-trigeminal fibers (Mishima et al., 1983). The predominant view, however, is that rhythmic masticatory movements are
organized in the brain stem reticular formation (reviewed in: Nakamura and Katakura, 1995; Travers et al., 1997). The short-latency responses observed in Mo5 neurons from cortical stimulation might result from descending cortical projections (Takeuchi et al., 1988) onto Mo5 dendrites that extend into the lateral tegmental field. Most direct projections originate from the medulla and pons with a small contribution from the midbrain; major direct projections are summarized in Fig. 3. Midbrain Pathways Midbrain projections to Mo5 consist almost entirely of cells from the rostral extension of the ipsilateral Me5. Axon terminals of individual Me5 cells are distributed preferentially in the dorsolateral region of Mo5 (Dessem et al., 1997; Lingenhohl and Friauf, 1991; Matesz, 1981; cat: Shigenaga et al., 1989) and monosynaptically excite masseteric neurons in response to peripheral stimulation of either muscle spindles or periodontal ligament (Jerge, 1963). Recent studies tracing the trajectory of intracellularly filled Me5 neurons indicate that muscle spindle afferents most sensitive to muscle stretch project ipsilaterally directly onto trigeminal motoneurons (Dessem et al., 1997). Muscle spindle afferents signaling muscle length can influence trigeminal motoneurons bilaterally via the supratrigeminal area. Glutamate
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Pons regio h
A7 Pr5 (SubC) NE
Medulla PCRt/IRt MdD/MdV Gi LPGi raphe
EAA IAA ACh M-ENK Midbrain Mo5 5-HT
EAA
MeV
SP
EW
Sp5 FIGURE 3 Afferent projections to the trigeminal motor nucleus. Abbreviations: ACh, acetylcholine; EAA, excitatory amino acid; EW, Edinger–Westphal nucleus; Gi, gigantocellular nucleus; IAA, inhibitory amino acids; IRt, intermediate subdivision of reticular formation; LPGi, lateral paragigantocellularis; MdD, dorsal subdivision of the reticular formation (MdD); MdV, ventral subdivision of the reticular formation; M-ENK, methionine–enkephalin; Me5, mesencephalic trigeminal nucleus; NE, noradrenaline; PCRt, parvicellular reticular formation; Pr5, principal trigeminal sensory nucleus; regio h, reticular formation surrounding the motor trigeminal nucleus; SP, substance P; Sp5, spinal trigeminal nucleus; SubC, nucleus subceruleus; 5-HT, serotonin.
acting on a non-N-methyl-D-aspartic (non-NMDA) receptor may mediate transmission between Me5 and Mo5 (guinea pig: Chandler, 1989). Other midbrain projections to Mo5 include a projection from the Edinger–Westphal nucleus, immunohistochemically identified as containing substance P (cat: Fort et al., 1990) and an indirect pathway from the red nucleus. The red nucleus may influence Mo5 via the juxtatrigeminal area, that part of the lateral reticular formation interposed between Pr5 and the ventrolateral aspect of Mo5 (Godefroy et al., 1998; cat: Mizuno et al., 1974). The transynaptic transfer of pseudorabies virus (PRV) further suggests that the red nucleus influences Mo5 motoneurons via multisynaptic pathways (Fay and Norgren, 1997a). Pontine Projections Pontine projections to Mo5 begin rostrally at the level of the decussation of the brachium conjunctivum, just medial to the lateral lemniscus in an area corresponding to the A7 group (Grzanna et al., 1987; Lyons and Grzanna, 1988; Vornov and Sutin, 1983; cat: Fort et al., 1990). This projection is the primary source of noradrenaline (NE) input to Mo5 (Fuxe, 1965; Levitt and Moore, 1979; Vornov and Sutin, 1983), although other noradrenergic sources to Mo5 include cells in the subceruleus nucleus (SubC) (Grzanna et al., 1987; cat: Fort et al., 1990). Noradrenergic pathways influence both reflex and rhythmic Mo5 activity. The masseteric reflex induced by electrical stimulation of Me5 is
enhanced either by systemic treatment with the catecholamine precursor L-dihydroxyphenylalanine (L-DOPA) (Morilak and Jacobs, 1985) or by direct electrical stimulation of the A7 area (Vornov and Sutin, 1986). As with excitatory amino acids and serotonin (5hydroxytryptamine, 5-HT), the iontophoresis of NE onto anterior digastric motoneurons potentiates rhythmic responses evoked by cortical stimulation (Katakura and Chandler, 1990). Pontine cell groups projecting bilaterally to Mo5 include cells surrounding Mo5 in the supratrigeminal and intertrigeminal nuclei (Appenteng et al., 1990; Rokx et al., 1986; Travers and Norgren, 1983; Vornov and Sutin, 1983; cat: Mizuno et al., 1983; rabbit: Inoue et al., 2002). This area (rabbit: Regio h, Meesen and Olszewski, 1949) receives numerous inputs that potentially influence Mo5 neurons including projections from the red nucleus (Godefroy et al., 1998; cat: Mizuno et al., 1974) and midline pontine and medullary reticular formation (RF) (rabbit: Kolta et al., 2000). These structures were also labeled transynaptically with PRV following injections into masticatory muscles and relatively long survival times, suggesting an indirect influence on Mo5 neurons (Fay and Norgren, 1997a). The principal trigeminal nucleus, primarily the dorsomedial region, also projects bilaterally to Mo5. This part of Pr5 receives cutaneous afferent projections from the oral region (Hamilton and Norgren, 1984) and is part of a jaw opening reflex pathway (reviewed in Nakamura, 1980). A few cells in Pr5 contain GABA and
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could be inhibitory to jaw closing motoneurons during jaw opening activity (Saha et al., 1991b). Inhibition of masseteric motoneurons during jaw opening is also mediated by cells in the supratrigeminal area (Kidokoro et al., 1968), which receives projections directly from primary trigeminal afferents and indirectly via Pr5 (Mizuno, 1970; Torvik, 1956). Medullary Projections Projections to Mo5 from the medulla are from distributions of cells continuous with those from the pons (Cunningham and Sawchenko, 2000; Fay and Norgren, 1997a; Li et al., 1995; Travers and Norgren, 1983; Vornov and Sutin, 1983; cat: Holstege et al., 1977; Mizuno et al., 1983). Clusters of small-sized neurons in the parvicellular (PCRt) and intermediate zone (IRt) of the reticular formation project, primarily ipsilaterally, to Mo5, whereas clusters of larger neurons, more medially situated in the reticular formation, project bilaterally. At the level of 12 the medial distribution is primarily contralateral in the reticular nucleus of the medulla pars dorsalis (MdD) and pars ventralis (MdV). Based on dual injections of different retrograde fluorescent tracers, a small number of lateral medullary RF cells project bilaterally to Mo5 (Li et al., 1993c). Double-label studies have also demonstrated that a small number of cells in the RF project to both Mo5 and 12 or Mo5 and 7 (Li et al., 1993b). Somewhat more double-labeled cells were obtained with the Mo5 and 7 combination compared to the number obtained with Mo5 and 12. Neurons in the rostral lateral medullary RF (PCRt and IRt) appear to play an important role in the generation and coordination of rhythmic oral behavior as muscimol infusions into this region suppress both anterior digastric and lingual EMG activity associated with licking (Chen et al., 2001). Although the majority of direct premotor neurons to Mo5 use excitatory and inhibitory amino acids (Li et al., 1996; Rampon et al., 1996; guinea pig: Turman and Chandler, 1994; rabbit: Kolta et al., 2000), some cells in PCRt and MdD that project to Mo5 are cholinergic, and a population of more medially situated cells in the gigantocellular nucleus (Gi) were immunohistochemically identified as containing methionine–enkephalin (cat: Fort et al., 1990). Ultrastructural studies indicate that PCRt neurons form both symmetrical (inhibitory) and asymmetrical (excitatory) synapses on dendrites and soma in Mo5 (Mogoseanu et al., 1993). In addition, the gasseous neuromodulator nitric oxide depolarized Mo5 neurons, and NADPH-containing neurons in the medullary RF may be the source of nitrergic input to Mo5 (Abudara et al., 2001). Fluorogold (Cunningham and Sawchenko, 2000; Li et al., 1995) or fluorescent dextran injections (rabbit:
Kolta et al., 2000) into Mo5 further labeled neurons in the ventral medulla including the caudal raphe and paragigantocellular nuclei. These neurons may control state-dependent atonia during sleep (Hajnik et al., 2000) or the recruitment of masticatory muscles when respiratory drive is high (see Jacquin et al., 1999). Cells from the spinal trigeminal complex (pars oralis, interpolaris, and caudalis) project to Mo5 (Cunningham and Sawchenko, 2000; Li et al., 1995; Travers and Norgren, 1983; Vornov and Sutin, 1983; cat: Yoshida et al., 2001). The projection is predominantly ipsilateral. Differential projections to Mo5 have been studied by making injections of PRV into jaw opener and jaw closer muscles (Fay and Norgren, 1997a) and by injecting small volumes of conventional retrograde tracers directly into specific motor pools (Li et al., 1995). Some differences were apparent. Mesencephalic 5, the medial parabrachial nucleus (MBN), the supratrigeminal nucleus, and the dorsal cap of Pr5, oralis, and interpolaris all had more extensive projections to closer motoneurons in the dorsal subdivision compared to opener motoneurons in the ventromedial subdivision. In contrast, the lateral parabrachial nuclei (PB), ventrally situated neurons in the trigeminal sensory complex, and neurons in the α subdivision of the Gi all preferentially projected to opener motoneurons in the ventromedial subdivision. Serotonergic projections Serotonergic projections to Mo5 (Cropper et al., 1984; Fritschy et al., 1988; Palkovits et al., 1974; Schaffar et al., 1982, 1984; Steinbusch, 1981) account for approximately 13% of all synapses within Mo5 and are primarily axodendritic (Saha et al., 1991a; Takeuchi et al., 1983). In the midbrain and pons, retrograde labeling combined with immunohistochemistry identified the raphe dorsalis as one source of 5-HT to Mo5 (Fritschy et al., 1988; Li et al., 1993a; cat: Fort et al., 1990); however, autoradiographic studies identified the raphe centralis superior (median raphe) and not the raphe dorsalis as the principal source of raphe projections to Mo5 (cat: Bobillier et al., 1976). Further caudal in the brain stem, serotonergic-containing neurons in the raphe magnus, pallidus, and obscurus project to Mo5 as do neurons from the paragigantocellular nucleus (Fort et al., 1990; Fritschy et al., 1988; Li et al., 1993a). Electrical stimulation of the caudal raphe depolarized Mo5 neurons, an action that is blocked with serotonin antagonists (cat: Nagase et al., 1997). The motor trigeminal nucleus, together with the facial and hypoglossal nuclei show particularly dense labeling for 5-HT2A and 5-HT3 receptor subtypes (Fay and Kubin, 2000; Morales et al., 1998). Microiontophoretic application of 5-HT onto either masseter or anterior digastric motoneurons did not produce a change in firing rate (Kurasawa et al., 1990).
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Serotonin did, however, potentiate an excitatory response from these motoneurons induced by iontophoresis of glutamate into Me5, activation of jawstretch afferent fibers, or electrical stimulation of Me5 (Kurasawa et al., 1990) (cat: Ribeiro-do-Valle et al., 1991). More recently, Trueblood and colleagues demonstrated that serotonin increased both NMDA and nonNMDA-mediated responses in Mo5 neurons that were induced by electrical stimulation of Me5 (guinea pig: Trueblood et al., 1996). Serotonergic inputs are also involved in rhythmic jaw movements. Iontophoresis of 5-HT onto trigeminal motoneurons increased the number of rhythmically occurring spikes evoked by cortical stimulation (Katakura and Chandler, 1990). Serotonin may also play an important role beyond simply altering excitability to neuronal inputs. In a tissue slice preparation, Mo5 neurons showed bursting patterns when serotonin was applied (Hsiao et al., 1998), suggesting that intrinsic motoneuron membrane properties contribute to shaping rhythmic masticatory movements (guinea pig: Del Negro et al., 1999; Hsiao et al., 1997, 1998). Amino acid neurotransmitters Ultrastructural studies combined with immunohistochemistry have identified GABAergic, glycinergic, and glutaminergic synapses in the motor trigeminal nucleus (Bae et al., 2002; Yang et al., 1997a, 1997b) All three neurotransmitters formed both axosomatic and axodendritic synaptic terminals. In addition to labeled boutons exclusive for GABA (22%) and glycine (32%), glycine and GABA coexisted in 46% of the labeled boutons (Yang et al., 1997b). Similar results were obtained in an ultrastructural analysis of intracellularly filled and identified masseter motoneurons. However the proportion of coextensive GABA/glycine terminals was somewhat lower (cat: Bae et al., 1999). Axoaxonic synapses were evident in Mo5 with GABA localized presynaptically to glutamate-labeled axons (Yang et al., 1997a). Glutamate receptors on trigeminal motoneurons have not been extensively characterized but include NMDA receptors (Turman et al., 1999; Rema and Ebner, 1996). GABAergic and glycinergic neurons with projections to Mo5 originate primarily from Regio h (mostly supratrigeminal and the region medial to Mo5) and from PCRt (Li et al., 1996; Rampon et al., 1996; rabbit: Kolta et al., 2000). Fewer such cells originate from the nucleus raphe magnus and the sensory trigeminal complex (Pr5 and interpolaris). There is extensive overlap in the regional distribution of glutamatergic projections to Mo5 with GABAergic and glycinergic projections originating from both Regio h and PCRt (guinea pig: Turman and Chandler, 1994; rabbit: Kolta et al., 2000). An extensive body of literature implicates excitatory and inhibitory
amino acid neurotransmitters in the generation of rhythmic masticatory-like activity elicited by cortical stimulation (reviewed in Nakamura and Katakura, 1995), as well as natural consummatory behavior (Chen, Z. and Travers, J.B. Inactivation of amino acid receptors in the medullary reticular formation modulate and suppress ingestion and rejection in the awake rat. American Journal of Physiology, 285:R68–R83, 2003).
FACIAL NUCLEUS [REFER TO INT. –1.3 TO –2.3 MM] Intrinsic Organization Myotopic Organization Cells within 7 are segregated into several subdivisions consisting largely of cell groupings that are separated by white matter, but not by obvious cytoarchitectonic differences (Friauf and Herbert, 1985; Klein and Rhoades, 1985; Martin and Lodge, 1977; Martin et al., 1977; Papez, 1927; Semba and Egger, 1986; Szekely and Matesz, 1982; Tsai et al., 1993; Watson et al., 1982). Lateral, dorsolateral, intermediate, and medial subdivisions are readily apparent in most Nissl-stained coronal sections. These subdivisions are apparent over the rostrocaudal length of the nucleus; however, the medial division does not extend as far caudally as the intermediate and lateral subdivisions and the dorsolateral subdivision does not extend as far rostrally (Martin and Lodge, 1977; Semba and Egger, 1986). In some sections, a ventromedial cluster of cells, distinct from both the intermediate and the medial divisions, is apparent (Klein and Rhoades, 1985; Martin and Lodge, 1977; Semba and Egger, 1986) and in other sections a dorsal “cap” over the intermediate and medial divisions can also be distinguished (Faulkner et al., 1997; Friauf and Herbert, 1985; Watson et al., 1982). The divisions designated in the atlas [Int. −2.3 mm] correspond both to aggregates of neurons evident in Nissl-stained sections and myotopic representations derived from experimental studies (vide infra). The organization of 7 has been mapped for the representation of facial nerve branches within the nucleus (Faulkner et al., 1997; Martin and Lodge, 1977; Papez, 1927; Semba and Egger, 1986; Szekely and Matesz, 1982; Tsai et al., 1993) and for the representation of individual muscles (Faulkner et al., 1997; Friauf and Herbert, 1985; Klein and Rhoades, 1985; Shohara and Sakai, 1983; Watson et al., 1982). Minor discrepancies among these studies may be accounted for by the multiple innervation of a single muscle by different nerve branches and the innervation of several muscles by one nerve branch (Watson et al., 1982). Nevertheless,
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a general pattern of organization appears across several species in which dorsal muscles are represented dorsally, ventral muscles ventrally, and the anterior– posterior axis lateromedially (Friauf and Herbert, 1985; Klein and Rhoades, 1985; Martin and Lodge, 1977; Papez, 1927; cat: Courville, 1966a; Kume et al., 1978; Papez, 1927; opossum: Dom, 1982; Papez, 1927; Provis, 1977). This topographical organization for the rat is shown in Fig. 4 in which it can be seen that motoneurons innervating the proboscis are lateral within 7, peri-oral and orbital motoneurons intermediate, and facial motoneurons innervating the ear and neck medial. Detailed descriptions of the myotopic organization of individual auricular muscles indicate that although there is considerable overlap within the medial subdivision, motoneurons innervating the interscutular and posterior levator muscles are sandwiched between motoneurons innervating the transverse auricular muscle ventromedially and motoneurons innervating the anterior auricular muscle dorsally (Friauf and Herbert, 1985). Within the lateral subdivision, motoneurons innervating the intrinsic muscles of dorsally situated vibrissae are located lateral to those innervating more ventrally situated vibrissae (Klein and Rhoades, 1985). The anterior–posterior position of individual vibrissae is not myotopically organized within 7. Obicularis oculi motoneurons have also been studied in some detail (Faulkner et al., 1997). Approximately
257 motoneurons per eyelid are distributed in a dorsal “cap” that spans the mediolateral extent of 7. As with other motor nuclei, 7 is cholinergic; however, CGRP (Skofitsch and Jacobowitz, 1985) and urotensin II (Dun et al., 2001) are also present in some 7 cells as is mRNA for CCK (Sutin and Jacobowitz, 1990) and urocortin (Bittencourt et al., 1999). Other muscles innervated by 7n include the posterior digastric, stylohoid, and stapedius and are innervated by motoneurons outside the main motor nucleus (Huber and Hughson, 1926–27; Provis, 1977). Motoneurons innervating both the posterior belly of the digastric and stylohyoid (active primarily during jaw opening) are found dorsal to the anterior pole of 7 along the exiting facial root and form the accessory facial nucleus (Acs7) (Hutson et al., 1979; Rokx and van Willigen, 1985; Semba and Egger, 1986; Shohara and Sakai, 1983; Szekely and Matesz, 1982; Watson et al., 1982). Within Acs7, motoneurons innervating the stylohyoid muscle are ventral to those innervating the posterior belly of the digastric (Shohara and Sakai, 1983). The size and shape of cells in Acs7 is similar to those in 7 although there is a tendency for the soma and dendrites to be elongated in the dorsoventral direction (Szekely and Matesz, 1982). The axonal trajectory of Acs7 neurons is similar to that of other facial motoneurons but the axons form a distinct bundle parallel to the main exiting root. The location of Acs7, dorsal to
FIGURE 4 The myotopic organization and afferent projections to the facial nucleus (7) are depicted in a coronal section. Subdivisions within 7 include lateral (L), dorsolateral (DL), intermediate (I), and medial (M). Some subdivisions receive differentially strong or specific projections from structures indicated. Numerous regions in the medulla, pons, and midbrain, however, project to all subdivisions. Abbreviations: CG, central gray; Gi, gigantocellular nucleus, IRt, intermediate subdivison of the reticular formation; KF, Kolliker–Fuse nucleus; MdD, dorsal subdivision of the reticular formation; MdV, ventral subdivision of the reticular formation; M-ENK, methionin – enkephalin; NST/RF, nucleus of the solitary tract and subjacent reticular formation; PB, parabrachial nucleus; PCRt, parvocellular reticular formation; R, red nucleus; SubC, nucleus subceruleus; SP, substance P; Sp5, spinal trigeminal nucleus. Adapted from Watson et al., 1982.
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the rostral end of 7, places these cells nearly continuous with trigeminal motoneurons innervating the anterior belly of the digastric with which they share both common morphological (Szekely and Matesz, 1982) and functional characteristics (Basmajian, 1979). Facial motoneurons innervating the stapedius muscle of the middle ear have not been studied in the rat but have been located anterior to 7, adjacent to the superior olive in the cat (Lyon, 1978).
cat: Courville, 1966b; Edwards, 1972; Henkel and Edwards, 1978; Holstege et al., 1977; Takeuchi et al., 1979; opossums: Dom et al., 1973; Panneton and Martin, 1978, 1979, 1983). Similar to Mo5, there appear to be no forebrain projections to 7 in rat. In several instances, welldefined central projections to 7 differentiate between those subdivisions that innervate muscles of the orofacial region and those that innervate the facial muscles of the ear and eye.
Cytoarchitectonics and Dendritic Architecture
Midbrain Projections
Neurons within 7 are stellate shaped, ranging from 15 to 55 μm in diameter (Friauf, 1986; Martin et al., 1977; Szekely and Matesz, 1982; Watson et al., 1982). Estimates of the number of cells in 7 range from 3400 to 5800 (Friauf and Herbert, 1985; Martin et al., 1977; Semba and Egger, 1986; Watson et al., 1982) with the lower estimates including a correction factor for split cells (Martin et al., 1977; Semba and Egger, 1986). The dendritic arborization of individual HRP-filled neurons located in the medial, intermediate, and lateral subdivisions has been examined in some detail (Friauf, 1986). Primary dendrites extend in all directions but the overall dendritic field remained within a subdivision by branching primarily in the rostrocaudal direction. Nevertheless, dendritic fields of neurons in the lateral and intermediate subdivisions overlapped somewhat in the mediolateral direction but dendrites of neurons in the intermediate and medial subdivisions did not. Thus, within 7 itself, dendritic fields were functionally segregated into those involved with orofacial function (intermediate and lateral subdivisions) and those innervating the auricular muscles (medial subdivision). The overlap of dendritic fields between facial motoneurons from all the subdivisions was more apparent in the RF dorsal to 7. Unlike Mo5, there is no evidence for either interneurons or axon collaterals in 7. Nevertheless, not all neurons in 7 innervate facial muscles. A small projection from 7 to the cerebellar flocculus (cat: Kotchabhakdi and Walberg, 1977) does not originate from the cells that project to the facial musculature (Roste, 1989) and a few cells in 7 travel with the hypoglossal nerve to innervate lingual musculature (O’Reilly and Fitzgerald, 1990) (dog: Chibuzo and Cummings, 1982).
In the midbrain, cells anterior to the contralateral nucleus of the lateral lemniscus, i.e., the paralemniscal zone (cat: Henkel and Edwards, 1978) or retrorubral nucleus (Isokawa-Akesson and Komisaruk, 1987), project specifically to the medial subdivision of 7 (Hinrichsen and Watson, 1983; Li et al., 1997; Travers and Norgren, 1983). Some of these projection neurons are either glycinergic or GABAergic (Li et al., 1997). In the cat, this region of the midbrain receives input from the superior colliculus and has been implicated in pinna orientation to sound (Henkel and Edwards, 1978). Cells in the central gray, periocular nuclei (Edinger– Westphal nucleus, interstitial nucleus of Cajal, and Darkschewitch nucleus), olivary pretectal nucleus, and midbrain reticular formation also project to 7 and provide a pathway for facial movements associated with emotional behaviors (rage), reflexes of the eye (blinking), and vocal–facial behavior (Morcuende et al., 2002; cat: Fort et al., 1989; opossum: Panneton and Martin, 1983). Using the rabies virus as a transneuronal tracer, Morcuende and colleagues (2002) elegantly demonstrated specific projections from the periolary nuclei, red nucleus, oculomotor nuclei, and deep cerebellar nuclei to the orbicularis oculi motoneurons in the dorsolateral subdivision of 7. Some of the midbrain pathways appear neurochemically specific. A subset of neurons in the central grey and Edinger–Westphal nucleus, retrogradely labeled from injections of cholera toxin into 7, was immunocytochemically labeled for substance P (cat: Fort et al., 1989). Consistent with this observation, the greatest density of substance P immunoreactivity in 7 was concentrated over motoneuron pools located in the intermediate and dorsal subdivisions that innervate the orbital facial muscles (Senba et al., 1985). Retrogradely labeled cells in the olivary pretectal nucleus were immunocytochemically labeled for methionine–enkephalin (cat: Fort et al., 1989), however, the greatest enkephalinergic (ENK) immunoreactivity in 7 was concentrated over facial motoneurons in the medial subdivision that innervate the ear (Senba et al., 1985). The lateral and intermediate subdivisions of 7 receive projections from the contralateral red nucleus and
Afferent Projections Different divisions of 7 receive substantial and differential input from nuclei of the midbrain, pons, and medulla (Erzurumlu and Killackey, 1979; Fay and Norgren, 1997b; Hinrichsen and Watson, 1983; Isokawa-Akesson and Komisaruk, 1987; Li et al., 1997; Mogoseanu et al., 1994; Pinganaud et al., 1999; Senba and Tohyama, 1983a, 1983b; Travers and Norgren, 1983;
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provide a relay for cortical and cerebellar input to 7 (Hattox et al., 2002, Isokawa-Akesson and Komisaruk, 1987; Hinrichsen and Watson, 1983; Travers and Norgren, 1983) (opossum: Panneton and Martin, 1983). Electrical stimulation of the red nucleus produced movement of both the vibrissae and the eyelid (Isokawa-Akesson and Komisaruk, 1987). Pontine Pathways Differential projections to the subdivisions of 7 are evident from the pons. More cells in the ipsilateral Kolliker–Fuse (KF), supratrigeminal, and parabrachial (PB) nuclei project to the lateral and intermediate divisions of 7 than project to the medial subdivision (Isokawa-Akesson and Komisaruk, 1987; Hinrichsen and Watson, 1983; Travers and Norgren, 1983; opossum: Panneton and Martin, 1983). The PB region receives second-order vagal input (Norgren, 1978; Ricardo and Koh, 1978) and may be involved in exploratory sniffing, nasal breathing, and vibrissae movements, activities requiring coordination between respiratory and facial motoneurons. Likewise, the PB receives second-order gustatory input (Norgren, 1978) and could mediate gustatory-evoked facial responses. Projections from Pr5 to 7 are relatively sparse and are limited mainly to the lateral divisions (Erzurumlu and Killackey, 1979; Hattox et al., 2002; Travers and Norgren, 1983). A greater number of cells in the reticular formation dorsal to the superior olive at the level of Mo5 project to the medial division of 7 than project to the lateral division. Projections from the supratrigeminal region (Rokx et al., 1986) may serve as interneurons to mediate trigeminal reflex inhibition of intermediate subdivision 7 motoneurons (Minkels et al., 1995). Likewise, neurons in both the supratrigeminal area and PB may serve as interneurons for basal ganglia control of orofacial movement via projections from the entopeduncular nucleus (Takada et al., 1994). Catecholaminergic projections to 7 from the KF, nucleus subcoeruleus, and A5 region (Grzanna et al., 1987; Levitt and Moore, 1979; cat: Fort et al., 1989) project to all of the subdivisions of 7 (Senba et al., 1985). Medullary Projections In the medulla, most of the projections to 7 originate from cells in the reticular formation, bilaterally distributed in PCRt and IRt at the level of 7, and MdD and MdV further caudally (Li et al., 1997; Ter Horst et al., 1991; Travers and Norgren, 1983). A recent study using the more sensitive retrograde tracer cholera toxin, however, labeled additional populations of prefacial neurons in more medial, e.g., gigantocellular nucleus, areas of the medullary RF (Hattox et al., 2002). Doublelabel experiments with injections into both 7 and 12 or
7 and Mo5 established that as many as 10% of the labeled cells projected to both motor nuclei (Dauvergne et al., 2001; Li et al., 1993b). A somewhat higher percentage of labeled neurons (15%) projected bilaterally to 7 (Li et al., 1993c). Many of these cells are either GABAergic or glycinergic (Li et al., 1997). Ultrastructural studies confirm a monosynaptic connection between the medullary RF and 7 and indicate the presence of both symmetrical and asymmetrical synapses (Mogoseanu et al., 1994). Different regions of the medullary RF project to different divisions of 7, although these differences are not as pronounced as projections from the midbrain and pons. At the level of 12 many reticular neurons, bilaterally distributed in MdD, MdV, and along the medial border of the ipsilateral Sp5C project to the intermediate and lateral divisions of 7 (Hinrichsen and Watson, 1983; Travers and Norgren, 1983). Cells in the caudal medulla that project to the medial subdivision of 7 tend to be ventrally located, i.e., dorsal to the lateral reticular nucleus and medial to Sp5C, and include cells in and around the nucleus ambiguus (Hinrichsen and Watson, 1983; Isokawa-Akesson and Komisaruk, 1987; Senba and Tohyama, 1983a; Travers and Norgren, 1983). Reticular neurons that project preferentially to the medial division of 7 extend into the cervical levels of the spinal cord, originating in the intermediolateral gray column and lateral part of the ventral horn (Hinrichsen and Watson, 1983; Senba and Tohyama, 1983a; cat: Takeuchi et al., 1987). Disynaptic spinofacial reflexes may be mediated in part by spinofacial projection neurons that receive primary afferent terminals via dendrites that extend into spinal lamina IV (cat: Takeuchi et al., 1987). Some projections reach the facial nucleus from the ventral medulla and may be involved with respiratory (Fay and Norgren, 1997b; Hwang et al., 1998) or gasping (Fung et al., 1997) activity. Other medullary projections to 7 originate from the sensory trigeminal complex (Erzurumlu and Killackey, 1979; Hattox et al., 2002, Hinrichsen and Watson, 1983; Pinganaud et al., 1999; Travers and Norgren, 1983). The most complete description of these pathways employed both anterograde and retrograde tracers and further tested for collateral projections to 12 using dual tracers (Pinganaud et al., 1999). All subdivisions of the sensory complex projected to 7 but there were substantive differences in the patterns of projections. Neurons from the spinal trigeminal complex were located throughout the nuclei but clustered preferentially within the dorsal part of 5Sp. Projections were densest to the lateral subdivisions of 7 and decreased systematically more medially. The projection from principal 5 was from neurons almost exclusively in the ventral part of the nucleus. These trigeminofacial and spinal dorsal horn
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projections appear topographically organized such that facial motoneurons receive cutaneous input from areas overlying the muscles they innervate (Panneton and Martin, 1983). Thus, projections from the mandibular branch of 5 to the dorsal region of 5Sp can influence vibrissae motoneurons located intermediate and lateral in 7. Likewise, periocular afferents that terminate in the ventral part of 5P project onto obicularis oculi motoneurons distributed dorsally within 7 to mediate a disynaptic blink reflex (Pellegrini et al., 1995; cat: Hiraoka and Shimamura, 1977). Minor projections to 7 include projections to the medial division of 7 from cells in the medial vestibular nuclei (Hinrichsen and Watson, 1983; cat: Shaw and Baker, 1983; opossum: Panneton and Martin, 1983) and projections from the nucleus of the solitary tract (sol) to the intermediate subdivision (Norgren, 1978; Travers and Norgren, 1983). Cholinergic and peptidergic pathways Cholinergic terminals in 7 have been ultrastructurally characterized (Davidoff and Irintchev, 1986). One source of this cholinergic input is from cells in the MdD, lateral to 12 and ventral to the sol (cat: Fort et al., 1989). Substance P projections to the intermediate and dorsolateral subdivisions of 7 also originate from this region of the reticular formation (Senba and Tohyama, 1985). Other sources of substance P projections to 7 include the ventrolateral medullary reticular formation and the nuclei raphe pallidus and obscurus. Neurons in these regions, immunohistochemically identified as containing both substance P and 5-HT, project primarily to the ventral regions of 7 (cat: Fort et al., 1989). The ventrolateral medullary reticular formation is also a source of ENK projections to 7, primarily to the medial subdivision (Finley et al., 1981; Senba and Tohyama, 1983a, 1983b; cat: Fort et al., 1989). As with substance P, enkephalinergic projection neurons to 7 from the nuclei raphe obscurus and pallidus also contained 5-HT (cat: Fort et al., 1989). Serotonergic pathways Serotonergic fibers have been identified in 7 (Aghajanian and McCall, 1980; Palkovits et al., 1974; Steinbusch, 1981) and appear either throughout 7 (Senba et al., 1985) or concentrated in the ventrolateral subdivision (cat: Fort et al., 1989). The sources of serotonergic projections appear to be raphe nuclei obscurus, magnus, and pallidus (Senba et al., 1985; cat: Fort et al., 1989) and form both axosomatic and axodendritic synapses (Aghajanian and McCall, 1980). The iontophoretic application of 5-HT does not directly activate facial motor neurons but facilitates excitatory responses induced by other means (McCall and Aghajanian, 1979). In vivo studies indicate that this facilitation is postsynaptic and
mediated by receptor subtypes 5-HT2 and 5-HT1C (Rasmussen and Aghajanian, 1990).
HYPOGLOSSAL NUCLEUS Intrinsic Organization Myotopic Organization The tongue consists of both extrinsic (genioglossus, GG; styloglossus, STY; hyoglossus, HY; palatoglossus, PG) and intrinsic (vertical, V; transverse, T; superior longitudinal, SL; inferior longitudinal, IL) musculature. Although the geniohyoid (GH) is not a true lingual muscle (Chibuzo and Cummings, 1982), it has a common embryological origin with lingual muscles (Edgeworth, 1907) and often functions together with the GG, especially during tongue protrusion (Cunningham and Basmajian, 1969; Travers and Jackson, 1992). The palatoglossus (poorly defined in rat) functions as a pharyngeal muscle (Lowe, 1981). Motoneurons innervating the lingual musculature originate from 12 and travel in the hypoglossal nerve (12n) (Fig. 5). However, a small population of motoneurons within 7 exit the brain stem via 12n to innervate lingual muscles (O’Reilly and Fitzgerald, 1990; dog: Chibuzo and Cummings, 1982). A few motoneurons from the ventral region of 12 travel in the ansa cervicalis to innervate motor fibers of the intrinsic and GH muscles (O’Reilly and Fitzgerald, 1990). The hypoglossal nucleus consists of a dorsal and ventral subdivision (Aldes, 1995; Barnard, 1940; Kitamura et al., 1983, 1985; Krammer et al., 1979; Lewis et al., 1971; McClung and Goldberg, 1999; Odutola, 1976; O’Reilly and Fitzgerald, 1990; Uemura-Sumi et al., 1988). Geniohyoid motoneurons form a distinct cluster of neurons ventrolateral to the main nucleus. Axons arising from the dorsal subdivision travel in the lateral branch of 12n to innervate muscles that retract the tongue; ventral subdivision axons, together with GH axons, travel in the medial branch to innervate muscles that protrude the tongue. In general, motoneurons innervating the intrinsic musculature are medial to those innervating the extrinsic musculature. The main cell groupings of 12 are schematically depicted in Fig. 6. Each styloglossus muscle is innervated by approximately 45 motoneurons located at the rostral one-third of the dorsal subdivision (Guo et al., 1996; McClung and Goldberg, 1999). The hyoglossus is innervated by approximately twice as many motoneurons in the dorsal subdivision, caudal to the STY motoneuron distribution. Intrinsic lingual motoneurons that retract the tongue are also located in the dorsal subdivision. The hydrostatic model of lingual function predicts that
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IL V/T
SL
HY
V/T
GG
STY
R
GG
GH
SL V/T
HY GG GH
C
FIGURE 5 Organization of the hypoglossal nerve. Abbreviations: AC, ansa cervicalis; C1, C2, C3, ventral roots of first three cervical nerves; DXII, distal hypoglossal nerve; GG genioglossus; GH, geniohyoid; HB, hyoid belly of geniohyoid; HG, hyoglossal; JNG, jugulonodose ganglion; LD, lateral division of hypoglossal nerve; MB, mandibular belly of geniohyoid; MD, medial division of hypoglossal nerve; PXII proximal trunk of hypoglossal nerve; S, sympathetic; Sal, salivatory nucleus; SCG, superior cervical ganglion; SG, styloglossus; 7, facial nucleus, 7n, facial nerve; 12d, dorsal subdivision of hypoglossal nucleus; 12v, ventral subdivision of hypoglossal nucleus. From O’Reilly and Fitzgerald, 1990.
contraction of (inferior and superior) longitudinal muscles shorten the tongue (Kier and Smith, 1985), and this prediction has been borne out directly by measuring retraction forces following microstimulation of individual longitudinal motor units (Sokoloff, 2000; Sutlive et al., 1999). Superior and inferior longitudinal motoneurons are located medial to STY and HY motoneurons with the inferior longitudinal motoneurons distributed rostral to superior longitudinal motoneurons. The number of intrinsic motoneurons greatly exceeds extrinsic motoneurons, with longitudinal motoneurons making up about 75% of neurons in the dorsal subdivision (McClung and Goldberg, 1999). Motoneurons that protrude the tongue are located in the ventral compartment with (extrinsic) genioglossus motoneurons located lateral to motoneurons innervating the intrinsic horizontal and vertical muscles (Aldes, 1995; Uemura-Sumi et al., 1988). Motoneurons in the ventral compartment innervating the intrinsic muscles are topographically represented such that the
FIGURE 6 Myotopic organization of 12 from rostral (R) to caudal (C). Muscle abbreviations: GG, genioglossus; GH, geniohyoid; HY, hyoglossus; IL, inferior longitudinal; SL, superior longitudinal; STY, styloglossus; T, transverse; V, vertical. Adapted from Aldes, 1995.
tip of the tongue is represented caudal within 12 and the base of the tongue rostral (Aldes, 1995). Immunohistological labeling for various neurotransmitters, their precursors, derivatives, or receptors frequently demarcate or fall within myotopic subdivisions of 12. The distribution of catecholaminergic fibers, for example, determined by immunohistochemical labeling of tyrosine hydroxylase (TH) was evident throughout 12 but particularly dense in the ventromedial quadrant of the caudal half of 12 (Aldes et al., 1988b). In contrast, 5-HT immunoreactivity was particularly dense in both the dorsal division of the caudal two-thirds of 12 and in the ventrolateral region, over GH motoneurons. Although receptor binding sites for 5-HT1A and 5-HT1B were particularly dense in the dorsal subdivision of 12 (Manaker and Zucchi, 1998), corresponding to the distribution of immunoreactive 5-HT terminals (Aldes et al., 1988b), similar binding sites were noticeably absent in the ventrolateral region of 12 (GH motoneurons) despite the presence of concentrations of immunoreactive terminals. Immunocytochemical labeling of the converting enzymes dopamine β-hydroxylase (DBH) and phenylethanolamine (PNMT) was greatest in the ventromedial region of 12. This pattern of label confirmed the distribution of catecholamine (CA) innervation observed previously and further specified
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NE as the major source of CA innervation of 12 (Aldes et al., 1988a). Ionotropic glutamate receptor subunits also show some myotopic variation within 12 (Garcia del Cano et al., 1999). In particular, GluR1 (AMPA) was particularly absent in 12 motoneurons except for caudally located cells. In contrast, other AMPA (GluR2/3, GluR4), kainate (GluR5/6/7), and NMDA (NR1) receptors were more evenly distributed on 12 motoneurons. Putative interneurons in the dorsolateral quadrant of 12 stained well for GluR1. Physiological studies indicate that NMDA and non-NMDA receptors are co- localized within 12 (O’Brien et al., 1997). Immunohistochemical labeling for adenosine deaminase was restricted to the dorsal division of 12 (Senba et al., 1987a). Adenosine may function in neurotransmission or other neuromodulatory actions (Cooper et al., 1996; Stone, 1981). Adenosine labeling was transient in both 12 and (oro)facial motoneurons during development and disappeared by postnatal day 25. A possible correlation between the transient expression of adenosine and suckling behavior was noted by Senba and colleagues (Senba et al., 1987b). Enkephalinergic input to 12 was also differentially distributed (Aldes, 1998). Immunohistochemically labeled ENK terminals were particularly dense over the ventrolateral subdivision, corresponding to the location of GG motoneurons. Cytoarchitectonics Each half of the hypoglossal nucleus contains approximately 3500 neurons (Lewis et al., 1971). Most of the cells within 12 are motoneurons but there is anatomical evidence (Boone and Aldes, 1984; Cooper, 1981; Takasu and Hashimoto, 1988; monkey: Takasu et al., 1987) for a small population of interneurons, confirming evidence obtained earlier from neurophysiological studies (cat: Green and Negishi, 1963; Sumi, 1969). Motoneurons Cytoarchitectonic characteristics of size, shape, and dendritic orientation further differentiate motoneurons in different regions of 12 (Aldes, 1995; Boone and Aldes, 1984; Cooper, 1981; Kitamura et al., 1983; McClung and Goldberg, 1999; Odutola, 1976). Cells in the dorsal division appear fusiform, oriented along the mediolateral axis and range from 17 to 40 μm in diameter. Dorsal subdivision motoneurons innervating intrinsic muscles were significantly smaller (X=25.7 μm) compared to extrinsic muscle motoneurons (X=30.25 μm) (derived from McClung and Goldberg, 1999). Likewise, cells in the central region of the ventral subdivision that innervate intrinsic muscles were smaller on average (X=23 μm) and more globular in shape than the larger more lateral multipolar motoneurons in the ventral division (X=29.5 μm) (Aldes, 1995). Cell diameters (average
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= 28.7 μm) were unimodally distributed in the ventrolateral division, suggesting to Kitamura and colleagues (Kitamura et al., 1983) a lack of γ efferents, but subsequent studies (O’Reilly and Fitzgerald, 1990; Smith, 1989) have clearly confirmed the earlier observation (Maier, 1979) that both the GH and longitudinal muscles possess a few muscle spindles. Hypoglossal motoneurons are cholinergic (e.g., Connaughton et al., 1986; Wamsley et al., 1981) and a subset colocalize GABA (Davidoff and Schulze, 1988). Peptides in 12 motoneurons include both galanin and CGRP (Moore, 1989) as well as urotensin II (Dun et al., 2001). Messenger RNA for both urocortin (Bittencourt et al., 1999) and CCK (Abelson and Micevych, 1991; Cortes et al., 1990) is also found in 12 motoneurons. Interneurons Interneurons in 12 were initially identified as cells not labeled following the application of HRP to lingual muscles (Boone and Aldes, 1984). These neurons were smaller (10–18 μm) than labeled motoneurons (25–50 μm), had fewer dendritic processes, and were confined to the ventrolateral or dorsolateral borders of the nucleus. Evidence obtained from Golgiimpregnated neurons localized to 12 and subsequently (re)sectioned for ultrastructural analysis confirmed that small neurons make synaptic contact within the borders of 12 (Takasu and Hashimoto, 1988). An example obtained from a juvenile rat demonstrated multiple axodendritic synapses between an axon collateral to a small interneuron and a hypoglossal motoneuron. The GABAergic nature of interneurons is suggested by both radioactive uptake studies and immunohistochemical staining for GABA and its synthetic enzyme, glutamic acid decarboxylase (GAD) (Aldes et al., 1988c; Simon et al., 1985; monkey: Takasu et al., 1987). Immunocytochemical labeling of GABA and GAD fibers were evident throughout 12, although staining appeared denser in ventral regions of the nucleus, particularly in the caudal half (Aldes et al., 1988c). A few positively stained GABAergic neurons were located laterally within 12 and along the dorsolateral border, i.e., in the same location as HRP-identified interneurons. Neurons staining positive for GABA were small, 12–18 μm, round, and few in number. GABA is inhibitory to 12 motoneurons (Altmann et al., 1972; Gregg and Carpenter, 1982). Interneurons in 12 may also have collaterals outside the nucleus (Popratiloff et al., 2001). Injections of Fluorogold into the facial nucleus consistently labeled a few small neurons laterally located within 12. Dendritic Architecture Neurons in 12 can be further classified based on dendritic morphology. Using Golgi-stained material, Ramon Y. Cajal (1972) designated hypoglossal cells as
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“external” when dendrites extended beyond the borders of the nucleus and “internal” when dendrites were confined to the nuclear region. Two particularly dense dendritic zones within 12 include the dorsalmost part of the nucleus, just ventral to the dorsal motor nucleus of the vagus (10) and the midline of the nucleus around the central canal (Lorente de No, 1947). Some motoneuron dendrites extend into the contralateral nucleus (Altschuler et al., 1994; Wan et al., 1982). Dendritic orientation of cells labeled from either the Golgi technique (Odutola, 1976) or cholera toxin HRP (Wan et al., 1982) further distinguish between cells in the various subdivisions. Dendrites of cells of the dorsal division can be either internal or external (Odutola, 1976). External dendrites may reach 1 mm in length, extending laterally into the adjacent reticular formation (MdD and MdV) and, in some cases, reach Sp5 (Wan et al., 1982). Dendrites from these cells also extend into the ipsilateral SOL and a very few traverse 10 to reach the contralateral nucleus of the solitary tract (SOL) (Wan et al., 1982). Dendritic fields from cells in the ventral division include an apical dendrite that ramifies within the dorsal divisions of 12 and basal dendrites that ramify laterally within 12 and the adjacent reticular formation (Odutola, 1976), extending ventrally into the medial longitudinal fasciculus (MLF) and nucleus raphe obscurus (Wan et al., 1982). Dendrites from multipolar cells in the center of 12 fan out to ramify throughout the nucleus (Odutola, 1976). Dendrites from motoneurons within a given compartment also form dendritic bundles in the rostral/caudal dimension (Fig.7) and may provide a substrate for simultaneous activation of synergistic motoneurons (Altschuler et al., 1994).
Afferent Projections Afferent projections reach 12 from cells in the midbrain, pons, and medulla (Aldes, 1980; Borke et al., 1983; Cooper and Fritz, 1981; Dobbins and Feldman, 1995; Fay and Norgren, 1997c; Travers and Norgren, 1983). Many of these projections are from specific RF regions organizing the complex oromotor functions of mastication, licking, swallowing, and respiration (Hwang and St. John, 1987; Nakamura and Katakura, 1995; Rekling and Feldman, 1998; Travers et al., 1997). Other RF projections control state-dependent muscle tone in the tongue (Hajnik et al., 2000) and projections from the nucleus of the solitary tract and sensory trigeminal complex mediate lingual reflexes (Lowe, 1981). Forebrain Pathways There appear to be no direct cortical projections to 12 in the rat (Travers and Norgren, 1983; Walberg, 1957).
FIGURE 7 Photomicrograph of cholera toxin-labeled geniohyoid motoneurons in horizontal plane. Arrowheads point to dendritic bundles running in rostrocaudal orientation. From Altschuler et al., 1994.
Descending pathways, however, activate oromotor responses of mastication and licking that are organized in the brain stem reticular formation (reviewed in Nakamura and Katakura, 1995; Travers et al., 1997). Damage to a small zone of anterior-lateral (orbital) cortex inhibits some tongue protrusion activity but not protrusions occurring during rhythmic licking (Whishaw and Kolb, 1989). Cortical sites that support microstimulation-elicited ororhythmic responses send projections to widespread regions of the lateral medullary and pontine reticular formation (Zhang and Sasamoto, 1990). These regions in the brain stem overlap the location of neurons that respond rhythmically during licking (Travers et al., 2000) or to cortical microstimulation (Moriyama, 1987; cat: Sahara et al., 1996) as well as the location of neurons that project to 12 (Travers and Norgren, 1983; cat: Sahara et al., 1996). Descending projections from limbic structures to the midbrain provide additional pathways through which forebrain structures involved in feeding can ultimately influence 12 motoneurons (White, 1986). Midbrain Projections In the midbrain, a few cells in the contralateral reticular formation project to 12 as demonstrated with HRP (Aldes, 1980; Aldes and Boone, 1984; Travers and Norgren, 1983). A similar study (opossum: Panneton and Martin, 1979), however, localized midbrain projections primarily from within the central gray. Some controversy exists as to whether Me5 projects directly to 12 via Probst’s tract (see Lowe, 1981). Although this projection was evident using degeneration techniques (cat: Mizuno and Sauerland, 1970; Szentagothai, 1948), relatively few Me5 cells were labeled in the retrograde
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HRP experiments. This projection, however, may be to dendrites of 12 motoneurons extending laterally into the adjacent RF (Matesz, 1981; Ruggiero et al., 1982) and thus provide a substrate for proprioceptive interactions between the muscles of mastication and lingual muscles (Lowe, 1981). Proprioceptive information from jaw muscles may also reach 12 through the supratrigeminal region in the pons (Mizuno, 1970). This region receives monosynaptic input from Me5 (Matesz, 1981) and projects to 12 (Travers and Norgren, 1983). Pontine Projections Several distributions of neurons in proximity to Mo5 project to 12. These include the ventral PB and intertrigeminal nuclei (bilaterally), the KF (ipsilaterally), and the supratrigeminal area (Aldes, 1980; Borke et al., 1983; Fay and Norgren, 1997c; Luo et al., 2001; Saper and Loewy, 1980; Travers and Norgren, 1983). The KF, part of the lateral tegmental group of catecholaminecontaining cells (Stevens et al., 1982), may be a source of NE projections to 12 (Levitt and Moore, 1979). Another source of pontine CA projections to 12 is from the SubC (Aldes, 1990). Injections of HRP into 12 labeled scattered cells ventral to locus coeruleus and medial to Mo5 in the SubC and injections of tritiated amino acids into SubC produced reciprocal anterograde label within 12. Projections from the supratrigeminal region were prominent to the dorsal subdivision of 12 (Luo et al., 2001). A subpopulation of supratrigeminal neurons stained for GABA or glycine as did other projection neurons to 12 from neuron groups near Mo5 (Li et al., 1997). A primarily ipsilateral projection from Pr5 reaches 12 from a distribution of relatively large cells (30–50 μm) located dorsomedially in the caudal two-thirds of the nucleus (Aldes, 1980; Aldes and Boone, 1985; Borke et al., 1983; Travers and Norgren, 1983). Pr5 is topographically organized such that somatosensory afferent axons from the tongue project to the dorsomedial region (Hamilton and Norgren, 1984). Thus, somatosensory input from the tongue can influence hypoglossal motoneurons through disynaptic pathways. Similarly, descending cortical fibers from the face region of somatosensory cortex can influence lingual motoneurons via Pr5 (discussed in Aldes and Boone, 1985). Medullary Projections Reticular formation The majority of cells projecting to 12 originate from the medullary RF (Aldes, 1980; Borke et al., 1983; Borke and Nau, 1985; Cooper and Fritz, 1981; Dobbins and Feldman, 1995; Fay and Norgren 1997c; Travers and Norgren, 1983; Zhang and Luo, 2003; cat: Basbaum et al., 1978; Holstege et al., 1977). The central core of the medullary brain stem, encompassing most
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of the Gi, is not involved in these direct projections; however, there are direct projections from the midline raphe and ventral subdivisions of the gigantocellular and paragigantocellular nuclei (Aldes et al., 1989; Henry and Manaker, 1998; Manaker and Tischler, 1993; Travers and Rinaman, 2002; cat: Bobillier et al., 1976). Dorsal medulla In the dorsal medulla, reticular neurons projecting to 12 form a continuous column along the rostrocaudal axis. At the spinomedullary junction, projection cells are bilaterally distributed lateral to 12 in the MdD and MdV (less). Rostral to 12, these cells are bilaterally distributed in the IRt and, to a lesser extent, in the PCRt. It is unclear if there is spatial segregation of reticular neuron projecting to different lingual motoneurons. Neurons projecting to lingual retractor motoneurons have been described as either dorsal to those projecting to protrudors (Dobbins and Feldman, 1995) or ventral (Fay and Norgren, 1997c). Some RF neurons project to more than one oromotor nucleus (Amri et al., 1990; Li et al., 1993b; Popratiloff et al., 2001), and some RF interneurons project to multiple pools of 12 motoneurons (Travers and Rinaman, 2002). Double-label studies with injections of retrograde fluorescent markers into combinations of 12, Mo5, and 7 double-labeled approximately 5–6% of labeled RF neurons, scattered among single projection cells. The medullary RF is a likely source of cholinergic input to 12 (Connaughton et al., 1986; Davidoff and Irintchev, 1986). Cells in the medullary RF projecting to 12 also stain positively for GABA and glycine (Li et al., 1997). The dorsal medullary RF projections to 12 are likely involved in the lingual component of consummatory behavior. Neurons lateral to 12 are active during both licking and swallowing (Gestreau et al., 1996; Ono et al., 1998; Travers et al., 2000), and the area subjacent to the caudal SOL is part of the central pattern generator for swallowing (Jean, 2001). Projection neurons more rostral in the medulla in the IRt are also active during licking (Travers et al., 2000) and muscimol infusions into this region suppress this behavior (Chen et al., 2001). Ventral medulla Neurons in the ventral RF form a critical substrate for respiratory rhythmogenesis (reviewed in Rekling and Feldman, 1998) and direct projections to 12 have been demonstrated in both rat (Lipski et al., 1994) (Fig. 8) and cat (Ono et al., 1994). In the rat, neurons active during both inspiration and expiration were found quite far rostral in the ventrolateral medulla, just caudal to the facial nucleus, and appeared to overlap with the rostral ventrolateral reticular formation (Ezure et al., 1988). In cat, some neurons in the ventral medulla project to both the phrenic nucleus and 12 (Ono et al., 1994).
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FIGURE 8 Reconstruction of an intracellularly filled respiratoryrelated neuron in the ventral medulla show axons (no dendrites) that ramify in both dorsal and ventral subdivisions of 12 and the nucleus of the solitary tract. Arrow indicates spinally projecting axonal branch. Abbreviations: PY, pyramidal tract; SOL, nucleus of the solitary tract; 12, hypoglossal nucleus. From Lipski et al., 1994.
Neurons in the paragigantocellular and ventral gigantocellular nuclei also project to 12. These neurons were not well-labeled using HRP (Borke et al., 1983; Travers and Norgren, 1983; Yang et al., 1995), but were somewhat more visible using Fluorogold (Manaker and Tischler, 1993), Fast blue (Yang et al., 1995), or cholera toxin (Travers and Rinaman, 2002). Neurons in this region control muscle atonia during sleep (Hajnik et al., 2000). Stimulation of ventral and medial RF sites including the ventral gigantocellular and paragigantocellular nuclei decreased muscle tone in neck muscles and it was recently reported that stimulation of this region released an inhibitory neurotransmitter, glycine, in 12 (Kodama et al., 2000). Other reports of electrical stimulation in gigantocellular nucleus, however, in sites that appear to overlap with the previous study, suggest a primarily excitatory effect on hypoglossal motoneurons (Yang et al., 1995). Raphe nuclei Neurons in the caudal raphe (obscurus, pallidus, and magnus) project to 12 (Henry and Manaker, 1998; Manaker and Tischler, 1993). Many projection neurons, mostly from obscurus and palidus stained for 5-HT and serotonergic terminals in 12 have been identified ultrastructurally (Aldes et al., 1989). A number of 5-HT projection neurons also contained substance P; a smaller number contained enkephalin (Henry and Manaker, 1998). The physiological effects of 5-HT on 12 motoneurons are complex. Microinjections of 5-HT directly onto 12 motoneurons increased activity levels (Kubin et al.,
1992) and microdialysis delivery of 5-HT raised GG activity in an awake rat across sleep–wake cycles (Jelev et al., 2001). On the other hand, hypoglossal motoneurons were inhibited by the infusion of 5-HT in a tissue slice preparation, and response decrements also occurred to electrical or chemical excitation of the raphe (Monteau et al., 1990; Morin et al., 1990). It has been proposed that serotonin may depolarize hypoglossal motoneurons postsynaptically, but inhibit excitatory glutamatergic input presynaptically (Singer and Berger, 1996). Because raphe neurons are more active during awake states, glutamatergic inputs, possibly respiratory-related could thus be selectively suppressed and allow raphe neurons to augment hypoglossus function associated with other oromotor functions such as feeding. Binding sites for 5-HT1A and 5-HT1B receptors are widely distributed across the hypoglossal nucleus but are sparse in the ventrolateral nucleus that contains geniohyoid motoneurons (Manaker and Zucchi, 1998). Messenger RNA for 5-HT1B, 5-HT2A, and 5-HT2B receptors were found in 12 but mRNA for 5-HT1A was not (Okabe et al., 1997) Trigeminal and solitary nucleus input A second bilateral distribution of medullary cells projecting to 12 originates from the spinal trigeminal complex (Aldes, 1980; Borke et al., 1983, 1988; Borke and Nau, 1987; Pinganaud et al., 1999; Travers and Norgren, 1983). Projection neurons are clustered primarily in the dorsal part of Sp5 in the area receiving the bulk of the trigeminal afferents from the tongue (Jacquin et al., 1983), although some projection neurons are scattered throughout the nuclei. Similarly, small injections of anterograde tracers into Sp5C labeled both dorsal and ventral subdivisions of 12 (Pinganad et al., 1999). In the cat these neurons are associated with polysynaptic trigeminolingual reflexes elicited from electrical stimulation of the trigeminal nerve (reviewed in Lowe, 1981). Multiple routes from Sp5 to 12 include projections via short axon interneurons in the adjacent RF (Scheibel, 1955a, 1955b; Valverde, 1961) and by the extension of 12 motoneuron dendrites into this area (Odutola, 1976; Wan et al., 1982). A more recent study using anterograde tracers injected into Sp5 demonstrated that most RF projections terminate in the PCRt and MdD with fewer in the IRt and MdV and the least in the Gi (Zerari-Mailly et al., 2001). Cortical projections to Sp5 have also been proposed as part of a corticohypoglossal pathway in the cat (Porter, 1967). Inhibitory interneurons adjacent to 12 have also been implicated in trigeminohypoglossal reflexes (Sumino and Nakamura, 1974). Relatively few cells from the SOL project to 12. Those that do are ipsilateral, located primarily in the caudal half of the nucleus (Borke et al., 1983; Norgren, 1978; Travers and Norgren, 1983) in an area that receives
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afferents via the glossopharyngeal and vagus nerves (Contreras et al., 1982; Hamilton and Norgren, 1984; Torvik, 1956). Hypoglossal reflexes induced by stimulation of these nerves (reviewed in Lowe, 1981) may be mediated by interneurons in SOL or by direct synaptic contact via hypoglossal dendrites that extend into SOL (Odutola, 1976; Wan et al., 1982). Neuropeptide input Synaptic terminals within 12 that contained substance P and enkephalins have been described in studies combining immunohistochemistry and electron microscopy (Connaughton et al., 1986; Gatti et al., 1996; Hinrichsen and Weston, 1999). Substance P terminals appeared distributed throughout 12 (Gatti et al., 1996); however, ENK terminals were densest in the ventral compartment of 12, particularly at rostral levels that include GG muscles (Aldes, 1998). ENK endings were predominantly axodendritic; however, substance P terminals can be either axosomatic or axodendritic. In rat, it appears that substance P terminals are on interneurons (Hinrichsen and Weston, 1999), but in cat there is clear anatomical and physiological data for substance P terminals directly onto motoneuron soma and dendrites (Gatti et al., 1996, 1999). A major source of substance P is probably from the caudal raphe (Henry and Manaker, 1998). Substance P and enkephalin colocalize in different populations of 5-HT-containing cells in the caudal raphe; however, this represents a relatively sparse ENK projection (Henry and Manaker, 1998). Other sources of ENK input to 12 could come from the medullary RF, the SOL, or the PB (discussed in Connaughton et al., 1986), the spinal trigeminal complex (Borke and Nau, 1987), or sites implicated in respiratory function with projections to 12 including the KF and ventrolateral medullary RF (discussed in Aldes, 1998). Another peptide present in 12 is thyrotropinreleasing hormone (TRH) (Hokfelt et al., 1975; Kubek et al., 1983). In a tissue slice preparation, TRH depolarized 12 neurons, increased spontaneous activity, and potentiated responses evoked by iontophoresis of NMDA (Rekling, 1990, 1992). Lingual proprioceptors Another set of afferent projections to 12 are proprioceptive (Lowe, 1981). Approximately six muscle spindles were consistently observed in the GH (O’Reilly and Fitzgerald, 1990; Smith, 1989) and a smaller, more variable number in the longitudinal, HY, and GG muscles. No muscle spindles were observed in the other extrinsic or intrinsic muscles. Although few in number, these muscle spindles are proportional to those found in primates when expressed as a ratio of spindle number/muscle volume (Smith, 1989). Intrinsic muscle proprioceptor afferent fibers with cell bodies in spinal C2 and C3 travel in the ansa
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cervicalis; those from extrinsic muscles (including the GH) have their cell bodies in the jugulonodose or trigeminal ganglia and travel with 12n (O’Reilly and Fitzgerald, 1990; Neuhuber and Mysicka, 1980; dog: Chibuzo and Cummings, 1981: cat: Nazruddin et al., 1989). Fibers traveling in 12n with cell bodies located in the trigeminal or jugulonodose ganglia terminated in Sp5i and Sp5c (Fig. 5). In addition, 12n axons with cell bodies in the trigeminal ganglion also terminated in Pr5 in contrast to the central end of jugulonodose ganglion cells that terminated in the caudal SOL. Spinal afferents from the tongue terminated in lamina I and V of the cervical dorsal horn. In all cases, terminal endings were not evident within 12, indicating a lack of monosynaptic contacts (see also Lodge et al., 1973). Lingual proprioceptive input also influences other related oral motor nuclei and electrical stimulation of 12n elicits responses in both facial (Tanaka, 1975) and trigeminal motoneurons (e.g., cat: Nakamura et al., 1978; Takata et al., 1979). These projections do not constitute a complete description of all the direct influences on hypoglossal motoneurons. Extensive dendritic arborizations of 12 motoneurons throughout the adjacent RF, nucleus raphe magnus, and MLF make further monosynaptic influence from other regions of the CNS a certainty. Cerebellar influences on 12, for example, may be mediated by 12 motoneuron dendrites in the MLF (Wan et al., 1982). Projections onto 12 dendrites extending into the RF may also mediate sensory input to 12 from visual, somatosensory, and vestibular sources (Elmund et al., 1983; Mameli and Melis, 1992; Mameli et al., 1988).
SUMMARY AND CONCLUSIONS Each of the orofacial motor nuclei is organized into multiple subdivisions defined both myotopically and cytoarchitectonically. In the case of Mo5 and 12, muscle antagonists are segregated in distinct subdivisions in which motor agonists have adjacent representation. In 7, a pronounced topography related to peripheral musculature is evident. Myotopic subdivisions are further defined by the specificity of the central projections they receive. Mesencephalic 5 and the supratrigeminal region project preferentially to jaw closer motoneurons in Mo5; lateral PB and Gi project preferentially to jaw-opener motoneurons. Within 7, aural musculature motoneurons in the medial subdivision receive highly specific projections from the paralemniscal zone in the midbrain and ENK projections from the olivary pretectal nucleus. These projections contrast with those to the orally related intermediate and lateral divisions of 7 from the KF and ventral PB in the pons and the MdD in the medulla.
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Although these central projections serve to differentiate between motor nuclei subdivisions, there is also overwhelming evidence of overlap in the central projections to the oromotor nuclei that unifies them functionally. Neurons in the PCRt and IRt rostrally, the MdD and MdV caudally, and the ventral medulla have extensive projections to the oromotor nuclei, and double-label studies reveal single neurons within these fields with multiple projections. Although such projections no doubt serve as outputs from central pattern generators for mastication, swallowing, and respiration, systems, driving the oromotor nuclei may more accurately be characterized as interacting multifunctional systems (Marder, 2000; Marder and Calabrese, 1996). Such systems must not only act as pattern generators to, for example coordinate between lingual and trigeminal motoneurons during mastication but must also coordinate muscle participation between competing functions, e.g., respiration and swallowing. The substrates appear multifunctional in that neurons involved in patterning one function, e.g., licking may also participate in another, e.g., swallowing (Ono et al., 1998; Travers et al., 2000). Following the progress made in invertebrate systems (Marder, 2000; Marder and Calabrese, 1996), the identification of neuromodulators within the afferent pathways driving oromotoneurons as well as the motoneurons themselves provides future direction for exploring complex oromotor function.
