The Primate Nervous System, Part III

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THE PRIMATE NERVOUS SYSTEM PART I11

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HANDBOOK OF CHEMICAL NEUROANATOMY Series Editors: A. Bjorklund and T. Hokfelt

Volume 15

THE PRIMATE NERVOUS SYSTEM, PART TIT Editors :

F.E. BLOOM Department of Neuropharmacology, The Scripps Research Institute, La Jolla, CA 92037. USA

A. BJORKLUND Department of Medical Cell Research, Wallenberg Neuroscience Center, University of Lund, S223 62 Lund, Sweden

T. HOKFELT Department of Histology and Neurosciences, Karolinska Institute. S104 01 Stockholm, Sweden

1999

ELSEVIER Amsterdam

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Lausanne - New York

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Oxford

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Shannon - Singapore - Tokyo

EESEVIER SCIENCE B.V. Sara Burgerhartstraat 25 P.O. Box 21 1, 1000 A E Amsterdam, The Netherlands

0 1999 Elsevier Science B.V. All rights reserved.

This work is protected under copyright by Elsevier Science, and the following terms and conditions apply to its use: Photocopying Single photocopies of single chapters may be made for personal use as allowed by national copyright laws. Permission of the Publisher and payment of a fee is required for all other photocopying, including multiple or systematic copying, copying for advertising or promotionalpurposes, resale, and all forms of documentdelivery. Special rates are available for educational institutions that wish to make photocopies for non-profit educational classroom use. Permissions may be sought directly from Elsevier Science Rights & Permissions Department, PO Box 800, Oxford OX5 IDX, UK; phone: (+44) 1865 843830, fax: (+44) 1865 853333, e-mail: [email protected]. You may also contact Rights & Permissions directly through Elsevier’s home page (http:Nwww.elsevier.nl),selecting first ‘Customer Support’, then ‘General Information’, then ‘Permissions Query Form’. In the USA, users may clear permissions and make payments through the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, USA; phone: (978) 7508400, fax: (978) 7504744, and in the UK through the Copyright Licensing Agency Rapid Clearance Service (CLARCS), 90 Tottenham Court Road, London WIP OLP, UK; phone: (+44)171 631 5555; fax: (+44)171 631 5500. Other countries may have a local reprographic rights agency for payments. Derivative Works Tables of contents may be reproduced for internal circulation, but permission of Elsevier Science is required for external resale or distribution of such material. Permission of the Publisher is required for all other derivative works, including compilations and translations. Electronic Storage or Usage Permission of the Publisher is required to store or use electronically any material contained in this work, including any chapter or part of a chapter. Except as outlined above, no part of this work may be reproduced,stored in a retrieval system or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without prior written permission of the Publisher. Address permissions requests to: Elsevier Science Rights & Permissions Department, at the mail, fax and e-mail addresses noted above. Notice No responsibility is assumed by the Publisher for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions or ideas contained in the material herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made.

First edition 1999 Library of Congress Cataloging in Publication Data A catalog record from the Library of Congress has been applied for.

ISBN: ISBN:

@

0-444-50043-X (volume) 0-444-90340-2 (series)

The paper used in this publication meets the requirements of A N S I N S O 239.48-1992 (Permanence of Paper). Printed in The Netherlands.

List of Contributors G.F. ALHEID Department of Physiology and Institute for Neuroscience Northwestern University Morton, Rm. 5-654 303 E. Chicago Ave. Chicago, IL 60611-3008 USA

L. HEIMER Departments of Otolaryngology Head and Neck Surgery, and Neurological Surgery Health Sciences Center, Box 396 University of Virginia Charlottesville, VA 22908 USA

D.G. AMARAL Center for Neuroscience University of California, Davis 1544 Newton Court Davis, CA 95616 USA

Y. KOBAYASHI Department of Psychiatry Center for Neuroscience and California Regional Primate Research Center University of California, Davis Davis, CA 95616 USA and Department of Anatomy Kyorin University School of Medicine 6-20-2 Shinkawa Mitaka, Tokyo 181 Japan

C. BERGSON Medical College of Georgia Department of Pharmacology and Toxicology, Room CB3730 Augusta, GA 30912-2300 USA P.S. GOLDMAN-RAKIC Section of Neurobiology Yale University School of Medicine 333 Cedar Street New Haven, CT 06520-8001 USA

Section of Neurobiology Yale University School of Medicine 333 Cedar Street New Haven, CT 06520-8001 USA

A.M. GRAYBIEL Department of Brain and Cognitive Sciences Massachusetts Institute of Technology Bldg E25, Room 618 Cambridge, MA 02139 USA

M.S. LIDOW Department of Oral and Craniofacial Biological Science University of Maryland Dental School 666 West Baltimore Street, Room 5-A-12 Baltimore, MD 21201-1586 USA

L.S. KRIMER

J. MARKSTEINER Department of Psychiatry University of Innsbruck Anichstrasse 35 A-6020 Innsbruck Austria J.S. DE OLMOS Instituto de Investigacion Medica Mercedes y Martin Ferreyra Cordoba Argentina J. PEARSON 698 State Street Portsmouth, NH 03801 USA JOHN B. PENNEY t Neurology Research Massachusetts General Hospital Warren 508 55 Fruit Street Boston, MA 02114 USA N. SAKAMOTO Department of Anatomy Yokohama City University School of Medicine Fukuura 3-9, Kanazawa-ku Yokohama 236-0004 Japan

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K. SHINODA Department of Anatomy II Yamaguchi University School of Medicine 1144 Kogushi, Ube Yamaguchi 755 Japan R.C. SWITZER III NeuroScience Associates 10915 Lake Ridge Drive Knoxville, TN 37922 USA G.V. WILLIAMS Section of Neurobiology Yale University School of Medicine 333 Cedar Street New Haven, CT 06520-8001 USA S.M. WILLIAMS Department of Neurobiology Duke University Medical Center Bryan Research Bldg. for Neurobiology Research Drive, Room 319 Durham, NC 27710 USA

Preface This volume is the third and final part of the planned coverage of the neurochemical circuitry of the primate central nervous system. The five chapters included in this volume complement and integrate magnificently with the two prior volumes. Furthermore, these chapters further extend the goals of the primate series to develop a broadly based coverage of human and non-human primate chemical neuroanatomic details in a concentrated publication in order to make clear the known and desirable appreciation for differences between and among subsets of primate brains. In this final volume, the coverage of brain regions includes those which lie at the core of some of the most intensively studied human neurological and psychiatric disorders. Heimer, with his colleagues Alheid, de Olmos and Sakamoto, provides a two-fold exposition on the human forebrain. They first present a detailed and comprehensive overview and mini-atlas in chemically defined details of the entire human forebrain. Then, in a second extensive assessment and analysis, Heimer, Alheid and colleagues specifically focus on the basal forebrain, a region critical for a wide range of human problems ranging from substance abuse to Alzheimer's disease. Graybiel and Penney provide a critical synthesis of the primate basal ganglia, a region under intense scrutiny for the organization of motor programs, and for their dysfunctions in Parkinson's disease, Huntington's disease and other problems. Kobayashi and Amaral portray the chemical and anatomic details of the primate hippocampal formation in extenso, and with specific concern over the memory and emotional functions attributed to this complex. Lastly, Goldman-Rakic and colleagues examine the rapidly growing literature on the mesocortical projection of dopaminergic circuits onto the primate frontal cortex, a system highly linked to higher order mental abstractions, as well as the dysfunctions of schizophrenia. As extensive as these chapters and those of the prior volumes have been, scholars will recognize that the laying out of these status reports on our still vastly incomplete examination of the primate brains is an opportunity for progress. While we may now recognize the main properties of their major circuitry, we may now also recognize the need for far more detailed assessments of the inter-individual differences in qualitative and quantitative aspects of their circuits. If these volumes will have served their purpose, they will be really just another beginning for those who will complete these needed details. Tragically, during the production of this volume, Dr. J. Penney died quite unexpectedly. His contributions to our science and to the specific insights into the basal ganglia will long be remembered, and we dedicate this volume to his memory. La Jolla, Lund and Stockholm, July 1999 FLOYD E. BLOOM

ANDERS BJORKLUND

TOMAS HOKFELT

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Contents I.

THE HUMAN BASAL FOREBRAIN. PART I. AN OVERVIEW N. SAKAMOTO, J. PEARSON, K. SHINODA, G.F. ALHEID, J.S. DE OLMOS AND L. HEIMER 1. Introduction 2. Surface topography 2.1. Basal cortex 2.2. Olfactory peduncle and olfactory tract 2.3. Olfactory tubercle and anterior perforated space 2.4. Olfactory trigone 3. Overview of basal forebrain structures 3.1. Area diagonalis (diagonal band of Broca) and basal nucleus of Meynert 3.2. Olfactory bulb projection areas 3.3. The claustrum 3.4. Dorsal striatum and dorsal pallidum 3.5. Ventral striatum and ventral pallidum 3.6. Striatum in the temporal lobe 3.7. Extended amygdala 3.8. Amygdaloid body 3.9. Small-celled islands 4. Coronal sections through the basal forebrain 4.1. Materials and methods 5 . Acknowledgements 6. References Mini-atlas of coronal sections through the basal forebrain

1 1 2 2 3 6 6 6 7 7 8 9 9 10 11 11 11 11 12 13 15

11. THE HUMAN BASAL FOREBRAIN. PART 11.- L. HEIMER, J.S. DE OLMOS, G.F. ALHEID, J. PEARSON, N. SAKAMOTO, K. SHINODA, J. MARKSTEINER AND R.C. SWITZER I11 Introduction 1.1, ‘Basalis’ region 1.1.1. ‘Basalkerncomplex’ of Brockhaus 1.1.2. Basal nucleus of Meynert 2. Ventral striatopallidal system 2.1. Ventral striatum 2.1.1. The heterogeneity of ventral striatum 2.1.2. Interface islands 2.1.3. Core and shell subdivisions of the accumbens 2.2. Ventral pallidum 3. Extended amygdala 3.1. Bed nucleus of stria terminalis 3.1.1. Lateral division of bed nucleus 1.

57 60 60 63 64 65 67 82 89 90 93 98 98 ix

4.

5.

6. 7.

8. 9. 10.

3.1.2. Medial division of bed nucleus 3.2. Sublenticular components of extended amygdala 3.2.1. Central division of the sublenticular extended amygdala 3.2.2. Medial division of sublenticular extended amygdala 3.3. Centromedial amygdala 3.3.1. Central amygdaloid nucleus 3.3.2. Medial amygdaloid nucleus 3.4. Stria terminalis components of the extended amygdala 3.4.1. Supracapsular part of the stria terminalis 3.4.2. Subcapsular part of the stria terminalis 3.5. Transition areas between extended amygdala and the striatopallidal system Olfactory system 4.1. Primary non-amygdaloid olfactory bulb projection areas 4.1.1. Anterior olfactory nucleus (retrobulbar area) 4.1.2. Primary olfactory cortex (‘piriform cortex’) 4.1.3. Insular and temporopolar periallocortical areas 4.1.4. Ventral striatum vs olfactory tubercle 4.2. Olfactory association areas in the orbitofrontal cortex 4.3. Olfactory amygdala 4.4. Olfactory entorhinal field Superficial amygdala and the laterobasal complex 5.1. General structure of the amygdala 5.2. Superficial amygdala 5.2.1. Is the superficial amygdala a cortical or subcortical structure? 5.2.2. Superficial amygdala: a plethora of terms 5.2.3. Review of superficial amygdaloid structures 5.3. Laterobasal amygdaloid complex 5.3.1. Lateral amygdaloid nucleus 5.3.2. Basolateral amygdaloid nucleus 5.3.3. The basomedial amygdaloid nucleus 5.3.4. The paralaminar amygdaloid nucleus 5.4. Intramedullary gray substance and intercalated (interface) islands Concluding remarks Appendix: comparison of nomenclature for the human amygdala 7.1. Preface 7.2. Footnotes to tables Acknowledgements Abbreviations References

105 105 107 114 114 116 122 124 125 138 144 146 147 I47 148 151 152 153 154 155 156 156 161 161 162 169 176 178 181 183 185 186 187 187 187 188 206 206 209

111. CHEMICAL ARCHITECTURE OF THE BASAL GANGLIAA.M. GRAYBIEL AND J.B. PENNEYt 1. Introduction 2. Systems approach to the basal ganglia 2.1. The basal ganglia proper and their allied nuclei 2.2. The connections of the basal ganglia: An overview X

227 228 228 23 1

2.2.1. 2.2.2. 2.2.3. 2.2.4.