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13 Central Nervous System Control of Micturition GERT HOLSTEGE Department of Anatomy and Embryology Faculty of Medical Sciences, University of Groningen Groningen, The Netherlands
Micturition does not take place at random, but is directly related to the survival of the individual or species. An individual animal micturates only when the environment is relatively safe, because the animal is vulnerable during the release of urine. Moreover, many animals use urine as a marker for territorial demarcation or sexual attraction (by leaving a scent trace a female lets the males know that she is in estrus). These facts explain why micturition is under strong control of the emotional motor system (Blok and Holstege, 1996, Holstege, 1998). The present chapter discusses the bladder and bladder sphincter motoneurons, their regulation by the sacral cord, and how the sacral cord centers are regulated by distinct regions in brain stem, diencephalon, and cortex. Micturition depends on a coordinated action between the smooth (detrusor) muscle of the bladder and the striated external urethral sphincter (EUS), which closes the bladder outlet. During the storage of urine, the detrusor muscle remains relaxed and the EUS is tonically contracted. This activation pattern is reversed during micturition: the EUS relaxes and the bladder contracts, resulting in expulsion of urine. The motoneurons of both bladder and EUS are located in the sacral spinal cord. Their mutual coordination, however, takes place in the pontine micturition center (PMC) in the brain stem. For example, transection of the spinal cord in animals as well as in humans interrupts the descending fibers from the PMC to the sacral cord. The result is dyssynergic micturition, which means that contraction of the bladder is accompanied by simultaneous contraction of the sphincter. Consequently, in
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order to expel urine through the tonically closed urethral sphincter, the bladder has to produce an extremely high intravesical pressure. The result is a thick bladder wall and a small bladder capacity, the so-called overflow bladder. Brain lesions rostral to the pons never result in bladder–sphincter dyssynergia, but in urge incontinence, i.e., hyperactivity of the bladder and inability to delay voiding. Apparently, the PMC coordinates micturition as such, but regions rostral to the pons determine the beginning of micturition.
MOTONEURONS INNERVATING BLADDER AND URETHRAL SPHINCTER Bladder Motoneurons The smooth musculature forming the detrusor muscle of the bladder and the smooth musculature of the descending colon is innervated, via the pelvic nerve, by parasympathetic preganglionic motoneurons in the sacral intermediolateral cell group or sacral parasympathetic nucleus (SPN). In rat the SPN is located in the L6–S1 spinal segments (Nadelhaft and Booth, 1984). In cat (Morgan et al., 1979) and human the SPN is located in the S2–S3 spinal cord, and in cat a viscerotopic organization has been demonstrated wherein the colon is innervated primarily by cells in a dorsal band and the urinary bladder by cells in a lateral band (Nadelhaft et al., 1980). There is also a spatial segregation within the SPN in rat, in which penis motoneurons
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are located rostral (rostral L6–rostral S1) to the bladder motoneurons (caudal L6-caudal S1; Banrezes et al., 2002). Sympathetic preganglionic motoneurons, located in the intermediolateral cell group of the upper lumbar cord (L1–L4), also innervate the bladder. Their fibers run via the pelvic and hypogastric nerves to have direct access to the bladder or to have indirect access via connections with the paravesical ganglia of the parasympathetic system. Sympathetic fibers have inhibitory effects on the detrusor muscle and excitatory effects on the smooth musculature of the urethra and the base of the bladder, perhaps via suppression of transmission between parasympathetic preganglionic and postganglionic neurons within the pelvic ganglia (see De Groat et al., 1999, for review).
1985), and human (Schrøder, 1981) pelvic floor motoneurons are located in one nucleus on the ventrolateral border of the ventral horn in the upper sacral cord. In these species the motoneurons innervating the anal sphincter are located dorsomedially, and those innervating the bladder sphincter are located ventrolaterally. In the pig (Blok et al., 1996) and Mongolian gerbil (Ulibarri et al., 1995), anal sphincter motoneurons are located in a completely different location, dorsal and dorsolateral to the central canal, in the area of the intermediomedial cell group (IMM) (Fig. 1). In nonexperimental sections, the ON can be recognized by its wealth of longitudinally oriented dendrites (Dekker et al., 1973), indicating that the motoneurons have many connections within the nucleus itself. In the rat, in the dorsolateral nucleus, as well as in the spinal nucleus of the bulbocavernosus, so-called gap junctions have been demonstrated, the number of which were influenced by testosterone levels (Matsumoto et al., 1989). Such gap junctions could not be detected in the ON of the cat (Takahashi and Yamamoto, 1979). ON motoneurons belong to a distinct class of motoneurons. They belong to neither somatic nor autonomic (sympathetic and parasympathetic) motoneurons. Similar to somatic motoneurons ON motoneurons innervate striated muscles of the pelvic floor, including the urethral and anal sphincters (cat: Sato et al., 1978; human: Schrøder, 1981), and are under voluntary control. Animals and humans can voluntarily contract the two sphincters, although not separately. Arguments against ON motoneurons to be somatic are: (1) in contrast to most other motoneuronal cell groups, they do not receive direct cortical afferents (Iwatsubo et al., 1990); (2) they play a role in “autonomic” motor activities such as micturition, ejaculation, defecation, and parturition; (3) they receive direct hypothalamic afferents (Holstege, 1987); (4) they have an appearance similar to that of autonomic motoneurons; (5) unlike all other somatic motoneurons, they are not affected in
Pelvic Floor Motoneurons The pudendal nerve innervates the intrinsic external urethral sphincter, which forms part of the pelvic floor musculature. In most vertebrates the pelvic floor motoneurons are located in the so-called nucleus of Onuf (ON), after Onufrowicz, who called himself Onuf, and who described this nucleus already in 1899. Onuf thought that the nucleus was involved in sexual activity and not in continence for feces and urine. For a long time ON was called group Y (Romanes, 1951), and only 25 years ago ON has been identified as containing pelvic floor motoneurons (Sato et al., 1978). In rat (Schrøder, 1980; McKenna and Nadelhaft, 1986), ON consists of two separate nuclei. The dorsolateral nucleus contains motoneurons innervating the ischiocavernosus muscle and the external urethral sphincter and differs between male and female rats (Jordan et al., 1982). The dorsomedial nucleus innervates the bulbospongiosus muscle and the anal sphincter (McKenna and Nadelhaft, 1986). In other species like hamster (Gerrits et al., 1997), cat (Sato et al., 1978; Kuzuhara et al., 1980; Ueyama et al., 1984), dog (Kuzuhara et al., 1980), monkey (Roppolo et al.,
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FIGURE 1 Schematic overview of the pelvic floor motoneurons in various mammalian species. A, external anal sphincter; U, external urethral sphincter.
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amyotrophic lateral sclerosis, (Mannen et al., 1977); and (6) they degenerate in Shy–Dräger syndrome (Mannen et al., 1982; Chalmers and Swash, 1987), which is characterized by degeneration of autonomic (sympathetic and parasympathetic) but not somatic motoneurons. In conclusion, ON motoneurons have properties of both somatic and autonomic motoneurons and occupy a position in between these two kinds of motoneurons.
SACRAL CORD MICTURITION REFLEXES Behavioral evidence for the existence of sacral micturition reflexes was given by De Groat et al. (1975, 1981), who observed that micturition as well as defecation are elicited in neonatal kittens when the mother licks the perineal region. This is the primary stimulus for micturition, because separation of the kittens from the mother results in urinary retention. The perineal-tobladder reflex is quite prominent during the first 4 postnatal weeks, after which it becomes less effective and usually disappears by the age of 7–8 weeks, the approximate age of weaning. Thoracic cord transections of the spinal cord did not abolish the perineal-tobladder reflex, indicating that it is a sacral cord reflex. After 7–8 weeks the bladder-to-bladder reflexes, which involve supraspinal structures, have replaced the perineal-to-bladder reflex. Transection of the spinal cord in older kittens or adult cats causes reemergence of perineally induced micturition within 1–2 weeks. The same is true in humans in which this spinal cord reflex system is functionally nonexistent, except in patients with spinal cord transection rostral to the sacral cord. Apparently, in adult animals and humans pathways exist within the sacral cord that can produce bladder and sphincter contractions, although these contractions are not necessarily well coordinated (i.e., they are dyssynergic).
BRAIN STEM–SPINAL CORD PATHWAYS COORDINATE BLADDER AND SPHINCTER MOTONEURONS Diffuse Descending Systems The SPN and the ON play a role not only in micturition but also in several other mechanisms. For example, level-setting mechanisms (see Holstege, 1991, for review) send fibers to almost all parts of the spinal cord including SPN and ON motoneurons. These serotonergic and other projections from the caudal raphe nuclei and the adjoining ventral tegmentum of the
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medulla to the SPN and the ON are sometimes mistaken for specific micturition control systems. Also the noradrenergic projections from the dorsolateral pontine tegmentum (locus coeruleus and nucleus subcoeruleus) and the dopamine projections from the A11 cell group in the rostral mesencephalon (Holstege et al., 1996) take part in very diffuse descending systems but seem not to play a specific role in micturition control. Nevertheless, studies of serotonin (5-HT) receptors and reuptake mechanisms might represent targets for the development of new drugs for treatment of patients suffering from bladder (detrusor) overactivity and urinary incontinence. One might expect, however, many side effects of these drugs, because of the diffuse nature of these projections (DeGroat, 2002).
Abdominal Pressure Control Systems The pelvic floor forms the bottom of the abdominal cavity. Increased abdominal pressure is needed for strong expiration, vocalization, vomiting, and parturition, and the pelvic floor plays an important role in these motor activities. It is not surprising, therefore, that the nucleus retroambiguus, which controls abdominal pressure by innervating abdominal wall muscle motoneurons, also innervates ON motoneurons (Holstege and Tan, 1987) (Fig. 2).
Micturition Control in Animals Since the work of Barrington (1925) it is known that a crucial structure of the micturition reflex is located in the dorsolateral pontine tegmentum, because bilateral lesions in this area in the cat result in urinary retention. In the cat two different pontine projection systems have been identified. One group of neurons in the medial part of the dorsolateral pons projects to the parasympathetic bladder motoneurons in the sacral intermediolateral cell column (Loewy et al., 1979, in rat; Holstege et al., 1979, 1986, in cat) (Fig. 3 left), whereas neurons in the lateral part of the dorsolateral pons specifically project to the nucleus of Onuf (Holstege et al., 1979, 1986; Fig. 3 right). The medial cell group was called M-region (M = medial) and the lateral cell group L-region (L = lateral). The M-region is also called the pontine micturition center (PMC) or Barrington’s nucleus. Ultrastructurally, it has been demonstrated that the PMC projection to the bladder parasympathetic motoneurons in the sacral cord is monosynaptic and excitatory (Blok and Holstege, 1997). In accordance with these findings, electrical and chemical stimulation in the PMC in the cat produces a steep rise in the intravesical pressure and an immediate and sharp decrease in the urethral pressure and pelvic floor electromyogram
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Phrenic motoneurons C5-C6 External intercostal motoneurons T1-T13 Abdominal muscle motoneurons T5-L3 Onuf (pelvic floor) motoneurons S1-S2 FIGURE 2 Schematic overview of the pathways controlling respiration and abdominal pressure. For the sake of clarity the few ipsilaterally descending pathways have not been indicated.
(Holstege et al., 1986, in cat; Mallory et al., 1989, in rat) (Fig. 4). In all likelihood, this decrease is the result of the PMC projection to GABA- and glycinergic interneurons in the sacral intermediomedial cell group (Blok et al., 1997a; Sie et al., 2001). Retrograde tracing studies with the pseudorabies virus have shown that this area contains interneurons projecting to the nucleus of Onuf (Nadelhaft and Vera, 1996), and electrical stimulation in the intermediomedial cell column results in an inhibition of the EUS via GABAergic interneurons in the intermediomedial cell group (Blok et al., 1998). Bilateral lesions in the PMC result in total urinary retention leading to depressed detrusor activity and increased bladder capacity (Griffiths et al., 1990; Holstege et al., 1986). In rats, unilateral chemical lesions of the PMC attenuate the bladder response (Mallory et al., 1989). Stimulation in the L-region results in strong excitation of the pelvic floor musculature and an increase in the urethral pressure (Holstege et al., 1986) (Fig. 5). Bilateral lesions in the L-region give rise to an inability to store urine; bladder capacity is reduced and urine is expelled prematurely by excessive detrusor activity, accompanied by urethral relaxation. Outside the episodes of detrusor activity, the urethral pressure is
not depressed below normal values (Mallory et al., 1989). These observations suggest that during the filling phase the L-region has a continuous excitatory effect on the nucleus of Onuf resulting in inhibition of urethral relaxation coupled with detrusor contraction. Perhaps the L-region should be considered as a “continence” center, especially since the PET scan results suggest the existence of such a center in humans (see below).
AFFERENT SYSTEMS Peripheral Afferent Nerves Most afferent fibers from the bladder enter the sacral cord via the pelvic nerve. The peripheral fibers of the dorsal root ganglia neurons of the pelvic nerve contact the bladder wall mechanoreceptors. The proximal fibers, many of which contain calcitonin gene-related peptide (CGRP) (Chung et al., 1993), enter Lissauer’s tract and terminate mainly in Rexed’s (1954) laminae I, V, VII, and X of the lumbosacral spinal cord at segments L4–S2 (Morgan et al., 1981). The majority of these afferents are thin myelinated and unmyelinated axons, and their
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Spinal Cord-Brain Stem Pathways Involved in the Micturition Reflex To empty the bladder at an appropriate time, bladder filling information from sensory neurons in the sacral cord must reach the PMC. To a limited extent in rat (Ding et al., 1997; Blok and Holstege, 2000), but not in cat (Blok et al., 1995), the lumbosacral cord projects directly to PMC neurons. This raises the question of what other area relays bladder filling information to the PMC. The micturition reflex is not abolished by precollicular decerebration (Tang and Ruch, 1956), which means that lumbosacral projections to forebrain areas, such as the thalamus and the hypothalamus, are not essential for this reflex. However, the very strong projections from the lumbosacral cord to the lateral and dorsal parts of the mesencephalic periaqueductal gray (PAG) probably play a much more important role (Blok et al., 1995; VanderHorst et al., 1996) (Fig. 6). The lateral PAG is the only brain stem structure known to project specifically to the PMC (Blok and Holstege, 1994). Moreover, stimulation of afferent bladder nerves in the rat evokes short latency potentials (13 ± 3 ms) in the most caudal PAG, while much longer latency potentials (42 ± 7 ms) are found in the PMC (Noto et al., 1991). In the cat electrical stimulation of the PAG has been shown to evoke complete micturition (Skultety, 1959), facilitate bladder reflexes, and reduce bladder capacity (Kruse et al., 1990). The PAG has also been implicated in the control of micturition in humans (see below).
FIGURE 3 Bright-field photomicrographs of autoradiographs showing the tritiated leucine injection areas and dark-field photomicrographs showing the spinal distributions of labeled fibers after an injection in the area of the M-region (on the left) and after an injection in the area of the L-region (on the right) in the cat. Note the dense distribution of labeled fibers to the sacral intermediolateral (parasympathetic motoneurons) and intermediomedial cell groups after an injection in the M-region (S2 segment on the left). Note also the pronounced projection to the nucleus of Onuf (arrows in the S1 segment) in the case with an injection in the L-region (right).
conduction velocities are in the A∂ and C fiber range, respectively (Hulsebosch and Coggeshall, 1982). Most A∂ fibers originate from slowly adapting mechanoreceptors in the bladder wall, because excitation of these fibers results in activation of the micturition reflex. In all likelihood, the A∂ fibers are the peripheral afferent fibers for this reflex (DeGroat et al., 1982; Mallory et al., 1989), because the unmyelinated C fibers in the pelvic nerve do not respond to distention and contraction of the urinary bladder (Jänig and Morrison, 1986).
FOREBRAIN INVOLVEMENT IN THE CONTROL OF MICTURITION The forebrain is not essential for the basic micturition reflex, but it is thought to determine the beginning of micturition (Blaivas, 1982). In the cat, stimulation of forebrain structures, such as the anterior cingulate gyrus, the preoptic area of the hypothalamus, the amygdala, the bed nucleus of the stria terminalis, and the septal nuclei, have been shown to elicit bladder contractions (Gjone and Setekleiv, 1963; Gjone, 1966). Although most of these regions send fibers to the PAG and other parts of the brain stem (see Holstege, 1991, for review), only the preoptic area has been shown to project directly to the PMC (Holstege, 1987, in cat, Rizvi et al., 1994, in the rat). One might speculate that the projections from the many limbic structures to the PAG are tools of the emotional motor system for giving a “safe signal” to the PMC to start micturition and that the direct projection of the preoptic area to the PMC controls micturition for sexual and territorial marking. Figure 7 shows a schematic overview of all the pathways that are thought to play a role
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FIGURE 4 Recordings of urethral pressure, pelvic floor EMG, intravesical pressure, and stimulus timing during M-region stimulation in the cat. Note the immediate fall in urethral pressure and pelvic floor EMG after the beginning of the stimulus and the steep rise in the intravesical pressure about 2 s after the beginning of the stimulus. This pattern mimics complete micturition (from Holstege et al., 1986).
FIGURE 5 Recordings of urethral pressure, pelvic floor EMG, intravesical pressure, and stimulus timing during L-region stimulation in the cat. Note the immediate increase in the urethral pressure and the pelvic floor EMG at the beginning of each period of stimulation (from Holstege et al., 1986).
in micturition control. The PET studies of Blok et al. (1997b, 1997c, 1998a, 1998b) suggest that this might also be true in humans (see below).
MICTURITION CONTROL IN HUMANS Blok and Holstege have demonstrated that with
respect to pelvic floor activities such as micturition in men and women (Blok et al., 1997a, 1998b), as well as in voluntary contraction (Blok et al., 1997c), the supraspinal control systems seem to be similarly organized in humans and cats. Of the volunteers that were asked to micturate, while lying with their heads in the PET scan, half of them could satisfactorily perform the task. In this group the same regions as those observed in the cat
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FIGURE 6 Schematic overview of the location of the pelvic and pudendal primary afferents, the PAG projecting neurons, and the sacral parasympathetic preganglionic motoneurons (from VanderHorst et al., 1996).
were found to be active in humans, i.e., an area in the dorsal pontine tegmentum, probably representing the PMC (Fig. 8, left), an area in the PAG (Fig. 9, left), and one in the hypothalamus or the preoptic region (Fig. 9, right). The other group of volunteers, who were willing to micturate, but, for emotional reasons, could not perform, tightly contracted their pelvic floor. The PET scan results in these volunteers revealed an area in the ventrolateral pontine tegmentum, which might represent the L-region or continence center (Fig. 8, right). With respect to the voluntary contraction of the pelvic floor it was found that none of the micturition control regions were active, but only the motor cortical regions that were directly involved in voluntary pelvic floor contraction (Blok et al., 1997c). It also means that the motor cortical system is completely separate from the basic micturition control system that takes part in the emotional motor system (Holstege, 1998). The PET scan results in men and women (Blok et al., 1997b, 1997c, 1998a, 1998b) point to two cortical areas involved in micturition. The right dorsolateral prefrontal cortex is active when micturition takes place and also when the volunteers are asked to micturate, but cannot perform. Another part that might play a role in micturition is the rostral part of the right cingulate gyrus, which receives strong afferent connections from many parts of the limbic system. It is interesting that those parts of the rostral cingulate gyrus that are active during successful micturition differ from those that are activated during nonsuccessful micturition (Fig. 10). Conversely, activation in the right anterior cingulate gyrus was significantly decreased during voluntary withholding of urine (Blok et al., 1997b). Possibly, activation of the prefrontal cortex and the anterior cingulate gyrus are not specifically involved in micturition, but
in general mechanisms, such as attention and response selection (Pardo et al., 1990) or emotional distress and pain (Drossman et al., 2003). Forebrain lesions including the anterior cingulate gyrus are known to cause urge incontinence (Andrew and Nathan, 1966), which might be due to an attention deficit that interferes with the patient’s ability to recognize a full bladder. A striking observation of the PET studies of Blok et al. (1997b, 1997c, 1998b) was that the control areas were found predominantly on the right side of the brain and brain stem (cortex and pons), which corresponds with studies reporting that urge incontinence is correlated with lesions in the right hemisphere (Kuroiwa et al., 1987).
CONCLUSIONS The organization of the central nervous system control of the basic micturition reflex is probably the same in humans and cats, but differs from that in rat. Several levels of the central nervous system are involved in the control of micturition. Sensory information concerning bladder filling is relayed, via the pelvic nerve and dorsal root ganglion cells, to the sacral cord, where second-order sensory neurons are located. These neurons convey the information to the caudal PAG where it is processed and filtered. When the amount of urine in the bladder makes voiding desirable, PAG neurons activate the premotor interneurons in the Mregion, which, via long descending fibers to the bladder motoneurons in the sacral cord, let micturition take place. Projections from many limbic structures to the PAG, and the projections from the preoptic area to the M-region, may influence this spinal–brain stem–spinal reflex and may determine the beginning of micturition.
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FIGURE 7 On the left a schematic overview of the micturition pathways with the ascending and descending components in the cat. On the right an overview of the possible pathways involved in continence control. The question mark indicates that it is not yet known what controls the L-region, although the structures involved, in all likelihood, are located in the limbic system.
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FIGURE 8 PET scan results during normal micturition (left) and nonsuccessful micturition, leading to “emotional” contraction of the pelvic floor (right).
FIGURE 10 (Top) PET scan results showing activation in the anteFIGURE 9 PET scan results showing on the left activation in the area of the periaqueductal gray (arrow) and on the right in the hypothalamus.
References Andrew, J., and Nathan, P. W. (1964). Lesions of the anterior frontal lobes and disturbances of micturition and defecation. Brain 87, 233–262. Banrezes, B., Andrey, P., Maschino, E., Schirar, A., Peytevin, J., Rampin, O., and Maurin, Y. (2002). Spatial segregation within the sacral parasympathetic nucleus of neurons innervating the bladder or the penis of the rat as revealed by three-dimensional reconstruction. Neuroscience 115, 97–109. Barrington, F. J. F. (1925). The effect of lesions of the hind- and midbrain on micturition in the cat. Q. J. Exp. Physiol. Cogn. Med. 15, 81–102. Blaivas, J. G. (1982). The neurophysiology of micturition: A clinical study of 550 patients. J. Urol. 127, 958–963. Blok, B. F. M., DeWeerd, H., and Holstege, G. (1995). Ultrastructural evidence for the paucity of projections from the lumbosacral cord to the M-region in the cat: A new concept for the organization of the micturition reflex with the periaqueductal gray as central relay. J. Comp. Neurol. 359, 300–309. Blok, B. F. M., DeWeerd, H., and Holstege, G. (1997a). The pontine micturition center projects to sacral cord GABA immunoreactive neurons in the cat. Neurosci. Lett. 233, 109–112. Blok, B. F. M., and Holstege, G. (1994). Direct projections from the periaqueductal gray to the pontine micturition center (Mregion): An anterograde and retrograde tracing study in the cat: Neurosci. Lett. 166, 93–96.
rior cingulate gyrus, comparing successful micturition with voluntary withholding of urine. (Bottom) PET scan results comparing unsuccessful micturition with voluntary withholding of urine. Note that a different part of the cingulate gyrus is active during both activities.
Blok, B. F. M., and Holstege, G. (1996). Neuronal control of micturition and its relation to the emotional motor system. Prog. Brain Res. 107, 113–126. Blok, B. F. M., and Holstege, G. (1997). Ultrastructural evidence for a direct pathway from the pontine micturition center to the parasympathetic preganglionic motoneurons of the bladder of the cat. Neurosci. Lett. 222, 195–198. Blok, B. F. M., and Holstege, G. (2000). The pontine micturition center in rat receives direct lumbosacral input: An ultrastructural study. Neurosci. Lett. 282, 29–32. Blok, B. F. M., Maarseveen, J. T. P. W., and Holstege, G. (1998a). Electrical stimulation of the sacral dorsal gray commissure evokes relaxation of the external urethral sphincter in the cat. Neurosc. Lett. 249, 68–70. Blok, B. F. M., Roukema, G., Geerdes, B., and Holstege, G. (1996). Location of external anal sphincter motoneurons in the sacral cord of the female domestic pig. Neurosci. Lett. 216, 203–206. Blok, B. F. M., Sturms, L. M., and Holstege, G. (1997b). A PET study on cortical and subcortical control of pelvic floor musculature in humans. J. Comp. Neurol. 389, 535–544. Blok, B. F. M., Sturms, L. M., and Holstege, G. (1998b). Brain activation during micturition in women. Brain 121, 2033–2042. Blok, B. F. M., Willemsen, A. T. M., and Holstege, G. (1997c). A PET study on the brain control of micturition in humans. Brain 120, 111–121. Chalmers, D., and Swash, M. (1987). Selective vulnerability of urinary Onuf motoneurons in Shy–Dräger syndrome. J. Neurol. 234, 259–260.
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Chung, K., Lee, W. T., and Park, M. J. (1993). Spinal projections of pelvic visceral afferents of the rat: A calcitonin gene-related peptide (CGRP) immunohistochemical study. J. Comp. Neurol. 337, 63–69. De Groat, W. C. (2002). Influence of central serotonergic mechanisms on lower urinary tract function. Urology 59(5 Suppl.), 30–36. De Groat, W. C., Booth, A. M., Milne, R. J., and Roppolo, J. R. (1982). Parasympathetic preganglionic neurons in the sacral spinal cord. J. Auton. Nerv. Syst. 523–543. De Groat, W. C., Douglas, J. W., Glass, J., Simonds, W., Weimer, B., and Werner, P. (1975). Changes in somatovesical reflexes during postnatal development in the kitten. Brain Res. 94, 150–154. De Groat, W. C., Downie, J. W., Levin, R. M., Long Lin, A. T., Morrison, J. F. B., Nishizawa, O., Steers, W. D., and Thor, K. (1999). Basic neurophysiology and neuropharmacology. In: “Incontinence” (Abrams, P., Khoury, S., and Wein, A., Eds.), pp. 107–154. Plymbridge Distributors, Ltd, Plymouth. De Groat, W. C., Nadelhaft, I., Milne, R. J., Booth, A. M., Morgan, C., and Thor, K. (1981). Organization of the sacral parasympathetic reflex pathways to the urinary bladder and large intestine. J. Auton. Nerv. Syst. 3, 135–160. Dekker, J. J., Lawrence, D. G., and Kuypers, H. G. J. M. (1973). The location of longitudinally running dendrites in the ventral horn of cat spinal cord. Brain Res. 51, 319–325. Ding, Y. Q., Zheng, H. X., Gong, L. W., Lu, Y., Zhao, H., and Qin, B. Z. (1997). Direct projections from the lumbosacral spinal cord to Barrington’s nucleus in the rat: A special reference to micturition reflex. J. Comp. Neurol. 389, 149–160. Drossman, D. A., Ringel, Y., Vogt, B. A., Leserman, J., Lin, W., Smith, J. K., and Whitehead, W. (2003). Alterations of brain activity associated with resolution of emotional distress and pain in a case of severe irritable bowel syndrome. Gastroenterology 124, 754–761. Gerrits, P. O., Sie, J. A. M. L., and Holstege, G. (1997). Motoneuronal location of the external urethral and anal sphincters: A single and double labeling study in the male and female golden hamster. Neurosci. Lett. 226, 191–194. Gjone, R. (1966). Excitatory and inhibitory bladder responses to stimulation of “limbic,” diencephalic and mesencephalic structures in the cat. Acta Physiol. Scand. 66, 91–102. Gjone, R., and Setekleiv, J. (1963). Excitatory and inhibitory bladder responses to stimulation of the cerebral cortex in the cat. Acta Physiol. Scand. 59, 337–349. Griffiths, D., Holstege, G., De Wall, H., and Dalm, E. (1990). Control and coordination of bladder and urethral function in the brain stem of the cat. Neurourol. Urodyn. 9, 63–82. Holstege, G. (1987). Some anatomical observations on the projections from the hypothalamus to brainstem and spinal cord: An HRP and autoradiographic tracing study in the cat. J. Comp. Neurol. 260, 98–126. Holstege, G. (1991). Descending motor pathways and the spinal motor system: Limbic and non-limbic components. Prog. Brain Res. 107, 307–421. Holstege, G. (1998). The emotional motor system in relation to the supraspinal control of micturition and mating behavior. Behav. Brain Res. 92, 103–109. Holstege, G., Griffiths, D., de Wall, H., and Dalm, E. (1986). Anatomical and physiological observations on supraspinal control of bladder and urethral sphincter muscles in the cat. J. Comp. Neurol. 250, 449–461. Holstege, G., Kuypers, H. G. J. M., and Boer, R. C. (1979). Anatomical evidence for direct brain stem projections to the somatic motoneuronal cell groups and autonomic preganglionic cell groups in cat spinal cord. Brain Res. 171, 329–333. Holstege, G. and Tan, J. (1987) Supraspinal control of motoneurons innervating the striated muscles of the pelvic floor including urethral and anal sphincters in the cat. Brain 110, 1323–1344.
Holstege, J. C., Van Dijken, H., Buijs, R. M., Goedknegt, H., Gosens, T., and Bongers, C. M. (1996). Distribution of dopamine immunoreactivity in the rat, cat and monkey spinal cord. J. Comp. Neurol. 376, 631–652. Hulsebosch C. E., Coggeshall R. E. (1982). An analysis of the axon populations in the nerves to the pelvic viscera in the rat. J Comp Neurol. 211, 1–10. Iwatsubo, T., Kuzuhara, S., Kanemitsu, A., Shimada, H., and Toyokura, Y. (1990). Corticofugal projections to the motor nuclei of the brainstem and spinal cord in humans. Neurology 40, 309–312. Jänig, W., and Morrison, J. F. (1986). Functional properties of spinal visceral afferents supplying abdominal and pelvic organs, with special emphasis on visceral nociception. Prog. Brain Res. 67, 87–114. Jordan, C. L., Breedlove, S. M., and Arnold, A. P. (1982). Sexual dimorphism and the influence of neonatal androgen in the dorsolateral motor nucleus of the rat lumbar spinal cord. Brain Res. 249, 309–314. Kruse, M. N., Noto, H., Roppolo, J. R., and De Groat, W. C. (1990). Pontine control of the urinary bladder and external urethral sphincter in the rat. Brain Res. 532, 182–190. Kuroiwa, Y., Tohgi, H., Ono, S., and Itoh, M. (1987). Frequency and urgency of micturition in hemiplegic patients: Relationship to hemisphere laterality of lesions. J. Neurol. 234, 100–102. Kuzuhara, S., Kanazawa, I., and Nakanishi, T. (1980). Topographical localization of the Onuf’s nuclear neurons innervating the rectal and vesical striated sphincter muscles: A retrograde fluorescent double labeling in cat and dog. Neurosci. Lett. 16, 125–130. Loewy, A. D., Saper, C. B., and Baker, R. P. (1979). Descending projections from the pontine micturition center. Brain Res. 172, 533–539. Mallory, B., Steers, W. D., and De Groat, W. C. (1989). Electrophysiological study of micturition reflexes in rats. Am. J. Physiol. 257, R410–421. Mannen, T., Iwata, M., Toyokura, Y., and Nagashima, K. (1977). Preservation of a certain motoneurone group of the sacral cord in amyotrophic lateral sclerosis: Its clinical significance. J. Neurol. Neurosurg. Psychiatry 40, 464–469. Mannen, T., Iwata, M., Toyokura, Y., and Nagashima, K. (1982). The Onuf’s nucleus and the external anal sphincter muscles in amyotrophic lateral sclerosis and Shy–Drager syndrome. Acta Neurophathol. 58, 255–260. Matsumoto, A., Arnold, A. P., and Micevych, P. E. (1989). Gap junctions between lateral spinal motoneurons in the rat. Brain Res. 495, 362–365. McKenna, K. E., and Nadelhaft, I. (1986). The organization of the pudendal nerve in the male and female rat. J. Comp. Neurol. 248, 532–549. Merrill, E. G. (1970). The lateral respiratory neurones of the medulla: Their associations with nucleus ambiguus, nucleus retroambigualis, the spinal accessory nucleus and the spinal cord. Brain Res. 24, 11–28. Morgan, C., Nadelhaft, I., and De Groat, W. C. (1979). Location of bladder preganglionic neurons within the sacral parasympathetic nucleus of the cat. Neurosci. Lett. 14, 189–195. Morgan, C., Nadelhaft, I., and De Groat, W. C. (1981). The distribution of visceral primary afferents from the pelvic nerve to Lissauer’s tract and the spinal gray matter and its relationship to the sacral parasympathetic nucleus. J. Comp. Neurol. 201, 415–440. Nadelhaft, I., and Booth, A. M. (1984). The location and morphology of preganglionic neurons and the distribution of visceral afferents from the rat pelvic nerve: A horseradish peroxidase study. J. Comp. Neurol. 226, 238–245. Nadelhaft, I., DeGroat, W. C., and Morgan, C. (1980). Location and morphology of parasympathetic preganglionic neurons in the sacral
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C H A P T E R
14 Anatomical Substrates of Hypothalamic Integration RICHARD B. SIMERLY Division of Neuroscience, Oregon National Primate Research Center Oregon Health & Sciences University, Beaverton, Oregon, USA
The primary biological imperatives imposed on an organism are to first ensure its survival and second to propagate its species. To satisfy these imperatives an animal must coordinate complex physiological processes with diverse environmental conditions and elaborate appropriate adaptive responses to specific sensory cues. Thus, the maintenance of homeostasis represents a key component of biological adaptation and depends upon the successful integration of endocrine, visceral, and somatomotor control mechanisms. An extensive body of literature supports an important role for the hypothalamus in mediating this integration and the hypothalamus is generally viewed as an essential interface between the endocrine, autonomic, and somatomotor systems. In mammals the hypothalamus has been shown to regulate the cardiovascular system, the thermoregulatory responses, and the abdominal viscera, as well as defensive–aggressive behavior and ingestive behaviors that provide nutrients and water. In addition, the hypothalamus plays an essential role in assuring the survival of the species by controlling the expression of sexual and maternal behaviors. Of fundamental importance to the function of the hypothalamus is its intimate relationship with the pituitary gland and the now clearly established pathways for neural control of endocrine secretion patterns (Harris, 1948; Sawyer, 1978; Swanson, 1986). In addition, the hypothalamus has extensive connections with the major ascending and descending fiber systems that allow it to sample and influence activity in all major parts of the brain and spinal cord. Thus,
The Rat Nervous System, Third Edition
the unique relationship between the hypothalamus and the pituitary gland, together with its position in the neuraxis, make the hypothalamus the logical neurological substrate for the integration of diverse and dynamic environmental cues with the biological requirements of the individual. Although several interesting and insightful hypotheses have been advanced to explain hypothalamic function (Stellar, 1954; Szentágothai et al., 1962; Valenstein et al., 1969; Morgane, 1979), only recently has the relationship between form and function begun to be elucidated. This is due, at least in part, to the fact that cell groups in the hypothalamus are not clearly differentiated and the region is traversed by diffuse fiber systems that rank among the most complex fiber systems of the nervous system. Nevertheless, work carried out with modern neuroanatomical methods has yielded new insight into the organization of the hypothalamus and suggests that functionally distinct neural systems can be identified and studied in great detail (Swanson, 1999). This chapter presents an overview of hypothalamic anatomy and attempts to illustrate some of the ways in which functional integration is accomplished. Space does not allow for a complete description of the connections and neurochemistry of the hypothalamus, but interested readers may consult excellent reviews of these subjects by Nauta and Haymaker (1969), Palkovits and Zaborszky (1979), Zaborszky (1982), Hoffman et al. (1986), Silverman and Pickard (1983), Swanson (1986, 1987), Markakis and Swanson (1997).
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MORPHOLOGICAL ORGANIZATION OF THE HYPOTHALAMUS The hypothalamus occupies the ventral half of the diencephalon on both sides of the third ventricle and lies immediately above the pituitary gland. Dorsally, the hypothalamus is bounded along most of its length by the zona incerta, and the medial edge of the cerebral peduncle corresponds to its lateral border. Caudally, the hypothalamus merges with the periaqueductal gray and ventral tegmental area of the midbrain. The preoptic region represents the rostral-most part of the hypothalamus and is bordered dorsally by the anterior commissure and anteroventrally by the nucleus of the diagonal band of Broca. The medial preoptic area does not extend beyond the lamina terminalis, but the lateral preoptic area (see below) appears to extend medially, where it replaces the medial preoptic area at rostral levels (Simerly and Swanson, 1988). The hypothalamic parcellation scheme adopted for the third edition of The Rat Nervous System is that described in detail by Swanson (1987, 1998) and is based on the work of Gurdjian (1927) and Krieg (1932). This nomenclature and organizational scheme is the most commonly used and in general is supported by neurochemical and hodological studies. Reference to other interpretations of hypothalamic anatomy and nomenclature can be found in the work of Diepen (1962) and Bleier et al. (1979, 1985). Crosby and Woodburne (1940) recognized that the hypothalamus is best regarded as three distinct longitudinal zones (periventricular, medial, and lateral) and this perspective is supported by physiological and behavioral analyses (Swanson, 1987). The periventricular zone contains most of the neurons that project to the pituitary and is therefore primarily involved in regulating secretion of hormones from this gland. The medial zone of the hypothalamus consists of a rostrocaudally organized series of distinct cell groups that receive their major inputs from various parts of the limbic region of the telencephalon such as the septum and the amygdala. Neurons located in the lateral zone of the hypothalamus are scattered among the fibers of the medial forebrain bundle and can be viewed as a bed nucleus for this complex fiber system. Based on the organization of cell groups in the medial zone, Le Gros Clark (1938) divided the hypothalamus into four rostrocaudal levels designated the preoptic, supraoptic (replaced here by the more common term anterior), tuberal, and mammillary regions. The superposition of LeGros Clark’s regions onto Crosby and Woodburne’s zones divides the hypothalamus into 12 compartments that contain all of the recognized hypothalamic nuclei (Fig. 1). Although this
general organizational plan remains a useful framework for understanding the functional organization of the hypothalamus, certain exceptions and modifications are suggested by recent anatomical data (Swanson, 2000).
Periventricular Zone The hypothalamus represents the final common pathway for the neural control of the anterior, intermediate, and posterior lobes of the pituitary gland and most of the neurons that contain hormone-releasing hormones reside in the periventricular zone (Swanson, 1986; Markakis and Swanson, 1997). Two notable exceptions to this organizational plan are the supraoptic and accessory supraoptic nuclei, which consist of magnocellular cells that during development migrate away from the periventricular zone, and gonadotropinreleasing hormone neurons, which are derived from the olfactory epithelium and migrate to the septal and preoptic regions of the forebrain. By analogy with the motor neurons in the spinal cord, these neuroendocrine neurons have been referred to as “the motoneurons of the neuroendocrine system,” since these cells are the effector units of the neuroendocrine hypothalamus in a way similar (to the way that the) motor neurons are the effector units of neuromuscular pathways (Swanson, 1986; Swanson et al., 1987). In addition, the periventricular zone contains other cell groups that are intimately connected to the neuroendocrine cells and thereby play important roles in controlling neuroendocrine secretion. Cytoarchitectonically the periventricular zone is characterized by small, vertically oriented fusiform neurons and is traversed by a complex array of ascending and descending fibers that are part of the periventricular system connecting the periventricular zone of the hypothalamus with the midline thalamus and the midbrain periaqueductal gray (Sutin, 1966; Nauta and Haymaker, 1969). The periventricular zone is composed of the four periventricular nuclei (preoptic, anterior, intermediate (or tuberal), and posterior) and six other distinct cell groups that represent differentiated parts of this zone. Swanson (2000) has recently proposed that a hypothalamic periventricular region should also be recognized that consists of neurons in the periventricular zone that do not project to the median eminence (are not neuroendocrine) and the diffusely organized parts of the medial zone (those neurons not included in the large nuclei). Although such a region is hard to conceptualize in purely anatomical terms, the proposal that neurons in this region constitute a visceromotor pattern generator network represents a potentially important functional notion that deserves experimental attention.
IV. DIENCEPHALON, BASAL GANGLIA, AMYGDALA AND SEPTUM
Regions Preoptic
Anterior
Tuberal
LPO
LH
LH
Mammillary MCLH
LH
Lateral
Zones
MCPO PS MPA Medial
PD MPO
PePO
SCh
DMH AH
Pa
SuM
TU PHA PMV
RCh
TA
PeA
PeI
VMH Arc
LM
T M V
PMD MM
TMD
PeP
Areas and Nuclei Periventricular zone Preoptic periventricular n. (PePO) Vascular organ of the lamina terminalis (vo) Median preoptic n. (MnPO) Anteroventral periventricular n. (AVPV) Suprachiasmatic preoptic n. (PSCh)
Medial zone Medial preoptic a. (MPA) Medial preoptic n. (MPO) Anterodorsal preoptic n. (AD) Anteroventral preoptic n. (AV) Parastrial n. (PS) Posterodorsal preoptic n. (PD)
Lateral zone Lateral preoptic a. (LPO) Magnocellular preoptic n. (MCPO)
Periventricular zone Anterior periventricular n. (PeA) Suprachiasmatic n. (SCh) Paraventricular n. (Pa)
Medial zone Anterior hypothalamic a. (AHA) Anterior hypothalamic n. (AH) Retrochiasmatic area (RCh) Nucleus circularis (NC)*
Lateral zone Lateral Hypothalamic a. (LH) Supraoptic n. (SO)*
Periventricular zone Tuberal periventricular n. (PeI) Arcuate n. (Arc)
Medial zone Tuberal a. (TA) Ventromedial n. (VMH) Dorsomedial n. (DMH)
Lateral zone Lateral hypothalamic a. (LH) Tuberal n. (TU)
Periventricular zone Posterior periventricular n. (PeP) Dorsal tuberomammillary n. (TMD)**
Medial zone Dorsal premammillary n. (PMD) Ventral premammillary n. (PMV) Mammillary complex medial mammillary n. (MM) lateral mammillary n. (LM) supramammillary n. (SuM) Posterior hypothalamic area
14. ANATOMICAL SUBSTRATES OF HYPOTHALAMIC INTEGRATION
IV. DIENCEPHALON, BASAL GANGLIA, AMYGDALA AND SEPTUM
AD AV MnPO PSCh Periventricular vo AVPV
SO AHA NC
Lateral zone Lateral hypothalamic area (LH) Magnocellular n. of LHA Ventral tuberomammillary n. (TMV)
FIGURE 1 Organization of the hypothalamus. A highly schematic representation of the morphological organization of the hypothalamus to show a simplified view of its zones, regions, areas, and nuclei. Abbreviations used: a, area; n, nucleus. Notes: *The supraoptic n. and n. circularis are best considered a displaced part of the periventricular zone. **Despite the location of the TMD in the periventricular zone, the connections and presumed function of both parts of the tuberomammillary n. are more closely related to the lateral zone.
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Preoptic Region In addition to the periventricular preoptic nucleus (PePO) the preoptic part of the periventricular zone contains three identifiable cell groups. The median preoptic nucleus (MnPO) is a dense cluster of small cells in the lamina terminalis that extends along the anterior border of the third ventricle from the tip of the preoptic recess of the third ventricle dorsocaudally to a small triangular area between the descending columns of the fornix (Atlas plates 18–20). The MnPO plays a critical role in neural circuits controlling cardiovascular responses and fluid homeostasis (Saper and Levisohn, 1983; Saper, 2003). Consistent with this role it receives strong inputs from the subfornical organ and the parabrachial nucleus (Lind et al., 1982; Saper and Levisohn, 1983; Fulwiler and Saper, 1984; Lind, 1987; Bester et al., 1997) and sends projections to the paraventricular nucleus and magnocellular cell groups, as well as to the dorsomedial hypothalamic nucleus (Gu and Simerly, 1997; Thompson and Swanson, 1998). The anteroventral periventricular nucleus (AVPV) occupies a ventral position in the periventricular zone of the preoptic region and is located immediately caudal to the vascular organ of the lamina terminalis. This oval cluster of densely packed, darkly stained neurons is readily distinguishable from the periventricular preoptic nucleus, which lies immediately caudal and dorsal to the AVPV, and is limited laterally by a cell-sparse region that separates the AVPV from the anteroventral preoptic nucleus (Atlas plates 19 and 20). Ventrally the AVPV is separated from the optic chiasm by the suprachiasmatic preoptic nucleus (PSCh), which consists of obliquely oriented fusiform cells also known as the ventromedial preoptic nucleus (Paxinos and Watson, 1998). The morphology of the AVPV and PSCh were first defined by Bleier et al. (1979, 1985) who referred to them as dorsal and ventral subdivisions of the “medial preoptic nucleus,” a term that is generally used to describe the major preoptic nucleus of the medial zone (Gurdjian, 1927; Christ, 1969; Simerly et al., 1984b). This discrepancy in nomenclature derives from different interpretations of Gurdjian’s description of preoptic nuclei (Gurdjian, 1927; see Simerly, 1995a, for review). However, on the basis of cytoarchitectonic (Simerly et al., 1984b), neurochemical (Simerly et al., 1985; Simerly and Swanson, 1987; Simerly, 1989; Herbison, 1992), connectional (Simerly and Swanson, 1988; Gu and Simerly, 1997; Simerly, 1998), and functional grounds (Wiegand and Terasawa, 1982; Herbison, 1998; Le et al., 1999), the AVPV and PSCh are clearly part of the periventricular zone of the hypothalamus. The AVPV has also been included in a region called the “nucleus preopticus,
pars suprachiasmatica” (König and Klippel, 1963), and in a region termed the “AV3V” region, which is defined functionally on the basis of its involvement in the regulation of fluid and electrolyte metabolism (Saper and Levisohn, 1983; Lind and Ganten, 1990; Saper, 2003). The afferents of the AVPV have not been mapped in detail, but results of retrograde (Wiegand and Price, 1980; Wiegand, 1984; Simerly, 1998) and anterograde tracing studies (Simerly and Swanson, 1988; Gu and Simerly, 1997) support its proposed functional role as a nodal point in neural circuitry controlling gonadotropin secretion (Wiegand and Terasawa, 1982). Of primary importance are the strong inputs from the posterior and medial nuclei of the amygdala and from the principal nucleus of the bed nuclei of the stria terminalis (Simerly et al., 1989; Canteras et al., 1992a; Hutton et al., 1998), which presumably convey olfactory information (Halpern, 1987; Segovia and Guillamön, 1993; Guillamon and Segovia, 1996). The AVPV also receives a strong input from the ventral part of the lateral septal nucleus, which relays multimodal information from the hippocampal formation to periventricular and medial parts of the hypothalamus (Risold and Swanson, 1996, 1997b; Risold, 2003). The AVPV is heavily innervated by all parts of the periventricular zone of the hypothalamus, the medial preoptic nucleus, and the dorsomedial hypothalamic nucleus and receives a particularly dense input from the ventral premammillary nucleus as well (Wiegand, 1984; Ter Horst and Luiten, 1986; Simerly and Swanson, 1988; Canteras et al., 1992b; Thompson et al., 1996). Circadian regulation of AVPV activity may be conveyed by direct inputs from the suprachiasmatic nucleus, which appear stronger in females (Watts et al., 1987; Van der Beek et al., 1997). The AVPV also receives afferents from many of the same brain stem nuclei that provide inputs to the medial part of the medial preoptic nucleus (Simerly and Swanson, 1986), such as the nucleus of the solitary tract, ventrolateral tegmentum, and periaqueductal gray. Consistent with its proposed functional role, neurons in the AVPV appear to provide direct inputs to gonadotropin-releasing hormone containing neurons in the region adjacent to the vascular organ of the lamina terminalis, as well as to tuberoinfundibular dopaminergic neurons in the arcuate nucleus (Gu and Simerly, 1997). A broader role in neuroendocrine regulation is suggested by the observation that the heaviest projections from the AVPV are to nuclei within the periventricular zone of the hypothalamus, including the paraventricular nucleus, and these regions also regulate autonomic function (Westerhaus and Loewy, 1999). In addition, strong connections between the AVPV and the subfornical organ, the median preoptic nucleus, and the
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parastrial nucleus (see below) suggest a possible role for these neurons in the regulation of fluid homeostasis (Lind and Ganten, 1990; Simerly, 1995a; Saper, 2003). Although the AVPV has not been implicated in the neural control of behavior, and does not generally provide major inputs to medial zone nuclei, it does send strong projections to the medial part of the medial preoptic nucleus and dorsomedial hypothalamic nucleus. The only major telencephalic projection of the AVPV is to the ventral part of the lateral septal nucleus (Gu and Simerly, 1997) and it sends more diffuse projections to the bed nuclei of the stria terminalis (BST). Anterior Region The anterior periventricular nucleus (PeA) is a caudal extension of the PePO and has a similar morphological appearance, although the width of the PeA is somewhat greater. Two of the most recognizable and clearly differentiated of all hypothalamic nuclei reside in the anterior part of the periventricular zone. The first of these, the suprachiasmatic nucleus (SCh), consists of small, closely packed, darkly staining neurons. It is bordered anteroventrally by the optic chiasm and posteroventrally by the supraoptic commissure. The SCh is generally divided into dorsomedial and ventrolateral parts that can be seen readily in Nissl or histochemically stained frontal sections (Fig. 2) (van den Pol, 1980). The SCh receives a direct input from the retina and many studies have established its critical role in the control of rodent circadian and diurnal rhythms (Moore and Lenn, 1972; Rusak and Zucker, 1979; Moore, 1983). Because biological rhythmicity appears to be relatively free of feedback modulation (Zucker, 1983) it is not surprising that the SCh receives few other inputs, although the ventral part of the nucleus receives a strong serotonergic input from the midbrain raphe nuclei (Conrad et al., 1974; Moore et al., 1978; Moga and Moore, 1997) and a projection from the ventral
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lateral geniculate nucleus that contains neuropepitede (NPY) (Swanson et al., 1974; Moore et al., 1984; Watts and Swanson, 1987). The projections of the SCh have been analyzed in detail with the surprising finding that the strongest terminal field lies in a region designated the “subparaventricular zone,” which is bordered by the periventricular nucleus, the paraventricular hypothalamic nucleus, and the anterior hypothalamic nucleus (Swanson and Cowan, 1975a; Watts et al., 1987). Moreover, recent observations with retrograde tracers indicate that the subdivisions of the SCh have distinct projections (Leak and Moore, 2001). Another well-differentiated nucleus in the anterior part of the periventricular zone is the paraventricular nucleus, which perhaps best typifies the functional importance of the periventricular zone in that it contains neurons that express hypothalamic-releasing hormones (such as corticotropin-releasing hormone) and project to the median eminence. It also contains neurons that provide direct projections to regions containing preganglionic autonomic neurons, as well as to neurons that send projections to the posterior pituitary (Sawchenko and Swanson, 1983a, 1983b; Swanson and Sawchenko, 1983; Armstrong, 2003). Accordingly, the paraventricular nucleus is thought to play a central role in mediating hypothalamic responses to stress, feeding, and drinking behavior and participates in a variety of autonomic responses (Swanson and Mogenson, 1981; Loewy, 1991; Sawchenko, 1991, 1998; Sawchenko et al., 1996; Elmquist et al., 1999). The nucleus is composed of parvicellular and magnocellular divisions, and each division is composed of distinct subdivisions that have characteristic connections and distributions of neurotransmitter–specific populations of neurons (Armstrong et al., 1980; Swanson and Kuypers, 1980b). As a whole, the parvicellular parts of the paraventricular nucleus share strong bidirectional connections with other nuclei in the periventricular zone such as the AVPV and the
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FIGURE 2 The suprachiasmatic nucleus (SCh). (A,B) Fluorescence photomicrographs of the same field, taken with two different filter systems, to show the localization of vasopressin-immunoreactive neurons (A) to the dorsal part of the SCh. (C) Fluorescence photomicrograph of an adjacent section to show a dense plexus of serotonin (5-HT)-immunoreactive fibers and terminals in the ventral part of the SCh (original magnification, ×60).
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arcuate nucleus (Levin et al., 1987; Gu and Simerly, 1997; Li et al., 2000) as well as with the medial part of the medial preoptic nucleus, dorsomedial nucleus, and ventral premammillary nucleus (Sawchenko and Swanson, 1983b; Simerly and Swanson, 1986, 1988; Canteras et al., 1992b; Thompson et al., 1996). The paraventricular nucleus is considered in detail in Chapter 15 by Armstrong. The magnocellular neurons of the supraoptic nucleus have much in common with magnocellular neurons of the paraventricular nucleus and, as such, may be considered to be a part of the periventricular zone that was displaced by the optic chiasm (Cunningham and Sawchenko, 1988; Cunningham et al., 1990). Tuberal Region The majority of the tuberal part of the periventricular zone is occupied by the intermediate periventricular nucleus, which is continuous with the PeA and extends caudal to the arcuate hypothalamic nucleus (Arc) (van den Pol and Cassidy, 1982) along the walls of the mammillary recess. The Arc begins just rostral to the infundibular recess and lies along the walls of this recess throughout its length. Two distinct cytoarchitectonic subdivisions of the Arc are generally recognized: a small-celled dorsomedial part and a larger ventrolateral part that contains medium-sized neurons. These two subdivisions of the Arc are apparent in histochemically stained material (Meister and Hauokfelt, 1988; Simerly and Young, 1991) and many Arc neurons contain hypophysiotropic hormones that are released from the terminals located in the neurohemal zone of the median eminence into the hypophysial portal system which carries them to the anterior pituitary (Harris, 1948; Sawyer, 1975, 1978). The strongest inputs to the Arc are from other parts of the periventricular zone, including the paraventricular hypothalamic nucleus and the anteroventral periventricular nucleus, as well as from medial parts of the medial zone, such as the medial subdivision of the medial preoptic nucleus, the dorsomedial nucleus (Thompson and Swanson, 1998) and the ventral premammillary nucleus (Zaborzsky, 1982; Sawchenko and Swanson, 1983b; Simerly and Swanson, 1988; Canteras et al., 1992b). Similarly, the projections of the Arc are largely confined to the periventricular zone, but notably avoid the suprachiasmatic nucleus, with the densest terminal fields found in many of the regions that supply strong afferents to the Arc (Fig. 3), Extrahypothalamic connections are sparse, but the Arc receives strong inputs from the principal nucleus of the BST and the posterodorsal part of the medial nucleus of the amygdala (Simerly et al., 1989; Canteras et al., 1992a; Gu et al., 2003), as well as from the ventral part of the
lateral septal nucleus (Risold and Swanson, 1997b). It also receives substantial inputs from several brain stem sites thought to convey ascending visceral sensory information to the Arc (Jones and Moore, 1977; Azmitia and Segal, 1978; Ricardo and Koh, 1978; Swanson, 1987). Mammillary Region The mammillary part of the periventricular zone is occupied solely by the caudal part of the posterior periventricular nucleus (PeP) which surrounds the posterior end of the third ventricle. This diffuse cell mass is continuous dorsally with the dorsomedial hypothalamic nucleus and ventrally with the Arc. Because its cells resemble those of the Arc it is often included as part of this nucleus, but on neurochemical and connectional grounds it appears to more closely resemble the other periventricular nuclei (Everitt et al., 1986; Swanson, 1987) and contains few neurons that project to the median eminence (Wiegand and Price, 1980).
Medial Zone The medial zone of the hypothalamus contains a series of large nuclei that collectively play key roles in the initiation of motivated behaviors such as copulatory, aggressive, and appetitive behaviors (see Swanson, 1987, 2000). Accordingly, the connections of these nuclei are exceedingly complex with each nucleus possessing strong connections with widely distributed parts of the telencephalon, diencephalon, and brain stem that are thought to mediate the somatomotor integration necessary for the elaboration of appropriate adaptive responses to specific exteroceptive cues. In addition, many of the nuclei of the medial zone are in a position to be influenced by every major sensory modality. Much of this sensory information is relayed by nuclei in the limbic region of the telencephalon (Swanson, 1983a) and these limbic afferents may represent the key to understanding the functional anatomy of the medial zone of the hypothalamus (Risold and Swanson, 1996; Swanson and Petrovich, 1998; Swanson, 2000; Petrovich et al., 2001; Fig. 4). Superimposed on the limbic inputs are afferents from a well-defined set of brain stem nuclei, some of which relay visceral sensory information (see Saper, 2003). A notable feature of nuclei in the medial zone is that they share strong bidirectional connections with most limbic and brain stem regions that supply medial zone afferents. In addition, nuclei in the medial zone of the hypothalamus share strong intrahypothalamic connections with each other, and all project to cell groups in the periventricular zone, thereby providing a route for limbic modulation of neuroendocrine function. Medial nuclei also have connections with the lateral zone of the hypothalamus, which may be involved in
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FIGURE 3 Projections of the arcuate nucleus (Arc). (A) Bright-field photomicrograph to illustrate the appearance and location of a Phaseolus vulgaris leucoagglutinin (PHA-L) injection site centered in the Arc. (B–D) Dark-field photomicrographs that illustrate projection axons and terminals, emanating from the injection site shown in panel A, observed in the anteroventral periventricular nucleus (AVPV), the medial part of the medial preoptic nucleus (MPOm; c, central part of the MPO), and the medial parvocellular part of the paraventricular nucleus (PaMP; original magnification, ×50). This largely periventricular projection pattern was typical of nuclei located in the periventricular zone.
mediating generalized aspects of behavioral state and arousal (Wayner et al., 1981), and contain subpopulations of neurons that appear to participate in a variety of complex behaviors (Pfaff et al., 1994; Canteras et al., 1997; Siegel, 1999; Watts, 2000; Willie et al., 2001; Blaustein and Erskine, 2002; Hull et al., 2002; Schneider and Watts, 2002; Thompson and Swanson, 2002).
Like the periventricular zone, the medial zone of the hypothalamus can be divided into preoptic, anterior, tuberal, and mammillary levels. Thus, the medial zone is divided into discrete areas designated (from rostral to caudal) the medial preoptic, the anterior, the tuberal, and the posterior hypothalamic areas and the mammillary region. Each of these areas consists of a
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FIGURE 4 Limbic inputs to the hypthalamus Photomicrographs to illustrate the appearance of an injection of PHA-L centered in the nucleus of the BST (BSTp) of a male rat and the inputs to the AVPV, ventral premammillary nucleus (PMV), and medial preoptic nucleus (MPO). (Data from Hutton et al., 1998; Gu et al., 2003) (See Ju and Swanson, 1989, for nomenclature, but see also Alheid et al., 2003)
somewhat undifferentiated hypothalamic gray in which several cellular condensations, or nuclei, are embedded. As described in detail by Swanson (1987), axonal transport studies have revealed fundamental organizational principals regarding the functional role of medial zone nuclei. Briefly, the mammillary region appears to be primarily involved in the modulation of cortical information processing, whereas the other nuclei of the medial zone are more directly involved in the production of behavioral responses to visceral, gustatory, and olfactory stimuli. These generalizations are supported by a large body of evidence that defines critical roles for the major nuclei of the medial preoptic, anterior, and tuberal regions of the hypothalamus in the expression of homeostatic and reproductive behaviors,
and the anatomical relationships of the mammillary region suggest that it may indirectly participate in the modulation of auditory and visual influences on these essential behaviors. Preoptic Region The preoptic region is the most complex and differentiated part of the medial zone of the hypothalamus and, not surprisingly, causes the most confusion in the literature regarding its morphological limits, cytoarchitecture, and nomenclature. Because of this, the normal morphology of the medial preoptic area is addressed here in some detail. At least five distinct cell groups are embedded in the undifferentiated gray that makes up the medial preoptic area (MPA). The large oval-shaped
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medial preoptic nucleus (MPO) extends nearly the entire length of the preoptic region and is composed of three distinct subdivisions: a cell-sparse lateral part (MPOl), a cell-dense medial part (MPOm), and a compact, very cell-dense central part (MPOc) that is embedded in the medial subdivision (Simerly et al., 1984b). The MPO as described here corresponds to Gurdjian’s “medial preoptic nucleus” as depicted in Fig. 12, p. 23, of Gurdjian (1927), and to his “nucleus b” of the medial preoptic area (p. 79). Bleier et al. (1979, 1985) designate this nucleus as the “anterior hypothalamic nucleus,” and the term “medial preoptic nucleus” has also been
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used to refer to the medial preoptic area as a whole (Le Gros Clark, 1938; König and Klippel, 1963; Nauta and Haymaker, 1969; Palkovits and Zaborszky, 1979). The connections of the MPO are among the most complex of any cell group of the hypothalamus (Simerly, 1995b, 1998). In addition to extensive intrahypothalamic connections, the MPO receives strong inputs from the posterior and medial nuclei of the amygdala, the principal nucleus of the BST (Fig. 5), caudal and ventral parts of the lateral septal nucleus (Canteras et al., 1992a, 1995; Risold and Swanson, 1997b; Hutton et al., 1998; Risold, 2003), and distinct brain stem regions including the
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FIGURE 5 Projections of medial zone nuclei Dark-field photomicrographs that illustrate marked differences in the patterns of projections from the medial preoptic nucleus (MPO) and central part of the anterior nucleus (AHC; B) to the tuberal region of hypothalamus. Note the dense projections from the MPO to the arcuate nucleus and ventrolateral part of the VMH (A; original magnification, ×40). In contrast, projections from the AHC avoid nuclei in the periventricular zone such as the paraventricular nucleus (PaV; B; original magnification, ×50) and do not innervate the ventrolateral part of the VMH (C; original magnification, ×50).