The direct pathway The indirect pathway The striosomal output pathway General modular architecture of the striatum : striosomes and matrisomes 2.2.5. Loop systems of the basal ganglia 2.3. Transmitter-related compounds associated with basal ganglia pathways 2.4. Neuropeptides in basal ganglia pathways 2.5. Neurotransmitter-related compounds in striatal interneurons 3. Functional concepts about the basal ganglia 3.1. Movement disorders 3.1.1. Ballism 3.1.2. Parkinson’s disease 3.1.3. Huntington’s disease 3.1.4. Dystonia 3.2. Neuropsychiatric disorders 4. Chemically specified subsystems : receptor systems in the basal ganglia 4.1. Receptors associated with basal ganglia afferents 4.1.1. Glutamate receptors 4.1.2. Dopamine receptors 4.1.3. Serotoninergic receptors 4.1.4. Adrenergic receptors 4.1.5. Glycine receptors 4.2. Receptors associated with intrinsic basal ganglia pathways 4.2.1. GABA receptors 4.2.2. Cholinergic receptors 4.2.3. Adenosine receptors 4.2.4. Opiate receptors 4.2.5. Tachykinin receptors 4.2.6. Cannabinoid receptors 4.2.7. Somatostatin receptors 5. Future directions 5.1. Functional considerations: The involvement of basal ganglia dysfunction in the production of disordered movement 6. Acknowledgement 7. References

232 232 235 235 237 240 245 247 247 247 248 249 252 255 256 257 258 258 26 1 262 263 263 263 263 265 265 265 266 266 267 267 267 270 270

IV. CHEMICAL NEUROANATOMY OF THE HIPPOCAMPAL FORMATION AND THE PERIRHINAL AND PARAHIPPOCAMPAL CORTICES - Y. KOBAYASHI AND D.G. AMARAL

1. Introduction 1.1. Why the hippocampal formation? 1.2. Why include the perirhinal and parahippocampal cortices? 1.3. Organization of the chaptcr 2. Overview of the components of the medial temporal lobe 3. Cytoarchitectonic organization of the hippocampal formation

285 286 286 288 293 297

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Regional and cytoarchitectonic features of the perirhinal and parahippocampal cortices 5. An overview of the connectivity of the hippocampal formation 5.1. Intrinsic connections of the hippocampal formation 5.2. Connections between the perirhinal and parahippocampal cortices and the hippocampal formation 5.3. Other extrinsic connections of the hippocampal formation 6. Dentate gyrus 6.1. Glutamate system 6.1.1. Glutamate 6.1.2. Glutamate receptors 6.1.3. NMDA receptors 6.1.4. AMPA/kainate receptors 6.1.5. Metabotropic glutamate receptors 6.1.6. Aspartate 6.2. Cholinergic system 6.2.1. Cholinergic fiber systems 6.2.1.1. Molecular layer 6.2.1.2. Granule cell layer 6.2.1.3. Polymorphic cell layer 6.2.2. Cholinergic receptor systems 6.3. GABAergic system 6.3.1. GABAergic fiber innervation 6.3.2. GABAergic cell bodies 6.3.3. GABAergic receptors 6.4. Monoamines 6.4.1. Noradrenaline 6.4.2. Adrenaline 6.4.3. Dopamine 6.4.4. Serotonin 6.5. Peptides 6.5.1. Substance P 6.5.2. Cholecystokinin 6.5.3. Vasoactive intestinal peptide 6.5.4. Neurotensin 6.5.5. Somatostatin 6.5.6. Neuropeptide Y 6.5.7. Opioid peptides (dynorphin, enkephalin) 6.5.8. Galanin 6.6. Calcium-binding proteins 6.6.1. Parvalbumin 6.6.2. Calbindin 6.6.3. Calretinin 6.7. Hormone receptor sites 6.8. Enzymes 6.8.1. Cytochrome oxidase 6.8.2. Nitric oxide synthase and NADPH-diaphorase 6.9. Trophic factors 6.9.1. Nerve growth factor 4.

xii

304 306 306 336 336 337 337 337 337 337 338 338 339 339 339 339 340 340 34 1 341 34 1 342 343 343 343 344 344 344 345 345 346 346 346 346 347 347 347 348 348 350 350 35 1 351 351 352 352 352

353 353 353 7. Hippocampus 353 7.1. Glutamate system 353 7.1.1. Glutamate 353 7.1.2. NMDA receptors 354 7.1.3. AMPA-kainate receptors 354 7.1.4. Metabotropic glutamate receptors 354 7.1.5. Aspartate 355 7.2. Cholinergic system 355 7.2.1. Cholinergic fiber systems 356 7.2.2. Cholinergic receptors 356 7.3. GABAergic system 356 7.3.1. Fiber innervation 357 7.3.2. GABAergic cell bodies 359 7.3.3. GABAergic receptors 359 7.4. Monoamines 359 7.4.1. Noradrenaline 7.4.2. Dopamine 359 360 7.4.3. Serotonin 360 7.5. Peptides 360 7.5.1. Substance P 3 60 7.5.2. Cholecystokinin 361 7.5.3. Neurotensin 361 7.5.4. Somatostatin 361 7.5.5. Neuropeptide Y 362 7.5.6. Opioid peptides 362 7.5.7. Galanin 362 7.6. Calcium-binding proteins 362 7.6,l. Parvalbumin 7.6.1.1. Distribution of parvalbumin-positive fibers 362 7.6.1.2.Distribution of parvalbumin-positive cell bodies 363 364 7.6.2. Calbindin 365 7.6.3. Calretinin 365 7.7. Hormone receptor sites 365 7.8. Enzymes 365 7.8.I . Cytochrome oxidase 366 7.8.2. Nitric oxide synthase and NADPH-diaphorase 366 7.8.3. Other enzymes 366 7.9. Trophic factors 366 7.9.1. Nerve growth factor 366 7.9.2. Ciliary neurotrophic factor 366 7.9.3. Brain-derived neurotrophic factor 366 8. Subiculum 366 8.1. Glutamate system 366 8.1.1. Glutamate 367 8.1.2. NMDA receptors 367 8.1.3. AMPA-kainate receptors 8.1.4. Metabotropic glutamate receptors 367

6.9.2. Ciliary neurotrophic factor 6.9.3. Brain-derived neurotrophic factor

...

Xlll

8.1.5. Aspartate 8.2. Cholinergic system 8.2.1. Cholinergic fiber systems 8.2.2. Cholinergic receptors 8.3. GABAergic system 8.3.1. Fiber innervation 8.3.2. GABAergic cell bodies 8.3.3. GABAergic receptors 8.4. Monoamines 8.4.1. Noradrenaline 8.4.2. Dopamine 8.4.3. Serotonin 8.5. Peptides 8.5.1. Substance P 8.5.2. Cholecystokinin 8.5.3. Neurotensin 8.5.4. Somatostatin 8.5.5. Neuropeptide Y 8.5.6. Opioid peptides 8.5.7. Galanin 8.6. Calcium-binding proteins 8.6.1. Parvalbumin 8.6.1.1. Distribution of parvalbumin-positive fibers 8.6.1.2. Distribution of parvalbumin-positive cells 8.6.2. Calbindin 8.6.3. Calretinin 8.7. Hormone receptor sites 8.8. Enzymes 8.8.1. Cytochrome oxidase 8.8.2. Nitric oxide synthase and NADPH-diaphorase 8.9. Trophic factors 8.9.1. Nerve growth factor 8.9.2. Ciliary neurotrophic factor 8.9.3. Brain-derived neurotrophic factor 9. Presubiculum and parasubiculum 9.1. Glutamate system 9.1.1. AMPA receptors 9.2. Cholinergic system 9.2.1. Cholinergic fiber systems 9.2.1.1. Presubiculum 9.2.1.2. Parasubiculum 9.2.2. Cholinergic receptors 9.3. GABAergic system 9.3.1. Fiber innervation 9.3.2. GABAergic cell bodies 9.3.3. GABAergic receptors 9.4. Monoamines 9.4.1. Noradrenaline 9.4.2. Dopamine

xiv

367 367 367 368 368 368 368 368 369 369 369 369 369 369 369 369 370 370 370 370 370 370 370 37 1 371 371 372 372 372 372 372 372 372 372 373 373 373 373 373 373 373 374 314 374 374 375 375 375 375