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ventral tegmental area, nucleus of the solitary tract, and parabrachial nucleus (Berk and Finkelstein, 1981; Simerly and Swanson, 1986; Murphy et al., 1999). Each of the inputs to the MPO are distributed topographically within its three subdivisions, with projections from hypothalamic nuclei of the periventricular zone terminating primarily in the MPOm, and projections from the ventral subiculum, caudal part of the lateral septum, and brain stem serotonergic neurons ending in the MPOl (Simerly et al., 1984a; Simerly and Swanson, 1986; Canteras and Swanson, 1992b; Kishi et al., 2000). The projections of the MPO are equally extensive (Swanson, 1976; Conrad and Pfaff, 1977; Simerly and Swanson, 1988) and include regions thought to mediate the neuroendocrine, autonomic, and somatomotor responses that are important components of the many functions associated with this nucleus such as reproductive and maternal behavior (Numan, 1992; Meisel and Sachs, 1994; Pfaff et al., 1994). Like its inputs, the projections of each subdivision of the MPO are unique. The MPOc is the most sexually dimorphic part of the MPO and sends its strongest projections to other sexually dimorphic parts of the forebrain such as the ventral lateral septal nucleus, the ventrolateral part of the ventromedial nucleus of the hypothalamus, the ventral premammillary nucleus, the principal nucleus of the BST, and the posterodorsal part of the medial nucleus of the amygdala. The MPOm sends its strongest projections to the parts of the hypothalamus involved in the regulation of hormone secretion from the anterior pituitary such as the AVPV, the arcuate nucleus, and the paraventricular nucleus. The cellsparse lateral part of the MPO has the most diffuse projections with a projection to the lateral septum and perifornical region of the hypothalamus, as well as projections to several brain stem nuclei. In addition to the MPO, four smaller nuclei can be distinguished in the medial preoptic area, although little is known regarding the functional role of these nuclei. The first of these smaller cell groups is the anteroventral preoptic nucleus, which lies at the base of the medial preoptic area between the AVPV and the nucleus of the diagonal band of Broca and is separated from each nucleus by clearly demarcated cell-sparse zones. Cells located in this intermediate zone have been termed the ventrolateral preoptic nucleus (VLPO) by Saper and colleagues, and contain GABAergic and galanin containing neurons that provide direct projections to the tuberomammillary nucleus (Sherin et al., 1996, 1998). In addition, the VLPO appear to play an important role in production of sleep, whereas the anteroventral preoptic nucleus seems to participate in neural pathways related to temperature control (Lu et al., 2000). The anterodorsal preoptic nucleus (ADPO)
lies in the dorsal part of the medial preoptic area and appears roughly round in frontal sections through rostral levels of the preoptic region, but caudally it merges imperceptibly with undifferentiated parts of the medial preoptic area. In the nomenclature of Bleier et al. (1979, 1985) the ADPO together with the ventral part of the lateral septal nucleus make up the “septohypothalamic nucleus.” However, the ADPO and the lateral septum are quite different in terms of their cytoarchitecture (Swanson and Cowan, 1979; Simerly et al., 1984b), neurochemistry (Simerly et al., 1988), and connections (Swanson and Cowan, 1979; Simerly and Swanson, 1988). Immediately lateral to the ADPO is a triangular region of low cell density that contains the precommissural component of the stria terminalis. This region was studied in detail by Raisman and Field (1973), who referred to it as the “strial part of the preoptic area.” Raisman and Field also identified a distinct “round nucleus” just lateral to the strial area (StA). This round cluster of cells is replaced caudally by a lens-shaped group of fusiform cells and these two cell groups here are referred to collectively as the parastrial nucleus (PS) (Simerly et al., 1984b; Ju and Swanson, 1989). The PS receives a strong input from the AVPV (Gu and Simerly, 1997) and is notable for its direct projections to magnocellular neurons in the paraventricular nucleus (Simerly and Swanson, 1988). The posterodorsal preoptic nucleus (PDPO) is a small cluster of large, darkly staining neurons that lie at caudal levels of the preoptic region near the posterior tip of the PS, just ventrolateral to the anterior magnocellular part of the paraventricular nucleus (Swanson and Kuypers, 1980b) along the medial border of the BST. Although the PS and PDPO are often considered to be part of the BST, neither nucleus receives inputs from the amygdala and each appears to be more closely related to hypothalamic circuits. Due to its direct projections to magnocellular neurons the parastrial nucleus is likely involved in regulation of fluid homeostasis, whereas the posterodorsal nucleus has been implicated in the neural control of male sexual behavior (Coolen et al., 1998). Because the caudal border of the medial preoptic area is difficult to identify in Nissl-stained sections, it is often included erroneously within the anterior hypothalamic area. Axonal transport studies clearly indicate that the projections of the MPO and medial preoptic area are quite different from those of the cell groups in the anterior hypothalamic region (Fig. 5) (Saper et al., 1978; Simerly and Swanson, 1988; Risold et al., 1994) and therefore support the interpretation of Saper et al. (1978) regarding the caudal limits of the preoptic area. The caudal part of the medial preoptic area, including much of the caudal MPO and BST, has also been
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referred to as the “preoptic–anterior hypothalamic junctional area” (de Olmos and Ingram, 1972). In addition, the term “striohypothalamic nucleus” (Paxinos and Watson, 1998) has been used to define a region between the BST and the dorsolateral aspect of the MPO. However, the results of anterograde tract-tracing studies indicate that the area designated “striohypothalamic nucleus” is part of the terminal field formed by projections of neurons in the medial amygdala to the principal nucleus of the BST and to the MPO (Simerly et al., 1989) and that this region (see Ju and Swanson, 1989) contains numerous fibers en route to the MPO. Anterior Region Compared with the medial preoptic area, the anatomical organization of the anterior hypothalamic area (AHA) is rather simple. The bulk of the AHA is occupied by the oval-shaped anterior hypothalamic nucleus (AH), which is first recognizable near the rostral end of the suprachiasmatic nucleus and lies ventrolateral to the caudal pole of the medial preoptic nucleus. As it increases in size it replaces the medial preoptic area, and caudally the AH is displaced dorsally by the ventromedial hypothalamic nucleus before merging with the rostral end of the dorsomedial hypothalamic nucleus. On cytoarchitectural grounds the AH can be divided into anterior, central, and posterior components (Saper et al., 1978). In addition, a small discrete cluster of neurons (AHd; Atlas plates 26 and 27) in the dorsal aspect of the caudal part of the AH can be recognized and has been designated elsewhere as the stigmoid nucleus (Paxinos and Watson, 1998) or dorsal tuberal nucleus (Bleier et al., 1979; Bleier and Byne, 1985). In general, the connections of the AH appear to be a subset of the connections of the medial preoptic nucleus: complex connections with other parts of the medial zone, sparse inputs from the lateral zone, and only limited inputs from telencephalic regions such as the ventral subiculum, BST, and ventral part of the lateral septal nucleus (Swanson, 1987). The overall pattern of projections from each subdivision of the AH is similar, but there are distinct differences in the relative densities of inputs to specific regions. The major efferents of the AH are to those parts of the medial zone that provide AH afferents and to widespread areas of the lateral zone with a particularly dense terminal field in the perifornical region, as well as to the paraventricular nucleus of the thalamus (Conrad and Pfaff, 1976; Saper et al., 1978; Risold et al., 1994). Significant projections are also directed toward the anterior periventricular and paraventricular nuclei of the hypothalamus and a strong descending projection ends in the periaqueductal gray. The rest of the anterior hypothalamic area is occupied by an undifferentiated
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hypothalamic gray. Ventral to the third ventricle, and between the optic chiasm and the arcuate hypothalamic nucleus, lies a region designated the retrochiasmatic area (RCh) which contains fibers of the supraoptic commissure and neurons that project to the brain stem and spinal cord (Swanson and Kuypers, 1980a). Tuberal Region The tuberal area (TA) of the hypothalamus contains two large and well-differentiated nuclei: the ventromedial (VMH) and dorsomedial (DM) hypothalamic nuclei. The VMH is the largest cell group in the tuberal region and is composed of two distinct cell condensations designated the dorsomedial (VMHDM) and ventromedial (VMHVL) subdivisions (Gurdjian, 1927), which are separated from each other by a cell-sparse zone (VMHc). A fourth subdivision is apparent at anterior levels and is designated the anterior part (VMHA) (Canteras et al., 1993). The VMH is surrounded by a thick fiber capsule or “shell” (Millhouse, 1973) that separates it from the surrounding hypothalamic gray. The major telencephalic afferents to the VMH are from the amygdala and ventral subiculum, with inputs from the posterior nucleus of the amygdala (Canteras et al., 1992a) and ventral subiculum (Canteras and Swanson, 1992b; Kishi et al., 2000) innervating the ventrolateral part of the shell of the VMH. In contrast, the medial and basolateral nuclei of the amygdala send fibers to the cellular core of the nucleus (Krettek and Price, 1977, 1978). The VMH also receives inputs from all parts of the medial zone of the hypothalamus (except the medial and lateral mammillary nuclei) with the input from the DM being especially strong to the VMHDM (Ter Horst and Luiten, 1986). In addition, the VMH receives inputs from the lateral zone, the posterior hypothalamic area, and the suprachiasmatic nucleus (Saper et al., 1979; Watts et al., 1987; Fahrbach et al., 1989). Among the brain stem inputs to the VMH, afferents from the parabrachial nucleus have received the most attention due to the possible importance of this pathway in feeding behavior (Fulwiler and Saper, 1984, 1985; Bester et al., 1997). The VMH sends massive projections to other parts of the medial zone of the hypothalamus and tends to avoid periventricular regions and the lateral zone. The VMH also sends widespread projections to the amygdala and the septum, with the strongest projection to the bed nuclei of the stria terminalis, as well as providing descending projections to brain stem regions such as the periaqueductal gray (Saper et al., 1976b; Canteras and Simerly, 1994) that are known to project either to the spinal cord or to the basal ganglia. These descending projections are consistent with the proposed role of the VMH in mediating somatomotor aspects of
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complex motivated behaviors (Pfaff et al., 1994). The subdivisions of the VMH appear to have quantitatively different projections, but the overall pattern of projections is qualitatively similar. In general, the VMHVL shares connections with regions of the forebrain and brain stem that also contain high densities of neurons that express sex steroid receptors (Fig. 6) and are involved in mediating reproductive behavior, such as the medial amygdala and the medial preoptic area, while the VMHDM shares strong connections with regions involved with appetitive behaviors, such as the paraventricular nucleus and dorsomedial hypothalamic nuclei (Saper et al., 1976b; Canteras and Simerly, 1994; see Keay and Bandler, 2003, for review of PAG anatomy). In addition, the central, lateral, and medial nuclei of the amygdala receive substantial inputs from the VMH; other forebrain regions that receive inputs from the VMH include the BST, the nucleus accumbens, and the infralimbic cortex. Each part of the VMH sends a massive projection to the periaqueductal gray (PAG) that is topographically organized with the VMHDL preferentially innervating rostral and dorsal parts, and the VMHVL providing more widespread inputs to caudal parts of the PAG (Canteras and Simerly, 1994).
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Immediately lateral to the VMHVL lies the tuberal nucleus (TU), which consists of an oval cluster of smallto medium-sized neurons embedded in the tuberal part of the lateral hypothalamic area. The TU was originally described by Malone (1910) and is also known as the lateral tuberal nucleus (Diepen, 1962; Nauta and Haymaker, 1969). Bleier and colleagues (1979, 1985) named this cell group the medial tuberal nucleus and referred to what is described here as the magnocellular nucleus of the lateral hypothalamus (see below) as the lateral tuberal nucleus. Paxinos and Watson (1998) utilized the term medial tuberal nucleus and recognized a lateral condensation of neurons that is demarcated in Timm’s and acetylcholinesterase stained preparations, which they termed the nucleus terete (Te; “Atlas” plates 31 and 32). Many neurons in the TU express estrogen receptor mRNA (Simerly et al., 1990) and the connections of the TU appear to represent a subset of those described for the VMHVL. Thus, the TU provides dense inputs to other hypothalamic nuclei that contain high densities of neurons that express sex steroid receptors, including the medial preoptic nucleus, the VMHVL, and the ventral premammillary nucleus. However, the TU appears to provide stronger inputs
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FIGURE 6 Hormone–sensitive neurons in the hypothalamus Dark-field photomicrographs to show the distribution and density of neurons in the arcuate nucleus (Arc) and ventrolateral part of the ventromedial (VMHVL) nucleus that express estrogen receptor (ER) mRNA (A). Panel B illustrates the density of androgen receptor (AR) mRNA containing neurons in the ventral premammillary nucleus (PMV; X40). Note the relative absence of neurons that express ER or AR mRNA in adjacent cell groups. (C) Cluster of neurons in paraventricular nucleus (PaV) that express ERβ mRNA. (D) Expression of PR mRNA in the AVPV of a female rat (original magnification, ×50).
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than the VMHVL to regions that participate in regulating neurosecretion, such as the arcuate, anterior periventricular, and paraventricular nuclei of the hypothalamus, and its projections to the amygdala, midbrain, and caudal brain stem are weaker than those of the VMHVL (Canteras and Simerly, 1994). The DM occupies the dorsal half of the tuberal area between the anterior hypothalamic nucleus, rostrally, and the posterior hypothalamic area, caudally. It is generally considered to be composed of three parts which are best appreciated at mid levels through the nucleus where the cell-dense posterior part of the DM (which corresponds to the compact part of the DM of Paxinos and Watson (1998) separates the dorsally positioned anterior subdivision from the ventral part of the nucleus (Atlas plate 31). The DM receives afferents from the BST and the ventral part of the lateral septal nucleus, and all parts of the brain stem that provide inputs to the MPO except for the nuclei of the raphe (Thompson and Swanson, 1998). In addition, the DM receives inputs from most parts of the hypothalamus including the AVPV, MPO, AH, VMH, and SCh. Although descending fibers from the DM provide inputs to the periaqueductal gray and appear to innervate Barrington’s nucleus, the parabrachial nucleus, and the nucleus of the solitary tract, the projections of the DM are mostly intrahypothalamic (Ter Horst and Luiten, 1986; Thompson et al., 1992). Thus, the most densely innervated areas are the anterodorsal and suprachiasmatic preoptic nuclei, the parastrial nucleus, the preoptic and anterior periventricular nuclei, and the parvicellular parts of the paraventricular nucleus. The functional role of the DM remains a matter of discussion, but it has been implicated in the regulation of ingestive behavior, stress, reproduction, circadian rhythms, and thermogenesis (Bernardis and Bellinger, 1998; Sawchenko, 1998), (Gunnet and Freeman, 1983; Rothwell, 1994; Polston and Erskine, 1995; Coolen et al., 1996; Thompson and Swanson, 1998, 2002). Mammillary Region The mammillary part of the medial zone of the hypothalamus is occupied by the mammillary complex— which consists of the medial and lateral mammillary (mammillary body) and supramammillary nuclei— together with the premammillary nuclei (dorsal and ventral) and the posterior hypothalamic area. Although we also consider the tuberomammillary nucleus here, it should be considered as part of the lateral zone of the hypothalamus because of its widespread telencephalic projections and postulated role in modulating behavioral state (Köhler et al., 1985). The mammillary body is divided into a medial mammillary nucleus (MM) that occupies the majority of the mammillary
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body and a lateral mammillary nucleus (LM) that is easily distinguished by its large, darkly stained neurons. The MM is further subdivided into three parts: a small medial part (MMm) located at the midline, the lateral part (MMl) which is by far the largest, and the posterior part (MMp). Perhaps the most important input to the mammillary body is that from the subicular region of the hippocampal formation that travels along the postcommissural fornix (Swanson and Cowan, 1975b; Canteras and Swanson, 1992b; Kishi et al., 2000; Witter and Amaral, 2003). Other limbic inputs include afferents from the lateral septal nucleus and BST, which appear to preferentially terminate in the LM, while the medial septal–diagonal band complex preferentially innervates the medial nucleus (Swanson and Cowan, 1979). In contrast to the other nuclei of the medial zone, the mammillary body receives only modest inputs from the brain stem, although the dorsal tegmental nucleus of Gudden sends a projection to the LM and the ventral tegmental nucleus appears to preferentially innervate the MM. The projections of the mammillary body are equally unique among medial zone nuclei. Projection axons form two major fiber tracts: a descending mammillotegmental tract containing fibers from both the MM and the LM that terminate in the tegmental nuclei of Gudden, and the ascending mammillothalamic tract that terminates in the anterior complex of the thalamus. The anterior thalamic nuclei in turn send projections to a continuous strip of limbic cortex that includes the anterior limbic area, retrosplenial area, presubiculum, and parasubiculum and receives inputs from visual and auditory areas of the isocortex. The connections of the mammillary body serve to distinguish it from the other nuclei of the medial zone and separate this zone into distinct rostral and caudal (mammillary) components. In contrast to the strong olfactory, gustatory, and visceral sensory information that regulates the MPO, AH, DM, and VMH, the mammillary body appears to be most strongly influenced by visual and auditory information. In addition, the mammillary body lacks the extensive intrahypothalamic connections typical of the other medial zone cell groups. Finally, the MPO, AH, DM, and VMH all send projections to regions of the brain stem and spinal cord that control somatomotor and autonomic responses, whereas the mammillary body appears to lack such projections, although at least some intrahypothalamic connections have been reported (Gonzalo-Ruiz et al., 1992), and its cortical connections may provide an indirect pathway for inputs to the striatum (Swanson, 1987). The premammillary nuclei lie at the level of the mammillary recess of the third ventricle immediately caudal to the ventromedial hypothalamic nucleus and rostral to the mammillary body. The dorsal
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premammillary nucleus (PMD) appears as a trapezoidalor rectangular-shaped cluster of pale neurons in Nisslstained frontal sections and is bordered laterally by the fornix column and medially by a cell-poor zone that separates the two nuclei. The ventral premammillary nucleus (PMV) is somewhat easier to distinguish and was first recognized by Gurdjian (1927) as a compact cluster of darkly staining neurons. It is most clearly delimited by retrograde labeling, for example, after injections of tracers into the medial preoptic nucleus (Simerly and Swanson, 1986), or by labeling neurons in the PMV that express sex steroid receptors (Fig. 8) (Pfaff and Keiner, 1973; Simerly et al., 1990). The major inputs to the PMV arise in sexually dimorphic forebrain regions that compose a distinct circuit (see Simerly and Swanson, 1986; Simerly and Swanson, 1988; Canteras et al., 1992b) that includes the posterior nucleus of the amygdala, the medial preoptic nucleus, the principal nucleus of the BST (a.k.a. BSTMP) (Paxinos and Watson, 1998), and the posterodorsal part of the medial nucleus of the amygdala (see Simerly, 1995b, for review). Thus, olfactory information relayed by these nuclei appears to provide the major sensory input to the PMV. The PMV contributes strong inputs to most parts of the periventricular zone, including the anteroventral periventricular and arcuate nuclei, as well as sends projections to other sexually dimorphic regions that innervate it, which may represent feedback connections (Canteras et al., 1992b). The connections of the PMV are consistent with functional data that suggest a possible role in mediating certain aspects of reproductive behavior and physiology (Beltramino and Taleisnik, 1978, 1980; Akesson and Micevych, 1995), and perhaps aggressive behavior as well (Van den Berg et al., 1983). In contrast, the PMD has quite a different pattern of connections and Canteras and Swanson (1992a) have suggested that it may be viewed as a rostral component of the mammillary body that serves as an interface between the anterior nuclei of the medial zone and the mammillary body. Unlike the mammillary body, which lacks strong inputs from the hypothalamus, the PMD receives its major input from the anterior hypothalamic nucleus (Saper et al., 1978; Risold et al., 1994), which in turn receives inputs from the prefrontal cortex, the amygdala, and the hippocampus. The PMD is also innervated by the interfascicular nucleus of the BST and receives substantial input from the infralimbic and prelimbic areas, as well as from the lateral septal nucleus (Comoli et al., 2000). In addition to inputs from the anterior hypothalamus, the PMD is innervated by the perifornical region and the anterior and dorsomedial parts of the ventromedial hypothalamic nucleus. The projections of the PMD more closely resemble those of the mammillary body than those of the PMV. Like the
mammillary body the PMD sends a branched projection that ends in the anterior thalamus and brain stem, but it also provides afferents to the anterior hypothalamic nucleus and a descending projection to the periaqueductal gray, superior colliculus, and adjacent parts of the reticular formation (Canteras and Swanson, 1992a). Thus, the PMD represents an interface between medial zone nuclei of the rostral hypothalamus and mammillary nuclei. By virtue of its projections to the hippocampus (by way of the anteromedial nucleus of the thalamus and its projections) and to motor-related brain stem regions, it provides a means for communication between medial zone nuclei and brain regions involved in spatial memory and diverse behavioral responses including expression of fear and defensive responses to environmental stimuli (Canteras et al., 1997; Comoli et al., 2000). The supramammillary nucleus (SuM) lies between the mammillary body and the posterior hypothalamic area and is bordered dorsolaterally by the ventral tegmental area (VTA). It can be divided into a largecelled lateral part and small-celled medial part that contains many dopaminergic neurons (Swanson, 1982). Although its inputs have not been examined systematically, it appears to receive a massive input from the ventral part of the septal nucleus, the BST, the medial preoptic nucleus, and the lateral zone of the hypothalamus (Saper et al., 1979; Swanson and Cowan, 1979; Simerly and Swanson, 1988; Risold and Swanson, 1997b; Dong et al., 2000). The SuM projects to most major telencephalic regions, including the entire cortical mantle, including a prominent projection to the dentate gyrus and the entorhinal cortex. It provides weaker inputs to other parts of the hippoccampal formation and avoids the corpus striatum (Haglund et al., 1984; Vertes, 1992). The SuM also sends a projection to the central nucleus of the amygdala (Swanson, 1982). Descending projections of the SuM appear to be relatively minor, but a few fibers appear to end in the periaqueductal gray (Vertes, 1992). The posterior hypothalamic area (PHA), the most caudal and dorsal hypothalamic region, is limited laterally by the mammillothalamic tract and merges in the midline at the level of the mammillary recess. It begins just dorsal to the DM—a region often referred to as the dorsal hypothalamic area–which it replaces caudally until it merges with the periaqueductal gray of the midbrain. The connections of the PHA appear to have much in common with those of the periaqueductal gray. The PHA receives inputs from the amygdala, the septum, and the hippocampal formation, as well as from much of the hypothalamus, and many of these connections appear to be bidirectional (Abrahamson and Moore, 2001; Cavdar et al., 2001). The PHA sends the
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majority of its ascending projections via the medial forebrain bundle (mfb) and provides significant inputs to cortical regions related to limbic structures such as perirhinal, insular, limbic, and prelimbic regions of the cerebral cortex (Vertes et al., 1995). In addition, the PHA innervates subcortical regions in the hypothalamus, thalamus, amygdala, septum, and basal forebrain. Because of the close association between the PHA and the forebrain regions connected to the hippocampus it has been suggested that the PHA may play a role in various aspects of emotional behavior (Vertes et al., 1995). The majority of the tuberomammillary nucleus (TM) lies along the base of the caudal diencephalon and is best considered as a nuclear complex that forms a shell around ventral parts of the mammillary body. It can be divided into two magnocellular parts with scattered cells in between. Thus, the complex consists of a dorsomedial TM that appears as a dense cluster of large neurons along the dorsal aspect of the mammillary recess, just dorsal to the rostral part of the posterior periventricular nucleus (Atlas plate 34); a ventral nucleus (TMV) that is considerably larger than the TMD and lies along the base of the hypothalamus ventral and lateral to the PMV (Atlas plates 34 and 35); and a diffuse component (TMdif) that consists of scattered, darkly staining neurons between the TMD and the TMV within the posterior periventricular nucleus (Köhler et al., 1985). Various parcellation schemes have been used to classify these cell groups (for review see Ericson et al., 1987), but it was the advent of immunohistochemical methods that distinguished the TM from the more rostral supraoptic magnocellular neurons and clarified the organization of the complex. Most, if not all, neurons in the TM stain with antisera to histidine decarboxylase and amino decarboxylase, and all parts of the TM receive catecholaminergic afferents from the C1–C3 and A1–A2 cell groups in the brain stem, as well as serotonergic inputs from the B5–B9 cell groups (Ericson et al., 1989). The TM also receives afferents from the lateral septal nucleus and the bed nuclei of the stria terminalis, the medial preoptic nucleus, the lateral preoptic and hypothalamic areas, and the ventromedial nucleus (Ericson et al., 1991). The projections of the TM resemble those of the locus coeruleus and dorsal raphe in that they are distributed to widespread parts of the brain, including the entire cortical mantle, the basal ganglia, the septum and amygdala, parts of the thalamus, the cerebellum, and several brain stem nuclei. The extensive pattern of projections has led to the suggestion that the TM plays a role in the modulation of arousal and behavioral state and, therefore, conceptually belongs to the lateral zone of the hypothalamus. However, the strongest projections of TM neurons are to the hypothalamus, with particularly
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dense terminal fields in the paraventricular and supraoptic nuclei (Ericson et al., 1987), suggesting an important role for the TM in regulating neuroendocrine function as well.
Lateral Zone Although the functional importance of the lateral zone of the hypothalamus has been appreciated for several decades (Stevenson, 1969; Hitt et al., 1970; Siegel and Edinger, 1981), it is safe to say that no aspect of hypothalamic circuitry is less clear. Few distinct regions can be distinguished on cytoarchitectural or neurochemical grounds and attempts to functionally dissect this complex region have largely been impeded by technical limitations. The primary reason for this is that the lateral zone is traversed by the mfb, undoubtedly the most complex fiber system in the mammalian brain (Veening et al., 1982). The mfb contains ascending and descending fibers that arise from more than 50 different cell groups which extend from the prefrontal cortex, through the hypothalamus and ventral brain stem reticular formation, to sacral levels of the spinal cord, and many of these projections appear to contribute inputs to cells in the lateral zone. Thus, it has proven difficult to interpret experimental findings based on methods that fail to distinguish between specific manipulations of neurons and perturbations of fibers passing through the lateral zone. Nevertheless, the lateral zone of the hypothalamus has been implicated in the processing of sensory information and the expression of behaviors associated with hunger and thirst (Swanson and Mogenson, 1981; Swanson, 1987; Elmquist et al., 1999; Siegel, 1999; Watts, 2000), aggression (Kruk, 1991; Siegel et al., 1999), and reproduction (Pfaff et al., 1994). In more general terms, the functional evidence suggests that the lateral zone is involved in mediating general arousal and sensory sensitization associated with motivated behavior and may modulate spinal pathways and so affect the likelihood that specific behavioral patterns will be expressed (Swanson, 1987). However, by virtue of its strong connections with telencephalic regions such as the cerebral cortex, the amygdala, and the septum, and its connections with parts of the periventricular zone, it is in a good position to coordinate motivational aspects of behavior with visceromotor responses. Like the other zones of the hypothalamus the lateral zone can be divided into preoptic, anterior, tuberal, and mammillary regions. However, because clear criteria for subdivision have not emerged it is generally considered to have only two major divisions, the lateral preoptic area (preoptic level) and the lateral hypothalamic area (anterior, tuberal, and mammillary levels).
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Lateral Preoptic Area (LPA)
forebrain bundle, a definition that is supported by the results of anterograde tract-tracing studies (Fig. 7) (Swanson, 1976; Simerly and Swanson, 1988). The only distinct nucleus in the preoptic part of the lateral zone is the magnocellular preoptic nucleus (MCPO), which is differentiated from the dorsally adjacent LPA and substantia innominata by its large darkly staining neurons. This cell group has been called the “nucleus interstitialis septo-hypothalamicus” by Gurdjian (1927)
The LPA is characterized by lightly stained (thionin) medium-sized neurons scattered amongst the fibers of the dorsomedial division of the medial forebrain bundle. It is bordered dorsally by the BST and the substantia innominata, and caudally it merges imperceptibly with the lateral hypothalamic area. The medial border of the LPA (designated Lpo in Fig 7) corresponds rather precisely with the medial border of the medial
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FIGURE 7 Lateral zone projections. (A) Bright-field photomicrograph to illustrate the appearance and location of a PHA-L injection site centered in the lateral preoptic area (LPO). (B, C) Dark-field photomicrographs that illustrate projection axons and terminals, emanating from the injection site shown in panel A, observed in the lateral hypothalamic area (LH) and lateral habenula (LHb; B and C) and in the posterior hypothalamic area (C; original magnification, ×50). Note the relative absence of labeled fibers in the periventricular and medial zones of the hypothalamus. See Fig. 1 for other abbreviations.
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and the “nucleus of the horizontal limb of the diagonal band” by Price and Powell (1970). However, the MCPO is clearly separated from the ventrolateral tip of the nucleus of the diagonal band which forms the medial border of the MCPO. Because the MCPO consists mostly of large cholinergic neurons that project to the olfactory bulb and isocortex (Swanson, 1976; Woolf et al., 1984), it may be considered a differentiated component of the substantia innominata in the rat that corresponds in part to the basal nucleus of Meynert of primates (Saper, 1984, 2000; Saper and Chelimsky, 1984). The projections of the LPA travel almost exclusively in the medial forebrain bundle. In contrast to the projections of the medial preoptic nuclei, the LPO provides widespread inputs to the cerebral cortex and hippocampus, as well as inputs to the mediodorsal and reticular nuclei of the thalamus (Swanson, 1976; Simerly and Swanson, 1988). In addition, the dorsomedial hypothalamic nucleus, supramammillary nucleus, and ventral tegmental area receive significant inputs from the LPO. Descending projections extend into the medulla with particularly dense terminal fields in the parabrachial and pedunculopontine nuclei. Lateral Hypothalamic Area (LHA) The LHA may be further divided into three rostrocaudal subregions that correspond to the anterior (LHAa), tuberal (LHAt), and mammillary (posterior) (LHAp) levels of the hypothalamus. Despite containing several cell condensations the LHA has not been further subdivided, although each major subdivision appears to have a unique set of connections (Saper et al., 1979). The LHAa is continuous with the LPA and is bounded medially by the anterior hypothalamic area and the descending columns of the fornix. Laterally it merges with the substantia innominata and the amygdala. The LHAt replaces the LHAa at tuberal levels and is bordered laterally by the optic tract and the internal capsule and, more caudally, by the subthalamic nucleus. The TU is embedded in the LHAt and consists of an oval cluster of neurons lying lateral to the VMH. Many TU neurons express estrogen receptors (Simerly et al., 1990) and have connections that are similar to those of the VMH (Canteras and Simerly, 1994). At the level of the mammillary complex, the LHAt is replaced by the LHAp which merges caudally with the ventral tegmental area. Medially the LHAp is limited by the fornix, the mammillothalamic tract, and the posterior hypothalamic area and is separated dorsally from the thalamus by the zona incerta and the fields of Forel. The connections of the LHA are extremely complex and, although it is clear that fibers in the medial forebrain bundle innervate neurons in the lateral zone
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(Millhouse, 1979; Veening et al., 1982), for the most part the region-specific pattern of lateral zone afferents has not been established. The results of retrograde tracttracing studies have proven difficult to interpret because of the possibility of retrograde labeling produced by uptake of tracers by fibers of passage. This problem is severe in the lateral zone because all regions that contribute fibers to the medial forebrain bundle also project to one or more nuclei in the medial zone (see Swanson, 1987, for references). Information derived from anterograde tract-tracing studies suggests that restricted parts of the amygdala, septum, and hippocampal formation supply strong inputs to the LHA, as do the substantia innominata and lateral preoptic areas. In general, cell groups in the periventricular zone do not send many projections to the LHA, but the arcuate nucleus is an exception and sends direct inputs to peptidergic neurons in the LHA that are thought to play an important role in feeding (Elias et al., 1999). Other parts of the periventricular zone, such as the anteroventral periventricular nucleus, have relatively weak descending projections to the lateral zone that appear to end primarily in the perifornical region and in the ventrolateral part of the LHAt (Gu and Simerly, 1997). Although brain stem regions also appear to provide inputs to the LHA, the detailed organization of these pathways is yet to be defined. Evidence from systematic anterograde tract-tracing studies indicates that the outputs of the lateral zone of the hypothalamus closely resemble those of the medial zone as a whole. Thus, widespread projections have been demonstrated that include inputs to the entire cerebral cortical mantle (including the hippocampal formation), parts of the amygdala and septum, the substantia innominata, parts of the thalamus, nearly every part of the periventricular and medial zones of the hypothalamus, numerous brain stem cell groups, and the spinal cord. As a whole the hypothalamus provides the largest nonthalamic input to the cerebral cortex. This input is derived primarily from neurons in the lateral zone of the hypothalamus (Saper, 1985, 2000), in addition to the cortical inputs supplied by the tuberomammillary and supramammillary nuclei alluded to above. The lateral zone also projects to many parts of the septum and amygdala, but this projection is much more diffuse than the massive input it receives from these telencephalic regions, suggesting that it represents a possible feedback pathway. With respect to projections from the lateral zone to the thalamic nuclei, both the LPA and the LHA appear to provide inputs to the lateral habenula, the paraventricular nucleus of the thalamus, the nucleus reunions, and the zona incerta, as well as to the intralaminar nuclei (Swanson, 1976; Saper et al., 1979; Berk and Finkelstein,
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1982; Simerly and Swanson, 1988). These thalamic cell groups, in turn, may relay afferent information from the lateral zone to the hippocampal formation, amygdala, septum, prefrontal cortex, and nucleus accumbens. Neurons in the lateral zone send projections to widespread regions in the brain stem and most of these connections are bidirectional. These regions include nuclei that relay visceral sensory information to the forebrain, such as the nucleus of the solitary tract and the parabrachial nucleus (Saper and Loewy, 1980; Ter Horst et al., 1989; Bester et al., 1997), and nuclei involved in mediating somatomotor control mechanisms, such as the ventral tegmental area and substantia nigra, the posterior hypothalamus, and periaqueductal gray, as well as the locus coeruleus and various nuclei of the raphe (Swanson, 1976; Saper et al., 1979). Finally, there are direct projections from the LHA to the spinal cord that are distributed such that it may directly influence sensory, somatomotor, and autonomic spinal mechanisms (Saper et al., 1976a; Hosoya and Matsushita, 1983).
HYPOTHALAMIC INTEGRATION At the outset of this review the hypothalamus was described as providing a suitable neurological substrate for coordinating the needs of the individual animal with dynamic changes in its environment. The appropriate display of adaptive responses to specific cues from the environment involve complex endocrine, autonomic, and somatomotor mechanisms that must be integrated for these responses to be of optimal benefit to the animal. Moreover, because the simultaneous expression of multiple behaviors is not adaptive, these responses must be coordinated and be subject to a hierarchy of homeostatic priorities, a process termed “motivational time-sharing” by McFarland (1974). For example, animals do not generally feed while copulating or simultaneously display defensive and courtship behaviors. These functional requirements, therefore, imply not only integration of endocrine, autonomic, and somatomotor aspects of each adaptive response but also coordination and communication between neural systems mediating different functional responses. Behaviors are generally considered to consist of three phases: initiation, procurement, and consummation (see Beach, 1967; Swanson and Mogenson, 1981, for reviews). The initiation phase involves the perception of a stimulus, while the procurement phase consists of behaviors that are directed toward a specific goal. The consummatory phase is characterized by preprogrammed motor responses thought to be established by central pattern generators. By analogy, endocrine responses can also be divided into three distinct phases.
Hormone secretion from the anterior lobe of the pituitary gland (functional output or consummation) is controlled by neuroendocrine neurons in the hypothalamus whose intrinsic activity is controlled by neural circuits that regulate the pattern of hormone secretion into the portal circulation (pattern generation). These neural circuits are in turn activated, or modulated, by both neural and humoral afferent information (initiation). Thus, a prerequisite to understanding the neurobiology of hypothalamic integration is the characterization of not only the neural pathways that convey specific signals to the hypothalamus but also of circuits that mediate the procurement and consummatory aspects of goal-directed behaviors or, alternatively, the secretion patterns of hypothalamic hormones. Superimposed on the organization of these neural pathways are patterns of neural activity that are regulated by changes in physiological state (e.g., estrous cycle, availability of metabolic fuels, circulating hormones, etc.) that alter the transmission of information through hypothalamic circuits. Although hypothalamic circuits are considerably more complex than the three neuron reflex arcs studied by Sherrington (1906), hypothalamic circuits can be viewed as essentially consisting of sensory and motor components, with intrahypothalamic integrative circuits interposed between the sensory and motor parts of the circuit. As outlined above, the hypothalamus receives sensory activation from visceral sensory regions such as the nucleus of the solitary tract and subfornical organ, as well as olfactory and other sensory information from limbic regions such as the amygdala and hippocampal formation. Superimposed on hypothalamic regions receiving these sensory pathways are projections from the brain stem reticular formation that may effect a more generalized arousal. With respect to motor pathways, the hypothalamus sends direct and massive projections to preganglionic autonomic neurons and all parts of the pituitary gland, as well as projections to regions that mediate somatomotor responses. Thus, the hypothalamus represents an interface between sensory and motor pathways that has intimate connections with the pituitary gland, thereby providing an effective means of coordinating stimulus-specific behaviors with appropriate autonomic and endocrine responses. The integrative mechanisms underlying this process occur at the level of intact neural systems, individual hypothalamic nuclei, and single cells and at the molecular level. Integration at the Neural Systems Level A great deal remains to be learned regarding the organization of the neural systems that mediate homeostatic responses, but certain patterns are emerging that
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suggest ways in which essential behaviors and endocrine responses are coordinated (Risold et al., 1997; Swanson, 2000). One such mechanism is for separate sensory pathways to converge onto functionally distinct parts of the hypothalamus. For example, pheromonal information is relayed to the hypothalamus from the vomeronasal organ by the medial amygdala and principal nucleus of the BST (Fig. 8). Each of these limbic regions provide strong inputs to both the anteroventral periventricular nucleus and the parvicellular division of the paraventricular nucleus. The anteroventral periventricular and paraventricular nuclei also receive strong inputs from the ventral part of the lateral septal nucleus, which is innervated topographically by the ventral subiculum and hippocampal field CA1. Thus, these two periventricular zone nuclei receive convergent sensory information: olfactory cues conveyed to the hypothalamus by the medial amygdala and BST, and information related to exploratory behavior conveyed to the hypothalamus by the ventral lateral septum. In a similar way, parallel limbic inputs to sexually dimorphic nuclei in the hypothalamus from the hippocampal formation and accessory olfactory pathway converge onto subcircuitries that regulate reproductive behavior and neuroendocrine responses (Simerly, 2002). In this way sexually relevant sensory cues can coordinate display of reproductive behavior with accompanying changes in reproductive physiology. Analysis of hypothalamic connections suggests that there are functionally distinct sets of pathways that mediate different homeostatic functions. Reproductive behavior is mostly dependent on the activities of the medial preoptic nucleus and ventrolateral part of the ventromedial hypothalamic nucleus, which play decisive roles in male and female copulatory behavior, respectively (Meisel and Sachs, 1994; Pfaff et al., 1994). Agonistic behavior is primarily controlled by a circuit between the anterior hypothalamic nucleus, the dorsomedial part of the ventromedial nucleus, and the dorsal premammillary nucleus (Canteras and Swanson, 1992a; Canteras et al., 1997). In contrast to the predominate role of these medial zone nuclei in social behaviors, nuclei of the periventricular zone are chiefly involved in neuroendocrine regulation and visceromotor responses (Markakis and Swanson, 1997). The major components of this system are the anteroventral periventricular nucleus, the periventricular and paraventricular hypothalamic nuclei, and the arcuate nucleus. Strong intrahypothalamic connections link these cell groups and they receive similar sensory inputs, either directly by regions such as the ventral lateral septal nucleus and the principal BST or via relays from medial zone nuclei such as the medial part of the medial preoptic nucleus and dorsomedial hypothalamic nucleus. These same
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FIGURE 8 Integration at the neural systems level. Pheromonal information from the accessory olfactory bulb (AOB) is relayed to the hypothalamus by cell groups in the amygdala and the BST. This information differentially impacts subsystems in the hypothalamus involved in defensive and reproductive behaviors. The reproductive subsystem has strong connections with periventricular nuclei that control endocrine and autonomic responses, whereas the defensive subsystem projects to several nuclei in the rostral thalamus thought to participate in attention and learning (modified from Fig. 2 of Risold et al., 1997, with permission ).
major sensory routes provide input to the medial preoptic nucleus and the ventrolateral part of the ventromedial nucleus. Therefore, a potential mechanism for functional integration is for a single sensory modality to affect multiple functional neural systems. For example, olfactory influences emanating from the vomeronasal organ play an important role in modulating gonadotropin secretion and the display of copulatory behavior (Wysocki, 1979; Johns, 1986). This olfactory information is relayed to the hypothalamus primarily by the medial nucleus of the amygdala and the principal nucleus of the BST (see Simerly, 1990), both of which provide strong inputs to the medial preoptic nucleus and ventromedial nucleus (Fig. 6) (Swanson and Cowan, 1979). The medial nucleus of the amygdala and the principal nucleus of the BST also provide strong inputs to the anteroventral periventricular and ventral premammillary nuclei, which in turn project to regions
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such as the paraventricular and arcuate hypothalamic nuclei, which contain high densities of neurons that secrete hypothalamic-releasing factors. Thus, the distribution of a distinct sensory input to neural systems modulating different functions provides a direct means of coordinating behavioral and endocrine responses to a single stimulus. Similarly, regions involved in mediating motor aspects of behavior can receive inputs from hypothalamic cell groups involved in initiating different behaviors, as illustrated by the strong projections from the medial preoptic nucleus (male copulatory behavior) and the ventromedial nucleus (female copulatory behavior) to the periaqueductal gray. Although the same major regions that supply telencephalic sensory inputs to the subsystem of hypothalamic nuclei involved in reproduction also send inputs to the subsystem that mediates agonistic behavior, these inputs are topographically organized such that each subsystem is differentially regulated by the telencephalon (Fig. 8) (see Risold et al., 1997). Connections between various parts of functionally distinct neural systems, such as those that exist between the medial preoptic and ventromedial nuclei, or between dorsomedial hypothalamic and anteroventral periventricular nuclei, may serve to coordinate the activity of these systems and provide for the display of appropriate responses. An important illustration of this principle relates to how animals integrate intrinsic physiologic stressors with those that require interpretation by the animal. The paraventricular nucleus acts as the final common pathway for the regulation of glucocorticoid secretion and receives convergent inputs that transmit visceral sensory information, via brain stem afferents, and telencephalic afferents from the limbic region of the forebrain that convey information from the external environment requiring interpretation before elaborating the appropriate adaptive response (Herman and Cullinan, 1997). Integration at the Level of Hypothalamic Nuclei Insight into the function of a hypothalamic nucleus can be gained by considering the functions of the structures it innervates, the types of information it receives from regions that supply afferents to it, and the amount of information processing that occurs within the nucleus. Most hypothalamic nuclei can be divided into components that share a distinct pattern of connections or cytoarchitectural and neurochemical characteristics. The spatial segregation of functionally distinct cell types in the periventricular zone is best illustrated by the paraventricular nucleus of the hypothalamus (PaV) (Swanson and Kuypers, 1980b; see Fig. 9). The projections of essentially separate populations of neurons in the PaV to the posterior pituitary, to the anterior pituitary,
and to autonomic preganglionic neurons divide the PaV into three distinct components. However, on homological, cytoarchitectonic, and neurochemical grounds these components can be subdivided further to form eight distinct subdivisions which represent an unusual degree of anatomical complexity and suggest that each subdivision may play a unique role in mediating visceral responses (Swanson and Sawchenko, 1983). This compartmentalization also suggests several possible mechanisms whereby disparate visceral responses are integrated. For example, different cell types in the PaV may receive a common input, such as the brain stem afferents from the nucleus of the solitary tract, which convey visceral sensory information to both the oxytocin neurons in the magnocellular division of the PaV and the corticotropin-releasing hormone neurons in the parvicellular division of the nucleus (Sawchenko et al., 1996). Additional integrative mechanisms operating at the level of the PaV are for different cells to have outputs that converge onto the same motor effector circuit or to be coupled by recurrent collaterals or connections with interneurons (Rho and Swanson, 1987). The organizational principals identified for the PaV may also apply to medial zone nuclei. As reviewed above, a variety of anatomical criteria indicate that the MPO is composed of three distinct sexually dimorphic subdivisions: a cell-sparse lateral subdivision and celldense medial and central subdivisions that are larger in males (Simerly et al., 1984b). As is the case for the PaV, sensory inputs are not uniformly distributed throughout the subdivisions of the MPO. Olfactory information relayed to the MPO by the medial amygdala and principal nucleus of the BST is primarily distributed to the medial and central parts of the MPO. Other classes of cortical information reach the MPO via the infralimbic cortex, subiculum, and rostral septal nucleus and end primarily in the lateral part of the MPO (Simerly and Swanson, 1986; Swanson, 2000), although projections from the ventral lateral septal nucleus are mostly distributed in the medial part of the MPO (Risold and Swanson, 1997a). Ascending noradrenergic inputs from the brain stem, which probably carry visceral sensory information, are distributed primarily to the central and medial parts of the MPO, whereas serotonergic afferents are largely localized to the lateral part of the nucleus. Thus, each compartment of the MPO receives a unique complement of inputs and may therefore respond differently to specific sensory modalities. However, because dendritic fields of one compartment may extend into an adjacent compartment, there may be some degree of overlap in sensory responsiveness. Nevertheless, afferents that terminate on distal dendrites have a functional impact distinctly different than that of inputs that terminate
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FIGURE 9 Integration at the level of hypothalamic nuclei. Schematic drawing of a midsagittal section through the rat brain to illustrate possible convergence of major sensory pathways onto CRH neurons in the paraventricular nucleus. Abbreviations used: C1, adrenergic cell groups; CG, central gray; HYP, hypothalamus; IGL, intergeniculate leaflet; LIMBIC, limbic region; LDT, laterodorsal tegmental nucleus; MePO, median preoptic nucleus; NTS, nucleus of the solitary tract; PB, parabrachial nucleus; PIN, posterior intralaminar nucleus; PP, peripeduncular nucleus; PPN, pedunculopontine nucleus; PVT, paraventricular nucleus of the thalamus; SFO, subfornical organ. (Reproduced from Sawchenko, P. E., Imaki, T., Potter, E., Kovacs, K., Imaki, J., and Vale, W. (1993) The functional neuroanatomy of corticotropin-releasing factor. Ciba Foundation Sympasium 172, 5–29, 1998, with permission).
directly onto the cell soma. Because each component of the MPO also displays a unique pattern of projections (Simerly and Swanson, 1988), the functional impact of information conveyed by these outputs depends at least in part on the distribution and intensity of afferents to each part of the MPO. Convergent inputs to a region that arise from multiple parts of a nucleus, such as those from the central and medial parts of the MPO to the arcuate nucleus, may provide for the integration of processed sensory cues. Each compartment of a nucleus may also display a unique neurochemical organization with the majority of neurons that display a particular transmitter phenotype localized to one compartment. This is especially true for the magnocellular neurons of the PaV, although under certain hormonal conditions vasopressin is induced in parvicellular neurons (Sawchenko et al., 1984). In a similar way, each neurotransmitter-specific cell type found in the MPO is largely localized to one of its three subdivisions (Simerly et al., 1986). For instance, cholecystokinin- and thyrotropin-releasing hormoneimmunoreactive neurons are nearly entirely localized to the central part of the MPO, whereas neurotensin and corticotropin-releasing factor-immunoreactive cells are localized to the lateral part of the nucleus. Similarly, neurotransmitter-specific terminals appear to be distributed in accordance with the three subdivisions of the MPO as illustrated by substance P- and enkephalin-immunoreactive fibers, which are localized primarily to the medial and lateral parts of the MPO, respectively. In addition, each compartment of a nucleus may contain unique patterns of neurotransmitter
receptors adding additional complexity to the complete response profile of hypothalamic nuclei. The hypothalamus is particularly responsive to the regulatory effects of circulating factors. Steroid and thyroid hormones have free access to hypothalamic neurons, and many aspects of hormone responsiveness depend on the expression of specific nuclear receptors by discrete subpopulations of cells in the hypothalamus. Autoradiographic, immunocytochemical, and in situ hybridization methods have been used to demonstrate the distribution of neurons that express steroid and thyroid hormone receptors including androgen, estrogen, progesterone, corticosteroids, and thyroid hormone receptors (see Simerly, 1993, for review). That hormone-sensitive neurons are often distributed in accordance with cytoarchitectonic subdivisions of hypothalamic nuclei (Simerly et al., 1990) suggests that functions mediated by such nuclear compartments may be differentially modulated by changes in levels of circulating hormones. Conversely, expression of hormone receptors by otherwise separate populations of neurons may serve to coordinate the activity of these hormone-sensitive neurons. Strong projections from telencephalic regions that contain high densities of neurons that express steroid hormone receptors to hypothalamic nuclei that also receive hormonesensitive intrahypothalamic inputs indicate that the regulatory effects of hormones can be amplified by convergent inputs from hormone-sensitive regions. For example, the medial part of the medial preoptic nucleus receives strong inputs from the posterodorsal part of the medial amygdaloid nucleus and principal
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nucleus of the BST, as well as from the anterior periventricular, arcuate, ventral premammillary, and ventromedial nuclei of the hypothalamus, all of which have numerous cells that express high levels of receptors for sex steroid hormones. Taken together with the fact that most neurons in the medial part of the MPO express high levels of sex steroid receptors it is clear that the influence of sex steroids acting locally can be complemented by that of the same hormones acting on afferent populations of neurons, thereby bringing together disparate hormonally regulated sensory influences at the level of the MPO. In addition to steroid and thyroid hormones other factors secreted in the periphery travel in the blood to regulate the activity of hypothalamic circuits. The adipocyte-derived leptin hormone acts to inhibit food intake and stimulates catabolic autonomic and neuroendocrine responses that tend to direct nutrient stores away from the fat compartment (Woods et al., 1998).
The effectiveness of leptin in regulating energy stores is due to its direct access to hypothalamic neurons that control feeding behavior and other aspects of energy metabolism (Fig. 10) (see Sawchenko, 1998; Elmquist et al., 1999; Watts, 2000; Woods et al., 2000). Distinct subsets of hypothalamic neurons may respond to humoral factors such as leptin by virtue of their location in a region where the blood–brain barrier is compromised or through connections with circumventricular organs. The arcuate nucleus of the hypothalamus meets both of these features since it resides above the median eminence and shares connections with regions such as the subfornical organ and ovlt. The arcuate nucleus has long been associated with obesity (Olney, 1969), expresses high levels of leptin receptor (Fei et al., 1997; Elmquist et al., 1998a; Hakansson et al., 1998), and has high densities of neurons that express fos protein following intravenous injection of leptin (Woods and Stock, 1996; Elmquist et al., 1998b). Moreover, the
FIGURE 10 Neurohumoral integration in feeding pathways. Schematic representation of the organization and chemical specificity of projections from leptin–sensitive neurons in the arcuate nucleus to the dorsomedial nucleus of the hypothalamus (DM), the paraventricular nucleus (PVH), and the lateral hypothalamic area (LHA). Neurons in the arcuate nucleus that express neuropeptide Y (NPY) and agouti-related protein (AgRP; black circles), or that express proopiomelanocortin (POMC) products (gray circles), project directly to discrete populations of LHA neurons that express melanin-concentrating hormone (MCH; black circles) or hypocretin/orexin (H/O; gray circles), which have been implicated in the control of feeding behavior. MCH and H/O neurons are thought to send widespread projections to regions involved in generalized arousal and sensorimotor integration. Abbreviations used: CRF, corticotropin-releasing factor; IML, intermediolateral cell column; PAG, periaqueductal gray; TRH, thyrotropin-releasing hormone; VMH, ventromedial nucleus; ZI, zona incerta. (Reproduced from Sawchenko, 1998, with permission)
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projections of the arcuate nucleus to other sites implicated in the control of feeding such as the paraventricular and dorsomedial nuclei that also show leptin-induced increases in fos expression suggest that the arcuate nucleus is a principal monitor of leptin signaling in the brain. Integration of leptin signals with other systems mediating a variety of homeostatic mechanisms, such as reproduction (Mantzoros, 2000; Schneider et al., 2000), may take place at the level of the arcuate nucleus by virtue of common populations of peptidergic neurons with divergent connections. For example, injections of leptin activate both NPY and POMC neurons in the arcuate nucleus, which project to regions such as the paraventricular and dorsomedial nuclei and appear to convey leptin-based signals (Elias et al., 2000), but arcuate neurons also project to gonadotropin-releasing hormone cells in the preoptic region (Chen et al., 1989; Li et al., 1999). Thus, different physiological functions may be coordinated by interactions between neurons located in the arcuate nucleus through common activation by leptin, or possibly through intercellular communication. Similarly, projections to the anterior and ventral parts of the dorsomedial hypothalamic nucleus from the anteroventral periventricular nucleus, presumably carrying information sensitive to sex steroid regulation, overlap with those from the arcuate nucleus that may be influenced by leptin. Thus, convergent humor signals may regulate the activity of neurons in the dorsomedial nucleus via these convergent neural pathways (Gu and Simerly, 1997; Thompson and Swanson, 1998; Qiu et al., 2001). However, since the leptin-induced foscontaining neurons are in the posterior part of the dorsomedial nucleus, coupling of these different hormonally regulated sets of signals must take place at the level of the dorsomedial nucleus, perhaps through local connections between nuclear subdivisions. Therefore, it is important to bear in mind that some of the distinct classes of neurons defined by the criteria outlined above may be coupled within a nucleus by gap junctions, recurrent collaterals, or connections with interneurons, thereby providing for an additional level of information processing and integration. Integration at the Cellular Level Despite the organization of hypothalamic nuclei into compartments with distinct connections, rarely are such compartments homogeneous with respect to the neurochemical phenotype of individual cells. For instance, neurons in the medial parvicellular part of the PaV that contain corticotropin-releasing hormone (CRH) can coexpress at least seven other neuropeptides (enkephalin, vasopressin, neurotensin, angiotensin II, vasoactive intestinal polypeptide, PHI, and cholecystokinin). Technical limitations have prevented deter-
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mining if single CRH neurons are capable of expressing all of these molecules, but triple-labeling studies have shown that at least some CRH neurons coexpress two other peptides (Swanson et al., 1987; Sawchenko, 1991). Little is currently known, however, regarding the cellular mechanisms responsible for patterns of coexpression within subpopulations of CRH neurons. Moreover, these patterns of coexpression are often dynamic with fluctuations in the expression of some, but not other, coexpressed peptides within individual neurons (Sawchenko et al., 1992; Kovács and Sawchenko, 1996). Such differential regulation of coexpressed neuropeptides may represent a cellular mechanism for “chemical switching” of information through hypothalamic circuits (Swanson, 1983b, 1991). For example, neurons in the medial nucleus of the amygdala that project to the hypothalamus coexpress cholecystokinin (CCK) and substance P, yet changes in levels of circulating sex steroid hormones affect only levels of cholecystokinin (Simerly et al., 1989). Thus, when circulating levels of estrogen are high, as they are during proestrus, cellular levels of cholecystokinin are induced and decrease in response to lowered levels of circulating hormone. In contrast, cellular expression of substance P in these cells remains unchanged during the estrous cycle, or in response to acute changes in circulating estrogen. Taken together with similar finding in other pathways (Swanson, 1991), these observations suggest a possible cellular mechanism for gating sensory information through hormone-sensitive circuits. If we assume that release of coexpressed peptides at individual synapses is proportional to cellular content, then the functional impact of this release might preferentially promote activation of postsynaptic neurons that express cholecystokinin receptors, relative to those that express only receptors for substance P. If similar events occur in the vomeronasal pathway, activation of neurons in the medial amygdala by olfactory stimuli during periods when cholecystokinin levels are increased will lead to a preferential activation of postsynaptic cells that express high levels of CCK receptors, thereby effecting a hormone- dependent “switching” of sensory information to discrete subpopulations of hypothalamic neurons (Simerly, 1990). Similarly, endocrine changes bring about alterations in the expression of neuropeptides contained in neurons that express CRH (Swanson et al., 1987; Sawchenko, 1991) and gonadotropinreleasing hormone (Marks et al., 1992), which may alter the impact of these releasing factors on hormone secretion from the anterior pituitary. The distribution of neurotransmitter receptors in the hypothalamus has been studied extensively with autoradiographic methods. This approach has contributed greatly to clarifying which hypothalamic cell
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groups are responsive to various neurochemical signals. However, these binding techniques do not afford cellular resolution and it is likely that considerable heterogeneity exists with respect to the receptor profiles of subpopulations of hypothalamic neurons. For example, the AVPV receives a dense innervation by fibers that contain substance P immunoreactivity that is distributed throughout the nucleus, but it is not known if each of the many neurotransmitter-specific cell types found in the AVPV express substance P receptors. The cloning of cDNAs that encode neurotransmitter receptors and the use of in situ hybridization histochemistry, together with generation of receptor subunit-specific antibodies, has made possible the localization of receptor expression to individual neurons. It is a common observation in histochemical studies that some, but not all, neurons in a hypothalamic nucleus express particular receptors, but more colocalization studies are needed in order to determine if the pattern of expression represents distinct populations of neurons. In addition, cell-type-specific patterns of receptor regulation may subdivide further the functional classes of hypothalamic neurons and provide for additional mechanisms whereby the flow of information through functionally distinct circuits is regulated. Because it is likely that individual neurons receive multiple neurochemically distinct inputs it will be important to determine if synapse-specific regulation of neuronal responsiveness such as that demonstrated for neurons in the hippocampus (Malinow et al., 2000) exists in hypothalamic circuits. It has been shown that hormonal modification of synaptic organization (Matsumoto, 1991; Segarra and McEwen, 1991; Garcia-Segura et al., 1994; Mong et al., 2001) and intracellular receptor distribution (Coirini et al., 1989; Eckersell et al., 1998) occur, demonstrating that such cellular plasticity is likely to be a common aspect of cellular integration of multiple signals in the hypothalamus. Neural pathways from neurons responding to leptin may converge onto neurons in the paraventricular nucleus and contribute to cellular integration of chemically specific signals related to food intake. Neuropeptide Y (NPY) and agouti-related peptide (AGRP) are coexpressed within arcuate neurons and their projections. Together with melanocortin peptides, such as α-MSH, NPY, and AGRP represent key regulatory peptides since they are orexigenic and melanocortins are anorexigenic. AGRP is a potent antagonist of melanocortin signaling at MC4 melanocortin receptors, and in the paraventricular nucleus this interaction is likely presynaptic since MC4 receptors do not appear to be expressed on paraventricular neurons in abundance (Cowley et al., 1999). Moreover, melanocortins and NPY appear to be functional antagonists in the
paraventricular nucleus and have opposing actions on GABA-evoked currents within individual paraventricular nucleus neurons (Cowley et al., 1999). Thus, it has been proposed that POMC and NPY/AGRP neurons in the arcuate nucleus project to GABAergic neurons in the paraventricular nucleus to regulate GABA release. Since both NPY/AGRP and POMC neurons respond to leptin, their coordinate action on GABA release in the paraventricular nucleus provides an efficient means of integrating orexigenic and anorexigenic signals at the level of individual paraventricular nucleus neurons. Despite the complexity of cellular interactions in the hypothalamus some of the mechanisms underlying neurohumoral integration are beginning to emerge. It is already clear that subpopulations of neurotransmitterspecific neurons have unique signal transduction properties. For instance, progesterone treatment appears to cause an induction of the immediate early gene c-fos in a subpopulation of gonadotropin-releasing hormone neurons (Lee et al., 1990), and estrogen and progesterone cause changes in noradrenergic neurotransmission at both the receptor and the second messenger level (Petitti and Etgen, 1990). Estrogen can also alter neuronal responsiveness to GABA and glutamate (Wong and Moss, 1992; Moss et al., 1997; Gu et al., 1999a, 1999b), indicating that information transmitted by these neurotransmitters can have quite different effects on populations of hypothalamic neurons depending on whether they possess the ability to respond to changes in circulating levels of estrogen. Similarly, the leptin-sensitive NPY and POMC containing neurons in the arcuate nucleus that innervate melanocortin and hypocretin/orexin neurons in the lateral hypothalamus show different cellular responses to leptin (Elias et al., 1999). Thus, hypothalamic nuclei may be composed of distinct compartments that are made up of subpopulations of neurons with different regulatory profiles and response characteristics. It is also important to keep in mind that different parts of the hypothalamus may have unique compliments of glial cells. The increasing appreciation of the diverse roles played by glial cells in regulating microenvironments and cell–cell communication (Chowen et al., 2000; Araque et al., 2001; Bezzi and Volterra, 2001) provides a broad array of cellular mechanisms for specifying regionally distinct aspects of cellular integration. Integration at the Molecular Level Given the diverse array of environmental stimuli that affect neuropeptide gene expression in the hypothalamus, the molecular mechanisms underlying transcriptional activation in hypothalamic neurons will prove to be exceedingly complex. This is not surprising since
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hypothalamic neural circuits are made up of neurons that have much in common with neurons in other parts of the brain, and progress toward understanding how neurons integrate diverse signals at the molecular level is proceeding rapidly. The ability of a particular stimulus to alter gene expression depends on the presence of the appropriate signal transduction pathway, including the expression of molecules to initiate signaling (e.g., neurotransmitter or hormone receptors), an appropriate complement of transcription factors that couple the stimulus with the genome, and the presence of corresponding enhancer elements in the promoter region of the target gene (Goodman, 1990; Habener, 1990; Herdegen and Leah, 1998). For example, responsiveness to direct activation of gene expression by steroid and thyroid hormones can be dependent on the presence of the hormone receptor and a hormone response element in the hormone-sensitive gene (Yamamoto, 1985; Evans, 1988; Tsai and O’Malley, 1994; Beato and Sanchez-Pacheco, 1996; Jenster et al., 1997; Zhang and Lazar, 2000; Aranda and Pascual, 2001). Similarly, genes that display transynaptic transcriptional activation generally contain binding sites for sequence-specific trans-acting factors that respond to changes in levels of intracellular second messengers such as cAMP and calcium (Montminy, 1997; De Cesare and Sassone-Corsi, 2000). This traditional view of hormonal and transynaptic regulation of gene expression remains essentially valid, but the isolation of proteins that function as coregulators of transcription through multiple protein–protein interactions has revealed regulatory mechanisms that profoundly complicate our understanding of transcriptional control. Although little is known regarding the role of transcription factors and coregulators in hypothalamic pathways, considerable progress is being made toward understanding stimulus transcription coupling in clonal cell lines, and emerging evidence suggests new molecular mechanisms for the integration of diverse stimuli at the level of individual genes. Just as diverse neural pathways can converge onto single neurons, distinct signal transduction cascades transmitting a variety of stimuli can converge at the molecular level. One of the most dramatic examples of this type of convergence leads to the activation of the cAMP response element binding protein (CREB), which is a stimulus-induced transcription factor that plays an important role in transynaptic regulation of gene expression (Montminy, 1997). CREB is a member of the bZip superfamily of proteins and is a target of multiple signaling pathways activated by a diverse array of stimuli through phosphorylation at a specific serine residue (see Shaywitz and Greenberg, 1999, for review). In addition, CREB can integrate signaling events by
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forming heterodimers with other bZip factors, such as ATF-1 and CREM, or through protein–protein interactions with CREB binding protein (see below). Cross talk between signal transduction pathways that link extracellular signals with the nucleus represents another important mechanism for integration of homeostatic processes. For example, CREB phosphorylation is induced by protein kinase A in response to elevated levels of cAMP caused by G protein-coupled receptor activation. CREB phosphorylation is also induced by calcium acting through multiple calcium/calmodulindependent kinases, thereby providing a means of linking membrane depolarization with CREB activation. CREB also plays an important role in mediating growth factor induction of transcription by serving as a target for members of the Ras–MAP kinase cascade or through cooperation with other growth factorinduced transcription factors such as those that act at serum response elements. An additional level of communication between distinct signaling pathways is suggested by the observation that estrogen can induce phosphorylation of MAP kinases and extracellularsignal-regulated kinases in vitro and in vivo (Singer et al., 1999; Singh et al., 1999; Toran-Allerand et al., 1999). Thus, it is likely that in hypothalamic cells the nucleus is linked to afferent signals conveyed by hormones, growth factors, and neurotransmitters through multiple interacting signal transduction pathways such as those that lead to CREB phosphorylation. Of particular importance for the control of gene expression in the hypothalamus is the role of steroid and thyroid hormones. Because the hypothalamus regulates secretion of the tropic hormones that control the activity of the peripheral endocrine organs, steroid and thyroid hormones secreted by the adrenal gland, gonad, or thyroid gland exert some of their strongest central effects on hypothalamic circuits. Steroid and thyroid hormone receptors bind to hormone response elements, which function like transcriptional enhancers. But, unlike other enhancers, their activity depends on the presence or absence of ligand. For instance, when estrogen and thyroid hormone receptors bind their cognate hormones the hormone–receptor complex acts as a trans-acting transcription factor that binds to cisacting enhancer-like hormone response elements located within or near responsive genes to influence promoter activity. Because the capacity of these ligand-activated hormone receptors to recognize and regulate target genes is often determined by their ability to bind hormone response elements of hormone-sensitive genes, similarities in the structure of the DNA binding domains of related receptors implies that such receptors may activate overlapping sets of genes by acting through common response elements. For instance, the thyroid
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hormone receptor can bind to the estrogen response element with high affinity in vitro, but fails to activate transcription from these same elements in vivo (Umesono et al., 1988). Moreover, thyroid hormone receptors are capable of inhibiting the ability of estrogen to activate transcription (Glass et al., 1988). In vivo data supporting similar receptor interactions have been reported in the hypothalamus with clear implications for the molecular control of behavior (Pfaff et al., 2000). For example, pretreatment of female rats with thyroid hormone inhibits the actions of estrogen on proenkephalin gene expression (Zhu et al., 2001), and receptor-specific activities of thyroid hormone receptor subtypes influence copulatory behavior (Dellovade et al., 2000). On the other hand, two distinct adrenal steroid hormone receptors, the glucocorticoid receptor and the mineralocorticoid receptor, bind corticosterone with different affinities and can activate gene expression from common promoters (Arriza et al., 1988; Evans and Arriza, 1989; Reichardt and Schutz, 1998). Estrogen can also affect gene expression by binding to different forms of the estrogen receptor, which are coexpressed in several hypothalamic sites, but differ somewhat in their ability to regulate hormoneresponsive genes (Paech et al., 1997; Shughrue et al., 1997; Pettersson and Gustafsson, 2001). Thus, the codistribution of neurons that express related receptors with such interactive properties suggests that coexpression of these trans-acting factors by individual neurons provides considerable combinatorial potential for regulation of gene expression by different endocrine systems. Despite documented effects of steroid hormones on gene expression, in many cases the hormone-responsive genes lack consensus hormone response elements, suggesting that observed regulatory patterns are not due to direct action of the hormone-bound receptors on transcription of such genes. The lack of distinct hormone response elements in hormone-sensitive neurotransmitter genes may relate to the diversity and cellspecific regulation of interactions between steroid hormone receptors and other nuclear trans-acting factors, neurotransmitter receptors, and second messengers that respond to a variety of hormonal and neural cues. For example, estrogen and progesterone have been shown to induce expression of Fos immunoreactivity in the hypothalamus (Hoffman et al., 1990; Insel, 1990; Le et al., 1999), and together with the coordinately expressed protooncogene c-jun, are thought to be representative of general transcription factors (designated Fos or Jun) that are induced by environmental signals and which bind to DNA at regulatory sites termed activator-protein-1 (AP-1) regulatory elements (Morgan and Curran, 1991). CREB may also mediate hormonal regulation of gene expression since phosphorylation of
CREB can be regulated by estrogen (Gu et al., 1996; Zhou et al., 1996), progesterone (Gu et al., 1996), and glucocorticoids (Kovács and Sawchenko, 1996). Thus, the induction of trans-acting factors such as Fos or CREB may mediate the induction of hormone-sensitive genes that lack conventional hormone response elements. The action of hormones like estrogen may converge with transduction pathways that act at AP-1 sites through molecular interactions between estrogen receptors and Fos or Jun (Kushner et al., 2000; Pettersson and Gustafsson, 2001). More central to the action of steroid hormone receptors are coregulators that function as coactivators to increase transactivation by steroid hormone receptors or as corepressors to lower transcriptional activity of target genes (Shibata et al., 1997; McKenna et al., 1999). Cell-type-specific patterns of expression of these coregulators allow different populations of hypothalamic cells to integrate the activity of hormone-activated gene networks with a diverse array of environmental signals. Interaction between families of transcription factors that coordinately regulate gene expression is perhaps best illustrated by the CREB binding protein (CBP) and its close relative p300 (Goodman and Smolik, 2000). These important proteins have binding sites for a wide variety of transcription factors, including not only CREB, but also Fos and Jun (Vo and Goodman, 2001). The observation that CBP can also bind estrogen and thyroid hormone receptors indicates that these protein–protein interactions represent a powerful means of integrating diverse molecular signals at the transcriptional level. Although these mechanisms of molecular integration are only now beginning to be clearly defined, the evidence to date indicates that the activity of a given gene is controlled by changes in the relative ratios of interacting transcription factors expressed within a cell, each of which may respond to distinct cellular signaling pathways in a cell-type-specific manner according to the activity of coexpressed factors. Thus, neurons within the hypothalamus of the rat (and likely most other mammals) possess the potential to receive convergent sensory information from the environment and to integrate this information with neural and humoral signals related to the internal state of the animal. This process is mediated through a variety of complex neurological, cellular, and molecular mechanisms that collectively provide the required breadth and accuracy of adaptive responses necessary for the survival and propagation of the species.