9.4.3. Serotonin 9.5. Peptides 9.5.1. Substance P 9.5.2. Cholecystokinin 9.5.3. Neurotensin 9.5.4. Somatostatin 9.5.5. Neuropeptide Y 9.5.6. Opioid peptides 9.5.7. Galanin 9.6. Calcium-binding proteins 9.6.1. Parvalbumin in the presubiculum 9.6.1.1. Distribution of parvalbumin-immunoreactive fibers 9.6.1.2. Distribution of parvalbumin-immunoreactive cells 9.6.2. Parvalbumin in the parasubiculum 9.6.2.1. Distribution of parvalbumin-immunoreactive fibers 9.6.2.2. Distribution of parvalbumin-immunoreactive cells 9.6.3. Calbindin 9.6.4. Calretinin 9.7. Hormone receptor sites 9.8. Enzymes 9.8.1. Cytochrome oxidase 9.8.2. Nitric oxide synthase and NADPH-diaphorase 9.9. Trophic factors 10. Entorhinal cortex 10.1. Glutamate system 10.1.1. AMPA-kainate receptors 10.2. Cholinergic system 10.2.1. Cholinergic fiber systems 10.2.2. Cholinergic receptors 10.2.2.1. Muscarinic receptors 10.2.2.2. Nicotinic receptors 10.3. GABAergic system 10.3.1. Fiber innervation 10.3.2. GABAergic cell bodies 10.4. Monoamines 10.4.1. Noradrenaline 10.4.2. Dopamine 10.4.3. Serotonin 10.5. Peptides 10.5.1. Substance P 10.5.2. Cholecystokinin 10.5.3. Neurotensin 10.5.4. Somatostatin 10.5.5. Neuropeptide Y 10.5.6. Opioid peptide

375 375 375 375 375 376 376 376 376 376 376 376 376 377 377 377 377 377 378 378 378 378 378 378 378 378 379 379 380 380 380 38 1 38 1 38 1 382 382 382 383 383 383 384 384 384 385 385 xv

10.5.7. Galanin 10.6. Calcium-binding proteins 10.6.1. Parvalbumin 10.6.1.1. Distribution of parvalbumin-immunoreactive fibers 10.6.1.2. Distribution of parvalbumin-immunoreactive cells 10.6.2. Calbindin 10.6.3. Calretinin 10.7. Hormone receptor sites 10.8. Enzymes 10.8.1. Cytochrome oxidase 10.8.2. Nitric oxide synthase and NADPH-diaphorase 10.9. Trophic factors 10.9.1. Nerve growth factor 10.9.2. Ciliary neurotrophic factor 10.9.3. Brain-derived neurotrophic factor 11. Perirhinal cortex 1 1.1. Glutamate system 11.2. Cholinergic system 11.3. GABAergic system 11.4. Monoamines 11.4.1. Noradrenaline 11.4.2. Dopamine 11.4.3. Serotonin 11.5. Peptides 1 I S.1. Somatostatin 11.5.2. Neuropeptide Y 11.6. Calcium-binding proteins 11.6.1. Parvalbumin 11.7. Hormone receptor sites 11.8. Enzymes 11.8.1. Nitric oxide synthase and NADPH-diaphorase 11.9. Trophic factors 11.9.1. Nerve growth factor 12. Parahippocampal cortex 12.1. Glutamate system/cholinergic system/GABAergic system/monoamines 12.2. Peptides 12.2.1. Substance P 12.3. Calcium-binding proteins 12.4. Hormone receptor sites 12.5. Enzymes 12.5.1. Nitric oxide synthase and NADPH-diaphorase 12.6. Trophic factors 13. Concluding remarks 14. Abbreviations 15. References

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385 385 385 385 386 386 387 387 387 387 387 388 388 388 388 388 388 388 388 388 388 389 389 389 389 389 389 389 389 390 390 390 390 390 390 390 390 390 390 39 1 39 1 39 1 39 1 392 393

V.

THE PRIMATE MESOCORTICAL DOPAMINE SYSTEM P.S. GOLDMAN-RAKIC, C. BERGSON, L.S. KRIMER, M.S. LIDOW, S.M. WILLIAMS AND G.V. WILLIAMS 1. 2. 3. 4.

5.

6. 7. 8. 9.

10. 11.

Introduction Primate specialization in the brainstem origin and organization of the mesocortical dopamine system Qualitative organization of the dopamine innervation of cerebral cortex Quantitative analysis of dopamine contacts on pyramidal and nonpyramidal neurons Electronmicroscopic evidence of dopamine synaptic triads and D 1 receptor localization in spines Dopamine innervation of the microvasculature Dopamine D1 and D2 family of receptors in the cerebral cortex 7.1. Localization of the D1 family of DA receptors in prefrontal cortex 7.2. Localization of the D2 family of DA receptors in prefrontal cortex Role of dopamine receptors in cortical function Regulation of cortical dopamine receptors as targets of antipsychotic drugs 9.1. Effect of antipsychotic medications on the D2 receptors in the primate cerebral cortex Summary and future directions References

Subject Index

403 403 406 408 409 41 1 412 412 413 416 420 420 422 423 429

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CHAPTER I

The human basal forebrain. Part I. An overview N. SAKAMOTO, J. PEARSON, K. SHINODA, G.F. ALHEID, J.S. DE OLMOS AND L. H E I M E R

1. I N T R O D U C T I O N Most of the detailed anatomy of the basal forebrain has been established in rats over the period of the last two decades. This introduction is entirely based on sections of the human brain. (When needed for clarification of an anatomical detail or choice of terms, occasional reference to non-human primates will be made in this and the succeeding chapter). A rapidly increasing collection of papers on monkeys and humans is expanding our understanding of primate chemical neuroanatomy. Our description will focus on those cytoarchitectonic and neurochemical markers which are most relevant to understanding the organization of the human basal forebrain. In this chapter the surface topography of the basal forebrain will be discussed and its underlying structures will be introduced. We provide a mini-atlas of the human forebrain consisting of coronal Klfiver-Barrera (K1-B) stained serial sections with matching sections stained for enkephalin (ENK), substance P (SP) and acetylcholinesterase (ACHE) that will also serve as a base for the more detailed anatomical descriptions in the next chapter. Accordingly, the individual sections in the atlas are identified in both chapters with their atlas titles K1-B 1, K1-B 2..., E N K 1, E N K 2... etc., rather than figure numbers related to this chapter alone; abbreviations for both chapters are combined and included at the end of chapter II. The mini-atlas extends from the orbitofrontal cortex slightly behind the point where the olfactory stalk attaches to the orbital surface to a level through the posterior end of the amygdaloid body and the rostral subthalamic nucleus. The first 9 levels (K1-B 1-9) are chosen at roughly equal intervals; the distances between each of the last 3 coronal levels (K1-B 10-12) are approximately double those of the others. In order to facilitate discussion of the various functional-anatomical basal forebrain systems in the following chapter, we have applied color-highlighting for several forebrain areas (magenta for olfactory bulb projection areas, yellow for central division of extended amygdala and green for medial division of extended amygdala).