Acknowledgments I thank Drs. Larry Swanson and Paul Sawchenko for providing illustrations and Mara Nelson for preparing the manuscript. Work in
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the author’s laboratory is supported by NIH Grants NS37952, DK55819, and RR00163.
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15 Hypothalamic Supraoptic and Paraventricular Nuclei WILLIAM E. ARMSTRONG Department of Anatomy and Neurobiology,University of Tennessee College of Medicine,Memphis, Tennessee, USA
Magnocellular Neurosecretory System
nucleus (responsible for most of MEE dopamine), a principal source of these neurons lies in the medial aspects of the Pa. Additional parvocellular neurosecretory neurons are found in the hypothalamic and preoptic periventricular stratum (containing dopamine and somatostatin), medial septal nucleus, and nucleus of the diagonal band of Broca (containing luteinizing hormone-releasing hormone). Parvocellular neurosecretory neurons influence the secretion of anterior lobe hormones (e.g., growth hormone, adrenocorticopin hormone, or ACTH, luteinizing hormone, thyroidstimulating hormone) via the release of stimulatory and inhibitory factors from axonal terminals in the MEE. Among these are parvocellular AVP and OX neurons found in the medial portions of the Pa (Vandesande et al., 1977).
Neurons in the supraoptic (SO) and paraventricular nuclei (Pa) projecting to the neural lobe of the hypophysis are large relative to nearby hypothalamic neurons and are traditionally referred to as magnocellular neurosecretory cells. These magnocellular neurons synthesize the neurohormones arginine vasopressin (AVP) and oxytocin (OX) and transport these peptides (l1000 MW) to axonal swellings near fenestrated capillaries in the neural lobe, thus forming the hypothalamoneurohypophysial system (Bargmann and Scharrer, 1951) (Figs. 1, 3, and 4). This system constitutes the final common path for the action potential-dependent release of these hormones to the bloodstream in response to various stimuli ranging from lactation, labor, and nausea/gastric distension (selective for OX) to perturbations in water balance and blood pressure (both AVP and OX) (Renaud and Bourque, 1991; Armstrong, 1995, Poulain and Wakerley, 1982).
PITUITARY GLAND The pituitary gland lies beneath the brain at the mesodiencephalic junction (Atlas Figs. 79–83) and is formed by two distinct parts: a neural part, the neurohypophysis, and a glandular component deriving from oral epithelium called the adenohypophysis (Fig. 1). The neurohypophysis derives from diencephalic tissue and consists of the neural, or posterior lobe (pars nervosa), the pituitary stalk, and the median eminence. The neural stalk (or infundibular stem) is the distal continuation of axons in the internal layer of the median eminence (MEI) (Atlas Fig. 79), which originate primarily from AVP- and OX-secreting magnocellular neurons of
Parvocellular Neurosecretory System Neurons from several hypothalamic nuclei form the parvocellular neurosecretory system (Fig. 1), often called the tuberohypophysial system because of the prominent involvement of the arcuate nucleus and its location in the floor of the hypothalamus (tuber cinereum). In contrast to the magnocellular system, axons of parvocellular neurosecretory neurons project to the external layer of the median eminence (MEE) (Lechan et al., 1982; Wiegand and Price, 1980). In addition to the arcuate
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FIGURE 1 A schematic, midsaggital view of the pituitary gland and its major relationships with neuroendocrine hypothalamus. Magnocellular neurons of the paraventricular (PaMC), supraoptic (SO), and accessory neurosecretory (Acc) nuclei send axons through the internal layer of the median eminence (MEI) and infundibular (neural) stalk (InfS) to terminate in the posterior (neural) lobe of the pituitary (PPit) and release oxytocin (OX) and vasopressin (AVP) into the general circulation. Parvocellular neurons of the paraventricular (PaPC), periventricular (Pe), arcuate (Arc), medial septum (MS), and diagonal band of Broca (DB) project axons to the portal capillary plexus of the external layer of the median eminence (MEE). From here, hypothalamic releasing and inhibiting factors are carried into the anterior lobe (APit) via portal veins to modulate release of the APit hormones from secretory cells. Additional innervations of the MEE, PPit, and intermediate lobe (IPit) are not shown. In addition, a few neurons may innervate both the MEE and the PPit.
the SO and Pa. Neural lobe morphology is characterized by the terminal arborizations of these axons, a rich, fenestrated vasculature, and glial cells (pituicytes), the latter of which form intimate and dynamic morphological relationships with the terminals (Hatton, 1990). Additional inputs to the neural lobe arise from brain stem catecholaminergic neurons in the nucleus of the solitary tract (Sol) (Garten et al., 1989) and rostral periventricular dopamine neurons (Kawano and Daikoku, 1987). Finally, small numbers of neural lobe axons have been found to contain a great variety of neuroactive peptides, GABA, and serotonin, among other substances, which may modulate hormone release at the terminal level (Falke, 1991). The adenohypophysis consists of the anterior lobe (pars distalis), the intermediate lobe (pars intermedia), and the pars tuberalis. The anterior lobe is the largest part and in the rat is not strictly located anterior to the neural lobe, but rather surrounds all but its dorsal aspect. The anterior lobe also contains fenestrated vessels, is composed principally of various hormonesecreting cells, and connects to the MEE by small portal vessels running along the neural stalk. These vessels deliver the releasing and inhibiting factors to the anterior lobe upon their secretion from hypothalamic axons into the fenestrated capillary plexus of the MEE, which feeds into portal veins. The intermediate lobe is unique in containing a large population of gland cells derived from neural crest which synthesize members of the proopiomelanocortin family of peptides, including β-endorphin and α-melanocyte-stimulating hormone (Mains and Eipper, 1979). These cells receive a substantial neural innervation from dopamine (Björklund et al., 1973), serotonin (Mezey et al., 1984), and GABAcontaining axons (Tappaz et al., 1983), including direct
synapses onto the gland cells (see Saland, 2001, for review). The pars tuberalis is relatively small in rat, forming a rostral extension of anterior lobe cells along the neural stalk.
SUPRAOPTIC NUCLEUS Cytoarchitecture and Efferent Projections Distribution of Principal (Projection) Neurons The largest component of the SO is the anterior, or principal, division. This division begins rostrally as scattered, large and darkly staining neurons lateral to the optic chiasm (Atlas Fig. 21) and condenses caudally to abut the lateral border of the optic tract (Figs. 2 and 3; Atlas Figs. 22–27). Posteriorly, a retrochiasmatic continuation (SOR), separated from the SO by the optic tract, is a thin sheet of neurons lying along the pial surface between the optic tract and the third ventricle (Fig. 3; Atlas Figs. 28–32). Both the SO and the SOR project heavily and primarily to the neural lobe (Sherlock et al., 1975). Most SO neurons produce either OX or AVP and project to the neural lobe. Although AVP neurons slightly outnumber OX neurons, the large size of the SO relative to the Pa makes it quantitatively the most important site for production of both hormones. While, in general, neurons producing OX lie more anterodorsally and AVP neurons posteroventrally in the nucleus, there is considerable overlap of the two types within the SO (Swaab et al., 1975; Vandesande and Dierickx, 1975; Hou You et al., 1986). In the rat, the ratio of AVP to OX neurons in the SOR is greater than that in the principal SO (Rhodes et al., 1981).
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FIGURE 2 The anterior, or principal, supraoptic nucleus (SO) in coronal section. (A) Nissl-stained, 5-μm paraffin section illustrates the magnocellular neurons of the SO situated lateral to the junction of the optic chiasm (ox) with the optic tract (opt). The perinuclear zone (PZ) is a cell-poor region surrounding the SO whose neurons may relay inputs from limbic and other structures to magnocellular neurons. The approximate region of the PZ is indicated with small arrowheads, but the boundaries of this region are currently undefined. Note another cellpoor zone at the base of the SO, abutting the pial surface (large arrowheads). This region contains glial cells and, as shown in panel (B), the dendrites of SO neurons. (B) Immunocytochemical localization of AVP in a coronal vibratome (i.e., unembedded) section (30 μm) through the SO. The section has been counterstained for Nissl substance. The AVP-reactive neurons are concentrated ventrally. Note the extent of the ventral dendritic lamina (large arrowheads). The axons of SO neurons are thin and beaded and emit dorsally. One such process is seen arising from a dendrite to join the dorsally emerging supraopticoneurohypophysial tract (small arrowheads). AVP antibody courtesy of Dr. G. Nilaver.
Neurons in the SO producing OX and AVP may colocalize a variety of other peptides and potential neuroactive substances release (Meister, 1993), some of which act within the neural lobe (Falke, 1991) or locally within the SO (Brown et al., 1998) to modulate neurohypophysial hormone release. These include galanin and dynorphin, which primarily coexist with AVP, cholecystokinin (CCK), and corticotropin-releasing hormone (CRH), which primarily coexist with OX neurons and nitric oxide synthase (Nylen et al., 2001; Yamada et al., 1996) and cocaine–amphetamine-regulated transcript (CART) (Vrang et al., 1999), which are found in both OX and VP cells. A caveat is that OX and AVP coexist in 15–20% of magnocellular neurons in the lactating female rat (Mezey and Kiss, 1991), suggesting that the distribution of OX and AVP may be state-dependent. Indeed, single cell analysis of amplified mRNA suggests a potential for OX and AVP coexpression in most SO neurons (Xi et al., 1999). The same may be true of other coexpressed peptides. For example, neuropeptide Y (NPY) expression is revealed in the magnocellular neurons only after osmotic stimulation (Larsen et al., 1992). Morphology and Efferent Path of Magnocellular Supraoptic Neurons Supraoptic neurons exhibit a relatively simple cytoarchitecture (Armstrong, 1995). Neurons in both the SO and the SOR have round- to egg-shaped somata
(20–35 μm) and possess two to three primary dendrites (range, 1–5) that typically project ventrally and branch sparsely (Figs. 2B and 4A). The dendrites collect in bundles in a lamina between the cell bodies and the pial surface to form a receptive plexus for incoming axons (Sofroniew and Glasmann, 1981; Armstrong et al., 1982b) (Fig. 2B). The somata have a rough appearance caused by spines and irregularly shaped appendages (Randle et al., 1986; Smith and Armstrong, 1990; Stern and Armstrong, 1998). The dendrites are not heavily spinous, but do exhibit irregularly shaped appendages and are often varicose. Dendritic varicosities sometimes contain the dense core granules housing OX or AVP. The evidence for dendritic release of OX, AVP, and dynorphin, and the autoregulatory effects of these peptides, is substantial (Ludwig, 1998). The axons of SO neurons arise from a primary dendrite or directly from the soma and course dorsally before turning medially in a wide arc (tract of Greving) to project posteriorly to reach the MEI (Randle et al., 1986; Smith and Armstrong, 1990). Posteriorly, the axons become more varicose and within the neural lobe are punctuated by numerous small and occasionally large (10–15 μm) swellings traditionally known from neurosecretory stains as Herring bodies (Figs. 4B–4D). The apposition of these swellings to the basal lamina near fenestrated vessels forms the neurohemal contact zone (Fig. 4D). Within the neural lobe, OX fibers are preferentially distributed peripherally while AVP fibers are
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FIGURE 3 The distribution of magnocellular neurosecretory neurons is shown with the major divisions of the supraoptic (SO), paraventricular (Pa), and accessory nuclei (Acc) and their efferent projections. On the left are tracings from coronal sections of the distribution of magnocellular neurons containing either vasopressin (AVP) or oxytocin (OX) revealed with immunocytochemistry using an antibody crossreacting with both AVP- and OX-associated neurophysins (anti-rat neurophysin, courtesy of Dr. A. G. Robinson). The reactive cells are plotted in the four representative sections and shown in relation to the subdivisions of the Pa, SO, and Acc. Solid areas are virtually filled with reactive neurons. On the right, groups of neurons are marked to show the relative density of OX and AVP types according to the literature. Horizontal lines indicate a majority of OX neurons, vertical lines a majority of AVP neurons, and hatched areas a more equal mixing of the two. The great majority of Acc neurons in panels (A) and (B) are OX-containing, while further caudally (C and D) the Acc groups are more mixed. Also on the right, some major efferent connections of the nuclei and their subdivisions are shown, with distal targets enclosed by dashed lines. In the Pa, it should be pointed out that most of the neurons in the dorsal medial cap (PaDC), medial parvocellular (PaMP), ventral (PaV), and posterior (PaPo) groups project to the targets indicated, but not all of the OX and AVP neurons shown in each division contribute to the projection. In addition, many neurons in these subdivisions do not contain OX or AVP. AC, anterior commissural nucleus; Bs, brain stem; BSTV, bed nucleus of the stria terminalis; Cir, nucleus circularis; MEE, external layer of the median eminence; f, fornix; ic, internal capsule; LH, lateral hypothalamus; LPO, lateral preoptic area; MFB, nuclei of the medial forebrain bundle; opt, optic tract; ox, optic chiasm; PaLM, paraventricular nucleus, lateral magnocellular division; PaMM, paraventricular nucleus, medial magnocellular division; PeM, magnocellular periventricular nucleus; PPit, posterior pituitary; PoF, posterior fornical nucleus; sm, stria medullaris; SpC, spinal cord; 3V, third ventricle.
localized centrally (van Leeuwen et al., 1979; Tian et al., 1991). When viewing axons traced to the MEI from intracellularly labeled supraoptic neurons, short (~10 μm), filiform processes are occasionally seen, but not collateral arbors (Randle et al., 1986; Smith and Armstrong, 1990). However, branches within the lateral hypothalamus from SO axons have been observed with other techniques and may account for some of the collaterals seen in AVP-positive axons in this region (Mason et al., 1984; Ray and Choudhury, 1990). Immunochemically, synapses positive for AVP (Choudhury and Ray, 1990)
and OX (Theodosis, 1985) have been observed in the SO, but it remains uncertain whether these emanate from magnocellular axons. Supraoptic Interneurons A very small number of multipolar neurons with small somata are found within the SO and could function as interneurons (Dyball and Kemplay, 1982; Bruni and Perumal, 1984). An additional locus of interneurons is the perinuclear zone (PZ) immediately adjacent to the SO (Figs. 2A and 5). Many neurons in the PZ
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FIGURE 5 Photomontage of a PZ neuron filled with Neurobiotin and reacted with avidin–biotin peroxidase complex. A short axon from this neuron displays terminal-like varicosities in close proximity to SO neurons stained with thionine. Modified from Armstrong and Stern (1997).
FIGURE 4 Neurosecretory neuron and axons. (A) Photomontage of an SO neuron filled with Neurobiotin and reacted with avidin– biotin peroxidase complex (see Stern and Armstrong, 1998, for method). The axon originates from the soma and is indicated by an arrowhead. Arrows point to dendritic branches. The montage was created from digital micrographs through several focal planes in a 100-μm vibratome section. (B, C). Neural lobe axons labeled anterogradely from a pressure injection of biotinylated dextran in the SON, reacted with avidin–biotin peroxidase complex. (B) Axon with several small branches in a small area (arrowheads). (C) Axons with swellings present the classical image of strings of pearls. Note the thin intervaricose segments (arrows) and the large range of swelling sizes. (D) Electron micrograph of the neurohemal contact zone in the neural lobe. Note the large neurosecretory terminal (T) filled with dense core granules and surrounded by pituicyte (Pit) processes. The terminal abuts the basal lamina of the perivascular space (arrow) of a fenestrated capillary (Cap). Modified from Tian et al. (1991).
project to the SO (Iijima and Ogawa, 1981; Tribollet et al., 1985; Jhamandas et al., 1989; Roland and Sawchenko, 1993; Levine et al., 1994), and this zone is a target of many inputs known to influence the firing rate of OX and VP neurons. Thellier et al. (1994) place the densest population of locally projecting PZ neurons to a medial
region dorsal to the optic chiasm rather than immediately dorsal to the SO. PZ neurons are morphologically diverse (Armstrong and Stern, 1997) and can express many neuroactive substances including GAD or GABA (Tappaz et al., 1983; Theodosis et al., 1986; Okamura et al., 1990), choline acetyltransferase (Mason et al., 1983), substance P (Larsen, 1992), somatostatin (Mezey et al., 1991), estrogen receptor (Herbison et al., 1994), pituitary adenylate cyclase-activating polypeptide (PACAP) (Hannibal et al., 1995) and probably glutamate (Boudaba et al., 1997). All of these substances have been identified in fibers and some even in synaptic terminals within the SO. Much of the somatostatinergic input to the SO derives from the PZ (Mezey et al., 1991). PZ neurons are electrophysiologically distinct from SO neurons (Armstrong and Stern, 1997) and contribute functional inhibitory (Wuarin, 1997) and excitatory synapses (Boudaba et al., 1997) to the nucleus. The GABAergic neurons are thought to be important in mediating the response of AVP neurons to hypertension (Nissen et al., 1993; Grindstaff and Cunningham, 2001).
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Afferent Inputs The first chemically identified input to the SO was that from brain stem catecholamine neurons (Carlsson et al., 1962). This projection is primarily noradrenergic and originates from the A1 (the ventrolateral medulla) and A2 (caudal part of the Sol) cell groups (Sawchenko and Swanson, 1982a; Tribollet et al., 1985; Cunningham and Sawchenko, 1988; Day and Sibbald, 1988; Raby and Renaud, 1989). Cardiovascular and other visceral afferent (e.g., gut distension) signals controlling AVP and OX release could be routed through these brain stem nuclei (Renaud and Bourque, 1991). The projection from A1 is thought to favor AVP neurons and contacts both the SO (primarily the ventral region) and the SOR. While involved in the response of AVP to cardiovascular stimuli (both hypo- and hypertension), the precise action of noradrenaline in these responses is debatable. Noradrenergic neurons in A1 may colocalize NPY (Sawchenko et al., 1985), prolactinreleasing peptide or glucagon-like peptide-1 (Morales et al., 2000), PACAP (Shioda et al., 2000), and substance P (Bittencourt et al., 1991). Importantly, the corelease of ATP with noradrenaline could mediate some excitatory AVP cell responses to cardiovascular challenges (Buller et al., 1996). Some of the colocalized peptides can modulate noradrenaline’s actions on AVP release and are potent agents by themselves (Renaud and Bourque, 1991; Kapoor and Sladek, 2001; Shibuya et al., 2000). The A2 projection to the SO prefers more dorsally located OX neurons and is involved in OX release to gastric stimulation (Onaka et al., 1995). Some noncatecholaminergic neurons in the Sol contain the peptides activin/inhibin-β and somatostatin-28 and directly contact OX neurons (Sawchenko et al., 1990; Sawchenko and Pfeiffer, 1995). Smaller brain stem inputs to the SO have been summarized elsewhere (Hatton, 1990; Morris et al., 1987) and include the serotonergic innervation from raphe nuclei that projects to the dorsal (primarily OX-containing) SO. Brain stem afferents from the lateral parabrachial nucleus innervate the PZ and affect OX and AVP neurons through this relay (Jhamandas et al., 1991). The subfornical organ (SFO), the median preoptic nucleus (MnPO), and the organum vasculosum of the lamina terminalis (OVLT) (Camacho and Phillips, 1981; Sawchenko and Swanson, 1983; Tribollet et al., 1985) provide dense monosynaptic inputs important for the regulation of water balance and AVP secretion, although OX neurons may be contacted as well. These regions contain neurons sensing plasma osmolality (MnPO and OVLT) or peripheral AII (SFO) and provide powerful inputs to the SO (e.g., Richard and Bourque, 1995). Some of the SFO projection may utilize AII as an excitatory
neurotransmitter (Jhamandas et al., 1989). Afferents from the MnPO/OVLT are distributed uniformly within the SO and make largely symmetrical synapses with both dendrites and somata (Armstrong et al., 1996). However, both inhibitory and excitatory projections have been identified (Yang et al., 1994), and the osmosensing component of the OVLT projection to SO is mediated by glutamate (Richard and Bourque, 1995). Direct inputs to the ventral dendritic lamina of the SO from the olfactory bulb may be involved in mediating olfactory cues for the synaptic and dendritic reorganization of the SO occurring during pregnancy and lactation (Hatton, 1990; Meddle et al., 2000). A direct retinal input to the SO has been reported (Levine et al., 1994). Additional retinal information may pass to the SO through the PZ (Levine et al., 1994; Cui et al., 1997), which receives input from the suprachiasmatic nucleus (Stephan et al., 1981) and thus information regarding circadian rhythms and their entrainment to the diurnal cycle. Additional forebrain and hypothalamic inputs come from a wide variety of structures, including the bed nucleus of the stria terminalis, dorsomedial nucleus, anteroventral periventricular nucleus, medial preoptic area, rostral periventricular area, and tuberomammillary region (Hatton, 1990; Morris et al., 1987; Sawchenko and Swanson, 1983; Simerly and Swanson, 1988; also see Chapter 14 by Simerly, this volume). The diagonal band of Broca (Jhamandas et al., 1989) and lateral septum (Poulain et al., 1980) have a powerful, inhibitory influence on SO neurons, yet these regions send only sparse monosynaptic inputs. Instead, they more heavily contact the PZ (Jhamandas et al., 1989; Oldfield et al., 1985). Although a variety of neurotransmitters and neuromodulators have been located within the SO and SOR and are undoubtedly represented by the inputs discussed above, quantitatively the most important transmitter in the SO is GABA, which accounts for ~50% of all synapses in the SO (Theodosis et al., 1986; Decavel and van den Pol, 1990). Traditionally, GABA is considered to be of local origin, but recent studies indicate only sparse GABAergic inputs may arise from the area immediately adjacent to the SO (Roland and Sawchenko, 1993). The forebrain and hypothalamic distribution of neurons containing mRNA for GAD (Okamura et al., 1990; Cullinan et al., 1993; Roland and Sawchenko, 1993) suggests that other regions known to project to the SO also contain GABAergic neurons, including the periventricular preoptic area, bed nucleus of the stria terminalis, the tuberomammillary complex, the OVLT, the SFO, and the MnPO. The majority of the remaining synapses probably utilize the excitatory amino acid transmitter glutamate (Meeker et al., 1989; van den Pol, 1991; DeCavel and van den Pol, 1992). Glutamatergic
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inputs to the SON have been shown to derive from a number of nuclei, including, among others, the PZ, the dorsomedial nucleus, and the bed nucleus of the stria terminalis (Csaki et al., 2002). Following GABA and glutamate, noradrenaline accounts for ~10% of all SO synapses (Michaloudi et al., 1997). Histamine-containing neurons comprise much of the tuberomammillary input to the SO and SOR (Hatton, 1990). Dopamine has been localized in axons within the SO in the region of OX neurons, but its precise source is not clearly identified (Buijs et al., 1984; DeCavel et al., 1987).
PARAVENTRICULAR NUCLEUS The Pa is cytoarchitectonically more complex than the SO (Armstrong et al., 1980; Swanson and Kuypers, 1980; Swanson et al., 1986; Kiss et al., 1991). Unlike the SO, the Pa contains medium- and small-sized neurons that project to other CNS areas or to the MEE in addition to magnocellular OX and AVP neurons projecting to the neural lobe. The basis for Pa subdivisions is primarily the segregation of these projection neurons into groups with common outputs, but differences often are correlated with differences in biochemical types
TABLE 1
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and afferent inputs (Swanson et al., 1986), cell size and packing density (Kiss et al., 1991), and dendritic morphology (Armstrong et al., 1980; van den Pol, 1982; Ju et al., 1986, 1992; Rho and Swanson, 1989). Table 1 lists the cytoarchitectonic divisions used herein and their relationship to those of other schemes.
Magnocellular Neurosecretory Component Distribution of Principal Neurons The majority of Pa neurons sending axons to the neural lobe of the pituitary lie in two contiguous groups (Hatton et al., 1976): the medial magnocellular portion (PaMM) contains mostly OX neurons and lies anteromedially in the nucleus; the lateral magnocellular division (PaLM) contains primarily AVP neurons and forms a distinct, ball-shaped mass posterior and dorsolateral to the PaMM (Figs. 3 and 6; Atlas Figs. 26 and 27). A ring of OX neurons also lies around the densely packed PaLM. Like SO neurons, these cells are relatively large (20–35 μm). Less densely packed neurons containing OX and AVP, some of which project to the neural lobe, are found posterior in the Pa, medial and anterior to these divisions. Most of the substances found to colocalize with SO neurons can be found in Pa neurons projecting
Nomenclature for Paraventricular and Associated Nuclei
Terminology used herein
Other names
Magnocellular groups Medial (PaMM) (Armstrong et al., 1980; Hatton et al., 1976; Swanson et al., 1986)
Posterior magnocellular (Swanson and Kuypers, 1980) and magnocellular (Kiss et al., 1991)
Lateral (PaLM) (Armstrong et al., 1980; Hatton et al., 1976) Periventricular (PeM) (Armstrong et al., 1982a) Anterior commissural (AC) (Armstrong et al., 1980, 1982a; Kiss et al., 1991)a
Anterior magnocellular (Swanson and Kuypers, 1980; Swanson et al., 1986)
Median eminence projecting groups Anterior parvovellular (PaAP) (Swanson and Kuypers, 1980; Swanson et al., 1986) Medial parvocellular (PaMP) (Armstrong et al., 1980; Kiss et al., 1991; Swanson and Kuypers, 1980; Swanson et al., 1986)b Periventricular parvocellular (PeP) (Kiss et al., 1991; Swanson and Kuypers, 1980; Swanson et al., 1986) Extrahypothalamically projecting groups Ventral (PaV) (Swanson et al., 1986)c
Posterior (Armstrong et al., 1980, 1982a; Kiss et al., 1991)
Posterior (PaPo)
Lateral parvocellular (Swanson and Kuypers, 1980; Swanson et al., 1986)
Dorsomedial cap (PaDC) (Armstrong et al., 1980)
Dorsal parvocellular (Swanson and Kuypers, 1980; Swanson et al., 1986), dorsal (Kiss et al., 1991)
a
Referred to as Peterson’s AC. Kiss et al. (1991) divide the PaMP into anterior, medial, lateral, and caudal parts which encompass the PaAP, PaMP, and PeP as used herein. c Referred to as Koh and Ricardo’s ventral Pa. b
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FIGURE 6 Some divisions of the paraventricular nucleus (Pa) are shown in horizontal sections (30 μm) after reacting with an antibody to neurophysin that cross-reacts with both OX- and AVP-associated neurophysins (courtesy of Dr. A. G. Robinson). The most dorsal section is in panel (A); the most ventral in panel (D). These sections also illustrate the general orientation of dendrites (small arrowheads) from these neurons. (A) The anterior commissural (AC) and periventricular magnocellular (PeM) divisions, which contain almost exclusive populations of OX neurons in the dorsal, anterior hypothalamus are shown. Note the strong medial and posteromedial orientation of dendrites. (B) More ventrally, the top of the medial aspect of the posterior division of the Pa (PaPo) is visible. Some dendrites of both PaPo and AC neurons are indicated. Note some of the PaPo dendrites emit laterally, and some appear to cross the midline. (C) Further ventral, the lateral magnocellular Pa (PaLM) is visible as a dense ball of cells. The PaLM is mostly AVP-containing, and its dendrites are directed medially into the medial parvocellular zone (PaMP) and periventricular parvocellular (PeP) zones. This section is fully through the PaPo, which has many neurophysinpositive neurons whose morphology is quite different from those of the PaLM. Again, note the diverse orientation of PaPo dendrites. (D) In the most ventral section, the medial magnocellular Pa (PaMM) is visible. This group is mostly composed of OX neurons. Immediately caudal it is replaced by the ventral Pa (PaV), which is relatively poor in neurophysin-positive neurons.
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to the neural lobe (see above). Two OX-containing cell groups often are included in the Pa (Swanson and Kuypers, 1980): the periventricular magnocellular group (PeM) and the anterior commissural nucleus (AC). Both the PeM and the AC are considered herein as accessory neurosecretory nuclei and are dealt with in the final section of this chapter (also see Figs. 3A and 6; Table 1). A more detailed map of OX and AVP neurons in various regions of the Pa is available in HouYou et al. (1986). Morphology and Efferent Path of Magnocellular Paraventricular Neurons Magnocellular Pa neurons in the PaMM and PaML of the rat have an appearance similar to that of their SO counterparts, with the typical cell having two or three dendrites that branch relatively simply (Armstrong et al., 1980; van den Pol, 1982; Hatton et al., 1985; Rho and Swanson, 1989). These initially thick dendrites taper and invade the medial and ventromedial parts of the nucleus and form a dense plexus, which occasionally encroaches upon the third ventricular wall (Fig. 6) (Sofroniew and Glasmann, 1981; Armstrong et al., 1982a; Ju et al., 1986, 1992). While in lower vertebrates subependymal Pa dendrites can form ciliated, sensory type endings and contact the cerebrospinal fluid (Vigh and Vigh-Teichmann, 1998), such contact has not been verified for Pa dendrites in mammals. The medial parvocellular region is rich with axonal inputs (van den Pol, 1982), including a prominent catecholaminergic component (McNeill and Sladek, 1980). Thus, synaptic contacts upon OX and AVP neurons innervating the neural lobe can occur outside the confines of the subnucleus (see below). Like their SO counterparts, the dendrites of PaMM and PaML neurons are variably spinous, but can be quite varicose (Sofroniew and Glasmann, 1981; van den Pol, 1982). Many of the appendages are longer filiform processes or are irregularly shaped (van den Pol, 1982; Rho and Swanson, 1989). Like those in the SO, the dendrites of Pa neurons are capable of local secretion of peptide (Ludwig, 1998). Axons of the PaMM and PaLM egress laterally from either the soma or a primary dendrite (Armstrong et al., 1980; van den Pol, 1982; Hatton et al., 1985; Rho and Swanson, 1989) and course in a wide arc, passing over or beneath the fornix before turning medially above the SO to join the tract of Greving before reaching the MEI and the neural lobe. In the neural lobe, Pa axons are thought to distribute peripherally to those arising from the SO (Alonso and Assenmacher, 1981). Pa axons from magnocellular neurons may occasionally branch (van den Pol, 1982; Hatton et al., 1985; Ray and Choudhury, 1990), but the final destination and synaptic relationship of collaterals remain to be determined.
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Parvocellular Neurosecretory Component Distribution of Principal Neurons Small- to medium-sized neurons in the anterior (PaAP) and medial (PaMP) parvocellular portions of the nucleus (Fig. 3), including the parvocellular periventricular stratum (Swanson and Kuypers, 1980), give rise to a substantial input to the MEE (Armstrong and Hatton, 1980; Wiegand and Price, 1980; Lechan et al., 1982; Kawano and Daikoku, 1988; Kawano et al., 1991). The PaAP and PaMP are chemically diverse and contain neurons immunoreactive (with varying degrees of colocalization) for angiotensin II, atrial natriuretic peptide, bombesin, AVP, CART, CCK, CRH, PACAP, GRF, tyrosine hydroxylase (presumptive dopamine neurons), GABA, enkephalins, galanin, growth hormone-releasing hormone, neurotensin, peptide histidine leucine, somatostatin, thyrotropin-releasing hormone (TRH), and vasoactive intestinal peptide (Swanson et al., 1986; Swanson, 1987; Hökfelt et al., 1990; Hannibal et al., 1995; Broberger, 1999). Many of these cell types project to the MEE or extrahypothalamically (see below). Most of the CRH (Antoni et al., 1983) and TRH (Brownstein et al., 1982; Kawano et al., 1991) present in the MEE derives from the Pa. Approximately 70% of all somatostatin neurons in the rostral periventricular region and PaMP project to the MEE (Kawano and Dikoku, 1988; Merchenthaler et al., 1989). Some somatostatin neurons innervate OT neurons, perhaps by collaterals (Hisano et al., 1993a). Peptidergic neurons are roughly segregated within the PaMP on cytoarchitectonic grounds (Kiss et al., 1991), such that CRH neurons are found lateral to TRH neurons, which are in turn found lateral to periventricular dopamine and somatostatin neurons (Swanson et al., 1986). A projection of AVP axons from the Pa to the MEE has been known since at least 1977 (Vandesande et al., 1977) and is related to ACTH and glucocorticoid secretion (Silverman and Zimmerman, 1982). The AVP derives from parvocellular neurons in the PaMP and PaAP and its expression is normally weak. In colchicine-treated rats, AVP is expressed in over half of the CRH neurons (Whitnall and Gainer, 1988), and after adrenalectomy the majority of parvocellular CRH neurons colocalize AVP (Kiss et al., 1984; Sawchenko et al., 1984). In addition to receiving stress signals through brain stem and limbic pathways (Herman and Cullinan, 1997; see below), these neurons also possess glucocorticoid receptors for direct feedback (Uht et al., 1988). Morphology and Efferent Pathway In Golgi studies, the dendritic architecture of Pa neurons in parvocellular neurosecretory subnuclei appears similar to that of the general population of
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parvocellular Pa neurons. Like magnocellular neurons, parvocellular neurons in the PaMP have a relatively restricted dendritic arbor showing few branches, with a moderate endowment of appendages (van den Pol, 1982). In addition to a strong medial orientation of the dendritic tree, some PaMP neurons have ventrally and dorsally directed dendrites that run along the ventricular wall. In more recent studies, parvocellular neurosecretory neurons have been identified by combining retrograde tracing, intracellular injection, and immunocytochemical identification for CRH (Rho and Swanson, 1987, 1989). These studies have confirmed the relatively simple dendritic tree for CRH neurons and the presence of filiform spines. Like magnocellular neurons, the dendrites of the PaMP seldom leave the Pa, but do cross into adjacent subnuclei. The axons of the parvocellular neurosecretory cells in the Pa follow closely those of the magnocellular group, emitting laterally toward the fornix before turning ventrally and posteriorly en route to the MEE (Swanson et al., 1986; Rho and Swanson, 1989; Larsen et al., 1991). Clear examples of axonal branching have been observed for CRH neurons, with local arborizations within and just outside the Pa (Liposits et al., 1985; Rho and Swanson, 1987). Synaptic contacts positive for CRH (Liposits et al., 1985; Shioda et al., 1985; Silverman et al., 1989) could arise from these collaterals, although other sources of CRH cannot be ruled out. A similar argument and reservation could be made for TRH-positive (Kiss and Hálász, 1990; Hisano et al., 1993b) and somatostatin-positive (Hisano et al., 1993a) synapses in the Pa. Golgi stains of PaMP neurons have revealed locally arborizing axons (van den Pol, 1982), but it is uncertain whether or not these represent neuroendocrine neurons.
Nonendocrine Projection Neurons Distribution of Principal Neurons A third major group of variably sized Pa neurons projects caudally to the brain stem and spinal cord and is distinctly separate from the other two groups (e.g., Hoysoya and Matsushita, 1979; Armstrong et al., 1980; Swanson and Kuypers, 1980). These neurons primarily contact autonomic preganglionic and related nuclei and are treated in detail in Chapter 24 of this volume. The dorsomedial cap (PaDC), the ventral Pa (PaV), and the posterior subnucleus (PaPo) are the primary sources of these projections (Figs. 3 and 6). The PaDC is more involved with the projection to the intermediolateral cell column, and the PaV and PaPo contribute fibers to both the spinal cord and several brain stem regions, most notably the dorsal motor nucleus of the vagus,
other preganglionic autonomic nuclei, the Sol, the periaqueductal gray, the dorsal raphe nuclei, the locus coeruleus, the area postrema, the parabrachial nucleus, the pedunculopontine nucleus, and the ventrolateral reticular nucleus (region of A1 noradrenergic neurons) (Saper et al., 1976; Luiten et al., 1985; Shapiro and Miselis, 1985; Hoysoya et al., 1991; Shafton et al., 1998; Pyner and Coote, 2000). A very small proportion of this descending projection derives from paraventricular AVP neurons and a more substantial, but still small, element from OX neurons (Sofroniew and Schrell, 1982; Sawchenko and Swanson, 1982b; Jansen et al., 1995). Other peptides make contributions to the descending pathway, including bombesin (Costello et al., 1991), CRH (Sawchenko, 1987; Milner et al., 1993; Jansen et al., 1995), and angiotensin II (Jansen et al., 1995). Functionally, descending Pa projections may operate either via these peptides or with classical amino acid transmitters such as glutamate (e.g., Coote et al., 1998). With few exceptions, descending Pa axons do not branch to the neural lobe (Swanson and Kuypers, 1980), but there is overlap between brain stem- and spinal cord-projecting components (Swanson and Kuypers, 1980; Shafton et al., 1998; Pyner and Coote, 2000). Less well examined is the degree to which median eminence-projecting and extrahypothalamic-projecting Pa neurons overlap, but this is predicted to be small based on the topographic segregation of projection neurons in the Pa. In addition to the projection to the median eminence, neurons from the PaMP project to two other circumventricular organs, the SFO and the OVLT, as well as to the pineal gland (Larsen et al., 1991). Additional pathways to di- and telencephalic regions are a dorsal pathway to the region of the thalamic paraventricular nucleus; a ventrolateral projection to the medial and central nucleus of the amygdala; a rostroventral projection to the anteroventral periventricular nucleus (Larsen et al., 1991); and possible intrahypothalamic connections to the anterior hypothalamus, the dorsoand ventromedial nuclei, the arcuate nucleus, and the perifornical regions (Luiten et al., 1985; Ter Horst and Luiten, 1987; Larsen et al., 1991). Morphology and Efferent Pathway The size of PaV, PaDC, and PaPo neurons varies considerably, but more medium- and even large-sized neurons are found than are present in the PaMP and PaAP (Kiss et al., 1991). These neurons have longer dendrites that branch more often but are less spinous than either group of neuroendocrine cells (Rho and Swanson, 1989). Medially oriented dendrites of the PaPo may project anteromedially, posteromedially, and even across the midline (Figs. 6B and 6C), but many have a strong perpendicular orientation with respect to the 3V
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(Fig. 7) (Stern, 2001). In addition, fusiform neurons in the PaPo also have one or more lateral dendrites projecting toward and sometimes over the fornix. These lateral dendrites branch and can give rise to an axon, or one may gradually taper to appear axonal (Armstrong et al., 1980; van den Pol, 1982; Hatton et al., 1985; Shapiro and Miselis, 1985). Neurons in both the PaV and the PaPo with descending projections are heterogeneous in their dendritic morphology and their physiology, suggesting functional subsets within these divisions (Stern, 2001). The axonal projection paths of this group of Pa neurons are diverse (Saper et al., 1976; Luiten et al., 1985; Larsen et al., 1991; Ranson et al.,1998). Many axons in the PaV, PaDC, or PaPo emit from a primary dendrite or soma and project laterally or ventrolaterally (Armstrong et al., 1980; Van den Pol, 1982; Rho and Swanson, 1989; Stern, 2001) (Fig. 7). In some cases, these axons branch and the collateral returns to the Pa (Rho and Swanson,
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1989). Fibers innervating the dorsal thalamus emit directly dorsally, or course posteriorly along the midline before turning dorsally. Fibers innervating the amygdala take a ventrolateral course beneath the internal capsule or cerebral peduncle. Descending projections have been divided into a midline pathway innervating the periaqueductal gray, raphe, parabrachial nuclei, and locus coeruleus and another pathway which originates from the caudal portion of the Pa and stays medial until the midbrain, where it moves laterally and hugs the medial aspect of the cerebral peduncle (Luiten et al., 1985; Ranson et al., 1998). From the midbrain, this second pathway moves ventrally, and the medial pathway shifts laterally and ventrally. The two paths converge in the ventral medulla and from there send fibers to the area postrema, the Sol, the dorsal vagal complex, and the ventrolateral medulla (A1 region). The main projection to the spinal cord is through the dorsolateral funiculus, with branches innervating the intermediolateral cell column. Rostral projections (Larsen et al., 1991) travel along the ventricle or course anterolaterally to invade the bed nucleus of the stria terminalis and the medial preoptic area. Rostral periventricular fibers project to the OVLT and some turn dorsal to innervate the subfornical organ.
Paraventricular Interneurons
FIGURE 7 Drawing of a PaPo neuron. This neuron was identified as preautonomic following retrograde tracing from the dorsomedial medulla. The retrograde label was observed in a coronal slice in vitro, and the neuron was visually patched for whole cell electrophysiological recording and filled with biocytin. The dendrites had a strong mediolateral orientation, with medial dendritic branches (arrowheads) projecting near the third ventricle (3V). The axon projected ventrolaterally. Inset shows the location of the neuron in the Pa in coronal section. Modified from Stern (2001).
It is not certain whether some Pa cells are true interneurons (i.e., their axon solely innervates within the nucleus), but at the least there are axon collaterals from Pa neurons that make intrinsic connections. Some Golgi-impregnated parvocellular neurons in the PaMP have extensive axon collateral arbors that terminate in both the PaMP and the magnocellular PaLM groups (van den Pol, 1982). Some identified projection neurons, including CRH neurons, have recurrent axon collaterals (Rho and Swanson, 1989) that could be in part responsible for CRH-positive synapses within the periventricular zone (Silverman et al., 1989) and the magnocellular regions (Liposits et al., 1985), onto TRH neurons (Hisano et al., 1993b), and even recurrently onto CRH neurons (Liposits et al., 1985) Extensive intrinsic connections may account for the many axon terminals that are immunoreactive for peptides present in other Pa-projecting cell groups (e.g., TRH) and that are presynaptic to homo- and heterotypic elements (e.g., Kiss and Halasz, 1990; Hisano et al., 1993b), but an extrinsic origin cannot be discounted. In addition to peptides, classical neurotransmitters are likely involved with intrinsic Pa circuits. Like the SO, the Pa receives a dense GABAergic and glutamatergic input, part of which comes from neurons in or near the Pa as indicated by both anatomical (Roland and Sawchenko, 1993)
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and physiological studies (Tasker and Dudek, 1993; Boudaba et al., 1996, 1997).
Afferent Inputs Brain Stem Inputs Consistent with its diverse population of principal neurons, the Pa has a diverse source of inputs (Hatton, 1990; Armstrong, 1995; also see Chapters 14 and 24, by Simerly and by Saper, this volume). Like the SO, the most well described are dense projections from the brain stem nuclei rich in catecholamine neurons (Tribollet and Dreifuss, 1981; Sawchenko and Swanson, 1982a; McKellar and Loewy, 1981). As some of these connections relate to the role of the Pa in autonomic function, they are treated in detail in the chapter by Saper (Chapter 24). Different catecholamine groups have relatively different but overlapping targets within the Pa. The medullary A1 projection favors the AVP cells of the PaLM (but also innervates the PaMP), the A2 group favors the PaMP (but does not exclude the PaLM and PaMM), and the locus coeruleus (A6) projects to the more medial periventricular zone (Swanson et al., 1986; Cunningham and Sawchenko, 1988). While the majority of these fibers contain noradrenaline, with some colocalization in A1 with neuropeptide Y and galanin (Levin et al., 1987), there are smaller inputs from nearby adrenaline-containing nuclei (C1–C3) to the parvocellular parts of Pa, which colocalize neuropeptide Y (Sawchenko et al., 1985; Alonso, 1993). Within the PaMP, A1/C1 neurons undoubtedly target both TRH (Shioda and Nakai, 1993; Diano et al., 1998) and CRH (Kitazawa et al., 1987) neurons. In addition to the functions mentioned above for catecholaminergic pathways in the SO relative to OX and VP release, brain stem adrenergic and noradrenergic pathways also play important roles in physiological functions related to the parvocellular neurosecretory system. For example, these pathways are activated by both intero- and exteroceptive stress stimuli which activate CRH neurons and result in corticosterone release. In some cases, however, the activation of catecholaminergic cell groups may be secondary to the response of neurons (such as those in Pa) with which they make reciprocal connections (Li et al., 1996). A small number of Sol neurons projecting to the Pa (and probably to SO) are separate from catecholamine neurons. One group is immunoreactive for the gonadal peptide inhibin-β (activin) and favors the region of OX neurons (Sawchenko et al., 1988b), and a second group contains somatostatin and innervates parvocellular zones and also OX regions (Sawchenko et al., 1988a). The peptide PACAP is also present in several Sol and
ventrolateral medullary neurons (Legradi et al., 1994; Shioda et al., 2000). Some PACAP-positive terminals in the PaMP that innervate TRH- and CRH-positive neurons (Legradi et al., 1997, 1998) may derive from these inputs. Enkephalinergic inputs to the Pa also derive from lateral reticular and, to a small extent, Sol neurons (Beaulieu et al., 1996). While some afferents are relatively selective for Pa subgroups, the input topography also can reflect differences in dendritic vs somatic inputs. For example, the dendrites of OX and AVP neurons in the PaMM and PaML can cross into other Pa regions (Fig. 6), particularly into the PaDC, PaV, and PaMP, and it is known that noradrenergic synapses occur largely on Pa dendrites (Olschowka et al., 1981), some of which have been identified as AVP-containing and in the medial zone (Silverman et al., 1983; Ochiai and Nakai,1990). Second, local axon collaterals terminate in both parvo- and magnocellular regions. Third, some axons innervating the Pa bifurcate to supply both parvo- and magnocellular regions (van den Pol, 1982). Thus, while a particular input may prefer one cell type (e.g., Sol to OX and PaMP neurons, A1 to CRH and AVP neurons), a significant overlap may exist (Renaud and Bourque, 1991). Additional brain stem regions that provide a significant innervation of the Pa are the lateral parabrachial nucleus (Saper and Loewy, 1980), the median and dorsal raphe (containing serotonergic neurons) (Sawchenko et al., 1983; Petrov et al., 1992), and the ventral periaqueductal gray (Floyd et al., 1996). Forebrain and Hypothalamic Inputs SFO and MnPO inputs to the Pa are extensive (Miselis, 1981; Tribollet and Dreifuss, 1981; Silverman et al., 1981; also see Oldfield and Mckinley, Chapter 16, this volume) and may contact many subregions (Sawchenko and Swanson, 1983). Additional forebrain and hypothalamic inputs seem primarily directed to the nonmagnocellular subnuclei. These include afferents from most preoptic and hypothalamic nuclei, including the anteroventral periventricular nucleus, the arcuate nucleus, the dorsomedial nucleus, the lateral hypothalamus, the medial preoptic area, and the rostral periventricular area (Berk and Finkelstein, 1982; Sawchenko and Swanson, 1983; Simerly and Swanson, 1988; Standaert and Saper, 1988; Thompson et al., 1996; Csaki et al., 2000; Mihaly et al., 2001). A large portion of the galanin innervation of Pa comes from the dorsomedial nucleus (Levin et al., 1987). The arcuate nucleus provides ACTH/MSH (Sawchenko et al., 1982; Kiss et al., 1984) and NPY (Kalra and Crowley, 1992; Legradi and Lechan, 1998). The input from the anteroventral periventricular nucleus is immunoreactive for atrial natriuretic peptide (Standaert and Saper, 1988). Another prominent
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afferent source to the Pa is the bed nucleus of the stria terminalis (Silverman et al., 1981; Tribollet and Dreifuss, 1981; Sawchenko and Swanson, 1983), the projections of which can be divided according to the originating subdivision. The lateral division of the dorsal bed nucleus projects primarily to the PaAP, whereas denser and more widespread projections to many Pa subdivisions emanate from the fusiform subnucleus (Dong et al., 2001). Some forebrain inputs to the Pa, like those from the lateral septum and the ventral subiculum, may largely outline the nucleus rather than project within it (Sawchenko and Swanson, 1983). Nevertheless, direct projections to both OX and AVP dendrites from these regions have been confirmed with the electron microscope in this perinuclear position (Oldfield et al., 1985). The central and medial amygdaloid nuclei project largely to parvocellular regions of the Pa, including both MEE- and brain stem/spinal cord-projecting groups (Silverman et al., 1981; Tribolett and Dreifuss, 1981; Gray et al., 1989), but again, synapses with AVP and OX dendrites have been noted (Oldfield et al., 1985). This reinforces the need to consider dendritic cytoarchitecture and ultrastructure to fully explore synaptic connectivity. According to Prewitt and Herman (1998), direct amygdaloid projections to the Pa may be weak relative to central and medial nucleus projections to neurons in the bed nucleus of the stria terminalis, which in turn project to the Pa. Many of the hypothalamic and forebrain inputs to the Pa are thought to be glutamatergic (Csaki et al., 2000) or GABAergic (Roland and Sawchenko, 1993), including local inputs (Tasker et al., 1998). The perifornical and lateral hypothalamic regions also contain substantial numbers of neurons colocalizing CART and melanin concentrating hormone which project to the parvocellular parts of the Pa (Broberger, 1999; Peyron et al., 1998). The same regions house, in separate neuronal populations, hypocretin/orexin-containing neurons (Peyron et al., 1998; Broberger, 1999) which project to the Pa and widely in the CNS. Both peptides, and the Pa, have been implicated in energy balance (Meister, 2000), but hypocretin/orexin is also strongly associated with arousal state, and its absence correlates with narcolepsy (Sutcliffe and de Lecea, 2000). Originally described by Sofroniew and Weindl (1978), the suprachiasmatic nucleus (SCh) provides projections primarily to the parvocellular Pa (Berk and Finkelstein, 1981; Watts et al., 1987; Watts and Swanson, 1987). These projections give the Pa, and its hormonal and preautonomic outflow, direct access to circadian clock outputs. The SCh consists of two distinct regions with different connections and cell types. A dorsomedial shell, which contains VP neurons, is largely responsible for the Pa
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inputs (Sofroniew and Weindl, 1978; Vrang et al., 1995; Larsen, 1999; Teclemariam-Mesbah et al.,1999; Leak and Moore, 2001). The ventrolateral core, which receives direct retinal input and contains vasoactive intestinal polypeptide (VIP) and gastrin-releasing peptide neurons, projects much more strongly to the adjacent subparaventricular zone. However, a few direct Pa projections from the ventrolateral SCh, including VIP fibers, are suggested by close proximity of terminal-like profiles and the somata and dendrites of spinal cordprojecting neurons (Teclemariam-Mesbah et al., 1997; Vrang et al., 1997) and by transneuronal tracing studies (Teclemariam-Mesbah et al.,1999). Thus, outputs from both divisions of the SCh are important for circadian influences on sympathetic outflow (e.g., to the pineal for control of melatonin) by way of the intermediolateral cell column. Light microscopic evidence also supports direct SCh projections to CRH neurons in the PaMP (Vrang et al., 1995). Electrophysiologically, Pa neurons (including those in magnocellular subdivisions) can get conventional inhibitory or excitatory inputs from the SCh depending on their location in the Pa and their output target (Hermes and Renaud, 1993). Inputs to spinal cord-projecting neurons appear to be direct and mediated by GABA or glutamate (Cui et al., 2001). As with the SO, a variety of neurotransmitters and neuromodulators, and their receptors, have been located within the Pa (Hatton, 1990; Renaud and Bourque, 1991). Of these, GABA and glutamate are particularly important (Decavel and van den Pol, 1990; Decavel and van den Pol, 1992; Cullinan, 2000; Csaki et al., 2000). Considered with some of the above evidence, GABA synapses could arise from (1) interneurons; (2) collaterals of MEE-projecting neurons, including those colocalizing CRH; (3) local projection neurons in the subparaventricular zone, the perinuclear zone of the SO, and the anterior perifornical region; or (4) as discussed above for the SO, the several areas, such as the bed nucleus of the stria terminalis, which have many GABAergic neurons and which project to the Pa (van den Pol, 1982; Meister et al., 1988; Okamura et al., 1990; Rho and Swanson, 1989; Decavel and van den Pol, 1992; Cullinan et al., 1993; Roland and Sawchenko, 1993). Glutamatergic projections are thought to arise from a wide number of Pa inputs, but forebrain and hypothalamic inputs are particularly important (Csaki et al., 2000). In addition to adrenaline and noradrenaline, dopamine also provides a more substantial and homogenous synaptic input to the Pa than to the SO (Buijs et al., 1984; DeCavel et al., 1987). The source of dopamine remains to be clarified, but probably stems from some intrinsic parvocellular neurons and from other diencephalic sources (e.g., zona incerta, periventricular hypothalamus).
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ACCESSORY MAGNOCELLULAR NEUROSECRETORY NEURONS As illustrated in Figs. 3 and 6, about one-third of the magnocellular OX and AVP neurons lie outside the confines of the SO and the Pa (Rhodes et al., 1981). Two of these groups are almost exclusively composed of OX neurons and deserve special mention because they are often treated as part of the Pa (Swanson and Kuypers, 1980; Swanson et al., 1986). These are the AC and the PeM, both of which project to the neurohypophysis, as do additional accessory groups (e.g., Sherlock et al., 1975; Armstrong et al., 1980; Ju et al., 1986). The AC lies some 300–400 μm rostral to, and is discontinuous with, the other clusters of magnocellular Pa neurons (Armstrong et al., 1980; Kiss et al., 1991). Its dendritic orientations are strongly medial, toward the third ventricular wall, and posteromedial (Fig. 6) (Armstrong et al., 1980, 1982a; Ju et al., 1986, 1992). The PeM is closely associated with the AC, beginning at the same level but extending caudally (Armstrong et al., 1980; Ju et al., 1986). Neurons of the PeM have dendritic ramifications that form a dense subependymal plexus (Sofroniew and Glasmann, 1981; Ju et al., 1986, 1992). There are additional magnocellular accessory cell groups, the more prominent being the posterior and anterior fornical nuclei, the nucleus circularis, neurons within the medial forebrain bundle in the lateral hypothalamus, scattered neurons in the lateral preoptic area and lateral hypothalamus, and neurons within the boundary of the bed nucleus of the stria terminalis. The morphology of individual accessory neurons has been well studied by Sofroniew and Glasmann (1981), who noted that some of these cells had thick processes with terminal swellings and, occasionally, two axon-like processes. Accessory nuclei neurons are often associated with vasculature (Ambach and Palkovits, 1979) and their processes often project along blood vessels (Ju et al., 1986; Riva et al., 1999). Each cluster has a unique appearance. For example, the nucleus circularis contains cells that are tightly packed around blood vessels, exhibit extensive somatic–somatic appositions, and have only a sparse dendritic tree (Tweedle and Hatton, 1976; Ju et al., 1986). While accessory nuclei share some inputs with the SO and the PA, like that from the SFO (Miselis, 1981), their differing topography and dendritic structure may be associated with differences in connectivity and neurochemical expression. Examining a large variety of neuropeptides/neurotransmitters in two structures, Duan et al. (1998) found that the terminal-like patterns observed in the SO and the Pa were found in an accessory nucleus of the lateral hypothalamus, whereas nucleus circularis somata were seldom contacted. Some accessory nuclei show Fos responses to peripherally
administered CRF and urocortin that are different from those of the SO and Pa (Wang et al., 2000) and have different levels of coexpression of NADPH-diaphorase and acetylcholinesterase (Crespo et al., 1998). But in general, accessory nuclei respond to physiological stimuli such as dehydration (Ding et al., 1994) and hypovolemic challenge (Shen et al., 1992) in a fashion similar to that of the SO and Pa. In other species, some magnocellular accessory groups do not project to the neural lobe and may have central functions (Ferris, 1992).
CONCLUSION Understanding the functional circuitry of the Pa, SO, and related hypothalamic systems remains challenging on several fronts. The relationship between the release of hormones such as VP and OX and peripheral stimuli is well understood, even if many details of connectivity (e.g., how is the suckling stimulus transferred to OX neurons?) are not. For questions such as these, transneuronal tracing studies in combination with functional neuroanatomical probes (e.g., Fos localization) hold great promise. But perhaps the greatest general challenge is for detailed studies of connectivity to keep apace with new neurochemical discoveries. It is critical that colocalization of neuroactive substances in these nuclei, and their activity-dependent expression, not be studied at the expense of determining precise neuroanatomical relationships, especially synaptic connectivity. The necessity to combine these efforts is nowhere more important than in the Pa, where the wide variety of neurons, functions, and connectivity is truly daunting. The functional plasticity of this system and the meaning of functionally labile chemical maps remains a challenge for interpreting anatomical data. For example, more is known of the relationships of GABAergic and glutamatergic synaptic terminals in the SO than is known about their precise source. The ability to visually identify anatomically (through prior tracer placement) or neurochemically (with markers such as green fluorescent protein) defined neurons, or terminals, in complex electrophysiological recording experiments is another promising multidisciplinary effort. In this regard, the precise topographic distinctions among major Pa cell types and their separable efferent targets discovered over 20 years ago remain a solid foundation for expanding functionally related neuroanatomical studies in this nucleus.
Acknowledgments This chapter was completed while the author was supported by NIH Grants NS 23941 and HD 41002.
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in glucocorticoid-sensitive vasopressin and corticotropin-releasing factor neurons in the hypothalamic paraventricular nucleus. J. Neurosci. Res. 19, 405–411. Van den Pol, A. N. (1982). The magnocellular and parvocellular paraventricular nucleus of rat: Intrinsic organization. J. Comp. Neurol. 206, 317–345. Van den Pol, A. N. (1991). Glutamate and aspartate immunoreactivity in hypothalamic presynaptic axons. J. Neurosci. 11, 2087–2101. Vandesande, F., and Dierickx, K. (1975). Identification of the vasopressin producing and of the oxytocin producing neurons in the hypothalamic magnocellular neurosecretory system of the rat. Cell Tissue Res. 164, 153–162. Vandesande, F., Dierickx, K., and DeMey, J. (1977). The origin of the vasopressinergic and oxytocinergic fibers of the external region of the median eminence of the rat hypophysis. Cell Tissue Res. 180, 443–452. Van Leeuwen, F. W., De Raay, C., Swaab, D. F., and Fisser, B. (1979). The localization of oxytocin, vasopressin, somatostatin and luteinizing hormone releasing hormone in the rat neurohypophysis. Cell Tissue Res. 202, 189–201. Vigh, B., and Vigh-Teichmann, I. (1998). Actual problems of the cerebrospinal fluid-contacting neurons. Microsc. Res. Tech. 41, 57–83. Vrang, N., Larsen, P. J., Clausen, J. T., and Kristensen, P. (1999). Neurochemical characterization of hypothalamic cocaineamphetamine-regulated transcript neurons. J. Neurosci. 19, RC5, 1–8. Vrang, N., Larsen, P. J., Müller, M., and Mikkelsen, J. D. (1995). Topographical organization of the rat suprachiasmatic-paraventricular projection. J. Comp. Neurol. 353, 585–603. Vrang, N., Mikkelsen, J. D., and Larsen, P. J. (1997). Direct link from the suprachiasmatic nucleus to hypothalamic neurons projecting to the spinal cord: A combined tracing study using cholera toxin subunit B and Phaseolus vulgaris-leucoagglutinin. Brain Res. Bull. 44, 671–680. Wang, L., Martinez, V., Vale, W., and Tache, Y. (2000). Fos induction in selective hypothalamic neuroendocrine and medullary nuclei by intravenous injection of urocortin and corticotropin-releasing factor in rats. Brain Res. 855, 47–57. Watts, A. G., and Swanson, L. W. (1987). Efferent projections of the suprachiasmatic nucleus. II. Studies using retrograde transport of fluorescent dyes and simultaneous peptide immunohistochemistry in the rat. J. Comp. Neurol. 258, 230–252. Watts, A. G., Swanson, L. W., and Sanchez-Watts, G. (1987). Efferent projections of the suprachiasmatic nucleus. I. Studies using anterograde transport of Phaseolus vulgaris leucoagglutinin in the rat. J. Comp. Neurol. 258, 204–229. Wiegand, S. J., and Price, J. L. (1980). Cells of origin of the afferent fibers to the median eminence in the rat. J. Comp. Neurol. 192, 1–19. Whitnall, M. H., and Gainer, H. (1988). Major pro-vasopressinexpressing and pro-vasopressin-deficient subpopulations of corticotropin-releasing hormone neurons in normal rats. Neuroendocrinology 47, 176–180. Wuarin, J. P. (1997). Glutamate microstimulation of local inhibitory circuits in the supraoptic nucleus from rat hypothalamus slices. J. Neurophysiol. 78, 3180–3186. Xi, D., Kusano, K., and Gainer, H. (1999). Quantitative analysis of oxytocin and vasopressin messenger ribonucleic acids in single magnocellular neurons isolated from supraoptic nucleus of rat hypothalamus. Endocrinology 140, 4677–4682. Yamada, K., Emson, P., and Hokfelt, T. (1996). Immunohistochemical mapping of nitric oxide synthase in the rat hypothalamus and colocalization with neuropeptides. J. Chem. Neuroanat. 10, 295–316. Yang, C. R., Senatorov, V. V., and Renaud, L. P. (1994). Organum vasculosum lamina terminalis-evoked postsynaptic responses in rat supraoptic neurones in vitro. J. Physiol. 477, 59–74.