2. S U R F A C E T O P O G R A P H Y

Most of the systems of the basal forebrain reach the ventral surface of the brain and contribute to its topography. The surface anatomy can be partly delineated with reference to some olfactory structures within or in close relation to the anterior per-

Handbook of Chemical Neuroanatomy, Vol. 15." The Primate Nervous System, Part III F.E. Bloom, A. Bj6rklund and T. H6kfelt, editors 9 1999 Elsevier Science B.V. All rights reserved.

Ch. I

N. Sakamoto et al.

forated space (Figs. 1 and 2) and provides a valuable introduction to this complex region. 2.1. BASAL CORTEX Anteriorally, the surface of the basal forebrain is comprised of the orbitofrontal cortex (OF) laterally, and the gyrus rectus (GR) medially (Figs. 1D and K1-B 2). Immediately caudal to the anterior olfactory nucleus (AO) or retrobulbar area (K1-B 3) the orbitofrontal cortex tapers and is replaced by the frontal prepiriform cortex PirF (K1-B 4) and, deep to it, the ventral claustrum (VC1). More caudally still, the ventral limit of the basal forebrain is formed by the nucleus accumbens (Acb) and that part of the ventral striatum which receives olfactory input (K1-B 6 and 7). Together these comprise the anterior perforated substance. The subcallosal cortical area (SCA) diminishes posteriorally so that by the levels which include the rostral end of the anterior commissure (K1-B 6 and 7), the diagonal band (db) is fully exposed medially on the basal forebrain surface (Figs 1C and 2). 2.2. OLFACTORY PEDUNCLE AND OLFACTORY TRACT In most textbooks of anatomy an erroneous picture of the surface of this region depicts a common olfactory stalk or peduncle bifurcating into lateral and medial olfactory striae, or tracts, in front of the anterior perforated space. This space is flanked caudally by the diagonal band (db) which is located alongside the lateral margin of the optic tract (opt) as it proceeds in a caudolateral direction from the optic chiasm to the lateral geniculate nucleus (Figs 1C and 2). Although a medial olfactory tract or stria 1 has sometimes been indicated on the ventral surface of the primate brain (e.g. Fig. 24 in Economo and Koskinas 1925, Part I; Kuhlenbeck 1927; see Figs. 4-10 in Nauta and Haymaker 1969), a collection of medially directed bulbofugal fibers is not recognizable as an entity in the human brain, nor in any other mammalian brain (see also Price 1990). In other words, one of the building blocks in the notion of the 'limbic system', i.e. a medial olfactory tract which purportedly terminates in the septum (see Fig. 18-2 in MacLean 1989), does not exist. While a superficially located medial olfactory tract appears in most textbooks of neuroanatomy, its existence has been denied by most scholars for over a century (e.g. Retzius 1896; see also review by Stephan 1975). Apparently, what has often been identified as a medial olfactory tract in the human (see for instance Fig. 21 in Duvernoy 1991) is a gyrus which results from the medial deviation of the olfactory sulcus (olfs), which separates the neocortex of the gyrus rectus from medially located tissue in the posterior orbital region, including parts of the retrobulbar area (Figs 1C and 2). Both in the monkey and the human, the olfactory bulb projections were analyzed in experimental material many years ago by Meyer and Allison (1949) and Allison (1954). Their results are generally supported by those of later monkey experiments ~The term medial olfactory stria (although as mentioned above, the existence of such a structure can hardly be justified) should be distinguished from the medial olfactory radiation (molfr, see KI-B 3) which, according to Schaltenbrand and Bailey (1959) and Riley (1960), denotes a myelinated bundle which proceeds in a ventrolateral-dorsomedial direction deep to the retrobulbar area to join the radiation of the corpus callosum. The deep olfactory radiation (D6jerine 1895) or olfactory radiation (olfr in KI-B 2) is a time-honored term used for the collection of fibers which form a massive structure deep to the caudal part of the orbitofrontal cortex and the retrobulbar area; they are directly continuous with the external capsule laterally and the radiation of the corpus callosum medially. Although fibers related to the retrobulbar area are undoubtedly part of the deep olfactory radiation, other axon types are in all likelihood present in this multifarious bundle.

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using transported tracers (Turner et al. 1978; Price 1990; Carmichael et al. 1994). Projection fibers proceed in a caudal direction through the olfactory peduncle to the point of fusion between the peduncle and the orbital surface (Fig. 1). The bulbofugal fibers then continue in the form of a broad band, the olfactory tract (olf), in a caudolateral direction across the posterior orbital surface bending sharply medialward at the limen insulae 2 (see white arrowhead in Figs 1A and 2) to enter the dorsomedial surface of the parahippocampal gyrus. By removing the temporal pole, it is possible to identify the otherwise hidden sharp bend of the olfactory tract in the region of the limen insulae (Fig. 2). The olfactory tract is clearly visible in the monkey as it proceeds in a lateral direction in front of the anterior perforated space (Fig. 1A). In the human, however, the tract is barely visible as it proceeds more or less diagonally in a lateral and slightly posterior direction in front of the anterior perforated space (Figs 1C, D and 2). 2.3. OLFACTORY TUBERCLE AND ANTERIOR PERFORATED SPACE The term olfactory tubercle was introduced by Rudolf Albert von K611iker in 1896. Following a study by Elliot Smith in the early part of this century (1909), its olfactory nature was seldom questioned. The tubercle is readily identified in macrosmatic mammals, where it usually appears as a well-formed, oval, slightly elevated structure surrounded by a more or less pronounced groove. Experimental studies in macrosmatic laboratory animals such as the rat have confirmed that the entire tubercle receives olfactory bulb projection fibers (see review by Shipley et al. 1995). The problem of identifying an olfactory tubercle is difficult in the primate, but ~particularly so in the human, where a bulge is either absent (Fig. 1D) or only vaguely evident (Figs. 1C and 2), and where controlled studies of olfactory bulb projections are impossible. Some authors have considered all of the anterior perforated space in the human as homologous with the olfactory tubercle of macrosmatic mammals (e.g. Rose 1927a,b; Crosby and Humphrey 1941; Turner et al. 1978), while others have confined the use of the term olfactory tubercle in human to a slightly elevated part of the anterior perforated space behind the attachment of the olfactory stalk (Figs 1C and 2, see also Fig. 4-2 in Nauta and Haymaker 1969; Fig. 32 in Stephan 1975; Fig. 21 in Duvernoy 1991). More than 20 years ago (Heimer et al. 1977), we urged that the term 'olfactory tubercle' in the human should be restricted to that region of the anterior perforated space which is the most probable recipient of olfactory bulb input. Of necessity, this definition is somewhat nebulous since, without any means of experimental verification, it is difficult to determine which parts of the anterior perforated space are being infiltrated with olfactory bulb projection fibers in the human brain. Histochemical approaches may ultimately be more fruitful, and the methods of modern chemical neuroanatomy may eventually provide a satisfactory solution to this puzzle in the human. In the monkey, an elevated tubercle can usually be identified behind the attachment of the olfactory stalk to the posterior orbital area (Fig. 1A). It appears, however, that only part of this slightly convex gray mass receives olfactory bulb fibers (Turner et al. 1978; Carmichael et al. 1994). Carmichael and his collaborators have recently shown that olfactory bulb projections invade a large part of the anterior perforated space (i.e. 2Limen: from the Latin, meaning 'threshold.' Limen insulae is that part lying between the base of the brain (including the orbitofrontal cortex and anterior perforated space) and the insula.

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Fig. 1. Olfactory structures within or in close relation to the anterior perforated space. Whereas the monkey (A) has a clearly identifiable olfactory tubercle (Tu), it is more difficult to identify a tubercle in the human (B, C, and D). The region indicated by an asterisk in D is usually referred to as the olfactory trigone. Note the continuation between the olfactory peduncle (o. ped.) and the olfactory tract (olf) in the monkey (A). The olfactory tract continues in a caudolateral direction towards the limen insulae (white arrowhead) where it makes a sharp bend to enter the temporal lobe. The olfactory tract is more difficult to appreciate in the human (D). The large arrow in B points to the anterior choroidal artery and the small arrows to striate arteries. Further abbreviations: AO = anterior olfactory nucleus, Ant perf. = anterior perforated space, db = diagonal band, GR --- gyrus rectus, olfs = olfactory sulcus, opt = optic tract, ox = optic chiasm, U = uncus.

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Fig. 2. Higher magnification view of anterior perforated space. Although a vague bulge appears behind the anterior olfactory nucleus (AO), it is highly questionable if this should be considered to be homologous with the olfactory tubercle in macrosmatic mammals (see text). The surface topography only hints at the presence of an olfactory tract (between arrows) and its bend (white arrowhead) at the region of the limen insulae.

the part labeled TOL2 by Rose 1927a,b) in a strip-like fashion. If the presence of olfactory bulb projections is a criterion for designating part of the anterior perforated space as being homologous with the olfactory tubercle of nonprimates, the structure should presumably include these multiple bands (see Fig. 2 in Carmichael et al. 1994). As defined by direct input from the olfactory bulbs, only part of that region in which an elevation resembling a tubercle is found in monkeys (Fig. 1) and sporadically in the human (Fig. 2) appears to be truly olfactory in nature. Where no tubercle can be identified - which is most often the case in the human brain - there is no reason to imagine one. There is also nothing to be gained by dividing the anterior perforated space into striatal- and olfactory-related parts (Carmichael et al. 1994). With the advent of the concept of the ventral striatum, a distinction between 'olfactory' and 'striatal' in this part of the brain became moot, since, in macrosmatic mammals, all of the mediumcelled parts of the olfactory tubercle, including its dense cell layer, are now considered striatal in nature (Heimer and Wilson 1975; Heimer 1978; Millhouse and Heimer 1984) even though they are specialized to receive input from the olfactory bulb (e.g. White 1965; Heimer 1968; Price 1973). In fact, based on developmental, histological, connectional and histochemical characteristics, the olfactory tubercle of macrosmatic

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mammals is a specialized, albeit integral part of the basal ganglia. It contains both striatal and pallidal components. There are as many similarities between the olfactory tubercle and the rest of the striatopallidal complex in the rat as there are differences between the olfactory tubercle and the laterally adjoining primary olfactory cortex (see reviews by Heimer 1978; Heimer et al. 1995). In view of this fact, for non-primates the term olfactory striatum might be preferable to that of olfactory tubercle. While the anterior perforated space in the human is often equated with the laminated olfactory tubercle of nonprimates (e.g. Rose 1927b; Crosby and Humphrey 1941; Allison 1954; Turner et al. 1978) many early investigators emphasized the fact that striatum reaches the ventral surface in this region of the brain (e.g. Beccari 1911 ; Brockhaus 1942a,b; Macchi 1951). Economo and Koskinas (1925, p.32) presciently used the term 'colliculus nuclei caudati' (a term originated by D6jerine 1895) as a synonym for 'tuberculum olfactorium'. As discussed further in the following chapter their conclusion is in part confirmed in later studies by the use of 'striatal' markers such as acetylcholinesterase (e.g. Saper and Chelimsky 1984; Alheid and Heimer 1988; Alheid et al. 1990; Saper 1990) and choline acetyltransferase (e.g. Holt et al. 1996). The same is true for virtually every histochemical label that is found in high density in striatal areas compared to adjacent cortex (see folio.wing chapter). In microsmatic mammals, including the human, the ventral striatum reaches the surface of the brain as it does in macrosmatic species, but only part of this striatal extension is likely to be homologous to the olfactory tubercle or 'olfactory striatum' of the macrosmatics. As we shall discuss further in the next chapter, that part of the striatal complex which reaches the ventral surface of the human brain at the anterior perforated space has some locally unique characteristics. 2.4. OLFACTORY TRIGONE Another term of somewhat shaky legitimacy is that of the olfactory trigone, used mostly in the human to denote a 'triangular (surface) area between the diverging medial and lateral olfactory striae' (Lockhard 1991), or between the 'Gyrus olfactorius lateralis und medialis' (Stephan 1975), in front of the anterior perforated space. Because there is no medial olfactory stria (see above) and since the lateral olfactory stria is not always easy to recognize on the surface, the delineation of a human 'olfactory trigone' requires a creative imagination. The general location of the region to which the term is usually attached is indicated by an asterisk in Fig. 1D. Brockhaus (1942a), likewise, used the term tuber or trigonum olfactorium for the slightly elevated region in close relation to the olfactory tract as it makes its way laterally towards the limen insulae.