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Seven circumventricular organs (CVOs) are recognized in the brain of the rat and earn this classification because they are all located in the walls of the lateral, third, or fourth cerebral ventricles (Hofer, 1958). The subfornical organ, vascular organ of the lamina terminalis (OVLT), pineal gland, subcommissural organ, and median eminence/neurohypophysial complex are located at various positions in the wall of the third ventricle (Fig. 1A). The area postrema is found in the wall of the fourth ventricle (Figs. 1A and 2B). The choroid plexus can be found within the lumen of the lateral, third, or fourth ventricle (Figs. 1A, 1C, and 2B).
The ependymal cells forming the ventricular surfaces of the CVOs also are different in appearance from the regularly apposed cuboidal ependyma lining the rest of the ventricular surface. Ependymal cells of the CVOs can be elongated or columnar and of irregular appearance. They either are devoid of or have very few cilia on their luminal surface (Weindl and Joynt, 1971; Phillips et al., 1974; Dellman and Simpson, 1979; McKinley et al., 2003). This contrasts with the densely ciliated surfaces of normal ventricular ependyma. Another way in which the ependymal cells of the CVOs are different from normal ependyma is the presence of tight junctions between adjacent cells. This restricts the passage of marker molecules, such as horseradish peroxidase (HRP), between cerebrospinal fluid and the CVO interstitium and vice versa (Weindl, 1973; Krisch et al., 1978; Broadwell and Brightman, 1976; McKinley et al., 1990). Thus, it is thought that the blood–brain barrier is shifted from the level of the capillary endothelium to the ependyma in the CVOs. The choroid plexus and subcommissural organ are composed of one or more layers of modified ependymal cells and do not contain nerve cell bodies. These were termed ependymal CVOs by Kuhlenbeck (1970), whereas the remaining CVOs were termed paraependymal CVOs because they have subependymal elements that differ greatly from those of the ependymal cells. Only the subfornical organ, OVLT, and area postrema contain neuronal perikarya. They have many common features and have been classified as the sensory CVOs (Johnson and Gross 1993). These three CVOs have
GENERAL FEATURES Although there is not a uniformity of structure, several features distinguish CVOs from other regions of the brain. All are highly vascularized structures and possess unusual vascular arrangements, with many capillary loops reaching near to the ventricular surface (Duvernoy and Koritke, 1964). From a functional point of view, probably the most interesting aspect of the vascular morphology is the presence of capillaries having fenestrated endothelial cells in all CVOs except the subcommissural organ (Weindl, 1973; Weindl and Joynt, 1973). This results in the blood–brain barrier being disrupted in all but one of the CVOs, and, unlike the rest of the brain, there can be bidirectional movement of polar molecules between the hemal and the neural environments of the CVOs.
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FIGURE 1 (A) Location of the circumventricular organs shown on a sagittal section through the third ventricle of the rat brain. The choroid plexus of the lateral ventricle is not shown. The lateral part of the area postrema appears in the section because at this level the section is just lateral to the midline. The bar represents 1 mm. Stain; cresyl violet/luxol fast blue. (B) Enlarged view of the rat OVLT. Bar represents 250 μm. Stain: cresyl violet. (C) Enlarged view of the subfornical organ. Bar represents 100 μm. Stain, cresyl violet/luxol fast blue. Abbreviations used: ac anterior commissure; AP, area postrema; ChP, choroid plexus; ME, median eminence; MnPO, median preoptic nucleus; ox, optic chiasm; OVLT, vascular organ of the lamina terminalis; pc, posterior commissure; Pi, pineal gland; PiRe, pineal recess of the third ventricle; NH, neurohypophysis; SCO, subcommissural organ; SFO, subfornical organ; vhc, ventral hippocampal commissure; 3V, third ventricle.
extensive afferent and efferent neural connections and a distinctive cytoarchitecture and cytochemistry. The remainder of this chapter considers the structure, connectivity, and neurochemical characteristics of the three sensory CVOs. Brief individual descriptions of the other CVOs then follow.
SUBFORNICAL ORGAN The subfornical organ (also known as the intercolumnar tubercle in the older literature) was recognized initially in the brain of an Australian bat, Nictophylus timoriensis, by Elliot Smith (1898) and first
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FIGURE 2 (A) Enlarged view of the rat subcommissural organ in midsagittal section shown in Fig. 1A. Arrows indicate the extent of the subcommissural organ at the entrance to the aqueduct of Sylvius. The bar represents 100 μm. (C) Enlarged view of the area postrema at the entrance to the central canal in the midsagittal section. The bar represents 100 μm. Abbreviations used: AP, area postrema; Aq, aqueduct of Sylvius, cc, central canal; ChP, choroid plexus; hbc, habenular commusure; pc, posterior commissure; PiRe, pineal recess of the third ventricle; SCO, subcommissural organ; SFO, subfornical organ; 4V, fourth ventricle.
described in detail (in the human brain) by Putnam (1922). It is a prominent feature in Nissl-stained sections of the rat brain. Situated in the anterior dorsal wall of the third ventricle, at the confluence of the two interventricular foramina and the third ventricle, the subfornical organ of the rat lies ventral to the hippocampal commissure and caudoventral to the junction of the two fornical columns (Figs. 1A, 1C, and 3E). Its dorsal extremity connects to the tela choroidea, whereas the ventral stalk of the subfornical organ merges into the median preoptic nucleus. Rostrally the septal triangularis nucleus bounds the subfornical organ (Akert et al., 1961). The subfornical organ has been subdivided into several subregions by Sposito and Gross (1987). Two major subregions can clearly be defined on the basis of neural connectivity, receptor densities, vasculature, and function as shown by expression of the immediate early gene c-fos (McKinley et al., 2003). These are an inner “ventromedial core” and a peripheral “outer shell” (Figs. 3E and 3F; also see Figs 146 and 147 of Paxinos et al., 1999) As with other CVOs, the subfornical organ is highly vascularized (Fig. 3A). It contains an extensive network of capillaries taking the form of sinusoids and capillary loops (Spoerri 1963; Duvernoy and Koritke, 1964). The perivascular space is extensive and labyrinthine, and both fenestrated and nonfenestrated capillary endothelia are observed. Intravascularly administered horseradish peroxidase enters the total intercellular space of the subfornical organ, indicative that the entire organ is exposed to the hemal milieu (Broadwell and Brightman, 1976; McKinley et al., 1990). The ventrome-
dial core of the subfornical organ is reported to have the greatest density of capillaries and neurons (Sposito and Gross 1987). Neurons are distributed throughout the subfornical organ and have been classified into two types in the rat depending on whether or not they have vacuoles (Dellmann and Simpson, 1979; Dellman 1998). At the ventricular surface, the ependymal cells are flattened. Cilia are absent from many of the ependymal cells in the central part of the subfornical organ, whereas isolated ependymal cells around the periphery exhibit tufts of cilia (Phillips et al., 1974; McKinley et al., 2003).
Afferent Neural Connections Early studies in the rat, utilizing lesions and Golgi techniques, showed afferent neural input to the subfornical organ from the adjacent median preoptic nucleus and the triangular septal nucleus (Hernesniemi et al., 1972). A later study using anterogradely transported amino acids as tracers did not confirm the projection from the septal triangularis nucleus (Miselis et al., 1979). Other investigations, which utilize conjugates of HRP or fast blue injected into the subfornical organ, have confirmed that the median preoptic nucleus provides the richest afferent input to the subfornical organ (Lind et al., 1982, 1984; Saper and Levisohn, 1983). Approximately 20% of neurons in the median preoptic nucleus with projections to the subfornical organ also exhibit collateral branches projecting to the supraoptic nucleus (Oldfield et al., 1992). Another CVO in the lamina terminalis, the OVLT, also has neurons projecting to the subfornical organ (Lind et al., 1982; Gu and Simerly,
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FIGURE 3 (A, B) The circumventricular organs are the most vascularized structures in the brain. The extensive network of blood vessels in the rat subfornical organ is shown in A and the area postrema in B. Many looping and intertwining capillaries can be seen. The blood vessels have been filled with a mixture of Indian ink in gelatine that was injected through the heart postmortem. Bars = 200 μm. (C–F) Immunohistochemical detection of Fos expression in response to intravenous (iv) infusion of either angiotensin II or relaxin reveals functional subdivisions in the rat OVLT and subfornical organ. Fos-labeled cell nuclei are observed mainly in the lateral zone of the OVLT in response to infusion of angiotensin II (1 μg/h). The dorsal cap region of the OVLT shows considerably less Fos in response to iv infusion of angiotensin II (C), whereas the dorsal cap is the main site of Fos expression in response to iv infusion of relaxin at 25 μg/h (D). (E). Infusion of angiotensin II (0.3 μg/h) stimulates Fos expression in the ventromedial core of the subfornical organ, while infusion of relaxin (25 μg/h) stimulates Fos expression in the outer shell of the subfornical organ (F). Bars = 100 μm. Abbreviations used: AP, area postrema; cc, central canal; ChP, choroid plexus; cp, capillary plexus; dc, dorsal cap of the OVLT; Vhc, hippocampal commissure; lz, lateral zone of the OVLT; Sol, nucleus of the solitary tract; ox, optic chiasm or optic recess of the third ventricle; os, outer shell of the subfornical organ; vc, ventromedial core of the subfornical organ; 3V, third ventricle; 4V, fourth ventricle.
1997; McKinley et al., 2003), with up to 30% showing collaterals connecting to the supraoptic nucleus (Oldfield et al., 1992). Additional sites of afferent input to the subfornical organ are the paraventricular hypothalamic nucleus (Larsen et al., 1991); the medial preoptic,
dorsal preoptic, and anterior hypothalamic regions; and the medial septum, but these are present in densities lower than those in the lamina terminalis (Lind et al., 1982). Neurons in the zona incerta and reuniens nucleus of the thalamus also have projections to the subfornical
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organ, and along with the perifornical region of the anterior hypothalamus these connections appear to terminate in the ventromedial core of the subfornical organ and contain angiotensin II (Lind et al., 1984). Afferent neural connections to the subfornical organ from more caudal brain regions have also been identified. These projections are from the locus coeruleus (Miselis et al., 1987), the dorsal and median raphe (Lind, 1987), the lateral parabrachial nucleus (Gu and Ju, 1995), and the nucleus of the solitary tract (ZardettoSmith and Watson, 1987; Ciriello et al., 1996) to the subfornical organ.
Efferent Neural Connections As a result of studies using anterogradely transported amino acids (radiolabeled), three major efferent projections from subfornical organ neurons were initially identified. These were the median preoptic nucleus, the OVLT, and the supraoptic nucleus (Miselis et al., 1979). Subsequently, these findings have been confirmed, and connections to the paraventricular hypothalamic nucleus (both parvocellular and magnocellular regions), the anterior periventricular preoptic region, the dorsal perifornical area, the ventromedial region of the lateral preoptic region, and the lateral hypothalamus have been reported by two independent studies (Miselis, 1981; Lind et al., 1982). Some subfornical neurons have been found to have axons with branches projecting to both the supraoptic and the hypothalamic paraventricular nuclei (Weiss and Hatton, 1990), although these are not common and most neurons in the subfornical organ project only to the side of the supraoptic nucleus ipsilateral to the side of the subfornical organ in which they are located (Renaud et al., 1993). Other sets of terminal fields were identified when the anterogradely transported lectin Phaseolus vulgaris leucoagglutinin was injected into the subfornical organ. Neurons in the substantia innominata, the rostroventral parts of the bed nucleus of the stria terminalis, the rostral zona inserta, and the infralimbic area of the prefrontal cortex were the additional targets of subfornical efferents identified with this tracer (Swanson and Lind, 1986). Studies with retrogradely transported tracers show that, within the subfornical organ, neurons have a topographic distribution, depending on the destination of their projections. Neurons of the subfornical organ projecting to the median preoptic nucleus, supraoptic and paraventricular hypothalamic nuclei, zona incerta, prefrontal cortex, and substantia innominata are distributed mostly in an annular arrangement in the periphery of the subfornical organ, with very few retrogradely filled neurons in its ventromedial core (Miselis et al.,
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1979; Lind et al., 1982, 1984; Swanson and Lind, 1986). Two regions have been identified as the main targets of the subfornical organ neurons that occupy the ventromedial core of this CVO and these were the bed nucleus of the stria terminalis and the parvocellular subdivisions of the hypothalamic paraventricular nucleus (Swanson and Lind, 1986; McKinley et al., 2003). Recent neural tract-tracing studies in the rat which used the neurotropic virus pseudorabies injected into peripheral sites such as the kidney, gut, salivary glands, heart, forelimb muscle, and sympathetic ganglia, show that there are polysynaptic efferent neural pathways from the subfornical organ to these peripheral targets (Hubschle et al., 1998; Sly et al., 1999; Westerhaus and Loewy, 1999; Yang et al., 1999; McKinley et al., 2003). These results indicate that the subfornical organ has the potential to influence sympathetic nerves supplying many peripheral organs and tissues, as proposed by Miselis et al. (1987). Fibers emanating from the subfornical organ to the aforementioned terminal fields have two main trajectories. The first group of fibers exits from the anterior aspect of the subfornical organ and travels in a ventral direction rostral to the anterior commissure and along the anterior edge of the median preoptic nucleus to enter this nucleus as well as the OVLT and the preoptic periventricular and supraoptic nuclei. Other efferent fibers take a postcommissural route via the fornix and diverge with the stria terminalis to the medial and lateral hypothalamus, with terminations in the supraoptic and paraventricular nucleus. Some postcommissural fibers turn rostrally and join precommissural fibers bound for the median preoptic and supraoptic nuclei (Miselis, 1981; Lind et al., 1982).
Neuroendocrine Aspects Consistent with proposals that the subfornical organ is a site at which blood-borne humoral agents exert central actions are observations that this CVO contains receptor binding sites for a number of circulating hormones. These include amylin (Sexton et al., 1994), angiotensin II (Mendelsohn et al., 1984; Gehlert et al., 1986; Lenkei et al., 1997; Allen et al., 2000) (mostly the AT-1 receptor subtype), atrial natriuretic peptide (Quirion et al., 1984; Mendelsohn et al., 1987), calcitonin (Rouleau et al., 1984), glucagon-like peptide-1 (GLP-1) (Göke et al., 1995), relaxin (Osheroff and Phillips, 1991), somatostatin (Patel et al., 1986), and vasopressin (V1 receptor; Phillips et al., 1988). As well, the calcium receptor that responds to small changes in extracellular Ca2+ concentration (Rogers et al., 1997) and the lipopolysacharide CD14 receptor, which is implicated in neuroimmune responses such as fever (Lacroix et al.,
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1998), have been identified in the subfornical organ. Nitric oxide synthase (NOS) is abundant in neurons throughout all subdivisions of the subfornical organ (Jurzak et al., 1994; Alm et al., 1997). The actions of angiotensin II on the subfornical organ have been studied extensively (see Ferguson and Bains, 1997), and it is clear that this octapeptide acts on receptors in the subfornical organ to stimulate neural pathways subserving water drinking and pressor responses in the rat (Simpson et al., 1978; Simpson, 1981). Studies of c-fos expression show that circulating angiotensin II stimulates Fos production in neurons throughout the subfornical organ (McKinley et al., 1992; Rowland et al., 1996); however, neurons in the ventromedial core are more sensitive to angiotensin II and there appears to be a higher density of angiotensin II receptors within the ventromedial core of the subfornical organ than its periphery (Lenkei et al., 1997; McKinley et al., 1998; Allen et al., 2000). This distribution contrasts with the peripheral distribution within the subfornical organ of osmoresponsive neurons that project to the supraoptic nucleus (Oldfield et al., 1994). Of relevance to the actions of angiotensin II on the subfornical organ are observations of high concentrations of angiotensin-converting enzyme in this CVO (Brownfield et al., 1982; Chai et al., 1987), which may allow circulating angiotensin I to be converted to angiotensin II in the vicinity of subfornical neurons. Atrial natriuretic peptide antagonizes the dipsogenic action of angiotensin II (Masotto and Negro-Vilar, 1985), and these two peptides have an overlapping distribution of their receptors in the subfornical organ, as well as in the OVLT and the area postrema (Mendelsohn et al., 1987), suggesting that the inhibitory influence of atrial natriuretic peptide could be at the primary angiotensin-sensitive neuron in CVOs. The ovarian hormone relaxin may influence oxytocin secretion in pregnant rats via receptors in the subfornical organ (Summerlee et al., 1987). Circulating relaxin has been shown to increase the expression of c-fos in many neurons in the periphery of the subfornical organ that have efferent neural connections with the supraoptic and paraventricular nuclei (Sunn et al., 2001), and electrophysiological evidence confirms that relaxin stimulates neuronal activity in this CVO in the rat (Sunn et al., 2002). Systemically infused relaxin stimulates water drinking as well as vasopressin secretion in rats (Parry et al., 1994; Sinnayah et al., 1999) and the dipsogenic effect is abolished by ablation of the subfornical organ (Sunn et al., 2002). It is likely that the relaxin binding sites observed in the subfornical organ (Osheroff and Phillips, 1991) represent specific relaxin receptors that mediate water drinking induced by blood-borne relaxin.
In addition to receptors for angiotensin II, neurons containing this peptide have been immunohistochemically identified in the rat subfornical organ (Lind et al., 1985). These neurons are distributed mainly in the periphery of the subfornical organ and some have been shown to project to the median preoptic nucleus (Lind et al., 1984). Fibers containing angiotensin II (Lind et al., 1984, 1985; Oldfield et al., 1989), somatostatin (Krisch et al., 1978), and luteinizing hormone-releasing hormone (LHRH) (Krisch and Leonhardt, 1980; McKinley et al., 1990) terminate in the subfornical organ. Some terminals are found in the vicinity of perivascular spaces and do not make synaptic contact with other neurons, suggesting neurosecretion of peptides into the circulation of the subfornical organ (Krisch and Leonhardt, 1980; Oldfield et al., 1989).
VASCULAR ORGAN OF THE LAMINA TERMINALIS The vascular organ of the lamina terminalis forms the ventral part of the midline anterior wall of the third cerebral ventricle (Figs. 1A, 1B, and 3C). First described by Behnsen in 1927, it is commonly abbreviated as OVLT, from the Latin organum vasculosum laminae terminalis, and is also known as the supraoptic crest, medial prechiasmatic gland, or optic recess organ in the older literature. In the rat, it extends dorsally, approximately 1 mm from the optic chiasm and roof of the optic recess, the small anteroventral extension of the third ventricle. It is bounded both rostrally and caudally by liquor spaces, namely, the prechiasmatic cistern and the optic recess of the third ventricle, respectively. It is bounded by the diagonal band of Broca at its lateral edges, and the median preoptic nucleus is immediately dorsal. The OVLT and subfornical organ form the respective ventral and dorsal poles of a continuum of tissue that includes the intervening median preoptic nucleus and is collectively termed the lamina terminalis. Embryologically the subfornical organ and OVLT are derived from the same anterior pole of the neural tube and are progressively divided during development by the ingrowth of fibers that ultimately forms the anterior commissure. Therefore, it is not surprising that, in addition to the absence of a blood-brain barrier, those two regions share a commonality of structure, neural connections, receptor types, neurochemical content, and function (Landas and Phillips, 1987). The ependymal cells overlying the OVLT have tight junctions (both zonnula occludens and zonula adherens) near their apical surfaces. As previously mentioned, this is distinct from the cuboidal ependymal cells lining the remainder of the ventricular system, which lack
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junctions and therefore offer no impediment to the flow of substances between cerebrospinal fluid CSF and the parenchyma of the brain (Weindl and Joynt, 1971; McKinley et al., 1987; Landas and Phillips, 1987). The most prominent morphological feature of the OVLT, as with most CVOs, is that it contains a rich vascular plexus with specialized arrangements of the blood vessels (Duvernoy and Koritke, 1964; Mergner, 1961; Yamaguchi et al., 1993). It is this complex arrangement of blood vessels that has given rise to the compartmentalization of the OVLT into an external zone and an internal or parenchymal zone. Small branches of the preoptic artery (which are distributed from the anterior communicating artery) in the prechiasmatic cistern break up into a dense network of small vessels in the pia mater at the cisternal edge of the OVLT. Invaginations of pia mater that envelope capillary loops extend farther into the organ in a Y-shaped configuration when observed in horizontal section (Landas and Phillips, 1987), and these two vascularized regions compose the external zone. The internal zone contains a complex neuropil with neurons, fibers, glia, capillary loops, and perivascular spaces extending to near the ependyma. Many of the capillaries exhibit fenestrated endothelial cells (Rohlich and Wenger, 1969; Landas and Phillips, 1987; McKinley et al., 1987). The tight junctions normally present between the endothelial cells (the basis of the blood–brain barrier) are effectively shifted in part to the ventricular surface and partly to capillaries in the tissue at the boundary between the OVLT and adjacent brain regions (Krisch et al., 1978, 1987). The net effectiveness of junctions between specialized ependymal cells (tanycytes) at the ventricular surface and between convoluted basal processes extending to the boundaries of the OVLT is shown by the spread of blood-borne substances, such as horseradish peroxidase, through particular parts of the OVLT but not into the surrounding neuropil or into the ventricular CSF (Krisch et al., 1987). Based on neural connectivity, neuronal phenotype, and c-fos expression, three functional subdivisions of the rat OVLT can be made: a central capillary plexus, a dorsal cap region, and a lateral zone which extends caudally around the central capillary plexus into the periventricular tissue (Figs. 3C and 3D). The arterial blood supply to the fenestrated plexus of capillaries in the OVLT most commonly arises from one or two horizontally directed arterioles, which branch off the anterior communicating artery, and occasionally an arteriole that branches from an anterior cerebral artery, at the rostral margin of the organ (Ambach et al., 1970; Grafe and Weindl, 1987; see also Scremin et al., Chapter 34, for a depiction of the major arteries). The venous drainage of the OVLT is
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achieved by four to eight veins that run in a caudal direction, with the dorsal veins flowing into vessels directed toward the anterior commissure; the others extend caudally and ventrally into a venous sinus (Grafe and Weindl, 1987). This venous drainage is continuous with a surface network that eventually drains the preoptic and retrochiasmatic regions (Szabo, 1983). The arrangement of a fenestrated capillary plexus in the OVLT and the presence of neurohormones and neurotransmitters in a secretory configuration around perivascular spaces (see below) have led several workers to suggest a neuroendocrine role for the OVLT, analogous to the portal system of the median eminence (Weindl, 1973; Palkovits et al., 1978). The fact that the major venous drainage of the OVLT is to the medial preoptic region, where blood vessels are not fenestrated in the rat (Palkovits et al., 1978), is not consistent with the concept of a portal system. In this regard there is a poorly understood anastomosing vascular network that interconnects the OVLT with the subfornical organ, median preoptic nucleus, and choroid plexus (Szabo, 1983). The function for this network as a conduit for neurohormones is not clear, because the direction of blood flow is unknown. Between the centrally positioned vascular plexus and the outer margins of the OVLT is a complex internal zone consisting of a labyrinth of tanycyte processes, glial cells, and neural elements. The last are characterized by small, “primitive” neuronal cell bodies and nerve terminals. Often these terminals contain neurosecretory granules and are aligned without synaptic specializations along the basement membrane, which forms the outer margin of perivascular spaces surrounding fenestrated blood vessels. The growing list of neuropeptide releasing factors and putative transmitters contained within these terminals includes LHRH and somatostatin (Baker et al., 1975; Krisch and Leonhardt, 1980), angiotensin II (Oldfield et al., 1989), vasopressin and oxytocin (Weindl and Sofroniew, 1985), and atrial natriuretic peptide (Kawata et al., 1985). These terminals are derived from cell bodies, located largely outside the OVLT.
Afferent Neural Connections LHRH terminals arise from cell bodies in the adjacent preoptic area (Silverman et al., 1979; Palkovits et al., 1978). Similarly oxytocin fibers arise from cell bodies in the areas surrounding the OVLT (Weindl and Sofroniew, 1985). Vasopressin fibers project to the OVLT from parent cell bodies located in the suprachiasmatic nucleus (Buijs, 1978). Other areas known to project to the OVLT with nonspecified phenotype include the other components of the lamina terminalis, the subfor-
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nical organ, and the median preoptic nucleus (Miselis, 1981; Saper and Lewisohn, 1983), as well as the medial and lateral preoptic areas, the anterior lateral and dorsomedial hypothalamus, the locus coeruleus, the midbrain central gray (Camacho and Phillips, 1981; Palkovits et al., 1978), and the hypothalamic paraventricular nucleus (Larsen et al., 1991).
Efferent Neural Connections Efferent pathways from the OVLT have been studied by mapping the distribution of anterogradely transported tracer following its microinjection into the OVLT of the rat (Camacho and Phillips, 1981; Phillips and Camacho, 1987; Gu and Simerley, 1997; Uschakov et al., 2001). The major efferent pathway from the OVLT descends in the medial forebrain bundle, although a lesser number of fibers pass along the periventricular region of the hypothalamus (Gu and Simerley, 1997). There are reciprocal connections with the median preoptic nucleus and subfornical organ and hypothalamic paraventricular nucleus. A few efferent fibers ascend dorsally to reach the parastrial nucleus and the intermediate part of the lateral septal nucleus (Gu and Simerley, 1997). There also are direct neural inputs to the supraoptic nucleus which arise mainly from a compact group of neurons in the dorsal cap of the OVLT (as do the neurons in the OVLT that project to the magnocellular subdivisions of the paraventricular nucleus) and this has been confirmed by the retrograde transport of tracer molecules injected into the supraoptic nucleus. These neurons are activated by systemic hypertonicity or dehydration and may represent the major group of physiological osmoreceptors regulating vasopressin secretion (Oldfield et al., 1994; McKinley et al., 1994; Larsen and Mikkelsen, 1995; McKinley et al., 2003). Efferent connections to parvocellular regions of the paraventricular nucleus are also present (Gu and Simerley, 1997; Uschakov et al., 2001), and it is likely that the majority of these fibers come from the lateral zone of the OVLT (Sunn et al., 2001; McKinley et al., 2003). A strong projection from the OVLT to the lateral hypothalamic region has been confirmed by retrograde tracing experiments (Uschakov et al., 2001). Other regions of the hypothalamus that receive minor inputs from the OVLT are the arcuate and periventricular nuclei (Camacho and Phillips, 1981; Gu and Simerley, 1997). There are also connections to specific parts of the limbic system. These include efferent projections to the bed nucleus of the stria terminalis, which have been confirmed by retrogradely transported tracer, with this projection arising mostly from the more lateral parts of the OVLT rather than from the dorsal cap (Uschakov et al., 2001; McKinley et al., 2003).
Tracer retrogradely transports from the cingulate cortex to the dorsal cap of the OVLT (Uschakov et al., 2001) confirming that a direct projection from the OVLT to this region exists (Camacho and Phillips, 1981). More caudal brain regions that receive efferents from the OVLT are the periaqueductal gray and the lateral parabrachial nucleus (Gu and Simerley, 1997). Like the subfornical organ, tract-tracing investigations with the neurotropic virus pseudorabies show that there may be polysynaptic pathways from the OVLT to many peripheral organs and tissues (Hubschle et al., 1998; Sly et al., 1999; Westerhaus and Loewy 1999; McKinley et al., 2003). These data suggest that the OVLT connects to sympathetic nerves supplying the periphery, and this may be another means by which circulating factors may influence sympathetic vasomotor pathways. Such a scheme may provide the anatomical substrate for the effects of anteroventral third ventricle wall (AV3V) lesions attenuating experimentally induced hypertension (Brody et al., 1978).
Neuroendocrine Aspects As mentioned above, the OVLT is a site of dense LHRH containing fibers and terminals (Silverman et al., 1979) and may play a role in regulating estrous cycles (Wenger and Leonardelli, 1980). NO synthase is also present in neurons and fibers in the OVLT (Jurzak et al., 1994), although its function in the OVLT has yet to be delineated. Similar to the subfornical organ, the OVLT is rich in binding sites for several circulating peptides, such as amylin (Sexton et al., 1994), angiotensin II (Mendelsohn et al., 1984; Giles et al., 1999; Allen et al., 2000), calcitonin gene-related peptide (Sexton et al., 1986); atrial natriuretic peptide (Saavedra et al., 1992), and relaxin (Osheroff and Phillips, 1991), suggesting that neurons in the OVLT may be influenced by these circulating peptides. With regard to vasopressin secretion, as well as mediating osmotically stimulated vasopressin secretion, neurons in the dorsal cap of the OVLT (Fig. 3D) that project to the supraoptic and paraventricular nuclei may play a role in mediating influences of the ovarian pregnancy hormone relaxin on vasopressin secretion (Sunn et al., 2002). By contrast, neurons in the OVLT that exhibit angiotensin II AT1 receptors and respond with increased Fos production to intravenous angiotensin II (Fig. 3C) are situated mainly near the lateral boundaries of the organ and in its most caudal periventricular region (McKinley et al., 1992; Giles et al., 1999), and it is possible that they have a role in the centrally mediated pressor effect and sodium appetite induced by circulating angiotensin II (Simpson, 1981; Fitts and Masson, 1990).
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AREA POSTREMA The area postrema, first described in detail (in the human brain) by Wilson (1906), is situated at the apex of the calamus scriptorius in the dorsomedial medulla oblongata (Figs. 1A and 2B). In most species it appears as bilateral rounded eminences on either side of the fourth ventricle at its entrance to the central canal. In the rat the major part of these bilateral eminences have merged so that, in coronal sections, the area postrema has the appearance of a hump or quadrant of tissue dorsal to the nucleus of the solitary tract (Fig. 3B). The ependymal cells of the area postrema are flattened, and small neurons surrounded by astrocytic cells and processes are found throughout this CVO. Axodendritic synapses are common and axosomatic synapses are also present (Spacek and Parizek, 1969; Dempsey, 1973; Armstrong et al., 1982). Because of its rich vascularity, the area postrema appears spongy. On describing this vasculature, Duvernoy and Koritke (1964) commented on groups of capillaries that were spiral in form and that gave rise to many subependymal capillary loops (Fig. 3B). Two types of capillaries have been observed in the area postrema: large sinusoidal vessels and smaller capillaries. Fenestrated endothelial cells line many capillaries in the area postrema, causing the blood–brain barrier to be circumvented. Perivascular spaces that contain large nerve cells and processes containing both clear and dense-core vesicles are also observed (Roth and Yamamoto, 1968; Spacek and Parizek, 1969; Dempsey, 1973; Armstrong et al., 1982).
Afferent Neural Connections Afferent neural connections to the area postrema come from only a few regions of the rat brain. The most abundant afferent input comes from the hypothalamic region in the vicinity of the paraventricular and dorsomedial nuclei (Hosoya and Matsushita, 1981; van der Kooy and Koda, 1983; Shapiro and Miselis, 1985; Larsen et al., 1991). This connection appears to be a continuous group of cells extending from the lateral parvocellular subnucleus of the paraventricular hypothalamic nucleus to the perifornical region and dorsomedial nucleus of the hypothalamus. In horizontal sections, this group of cells and dendrites appears as oval rings extending from a periventricular to a perifornical location at each extremity (Shapiro and Miselis, 1985). A small number of cells in the lateral parabrachial nucleus have also been shown to project to the area postrema. There is also the possibility that the dorsal raphe and a few neurons in the A1 region of the ventrolateral medulla and A2 neurons within commissural and medial subnuclei of the nucleus of the solitary tract innervate the
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area postrema (Torack et al., 1973; Vigier and Portalier, 1979; Shapiro and Miselis, 1985). However, Shapiro and Miselis (1985) considered it unlikely that neurons in these regions were retrogradely labeled from injections of tracer into the area postrema because the tracer had probably diffused past the edge of the area postrema. In addition to this central input, the area postrema receives some fibers from the periphery. Vagal and glossopharyngeal fibers have been shown to terminate in the area postrema of the rat (Kalia and Sullivan, 1982; Altschuler et al., 1989).
Efferent Neural Connections Area postrema neurons connect mainly to adjacent regions of the nucleus of the solitary tract, particularly the dorsal part of its medial subnucleus (Torack et al., 1973; van der Kooy and Koda, 1983). The most dense terminal field is found in the C2 adrenergic group of neurons situated midway between the solitary tract and the area postrema. A dense terminal field of fibers from the area postrema also surrounds the A2 noradrenergic group (Cunningham et al., 1994). There are few if any connections within the dorsal motor nucleus of the vagus, but it has been suggested that some area postrema connections within the nucleus of the solitary tract are terminating on dendrites of vagal motor neurons with cell bodies in the vagal motor nucleus (Shapiro and Miselis, 1985). Other medullary targets of area postrema efferents may be the ventrolateral medulla, the dorsal aspect of the spinal trigeminal tract and nucleus, and the paratrigeminal nucleus (Shapiro and Miselis, 1985), although Cunningham et al. (1994) did not confirm these last two projections in a later study. They also doubted that fibers from the area postrema terminated in the ventrolateral medulla. However retrogradely transported tracers that were microinjected into the rostral ventrolateral medulla (RVLM) are transported back to noradrenergic cell bodies in the area postrema (Blessing et al., 1987; Badoer et al., 1994; Polson et al., 1996), evidence for a projection from the area postrema to the RVLM. The most prominent efferent projection of the area postrema outside the medulla is to the dorsal pontine region, the target of these fibers being the middle third of the lateral parabrachial nucleus (van der Kooy and Koda, 1983; Shapiro and Miselis, 1985; Cunningham et al., 1994). Two groups of neurons, one in the core and the other in the lateral zone of the area postrema, project to the specific subnuclei of the lateral parabrachial nucleus. In the case of the core, its projections are to the inner part of the external subnucleus, and the central and dorsal subnuclei, while the lateral zone projects to the outer part of the external subnucleus (Herbert et al.,
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1991). Cholecystokinin- and galanin-containing neurons are among those in the area postrema that provide this neural input to the lateral parabrachial nucleus (Herbert and Saper, 1990). The pericentral dorsal tegmental and dorsolateral tegmental nuclei may also receive inputs from the area postrema (van der Kooy and Koda, 1983).
Neuroendocrine Aspects Fuxe and Owman (1965) identified catecholamineand serotonin-containing neurons in the rat area postrema. Subsequently immunohistochemical investigations of tyrosine hydroxylase and dopamine βhydroxylase confirm the presence of a group of noradrenaline containing neurons in this CVO (Torack et al., 1973; Armstrong et al., 1982). Neurons containing GABA, substance P, enkephalin, neurotensin, and cholecystokinin, as well as serotonin-containing neurons, have also been identified by immunohistochemistry (Newton and Maley, 1984; Armstrong et al., 1981; Newton and Maley, 1985a, 1985b; Newton et al., 1985). Some of the serotonin-containing neurons have been shown to connect to the lateral parabrachial nucleus (Lanca and van der Kooy, 1985). Unlike the other sensory CVOs, little if any nitric oxide synthase is observed in the area postrema (Jurzak et al., 1994). Because the neuropil of the area postrema is accessible to circulating humoral agents, results from in vitro autoradiographic binding studies provide insights into possible hormonal influences that may be involved in the functions of the area postrema. Binding sites for amylin (Sexton et al., 1994), cholecystokinin (Moran et al., 1986), angiotensin (Lenkei et al., 1997; Allen et al., 2000), atrial natriuretic peptide (Mendelsohn et al., 1987; Saavedra et al., 1992), GLP-1 (Göke et al., 1995), somatostatin (Patel et al., 1986), vasoactive intestinal polypeptide (Shaffer and Moody, 1986), neuropeptide Y (Martel et al., 1986), vasopressin (Phillips et al., 1988), substance P (Helke et al., 1984), and insulin (Werther et al., 1987) have been observed in the area postrema. With regard to cholecystokinin, it has been shown that systemic infusion of this hormone induces Fos production in neurons of the area postrema, indicative that it is a receptor zone for circulating cholecystokinin (Luckman, 1992), although its major site of action appears to be on distal vagal afferents (Day et al., 1994). Like the other sensory CVOs, the area postrema exhibits the CD14 lipopolysacharide receptor (Lacroix et al., 1998). Neurons in the area postrema may participate in baroreflex and cardiovascular control (Undesser et al., 1985; Skoog and Mangiapane, 1988; Ferguson, 1991), with both angiotensin II and vasopressin acting on this CVO to influence these functions (Hasser et al., 2000).
The area postrema probably has a role in the control of food intake, body weight, and fluid homeostasis (Miselis et al., 1987). Earlier, it was proposed that the area postrema was a trigger zone for the vomiting reflex in cats (Borison and Brizzee, 1951). This idea has persisted since that time, with recent interest in the role of the area postrema in the actions of antinausea drugs such as the 5-HT3 antagonists (see Miller and Leslie, 1994, for review). Although rats do not vomit, there is evidence that the area postrema in this species has a role in the development of conditioned taste aversions associated with nausea (Berger et al., 1973; Coil and Norgren, 1981).
MEDIAN EMINENCE AND NEUROHYPOPHYSIS The median eminence is a circumventricular organ that would be inappropriate to consider in isolation from the associated pituitary gland. The internal lamina of the median eminence is continuous with the posterior pituitary or neurohypophysis, and both share embryological and functional properties. The median eminence, or more specifically the ependyma overlying it, forms the floor of the third ventricle immediately caudal to the optic chiasm. Similar to other CVOs, the ependymal cells of the median eminence are irregular in shape (generally flattened), lack cilia, and have intercellular junctions that restrict the passage of substances to and from the CSF (Kobayashi and Matsui, 1969; Page, 1986). In broad terms, the median eminence is divided into inner and outer laminae (see Armstrong, Chapter 15, for a diagram). The internal zone is immediately subjacent to the ependyma and consists of subependymal glial cells, pituicytes, the radially directed processes of tanycytes, and most importantly fibers of the supraopticoneurohypophysial tract, which traverse the inner zone of the median eminence en route to the posterior pituitary (Daniel and Pritchard, 1975; Haymaker et al., 1969; Page, 1986). The unmyelinated fibers of this tract contain vasopressin and oxytocin and are derived from magnocellular neurons in the paraventricular and supraoptic nuclei of the hypothalamus (see Armstrong, Chapter 15, for a detailed description). In addition to fibers en passage, nerve terminals are present in the internal zone, although the extent to which they form neurohemal or other contacts remains uncertain (Page and Dovey-Hartman, 1984). These terminals are derived from catecholaminergic neurons in the brain stem or arcuate nucleus and form the reticuloinfundibular and tuberohypophysial pathways (Björkland et al., 1973; Everett and Hokfelt, 1986). Peptidergic axons containing corticotropin-releasing
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factor (CRF) or products of the proopiomelanacortin pathway (Merchenthaler et al., 1982; Mezey et al., 1985) also terminate in the internal zone. The external zone contains a complement of glial cells, ependymal cells, and nerve terminals similar to that described for the internal zone, although terminals are distinctly neurohemal. Importantly, there is a fenestrated vascular network called the primary portal plexus, and, in close association with these vessels, an abundance of terminals containing neurohormones and releasing factors (Page, 1986). The pars tuberalis forms the ventral surface of the external zone of the median eminence and vessels of the portal system are found within this region. The arterial blood supply to the neurohypophysis arises entirely from the internal carotid artery (Wislocki and King, 1936). The adenohypophysis, on the other hand, does not receive a direct arterial blood supply (Green, 1951; Page and Bergland, 1977) but is perfused exclusively by long portal vessels emanating from the primary portal plexus and to a lesser extent from short vessels derived from the neurohypophysis (Wislocki and King, 1936; Xuereb et al., 1954; Page and Bergland, 1977). This is a critical feature of the structure and function of the anterior pituitary, because it is via these portal vessels that hypophysiotrophic hormones reach the anterior pituitary gland. This vascular anatomy, together with the lack of local nerve terminals in the adenohypohysis, led early workers to suggest that the glandular pituitary is under the control of humoral factors released into the vicinity of the portal vasculature (Green and Harris, 1947). Since these early observations, considerable emphasis has been placed on defining the nature and origins of the various hypophysiotrophic factors released into the portal vessels and ultimately responsible for the release of anterior pituitary hormones, including thyroid-stimulating hormone, luteinizing hormone, prolactin, and adrenocorticotropic hormone (ACTH). During the last 10–15 years, attempts to elucidate the different inputs to the median eminence and particularly the external lamina have relied on the use of retrogradely transported tracers (Weigand and Price, 1980; Lechan and Jackson, 1982; Silverman et al., 1987), immunocytochemistry (Hokfelt et al., 1975), and occasionally combinations of both (Silverman et al., 1987). Fibers in the supraopticoneurohypophysial tract of the internal zone are clearly derived from the supraoptic nucleus and to a lesser extent from the paraventricular nucleus. Other afferent inputs, more likely to contain hypophysiotrophic factors, arise from the parvocellular paraventricular nucleus, periventricular hypothalamus, arcuate nucleus, OVLT, preoptic region, diagonal band of Broca, medial septum, and brain stem (Weigand and Price, 1980). Combinations of immunocytochemistry
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and tracing studies, for example, have localized LHRH neurons projecting to the median eminence in the medial septum, the diagonal band of Broca, the preoptic region surrounding the OVLT, and the lateral hypothalamus (Silverman et al., 1987). Although combined experimental data of this type may not always be available, the anatomical overlap of regions supplying afferents to the median eminence with the distribution of hypophysiotrophic factors suggests the possible origins of many of these factors. Thyrotropinreleasing factor, for example, is derived from cells in the diagonal band of Broca, the medial septum, the arcuate nucleus, and the paraventricular nucleus (Hokfelt et al., 1975; Lechan and Jackson, 1982; Ishikawa et al., 1984). Dopamine, which has an inhibitory influence on prolactin release (Neill, 1985), is derived from cells in the arcuate nucleus, as are the cells of origin of fibers in the external lamina containing growth hormone-releasing hormone. The distribution of cells containing somatostatin is widespread but cells projecting specifically to the median eminence are situated in the periventricular hypothalamus (Eppelbaum et al., 1977). Corticotropinreleasing factor, the principal agent responsible for the release of ACTH, is contained in parvocellular neurons of the paraventricular nucleus (Vale et al., 1981; Sawchenko et al., 1984; Sawchenko, 1987). Vasopressin, which is also contained within parvocellular neurons, has long been known to be present in nerve terminals in the external lamina (Parry and Livett, 1973) and to have effects on ACTH release analogous to those of CRF in a variety of species, including the rat (Rivier and Vale, 1983). Those agents listed above are some of the major neurohormones contained in projections to the external lamina of the median eminence; however, there are others, such as cholecystokinin, neurotensin, oxytocin, neuropeptide Y, and dynorphin, that may have regulatory effects on the anterior pituitary and axonal trajectories to the median eminence, but are less well defined (Roth et al., 1983; Sawchenko et al., 1984; Sutton et al., 1988; Mezey et al., 1986).
SUBCOMMISSURAL ORGAN The subcommissural organ, located in the posterior wall of the third ventricle, forms the dorsal roof of the entrance to the aqueduct of Sylvius (Fig. 2A) and is immediately ventral to the posterior commissure of the rat (Rodriguez et al., 1987; Severs et al., 1987). This CVO consists of layers of elongated columnar ependymal cells, which appear to have a secretory function. Secretion of a glycoprotein into the CSF by subcommissural organ cells causes the formation of Reissner’s fiber. This noncellular condensation of glycoprotein con-
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tinues from the aqueduct of Sylvius through the whole length of the central canal of the spinal cord (Rodriguez et al., 1987; Sterba et al., 1987; Gobron et al., 1999). There are no neurons in the subcommissural organ, but there is neural innervation of the specialized ependyma. Serotonergic fibers from the raphe provide some of this neural input (Mollgard et al., 1978; Bouchard, 1979; Rodriguez et al., 1987). Like other CVOs, the subcommissural organ exhibits a dense capillary network running beneath the ependymocytes, with some capillaries extending into the ependyma (Duvernoy and Koritke, 1969). Unlike the other CVOs, capillaries in the subcommissural organ do not exhibit fenestrated endothelial cells; thus the blood–brain barrier is maintained in this region (Weindl and Joynt, 1973; Broadwell and Brightman, 1976; Severs et al., 1987; McKinley et al., 1990). The function of the subcommissural organ (and Reissner’s fiber) remains obscure, although a number of earlier speculations regarding a role in fluid and electrolyte homeostasis or gonadotropin secretion can be found in the literature (see Severs et al., 1987, for a review). It is also proposed that the molecules secreted in Reissner’s fiber may have a role in guiding the development of the brain and spinal cord (Gobron et al., 1999). Although the subcommissural organ is a distinctive feature in the brain of the rat and many other vertebrates, it seems to be absent from the human brain from soon after birth, although a remnant of it may remain in vestiges of the mesocelic recess (Rakic, 1965; McKinley and Oldfield, 1990).
PINEAL GLAND This endocrine gland, found throughout the vertebrate phylum, has been a subject of interest for many centuries. In mammals, the pineal gland is a midline, cone-like structure located in the dorsocaudal roof of the third ventricle. It develops as a thickening of the ependyma around the pineal recess of the third ventricle and is attached by peduncles to the habenular and posterior commissures (Kappers, 1981; Korf et al., 1998). In the rat, most pineal cells have migrated in a dorsocaudal direction so that the rat pineal is mostly superficial, with a relatively long stalk that connects to the habenular and posterior commissures (Fig. 1A). This stalk contains nerve fibers, blood vessels, connective tissue, and parenchymal cells (Pevet, 1983). The pineal gland of the rat does not contain any neurons, but has many secretory cells known as pinealocytes. The other major cell type is glial (Pevet, 1981). Phylogenetically, pinealocytes developed from photoreceptor neurons; however, in the rat these cells have no direct
sensitivity to light. Instead, a neural pathway from the eye via the sympathetic nervous system influences the secretion of melatonin and other indolamines from the pinealocytes (Kappers, 1981). This pathway originates in the retina, from where neural signals are relayed in the optic nerve via the retinohypothalamic pathway, which branches directly from the optic chiasm to reach the suprachiasmatic nucleus. Here, synaptic connections are formed with neurons projecting to the hypothalamic paraventricular nucleus. Another junction occurs here, and these neurons connect with sympathetic preganglionic neurons in the intermediolateral cell column of the spinal cord via a pathway that travels in the medial forebrain bundle and through the reticular formation. These sympathetic preganglionic neurons innervate the superior cervical ganglion, which in turn provides the nerve supply to the pineal and its melatonin-secreting cells through the nervi conari (Moore and Klein, 1974; Pickard and Turek, 1983; Tamarkin et al., 1985). Stimulation of melatonin by the pinealocytes is dependent on intact sympathetic innervation from the superior cervical ganglion, with darkness-stimulating and light-inhibiting melatonin secretion (Korf et al., 1998). Studies in which the neurotropic virus pseudorabies was injected into the rat pineal to trace the polysynaptic pathways to it from the hypothalamus confirm the above pathway and show that the neurons in the paraventricular nucleus that are involved in this pathway are situated in its dorsal, medial and lateral parvocellular subdivisions (Larsen et al., 1999; TeclamariamMesbah et al., 1999). Viral tracing from the pineal in rats in which the superior cervical ganglion had been bilaterally destroyed showed that neural inputs from the nucleus of the solitary tract and salivatory nucleus via a synaptic connection in the sphenopalatine ganglion may provide a parasympathetic input to the pineal (Larsen et al., 1999). Nerve fibers that probably come from the habenular and posterior commissures have been observed to travel in the pineal stalk and enter the gland, and there is evidence suggesting a direct central innervation from several brain regions (Guerillot et al., 1982; Daffly, 1983). Such central innervation of the pineal could not be confirmed when care was taken to prevent any spillage of horseradish peroxidase injected into the pineal for retrograde tracing studies (Patrickson and Smith, 1987).
CHOROID PLEXUS This ion transporting tissue has been grouped with the CVOs and is responsible for producing much of
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the cerebrospinal fluid formed in the central nervous system (Davson, 1960). The choroid plexus is found in the lateral, third (dorsal recess), and fourth ventricles and is attached to the ventricular walls (Fig. 1). It is a highly vascularized connective tissue that is enveloped by an extensively folded epithelial cover, giving it a “cauliflower-like” appearance when viewed with the scanning electron microscope. The epithelium consists of cuboidal cells that sit on a basement membrane. These cells exhibit microvilli on the luminal surface and, together with the folding, provide a large surface area for water and electrolyte transfer between the hemal milieu of the choroidal interstitium and the ventricular lumen. The core of the choroid plexus contains numerous capillaries with fenestrated endothelial cells. Vessels are surrounded by perivascular spaces, which are continuous with interdigitating intercellular spaces of the choroidal epithelia (McKinley et al., 1990). Although there is no barrier for the movement of tracer molecules such as horseradish peroxidase from blood to the perivascular spaces of the choroid plexus, the zonula occludens between adjacent epithelial cells provides the basis for a blood–cerebrospinal fluid barrier (Brightman et al., 1975). Sympathetic innervation from the superior cervical ganglion and a vagal input provide neural regulation of the vasculature of the choroid plexus (Edvinsson et al., 1974; Lindvall et al., 1977). The observation that the choroid plexus of the rat is rich in binding sites for many peptides (Chodobski and SzmydyngerChodobska, 2001) including insulin (Werther et al., 1987), vasopressin (Phillips et al., 1988), and atrial natriuretic peptide (Quirion et al., 1984) suggests that these peptides influence the function of this CVO, possibly as local paracrine factors. It is also possible that they are being taken up from the circulation by choroid plexus epthelium and secreted into the CSF. There is evidence that this occurs for thyroid hormones (Schreiber et al., 1990), leptin (Banks et al., 1996), and insulin-like growth factor I (Walter et al., 1999). Similar to some other CVOs, the choroid plexus throughout the rat brain contains high concentrations of angiotensin-converting enzyme (Yang and Neff, 1972). This enzyme is located on the microvilli at the ventricular surface of epithelial cells and also on the membranes of vascular endothelium (Brownfield et al., 1982; McKinley et al., 1990). The functional consequences of these histochemical findings remain to be determined.
Acknowledgments Use the acknowledgment on the title page.
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17 Thalamus HENK J. GROENEWEGEN and MENNO P. WITTER Research Institute Neurosciences Vrije Universiteit (RIN-VU) Department of Anatomy, VU University Medical Center (VUmc) Amsterdam, The Netherlands
The thalamus of rats, like in most other vertebrate species, forms the largest part of the diencephalon. The diencephalon, situated between the two cerebral hemispheres rostrally and the brain stem caudally, consists of several main nuclear cell groups: the epithalamus, the dorsal thalamus, the ventral thalamus, and the hypothalamus. The dorsal thalamus has close connectional and functional relationships with the cerebral cortex and, to a lesser extent, the basal ganglia and amygdala in the telencephalon and is the main subject of this chapter. The ventral thalamus, ontogenetically originating from an anlage ventral to that of the dorsal thalamus, is a heterogeneous constellation of nuclear groups, i.e., the reticular thalamic nucleus, the ventral lateral geniculate nucleus, the zona incerta, and the subthalamic nucleus. With respect to the ventral thalamus, in view of their close association with the circuitry of the dorsal thalamus, only the reticular thalamic and ventral lateral geniculate nuclei are dealt with in this chapter. For a discussion of the hypothalamus and the subthalamic region see Simerly (Chapter 14 of this volume) and Gerfen (Chapter 18 of this volume), respectively. A discussion of the epithalamus, i.e., the epiphysis, the habenular complex, and the stria medullaris, falls outside the scope of this chapter. An important issue that should be mentioned at the very beginning of this chapter concerns the traditional distinction between the dorsal and ventral thalamus on the basis of developmental arguments. As indicated above, the nuclei that make up the ventral thalamus are generally described as developing from part of the early diencephalon situated ventral to the dorsal thalamic
The Rat Nervous System, Third Edition
anlage. However, as argued by Puelles et al. (for more details see Chapter 1 and references therein), what has traditionally been called “dorsal thalamus” is actually “caudal thalamus” and what has been called “ventral thalamus” is actually “rostral thalamus.” This welldocumented reinterpretation of the development and “layout” of the nuclei that derive from the diencephalic brain vesicle on the basis of gene maps is not trivial and we accept Puelles” argument (as explained in Chapter 1 of this volume) as valid. However, we remain using the terms dorsal and ventral thalamus to keep in continuity with the literature until the new terminology gains ascendancy. The dorsal thalamus forms a complex of cytoarchitectonically, chemoarchitectonically, and hodologically different nuclei, their common characteristic being a reciprocal connectional relationship with distinct parts of the cerebral cortex. Traditionally, the dorsal thalamus is viewed as the final synaptic relay station before extrinsic and intrinsic information can reach the cerebral cortex. On the basis of the content of the information that reaches the various thalamic nuclei through the inputs to these thalamic nuclei, as well as the organizational aspects of the thalamic projections to the cerebral cortex, the dorsal thalamic nuclei have been characterized as specific versus nonspecific; the specific nuclei encompass sensory, motor, and associational relays and the nonspecific nuclei subserve arousal and attentional mechanisms. A global view of the function of the thalamus is that various streams of information that are directed toward the cerebral cortex are gated and modulated at the level of the thalamus. However,
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the precise nature and the mechanisms of these gating and modulatory functions still remain largely elusive. The main characteristics of the ventral thalamus, i.e., the reticular thalamic (Rt) and ventral lateral geniculate (VLG) nuclei, are its projections to the dorsal thalamus and, unlike other thalamic nuclei, the lack of projections to the cerebral cortex. Furthermore, all afferent and efferent projections of the dorsal thalamus, among them prominently the reciprocal fibers with the cerebral cortex, have to pass through the ventral thalamus. Most of these fiber systems, but certainly not all (see below), give off collaterals to the reticular nucleus. In this way the Rt forms feedback and feedforeward loops with the dorsal thalamic nuclei. Thus, the reticular and ventral lateral geniculate nuclei are strategically placed to modulate all incoming and outgoing information of the dorsal thalamus (e.g., Jones, 1985; Sherman and Guillery, 2001). While the VLG and the reticular nuclei have several characteristics in common, the VLG has a number of additional features that distinguishes it from the reticular nucleus and, therefore, the VLG is considered later in this chapter in conjunction with the lateral geniculate complex as a whole (see page 411). Moreover, the reticular nucleus has a specific visual sector like all other sensory modalities (Coleman and Mitrofanis, 1996). Given the restrictions in approach and length, the present chapter can only provide a global overview of the functional anatomy of the thalamus, with emphasis on data obtained from studies in rats. In the past two decades comprehensive monographs have been published on the thalamus (e.g., Jones, 1985; Steriade et al., 1997; Sherman and Guillery, 2001); for more detailed discussions the reader is referred to these and the original publications. Simple as the thalamic relay function to the cerebral cortex may seem, the precise functional role of the thalamus still remains largely unknown. The chapter by Price in the 2nd edition of The Rat Nervous System (Price, 1995) gave an excellent and comprehensive overview of the architecture and connections of the rat thalamus. The present chapter aims to update the knowledge of the anatomy of the rat thalamus on the basis of studies in the past decade and will attempt to place this knowledge in a functional context. In the first section, a number of recent ideas and insights of general interest to thalamic structure and function are reviewed, in subsequent sections specific aspects of functionally different groups of thalamic nuclei are addressed. Emphasis is placed on those nuclei or nuclear groups for which recent research has unveiled new insights. This is in particular the case for the reticular thalamic nucleus and the midline and intralaminar complex of the thalamus. Important details of the organization of various thalamic nuclei have come about through the application
of modern neuroanatomical techniques such as the juxta- or intracellular filling of neurons which show the fine details of single neurons and their (collateral) projection patterns. Likewise, combinations of anatomical tracing, immunocytochemistry, and/or the revelation of activity markers in specific behavioral paradigms have revealed important functional aspects of specific thalamic nuclei. These exciting recent results are discussed in the context of the description of the individual thalamic nuclei below.
SOME GENERAL ASPECTS OF THALAMIC ORGANIZATION The delineation of nuclei in the dorsal thalamus is primarily based on cytoarchitectonic, chemoarchitectonic, and connectional features. The entire complex of nuclei is rostrally, laterally, and ventrally “encapsulated” by fiber bundles, i.e., the external medullary lamina, in which the reticular thalamic nucleus is embedded. The caudal borders of the dorsal thalamus are less clearly defined, the nuclei of the posterior thalamic complex merge with cell groups of the central tegmental field of the mesencephalon. Medially and dorsally the thalamus borders the third and lateral ventricles, respectively, although in rats the third ventricle is largely obliterated as a consequence of the merging of the thalamic halves on both sides of the midline. An internal medullary lamina divides the thalamus into a dorsal and medial group, and a ventral, lateral and posterior group of nuclei. Embedded in the internal medullary lamina are the intralaminar nuclei which, with some of the nuclei in the midline regions of the thalamus, form a separate group on the basis of their dual projections to the cerebral cortex and the basal ganglia, i.e., the midline/intralaminar complex. The reticular thalamic nucleus, as part of the ventral thalamus, forms a thin sheet of neurons at the rostral and lateral borders of the dorsal thalamus, at the outside mostly bordered by fiber bundles of the internal capsule.
Classical Functional Subdivision of the Thalamus The classical categorization of thalamic nuclei is primarily based on the kind of information that is transferred through a particular nucleus or group of nuclei to the cerebral cortex (for a discussion of corticothalamic relationships in the context of specific cortical areas, see Chapter 23, this volume, by Palomero-Gallagher and Zilles). The main category is formed by the principal “relay” nuclei which receive specific sensory, motor, or associational information through ascending or
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descending fiber pathways and transmit this information to specific areas and layers of the cortex. The group of relay nuclei includes among others the anterior and mediodorsal complexes and the ventral and lateral group of nuclei, encompassing among others the ventrolateral, ventromedial, ventral anterior, lateral dorsal, lateral posterior, and posterior nuclei. In addition, the medial and lateral geniculate nuclei belong to the main category of relay nuclei. Another category is formed by the midline and intralaminar nuclei, also indicated as the nonspecific thalamic nuclei, which are considered to receive more general information, in particular from arousal and visceral regions in the brain stem and forebrain. These nuclei project to both the cerebral cortex, although in a somewhat less strictly topographical manner and to cortical layers different from the principal thalamic nuclei, and to subcortical areas like the basal ganglia and the amygdala. As already indicated above, the reticular thalamic nucleus must be considered as a different category in view of its specific position between the dorsal thalamic nuclei and the cerebral cortex and the absence of cortical projections.
Categorization of Thalamic Afferents in “Drivers” and “Modulators” Before dealing in more detail with the structure, connections, and functional aspects of the various thalamic nuclei within this classical categorization in subsequent sections, it is important to briefly discuss recent ideas about the classification of afferents of the thalamus into two main categories, i.e., drivers and modulators (Sherman and Guillery, 1996, 1998, 2001). This classification provides a basis for distinguishing between afferents that carry specific information to the thalamus, which is subsequently transmitted to the cerebral cortex, and other systems that modulate the transfer of (specific) information at the thalamic level. Sherman and Guillery (2001; for the in-depth discussion of this topic and the supporting literature, the reader is referred to this lucidly written monograph) make a strong case for such an organization in the firstorder, sensory thalamic nuclei, in particular the lateral geniculate nucleus, but they propose to explore and test the generality of these organizational principles for other, in particular, higher order thalamic nuclei. The distinction between thalamic afferent fibers as drivers and modulators is based on several criteria, i.e., light microscopical aspects, ultrastructural characteristics, and physiological properties of these fibers and their terminals in the thalamus (Sherman and Guillery, 2001). Sensory afferents, whether from somatosensory, visual, or auditory origin, are all very similar with respect to their light microscopical appearance: relatively thick,
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richly branching terminal fibers with, in most cases, large boutons, although variable in shape and number. These fibers have been indicated as the type II afferent fibers of the thalamus and are considered to be the “drivers” for the primary sensory relay nuclei. At the ultrastructural level, these driving afferents are associated with large terminals containing round vesicles (RL = round vesicles and large terminals). The RL-type terminals are often found in triadic arrangements; i.e., they are presynaptic to the dendrite of a thalamic relay neuron and an axoniform dendritic profile of an interneuron, the latter being also presynaptic to the dendrite of the relay neuron. These triads regularly form part of glomerular structures in which various presynaptic and postsynaptic elements are arranged, typically, but not in all cases, ensheathed by astrocytic processes. The receptive fields of the thalamic afferents are rather faithfully mapped through the thalamus onto the cortical neurons and cortical layers in receipt of these thalamic fibers. In general, driver inputs are excitatory and exert their effect mainly via ionotropic glutamate receptors (Sherman and Guillery, 2001). Cortical afferents in the primary sensory relay nuclei have a different light microscopical appearance: these fibers are thinner and carry small, drumstick-like appendices with boutons along the course through the thalamic nucleus in which they terminate. They are categorized as type I thalamic afferents. These fibers are much more sparsely branched and exhibit fewer terminallike structures, and individual fibers distribute their terminals over a wider area than the type II afferents. The type I fibers are considered to be modulatory. Ultrastructurally, the terminals of these fibers are associated with the category of smaller terminals with round vesicles (RS = round vesicles and small terminals). The receptive field properties of these afferents are generally much wider and less defined compared to those of the type II afferents and, in the case that these afferents are glutamatergic, they probably exert their effects primarily via metabotropic glutamatergic receptors. Apart from the primary sensory relay nuclei, the ventral anterior and the anterior thalamic nuclei receive type II afferents from subcortical sources, i.e., the deep cerebellar nuclei and the mammillary nuclei, respectively. The cerebellar and mammillary afferents are, therefore, considered to be the driving afferents of these nuclei. Interestingly, cortical afferents of, at least a number of, higher order thalamic relay nuclei are of the type II category of afferent thalamic fibers, possibly indicating that these cortical afferents serve as drivers for these association thalamic nuclei. Whereas the type I corticothalamic axons derive mainly from layer 6 of the cerebral cortex, the type II corticothalamic afferents have shown, at least in a number of cases, to arise from
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cells in cortical layer V (Fig. 1). However, the generality of this organization remains to be largely established. Type I afferents, the “modulatory” category of thalamic afferents, not only originate in the deeper layers of the cerebral cortex but also derive from a wide array of subcortical structures in the basal forebrain, diencephalon, and brain stem, carrying various neurotransmitter signals (Sherman and Guillery, 2001). The concept of drivers and modulators provides a challenging framework for the discussion and interpretation of thalamic structure and function. It provides the basis for a further understanding of what specific messages are transferred through the thalamus to the cerebral cortex and which systems modulate this information transfer. It further emphasizes that not only the sheer number or volume of afferents to the thalamus determines their significance but also the character of the message. In that respect, numerically smaller inputs might be more determinant for the functional aspect of a particular afferent system and, by inference, of a particular thalamic nucleus, than more numerous inputs (Sherman and Guillery, 2001). The driver/ modulator concept has been briefly outlined above to serve as a reference for the discussion of the individual thalamic nuclei in subsequent parts of this chapter. In doing so, a final caveat must be placed here. The present chapter focuses on the situation in the rat; several of the data that are used by Sherman and Guillery (2001) to support their concept of drivers and modulators derive from species other than the rat (e.g., cat and primates). Therefore, it remains to be largely established whether the thalamus of the different species are organized according to these same principles, even though this seems very likely. Nevertheless, important species differences have been noted, for example, with
respect to the presence of interneurons (Price, 1995) or of various neurons expressing calcium-binding proteins (Jones, 1998) in the thalamus of rats versus other species.