3. OVERVIEW OF BASAL FOREBRAIN S T R U C T U R E S

3.1. AREA DIAGONALIS (DIAGONAL BAND OF BROCA) AND BASAL NUCLEUS OF M E Y N E R T The diagonal band of Broca (db) superficially appears as a diagonally oriented tract between the medially located septal area and the amygdaloid body in the temporal lobe (Figs 1C and 2). Although some projections from the medial amygdala to the septum may be included in the region referred to as diagonal band of Broca (e.g. Caff6

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et al. 1987), septohypothalamic, corticopetal, corticostriatal and amygdalo-diencephalic projections are major fiber components in this region. Rose (1927b) and Stephan (1975) referred to this diagonally oriented region as 'area diagonalis', rather than diagonal band, in order to emphasize the fact that the underlying substance contains a mixture of neurons and a wide variety of fiber systems. Consistently identified among the diagonal band nuclei and within the basal nucleus of Meynert 3 are magnocellular hyperchromic neurons generally shown to be choline acetyltransferase positive (Mesulam et al. 1983). The nuclei of the diagonal band (VDB and HDB in K1-B 6 and 7) and the compact part of the basal nucleus of Meynert (B in K1-B 7-12) form an aggregate of neurons which traverses the basal forebrain obliquely between its rostromedial and caudolateral regions (see Fig. 5 in DeLacalle and Saper 1997). Anteriorally placed clusters of magnocellular basal nucleus neurons are also found, being especially frequent at the ventral aspect of the accumbens and among the fiber bundles of the external capsule below the ventral putamen at the level shown in K1-B 4. 3.2. OLFACTORY BULB PROJECTION AREAS The likely distribution of human olfactory bulb projection fibers (for references, see discussion in following chapter) is highlighted with magenta in the Kltiver-Barrera sections included in the mini-atlas at the end of this chapter. Rostroventrally (K1-B 2) the olfactory tract (olf) fibers terminate in the anterior olfactory nucleus (AO), which borders on the gyrus rectus (GR) medially (K1-B 1-3). Farther back, the broad band of olfactory tract fibers turns sharply in a lateral direction (Fig. 2 and K1-B 4), accompanied by the frontal part of the primary olfactory cortex (here labeled piriform cortex (Pir), to conform to common usage). Some fibers reach the ventral striatum at the levels shown in K1-B 6 and 7. At the limen insulae (Fig. 2), fibers deviate laterally from the main part of the olfactory tract to terminate in the ventral part of the agranular insula (K1-B 2-5); other bulbofugal projection fibers turn sharply in a medial direction onto the dorsal surface of the temporal lobe where they terminate in a rather extensive region within the parahippocampal gyrus both rostral (K1-B 1 and 2) and caudal (K1-B 4-9) to the place where the temporal lobe attaches to the rest of the brain. Included in the termination areas for olfactory bulb projection fibers in the temporal lobe are the temporal part of the primary olfactory cortex (PirT), temporopolar periallocortex (TPpall), amygdalopiriform transition areas (Apir), cortical amygdaloid nuclei (ACo and VCo) and the olfactory field (EO) of entorhinal cortex (ENT). The endopiriform nucleus (En) is often conceived of as the deep layer of the primary olfactory cortex (K1-B 5 and 6), but it is not the direct recipient of olfactory projections. The primary non-amygdaloid and amygdaloid olfactory bulb projection areas will be described more extensively in the following chapter. 3.3. THE CLAUSTRUM (C1) The claustrum (C1), which is represented by a sheet of gray matter located in large part between the extreme (ex) and the external (ec) capsules (K1-B 1), is included within all sections in the atlas. It is thin in its dorsal aspect underneath the dorsal part of the

3Meynert (1872) described this nucleus for the first time in the human brain as a cellular 'ganglion' in the substantia innominata. He included this 'ganglion' together with the nucleus of the diagonal band in the broader term 'ganglion ansae peduncularis'. The 'basal nucleus of Meynert' or 'Meynert's basal ganglion', has sometimes been referred to as the 'Nucleus substantiae innominatae' (e.g. Hassler 1938; Vogt and Vogt 1942).

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granular and dysgranular insula (Id in K1-B 3) but widens ventrally and is especially prominent in the temporal lobe (VC1 in K1-B 4-8). Only the olfactory tract and a thin layer of associated olfactory tissue (frontal piriform cortex, PirF) prevents the claustrum from reaching the basal brain surface posterolateral to the retrobulbar region (K1-B 4 and 5). The term ventral claustrum (VC1) was used by Macchi (1951) to denote this ventromedial continuation of the claustrum into the orbitofrontal region, as well as the rather massive component located in the temporal lobe (claustrum temporale of Brockhaus 1940). It should be appreciated that both in some earlier and some contemporary reports (e.g., see Morys et al. 1996), the term 'ventral claustrum' has been applied to the area designated as the 'endopiriform nucleus' (K1-B 5, 6). While the distinction between these two areas is discussed at greater length in the following chapter (see Section 4.1.2.), it is worth emphasizing here that these areas are distinct on cytoarchitectural grounds, as well as by dint of their presumed embryological origins (Bayer and Altman 1991) and phylogeny (see Striedter 1997 for a recent review). These two areas may also be discriminated on the basis of their connections (Sherk 1986; but see Witter et al. 1988). Interpretation of functional-anatomical reports relevant to them is likely to be confusing unless a distinction is made between ventral claustrum and the endopiriform nucleus. Widespread reciprocal connections, often topographically organized, with much of the cortex, make the claustrum an interesting area from the standpoint of sensory processing and sensorimotor integration. Some research supports the participation of claustrum in the discrimination of sensory features, as opposed to their mere detection (e.g. Horster et al. 1989; Vanduffel et al. 1997), while other reports note claustral involvement in a variety of behaviors, involving stress (Blake et al. 1987, Guidobono et al. 1991, Beck and Fibiger 1995a,b; Smith et al. 1995), or nociception (Persinger et al. 1997), and possibly the control of vocalization (Jtirgens et al. 1996). In these latter instances it is likely that the ventral portions of claustrum are more relevant. 3.4. DORSAL STRIATUM AND DORSAL PALLIDUM The dorsal striatopallidal system is discussed by Graybiel elsewhere in this volume (Graybiel 1999); here we only wish to remark on the general features of this territory insofar as they are relevant for comparison with their ventral counterparts. Since the initial development of the acetylcholinesterase method, the dense staining of the caudate nucleus, putamen and accumbens that comprise the striatum has been dramatically apparent (ACHE 2-12). Additionally, the continuity of the dorsal striatum with ventral striatum is readily seen (ACHE 3-4 and 5-6). This continuity is also evident in sections stained for enkephalin or substance P (ENK 1-5; SP 1-6). The entire dorsal pallidum is readily distinguished from the adjacent striatum because of the relative poverty of the cholinesterase reaction in the pallidal areas. The parcellation of the dorsal pallidum is clearly shown by the distribution of substance P and enkephalin. The external pallidal segment is distinguished laterally from striatum, and to a lesser extent medially from the internal pallidal segment by its extremely dense complement of enkephalinergic terminals (ENK 8-12). Conversely, the internal pallidal segment (and the pars reticulata of substantia nigra) is particularly dense in substance P terminal labeling compared to the striatum and external pallidal segment. This complementary staining pattern (Haber and Elde 1981; Haber and Watson 1985) is not absolute, but has been useful since it reflects the fact that, for the most part,