Reciprocity of the Thalamocorticothalamic Relationships It is almost a dogma that the thalamocorticothalamic relationships are organized such that each cortical area receiving an input from a specific thalamic nucleus faithfully reciprocates this input through a topographically organized cortical projection to the same thalamic nucleus. Apart from the fact that the relationships between the thalamus and the cortex are certainly not exclusively reciprocal (see below), it is also far from clear what this reciprocity functionally means and why the corticothalamic fibers outnumber their thalamocortical counterparts (Jones, 1985). In reference to the discussion above about the distinction between driver inputs and modulator inputs, it is important to realize that the cortical inputs form a mixed population. Whereas most cortical inputs to the primary relay nuclei have the characteristic of type I, modulatory fibers, cortical inputs to higher order thalamic nuclei have the type II characteristics and may form the main, driving input to these nuclei (Sherman and Guillery, 2001). Driver inputs, by terminating on more proximal parts of the dendrites of thalamic relay neurons, might have a stronger influence on these neurons compared to the (cortical) modulator inputs, which in general contact more distal parts of the dendrites of thalamic neurons. Therefore, like Sherman and Guillery argue, it may not be the numbers that count, but more the (ultrastructural) type of input and the position of the terminations on the dendritic tree.
FIGURE 1 Camera lucida drawings of terminal branches of corticothalamic neurons that originate in layer VI (A) or in layer V (B) of the barrel cortex (primary somatosensory cortex) and terminate in the VPM of the thalamus. The axons were filled following small injections of biocytin in specific layers of the barrel cortex, filling only a small number of neurons of which the projection fibers could be individually traced. The corticothalamic fibers originating in layer VI are thin with many short side-branches and small-sized boutons. In contrast, the fibers from layer V neurons, arising as collaterals from axons that are directed toward the brain stem and/or spinal cord, are thicker and have relatively few, but large boutons. From Fig. 2 of Bourassa et al. (1995).
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Another approach of the issue of reciprocity has been entertained by Deschenes et al. (1998) in comparing the pattern and strength of the cortical inputs to a particular thalamic nucleus with those of prethalamic projections to that same thalamic nucleus. As indicated above, thalamocorticothalamic relationships appear not to be strictly reciprocal (e.g., Hoogland et al., 1987; Murphy and Sillito, 1996; Deschenes et al., 1998; McFarland and Haber, 2002). Deschenes et al. (1998) have formulated the “rule of parity” which states that “. . . the distribution of corticothalamic projections across and within thalamic nuclei is determined by the branching patterns of the different classes of prethalamic afferents.” In general, the rule of parity leads to reciprocity in the thalamocorticothalamic relationships, but this is not true in all cases. Deschenes et al. (1998) base their hypothesis on various aspects of the central organization of the vibrissal system in rats, transmitted through the ventrobasal thalamic complex. The functional consequence of the rule of parity, i.e., a matching of prethalamic and corticothalamic fibers at the level of a particular thalamic nucleus, might be that there is not an exclusive feedback role for the corticothalamic system. Thus, depending on the behavioral context, either the corticothalamic or the thalamocortical system might play a feedback role, modulating the input from the alternate system. How and to what extent these varying roles of the corticothalamic system are related to their origin from distinct cortical layers (see above) remain to be established. Whether a rule of parity applies to all thalamic systems is unclear, but this hypothesis provides an important new perspective on the bottomup and top-down functional arrangements of the corticothalamic system. A consequence of the nonreciprocity of the thalamocorticothalamic system might also be that thalamic nuclei play a role in transmitting information from one cortical area to the other, either from sensory areas to association cortical areas (Guillery, 1995) or from association cortical areas to motor areas (McFarland and Haber, 2002).
PRINCIPAL THALAMIC “RELAY” NUCLEI Sensory Nuclei Lateral Geniculate Nucleus The lateral geniculate nucleus in rats is a relatively flattened, more or less oval-shaped nucleus on the dorsolateral surface of the caudal thalamus. It can be subdivided into a dorsal lateral geniculate nucleus (DLG) and a ventral lateral geniculate nucleus (VLG). Between the DLG and the VLG a third component is recognized,
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the intergeniculate leaflet (IGL). The DLG constitutes the main thalamic relay of visual information to the primary visual cortex, the VLG has a number of characteristics in common with the thalamic reticular nucleus, and only its lateral part receives direct retinal input. The IGL constitutes a relay between the retina and the hypothalamus and is involved in circadian functions. For a comprehensive treatment of the anatomical and functional aspects of the lateral geniculate complex, including the DLG, VLG, and IGL, see Sefton et al. (Chapter 32, this volume). Dorsal lateral geniculate nucleus (DLG) The dorsal lateral geniculate nucleus can be readily identified in Nissl-stained sections (Plate 37 in Paxinos and Watson, 1998) as well in acetylcholinesterase-stained sections in which the DLG shows moderate activity (Plate 39 in Paxinos and Watson, 1998). The cytoarchitecture of the DLG of rats is rather homogeneous. The majority of dorsal lateral geniculate neurons are thalamocortical projection cells. Unlike most other principal thalamic nuclei in the rat, the DLG contains several types of interneurons, namely, GABAergic, most of which coexpress NADPH diaphorase, and solely GABAergic or NADPH diaphorase-containing neurons (Ohara et al., 1983; Jones, 1985; Gabbott and Bacon, 1994). In contrast to many other mammalian species, the rat DLG is not clearly laminated, although fiber bundles running in a ventrolateral to dorsomedial orientation, parallel to the optic tract, impose a certain orientation on the neurons in the dorsal lateral geniculate nucleus. However, the largely segregated terminations of the optic fibers from the contralateral and ipsilateral eyes reveal a form of “hidden lamination” in the rat DLG (Reese, 1988; also Jones, 1985; Price, 1995). The lateral lamina directly adjacent to the optic tract, also called the “outer shell,” receives input from the contralateral eye. The medial part of the DLG, called the “inner core,” consists of two regions, the most medial region receives input from the contralateral eye and the lateral region is innervated by the ipsilateral eye (Reese, 1988; Jones, 1985). This organization refers to the caudolateral part of the DLG in which there is a binocular representation of the visual field; in the rostroventral part of the DLG retinal fibers from only the contralateral eye terminate, representing a large part of the temporal visual field (Reese, 1988). Calcium-binding proteins are differentially distributed in fibers and neurons in the dorsal lateral geniculate nucleus. Whereas calretinin and parvalbumin are present only in fibers, calbindin D28K is also expressed in (inter)neurons, in particular in the outer shell (Luth et al., 1993; Figure 230 in Paxinos et al., 1999). The plexus of calretinin fibers is most dense also in the outer shell (Figure 230 in Paxinos et al., 1999). Parvalbumin fibers
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are most probably derived from the retina and the reticular thalamic nucleus, and calretinin fibers from the retina (Luth et al., 1993; Arai et al., 1992). Calbindin D28K-containing fibers may be derived from the superior colliculus (Lane et al., 1997). Affernt and efferent Projections The DLG forms the main relay between the retina and the primary visual cortex (area 17 or V1), the optic terminations in the dorsal lateral geniculate nucleus being retinotopically organized (see above; Jones, 1985; Reese, 1988). The inner core receives, in its two ocular laminae, inputs from the contralateral nasal and the ipsilateral temporal retina, mapping the contralateral visual hemifield. The outer shell receives a projection from the complete contralateral visual hemifield only. These retinotopic maps in the contralateral and ipsilateral laminae of the DLG are in complete register. Lines of projection are oriented rostroventromedially from the optic tract at the thalamic surface through the different laminae of the DLG (Reese, 1988). Retinal inputs terminate as RL-type boutons, indicating that the retinal fibers are the “drivers” of the DLG (Jones, 1985; Sherman and Guillery, 2001; also II). The retinal afferents contact the dendrites of both the thalamocortical neurons and the interneurons, and they take part in glomerulus-like formations separated from the rest of the neuropil by glial elements. Cortical inputs to the dorsal lateral geniculate nucleus are primarily derived from the primary visual cortex (area 17). The different cortical layers of the primary visual cortex have differential projection patterns to the visual thalamus (Bourassa and Deschennes, 1995). Fibers originating in the upper part of layer VI project to the DLG and they terminate in rostrocaudally oriented bands or “rods” that run parallel to the lines of projection of retinal afferents. Neurons in the deeper part of layer VI project to the lateral part of the lateral posterior thalamic nucleus and these fibers give off collaterals to the DLG where they take part in the formation of the rods. Neurons in layer V of the visual cortex do not target the DLG, but their main axon descends to the brain stem while giving off collaterals to the ventral lateral geniculate nucleus and to the lateral posterior and lateral dorsal thalamic nuclei (Bourassa and Deschennes, 1995). Layer VI corticothalamic fibers issue collaterals to the reticular thalamic nucleus while layer V axons do not. The terminating fibers in the DLG, originating from layer VI have small “en passant” varicosities which show at the ultrastrutural level the characteristics of the RStype boutons and may be considered as “modulators” (Jones, 1985; Price, 1995; Bourassa and Deschennes, 1995; Sherman and Guillery, 2001) Subcortical inputs to the DLG arise in the ventral lateral geniculate nucleus, reticular thalamic nucleus,
superior colliculus, and several brain stem nuclei (Reese, 1988; Coleman and Mitrofanis, 1996; Moore et al., 2000). The inputs from the superior colliculus terminate in the peripheral zone of the outer shell and are probably associated with the calbindin DD28K-positive fiber plexus (Reese, 1988; Lane et al., 1997). Brain stem inputs include those from retinal input receiving nuclei like the nucleus of the optic tract, the olivary pretectal nucleus, and the parabigeminal nuclei (Schmidt et al., 1995). Further inputs are derived from the locus coeruleus (noradrenaline), the dorsal raphe nucleus (serotonin), and the laterodorsal tegmental nucleus (acetylcholine) (e.g., Papadopoulos and Parnavelas, 1990). The output of the DLG is primarily directed at the primary visual cortex (area 17), terminating in layer IV, while there are lesser inputs to layers I and VI (Ribak and Peters, 1975; Jones, 1985). The peristriate area 18 also receives a weak input from the DLG (Sanderson et al., 1991). The geniculocortical pathway uses glutamate as neurotransmitter (Kharazia and Weinberg, 1994; Saez et al., 1998). Ventral lateral geniculate nucleus The VLG, like the reticular thalamic nucleus, is embryologically derived from the ventral thalamus. The ventral lateral geniculate nucleus could be viewed as a caudodorsal extension of the reticular thalamic nucleus. Cytoarchitectonically, the VLG can be subdivided into a lateral, magnocellular part (VLGMC) and a somewhat smaller, medial parvicellular part (VLGPC). The two parts are separated by a fiber-rich, cell-free zone (Jones, 1985). Neurons in the magnocellular part contain nitric oxide synthase and enkephalin; those in the parvicellular part substance P and calretinin (Meng et al., 1998; for review see Harrington, 1997). Enkephalinergic neurons have also been identified in the VLG (Hermanson et al., 1995). Afferent and efferent projections Afferents to the ventral lateral geniculate nucleus make a clear distinction between the medial VLGPC and the lateral VLGMC. The VLGPC receives extensive inputs from the brain stem, in particular from the reticular formation, the deep layers of the superior colliculus, the periaqueductal gray matter, peribrachial regions, the laterodorsal tegmental nucleus, the locus coeruleus, the substantia nigra pars reticulata, and deep cerebellar nuclei (Kolmac and Mitrofanis, 2000; Vaudano and Legg, 1992). The VLGMC receives strong projections mainly from the retina and layer V of the visual cortex (Hickey and Spear, 1976; Takahashi, 1985; Bourassa and Deschennes, 1995) and very few fibers from the brain stem (Kolmac and Mitrofanis, 2000). Unlike the dorsal lateral geniculate nucleus, there are no projections from the VLG to
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the cerebral cortex. Instead, the VLG has rather extensive projections to the dorsal thalamus, comparable with the intergeniculate leaflet (see below). Thus, the medial, parvicellular part of the VLG projects to the parafascicular and lateral dorsal thalamic nuclei as well as to the reuniens and rhomboid nuclei in the midline. The lateral, magnocellular VLG sends fibers to the dorsal lateral geniculate and lateral posterior thalamic nuclei (Moore et al., 2000; Kolmac et al., 2000). Hypothalamic projections from the VLG reach the lateral and posterior hypothalamus and the perifornical area. The ventral lateral geniculate nucleus further projects to the zona incerta, the pretectal nuclei, the deep and intermediate layers of the superior colliculus, the dorsal and medial terminal nuclei of the accessory optic system, the periaqueductal gray, the peripeduncular region, and the accessory inferior olive (Moore et al., 2000). Intergeniculate leaflet The IGL is a distinct, dorsoventrally narrow region between the dorsal and ventral lateral geniculate nuclei, which extends virtually over the entire rostrocaudal length of the lateral geniculate complex (Hickey and Spear, 1976; Moore and Card, 1994). Like the ventral lateral geniculate nucleus, it is a derivative of the ventral thalamus. Precise borders of the IGL are difficult to establish in Nissl-stained sections but can more readily be identified with the staining for glial fibrillary acidic protein (GFAP) and several peptides like neuropeptide Y, substance P, and enkephalin, as well as the neurokinin1 receptor. The IGL contains several types of small- to medium-sized neurons most of which have their dendritic arborizations within the nucleus (Moore and Card, 1994; Piggins et al., 2001). Afferent and efferent connections The main sources of input to the intergeniculate leaflet are fibers from the retina and from the contralateral IGL. Retinal fibers terminate as RL-type terminals and may be considered the driving afferents of the IGL (Mikkelsen, 1992; Moore and Card, 1994). The neurons that give rise to the commissural connections contain enkephalin (Card and Moore, 1989). Further inputs to the IGL originate in the suprachiasmatic nucleus, posterior hypothalamic area, superior colliculus, and several brain stem nuclei, among them the locus coeruleus, the raphe, and the laterodorsal tegmental area (Moore et al., 2000). There is a dense substance P-immuoreactive plexus in the intergeniculate leaflet, the origin of which is unknown, however (Piggins et al., 2001). The efferents of the IGL primarily reach the hypothalamus, in particular the suprachiasmatic nucleus and anterior hypothalamic regions, forming the so-called geniculohypothalamic
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tract. Neurons in the IGL projecting to the suprachiasmatic nucleus contain neuropeptide Y (Card and Moore, 1989; Harrington, 1997). Mikkelsen (1994) showed direct projections from the intergeniculate leaflet to the subcommissural organ and the pineal gland. Further outputs of the IGL reach the midline thalamic nuclei, in particular, the paraventricular, but also the reuniens and rhomboid nuclei, as well as the dorsal and lateral hypothalamus and the zona incerta. Brain stem targets include the superficial layers of the superior colliculus, the periaqueductal gray, and several accessory optic nuclei (Moore et al., 2000). Functional aspects of the lateral geniculate complex The DLG must be considered as the main thalamic gateway for visual information from the retina to reach the cerebral cortex. This nucleus rather faithfully maps the external visual field onto the primary visual cortex (area 17, V1). The functional aspects of the DLG have been the subject of a vast body of literature and have recently been elegantly reviewed by others (e.g., Sherman and Guillery, 2001). For a further elaboration on this subject see Sefton et al. (Chapter 32, this volume). The functions of the VLG have been less wellestablished. In view of its origin from the ventral thalamus, as well as some of its connectional characteristics, i.e., the rather extensive projections to the dorsal thalamus (see above), the functions of the VLG might, at least in part, be compared with the those of the reticular thalamic nucleus (see also section “Reticular Nucleus”; Sefton et al., Chapter 32, this volume). However, the functional aspects of the VLG are probably much more differentiated. As a result of their differential sets of afferent and efferent fibers, the medial and lateral parts of the VLG (VLGPC and VLGMC, respectively) are bound to have different, although possibly related, functions. Whereas the lateral VLGMC is more intimately related to the dorsal lateral geniculate nucleus and visual cortices, the medial VLGPC is more closely associated with the hypothalamus, in particular, the suprachiasmatic nucleus. Yet, these two parts of the VLG also share a number of afferents and efferents, as well as with the IGL (see below). Therefore, in a recent review, Harrington (1997) has argued that this entire ventral lateral geniculate complex may be regarded to fulfill distinct, yet interrelated, functions in controlling visuomotor responses and circadian rhythms. Details of these functions, however, remain to be established. Functional aspects of the IGL seem to have been studied in slightly more detail (see also Sefton et al., Chapter 32, this volume). The retinal input to the IGL originates from a specific set of retinal ganglion cells that convey luminance information (Moore et al., 1995). Furthermore,
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the strong reciprocal connections of IGL with the suprachiasmatic nucleus as well as its connections with midline thalamic nuclei and the pineal gland fit in with an important role for the IGL in circadian functions (Moore and Card, 1994; Harrington, 1997). While the IGL projections to the suprachiasmatic nucleus provide an indirect way to influence autonomic and neuroendocrine circadian rhythms, there are also direct connections of IGL fibers with neuroendocrine neurons in other parts of the hypothalamus (Horvath, 1998). Ventral Posterior Complex The ventral posterior complex (VP) in rats occupies an extensive ventrolateral thalamic area, appearing immediately rostromedial to the medial geniculate complex in the caudal third of the thalamus and extending into the rostral third of the thalamus. The VP is bordered ventrally and laterally by the medial lemniscus and the reticular thalamic nucleus and dorsomedially by the posterior complex (see page 417). At rostral levels the posterior complex is gradually replaced by the ventrolateral nucleus, which is situated medial to the VP (see Figs. 28–38 in Paxinos and Watson, 1998). The ventral posterior complex is the main relay for sensory inputs to reach the cerebral cortex and it can be divided into at least three main parts: the ventral posterolateral nucleus (VPL) receiving spinal somatosensory inputs, the ventral posteromedial nucleus (VPM), receiving trigeminal somatosensory inputs, and the parvicellular medial parts of both the VPL and VPM, i.e., the VPPC (see page 419), which forms the main thalamic relay for gustatory and visceral ascending pathways. The VPL and VPM are distinguishable not only based upon their connectivity (see below) but also on the basis of cyto- and chemoarchitectonics. The VPM stands out as a more densely packed nucleus in Nissl-stained sections as compared to the VPL and the posterior complex (e.g., Plates 33 and 37 in Paxinos and Watson, 1998). The VPL and the posterior complex demonstrate a moderate level of activity for acetylcholinesterase (AChE), while the activity is very low in the VPM (e.g., Plates 31 and 35 in Paxinos and Watson, 1998). Most neurons in the VPM and VPL are medium-sized thalamocortical neurons. In contrast to other species, only very few GABAergic interneurons are present in the ventral posterior complex of rats (Harris and Hendrickson, 1987; Price, 1995). The neurons in the VPL are arranged in rostrocaudal and dorsoventral rows that are roughly parallel with the external medullary lamina and these rows curve partially around the rostral pole of the VPM (McAllister and Wells, 1981). In both the VPL and the VPM a dense plexus of parvalbumin fibers is present, while only few calretinin-
or calbindin D28K-positive fibers occur. In subregions of both the VPL and VPM, calbindin D28K-positive neurons are present (Arai et al., 1994; e.g., Figs. 188, 194, 202, and 208 in Paxinos et al., 1999). The VPM is for the most part organized in so-called barreloids, first described in mice and later also identified in rats (Van der Loos, 1976) (Fig. 2). Barreloids are the representations of individual whiskers at the level of the thalamus (see below) formed by cellular aggregates; barreloids can best be visualized using mitochondrial markers such as cytochrome oxidase (Land and Simons, 1985; Haidarliu and Ahissar, 2001). These microstructures in the VPM are most apparent in young rats, but can also be demonstrated in adults. Whereas thalamic barreloids are considered to convey the information from single whiskers, the dendrites of neurons in these barreloids may cross the boundaries into neighboring barreloids providing a neural substrate for crosstalk between barreloids (Desilets-Roy et al., 2002). Afferent and efferent connections The ventral posterolateral and ventral posteromedial nuclei receive their main ascending inputs from somatosensory afferents originating in the spinal cord, dorsal column nuclei, and trigeminal complex (see also Tracey, Chapters 7 and 25, and Waite, Chapter 26, this volume). These somatosensory projections are somatotopically organized such that afferents from the trunk and limbs terminate in the VPL and those from the head terminate in the VPM. Spinal and trigeminal fibers not only reach the VPL and VPM but also distribute over much wider areas of the thalamus, including the posterior nucleus (see page 417) and the intralaminar nuclei (see section “Midline and Intralaminar Thalamic Nuclei”). Spinothalamic fibers, transferring among others nociceptive signals, originate from different laminae of the dorsal horn as well as the central gray of the spinal cord and terminate as large boutons in the ventral posterolateral nucleus (e.g., McAllister and Wells, 1981; Burstein et al., 1990; Dado et al., 1994; Katter et al., 1996; Kobayashi, 1998). Nociceptive information may reach the VPL also indirectly via the caudal medullary reticular formation (medullary dorsal reticular nucleus) in addition to the direct spinothalamic pathway (Villanueva et al., 1998). Dorsal column nuclear afferents likewise terminate with large boutons in the VPL (McAllister and Wells, 1981; Villanueva et al., 1998). Spinal and lemniscal fibers, in part, converge on individual thalamocortical neurons, the lemniscal fibers on the soma, and more proximal parts of dendrites of the neurons than the spinothalamic fibers (Peschanski and Ralston, 1985). Lemniscal, but also spinothalamic, fibers probably use glutamate as neurotransmitter (De Biasi et al., 1994). Spinothalamic fibers have also been
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FIGURE 2 Schematic, three-dimensional reconstruction of the barreloids in the VPM of the rat taken from Haidarliu and Ahissar (2001). (a, b) Low-power and high-power photomicrographs of two perpendicularly cut, cytochrome-oxidase stained sections of the VPM of young rats (6 days postnatal), showing the darkly staining barreloids and the lighter interbarreloid areas. The precise planes of cutting are important for optimal visualization of the barreloids and are described in detail in Haidarliu and Ahissar (2001). (c) In this reconstruction, the orientation of the long axis of the VPM, viewed from caudodorsal to ventrorostral, is shown in a schematic drawing of a coronal section through the right hemisphere at the caudal pole of the VPM. (d) Three-dimensional reconstruction of the barreloids in the VPM. A, B, C, D, and E represent the five barreloid rows; α, β, γ, and δ represent straddlers. Abbreviations: D, dorsal; DLC, dorsolaterocaudal; L, lateral; LC, laterocaudal, R, rostral; RL, rostrolateral; SP, saittal plane; V, ventral. Slightly modified from Fig. 12 of Haidarliu and Ahissar (2001).
shown to contain substance P (Battaglia et al., 1992; Nishiyama et al., 1995). The spinal and principal trigeminal nuclei both project to the ventral posteromedial nucleus as well as, less densely, to the posterior complex (cf. also Waite, Chapter 26, this volume). Projections to the VPM are more focussed, those to the medial part of posterior nucleus more diffuse (Chiaia et al., 1991a). The whiskersensitive parts of the spinal and principal trigeminal nuclei appear to give rise to two trigeminothalamic pathways that reach different parts of the barreloids. These pathways possibly play different functional roles in the relay of information from the whiskers to the somatosensory cortex (Williams et al., 1994; Veinante and Deschenes, 1999; Veinante et al., 2000a; Pierret et al., 2000). From the principal trigeminal nucleus two types of thalamic projection fibers originate. Fibers of the first type, arising from small neurons confined to the socalled barrelettes in the principal trigeminal nucleus
which each have a receptive fields for a single whisker, project densely to the “core compartments” of single barreloids in the dorsomedial two-thirds of the VPM. The second type of fiber originates from larger neurons with receptive fields for multiple whiskers. These fibers terminate in much wider thalamic regions, including the ventral part of the VPM containing the so-called “tail compartments” of the barreloids (Pierret et al., 2000; Veinante and Deschenes, 1999). Specific parts of the spinal trigeminal complex, in particular its interpolar division but also the rostral part of the caudal division, reach the ventral one-third of the VPM, as well as in the interbarreloid areas in the dorsal VPM (Williams et al., 1994; Veinante and Deschenes, 1999). The fibers from the interpolar trigeminal division are thin and form small-sized bushy arbors within the ventral posteromedial nucleus. The VPL and VPM receive afferents from various other subcortical areas, among them a serotonergic
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input from the dorsal raphe nucleus and a GABAergic input from the thalamic reticular nucleus (see section “Reticular Nucleus”) (Cox et al., 1996; Kirifides et al., 2001). Reticular thalamic afferents originate from different types of neurons which have different termination patterns in the ventral posterior complex: some reticular fibers terminate as clusters; others have a wide and more diffuse termination pattern. This indicates that the inhibitory influences of the reticular thalamic nuceus serve different roles in the ventrobasal complex (Cox et al., 1996). The barreloids in the VPM are the thalamic modules in the pathways that lead from the whiskers via the barrelettes in the trigeminal complex to the barrels in the somatosensory cortex (S1). There is an almost exclusive one-to-one relationship from the individual peripheral whiskers to the corresponding cortical barrels. Thus, the thalamocortical projections from the barreloids in the VPM to the barrel cortex, like their corticothalamic counterparts, are very strictly topographically organized (Lu and Lin, 1993; Land et al., 1995; see below). In contrast, thalamocortical fibers from the posterior complex terminate only in the interbarrel areas (Lu and Lin, 1993). Thalamocortical axons from the VPL and VPM terminate predominantly in layer IV of the primary sensory cortex and they most likely use glutamate as neurotransmitter (Kharazia and Weinberg, 1994). Apart from the main terminations in layer IV, thalamocortical axons from the VPM issue also terminal branches in layers I and V/VI (Lu and Lin, 1993; Zhang and Deschennes, 1998). The corticothalamic projections related to the VPL and VPM are organized in a complex way and reflect the hypothesized way in which the afferents of the thalamus are organized as drivers and modulators (see section “Some General Aspects of Thalamic Organization). Corticothalamic projections from the barrel cortex originating from pyramidal neurons in the upper part of layer VI terminate exclusively in the VPM where they arborize in long rostrocaudally oriented bands or “rods.” A rod originating from a single barrel in the cortex makes contact with a series of barreloids that together represent an arc of whiskers (Hoogland et al., 1987; Bourassa et al., 1995). Neurons in the deeper parts of layer VI of the barrel cortex primarily project to the medial part of posterior thalamic nucleus but, in addition, they give off collaterals to the VPM where they participate in the formation of rods (Fig. 3). Neurons in layer VI located in the interbarrel areas project exclusively to the posterior nucleus (Wright et al., 2000). All corticothalamic fibers originating in layer VI give off collaterals to the reticular nucleus and they have long branches that have numerous en passant boutons (Bourassa et al.,
1995; Levesque et al., 1996; Wright et al., 2000). Corticothalamic fibers originating from pyramidal neurons in layer V neurons in the barrel field have main axons descending to the brain stem. They give off collaterals to the posterior and intralaminar thalamic nuclei, but there are no collaterals to the reticular nucleus and VPM. These layer V fibers terminate in a few clusters with large boutons in the posterior thalamic nucleus (Fig. 4) (Hoogland et al., 1991; Bourassa et al., 1995; Veinante et al., 2000b). Functional aspects The VPL and VPM are the primary thalamic relays for somatic sensory, i.e., nociceptive and tactile/kinestetic, information from the body and the head, respectively. For a comprehensive treatment of the pain system and the role of the thalamus in transmitting and modulating pain signals, see Chapter 27 by Willis et al. in this volume. In the rat VPM, the barreloid area representing the whisker field occupies a large part of the nucleus, signifying the importance of the rodent whisker system for navigation and exploration of the environment. This is in part an active process during which the whiskers are being moved in exploratory activities. It has been hypothesized that one of the two functionally different “channels” that reach the VPM, i.e., the pathway that originates in the spinal trigeminal complex, may play a role in this active “whiskering,” while the second channel originating in the principal trigeminal nucleus conveys information about passive deflections (Pierret et al., 2000). As indicated above, there exists an almost exclusive one-to-one relationship of individual whiskers with single barreloids in the ventral posteromedial nucleus. However, for the whisker system to function as an integrated system, which is of course necessary in order to interprete the detailed environmental information, integration of information from the different whiskers is taking place at several levels along the ascending pathway from the periphery to the barrel cortex. The ventral posteromedial nucleus is thought to play an important role in this process. This is signified by the complex interrelationships that exist between the VPM and the barrel cortex, as well as by the differentiated position of the reticular thalamic nucleus. For example, as indicated above, whereas individual barreloids project to single cortical barrels, return projections from the cortex take the form of rods in the VPM, “interconnecting” barreloids representing several or all whiskers in an arc (Hoogland et al., 1987; Bourassa et al., 1995). In the reticular and posterior thalamic nuclei efferents from a row of cortical barrels converge to a common termination site (Welker et al., 1988). The reticular nucleus, sending at least two types of fibers with distinct distribution patterns to the VPM, plays a signifi-
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FIGURE 3 Camera lucida reconstruction of the intrathalamic axonal arborizations of a corticothalamic fiber arising from a pyramidal neuron in the lower part of layer VI of the barrel cortex (primary somatosensory cortex). Individual axons were filled following small injections of biocytin in specific layers of the cortex, filling only a small number of neurons of which the projection fibers could be selectively traced. Note the collaterals in the reticular thalamic nucleus (TR) and the extensive arborizations in the posterior thalamic nucleus (Pom). Terminal fibers in the ventral posterior medial nucleus (VPm) take the form of a “rod.” This fiber and its terminals are reconstructed from several horizontal sections through the thalamus. The drawing in the right-hand corner shows the location of the terminals in a horizontal section of the thalamus. Slightly modified from Fig. 5 of Bourassa et al. (1995).
cant and differentiated role in the modulation of information at the level of the VPM (Cox et al., 1996). There is an extensive body of literature about the electrophysiological and functional aspects of the thalamic relay of somatic sensory information in rats, in particular in relation to the whisker system, but further elaboration on this subject is beyond the scope of this chapter. For a more comprehensive view on this subject, the reader is referred to recent reviews (e.g., Moore et al., 1999; Ahissar and Zackenhouse, 2001). Posterior Nucleus The posterior thalamic nucleus (Po; also indicated as posteror complex) is situated in the caudal part of the
thalamus, bordered caudally by the pretectal nuclei. In its caudal aspect, the Po is situated medial to the posterior intralaminar (PIL) and the medial geniculate (MGM) nuclei, more rostrally this position is taken by the ventral posterior complex, in particular the ventral posteromedial nucleus (Figures 30–42 in Paxinos and Watson, 1998). Dorsally, the Po is bordered by the lateral dorsal and lateral posterior nuclei; medial to the Po the intralaminar nuclei are situated. The posterior nucleus in rats is a heterogeneous area, in particular in its caudal aspects. Within the region generally considered to belong to the Po, several subnuclei have been identified on the basis of differential staining patterns, e.g. the ethmoid, scaphoid, and retroethmoid nuclei
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FIGURE 4 Camera lucida reconstruction of the intrathalamic axonal arborizations of a corticothalamic fiber arising from a pyramidal neuron in layer V of the barrel cortex (primary somatosensory cortex). The axons were filled following small injections of biocytin in the barrel cortex, filling only a limited number of neurons of which the projection fibers could be individually traced. The terminal fibers in the thalamus are issued as collaterals from axons that are directed toward the brain stem. There is strong clustering of axon terminals in the posterior thalamic nucleus (Po) and a few collaterals reach the central lateral nucleus (CL) of the intralaminar complex. Note the absence of collateral fibers in the reticular thalamic nucleus (TR). The drawing in the right-hand corner shows the location of the terminals in a horizontal section of the thalamus. Slightly modified from Fig. 8A of Bourassa et al. (1995).
(Paxinos et al., 1999). The Po appears as a relatively cell-sparse area in Nissl-stained sections, standing out against the cell-dense ventral posteromedial nucleus medially. In acetylcholineseterase-stained sections, the Po shows moderate activity for this enzyme and also on the basis of this staining the posterior nucleus can be reasonably well-delineated from its neighboring nuclei (Plates 31, 33, 35, and 37 in Paxinos and Watson, 1998). With respect to calcium-binding proteins, the Po contains a population of calbindin D28K-positive neurons, while calretinin and parvalbumin are present only in a light plexus of fibers (Arai et al., 1994; e.g., Figs. 195, 201, 202, 208, and 209 in Paxinos et al., 1999). Afferent and efferent connections Like the ventral posterior complex, the posterior complex receives a significant input from the spinal cord and brain stem trigeminal complex (Cliffer et al., 1991; Chiaia et al., 1991a, 1991b; see also Tracey, Chapter 25, and Waite,
Chapter 26, this volume). However, most of these ascending projections are less dense and they terminate in a more diffuse way in the Po than in the adjacent ventral posterior nuclei (e.g., Chiaia et al., 1991a; Villanueva et al., 1998). Moreover, projections to the posterior nucleus from the spinothalamic tract and the spinal trigeminal nucleus appear to be relatively more dense than those from the dorsal column nuclei and the principal trigeminal nucleus (Chiaia et al., 1991a; McAllister and Wells, 1981). Further inputs to the Po come from the inferior colliculus (LeDoux et al., 1987) as well as from the vestibular nuclei (Shiroyama et al., 1999). Reciprocal connections have been described between the posteromedial part of the Po and the region of the nucleus ruber (Roger and Cadusseau, 1987). Recent studies have demonstrated that the trigeminal complex gives rise to several types of fibers ascending to the thalamus which differentially distribute over the ventral posteromedial nucleus and the Po, as well as
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over other extrathalamic nuclei. While most fibers originating from the principal trigeminal nucleus terminate in a very specific manner in the barreloids in the ventral posteromedial nucleus, a smaller contingent of principal trigeminal fibers ascends to the Po. In addition, these fibers give off collaterals to the tectum, the zona incerta, the ventral part of ventral posteromedial nucleus, and the medial part of medial geniculate nucleus. The neurons in the principal trigeminal nucleus giving rise to the projections to the Po are sensitive to stimulation of multiple whiskers, in contrast to those that project to the barreloids in the ventral posteromedial nucleus which transmit signals from single whiskers only (Veinante and Deschenes, 1999). Thalamic projection fibers originating in the spinal trigeminal complex can also be categorized in several types: one type of fiber projects primarily to the ventral part of ventral posteromedial nucleus; the other type of fiber projects predominantly to the caudal part of the Po while giving off collaterals to, among others, the tectum, the zona incerta, and the ventral lateral thalamic nucleus (Veinante et al., 2000a). The Po, like the ventral posterior complex, projects to the primary and secondary sensory cortices, largely following a somatotopical organization (Fabri and Burton, 1991). Thalamocortical fibers from the posterior nucleus terminate in the upper part of layer VI as well as in layer I of the cortex (Zhang and Deschenes, 1998). In the barrel cortex, the projection fibers from the Po do not terminate within the barrels, but they preferentially target the interbarrel areas (Lin and Lu, 1993). Cortical projections to the Po primarily arise from the somatosensory areas S1 and S2, but additional projections originate from motor, premotor (frontal eye field), and insular cortices (Veinante et al., 2000b; Guandalini, 2001). While S1 projects predominantly to dorsal parts of the posterior complex, S2 targets more ventral and medial parts, although there exist substantial areas of overlap (Shi and Cassell, 1998b; Veinante et al., 2000b). The corticothalamic projections to Po arise predominantly from layer V pyramidal neurons as collaterals from axons that project to the striatum and descend into the brain stem (Fig. 4) (Levesque et al., 1996; Veinante et al., 2000b). The fibers originating in layer V of the barrel cortex, possibly predominantly originating from neurons in interbarrel cortical areas, exhibit giant terminals of the RL-type in the Po and they may be considered drivers in this nucleus (see section “Some General Aspects of Thalamic Organization”; Hoogland et al., 1987, 1991; Bourassa et al., 1995; Wright et al., 2000; Veinante et al., 2000b). The other cortical areas mentioned above, as well as the deep layer VI neurons in the cortical barrel field, project fibers with much smaller boutons in the
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Po and these may be considered modulators (Welker et al., 1988; Hoogland et al., 1991; Bourassa et al., 1995). Functional aspects It may be clear that the Po receives ascending inputs from various different modalities (see above), i.e., somatosensory, auditory, visual, and vestibular. Although there is probably convergence within the posterior nucleus of fibers carrying information about these different modalities, the somatosensory modality strongly dominates. Whereas the Po might be considered a primary relay thalamic nucleus, the driving input from layer V of the sensory cortex places this nucleus also in the category of higher order thalamic nuclei (see section “Some General Aspects of Thalamic Organization”). As may be clear from the discussions of the afferents and efferents of both the ventral posteromedial nucleus and the Po, the whisker system in rats occupies a large part of the somatosensory system, and the functional anatomy of this system has been analyzed in great detail (e.g., Moore et al., 1999; Ahissar and Zackenhouse, 2001). Therefore, the most concrete suggestions for a functional role of the Po have been made with respect to the behavioral functions of the whisker system. The whisker system not only provides information about passive movements of individual or groups of whiskers but the whiskers are also actively moved in certain frequencies to “explore” the surroundings. The fact that the Po receives its main cortical input from layer V neurons probably indicates that this concerns an “efference copy” of decending (motor) cortical signals to the brain stem. This has led Veinante et al. (2000b) to the suggestion that the Po plays a role at the interface between the sensory and motor aspects of the whisker system. More specifically, the posterior complex receives the motor signals for active whisker movements as well as the sensory feedback. The Po, together with parts of the trigeminal complex, might thus be involved in monitoring the dynamics of the self-initiated whisker movements, a mechanism that may be necessary for a sensory organ such as the whiskers that lack proprioceptors (Veinante et al., 2000b). Whether the Po has other functions at the interface between the sensory and motor systems remains to be established. The reciprocal connections between the posterior nucleus and the red nucleus provide an indication in that direction (Roger and Cadusseau, 1987; Cadusseau and Roger, 1990; Arnault et al., 1994). Gustatory and Visceral Nuclei The ventromedial part of the ventral posterior complex represents the relay for gustatory and visceral information from the periphery to the insular cortex (Norgren and Leonard, 1973; Cechetto and Saper, 1987).
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The medial part of the ventral posterior complex contains neurons that are smaller than those in the other parts of the VP, and it is therefore referred to as the parvicellular ventral posterior nucleus (VPPC). The VPPC is ventrolaterally bordered by the medial lemniscus and extends medially just ventral to the parafascicular thalamic nucleus and, more rostrally, ventral to the paracentral and central medial nuclei. The VPPC is rostrally “replaced” by the ventromedial nucleus (see Plates 34–37 in Paxinos and Watson, 1998). The VPPC is a rather thin sheet of neurons and it is generally divided into medial and lateral parts, i.e., the parvicellular part of the ventral posteromedial nucleus and the parvicellular part of the ventral posterolateral nucleus (e.g., Cechetto and Saper, 1987; Shi and Cassell, 1998a). Since the medial part of VPPC relays gustatory information (Cechetto and Saper, 1987; Lundy and Norgren, Chapter 28, this volume), this part of the nucleus is indicated by some authors as the gustatory nucleus (e.g., Shi and Cassell, 1998a). Apart from a moderate number of calbindin D28Kpositive neurons, the VPPC only contains moderate to low amounts of calcium-binding proteins in fibers (Arai et al., 1994). The medial part of the VPPC contains a dense plexus of calcitonin gene-related peptide-containing fibers (Yasui et al., 1989). Afferent and efferent connections Major ascending inputs to the VPPC are derived from the parabrachial nucleus (Norgren and Leonard, 1973; Cechetto and Saper, 1987; Bester et al., 1999; Krout and Loewy, 2000a). Other brain stem inputs to the VPPC arise from specific parts of the spinal and principal trigeminal nuclei, as well as from the laterodorsal tegmental nucleus, locus coeruleus, nucleus of the tractus solitarius, the A5 region, and the cuneate nucleus (Krout et al., 2002). The VPPC, in turn, projects to the lateral and central nuclei of the amygdala, the amygdalostriatal transition area directly dorsal to the central amygdaloid nucleus, and the more rostrally located ventral parts of the caudate– putamen (fundus striati). Cortical projections are primarily directed at the granular and dysgranular insular areas of both the posterior insular and parietal insular cortices, while the anterior insular cortices receive only a minor projection from the VPPC (Kosar et al., 1986a, 1986b; Cechetto and Saper, 1987; Turner and Herkenham, 1991; Nakashima et al., 2000). In most of these efferent VPPC projections to cortical and subcortical targets a mediolateral topographical arrangement exists. Cortical afferents to the VPPC are primarily derived from the insular cortical areas to which it projects. Thus, the granular and dysgranular posterior insular cortices project predominantly to the medial VPPC, while the granular and dysgranular parietal insular cortices send fibers primarily to the lateral part
of the VPPC (Shi and Cassell, 1998a, 1998b). The rostrally located dysgranular and agranular insular cortices have only very few projections to the VPPC (Shi and Cassell, 1998a). Functional aspects The main function of the VPPC is the transfer of gustatory and visceral information to the granular and dysgranular insular cortices. These insular areas are situated between olfactory cortical areas more ventrally, i.e., around the rhinal sulcus, and the sensorimotor cortices involved with mouth/tongue, head, and forelimbs in the frontoparietal areas just dorsal to the insular cortices. Combined anatomical and physiological studies have demonstrated that the gustatory area is situated more medially in the VPPC, and the visceral area is located more laterally (Kosar et al., 1986a, 1986b; Cechetto and Saper, 1987). In a recent, detailed tracing study, it has been shown that the parabrachial projections to the medial part of the VPPC originate from the two main gustatory relay nuclei in the parabrachial complex. Based on light microscopic observations, the parabrachial fibers in the VPPC have large terminals, suggesting primary sensory relay of information (Bester et al., 1999). The subdivision of the VPPC into a medial gustatory and a lateral visceral part is in line with the functional topography that has been established in the granular and dysgranular posterior insular cortices (Kosar et al., 1986a, 1986b; Cechetto and Saper, 1987; Shi and Cassell, 1998a, 1998b). Behavioral studies, using specific lesions of the gustatory part of the VPPC, suggest that this thalamic region is not essential for taste discrimination per se, but rather that it is important for more complicated behavioral functions in which the performance is dependent upon “manipulation” of gustatory information (Reilly and Pritchard, 1997). This could be in line with anatomical observations that parabrachial projections bypass the thalamus to reach directly the amygdala and insular cortices (Shipley and Sanders, 1982; Yasui et al., 1989). For a more comprehensive review of the rat gustatory system and the role of the thalamus in this system, see Chapter 28 by Lundy and Norgren in this volume. Medial Geniculate Nucleus The medial geniculate nucleus (MG) forms the most caudal extension of the thalamus and its caudal half is situated laterally alongside the mesencephalon. For a detailed discussion of the auditory thalamus see Malmierca and Merchán (Chapter 31, this volume). The rostral part of the MG is located ventromedially to the lateral geniculate complex. The MG is the principal auditory relay nucleus of the thalamus and consists of several subnuclei that all have different functions within
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the auditory system. The medial geniculate nucleus can be subdivided into medial (MGM), ventral (MGV), and dorsal (MGD) subnuclei (Jones, 1985; Clerici and Coleman, 1990). The “auditory” thalamus further consists of a number of smaller nuclei that are positioned medially and ventromedially to the main MG complex, i.e., the suprageniculate nucleus (SG), the posterior limitans thalamic nucleus (PLi), the posterior intralaminar thalamic nucleus (PIL), and the lateral part of the parvicellular subparafascicular nucleus (SPF; see section “Midline and Intralaminar Thalamic Nuclei”). A marginal zone (MZMG) “covers” the dorsal, lateral, and ventral aspects of the MGD and MGV. The MGD and MGV are separated by the so-called midgeniculate bundle which is mainly derived from the inferior colliculus. The MGV can be further subdivided into a ventral and an ovoid part based on fiber architectonics and cytoarchitectonics (Clerici and Coleman, 1990). The main cell type in MGV is small- to medium-sized and has bushy tufted dendrites forming fibrodendritic laminae that are regularly oriented in association with the fiber bundles from the inferior colliculus in a dorsolateral to ventromedial direction (Winer et al., 1999a). In the oval part of the MGV, the orientation of cells and colliculular afferent fiber bundles is more spiral-like (Clerici and Coleman, 1990). The MGD is rather heterogeneous in its neuronal composition and can be subdivided into several subnuclei. Neurons in the MGD have radiating, tufty dendrites (Winer et al., 1999a). Also in the MGM, the neuronal population is rather heterogeneous, ranging from small to magnocellular. Few interneurons (about 1%) have been identified in the MG complex, most of them being GABAergic (Winer and Larue, 1988; Winer et al., 1999a). Afferent and efferent projections Ascending afferents to the MG primarily originate in the inferior colliculus. While the MGV receives its afferents mainly from the central nucleus of the inferior colliculus, the MG complex as a whole collects fibers from the cortices of the inferior colliculus. Like the MGV, the MGM receives, in addition, collicular fibers from the central nucleus (Jones, 1985; LeDoux et al., 1987). The central nucleus of the inferior colliculus is strictly tonotopically organized, and the MGV transfers this highly organized information to the primary auditory cortex Te1 in the temporal lobe (Winer et al., 1999b). As such, the MGV, in particular the ovoid subnucleus, forms the main thalamic input for area Te1. The projections from the MGV terminate primarily in layers III and IV of Te1, but there are also projections to the junction of layers V and VI and to superficial layer I (Romanski and LeDoux, 1993; Cetas et al., 1999; Winer et al., 1999b). The projections from the MGV in Te1 are strongly
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convergent, highly topographic, and spatially focal, and they originate from only one type of neuron in the MGV. Its caudal part excepted, the MGV does not project outside area Te1. The cortical projections from the MGM and the MGD are more divergent, not only directed toward Te1 but, in a much denser pattern, also to surrounding cortical areas Te2 and Te3. These thalamocortical projections arise from several types of geniculate neurons and mostly terminate in the middle cortical layers (Roger and Arnault, 1989; Arnault and Roger, 1990; Winer et al., 1999b). Corticothalamic fibers from the temporal cortical areas Te1 (primary auditory cortex) and Te2 and Te 3 (together indicated as the “auditory belt” cortex) terminate in different parts of the medial geniculate complex (Shi and Cassell, 1997). Cortical area Te1 projects primarily to the MGV and more moderately to the ventral part of the MGD. Area Te3 sends its most dense projections to the dorsal part of the MGD, directly adjacent to the lateral posterior nucleus which also receives a dense input from Te2 (Shi and Cassell, 1997). Strikingly, the ovoid subnucleus of MGV is largely avoided by these corticothalamic projections, indicating a lack of reciprocity in the cortical connections of this part of the MGV. At the ultrastructural level, corticothalamic projections arising from the primary auditory cortex terminate as small and large (“giant”) terminals in the medial geniculate complex. The smaller, most numerous corticothalamic terminals are present throughout the MG complex, the larger terminals have been observed in the ventral part of the MGD (Rouiller and Welker, 1991) as well as in the dorsal part of the marginal division (MZMG; Bartlett et al., 2000). Excitatory collicular terminals are rather variable in size and include small and large profiles, the larger ones being predominant in the MGV (Bartlett et al., 2000). This heterogeneity in the morphology of the ascending, colliculogeniculate projections indicates a higher complexity in the auditory pathways than in the ascending projections to other sensory thalamic nuclei. Furthermore, part of the collicular afferents of the MGV and MGD appear to be inhibitory (Bartlett and Smith, 1999). Yet, the general organization of ascending driving inputs and descending modulatory cortical inputs seems to hold also for the MGV. Driving cortical inputs from the primary auditory cortex may reach parts of the medial geniculate complex (MGD and MZMG) other than that from which it receives its primary thalamic input, i.e., the MGV (see section “Some General Aspects of Thalamic Organization”). All medial geniculate nuclei, except the MGV, project to other temporal association cortices, like the perirhinal cortex, as well as to the amygdala. A common feature of the medially located MGM, SG, and PIL nuclei is that
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they target the upper part of layer I of the temporal association cortices, in addition to more specific projections to deeper layers of these cortices (Linke and Schwegler, 2000). The SG, in addition, projects to the medial agranular frontal cortex (Kurokawa and Saito, 1995). Projections to the amygdala, primarily terminating in the lateral nucleus and, to a lesser degree, the basal nuclei, arise from the medially located subnuclei MGM, SG, and PIL and the lateral part of the parvicellular subparafascicular nucleus (LeDoux et al., 1985, 1990; Turner and Herkenham, 1991; Namura et al., 1997; Doron and LeDoux, 1999, 2000). Apart from projections to the amygdala, the medial subnuclei of the medial geniculate complex also have reciprocal connections with basal ganglia structures. In particular the caudal parts of the striatum, including the amygdalostriatal transition zone, and the caudal globus pallidus participate in these connections with the MGM, SG, PIL, and lateral subparafascicular nucleus (Moriizumi and Hattori, 1992; Shammah-Lagnado et al., 1996). The MGM, as well as the SG and PIL, not only receives ascending auditory information from the inferior colliculus but is also reached by fibers from the superior colliculus (Linke, 1999). In addition, the MGM receives direct projections from the dorsal cochlear nucleus, bypassing the inferior colliculus. In view of the fact that both the superior colliculus and the dorsal cochlear nucleus transfer multimodal information, it seems likely that the medially located subnuclei of the MG complex do not only process auditory information (Malmierca et al., 2002). Functional aspects of the medial geniculate complex It is evident from anatomical and physiological data that the MGV is the main thalamic relay to the primary auditory cortex, subserving the specific tonal analysis of sounds (e.g., LeDoux et al., 1987; Romanski and LeDoux, 1993; Bordi and LeDoux, 1994a; Winer et al., 1999b). The functions of the MGD are less clear, but are most probably concerned with nontonal aspects of sounds and the integration with other sensory modalities. The projections from the inferior colliculus stem from a part of the colliculus that is not tonotopically organized and in the MGD the projections to the temporal cortices are also less strictly organized, terminating primarily in the auditory association cortices (LeDoux et al., 1987; Clerici and Coleman, 1990). The superficial, dorsal region of the MGD may even be a visual-recipient rather than an auditory-recipient area of the medial geniculate complex (Sun et al., 1996; Shi and Cassell, 1997). For a more detailed discussion of the functional aspects of the auditory thalamus, see Chapter 31 by Malmierca and Merchan in this volume. The functions of the MGM, as well as those of the
PIL, SG, and SPF nuclei, must be interpreted in the context of their connections with the temporal association cortices, the amygdala, and the basal ganglia (see above). In particular the relationships of these MG nuclei with the amygdala have been the focus of electrophysiological and behavioral studies. It is clear from such studies that these pathways, which connect the auditory system primarily with the limbic association areas of the brain, are associated with the emotional and mnemonic aspects of sounds. The extensive and elegant functional anatomical studies of LeDoux and colleagues have demonstrated that the MGM, the PIL, and the lateral part of the parvicellular subparafascicular nucleus play an important role in the association of emotionally negative, e.g., noxious, stimuli and the context in which these stimuli occur (fear conditioning; LeDoux, 1993, 2000). The convergence of auditory and somatosensory inputs, but possibly also of visual inputs via the superior colliculus (Linke et al., 1999), in these nuclei of the MG complex appear to form the neuronal basis for such associations that are behaviorally expressed via the amygdala (LeDoux et al., 1987; Bordi and LeDoux, 1994a, 1994b; Linke et al., 1999; LeDoux, 2000). In the context of fear conditioning, plastic changes have been demonstrated in both the MG complex and the amygdala (LeDoux, 2000; Maren et al., 2001; cf. also Komura et al., 2001). The MGM and the PIL have also been shown to form a crucial link in pathways that lead to the neuroendocrine expression of audiogenic stress via the amygdala and, ultimately, the hypothalamic paraventricular–hypophysis system (Campeau et al., 1997; Campeau and Watson, 2000). Thus, the medially located nuclei of the medial geniculate complex are important for the association of auditory and other sensory inputs and the “translation” of this information, via the amygdala and temporal association cortices, in behavior and emotional reactions. Finally, it is important to note that several nuclei of the medial geniculate complex not only project to the cerebral cortex or subcortical forebrain structures, but that in particular the medially located MGM, PIL, SPF, and SG also have descending projections to the inferior colliculus (Senatorov and Hu, 2002; Winer et al., 2002). Thus, parallel to descending cortical projections to brain stem auditory centers, these medially located MG nuclei are also in a position to provide feedback to the early relays in the ascending auditory pathways.
Motor Nuclei Vental Lateral and Ventral Anterior Nuclei The ventral lateral (VL)–ventral anterior (VA) complex occupies an extensive nuclear area intercalated between the ventral posterior nuclei ventrolaterally,
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the posterior and lateral dorsal nuclei dorsally, and, adjacent to its rostral extension, the intralaminar and anterior nuclei dorsomedially. Ventromedially, the VA/VL complex abuts the ventromedial nucleus (VM) (Figs. 25–32 in Paxinos and Watson, 1998). Cytoarchitectonically, the VA/VL complex is cell sparse and contains relatively large neurons. In rats, a distinction between the ventral anterior and the ventral lateral nuclei on the basis of cytoarchitectonics is difficult to make (Jones, 1985). In acetylcholinesterase-stained sections the VA exhibits very low activity for this enzyme and is therefore easily delineated from its surrounding nuclei, e.g., the reticular nucleus and the anterior complex (Plate 26 in Paxinos and Watson, 1998). In the VL, acetylcholinesterase activity is slightly higher than that in the VA. Calcium-binding proteins are sparse in both the VA and the VL (Arai et al., 1994). Neurons containing calbindin D28K are present in some parts of both nuclei, parvalbumin is only present in a moderately dense fiber plexus in VA and VL (e.g., Figs. 173, 174, and 180 in Paxinos et al., 1999). Afferent and efferent connections The VL/VA complex receives afferents mainly from the cerebellum and the basal ganglia, and it is in reciprocal contact with somatomotor and premotor cortical areas. Additional subcortical inputs derive from the vestibular nuclei (Shiroyama et al., 1999). Cerebellar inputs originate from the deep cerebellar nuclei (Faull and Carmen, 1978; Angaut et al., 1985; Sawyer et al., 1994a, 1994b; Aumann et al., 1994, 1996). The cerebellar projections stem primarily from the lateral and interpositus nuclei and they spread virtually over the entire VL. There exists a topographical arrangement in the cerebellothalamic pathways such that the dorsoventral and mediolateral axes of the lateral cerebellar nucleus correspond to the dorsoventral and mediolateral axes in the VL, respectively (Angaut et al., 1985). In a single axon tracing study, Aumann et al. (1996) observed different types of cerebellothalamic fibers. Although all axons project to both the ventral lateral and the intralaminar and adjacent thalamic nuclei, within the VL one type of fiber has very restricted, clustered terminal areas, whereas a second fiber type has a more widespread and diffuse termination pattern. In some cases the latter fibers even reach the VL in both hemispheres (Aumann et al., 1996). Cerebellothalamic inputs are most probably the driving inputs for the ventral lateral nucleus since their terminals exhibit large round boutons with closely packed small round vesicles, i.e., resembling the RL-type terminal (Sawyer et al., 1994a; see section “Some General Aspects of Thalamic Organization”). This morphology fits with the excitatory nature of the cerebellothalamic projections
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that have been established in electrophysiological experiments (e.g., Sawyer et al., 1994b). The large terminals originating from the cerebellum make up only a minority of the presynaptic terminals in VL, the majority being of the RS-type originating from the cerebral cortex. A third category is formed by mediumsized boutons with pleomorphic vesicles forming symmetrical synapses. The latter represent most probably the GABAergic terminals from the reticular thalamic nucleus and the substantia nigra pars reticulata and/or the entopeduncular nucleus (Sawyer et al., 1994a). However, in an anterograde tracer study combined with electron microscopy Finkelstein et al. (1996) could not confirm the symmetrical morphology of entopeduncular terminals in VA/VL but, instead, demonstrated asymmetrical synapses with round vesicles to be associated with pallidal projections. In line with the latter finding, it has recently been shown that cholinergic and glutamatergic fibers possibly make up a large part of the nigral and pallidal projections to the VL (as well as to the ventral medial nucleus), although a GABAergic projection could also be established (Kha et al., 2000, 2001). The basal ganglia input to the VA/VL complex, represented by the projections from the entopeduncular nucleus and the pars reticulata of the substantia nigra, is concentrated in the rostral and medial parts of the complex, i.e., the area corresponding mostly to VA (Sakai et al., 1998). In agreement with findings in other species, there appear to be only limited areas of overlap of cerebellar afferents with entopeduncular and nigral terminations in the VA/VL complex of rats (Carter and Fibiger, 1978; Deniau et al., 1992). The VA/VL complex receives a third strong input from the somatomotor cortex and, in addition, from a wide array of frontal and parietal cortical areas. In particular the rostromedially located ventral anterior nucleus is the target of (pre)frontal cortical afferents (e.g., Sesack et al., 1989; Conde et al., 1990; Reep and Corwin, 1999; Vertes, 2002). As mentioned above, these cortical inputs are most likely the source of the RS-type of inputs, i.e., modulatory inputs. In return, the ventral lateral nucleus is the main thalamic source of inputs to the somatomotor cortex, but the VL also projects to premotor cortical areas (Aldes, 1988). These fibers target layers III–V, but they terminate most densely in superficial layer I (Yamamoto et al., 1990; Aumann et al., 1998; Mitchell and Cauller, 2001). Functional aspects The VA/VL complex must be considered the main motor thalamic relay to the cerebral cortex. The largest volume of VA/VL is devoted to the cerebellar influences on the motor thalamocortical system. This cerebellothalamocortical pathway is most
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probably devoted to the coordination of multijoint movements (Sawyer et al., 1994b). The area of the VA/VL receiving basal ganglia inputs is smaller, including predominantly rostral and medial parts of the complex, i.e., the area that is best characterized as the ventral anterior nucleus (Sakai et al., 1998). The basal ganglia and thalamocortical system are involved in a number of parallel, functionally segregated circuits (e.g., Deniau et al., 1994; Groenewegen et al., 1990, 1999). In the circuits that are closest related to motor functions in rats, the VM is generally considered to be the thalamic relay. However, as discussed below (see following section), the VM might have a different position in these circuits than generally assumed: as a result of the rather widespread cortical projections the VM presumably plays an integrating role for the various parallel, functionally segregated basal ganglia–thalamocortical circuits (Groenewegen et al., 1999). In that respect, it would be interesting to gain more insight into the “position” of the ventral anterior nucleus in these circuits. The VA nucleus has a projection to the (pre)motor cortical areas more concentrated than that of the VM and may therefore be considered as the thalamic relay in the motor basal ganglia–thalamocortical circuit (Sakai et al., 1998). Ventral Medial Nucleus The ventromedial thalamic nucleus (VM) is a slender, rostrocaudally elongated nucleus in the rostromedial part of the ventral thalamic complex. Medially, the VM can be clearly distinguished from the cell-sparse nucleus submedius. The mammillothalamic tract ascends just medially to and through the most medial parts of the VM. Dorsally and laterally the VM is bordered by the VA and VL nuclei, as well as, more caudally, by the ventral posterior lateral and ventral posterior medial (VPL/VPM) complex (Figs. 26–34 in Paxinos and Watson, 1998). The VM can be distinguished from these nuclei in Nissl-stained sections since it is made up of slightly smaller neurons that are more densely packed (see also Herkenham, 1979). The presently defined VM largely corresponds with the basal VM as defined by Jones (1985). In acetylcholinesterase-stained sections the ventral medial nucleus only exhibits low activity. With respect to calcium-binding proteins, the VM contains calbindin D28K-positive neurons throughout the nucleus while calretinin-positive neurons are restricted to its medial part (Arai et al., 1994; e.g., figures 174 and 175 in Paxinos et al., 1999). A low density of calbindin D28K- and parvalbumin-positive fibers is present in the ventral medial nucleus. Afferent and efferent connections Subcortical inputs to the VM originate to a large degree in the entope-
duncular nucleus (the internal segment of the globus pallidus) and the substantia nigra pars reticulata. These afferents preferentially target medial parts of the VM, while the lateral part is less densely innervated (Carter and Fibiger, 1978; Herkenham, 1979; Deniau et al., 1994; Groenewegen et al., 1999). Recently, a strong projection from the medullary subnucleus reticularis dorsalis to the VM, with a dominance for its lateral part, has been described (Villanueva et al., 1998). Other substantial subcortical inputs are derived from the deep layers of the superior colliculus, the deep mesencephalic nucleus, the periaqueductal gray matter, the raphe nuclei, the peripeduncular region, the laterodorsal tegmental nucleus, the locus coeruleus, the parabrachial region, and the trigeminal complex (Herkenham, 1979; Krout and Loewy, 2000a, 2000b; Krout et al., 2001, 2002). Afferents from the cerebellum have also been identified (Angaut et al., 1985). Cortical afferents of the VM originate in widespread cortical areas of the frontal lobe (Herkenham, 1979; Seseack et al., 1989; Hurley et al., 1991; Vertes, 2002). The projections from the ventral medial nucleus reach widespread cortical areas, in particular in the rostral, frontal part of the hemisphere, but to a lesser degree also in more caudal areas (Herkenham, 1979; Conde et al., 1990; Reep et al., 1996). The laminar distribution of the thalamocortical fibers arising in the VM is remarkable in that they reach primarily the most superficial part of layer I of almost the entire cortical mantle (Herkenham, 1979; Desbois and Villanueva, 2001; Mitchell and Cauller, 2001). Some VM fibers reach also the deeper layers III and V of the dorsolateral part of the frontal cortex, including the motor cortex (Arbuthnott et al., 1990). Functional aspects Together with the VA/VL complex, the VM is in general considered to be part of the motor thalamus. In view of its position between, on the one hand, the basal ganglia output structures, i.e., the entopeduncular nucleus and the substantia nigra reticulata and, on the other hand, the frontal cortex including motor and premotor cortices, this appears as a logical assumption. However, as has already been concluded by Herkenham in 1979, the VM has a rather widespread projection to layer I of a large part of the cortical mantle, in particular in the frontal cortical areas. It might therefore be conceived that the VM plays a particular integrative rol. The ventral medial nucleus projects to the superficial layers of all (pre)frontal cortical areas that form the starting point for the above-mentioned (see page 422) basal ganglia–thalamocortical systems, indicating that the VM potentially has an influence on all these functionally distinct circuits (Groenewegen et al., 1999).
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This influence might be of attentional significance, preparing the various circuits for a specific motor or behavioral output. In this respect, it is of interest to note that the projection from the substantia nigra to the VM primarily originates from the dorsomedial aspect of the pars reticulata, an area which receives strong inputs from the core of the nucleus accumbens (Deniau and Chevalier, 1992; Deniau et al., 1994, 1996; Montaron et al., 1996). The nucleus accumbens has also been implicated in attentional mechanisms. This proposed attentional functional role of the VM may even be further specified in that the VM receives a strong input from caudal reticular brain stem nuclei conveying nociceptive signals (Villanueva et al., 1998). It has recently been confirmed that the VM transmits this nociceptive information from the whole body surface to the frontal cortex (Monconduit et al., 1999). This might imply that the VM is important for allowing pain signals to gain direct access to widespread cortical areas. A possible interpretation is that a fast access route for vital signals serves to prime the cerebral cortex for attentional reactions that should lead to coordinated motor and behavioral responses in reaction to painful stimuli (Monconduit et al., 1999; cf. also Herkenham, 1980). A similar role could be played by the caudal ventral medial nucleus with respect to deep pain (Floyd et al., 1996). It is of interest to note that in his caudal region of the VM calbindin D28K-positive neurons might be involved (Floyd et al., 1996; cf. also Jones, 1998).
ASSOCIATION THALAMIC NUCLEI Mediodorsal Nucleus The mediodorsal thalamic nucleus (MD) is situated medially and dorsally to the internal medullary lamina of the thalamus in which the intralaminar nuclei are embedded and ventrally to the stria medullaris/ habenular complex. In between the left and the right MD nuclei, the midline paraventricular (PV) and intermediodorsal (IMD) nuclei are situated. The mediodorsal nucleus is bordered rostrally by the parataenial nucleus (PT) and caudally by the parafascicular nucleus (PF), two nuclei also belonging to the midline/intralaminar thalamic nuclei. Therefore, the MD is virtually “encircled” by the midline and intralaminar thalamic complex with which it shares inputs from many cortical and subcortical sources (cf. Section VI). The MD in rats is generally subdivided into three parts, the medial (MDM), central (MDC), and lateral (MDL) segments (Leonard, 1969, 1972; Krettek and Price, 1977). The distinction between these segments is based on
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cytoarchitectonics and fiber architectonics, as well as on distinct input–output relationships (see below). The central segment is richest in myelinated fibers and, in that respect, stands out against the two other segments. The lateral segment has the highest activity for acetylcholinesterase (Plate 31 in Paxinos and Watson, 1998). The differential distribution of calcium-binding proteins also confirms a distinction between the three MD segments. This is most apparent with respect to calbindin D28K, which is present in both cell bodies and fibers in the medial and lateral segments, but much less so in the central segment (Arai et al., 1994; see also Figs. 181, 188, and 195, Paxinos et al., 1999). Stellate and fusiform cells make up the majority of the neuronal population of the MD, both considered to be thalamocortical neurons (Kuroda et al., 1992, 1998). Stellate cells are most abundant in the MDC, whereas in the MDM and the MDL fusiform neurons are relatively more numerous. Interneurons are very rare if existent at all in the rat mediodorsal nucleus. Dendrites of the stellate and fusiform neurons largely remain within the segment in which their parent cell body resides, stressing the morphological distinction between the three segments (Kuroda et al., 1992). Further heterogeneities are present within the three segments. On the basis of differences in fiber densities and connections, Ray and Price (1992) suggested that the MDL may be further subdivided into a dorsolateral and a ventrolateral part. Groenewegen (1988), primarily based on fiber connections, recognized a paralamellar part of the MD, comparable with a similar segment in primates. In general, the MDM and MDC together are thought to be homologuous with the medial magnocellular segment of the primate MD, and the rat MDL may be homologuous with the primate parvocellular, lateral segment of the mediodorsal nucleus. Afferent and Efferent Projections The different segments of the MD are characterized by different input–output relationships. The MD as a whole is reciprocally connected with the frontal cortex rostral to the motor and premotor cortices. The MD– cortical projections are considered to define the “prefrontal cortex” (cf. Uylings and Van Eden, 1990). In this respect, the prelimbic and dorsal anterior cingulate (Cg1) areas, located in the medial wall of the hemisphere, as well as the dorsal and ventral agranular insular areas, situated rostrally in the dorsal bank of the rhinal sulcus, receive the strongest input from the MD (e.g., Leonard, 1969, 1972; Groenewegen, 1988; Conde et al., 1990; Ray and Price, 1992). However, also the infralimbic area, the various different orbital areas, the ventral anterior cingulate (Cg2) area, and the medial agranular cortex (“shoulder” cortex) receive a consid-
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erable input from the MD (Groenewegen, 1988; Ray and Price, 1992; Reep et al., 1996). The MD–thalamocortical projections are to a large degree reciprocated by corticothalamic projections with the notable difference that the latter distribute bilaterally while the thalamocortical projections are strictly unilateral. There exists a striking specificity in the reciprocal MD–prefrontal connections, which is as follows. The rostral part of the MDM is primarily connected with the ventral prelimbic and infralimbic areas, while the caudal part of the MDM communicates with the dorsal agranular insular area. The MDC is reciprocally connected with the ventral agranular insular area. Finally, the MDL has reciprocal connections with the dorsal prelimbic, dorsal anterior cingulate and medial agranular areas (Groenewegen, 1988; Conde et al., 1990; Ray and Price, 1992; Guandalini, 2001; Vertes, 2002; Heidbreder and Groenewegen, 2003). However, relationships with these (prefrontal) cortical areas are by no means “exclusive” for the mediodorsal nucleus. The dorsal anterior cingulate, prelimbic, and infralimbic areas project to and receive input from a rather extensive medial zone of the thalamus. This medial thalamic zone encompasses, in addition to the MD, parts of the midline and intralaminar complex, prominently including the nucleus reuniens, and further the anteromedial (AM), submedius (Sub), and ventromedial (VM) nuclei, as well as the medial parts of the lateral dorsal (LD) and lateral posterior (LP) nuclei (see also corresponding sections in this chapter; Conde et al., 1990; Reep et al., 1996; Vertes, 2002). Likewise, the orbital areas have reciprocal relationships with different segments of the MD, but these areas are also extensively connected with the–nucleus submedius–(see below) and, to a lesser degree, the VM (Ray and Price, 1992; Reep et al., 1996). Anatomical and electrophysiological experiments have shown that the reciprocal corticothalamic MD projections use excitatory amino acids as neurotansmitters (Ray et al., 1992; Pirot et al., 1994; Kuroda et al., 1998). The projections from the MD to the prefrontal cortex terminate predominantly in layer III and to a lesser degree in layer I of the cortex, while the return projections to the ipsilateral mediodorsal nucleus originate in layer VI (Krettek and Price, 1977; Groenewegen, 1988). Nevertheless, the MD thalamocortical neurons are in direct reciprocal contact with the layer VI pyramidal neurons that give rise to the corticothalamic projections. The thalamocortical neurons contact also pyramidal neurons in layer III that give origin to projections to the contralateral MD (Kuroda et al., 1993, 1998). The reciprocal circuitry between the mediodorsal nucleus and the prefrontal cortex may be modulated by dopaminergic inputs from the ventral tegmental area, as well as through local GABAergic cortical interneu-
rons that, in turn, receive direct excitatory inputs from the mediodorsal nucleus (Kuroda et al., 1998; Fig. 5). The MD receives inputs from a wide variety of subcortical sources (Groenewegen, 1988; Ray et al., 1992), many of which have been characterized at the ultrastructural level (for review, Kuroda et al., 1998). The MDM receives fibers from the amygdala, different nuclei in the basal forebrain, like the nucleus of the diagonal band of Broca and the ventromedial part of the ventral pallidum, the lateral preopic area, the ventral tegmental area, and several other brain stem nuclei. Amygdaloid inputs to the MDM derive from the central, cortical, and basal nuclei of the amygdaloid complex (Reardon and Mitrofanis, 2000), and these fibers form RL-type terminals establishing asymmetric synapses on complex dendritic appendages and large dendritic shafts from which spines arise (glomeruli; Kuroda and Price, 1991a). No data are available on the possible transmitter content of the amygdaloid inputs. In the MDC, terminals similar to those described for the amygdaloid inputs to the MDM and containing neurotensin have been identified originating from the prepiriform cortex (Kuroda and Price, 1991a; Ray and Price, 1990). Both the MDC and the MDM further receive inputs from pallidal neurons located in the deep layers of the olfactory tubercle (Groenewegen, 1988). Ventral pallidal terminals (in the MDM and the MDC) are large, contain pleomorphic vesicles, and establish symmetric synapses (Kuroda and Price, 1991a). These terminals are for the most part GABAergic although also other transmitters may be used in the projections from this heterogeneous basal forebrain region (Ray et al., 1992; Churchill et al., 1996). The MDL primarily receives inputs from brain stem structures like the reticular part of the substantia nigra, the deep layers of the superior colliculus, and the laterodorsal tegmental nucleus. Weaker inputs derive from the medial part of the globus pallidus (Groenewegen, 1988). Inputs from the reticular substantia nigra are GABAergic and have ultrastructural characteristics very similar to those of the pallidothalamic fibers (Kuroda and Price, 1991a). By contrast, collicular inputs establish small, asymmetric contacts of the RS-type. The afferents from the laterodorsal tegmental nucleus to the MDL, on the other hand, are large with round vesicles and they establish asymmetric RL-type contacts with proximal dendrites. These tegmental afferents most probably use acetylcholine as neurotransmitter. At the ultrastructure level, the inputs from layer VI of the prefrontal cortex to the mediodorsal nucleus are of the RS-type, the most numerous type of terminal located primarily on the more distal parts of the dendrites (Kuroda and Price, 1991b; Kuroda et al., 1998). All MD segments receive input from the reticular thalamic nucleus (Rt), terminals
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FIGURE 5 A diagrammatic representation of the synaptic connections between prefrontal cortical (PFC) neurons and MD cells. The projections from the MD end as asymmetrical (excitatory) terminals (open triangles) predominantly on the spines of pyramidal layer III and layer V/VI neurons in the prefrontal cortex. In addition, aspiny nonpyramidal neurons, presumably GABAergic interneurons, are contacted by MD terminals. Some of the pyramidal neurons in layer III give rise to callosal fibers. Pyramidal neurons in the deeper layers provide return projections to the MD. This scheme is reproduced from Kuroda et al. (1998). These authors hypothesize that, since interneurons in the rat MD are scarce or absent, excitatory influences of MD neurons on cortical pyramidal neurons that project back to the MD may lead to reverberatory activity in this MD–PFC thalamocortical circuitry. Via the callosal projections, such activity may spread to the contralateral MD–PFC circuit. Inhibitory inputs (symmetrical synapses, closed triangles) originating from the ventral tegmental area terminate on the dendritic shafts of pyramidal neurons in layers III, V, and VI. This may provide a morphological basis for inhibitory influences on the reverberatory excitation between the MD and the PFC and on the contralateral excitation. The inhibitory cortical interneurons are possibly also involved in the modulation of these excitatory circuits. For further discussion, see Kuroda et al. (1998).
which are small to medium in size, contain pleomorphic vesicles, and terminate as asymmetric synapses. On the basis of this brief survey of the afferents of the MD and their ultrastructural characteristics, it may tentatively be concluded that the different mediodorsal segments receive driving inputs (type II fibers; cf. see section “Some General Aspects of Thalamic Organiza-
tion) from different sources. Drivers for the MDM originate in the amygdala, for the MDC in the prepiriform cortex, and for the MDL in the laterodorsal tegmental nucleus. This may indicate that the MDM is primarily involved in “limbic-emotional” functions, the MDC in olfactory functions, and the MDL in attentional functions, an interpretation that is supported by
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the different combinations of other inputs in the three MD segments (Groenewegen, 1988; Ray and Price, 1992; Kuroda et al., 1998) and their relationships with different parts of the (pre)frontal cortex (Heidbreder and Groenewegen, 2003). While neurons in layer VI and, to a lesser degree, in layer V of the frontal cortex project to the mediodorsal nucleus (Groenewegen, 1988; Cornwall and Phillipson, 1988b), it has not been studied in detail whether there exists a morphological distinction (i.e., type I [modulators] versus type II [drivers]) between the fibers and terminals from these different layers in the MD (Kuroda et al., 1998; Vertes, 2002). However, Negyessy et al. (1998) found, among the majority of ipsi- and contralateral small terminals of the RS-type (type I), large terminals with round vesicles in the MD originating from the ipsilateral but not the contralateral prefrontal areas. Therefore, the mediodorsal nucleus might derive cortical type II driver inputs from (parts of) the ipsilateral prefrontal cortex in addition to those from the prepiriform cortex to the MDC. The inputs to the various MD segments from different parts of the ventral pallidum and the reticular part of the substantia nigra must be viewed from the perspective of the involvement of the MD in a series of prefrontal cortex basal ganglia–thalamocortical circuits (Groenewegen et al., 1990, 1999; Ray and Price, 1992; Churchill et al., 1996; O’Donnell et al., 1997; Zahm, 2000). As indicated above, the ventral pallidal and nigral fibers make GABAergic contacts with MD thalamocortcial neurons (Kuroda and Price, 1991a, 1991b; Churchill et al., 1996). In view of the high spontaneous activity of their neurons, the ventral pallidum and substantia nigra exert a tonic inhibitory influence on the MD. However, as a result of corticostriatal activity which, via a higher activity of the GABAergic striatopallidal and striatonigral projections, leads to an inhibition of the pallidal and/or nigral neurons, the MD may be disinhibited (Deniau et al., 1994). Since the ventral pallidal and nigral terminals tend to end on the more proximal parts of dendrites of MD thalamocortical neurons (Kuroda et al., 1998), these inputs may have a major impact on the activity of the prefrontal cortical–mediodorsal thalamus reciprocal circuitry. Functional Aspects It seems likely that the different segments of the mediodorsal nucleus subserve different functions, but the “resolution” of behavioral studies using lesions or inactivations of MD is too coarse to reliably distinguish between different parts of MD. Furthermore, the MD is spatially very closely associated with the midline and intralaminar nuclei, which also hampers the interpretation of lesion studies.
Functions of the MD have been closely associated with those ascribed to the prefrontal cortex, i.e., in broad terms learning and “working” memory, behavioral control, and visceral functions. As such, the functions of the mediodorsal nucleus should preferably be considered in the context of “limbic” basal ganglia– thalamocortical circuits that are thought to subserve different functional roles (Groenewegen et al., 1990; Deniau et al., 1994; Zahm, 2000). Thus, the rostral MDM is involved in a circuit that encompasses the ventral prelimbic and infralimbic areas, the ventromedial striatum (including the shell of the nucleus accumbens), and the ventromedial part of the ventral pallidum. This circuit might be involved in behavioral control on the basis of visceral–limbic information. The caudal MDM is a way station in a circuit that includes the dorsal agranular insular area, the core of the nucleus accumbens, and the dorsomedial part of the substantia nigra pars reticulata. The MDC forms part of a circuit that includes the infralimbic, orbital, and ventral agranular insular areas of the prefrontal cortex and the pallidal neurons in the deep layers of the olfactory tubercle. This circuit is most probably involved in aspects of the olfactory guidance of behavior (see also Shipley et al., Chapter 29, this volume). Finally, the MDL is involved in a circuit that includes the dorsal prelimbic and dorsal anterior cingulate areas, as well as the medial agranular cortex (Fr2), the medial caudate putamen, and the medial globus pallidus. This circuit might be involved in attentional control of behavior. The medial thalamus, prominently including the mediodorsal nucleus, has since long been implemented in learning and memory (review, Markowitsch, 1982). Yet, it has been difficult to precisely establish the role of the MD in these functions, certainly also in distinction with the anterior thalamic nuclei and the midline/ intralaminar complex, including the nucleus reuniens (reviews, Aggleton and Brown, 1999; Van der Werf et al., 2002). Several authors suggest a role for the MD in spatial working memory, as determined in spatial delayed alternation tasks (e.g., Hunt and Aggleton, 1998; Kalivas et al., 2001). Other studies, employing lesions of the mediodorsal nucleus in tests of discrimination and reversal learning, showed an impairment of reversal learning, in particular when stimulus–reward contingencies were reversed (Chudasama et al., 2001). In line with these observations, electrophysiological studies show a subpopulation of neurons in the MDM that code for stimulus–reward associations which change their activity during extinction and reversal in the tasks used (Oyoshi et al., 1996). Such findings comply with the involvement of the MDM in a triangular relationship with the prefrontal cortex and the amygdala (cf. Price, 1995). Several studies indicate that the mediodorsal nucleus
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is part of a circuit through which epileptic activity is transferred. In models for epilepsy, i.e., through hippocampal kindling or chronic spontaneous limbic epilepsy, it was found that the medial thalamus, including the MD and reuniens nuclei, showed clear seizure activity (Bertram et al., 2001). In both these models as well as in a model of status epilepticus in immature rats (Kubova et al., 2001), loss of thalamic neurons was observed, in particular in the MD but also in other medial thalamic nuclei.
Nucleus Submedius The thalamic nucleus submedius (Sub) is a relatively small nucleus in the midrostrocaudal part of the thalamus. The Sub is situated in between the reuniens (Re) and rhomboid (Rh) nuclei medially and the VM laterally. In the literature, this nucleus has also been indicated as the nucleus gelatinosus (Krieg, 1944; Jones, 1985). The Sub is relatively cell-sparse and stands out against its neighboring nuclei also in neurofilamentstained sections (Fig. 184 in Paxinos et al., 1999). Although there exists a light plexus of parvalbuminpositive fibers in the Sub, calcium-binding proteins are virtually absent from this nucleus (Arai et al., 1994). In particular, calbindin D28K is conspicuously absent from the nucleus submedius making the nucleus readily identifiable in sections stained for this protein (Fig. 188 in Paxinos et al., 1999). The Sub is generally subdivided into rostromedial and caudodorsal parts on the basis of different fiber connections: the former part predominantly receives olfactory inputs and the latter somatic sensory inputs (see below). The caudodorsal part of the Sub exhibits a high acetylcholinesterase activity (see Plate 30 in Paxinos and Watson, 1998), most probably related to a substantial cholinergic input from the laterodorsal tegmental nucleus. Afferent and Efferent Connections Since the original description by Craig and Burton (1981) of afferents from the superficial layers of the spinal dorsal horn and spinal trigeminal nucleus, the Sub has been primarily associated with nociception and pain modulation. However, apart from these ascending sensory afferents, the Sub also receives input from olfactory structures (Price and Slotnick, 1983; Yoshida et al., 1992). The olfactory input terminates mostly in rostroventral parts of the nucleus and is derived from the deep layers of the prepiriform cortex and the endopiriform nucleus. These inputs are very comparable to those of the central segment of the MD (MDC), although the nucleus submedius receives input from a more restricted area in the olfactory cortex than MDC. However, the main cortical associations of
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the Sub are with the ipsi- and contralateral ventrolateral orbital area (VLO). Other cortical areas that receive projections from the Sub include the medial part of the lateral orbital cortex (Yoshida et al., 1992; Coffield et al., 1992; Reep et al., 1996). The dorsal peduncular cortex, located just ventral to the infralimbic cortex, and the dorsal subiculum send cortical fibers to the nucleus submedius (Witter et al., 1990; Yoshida et al., 1992). Forebrain inputs to the nucleus submedius are derived from the horizontal limb of the diagonal band, the lateral hypothalamus, and the reticular thalamic nucleus (Yoshida et al., 1992). Brain stem inputs originate in the deep layers of the superior colliculus, the brain stem reticular formation, the parabrachial nuclei, the laterodorsal tegmental nucleus, and the spinal trigeminal complex (Yoshida et al., 1991, 1992; Krout et al., 2001, 2002; Krout and Loewy, 2000a). In view of the presumed role of the Sub in nociception, the organization of afferents from the trigeminal complex and the dorsal horn of the spinal cord has received special attention (e.g., Craig and Burton, 1981; Dado and Giessler, 1990; Yoshida et al., 1991; Blomqvist et al., 1992; Iwata et al., 1992). In cats, it has been shown that the trigemino- and spinothalamic afferents of the Sub contain glutamate as transmitter (Ericson et al., 1995), while in rats trigeminothalamic neurons appear to express substance P (Li, 1999). The trigeminothalamic fibers, originating from the caudal spinal trigeminal complex, terminate as RL-type terminals on dendritic protrusions forming glomeruli, surrounded by glial elements (Ma and Ohara, 1987; Ma et al., 1988; Ericson et al., 1996). There are also more “simple” boutons-enpassage from both trigeminal and spinal origin in the nucleus submedius, at least in cats (Ericson et al., 1996). Cortical afferents most likely terminate as RS-type terminals while large boutons with flattened vesicles are also present (Ma et al., 1988). As in the sensory relay nuclei, the ascending spinal or trigeminal inputs are most probably the driving inputs for the Sub. In this respect, the nucleus submedius could also be considered to belong to the sensory thalamic nuclei. Functional Aspects Although it may have still not been definitely settled in rats to what extent superficial layer I neurons in the dorsal horn of the spinal cord or the spinal trigeminal complex contribute to the ascending projections to the Sub, functional studies clearly demonstrate a role for the nucleus submedius in nociceptive functions. Electrophysiological studies have shown nociceptive neurons in the Sub following peripheral noxic stimulation (Miletic and Coffield, 1989; Fu et al., 2002). Lesions of the Sub indicate that this nucleus may play a role in supraspinally mediated inhibition of nociceptive input
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(Roberts and Dong, 1994). It has been suggested that the nucleus submedius is a way station in a feedback loop that modulates nociceptive inputs. This loop would run via the Sub to the ventrolateral orbital cortex and, subsequently, descend to the periaqueductal gray matter through which inhibition of nociceptive input at the spinal or trigeminal level can be established (Zhang et al., 1995, 1996, 1999). Behavioral studies may be in line with this interpretation: for example, morphine injections in the Sub depress nociceptive behavior (Yang et al., 2002). However, other studies show that the nucleus submedius may exert its nociceptive modulatory effects at supraspinal levels (Okada et al., 1999). Finally, it has been suggested that the Sub is a crucial nodal point in the brain for the inhibitory effect of acupuncture manipulations in the suppression of certain visceromotor reflexes (Sumiya and Kawakita, 1997).
Anterior Nuclei Three distinct nuclei in the rostral one-third of the thalamus belong to the anterior thalamic compex, i.e., the anterodorsal (AD), anteroventral (AV), and anteromedial (AM) nuclei (Figs. 22–28 in Paxinos and Watson, 1998). The AM nuclei of both thalamic halves fuse in the midsagittal plane and form the interanteromedial nucleus (IAM) which extends slightly further caudally then the other anterior nuclei. Because of great similarities in afferent and efferent connectivity, the LD is often also included in the group of anterior nuclei (Price, 1995). The LD rostrally begins as a small nucleus (as a cap) dorsal to the AV and expands more caudally to occupy an extensive dorsal region in the thalamus, lying lateral to the habenular complex. Caudally, laterodorsal nucleus ends at the same level as the lateral habenula and is gradually replaced medially by the LP which extends and expands into the most caudal parts of the thalamus (Figs. 34–42 in Paxinos and Watson, 1998). In Nissl-stained sections, the anterodorsal nucleus is most conspicious because of its large, darkly staining cells. The anteromedial and anteroventral nuclei have smaller and lighter staining neurons and, although the cell density in the AV is lower than that in the AM, in Nissl-stained sections the border between these nuclei is difficult to draw. However, in sections stained for AChE activity, a clear distinction can be made between the anterior nuclei, the AM exhibiting the lowest and the AV the highest activity of this enzyme (see Plate 26 in Paxinos and Watson, 1998). Neurons positive for calcium-binding proteins, in particular for calbindin D28K, are present in the AM, but not in the other anterior nuclei. The three anterior nuclei contain to a varying degree positive neuropil for the calcium-binding proteins calbindin D28K, calretinin, and parvalbumin,
but they are not conspicuous thalamic structures in that respect (Arai et al., 1994). Within the anteroventral nucleus a distinction can be made between a ventrolateral (AVVL) and a dorsomedial (AVDM) part on the basis of calbindin immunoreactivity; AVVL (like AM) contains a moderately dense calbindin-positive neuropil, AVDM (like AD) is almost blank (Plate 174 in Paxinos et al., 1999). Afferent and Efferent Connections Inputs to the anterior thalamic nuclei are mainly derived from the limbic cortices in the medial wall of the cerebral hemisphere (see below), hippocampal region, and mammillary nuclei (Swanson and Cowan, 1977; Witter et al., 1990; Seki and Zyo, 1984; Shibata, 1992). In addition, serotonergic inputs originate from dorsal and median raphe nuclei (Gonzalo-Ruiz et al., 1995) and cholinergic fibers from the dorsolateral tegmental and pedunculopontine tegmental nuclei in the brain stem (Gonzalo-Ruiz and Lieberman, 1995). Reticular thalamic fibers originate from specific parts of the rostral, limbic portion of the reticular nucleus (Lozsadi, 1995; Shibata, 1992; Seki and Zyo, 1984). Inputs from the (para)hippocampal region arise mainly from the subiculum proper and the presubiculum and parasubiculum, while much smaller contributions derive from other parahippocampal areas (Swanson and Cowan, 1977; Witter et al., 1990; Van Groen and Wyss, 1990a, 1990b). The entire anterior thalamic complex, including the LD, receives subicular fibers. The presubiculum projects massively and bilaterally to the anterior nuclear complex of the thalamus, in particular to the anteroventral, anterodorsal, and laterodorsal nuclei. A marked topographical difference is present between the dorsal and ventral presubiculum in that the dorsal part, also called postsubiculum, preferentially projects to the LD and AD, whereas the ventral portion projects to the LD and AV (Seki and Zyo, 1984; Van Groen and Wyss, 1990a, 1990b). The parasubiculum sends a modest projection to the anterodorsal nucleus (Van Groen and Wyss, 1990a). The mammillothalamic projections are highly topographically organized, such that medial parts of the medial mammillary nuclei project to the IAM and medial AM, while progressively more lateral parts of the mammillary complex project to successively more lateral and dorsal parts of the anterior thalamic complex (Shibata, 1992). Mammillothalamic neurons contain glutamate and/or aspartate as neurotransmitter, while a subpopulation of these neurons expresses enkephalin (Gonzalo-Ruiz et al., 1998). The anterior nuclei as a complex project to the entire rostrocaudal extent of the medial prefrontal and anterior and posterior cingulate cortices (for a more detailed
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overview of the relationships of the anterior nuclei with the cingulate cortical areas, see Vogt et al., Chapter 22, this volume). Whereas the AD and the AV have their main projections to the caudal parts of the cingulate cortex (Sripanidkulchai and Wyss, 1986; Van Groen et al., 1995), the AM projects mainly to the rostral areas, including the dorsal and ventral anterior cingulate, prelimbic, and infralimbic areas and, like the AD and AV but less densely, also to the retrosplenial areas (Van Groen et al., 1999). Further projections from the anteromedial nucleus have been described to visual area 18b, the entorhinal and perirhinal areas, the subiculum and presubiculum, and the lateral and basolateral amygdaloid nuclei (Van Groen et al., 1999). The projections from AD, AV, and AM to different parts of the retrosplenial cortex as well as to the various subicular and parahippocampal areas are organized topographically, reciprocating the afferent patterns of origin, and to a large degree terminate in complementary patterns (Van Groen et al., 1999). The different nuclei distribute their fibers over different cortical layers: in the retrosplenial cortex the anterodorsal nucleus projects equally to layers I, III, and V, while the anteroventral nucleus projects most densely to layer Ia and less densely to layer V; the anteromedial nuclear projections reach layers I and V. In the dorsal part of the presubiculum, the AD and the AV both project to layers I and V, while the AD, in addition, targets layer II/III. In the anterior cingulate and medial prefrontal areas, the AM reaches layers I, V, and VI; in the entorhinal and perirhinal cortices layer V is targeted (Van Groen et al., 1995, 1999). Cortical projections to the anterior thalamic nuclei arise in virtually all limbic cortical areas that receive a projection from these nuclei and these corticothalamic projections to a large degree reciprocate the thalamocortical projections. However, this reciprocity is not strict. For example, the AM projects to a part of the anterior and posterior cingulate areas much wider than that from which it receives projections. The anteromedial nucleus projects to area 18b and the subiculum, but does not receive projections from these cortices (Van Groen et al., 1999). Further, the frontal eye field has a substantial projection to virtually the entire anterior complex (Guandalini, 2001). At the ultrastructural level, mammillothalamic fibers terminate through large boutons with round vesicles that make asymmetric synapses on the proximal dendrites, reminiscent of type II afferents (Dekker and Kuijpers, 1976). Subicular and cingulate terminals are small to medium size, also have round vesicles, and terminate via asymmetrical synapses on more distal dendrites (Oda, 1997). These afferents may therefore be categorized as type I afferents. According to Sherman and Guillery (2001), the mammillary afferents might
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be the drivers of the anterior thalamic nuclei, whereas the afferents from the other cortical regions have more the characteristics of modulators. This is an interesting conclusion in view of recent functional insights in the anterior nuclei (see below). However, at present electrophysiological evidence is lacking to support this “morphological” conclusion. Functional Aspects As can be concluded from the previous paragraph, the anterior thalamic nuclei are included in a neural circuit that involves the anterior and posterior cingulate cortices, the hippocampal region, in particular the subiculum and presubiculum, and the mammillary bodies. In the terminology of Aggleton and Brown (1999), the anterior thalamic nuclei are part of an “extended hippocampal system.” The connections of the anterior nuclei with the cingulate and hippocampal cortical areas are reciprocal, while the input from the mammillary complex is unidirectional. Functional studies have shown that this circuit, most probably in conjunction with afferent brain stem connections of the mammillary nuclei originating in the dorsal tegmental nuclei, is crucial for spatial orientation and spatial memory (for a review, see Aggleton and Brown, 1999). Behavioral studies using lesions of different way stations in the anterior thalamic–hippocampal circuitry, in which also the mammillary nuclei and the cingulate cortices are incorporated, indicate that this circuit is important for attentional processes and various kinds of learning and memory processes, in particular spatial, allocentric memory (Aggleton et al., 1996; Warburton et al., 2001; Van Groen et al., 2002). Lesions of the anterior thalamic nuclei, but also of the fornix and the mammillary nuclei disrupt specific aspects of spatial learning, but not of object learning (Aggleton et al., 1995; Sziklas and Petrides, 1999). The exact contribution of the anterior thalamic nuclei to spatial memory and attentional functions remains to be established, but is seems clear that these nuclei play an important role in the network between the hippocampus, the mammillary bodies, and the cingulate cortex. None of the distinct anterior nuclei appears to have a preeminent role, since lesions of all nuclei have an effect on spatial memory tasks; however, complete anterior thalamic lesions have the greatest effect (Aggleton et al., 1996). These recent, behavioral findings have renewed the interest in the functional anatomy of the classic “Papez circuit” and its role in episodic memory (Aggleton and Brown, 1999; Van Groen et al., 2002). A physiological correlate of the role of the anterior thalamic nuclei in spatial tasks might be the coding by anterior thalamic neurons for the spatial orientation of the head of the animal (e.g., Aggleton et al., 1996; Blair
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et al., 1997, 1999; Vann et al., 2000; Zugaro et al., 2000; Wilton et al., 2001). Thus, electrophysiological studies have shown that neurons in the anterior thalamic complex, as well as in the laterodorsal nucleus, signal the rat’s directional heading in the horizontal plane; these neurons are indicated as head direction (HD) or “directional” cells (Taube, 1995; Taube et al., 1990). Such HD cells are most prominently present in the anterodorsal and laterodorsal thalamic nuclei, but they are also found in anteroventral and anteromedial nuclei (Blair et al., 1997; Mizumori and Williams, 1993), as well as in the dorsal part of the presubiculum and lateral mammillary nucleus (Taube et al., 1990; Stackman and Taube, 1998). Interestingly, the activity of HD cells in the anterior thalamus is not dependent upon an intact hippocampus (Goodridge and Taube, 1997; Golob and Taube, 1997). By contrast, (bilateral) lesions of the lateral mammillary nucleus do abolish the HD activity in the anterodorsal nucleus (Blair et al., 1999). This indicates that the lateral mammillary nuclei play a crucial role in transmitting the directional signal to the anterior thalamus, a signal that may be related to the actual head direction, but also to the anticipated directioning of the head (Blair et al., 1997). This directional information is dependent upon visual inputs (Goodridge et al., 1998), but may also be derived, via the lateral mammillary nuclei and the dorsal tegmental nuclei in the brain stem, from the vestibular system (Stackman and Taube, 1997; Blair et al., 1999). However, it is clear that also other cues are important for the activity of HD cells, such as tactile and olfactory (Goodridge et al., 1998). In this context, it is of interest to note that Risold and Swanson (1995) have demonstrated a pathway from the lateral hypothalamus via the anteromedial thalamic nucleus to the retrosplenial cortex that might mediate pheromonal influences on attentional mechanisms and eye and head movements. Whereas the anterior thalamic nuclei and postsubiculum contain HD cells that monitor the direction of the rat”s head, the hippocampus itself contains socalled “place cells” which code for the position of the animal in a particular space. It has been argued by Muller et al. (1996) that the hippocampal “positional system” might act, under particular circumstances, as a cognitive map and that the role of the presubicular– anterior thalamic “directional system” is to put the map into register with the actual environment while acting. Thus, through interactions between both systems, the animal would be able to properly orient and execute behaviors in a learned environment (Muller et al., 1996).
Lateral Nuclei A large dorsolateral part of the rat thalamus can be recognized as the lateral thalamic complex, consisting of
the caudally located lateral posterior nucleus (LP) and the more rostrally and medially situated lateral dorsal nucleus (LD). The two nuclei constitute the dorsal surface of the thalamus, lateral to the habenular complex and, caudally, medial to the dorsal lateral geniculate nucleus (DLG). The LD stretches from the caudal part of the anterior thalamic complex to the rostral pole of the DLG. The lateral posterior nucleus starts at midthalamic levels in between the habenular complex medially and the laterodorsal nucleus laterally, and in the posterior direction the LP gradually replaces the LD. Posteriorly, the lateral posterior nucleus becomes situated medial to dorsal lateral geniculate and, in its most posterior extent, dorsal to the medial geniculate nuclei (see Figs. 26–42 in Paxinos and Watson, 1998). In Nissl stained sections the lateral nuclei appear rather homogeneous, but both the LD and the LP can be subdivided into several subnuclei (see Paxinos and Watson, 1998). These subdivisions are based on cytoarchitectonics and distinct patterns of connectivity with the cerebral cortex, and they can, to a certain degree, be recognized in acetylcholinesterase-stained sections showing slight differences in staining intensity in the various subnuclei (Takahashi, 1985; Plates 26, 31, 35 and 39 in Paxinox and Watson, 1998). Acetylcholineserase activity in the lateral posterior nucleus is higher than that in the laterodorsal nucleus in which there is only moderate activity of this enzyme. Although not throughout the entire LD and LP, the calcium-binding proteins calretinin and calbindin D28K are present in neurons in certain parts of these nuclei, while parvalbumin as well as the other two proteins are present in fibers in both nuclei (Arai et al., 1994; Paxinos et al., 1999). Afferent and Efferent Connections Like the anterior thalamic nuclei, the LD is strongly related to the retrosplenial cortex (Van Groen and Wyss, 1990a, 1992a; Shibata, 2000; see also Chapter 22, this volume). The projections from different parts of the retrosplenial cortex, originating predominantly from layer VI, but also from neurons in layer V, distribute in a topographical way over the various subnuclei of the LD (Shibata, 2000). Thus, a rostral-to-caudal axis in the retrosplenial cortex (area 29c to area 29a) corresponds to the ventromedial-to-dorsolateral axis of the laterodorsal nucleus (Fig. 6). Further cortical inputs to the LD originate in visual areas 17 and 18, the presubiculum, and entorhinal cortex (Thompson and Robertson, 1987a, 1987b; Shibata, 1996). Several other cortical areas project to different parts of the LD, for example, medial prefrontal areas provide an input to its most medial part of laterodorsal nucleus (e.g., Sukekawa, 1988; Vertes, 2002), but such inputs have not been studied systematically. Subcortical inputs to the LD arise in the reticular
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FIGURE 6 Schematic representation of the topographic arrangements between the retrosplenial areas 29a–c and 29d with the laterodorsal thalamic nucleus (LD). Area 29a projects to the dorsolateral part of the LD; while moving from area 29a via area 29b and the caudal part of 29c to the rostral part of 29c, the termination pattern in the LD shifts from dorsolateral to ventromedial in the LD (A, B). Area 29d projects to the ventrolateral part of the LD; a rostrocaudal gradient in area 29d corresponds with a mediolateral gradient in the LD (C, D). The terminal fields of area 29c and area 29d overlap in the central part of the LD. Reproduced from Shibata (2000).
thalamic nucleus, the pretectal nuclei, the intermediate layers of the superior colliculus, and the ventral lateral geniculate nucleus (Thompson and Robertson, 1987b; Coleman and Mitrofanis, 1996; Kolmac et al., 2000). The efferent projections from the LD reach various limbic and visual cortical areas, i.e., the cingulate and retrosplenial cortices, the subicular complex, and the entorhinal cortex. These projections are topographically organized and originate from different subnuclei of the laterodorsal nucleus (Van Groen and Wyss, 1992b). Compared to the LD, the occipital, parietal, and temporal sensory association cortices have inputs to the lateral posterior nucleus much stronger than those of the limbic cingulate, retrosplenial, and subicular cortices (e.g., Vaudano et al., 1991; Coleman and Mitrofanis, 1996; Shi and Cassell, 1997; Kolmac et al., 2000; Shibata, 2000). Inputs from the primary visual cortex to the LP arise mostly from collaterals of neurons in layer V that primarily project to the brain stem (Bourassa and Deschenes, 1995). The LP receives a dense projection from temporal area Te2, an auditory and visual association area, but not from areas Te1 and Te3 (Shi and Cassell, 1997). Functional Aspects Both the laterodorsal and the lateral posterior nuclei are considered to be association thalamic nuclei in that they do not receive direct motor or sensory inputs. However, as indicated above these nuclei receive strong inputs from sensory and motor association cortical areas as well as from limbic association areas. The LP is most
strongly related to visual association areas, the LD is more related to limbic cortices. In view of similarities in their connectivity patterns, the laterodorsal nucleus is strongly associated with the anterior thalamic complex. As a result of the strong relationships with cortical and subcortical visual structures, the LP is often considered the visual association thalamus and compared with the pulvinar in other species like cats and primates. A pulvinar, however, is lacking in rats (Jones, 1985). Like in the anterior thalamic complex, head direction cells have been identified in the LD (see page 430). However, the role of the LD in head orientation and spatial navigation appears to be different from that of the anterior thalamic nuclei and the pre- and parasubiculum (Golob et al., 1998). Yet, lesions of the LD clearly demonstrate that the laterodorsal nucleus serves a task in spatial learning and memory (Van Groen et al., 2002).
MIDLINE AND INTRALAMINAR THALAMIC NUCLEI The intralaminar and midline nuclei form a conspicuous collection of nuclei in the medial and dorsal part of the thalamic complex (Figs. 22–38 in Paxinos and Watson, 1998). The midline nuclei are located medially in the thalamus as a narrow band of small nuclei that are distributed over the entire dorsal-to-ventral extension of the thalamus. The intralaminar nuclei are located lateral to the mediodorsal nucleus and “embedded”
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within the internal medullary lamina. Several of the nuclei of the midline and intralaminar complex have a high activity for acetylcholinesterase (see Plates 24, 25, 30, 31, and 34 in Paxinos and Watson, 1998).
Midline Nuclei The midline nuclei include the paraventricular, parataenial, intermediodorsal, reuniens, and rhomboid nuclei. These nuclei occupy the midline of the rat thalamus from its very rostral tip to approximately twothirds of the rostrocaudal length of the thalamus. The paraventricular nucleus (PV) is located medially, spanning the entire rostrocaudal length of the midline/intralaminar complex. The PV lies directly ventral to the third ventricle, dorsal and medial to the mediodorsal nucleus. Rostrally, it follows the surface of the massa intermedia and curves ventrally to form a wedge between the anterior poles of the nucleus reuniens (Krieg, 1944). More caudally, the PV curves slightly laterally, ventral to the habenula, and ends just rostral to the posterior commissure. The paraventricular thalamic originates phylogenetically from a pronuclear mass that gives rise also to the pineal and the habenular nuclei which has led Jones (1985) to consider the PV as part of the epithalamus. The parataenial nucleus (PT) forms a slender, elongated nucleus located anteriorly in the thalamus in close proximity and lateral to the paraventricular nucleus. At its posterior end, the PT fuses with the mediodorsal nucleus. The PT is thought to originate together with the mediodorsal and reuniens nuclei from a common nuclear mass. In contrast to Price (1995), we include the parataenial nucleus in the group of midline/ intralaminar nuclei, primarily on the basis of its projections’ patterns (see below). The intermediodorsal nucleus (IMD) is located more posteriorly, in between the left and right mediodorsal nuclei. An IMD is not recognized in all species, and it is described in most detail in rats (Jones, 1985; Berendse and Groenewegen, 1990). In many studies, the IMD is considered as the medial part of the mediodorsal nucleus. However, on the basis of the slightly darker staining of the neurons as well as its afferent and efferent relationships (see below), the IMD can be clearly distinguished from this nucleus. The nucleus reuniens thalami (Re) is located in the anterior one-third of the thalamus. Anteriorly, it is divided into a left and a right component by the third ventricle; toward its tail the two structures fuse and become a mass of cells in the midline of the thalamus, lying immediately dorsal to the third ventricle. The Re consists of a conglomerate of loosely packed cells (Jones, 1985). Caudally, the main mass of the Re is bordered
by the so-called perireuniens or ventral reuniens nuclei on both sides. The rhomboid nucleus (Rh) is located ventral to the internal medullary lamina (Berendse and Groenewegen, 1990). At its rostral end, it is confluent with the anteromedial nucleus and has two wing-like lateral extensions. Caudally, these two structures merge in the midline. The nucleus is easily distinguished by its conspicuous shape and its large and darkly staining cells (Plate 29 in Paxinos and Watson, 1998). The midline nuclei most probably use excitatory amino acids as neurotransmitter. In addition, calciumbinding proteins are present in both cell bodies and neuropil. Calretinin-positive neurons are present virtually throughout the midline nuclei, with a preference for the PV and the Re (Arai et al., 1994; see e.g. Plates 175 and 188, Paxinos et al., 1999). Calbindin-positive neurons are predominantly located located in the reuniens and intermediodorsal nuclei. Parvalbumin is conspicuously absent from the midline nuclei (Arai et al., 1994). The neuropil of the paraventricular nucleus is very rich in neurotransmitters and neuropeptides, most of which are contained in afferent fibers (see below). In addition, a subpopulation of paraventricular neurons expresses preproenkephalin mRNA (Hermanson et al., 1995). Afferent Connections The paraventricular nucleus (PV) receives afferent fibers from a wide variety of cortical and subcortical structures (e.g., Cornwall and Phillipson, 1988a; Chen and Su, 1990; Hurley et al., 1991; Otake et al., 1995; Ruggiero et al., 1998; Krout and Loewy, 2000a, 2000b; Krout et al., 2002). Thus, the PV receives strong aminergic inputs consisting of a histaminergic input from the tuberomammillary nucleus (Panula et al., 1989), a dense dopaminergic input from the ventral tegmental area and the retrorubral region (Takada et al., 1990), a noradrenergic input from the locus coeruleus and the nucleus of the solitary tract, and a serotonergic input from the dorsal raph (Otake and Nakamura, 1995; Otake and Ruggiero, 1995; Krout et al., 2002). In addition, the paraventricular nucleus receives input from the parabrachial nucleus, extensive parts of the brain stem reticular formation, deep layers of the medial part of the superior colliculus, the bed nucleus of the stria terminalis, the dorsomedial and posterior hypothalamus, and the supramammillary nuclei (Vertes, 1992; Vertes et al., 1995; Bester et al., 1999; Krout et al., 2001, 2002). Whereas most of these inputs are shared with several of the other midline nuclei, inputs from the suprachiasmatic nucleus and the intergeniculate leaflet are virtually unique for the PV (Moore et al., 2000; Kawano et al., 2001). Inputs from the amygdalar complex originate in the central nucleus. Cortical input is derived from
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the infralimbic cortex and the subiculum (Groenewegen, 1988; Sesack et al., 1989; Hurley et al., 1991). Much less is known about the afferents of the parataenial nucleus, (PT), presumably as a result of its small size and the difficulty in selectively targeting the PT in tracing studies. In anterograde tracing studies, the PT is frequently overlooked or not mentioned. Cortical input to the parataenial nucleus arises from the infralimbic cortex (Hurley et al., 1991; Sesack et al., 1989) reaching mainly the dorsomedial part of the PT. Chen and Su (1990) described input from the ventral subiculum and the rostral half of the claustrum. Further, relatively weak inputs derive from the lateral septal nuclei, the bed nucleus of the stria terminalis, the medial amygdala, the amygdalohippocampal area, a band between the ventral pallidum and the nucleus accumbens, the reticular thalamic nucleus, the zona incerta, and the suprachiasmatic nucleus as well as scattered regions throughout the hypothalamus (Chen and Su, 1990). The PT appears to receive moderate to weak brain stem input from the dorsal and median raphe nuclei, the periaqueductal gray, the locus coeruleus, the parabrachial nucleus, the laterodorsal tegmental nucleus, and the nucleus of the solitary tract (Bobillier et al., 1979; Cornwall and Phillipson, 1988a; Chen and Su, 1990; Newman and Ginsberg, 1994; Krout and Loewy, 2000a; Krout et al., 2002). Inputs to the intermediodorsal thalamic nucleus (IMD) have been the focus of only a few studies; in most tracing studies the IMD is either ignored or taken as part of the larger group of midline nuclei. Recently, Loewy and colleagues (Krout and Loewy, 2000a, 2000b; Krout et al., 2002) have shown that the pattern of brain stem inputs to the IMD is largely comparable to that of the paraventricular nucleus except that the IMD hardly receives any input from medullary structures or from motor-related structures in the mesencephalon such as the substantia nigra or the pedunculopontine region. Cortical inputs, in particular from the infralimbic and ventral agranular insular cortices, are sparse (Hurley et al., 1991). Inputs to the nucleus reuniens (Re), originally described by Herkenham (1978), are derived from several cortical and subcortical sources. Cortical inputs originate from deep layers of the infralimbic, prelimbic, and perirhinal cortices (see also Sesack et al., 1989; Witter et al., 1990; Hurley et al., 1991; Vertes, 2002). The subicular input is topographically organized (Witter et al., 1990; Wouterlood et al., 1990). Amygdalar inputs are sparse and arise from the medial and anterior nuclei (Herkenham, 1978). Basal forebrain inputs come from the nucleus of the diagonal band and the bed nucleus of the stria terminalis. Diencephalic inputs include projections from the reticular nucleus of the thalamus,
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the lateral geniculate nucleus, the zona incerta, the medial and lateral preoptic area, the medial and lateral hypothalamus, and the premammillary and supramammillary nuclei (Risold et al., 1997; Vertes and Martin, 1988). Brain stem areas projecting to the Re are the ventral tegmental area; the mesencephalic reticular formation; the laterodorsal tegmental nucleus; the superior colliculus; the periaqueductal gray matter; the dorsal, median, and central raphe; the locus coeruleus; and the parabrachial nucleus (Krout and Loewy, 2000a, 2000b; Krout et al., 2001, 2002). Weak projections to the nucleus reuniens originate in the medullary reticular nuclei and the cuneate nucleus (Peschanski and Besson, 1984; Villanueva et al., 1998; Krout et al., 2002). Data on inputs to the rhomboid nucleus (Rh) are sparse. Subcortical inputs to the Rh arise mainly in the brain stem (Krout et al., 2002), including very prominently the raphe nuclei (also: Bobillier et al., 1979); the mesencephalic, pontine, and medullary reticular formation (also: Peschanski and Besson, 1984); the lateral dorsal tegmental nucleus; and several other mesencephalic nuclei, including the substantia nigra. In addition, the supramammillary nucleus sends fibers to the rhomboid nucleus (Vertes, 1992).
Intralaminar Nuclei The intralaminar thalamic nuclei are made up of a rostral group, consisting of the central medial, paracentral, and central lateral nuclei. The caudal group is composed of the parafascicular–center median complex, in rats appearing as a single nuclear mass, briefly referred to as the parafascicular nucleus. In addition, in the caudal one-third of the thalamus and the subparafascicular and posterior intralaminar nuclei are considered to belong to the posterior intralaminar complex. In Nissl-stained sections, most of the intralaminar nuclei can be rather easily recognized on the basis of packing of the neurons that is denser than that in the adjacent thalamic nuclei (Plates 29 and 33 in Paxinos and Watson, 1998). The central medial nucleus (CM) is easily identifiable as a centrally located group of large, deeply staining, and flattened cells clearly distinct from the midline nuclei lying dorsal and ventral to it. Laterally, however, the CM is continuous with the paracentral nucleus on both sides. In rats, the left and right parts of the CM nuclei fuse with each other to form a single, centrally positioned nucleus (Plate 29 in Paxinos and Watson, 1998). The paracentral nucleus (PC) is a thin strip of cells that is continuous with the CM medially and the central lateral nucleus (CL) laterally. Its cells are difficult to distinguish from those of the CL, but appear more flattened. The PC lies in the anterior and middle por-
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tion of the internal medullary lamina, intercalated between the MD and the ventral nuclei. In the caudal PC, a distinct oval subnucleus can be recognized, the oval paracentral nucleus. The central lateral nucleus (CL) is the most dorsal component of the intralaminar nuclei, located posteriorly and dorsally to the PC with which it is confluent. The CL is larger than the PC, but these nuclei share many connectional characteristics. Therefore, the central lateral and paracentral nuclei are often regarded as a single structure. The parafascicular nucleus (PF) represents a caudal component of the intralaminar complex. The PF stands out as a darkly staining nucleus, surrounding the fasciculus retroflexus. The lateral, larger part of the rat parafascicular nucleus, containing darker staining neurons than the medial part, is considered to be equivalent to the center median nucleus, whereas the medial part of the rat PF is homologous to the primate parafascicular nucleus (Jones, 1985). Ventrally, the PF rests almost directly upon the mesencephalon; dorsally it is bordered by the central lateral nucleus and the habenular complex. The parafascicular nucleus lies just lateral to the most rostral extension of the peraventricular gray matter. The subparafascicular nucleus (SPF) is a flat, horizontally oriented nucleus which stretches from a position just ventral to the parafascicular nucleus rostromedially toward the posterior intralaminar and peripeduncular nucleus caudolaterally. Neurons in the SPF have a horizontal orientation. Medially, the subparafascicular nucleus lies just dorsal to the medial lemniscus. The nucleus consists of a medial magnocellular part and a lateral parvocellular part (Faull and Mehler, 1985; LeDoux et al., 1987; Coolen et al., 2003a). The principal neurotransmitters used by the intralaminar nuclei are excitatory amino acids. Neurons containing calcium-binding proteins are relatively sparsely present in the intralaminar nuclei (Arai et al., 1994; Coolen et al., 2003a). Enkephalinergic neurons, as indicated by the presence of preproenkephalin mRNA, are present in the central medial and central lateral nuclei and to a much lesser degree in the paracentral and parafascicular nuclei (Hermanson et al., 1995). Afferent Connections The main sources of input to the rostral intralaminar nuclei, i.e., the central medial (CM), paracentral (PC), and central lateral (CL), are subcortical structures, in particular a wide variety of brain stem nuclei as well as the spinal cord. Thus, different parts of the mesencephalic, pontine, and medullary reticular formation, several nuclei within the raphe complex which include serotonergic cell groups, the cholinergic pedunculopontine and laterodorsal tegmental nuclei, the nucleus
prepositus hypoglossi, the spinal trigeminal nucleus, the medial and lateral vestibular nuclei, several nuclei of the parabrachial complex, the locus coeruleus, the nucleus incertus (nucleus O), distinct regions of the periaqueductal gray matter, deep layers of the superior colliculus, the nucleus of Darkschewitsch, and the pars reticulata and pars compacta of the substantia nigra send projections to the entire or to specific parts of the rostral intralaminar complex (Peschanski and Besson, 1984; Yamasaki et al., 1986; Hallanger et al., 1987; Vertes and Martin, 1988; Villanueva et al., 1998; Bester et al., 1999; Groenewegen et al., 1999; Shiroyama et al., 1999; Krout and Loewy, 2000a, 2000b; Krout et al., 2001, 2002; Goto et al., 2001; for review see Van der Werf et al., 2002). Indeed, it has recently been elegantly demonstrated by Loewy and colleagues (Krout and Loewy, 2000a, 2000b; Krout et al., 2001, 2002), using small injections of retrograde tracers in the CM, PC, and CL, that these nuclei receive a different combination of inputs from the various brain stem nuclei, as well as from different subregions within these nuclei or regions, suggesting a certain degree of specificity of these three nuclei. Compared to the central medial and paracentral nuclei, the central lateral nucleus seems to receive the strongest inputs from the brain stem (Van der Werf et al., 2002). In addition, the rostral intralaminar nuclei receive inputs from the deep cerebellar nuclei, the supramammillary nuclei, the zona incerta, and the reticular thalamic nucleus (Haroian et al., 1981; Vertes, 1992; Kolmac and Mitrofanis, 1997; Power et al., 1999; Power and Mitrofanis, 2001; Van der Werf et al., 2002). Cortical inputs to the rostral intralaminar nuclei have not been specifically studied in rats, but it may be concluded from the literature that in particular (pre)frontal cortices, including the anterior cingulate cortex, send projections to the rostral intralaminar nuclei (e.g., Sesack et al., 1989; B. F. Jones and M. P. Witter, unpublished data). Compared to the adjacent higher order thalamic nuclei, the cortical inputs to the intralaminar complex are relatively weak. The subcortical inputs from brain stem nuclei and spinal cord to the parafascicular thalamic nucleus (PF) are to a large degree comparable to those to the rostral intralaminar nuclei (see above; Haroian et al., 1981; Cornwall and Phillipson, 1988a; Lai et al., 2000; for overview see Van der Werf et al., 2002; Krout et al., 2002). As described, a distinction should be made between the lateral and the medial part of the PF. The lateral parafascicular nucleus receives relatively strong inputs, both in comparison with the medial PF as well as with the rostral intralaminar nuclei, from sensorimotor-related brain stem nuclei, such as the vestibular nuclei, the spinal trigeminal complex, the superior colliculus, and the substantia nigra (Shiroyama et al.,
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1999; Krout et al., 2002). The medial PF receives more autonomic and visceral-related inputs, e.g., from the nucleus solitarius, the periaqueductal gray matter, and the parabrachial complex (Bester et al., 1999; Krout et al., 2000a, 2000b, 2002). Compared to the rostral intralaminar nuclei, the parafascicular nucleus receives relatively strong inputs from forebrain structures, in particular structures involved in the basal ganglia circuitry such as the entopeduncular nucleus (e.g., Gonzalo et al., 2002). Cortical inputs to the PF are derived from layer V and, to a lesser extent, layer VI of the frontal and parietal cortices (Cornwall and Phillipson, 1988a). The subparafascicular nucleus (SPF), as indicated above, can be subdivided into a medial and a lateral part (Coolen et al., 2003a), each receiving a different set of inputs (Coolen et al., 2003b). Thus, the medial SPF, characterized by galanin-immunoreactive fibers, receives inputs from lumbar spinothalamic neurons and visceral-related brain stem and forebrain regions. In contrast, the lateral SPF, containing calcitonin generelated peptide (CGRP)-immunoreactive neurons and fibers, receives inputs from auditory- as well as visualrelated brain stem and forebrain regions (LeDoux et al., 1987; Coolen et al., 2003b). The lateral subparafascicular nucleus is strongly related to the auditory thalamus, including also the posterior intralaminar and the medial geniculate nuclei.
Efferent Projections of the Midline and Intralaminar Complex The efferent projections of the midline and intralaminar thalamic nuclei are collectively discussed in this paragraph since the outputs of both groups of nuclei are in a number of respects very similarly organized. Whereas other thalamic nuclei have their main projections to the cerebral cortex, most of the midline and intralaminar nuclei project extensively to both cortical and subcortical structures. Subcortical structures that are reached by midline and intralaminar thalamic nuclei include several components of the basal ganglia (Berendse and Groenewegen, 1990; Feger et al., 1994), the amygdala (LeDoux et al., 1990; Turner and Herkenham, 1991), and preoptic and hypothalamic regions (Coolen et al., 1998; review Van der Werf et al., 2002). Another common finding is that most of these nuclei project to one cortical or subcortical target only; i.e., except for collaterals within the thalamus axons distribute preferentially to one target (Su and Bentivoglio, 1990). Virtually all nuclei that belong to the midline and intralaminar complex send projections to both the striatum and the cerebral cortex (Berendse and Groenewegen, 1990, 1991; Groenewegen and Berendse,
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1994), although there are differences among the individual nuclei in the strength of the projections to either the cortical or the subcortical targets. Midline and intralaminar nuclei like the PV, IMD, CM, PC, CL, and PF nuclei have relatively strong projections to the striatum, while other nuclei, such as the Re and PT nuclei, have rather weak projections to the striatum. The projections from the first-mentioned group of nuclei to both the striatum and the cerebral cortex are highly topographically organized such that the projections from individual thalamic nuclei reach restricted parts of the striatum and specific regions of the cerebral cortex, in particular in the frontal lobe (Fig. 7). This topography can be broadly described as follows. The PV reaches the most ventromedial parts of the striatum, in particular the shell of the nucleus accumbens, as well as the ventral part of the medial prefrontal cortex, including the infralimbic and ventral prelimbic areas. The IMD projects to more lateral parts of the ventral striatum, including the core of the nucleus accumbens and ventral parts of the caudate–putamen, as well as the lateral prefrontal cortex, including the dorsal agranular insular cortex. Moving within the intralaminar complex from the CM, via the PC and the CL to the PF, the projection field in the striatum shifts from a ventromedial to a dorsolateral position in the caudate– putamen and, in the cerebral cortex, from the prelimbic, via the anterior cingulate (Cg1) cortices in the medial wall to the somatomotor cortex (M2 and M1) in the dorsal aspect of the hemisphere. Combined with the topographical arrangement of the (pre)frontal corticostriatal projections, this means that individual midline or intralaminar thalamic nuclei target cortical and striatal areas that are associated with each other via corticostriatal projections. Moreover, on the basis of single-cell tracing, Deschennes et al. (1996) concluded that the striatal and cortical projections from the caudal intralaminar nuclei arise from collaterals of the same neuron (see also Bubser and Deutch, 1998; Otake and Namura, 1998). Thus, the PV, IMD, CM, PC, CL, and PF may have a strong influence on the level of activity of a series of parallel, functionally segregated (pre)frontal cortical basal ganglia–thalamocortical circuits that also involve the mediodorsal, ventromedial, and ventral anterior thalamic nuclei (Fig. 8) (Groenewegen and Berendse, 1994). The “central position” of the mentioned midline and intralaminar nuclei in cortical–subcortical circuits is further emphasized by the fact that these thalamic nuclei project also to other forebrain structures that are involved in these circuits. For example, the PV and IMD project to specific parts of the amygdaloid complex and the medial temporal lobe that, in turn, project to the prefrontal and ventral striatal targets of the PV and IMD (e.g., Wright and Groenewegen,
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FIGURE 7 Schematic illustration showing the distinctive and common inputs of the midline paraventricular–intermediodorsal thalamic nuclei (PV–IMD) and the intralaminar parafascicular nucleus, in particular its lateral part (PFl). In addition, the relationships of these midline and intralaminar nuclei with the parallel, functionally segregated basal ganglia–thalamocortical circuits are shown. (A) The involvement of the PV–IMD in the prefrontal cortical and ventral striatal way stations of “limbic circuits” is illustrated. The projections of these thalamic nuclei to the basal amygdaloid complex which, in turn, projects directly to the same cortical and striatal targets as the thalamic PV and IMD, are also indicated (cf. Wright and Groenewegen, 1995, 1996). (B) The influence of the PFl on the cortical and striatal way stations of the “motor circuits” is shown. Note that the PFl also projects to the lateral part of the subthalamic nucleus that is intimately involved in the motor circuits. Abbreviations: ABL, basal amygdaloid complex; ac, anterior commissure; DStr, dorsal striatum; fr, fasciculus retroflexus; GP, globus pallidus; GPe, external segment of GP; GPi, internal segment of GP; HF, hippocampal formation; IMD, intermediodorsal thalamic nucleus; MD, mediodorsal thalamic nucleus; PF, parafascicular nucleus; PFC, prefrontal cortex; PFl, lateral part of PF; PV, paraventricular thalamic nucleus; SMC, somatomotor cortex; STh, subthalamic nucleus; VA, ventral anterior thalamic nucleus; VL, ventral lateral thalamic nucleus; VP, ventral pallidum; VStr, ventral striatum. Slightly modified from Groenewegen and Berendse (1994).
1995, 1996). Likewise, the projections from the different parts of the parafascicular nucleus to the subthalamic nucleus (Berendse and Groenewegen, 1991; Feger et al., 1994) “fit into” the topographical organization of the (pre)frontal cortical basal ganglia–thalamocortical circuits (Groenewegen and Berendse, 1994; Van der Werf et al., 2002). The efferent projections of the Re, Rh, and PT nuclei, in contrast with those of the nuclei discussed in the previous paragraph, are primarily directed toward the cerebral cortex and to a much lesser degree to the striatum (Van der Werf et al., 2002). All three nuclei send fibers to the prelimbic, infralimbic, and anterior cingulate areas, as well as to the (ventral) striatal regions associated with these cortices. The Rh has, in addition, rather widespread projections to motor, sensory, visceral, and temporal association cortical areas, in particular directed to layer I of those cortices. This pattern of projection is shared with the caudal part of the CM which, as argued by Van der Werf et al. (2002), might be more related to the Rh than to the rostral CM. While
the Rh has very sparse projections to the entorhinal cortex and the hippocampus, these areas are a main target for the projections of the Re (Herkenham, 1978; Wouterlood et al., 1990). Thus, the Re has heavy projections to the CA1 area and the subiculum of the hippocampal formation. The pre- and parasubiculum, as well as the entorhinal cortex, receive fibers predominantly in their superficial layers. Different parts of the Re, including the ventral reuniens nuclei, have slightly different projection patterns (Van der Werf et al., 2002). Apart from basal ganglia structures, several of the midline and intralaminar nuclei reach other subcortical structures. Most midline and intralaminar nuclei send collaterals to the rostral part of the reticular thalamic nucleus; the reuniens nucleus and the caudal part of the central medial nucleus, in addition, have some bilateral intrathalamic projections (Van der Werf et al., 2002). Different subnuclei of the amygdaloid complex are reached by individual (sub)nuclei of the midline and intralaminar complex, including its posterior representatives (Turner and Herkenham, 1991). The
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FIGURE 8 Schematic drawing of the topographical organization of the projections from the midline– intralaminar thalamic complex to the striatum (cf. Berendse and Groenewegen, 1990) and the frontal cortex (cf. Berendse and Groenewegen, 1991) and of the projections from the frontal cortex to the striatum (cf. Berendse et al., 1992). Interconnected parts of the midline and intralaminar complex, the cerebral cortex, and the striatum are indicated by corresponding colors. Solid lines indicate the convergence of connected parts of the thalamus, cerebral cortex, and striatum; broken lines mark the path of parallel circuits leading from the cerebral cortex via the basal ganglia and the thalamus back to the cortex. Abbreviations: ac, anterior commissure; CeM, central medial thalamic nucleus; CL, central lateral thalamic nucleus; DStr, dorsal striatum; fr, fasciculus retroflexus; GP, globus pallidus; GPi, internal segment of GP; IMD, intermediodorsal thalamic nucleus; LHb, lateral habenula; MD, mediodorsal thalamic nucleus; PC, paracentral thalamic nucleus; PF, parafascicular nucleus; PFC, prefrontal cortex; PFl, lateral part of PF; PFm, medial part of PF; PT, parataenial thalamic nucleus; PV, paraventricular thalamic nucleus; sm, stria medullaris; SMC, somatomotor cortex; SNR, pars reticulata of the substantia nigra; VA, ventral anterior thalamic nucleus; VL, ventral lateral thalamic nucleus; VP, ventral pallidum; VStr, ventral striatum. Slightly modified from Groenewegen and Berendse (1994).
paraventricular nucleus has projections to a wide variety of preoptic and hypothalamic nuclei. The medial part of the parvicellular subparafascicular nucleus projects to the medial preoptic area (Coolen et al., 1998). Descending projections, in particular from the parafascicular and subparafascicular nuclei, to viscero- and somatomotor-related structures in the brain stem and spinal cord (Yasui et al., 1992; Gaytan and Pasaro, 1998; Marini et al., 1999) The inferior colliculus (Winer et al., 2002), as well as to have been described.
Functional Aspects of the Midline and Intralaminar Complex Because of the small size of the individual midline/ intralaminar nuclei, the complex configuration of this collection of nuclei as a whole, and the intricate relationships of these nuclei with the neighboring thalamic nuclei, it has been very difficult up till now to experimentally and specifically probe their functions. Yet, on the basis of the specific input–output relationships, supplemented with the relatively scarce animal experimental and clinical data, inferences have been made about the functional role of the midline and
intralaminar thalamic nuclei. Thus, on the basis of the patterns of afferent connections from the brain stem (Krout et al., 2002) and a synthesis based on afferent and efferent connections (Van der Werf et al., 2002), it has been concluded that the midline/intralaminar complex is involved in visceral functions and has a role in arousal and awareness (Fig. 9). As is discussed below, the midline/intralaminar complex most probably does not act as a unitary structure in these functions. In a recent review, Van der Werf et al. (2002) proposed four functionally distinct clusters of individual midline and intralaminar nuclei on the basis of similarities in connectivity. Although all midline and intralaminar nuclei share a number of connectional characteristics (see above), each group of nuclei that is recognized has a set of afferent and efferent connections that clearly distinguishes it from the other groups. Thus, a dorsal group, having connections predominantly with the medial nucleus accumbens, the medial prefrontal cortex, and the amygdala, includes the PV, the IMD, and the PT. This group of midline nuclei, labeled as “viscerolimbic”, is suggested to play a major role in the awareness of viscerosensory stimuli. The PV is strongly influenced by monoaminergic inputs and
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FIGURE 9 Schematic representation of the broad influence of arousal-related brain stem nuclei on the midline and intralminar thalamic nuclei. Midline nuclei, in addition, receive visceral-related inputs. Through the midline and intralaminar nuclei, arousal- and visceral-related information may reach extensive areas of the cerebral cortex. This summary figure is based on a large set of tracing experiments with small injections of retrograde tracers in individual midline and intralaminar thalamic nuclei reported by Krout et al. (2002). Reproduced from Fig. 21 in Krout et al. (2002).
corticotropin-releasing hormone (Otake and Namura, 1995; Otake and Ruggiero, 1995) and receives input from the suprachiasmatic nucleus and the intergeniculate leaflet (Moore et al., 2000; Kawano et al., 2001), and is therefore thought to be involved in state-setting properties. A role of the PV in stress and fear has been documented (Beck and Fibiger, 1995; Chastrette et al., 1991), while also visceral processing and visceral feedback regulation have been attributed to the PV (Moga et al., 1995; Ruggiero et al., 1998). A lateral group, consisting of the PC and the CL and the anterior part of the CM, is concidered to have its predominant connections with the dorsal striatum and the anterior cingulate cortex. This group of nuclei is thought to be involved in executive functions, in particular in cognitive awareness (Van der Werf et al., 2002). This assumption is primarily based on human
studies. However, in line with this, lesions of the PC and CL in rats result in deficits of working memory rather than reference (long-term) memory (Young et al., 1996; Savage et al., 1997; Burk and Mair, 2001). A ventral group of nuclei, which is composed of the Re and the Rh and the posterior part of the CM, only sparsely projects to the striatum. Instead, the nuclei in this ventral group have rather widespread and strong projections to superficial and deep layers of gustatory, visceral, insular, auditory, and motor cortical areas (see above). In addition, the Re and, more sparsely, the Rh project to the hippocampus and entorhinal cortices. This group of nuclei is thought to play a role in polymodal sensory awareness (Van der Werf et al., 2002). In electrophysiological studies it has been shown that stimulation of the reuniens nucleus can modulate the information transfer in the hippocampus (Dolleman-
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Van der Weel et al., 1997; Dolleman-Van der Weel and Witter, 2000). Preliminary results of lesions of the Re support a role of this nucleus in awareness rather than in memory per se (Dolleman-Van der Weel et al., 1994). A posterior group consists of the centromedian– parafascicular complex but, as discussed above, in rats includes only the PF. The PF primarily projects to basal ganglia structures and, in addition, reaches the sensory and motor cortices. It is being postulated that the PF has an important role in the generation of motor responses following awareness of salient stimuli and, in this way, serves a role in limbic-motor functions (Van der Werf et al., 2002). Indications for an involvement of the parafascicular nucleus in the generation of motor responses follow from studies that show a role in the modulation of intracranial self-stimulation behavior and of active avoidance in which a motor response is needed to avoid a foot shock (GuillazoBlanch et al., 1999; Massanes-Rotger et al., 1998). Electrophysiological studies show that lesions of the PF may interrupt neocortical oscillatory activity in the theta range which is important for attentional, orienting, and ongoing motor responses (Marini et al., 1998). Finally, the functions of the posterior intralaminar nuclei, in particular the SPF, deserve attention. It has been known for some time that the lateral part of the parvicellular SPF is a way station in ascending auditory signals to the cerebral cortex and the amygdala (e.g., Yasui et al., 1990; Coolen et al., 2003a). The medial part of the parvicellular SPF, by contrast, appears to be involved in sexual behavior. As shown by Veening and Coolen (1998), employing the expression of c-fos as a marker for neuronal activity, the medial parvicellular SPF is specifically involved in a circuit underlying ejaculation behavior in male rats. This circuit involves an ascending spinothalamic pathway containing galanin as neurotransmitter, terminating in the medial parvicellular SPF (Coolen et al., 2003b) and a number of forebrain regions like the medial amygdala and the medial preoptic area (Veening and Coolen, 1998). In female rats, activity in the medial parvicellular SPF is related to vaginocervical stimulation (Coolen et al., 1996).
RETICULAR NUCLEUS The reticular thalamic nucleus (Rt) forms a thin neuronal sheet at the rostral, dorsolateral, lateral, and ventrolateral margins of the dorsal thalamus. The Rt is strategically “placed” between the dorsal thalamus and the cerebral hemisphere, such that all incoming and outgoing fibers of the thalamus have to pass through it, most of them giving off collaterals to a restricted part of the reticular nucleus (but see below). Reticular thal-
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amic neurons have a relatively extensive dendritic tree extending in a disk-like form in the same plane as the thin sheet formed by the Rt itself (Jones, 1985; Spreafico et al., 1991; Ohara and Havton, 1996). Frequent dendrodendritic junctions, i.e., synapses and puncta adhaerentia, have been noted in parallel bundles of dendrites of Rt neurons, indicating a special form of interneuronal communication within the reticular nucleus (Pinault et al., 1997; however, see also Liu and Jones, 1999). Reticular thalamic neurons are all GABAergic and express parvalbumin (Mitrofanis, 1992), while a subset of Rt neurons contains calretinin (Lizier et al., 1997). The full extent of the reticular nucleus can be very well appreciated in parvalbumin-stained sections (see relevant Plates in Paxinos et al., 1999). The Rt in rats is a relatively well-developed nucleus that provides an important GABAergic control of the dorsal thalamus; in rats, GABAergic interneurons are relatively sparse (Price, 1995). Arcelli et al. (1997) have noted that in different species there is an inverse relationship between the number of GABAergic interneurons in the dorsal thalamic nuclei and the cellular density of the Rt. Their interpretation is that an increase in complexity of local information processing in different thalamic nuclei is accompanied by a more extensive interneuronal circuitry and a relatively small reticular nucleus. The ventral lateral geniculate and subgeniculate nuclei, which seem to form a dorsolateral and caudal extension of the caudal reticular thalamic nucleus, may be considered the “reticular” part of the visual thalamus. These nuclei have a ventral thalamic embryonic origin and their structural and connectional characteristics are very similar to those of the Rt (Jones, 1985). A specific visual sector of the Rt, however, also exists (Coleman and Mitrofanis, 1996). During prenatal development, a considerable number of neurons exist within the internal capsule, directly laterally adjacent to the reticular thalamic nucleus, forming the so-called perireticular nucleus (Mitrofanis and Guillery, 1993). These neurons have been shown to project to the dorsal thalamus (Mitrofanis et al., 1995), but most probably not to the cerebral cortex (Coleman and Mitrofanis, 1999). The perireticular neurons are thought to play a role in guiding axons during development; the function of the relatively few surviving perireticular remaining neurons in adulthood remains to be established (Amadeo et al., 1998; Coleman and Mitrofanis, 1999).
Efferent and Afferent Projections Unlike the dorsal thalamic nuclei, the Rt does not project to the cerebral cortex but sends its fibers almost exclusively to the dorsal thalamus (see also Vaccaro
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and Mitrofanis, 1997). There might be a small projection from the Rt to the lateral hypothalamus (Barone et al., 1994). The projections from the Rt to the dorsal thalamic nuclei are highly specific and topographically organized. Individual dorsal thalamic nuclei receive projections from a specific subset of spatially closely related reticular thalamic neurons (e.g., Jones, 1985; Kolmac and Mitrofanis, 1997; Pinault and Deschennes, 1998). Based on a large number of juxtacellularly filled reticular thalamic neurons, Pinault and Deschennes (1998) have shown that the terminal fields of these neurons in dorsal thalamic nuclei are well-focused with a patchy distribution of boutons and that the Rt– dorsal thalamic projections are organized largely in parallel with only a slight degree of divergence. For the relationship of the ventrobasal complex with the Rt this divergence appears to lead to an intrathalamic pathway which links this first-order thalamic nucleus via the Rt with the higher order posterior thalamic nucleus (Crabtree et al., 1998). Whereas such interconnections between different dorsal thalamic nuclei via the the reticular nucleus might exist, the high degree of topography between the Rt and individual thalamic nuclei is remarkable. The result of this strict topography is that each individual, functionally distinct thalamic nucleus is represented in a restricted sector of the Rt (Jones, 1985; e.g., anterior nuclei: Gonzalo-Ruiz et al.,) 1995; intralaminar and midline nuclei: Kolmac and Mitrofanis, 1997; visceral thalamus: Hayama et al., 1994; Stehberg et al., 2001). The relationships with the midline thalamic nuclei appear to be the least strictly organized (Kolmac and Mitrofanis, 1997). Afferents to the Rt originate from the dorsal thalamic nuclei and cerebral cortex, but also from the basal forebrain and brain stem. The thalamic inputs to the Rt, collaterals of the thalamocortical axons, are strictly topographically organized and rather faithfully reciprocate the Rt–dorsal thalamic projections (Jones, 1985; Mitrofanis and Guillery, 1993). Likewise, corticothalamic axons issue a collateral to the Rt sector associated with the dorsal thalamic nucleus to which the corticothalamic fibers are directed. In this way, the different sectors of the Rt receive cortical and thalamic glutamatergic inputs (Kharazia and Weinberg, 1994; Eaton and Salt, 1996). The terminal fields of both cortical and thalamic afferents mostly form narrow disklike patterns that are oriented perpendicular to the parent axons and conform to the shape and orientation of the dendrites of reticular neurons (Mitrofanis and Guillery, 1993). However, even though the topography of projections between the cerebral cortex and the reticular nucleus as well as between the dorsal thalamic nuclei and the reticular nucleus shows such a strict point-to-point relationship, it is unclear how
precise the relationships are at the microcircuit level (Pinault and Deschennes, 1998; Guillery et al., 1998; Sherman and Guillery, 2001). Thus, it is, for example, unclear whether the point-to-point relationships are such that strict reciprocal relationships exist between individual dorsal thalamic and reticular neurons, whether cortical afferents project to reticular neurons that target precisely the same dorsal thalamic neurons as these corticothalamic fibers, or whether “adjacent” neurons in the dorsal thalamus are innervated by these reticular thalamic neurons. The actual organization of specific cortical–reticular–dorsal thalamic microcircuits, which may even differ for different dorsal thalamic nuclei, may make the difference between a precise inhibitory feedback, an inhibitory feedforward, or different forms of lateral inhibition in dorsal thalamic nuclei (cf. also Pinault and Deschennes, 1998b; Sherman and Guillery, 2001). As discussed by Sherman and Guillery (2001), an important aspect of the innervation of the Rt may be that the modulatory, but not the driving, afferents of the dorsal thalamus have a collateral projection to the reticular nucleus. For cortical inputs this means that corticothalamic afferents from layer VI, which terminate as type I fibers in the dorsal thalamus, do have a collateral to the Rt, whereas corticothalamic fibers from layer V, which are mostly collaterals of corticofugal fibers proceeding to the brain stem or spinal cord, do not project to the Rt (Fig. 10) (Deschennes et al., 1994; Bourassa et al., 1995). Likewise, ascending driving afferents, for example from somatosensory systems in general, do not have a collateral to the Rt. Whether this distinction between type I and type II afferents in relation to the reticular nucleus can be regarded as a general rule remains to be established.
Functional Aspects The prevailing interpretation of the functional role of the Rt is that it serves attentional brain mechanisms (e.g., “searchlight hypothesis”) (Crick, 1984; Guillery et al., 1998, McAlonan et al., 2000). The abovedescribed topographical and specific arrangement of the afferents and efferents of different sectors of the Rt indicates a specific role of the reticular nucleus for functionally distinct thalamic nuclei, contrasting with the general, more global reticular influence on thalamocortical mechanisms that has been proposed originally (Scheibel and Scheibel, 1966; Steriade et al., 1993). The Rt is important for the control of the firing mode of thalamocortical projection neurons and, in this way, for the selection of the information that is transferred from the thalamus to the cerebral cortex. The reticular nucleus plays an important role as pacemaker during
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FIGURE 10 Schematic representation of the intricate relationships of the reticular thalamic nucleus (Rt) with the dorsal thalamus and specific layers of the cerebral cortex (from Guillery et al., 1998). The reticular thalamic nucleus (Rt) receives collaterals from thalamocortical fibers originating in virtually all nuclei of the dorsal thalamus, while most of the corticothalamic fibers likewise issue a collateral to the Rt. However, as such collaterals are common for the corticothalamic fibers originating in layer VI, the “modulatory” corticothalamic projections (see page 408 of this chapter), collaterals are absent from corticothalamic fibers arising from more superficial layers. This is correlated with a distinction in firstorder and higher order thalamic nuclei and their cortical associations. So-called first-order (FO) thalamic nuclei receive their main “driving” afferents from ascending specific afferents, such as somatosensory or visual modalities, while so-called higher order (HO) thalamic nuclei receive their main driving afferents from layer V of the cerebral cortex (see page 408 of this chapter). Thalamic afferents originating from layer V of the cortex and primary ascending fibers are morphologically very comparable, terminating as RL-type boutons, and thought to be the drivers of the various thalamic nuclei (Sherman and Guillery, 2001; see page 408 of this chapter). However, neither descending layer V axons nor ascending sensory afferents issue a collateral to the reticular thalamic nucleus. Apart from the dorsal thalamic and deep cerebral cortical layers, the reticular thalamic nucleus is targeted by several brain stem and basal forebrain inputs. Slightly modified from Fig. 2 in Guillery et al. (1998).
synchronized firing of thalamocortical cells. Basically, two different firing patterns exist in the thalamocortical system, i.e., a “tonic” and a “burst mode” (Jahnsen and Llinás, 1984; McCormick and Fraser, 1990). In the tonic mode of thalamocortical activity, information from, for example, ascending sensory pathways, is almost linearly transferred through the thalamus to the cerebral cortex. Burst firing occurs during sleep, as well as during epileptic seizures. In the bursting mode, relay of information to the cerebral cortex is either prevented or nonlinearly transformed. Thus, in the latter case, thalamocortical neurons may still respond during burst firing but the message is not transferred to the cortex in the same form as during tonic firing (Guido et al., 1995; Guillery et al., 1998). During burst firing there is a higher signal-to-noise ratio, providing a mechanism to select specific, novel information to reach the cortex (Guido and Weynand, 1995; Guillery et al., 1998).
The precise physiological mechanisms by which the Rt exerts its gating role remain to be established. There might be a prominent role for the descending corticothalamic fibers, at least in the visual system (Montero, 2000), and this may provide a very topical mechanism within a specific sensory system to attend to a specific stimulus (see also Hartings et al. (2000) for the somatosensory, vibrissal system). Numerically, cortical inputs to the Rt dominate other inputs (Liu and Jones, 1999). Subcortical afferents, originating from the brain stem reticular formation, the basal forebrain, or the dorsal thalamus (i.e., the parafascicular nuleus) also exert their influence on particular sectors of the Rt, although apparently less focused (Kolmac and Mitrofanis, 2001). Notwithstanding the recently elucidated specificity in the connections and functions of the Rt, the nucleus might also act as a unit and generate general synchronized thalamocortical activity, in this way “closing” the thalamocortical gate like during
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sleep. The mechanisms by which the synchronicity of reticular neurons is achieved are largely unknown, but electrical synapses may play an important role (Landisman et al., 2002).
Acknowledgments The authors thank Ingrid Riphagen for performing an extensive literature search and Sanderien van Oudenaren for her help in preparing the reference list. Dr. Piet Hoogland gave critical and supportive comments on parts of the manuscript. The authors are also grateful for the assistance of Han Verbeek and Dirk de Jong who helped with the illustrations.
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Welker, E., Hoogland, P. V., and Van der Loos, H. (1988). Organization of feedback and feedforward projections of the barrel cortex: A PHA-L study in the mouse. Exp. Brain Res. 73, 411–435. Williams, M. N., Zahm, D. S., and Jacquin, M. F. (1994). Differential foci and synaptic organization of the principal and spinal trigeminal projections to the thalamus in the rat. Eur. J. Neurosci. 6, 429–453. Wilton, L. A., Baird, A. L., Muir, J. L., Honey, R. C., and Aggleton, J. P. (2001). Loss of the thalamic nuclei for “head direction” impairs performance on spatial memory tasks in rats. Behav. Neurosci. 115, 861–869. Winer, J. A., Chernock, M. L., Larue, D. T., and Cheung, S. W. (2002). Descending projections to the inferior colliculus from the posterior thalamus and the auditory cortex in rat, cat, and monkey. Hear. Res. 168, 181–195. Winer, J. A., Kelly, J. B., and Larue, D. T. (1999a). Neural architecture of the rat medial geniculate body. Hear. Res. 130, 19–41. Winer, J. A., and Larue, D. T. (1988). Anatomy of glutamic acid decarboxylase immunoreactive neurons and axons in the rat medial geniculate body. J. Comp. Neurol. 278, 47–68. Winer, J. A., Sally, S. L., Larue, D. T., and Kelly, J. B. (1999b). Origins of medial geniculate body projections to physiologically defined zones of rat primary auditory cortex. Hear. Res. 130, 42–61. Witter, M. P., Ostendorf, R. H., and Groenewegen, H. J. (1990). Heterogeneity in the dorsal subiculum of the rat: Distinct neuronal zones project to different cortical and subcortical targets. Eur. J. Neurosci. 2, 718–725. Wouterlood, F. G., Saldana, E., and Witter, M. P. (1990). Projection from the nucleus reuniens thalami to the hippocampal region: Light and electron microscopic tracing study in the rat with the anterograde tracer phaseolus vulgaris-leucoagglutinin. J. Comp. Neurol. 296, 179–203. Wright, A. K., Norrie, L., and Arbuthnott, G. W. (2000). Corticofugal axons from adjacent ‘barrel’ columns of rat somatosensory cortex: Cortical and thalamic terminal patterns. J. Anat. 196(Pt 3), 379–390. Wright, C. I., and Groenewegen, H. J. (1995). Patterns of convergence and segregation in the medial nucleus accumbens of the rat: Relationships of prefrontal cortical, midline thalamic, and basal amygdaloid afferents. J. Comp. Neurol. 361, 383–403. Wright, C. I., and Groenewegen, H. J. (1996). Patterns of overlap and segregation between insular cortical, intermediodorsal thalamic and basal amygdaloid afferents in the nucleus accumbens of the rat. Neuroscience 73, 359–373. Yamamoto, T., Kishimoto, Y., Yoshikawa, H., and Oka, H. (1990). Cortical laminar distribution of rat thalamic ventrolateral fibers demonstrated by the PHA-L anterograde labeling method. Neurosci. Res. 9, 148–154. Yamasaki, D. S., Krauthamer, G. M., and Rhoades, R. W. (1986). Superior collicular projection to intralaminar thalamus in rat. Brain Res. 378, 223–233. Yang, Z. J., Tang, J. S., and Jia, H. (2002). Morphine microinjections into the rat nucleus submedius depress nociceptive behavior in the formalin test. Neurosci. Lett. 328, 141–144. Yasui, Y., Kayahara, T., Nakano, K., and Mizuno, N. (1990). The subparafascicular thalamic nucleus of the rat receives projection fibers from the inferior colliculus and auditory cortex. Brain Res. 537, 323–327. Yasui, Y., Nakano, K., and Mizuno, N. (1992). Descending projections from the subparafascicular thalamic nucleus to the lower brainstem in the rat. Exp. Brain Res. 90, 508–518. Yasui, Y., Saper, C. B., and Cechetto, D. F. (1989). Calcitonin generelated peptide immunoreactivity in the visceral sensory cortex, thalamus, and related pathways in the rat. J. Comp. Neurol. 290, 487–501.
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C H A P T E R
18 Basal Ganglia CHARLES R. GERFEN Laboratory of Systems Neuroscience, NIMH
The basal ganglia connect the cerebral cortex with neural systems that effect behavior. Most cortical areas provide inputs to the basal ganglia, which in turn provide outputs to brain systems that are involved in the generation of behavior. Among the behavior effector systems targeted are thalamic nuclei that project to those frontal cortical areas involved in the planning and execution of movement; midbrain regions including the superior colliculus, which is involved in the generation of eye movements; the pedunculopontine nucleus, which is involved in orienting movements; and hypothalamic systems involved in autonomic functions. Two points concerning the function of the basal ganglia are emphasized. First, while the basal ganglia connect the cerebral cortex with a wide range of behavior effector systems, the basal ganglia operates in parallel with other output systems of the cerebral cortex. These other corticofugal systems may have a more primary role in the actual generation of behavior. For example, the frontal cortical areas involved in the planning and execution of movement behavior provide direct projections, via direct corticospinal projections, that are responsible for the generation of movement. Thus, the role of the basal ganglia in affecting cortically generated behavior remains unclear. Second, while the basal ganglia are connected with a wide range of behavior effector systems, not all regions of the basal ganglia are connected with all of the output systems. In other words, there is a conservation of regional functional organization of the cerebral cortex in the connections of the basal ganglia. In considering the neuroanatomical organization of the basal ganglia there are differing views. On the
The Rat Nervous System, Third Edition
one hand, the basal ganglia have been proposed to provide for interactions between disparate functional circuits, for example, between so-called “limbic” and “nonlimbic” functions. Another view holds that there are parallel functional circuits, in which distinct functions are for the most part maintained, or segregated, one from the other. This review is biased toward the view that there is maintenance of functional parallel circuits in the organization of the basal ganglia, with considerable interaction between adjacent circuits. The organization of the basal ganglia is intimately linked to that of the cerebral cortex, with distinct differences between those regions of the basal ganglia that receive inputs from neocortical, six-layered cortex, compared with those receiving inputs from allocortical areas. This review focuses primarily on the neocortical part of the basal ganglia. A general canonical organizational plan of the neocortical-related basal ganglia is described. Understanding the organization of the neostriatal part of the basal ganglia provides a framework for determining the general organizational principles of the parts of the basal ganglia connected with allocortical areas and the amygdala. The components of the canonical basal ganglia system, which is the subject of this review, include the neocortex, the striatum, which includes the caudate– putamen and the core of the nucleus accumbens, the globus pallidus (lateral segment), the subthalamic nucleus, the medial globus pallidus (also termed the medial globus pallidus), and the substantia nigra (Fig. 1). The major input to this system comes from layer 5 glutamatergic neurons from nearly all areas of the
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FIGURE 1 Main components of the basal ganglia shown on coronal diagrams of The Rat Brain in Stereotaxic Coordinates (Paxinos and Watson, 1998). The striatum, which includes the caudate–putamen (Cpu) and the core of the nucleus accumbens (acc), is the main input nucleus of the basal ganglia. The output nuclei of the basal ganglia are the medial globus pallidus (MGP) and substantia nigra pars reticulata (SNR). The striatum is connected through direct and indirect pathways with the output nuclei. The indirect pathway includes the globus pallidus (GP) and subthalamic nucleus (STh). Targets of the output of the basal ganglia include the mediodorsal (md), ventromedial (vm), ventrolateral (vl), and parafascicular (pf) thalamic nuclei; the intermediate gray layer (InG) of the superior colliculus (sc); and the pedunculopontine tegmental nucleus (PPT). Dopamine neurons are located in the ventral tegmental area (VTA), substantia nigra pars compacta (dorsal tier, SNCD; ventral tier, SNCV). Levels are taken from Paxinos and Watson (1998).
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FIGURE 1, cont’d Main components of the basal ganglia shown on coronal diagrams of The Rat Brain in Stereotaxic Coordinates (Paxinos and Watson, 1998). The striatum, which includes the caudate–putamen (Cpu) and the core of the nucleus accumbens (acc), is the main input nucleus of the basal ganglia. The output nuclei of the basal ganglia are the medial globus pallidus (MGP) and substantia nigra pars reticulata (SNR). The striatum is connected through direct and indirect pathways with the output nuclei. The indirect pathway includes the globus pallidus (GP) and subthalamic nucleus (STh). Targets of the output of the basal ganglia include the mediodorsal (md), ventromedial (vm), ventrolateral (vl), and parafascicular (pf) thalamic nuclei; the intermediate gray layer (InG) of the superior colliculus (sc); and the pedunculopontine tegmental nucleus (PPT). Dopamine neurons are located in the ventral tegmental area (VTA), substantia nigra pars compacta (dorsal tier, SNCD; ventral tier, SNCV). Levels are taken from Paxinos and Watson (1998).
neocortex. The output of this system is the projection of GABAergic neurons in the medial globus pallidus and the substantia nigra pars reticulata. This basal ganglia output targets thalamic nuclei, which project to frontal cortical areas involved in the planning and execution of movement behavior; the intralaminar thalamic nuclei, which provide inputs to the neocortex and the striatum; the intermediate layers of the superior colliculus, which are involved in the generation of eye and head movements; and the pedunculopontine nucleus, which is involved in orienting movements of the body. In between the neocortical inputs and the GABAergic output systems are the neuroanatomical circuits that comprise the prototypical basal ganglia. The main input structure of the basal ganglia is the striatum. Those regions of the striatum that receive inputs from neocortical areas are the caudate–putamen and core of the nucleus accumbens. The targets of the neocortical input are medium-sized spiny GABAergic
projection neurons, which account for over 90% of neurons in the striatum. These neurons are divided into two types, which give rise to the two main components of the prototypical basal ganglia circuit, the “direct” and “indirect” striatal projection systems. The “direct” striatal projection system is so-named as these neurons provide direct inputs to the output neurons of the basal ganglia in the medial globus pallidus and the substantia nigra pars reticulata. Indirect striatal projection neurons provide inputs to the globus pallidus, which together with the subthalamic nucleus compose the major components of the “indirect” basal ganglia circuit. GABAergic neurons in the lateral globus pallidus project back to the striatum, to the output neurons of the basal ganglia in the medial globus pallidus and substantia nigra, and to the subthalamic nucleus. The subthalamic nucleus, which itself receives inputs from the neocortex, provides excitatory projections to the output neurons of the basal ganglia.
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In the canonical basal ganglia circuit (Fig. 2), the neocortex provides excitatory inputs to the striatum, whose output, through the direct and indirect projection systems, provide both inhibitory and excitatory regulation of the output of the basal ganglia. The output neurons of the basal ganglia, GABAergic neurons in the medial globus pallidus and substantia nigra pars reticulata, display a relatively high level of tonic activity. In a long held model of basal ganglia function, the excitatory input from the cortex has been demonstrated to function through a disinhibitory mechanism. Thus, activation of the direct output neurons of the striatum by the excitatory input from the neocortex results in inhibition of the tonic inhibitory output of the basal ganglia. The role of the indirect circuit is more complex. On the one hand, the target of the indirect striatal output neurons are GABAergic neurons in the lateral globus pallidus, which project to the output neurons of the basal ganglia and to the subthalamic nucleus. Thus, cortical excitation of the indirect pathway inhibits the GABAergic pallidal output, resulting in disinhibition of the output neurons of the basal ganglia and the subthalamic nucleus. The subthalamic nucleus, which receives direct excitatory inputs from the cerebral cortex, provides excitatory inputs to the output neurons of the basal ganglia. Additionally, it has been demonstrated that the interconnections between the lateral globus pallidus and subthalamic nucleus generate an oscillatory pattern of activity that is conveyed to the output neurons of the basal ganglia. Given the complexities of the organization of these circuits at this time the specific mechanisms responsible for regulating the output of the basal ganglia remain to be established. However, in general terms the activity in the direct and indirect striatal output pathways may be viewed as providing counterbalanced or antagonistic regulation of the output of the basal ganglia. Overlain on the canonical basal ganglia circuit are a number of additional neuroanatomical features that add to the complexity of the organization of this system. Notable among these is the dopaminergic nigrostriatal system, which provides a massive dopaminergic input to the striatum from the midbrain dopamine neurons in the ventral tegmental area and substantia nigra pars compacta. In addition, this review describes the following features of basal ganglia organization: (1) the organization of the corticostriatal system, which incorporates both a general topographic organization with considerable overlap of corticostriatal inputs from cortical areas that are interconnected; (2) the patch and matrix compartmental organization of the striatum, which is related to the laminar organization of the cerebral cortex and provides differential inputs to the output systems of the basal ganglia and the nigros-
triatal dopaminergic system; and (3) the dual representation of striatal outputs in the lateral globus pallidus and output nuclei of the basal ganglia.1
CORTICAL INPUT TO THE STRIATUM The cerebral cortex provides a major input to the striatum. Corticostriatal afferents arise from cortical pyramidal neurons, located primarily in layer 5, with some being distributed in layer 3 and rarely in layer 6. These neurons utilize glutamate as neurotransmitter and provide the major excitatory input to the striatum. Subtypes of corticostriatal neurons may be characterized on the basis of their axonal collateral connections with cortical and subcortical areas and features of their axonal arborization within the striatum.
Subtypes of Corticostriatal Neurons Two main subtypes of corticostriatal neurons have been identified based on the distribution of their subcortical axon collaterals. One type may be considered a corticocortical/corticostriatal neuron, in that it provides axon collaterals that distribute only within the striatum and cerebral cortex (Wise and Jones, 1977; Wilson, 1987; Cowan and Wilson, 1994; Zheng and Wilson, 2002). This type of cell is very numerous in agranular cortical regions giving rise to bilateral corticocortical and corticostriatal projections. These neurons are located in a band at the superficial half of layer 5 and in the deep half of layer 3. Axons of these cells bifurcate twice or more times in the deep cortical layers to form approximately equal-sized branches. Two of them cross the midline to form contralateral projections. An additional branch follows the subcortical white matter laterally to enter the striatum without passing through the striatal part of the internal capsule and arborizes in the ipsilateral striatum. Additional collaterals travel horizontally, often crossing cytoarchitectonic boundaries to make synaptic connections in other cortical regions on the ipsilateral side. A second type of corticostriatal neuron is classified as a pyramidal tract or brain stem projecting neuron. These neurons are 1
In this review the entopeduncular nucleus is referred to as the medial globus pallidus. In the primate, the globus pallidus is divided into two parts, the lateral or external globus pallidus and the medial or internal segment of the globus pallidus. In the rat, the term globus pallidus generally refers to the lateral or external globus pallidus, whereas the entopeduncular nucleus is the equivalent of the internal or medial globus pallidus. As The Rat Brain in Stereotaxic Coordinates of Paxinos and Watson (1998) uses the term medial globus pallidus to refer to the entopeduncular nucleus, this terminology is used in this review.
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FIGURE 2 Connections of the basal ganglia associated with the neocortex shown on a sagittal diagram of the brain. (A) The major input and output connections of the basal ganglia. Layer 5 pyramidal neurons of most areas of the cerebral cortex provide a major input to the striatum, which comprises the caudate–putamen (CP) and the core of the nucleus accumbens (Acc). The output of the basal ganglia arises from GABAergic neurons in the medial lateral globus pallidus (MGP) and substantia nigra pars reticulata (SNR). These neurons provide inhibitory inputs to thalamic nuclei, including the ventrolateral (vl), mediodorsal (md), and ventromedial (vm) nuclei, as well as to the superior colliculus (SC) and pedunculopontine nucleus (PPN). (B) The direct and indirect striatal projection pathways from two subsets of striatal medium spiny neurons. Direct projecting neurons provide an axon with collaterals to the lateral globus pallidus (LGP) and to the medial globus pallidus (MGP) and substantia nigra pars reticulata (SNR). Indirect striatal projection neurons project to the lateral globus pallidus (LGP). These neurons are indirectly connected to the medial globus pallidus and substantia nigra through connections that involve the lateral globus pallidus and subthalamic nucleus (STN). (C) Feedback pathways of the basal ganglia include the dopaminergic nigrostriatal dopamine (DA) pathway from the substantia nigra pars compacta, a pallidostriatal pathway from the lateral globus pallidus to the striatum, and a thalamostriatal pathway from the intralaminar and parafascicular (pf) thalamus to the striatum and from the vl, md, and vm thalamic nuclei, which project to the frontal cortex.
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located primarily in frontal cortical areas and give rise to pyramidal tract projections to the brain stem or the spinal cord, which have been shown to contribute axon collaterals to the striatum (Cowan and Wilson, 1994; Donoghue and Kitai, 1981; Landry et al., 1984). Within the cortex, these neurons are distributed, for the most part, deeper than the first type of corticostriatal neuron, in the deeper parts of layer 5, and occasionally in layer 6. The striatal projection of this cell is formed by a very fine collateral formed from the much larger main axon in the course of its trajectory through the internal capsule. This projection has attracted some interest because of its potential for providing the neostriatum with a copy of the cortical motor signal. A subset of these neurons also appears to provide projections to the thalamus (Royce, 1983; Levesque et al., 1996, 1998). Corticostriatal neuron subtypes are also distinguished by having either a focal or extended distribution of axonal arborizations within the striatum (Cowan and Wilson, 1994; Kincaid et al., 1998; Wright et al., 1999). One subtype is characterized as having a focal axonal arborization pattern within the striatum (Fig. 3A). Such axons often arise as a collateral of the major axon of a pyramidal tract neuron as it courses through the striatum in white matter fascicles. Individual collaterals may extend up to 1 mm from the main axon, with a few side branches that may end with a small cluster of bouton-bearing terminal branches. A single axon may give rise to several of these striatal collateral branches, which may be separated by more than a millimeter in some cases. Synaptic varicosities are distributed at regular intervals on these types of collaterals; however, the number of varicosities is extremely sparse. Axon collaterals of neurons providing focal striatal afferents distribute focal axon collaterals within the cortex as well. Axon collaterals often spread within layer 5, with individual axon collaterals spreading into nearby cortical areas ascending into supragranular layers with focal arborizations in layer 1. The other subtype of corticostriatal afferent forms an extended axonal arborization pattern in the striatum, occupying an area with dimensions of 1 mm or greater (Fig. 3B). Within that volume the axon occupies space in a very sparse fashion, with individual branches running approximately parallel and separated by large uninnervated areas. These afferent fibers have very irregular distribution of synaptic varicosities, which, although sparse, appear clustered in particular regions. The intracortical distribution of axon collaterals of cortical neurons providing extended striatal afferents was rather widespread, arborizing locally within the area of the parent neuron, while other collaterals distributed to adjacent cortical areas, with extensive arborizations in layers 5 and 3. Thus, the patterns of intracortical and striatal
distributions of the focal and extended types of corticostriatal neurons appear to be somewhat correlated. There does not appear to be a simple classification scheme relating the subtypes of corticostriatal neurons based on their axonal arborizations within the striatum and whether they arise from collaterals of pyramidal tract axons or as afferents of neurons with pure cortical and striatal distributions. In an early paper it was reported that focal and extended corticostriatal afferents arose, respectively, from the pyramidal tract subtype and pure corticostriatal subtypes of corticostriatal neurons (Cowan and Wilson, 1994). However, a more recent study, analyzing a larger number of neurons, demonstrated that both extended and focal corticostriatal afferents arose from pyramidal tract neurons (Zheng and Wilson, 2002). As the determination of these different subtypes requires data gathered from individual neurons, at this point there is no way to estimate the relative number of the different subtypes. Nonetheless, there appear to be subtypes of corticostriatal neurons, whose distinct patterns of connections determine the organization of the patterns of information that the cerebral cortex provides to the striatum.
Patterns of Organization of Corticostriatal Afferents Cortical input to the striatum originates from most cortical areas, including primary and higher order sensory areas; motor, premotor, and prefrontal regions; and limbic cortical areas. It has been well established that this input is organized in a general topographic manner in that the spatial relationships between cortical areas are maintained in the projections to the striatum (Carman et al., 1965; Kemp and Powell, 1970; Webster, 1961; McGeorge and Faull, 1989; Ebrahimi et al., 1992). More complex is the issue of overlapping projections from functionally related areas. While it is clear that, in general, cortical areas provide input to a much broader area of the striatum than accounted for on the basis of topography alone, the varied and sometimes intricate pattern of this organization has led to a variety of interpretations as to the functional significance. While the widespread nature of corticostriatal organization is not in doubt, where some have seen patterns of overlap related to patterns of cortical connectivity (Yeterian and Hoesen, 1978), others have seen interdigitation (Selemon and Goldman-Rakic, 1985). Detailed mapping of the organization of corticostriatal inputs has begun to resolve these issues. Topographic Corticostriatal Organization The topographic organization of corticostriatal inputs is well established with the orderly mapping of inputs
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FIGURE 3 Tracings of dendrites (black) and cortical (A and B) and striatal axons (A′ and B′) of two subtypes of corticostriatal neurons, which had been intracellularly labeled. (A) The corticostriatal neuron depicted provides an axonal projection to the pyramidal tract. Axon collaterals within the cortex are distributed in relatively close proximity to the parent neuron. (A′) The pyramidal tract axon of this neuron extends collaterals in the striatum, which display a focal terminal arborization. (B) The corticostriatal neuron depicted, located in the medial agranular cortex (AGm), is a bilaterally projecting corticocortical neuron, with axon collaterals projecting bilaterally to the striatum. Axon collaterals of this neuron within the ipsilateral striatum are distributed both locally around the parent neuron in the AGm and extend to the adjacent lateral agranular motor cortical area (AGl). (B′) This neuron provides an axon that provides an extensive arborization pattern within the striatum and does not provide collaterals that extend beyond the striatum. These neuronal tracings are from Cowan and Wilson (1994).
of regions of the cortex into topographically related regions of the striatum. Thus, for example, frontal areas provide inputs to the rostral regions of the striatum, sensorimotor cortex provides inputs to the dorsal lateral region, and parietal cortex provides inputs to more caudal regions. The conservation of this general topographic organization of corticostriatal inputs through the rest of the basal ganglia circuits is the basis of the popular concept of the existence of functional parallel loops (Alexander et al., 1986). An example of the regional topographic organization of the corticostriatal projections is provided by the mapping of the
various motor cortical area projections (Ebrahimi et al., 1992). Such mappings demonstrate that the spatial relationship of motor cortical areas are preserved in the organization of inputs of these areas into the striatum, for example, frontal eye fields are medial to limb and body areas. The projections from functionally defined cortical areas may be rather precise in terms of representing somatotopic organization. Thus, areas such as the somatosensory cortex, which have a somatotopic organization, provide a similar somatotopic organization of corticostriatal afferents preserving the spatial
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organization of hindlimb and forelimb areas, for example (Brown et al., 1998). Such somatotopically organized corticostriatal representations may be quite precise. The striatal projections from adjacent “barrels” in the somatosensory barrel cortex have been shown to map to adjacent sites within the striatum (Wright et al., 1999). This study, using analysis of individual corticostriatal axons showed two types of corticostriatal afferent systems. One is discrete, which maintained, rather precisely, the relationship between barrels. The other is more diffuse, which provided for considerable overlap of the projections of different barrels within the striatum. Thus, the corticostriatal inputs map not only in a general manner but also in a quite precise topographic manner to the striatum; there also exists a corticostriatal system, which provides for overlapping and converging projections from different cortical areas. Convergent Corticostriatal Organization In addition to the topographic organization of the corticostriatal system, another organizational feature of the corticostriatal system is the fact that a given cortical area projects to an area of the striatum that is proportionately larger than the cortical area of origin, and so implies considerable divergence and convergence in the corticostriatal projection. This divergence is particularly extensive in the rostrocaudal dimension. From their work in primates, Yeterian and Van Hoesen (1978) made the observation that the parietal cortex and prefrontal cortex provide inputs that appear to overlap over a fairly extensive rostrocaudal area. As these areas are connected by corticocortical connections they suggested that corticostriatal organization is related to the cortical connections of the area from which the corticostriatal inputs arise. They formulated a rule, which suggested that areas of cortex that are interconnected by corticocortical connections provide overlapping inputs to the striatum, whereas areas of cortex that are not interconnected do not. Theirs was the first formulation of a concept to explain the widespread nature of corticostriatal projections from a given region. The problem of relating the organization of corticocortical connections to corticostriatal organization is confounded by the complex connection patterns in each of these systems. Although it is true, as described by Yeterian and Van Hoesen (1978), and later by Selemon and Goldman-Rakic (1985), that cortical areas provide inputs that extend over a considerable rostrocaudal domain, the innervation patterns are by no means uniform. In many instances projections from a given cortical area show distributed but discontinuous patterns of input to the striatum. Examples of such discontinuities have recurred in the literature beginning with the studies of Kunzle in the 1970s (Kunzle, 1975, 1977).
Particularly striking are the multiple representation zones within the striatum from somatosensory and motor cortical areas. Based on functional mapping studies employing 2-deoxyglucose, Brown has suggested that multiple innervation patterns in the striatum from somatosensory cortical areas reflect multiple somatotopically organized convergence zones in which cortical inputs from different functional modalities, such as motor and somatosensory areas, converge in a combinatorial manner (Brown, 1992; Brown and Feldman, 1993). In primates, Graybiel and her colleagues have examined the connectional basis of this organization in a set of studies in which they examined the relationship of corticostriatal inputs from cortical areas that had been mapped in terms of somatosensory and motor function (Flaherty and Graybiel, 1991, 1993; Parthasarathy et al., 1992). In one study the projections from different somatosensory areas were examined (Flaherty and Graybiel, 1991, 1993b). Electrophysiologically mapped regions of somatosensory areas 3a, 3b, and 1 were injected with anterograde tracers (Flaherty and Graybiel, 1991). They found that injections into matched body part representation sites in different cortical somatosensory areas provided inputs that overlapped in their projections into the striatum and that these projections displayed multiple innervation zones. Conversely, injections into different body part regions of cortical area S1 provided inputs to multiple nonoverlapping striatal regions. A similar organization was also found in motor cortical areas. Parthasarathy et al. (1992) examined the corticostriatal projections of two frontal cortical areas that are involved in eye movements, the supplementary eye fields, and the frontal eye fields. They found that the degree of overlap of corticostriatal inputs from injections of tracer into these cortical areas was directly correlated with the degree of cortical connectivity between the injected areas. Similar to the organization of somatosensory cortical inputs, there were multiple innervation zones within the striatum from these motor cortical areas. When striatal inputs from nonoculomotor supplementary motor cortex were compared with those from frontal eye fields, there was neither an overlap of inputs in the striatum nor was there evidence of interconnections between the cortical areas injected. In a third study the organization of corticostriatal projections of somatosensory (S1) and primary motor (M1) projections to the striatum were investigated in the squirrel monkey (Flaherty and Graybiel, 1993). They found, as had been reported before, that injections of tracers into each of these regions provided inputs that were directed to the putamen and distributed in multiple, discontinuous zones. What they also found was that when somatotopically related areas of M1
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and S1 were injected, such as the hand representation, that the discontinuous zones of each cortical projection zone overlapped in the ipsilateral putamen.
General Organization of Corticostriatal Inputs A working model of the organization of corticostriatal inputs is that each cortical area provides a principal input to a topographically related area of the striatum and secondary inputs to the principal topographic striatal areas of those cortical areas with which it is connected. This organization is apparent in the results described above for corticostriatal afferents from somatotopically organized cortical areas, which provide multiple somatotopically organized projections to the striatum. Moreover, projections of different somototopically organized cortical areas provide overlapping inputs of related body part representations. These relationships appear to apply not only to the somatotopic representations of multiple sensory or motor cortical areas but also to overlap of somatotopically related areas of motor and sensory corticostriatal afferents. The organization of corticostriatal inputs from somatotopically organized cortical areas displays some relatively straightforward principles of convergent organization. Individual cortical areas provide inputs to multiple striatal zones, which are somatotopically organized. Convergence occurs in the somatotopically organized overlap from other cortical areas that are somatotopically organized. However, even in these corticostriatal inputs there are other patterns of overlap. An example is provided in the organization of the striatal inputs from the barrel cortex (Wright et al., 1999). It has been shown that projections of individual cortical barrels provide inputs that target discrete zones of the striatum, with adjacent barrels projecting to adjacent zones of the striatum. Additionally, there are other projections from interbarrel areas of the barrel cortex that provide a diffuse projection that overlaps several of the more discrete barrel projections. Thus, even in this very precisely somatotopically organized cortical area, there are both precise somatotopically organized corticostriatal inputs and diffuse corticostriatal inputs. In these cases the different patterns of corticostriatal inputs mirror the organization of the intracortical connections of the parent neurons. In the case of those corticostriatal inputs from individual barrels, the intracortical connections are restricted within the barrel, whereas those interbarrel cortical neurons that provide diffuse corticostriatal inputs have intracortical connections that span several barrels. Data from the corticostriatal input patterns from individual corticostriatal neurons suggest a relationship between the pattern of intracortical connections
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and the pattern of distribution of corticostriatal inputs (Cowan and Wilson, 1994). Thus a corollary of the working model of the organization of corticostriatal afferents stated above is that patterns of corticostriatal axon distributions are related to the pattern of the intracortical connections of the parent corticostriatal neuron. While the organizational patterns underlying convergence of corticostriatal inputs from somatotopically organized cortical areas provide some comprehensible principles, the divergent/convergent principles underlying the organization of corticostriatal inputs from areas that do not have such straightforward functional organization are more difficult. Nonetheless, there are clearly patterns of overlap of inputs from so-called associational cortical areas, such as the parietal and prefrontal cortical areas. It is most likely that similar organization principles apply, namely, that cortical areas that are interconnected provide convergent inputs to the striatum as originally suggested by Yeterian and Hoesen (1978). The rules governing patterns of convergence corticostriatal inputs of such associational cortical areas likely reflect that rules governing the corticocortical connections between such areas. In summary, the organization of corticostriatal inputs appears to be governed by two general principles. The first is that there is a topographic organization of inputs. The second is that there are secondary patterns of inputs that appear to mirror the patterns of corticocortical connectivity. These secondary patterns of corticostriatal inputs provide for patterns of convergence among distributed sets of corticostriatal neurons. Such patterns of convergence of corticostriatal inputs are as varied as the patterns of connectivity between cortical areas.
Quantitative Data Regarding Corticostriatal Inputs All afferent inputs to the striatum that have been studied so far have formed axonal fields in which the individual axonal branches cross over the dendrites of individual spiny neurons, making synapses mostly en passant. This is the cruciform axodendritic pattern of innervation (Fox et al., 1971), which places each axon into position to contact the maximum number of neurons but minimizes the number of synapses possible with each postsynaptic cell. This is in contrast to the longitudinal axodendritic synaptic arrangement formed by striatopallidal fibers (Fox and Rafols, 1976), in which individual axonal branches form multiple synaptic contacts on the dendrites of postsynaptic neurons. Thus, the inputs of an individual corticostriatal neuron to the striatum may be considered extremely sparse in terms of the number of contacts it makes with a single striatal neuron. Wilson and his colleagues
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(Kincaid et al., 1998; Zheng and Wilson, 2002) have provided some informative quantitative information that provides some informative boundaries for the type of information processing that may be taking place within the basal ganglia. First, there appears to be roughly a 6:1 ratio in terms of the numbers of corticostriatal neurons (17,000,000) and striatal projection neurons (2,800,000). Second, the area over which the dendrites of a single medium spiny projection neuron spreads (400 μm in diameter) contains approximately 2850 other neurons. Third, approximately 380,000 corticostriatal neurons innervate the area of the dendritic field of a single medium spiny projection neuron, which contains 2850 neurons. Fourth, the axon of a single corticostriatal axon traversing this area has on average 40 synaptic boutons. If, as is estimated, each axon makes only a single, or a few contacts, with an individual medium spiny neuron, then each corticostriatal input makes contact with about 1% of the striatal neurons in the area across which it extends. Taken together these quantitative estimates indicate that the cortical input to a single striatal medium spiny projection neuron is rather unique; that is, no two striatal neurons share common inputs from the cortex. Based on their quantitative analysis of corticostriatal inputs Wilson and his colleagues (Kincaid et al., 1998; Zheng and Wilson, 2002) make several observations on the constraints of the information processing within the striatum. First, they make the point that individual striatal projection neurons receive inputs from a large number of cortical neurons, such that the cooperative effect of activity of those cortical neurons is required to provide sufficient excitatory input for the projection neuron to generate an action potential. Thus, each striatal neuron’s activity represents the coordinated activity of a distributed ensemble of a large set of cortical neurons, whose input converges on that neuron. Second, such an organization has been suggested to represent a competitive network, in which different patterns of cortical activity compete for representation in the striatum. Typically, in such competitive models, synaptic plasticity is proposed to be involved in the resolving competing representations. However, such models require considerable overlap of corticostriatal inputs to individual neurons rather than the observed unique inputs that striatal neurons receive. Thus, the organization of corticostriatal inputs appears to represent the end stage of a competitive network rather than a dynamic one in which different patterns of corticostriatal inputs are competing for synaptic sites. Third, the possibility that the striatum generates a compact representation of patterns of cortical activity is not supported by the organization of corticostriatal inputs. Wilson argues that since striatal neurons each
receive a unique set of corticostriatal inputs the 6 to 1 ratio of cortical input neurons to striatal target neurons does not allow for all patterns of cortical activity to be represented in the patterns of activity in the striatum. Thus, rather than removing redundancy in patterns of corticostriatal input activity, a large proportion of cortical patterns of activity must either be lost or treated as though they are similar when they are not.
STRIATUM The striatum comprises the caudate, putamen, and nucleus accumbens. The striatum is composed of one principal neuron cell type, the medium spiny projection neuron (Bishop et al., 1982; DiFiglia et al., 1976; Wilson and Groves, 1980). This medium spiny projection cell type makes up as much as 95% of the neuron population (Kemp and Powell, 1971). These neurons are rather homogeneously distributed such that the striatum lacks distinct cytoarchitectural organization when all neurons are stained in histologic sections, as contrasted with the laminar organization of the cortex, for example. Using retrograde axonal transport methods Grofova (1975) established that these neurons are the projection neuron of the striatum. Cortical input to the striatum targets spiny projection neurons (Somogyi et al., 1981), although not exclusively. Thus the spiny projection neuron is the major input target and the major projection neuron of the striatum (Fig. 4). The remaining striatal neurons are interneurons (Bishop et al., 1982; DiFiglia et al., 1976), in that they do not provide projection axons out of the striatum, but rather distribute axons within the striatum, most of which make synaptic contact with spiny projection neurons. Despite being relatively infrequent, striatal interneurons constitute a variety of morphologic and neurochemically defined types. Among these are the large aspiny neurons, which utilize acetylcholine as a transmitter (Bolam et al., 1984; Kawaguchi and Kubota, 1993), and medium aspiny neurons (Bishop et al., 1982; DiFiglia et al., 1976), which utilize GABA as a transmitter (Kita and Kitai, 1988). The latter class of interneurons may be further subdivided on the basis of different peptides and neurochemicals that they contain (Kita, 1993; Kubota and Kawaguchi, 1993; Kubota et al., 1993; Kawaguchi et al., 1995).
Medium Spiny Projection Neuron Medium spiny projection neurons take their name from their morphologic appearance (Bishop et al., 1982; Chang et al., 1982; DiFiglia et al., 1976; Wilson and Groves, 1980), with a cell body approximately 20–25
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μm in diameter, from which radiate 7–10 moderately branched dendrites that are densely laden with spines. The dendrites of an individual neuron extend over an area of approximately 200 μm in diameter. The distribution of the dendrites is not always uniform and may in fact be limited by compartmental boundaries within the striatum, such as those that form the “patch–matrix” compartments (Kawaguchi et al., 1989). Spiny projection neurons extend a local axon collateral that remains within the striatum. In most cases such collaterals distribute over an area roughly equal in size, but not necessarily in the same area, as the dendrites of the parent neuron (Bishop et al., 1982; Kawaguchi et al., 1990). In some cases the local axon collateral may have an extensive distribution over a very large area within the striatum, extending over 1 mm from the parent neuron (Kawaguchi et al., 1990). Medium spiny projection neurons also provide an axon collateral that projects out of the striatum to the lateral globus pallidus and/or medial globus pallidus/ substantia nigra (Kawaguchi et al., 1990). Two major subpopulations of medium spiny neurons, of approximately equal numbers, may be defined on the basis of their projection targets (Beckstead and Cruz, 1986; Gerfen and Young, 1988; Kawaguchi et al., 1990; Loopuijt and Kooy, 1985). One subset, provides an axon projection to the lateral globus pallidus. The other subset provides an axon collateral to the lateral globus pallidus and additional collaterals to the medial globus pallidus and/or the substantia nigra. These latter neurons constitute the “direct striatal projection pathway” as they, are directly connected to the output of the basal ganglia, which are GABAergic neurons in the medial globus pallidus and substantia nigra pars reticulata. The former neurons constitute the “indirect striatal projection pathway” as they are connected indirectly, through connections of the lateral globus pallidus and subthalamic nucleus, with the output neurons of the basal ganglia. Medium spiny projection neurons all contain glutamic acid decarboxylase (GAD) the synthetic enzyme for the neurotransmitter GABA (Kita and Kitai, 1988). In addition, most of those neurons projecting to the lateral globus pallidus alone contain the neuropeptide enkephalin, whereas most of those which project to the substantia nigra contain the neuropeptides substance P and dynorphin (Beckstead and Kersey, 1985; Gerfen and Young, 1988; Haber and Watson, 1983). Spiny projection neurons contain different complements of neurotransmitter receptors and other proteins that serve to characterize particular subpopulations of striatal output neurons. These are discussed in further detail below. Medium spiny projection neurons receive inputs from the cortex, thalamus, and amygdala, which make
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asymmetric synapses on dendritic spines and, to a lesser degree, dendritic shafts (Fig. 5). These inputs provide the major excitatory input to these neurons. In addition, a number of inputs from outside the striatum and from within the striatum provide inputs that function to modify the responsiveness of spiny neurons to the excitatory input. These include inputs from dopamine afferents from the substantia nigra, inhibitory GABA inputs from the axon collaterals of other spiny neurons, inhibitory inputs from GABA (and peptide containing) striatal interneurons, and inputs from cholinergic striatal interneurons. Inputs to Medium Spiny Neurons Cortical inputs Corticostriatal afferents make synaptic contact primariy with the expanded head of dendritic spines on spiny neurons (Bouyer et al., 1984; Hattori et al., 1978; Kemp and Powell, 1971; Somogyi et al., 1981). According to a quantitative study in rats (Xu et al., 1989), of all cortical synapses in the striatum, about 90% are formed with dendritic spines and about 5% with dendritic shafts. The remaining 5% are on somata. While most dendritic spine synapses are certainly formed with spiny projection cells, the smaller number of dendritic and somatic contacts include the combination of all the inputs onto interneurons, as well as contacts made with spiny cell dendritic shafts. The somata receiving cortical inputs generally do not resemble those of spiny neurons. Corticostriatal synapses are almost exclusively asymmetric and contain small rounded vesicles. Although cortical innervation of the striatum is relatively dense, as discussed above, input from any individual corticostriatal axon to an individual striatal spiny neuron is very sparse (Cowan and Wilson, 1994; Kincaid et al., 1998; Zheng and Wilson, 2002). Consistent with the asymmetric character of corticostriatal synapses onto spiny neurons electrophysiologic studies have demonstrated that corticostriatal input evokes a monosynaptic excitatory postsynaptic potential (EPSP) (Kitai et al., 1976; Wilson, 1986). At least two types of corticostriatal afferents have been identified on the basis of the electrophysiologic effects of these inputs (Jinnai and Matsuda, 1979; Wilson, 1986). One is a fast conducting collateral of neurons projecting to the brain stem and evokes an EPSP with a latency of 3 ms. A second type, which appears to be the major corticostriatal afferent, is a slower conducting afferent that evokes an EPSP with a latency of 10 ms. Thalamic inputs Thalamic inputs from the intralaminar nuclei, including the parafascicular/centromedian complex, provide inputs to the striatum that are similar to cortical afferents in that they form asymmetric synaptic contacts and have strong excitatory effects on
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D FIGURE 4 The medium spiny striatal projection neuron. (A) Photomicrograph of a single medium spiny projection neuron filled with biocytin. (A′) High magnification of intracellularly filled medium spiny neuron. (B) Tracings of an indirect and direct striatal projection neuron drawn in place on a sagittal brain diagram. The indirect striatal pathway neuron has a projection axon that extends into the lateral globus pallidus, where it arborizes, and does not extend beyond this nucleus. The direct striatal pathway neuron has a projection axon that extends some collaterals into the lateral globus pallidus (LGP) and extends to the medial globus pallidus (MGP) and substantia nigra. Higher magnification of the indirect and direct striatal pathway neurons show their dendrites (red/green) and local axon collaterals within the striatum (orange/blue). (C) Diagrammatic representation of the direct and indirect striatal pathway neurons. Both neurons are GABAergic and receive a glutamatergic corticostriatal input. Direct pathway neurons express the D1 dopamine receptor subtype, the Gs and Golf stimulatory G proteins, as well as the peptides substance P (SP) and dynorphin (DYN). These neurons project to the lateral globus pallidus (LGP), medial globus pallidus (MGP), and substantia nigra pars reticulata (SNR). Indirect striatal pathway neurons express the D2 dopamine receptor, which is coupled to the inhibitory Gi G protein, as well as the α2-adenosine receptor, which is coupled to the stimulatory Golf G protein. These neurons also express the peptide enkephalin (ENK). (D) Functional dissociation of direct and indirect striatal projection neurons. In dopamine-depleted striatum, D1 receptor agonist treatment results in phosphorylation of ERK1/2/MAPkinase (immunoreactive green neurons) selectively in direct striatal projection neurons, but not in indirect pathway neurons, which are labeled by ISHH localization of mRNA encoding ENK (red neurons). One neuron in this field is double labeled (yellow). From Gerfen et al. (2002).
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B connections of striatal medium spiny neurons FIGURE 5 Diagram of the connections of medium spiny striatal projection neurons. (A) Synaptic input to medium spiny striatal projection neurons showing the location spine the cortical glutamatergic synapses on the head of medium spiny neurons, inputs to the neck and interspine dendritic shafts from nigrostriatal dopamine inputs, or GABAergic input from other medium spiny neurons. Inputs to the cell body and proximal dendrites are from striatal GABAergic and cholinergic interneurons. (B) Diagram of the inputs to the proximal and distal parts of striatal medium spiny neurons. Inputs to distal parts of the dendrites are from the cerebral cortex, nigrostriatal dopamine afferents, and thalamus, whereas inputs to the proximal part of the neurons are from GABAergic parvalbumin (Pv) and cholinergic (ChAT) neurons.
the spiny cells. Early studies of Powell and Cowan (1956) suggested that the thalamostriatal pathway consisted of a single topographically organized projection. More recent studies (Dube et al., 1988; Xu et al., 1989) have shown that this pathway, like the corticostriatal
projection, is heterogeneous in nature. There are actually two independent thalamostriatal projections of the intralaminar nuclear complex, one originating from the parafascicular/centromedian nuclei and a separate one from rostral parts of the complex including the
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CHARLES R. GERFEN
central lateral and paracentral nuclei. The parafascicular projection, unlike the cortical input, makes its asymmetrical synaptic contacts preferentially with the shafts of dendrites rather than with the spines. In one study (Xu et al., 1989), 89% of synapses formed by fibers from the parafascicular nucleus were formed on dendritic shafts in the neostriatum, with only 11% on dendritic spines. This is almost exactly the reverse of the arrangement of cortical axons. The postsynaptic targets of the parafascicular projection have been shown to be spiny neurons, but perhaps neurons of a special class, which do not receive a cortical input or at least do not receive as dense a cortical input. In contrast to projections arising from the parafascicular/centromedian nuclei, fibers from the rostral intralaminar nuclei (e.g., central lateral or paracentral nucleus) form synapses similar to those formed by corticostriatal fibers. In the study by Xu et al. (1989), 93% of these were formed on dendritic spines and 7% on dendritic shafts. The projections from these two different sets of thalamic nuclei also differ in their innervation of patch and matrix compartments, as described in a subsequent section. Dopamine inputs Inputs from midbrain dopamine neurons that project to the striatum make synaptic contact with medium spiny neurons. These afferents have been identified at the ultrastructural level with immunohistochemical localization of either dopamine (Voorn et al., 1986) or the dopamine-synthesizing enzyme tyrosine hydroxylase (Arluison et al., 1984; Bouyer et al., 1984; Freund et al., 1984). Most of these afferents make symmetric synapses and contain large round and pleiomorphic vesicles. Of 280 synapses examined by Freund et al. (1984), 59% made synaptic contacts with dendritic spines. Unlike the axospinous synapses formed by cortical or thalamic inputs, these were symmetrical synapses, usually not made on the head of the spine, and these inputs shared the dendritic spine with another bouton forming an asymmetrical synapse (probably from the cerebral cortex or thalamus). Synapses were made onto dendritic shafts in 35% of the cases, and 6% made synapses with somata. It is often suggested that dopaminergic fibers may release dopamine nonsynaptically into the extracellular space, where it could interact with extrasynaptic receptors. Alternatively, dopamine may escape from the synaptic region and diffuse to extrasynaptic receptors on the postsynaptic neuron or other cell processes in the neuropil. With an eye for this possibility, it has been reported that dopamine-containing synapses are sometimes seen to be in close apposition with the presynaptic part of asymetric forming boutons, presumably of cortical or thalamic origin. However, these close appositions lack synaptic specializations, and they
have not been shown to be more common than appositions between any other parts of the neuron. Medium spiny cell local collateral input Medium spiny projection neurons have axon collaterals within the