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afferents to these two pallidal segments originate from at least two different populations of striatal neurons containing either enkephalin or substance P. 3.5. VENTRAL STRIATUM AND VENTRAL PALLIDUM Fundamental to the understanding of the rostral basalis region is the concept that the accumbens (Acb), as the major component of ventral striatum, extends to the ventral surface of the brain behind the gyrus rectus and lateral to the subcallosal area (K1-B 4 and 5). The accumbens, which is located at the confluence between the caudate nucleus and the putamen underneath the anterior limb of the internal capsule (K1-B 1-5), has a lower density of myelinated fiber bundles and the medium-sized neurons are relatively more crowded, somewhat smaller, and more intensely Nissl-stained than is the case for the bulk of putamen and caudate nucleus. Accumbens, together with neighboring regions of caudate nucleus and putamen below the anterior limb of the internal capsule, forms part of the ventral striatum which corresponds approximately to the fundus striati of Brockhaus (1942a), who included the bed nucleus of stria terminalis (BNST) in this term. In current usage, however, the term fundus striati as applied in the primate does not include the bed nucleus of stria terminalis. As we shall discuss more fully in the next chapter, ventral pallidal tissue (VP in K1-B 6-8) accompanies the accumbens and the rest of ventral striatum to the basal forebrain surface (SP 6). The additional presence of fibers peeling off the anterior commissure and traversing the ventral striatum (K1-B 6), together with neurons associated with the basal nucleus of Meynert and islands of small cells, conspire to make this part of the basal forebrain a highly complex region. The continuity between dorsal pallidum and ventral pallidum is made evident by enkephalin and substance P immunoreactivity. Enkephalin terminals typical of pallidal areas extend as a dense wedge below the anterior commissure (Enk 5-8), but are also found anteroventrally as a lacework of terminations that invest coarse dendrites within the nucleus accumbens itself (see following chapter). Substance P terminals on ventral pallidal dendrites are found in great profusion ventromedially below the anterior commissure (SP 6). It should be appreciated that in the basal forebrain substance P and enkephalin immunoreactivity are not uniquely associated with ventral pallidum, but may also represent terminations on elements of the sublenticular extended amygdala that mainly traverse the area just caudal to ventral pallidum but which may also invade caudomedial accumbens. The ventral pallidum and extended amygdala are described in greater detail in the next chapter. 3.6. STRIATUM IN THE TEMPORAL LOBE Striatal tissue is prominent in the more posterior sections of the basal forebrain located medial and ventral to the temporal limb of the anterior commissure (K1-B 11 and 12). This part of striatum is directly continuous with the rest of putamen and is generally referred to as the ventral putamen (PuV; putamen limitans by Brockhaus 1942a). The tail of the caudate nucleus (which is not included within the levels depicted by the mini-atlas) is closely related to association areas in the frontal and temporal lobes (e.g. Selemon and Goldman-Rakic 1985) and appears slightly more posteriorally where, in some sections, it is directly continuous with the temporal part of the putamen via cell bridges interpolated between the sublenticular bundles of the internal capsule. It is important to note that the gross anatomic subdivision of the striatum

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into caudate nucleus and putamen is not a good indicator of the functional division between 'association neostriatum' and 'motor neostriatum' (Selemon and GoldmanRakic 1985). Ventral putamen, for example, is related to association areas in the temporal lobe (e.g. Kemp and Powell 1970; van Hoesen et al. 1981; Middleton and Strick 1996) rather than to the cortical motor areas. The amygdalostriatal transition area (Astr) is interposed between the ventral putamen and caudally located parts of the amygdaloid body (K1-B 11 and 12). Little is known about this region which, like the ventral putamen, contains significant amounts of enkephalin (ENK 11-12) and is clearly differentiated from the ventral putamen by its weak staining for both substance P (SP 11-12) and acetylcholinesterase (ACHE 11-12). Ventral putamen likewise can be distinguished from the dorsal main part of putamen by its considerably stronger SP-staining (SP 11-12), but its weaker AChE staining (ACHE 11 and 12) is comparable to the situation in the medial part of caudate. 3.7. EXTENDED AMYGDALA The extended amygdala (EA) is a major component of the basal forebrain region. The term 'extended amygdala' (Alheid and Heimer 1988) was introduced to denote a cellular continuum that had been earlier described as 'an extension of the amygdala into the forebrain' (de Olmos et al. 1985). This macrostructure includes, in addition to the centromedial amygdaloid complex and the bed nucleus of stria terminalis, columns or groups of cells that bridge the gap between these two structures, both within the subpallidal or sublenticular region (K1-B 8-10) and as neurons within and alongside the entire length of the stria terminalis (K1-B, 11 and 12). The parts of the extended amygdala which include the central amygdaloid nucleus (Ce in K1-B 11 and 12) and the lateral bed nucleus of stria terminalis (BSTL in K1-B 5-9) are referred to as the central subdivision (yellow color) whereas the parts related to the medial amygdaloid nucleus (Me in K1-B 11 and 12) and the medial bed nucleus of stria terminalis (BSTM in KI-B 7-10) are termed the medial subdivision (green color). That part of the 'extended amygdala' which is situated transversely in the basal forebrain parallels the orientation of the basal nucleus of Meynert and the diagonal band. The central nucleus of the amygdala forms a distinctive round profile in coronal sections posteriorally (K1-B 11 and 12) and extends obliquely anteromedially (SLEA in K1-B 10; SLEA in ENK 10-11) where it ultimately divides into finger-like processes (K1-B 9; SLEA in ENK 9 and 10) extending towards the lateral part of the bed nucleus of the stria terminalis (KI-B 8). The medial nuclei of the amygdala has its posterior part located between the central nucleus and the optic tract (K1-B 11 and 12). More anteriorally it extends ventral to the central nucleus (K1-B 10) and has sublenticular extension towards the medial division of the bed nucleus of the stria terminalis (green in K1-B 9). At this point it is useful to emphasize the fact that the term 'extended amygdala' does not encompass the cortical amygdaloid nuclei (e.g., ACo and VCo in K1-B 9-11), which are closely related to the olfactory system (coded with magenta color), and the

10

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large laterobasal 4 complex (La = lateral, BL = basolateral, and BM = basomedial nuclei in K1-B 7-12), which is often conceived of as a modified portion of cortex (Johnston 1923; Crosby and Humphrey 1941; Lauer 1945; Hall 1972a,b; Millhouse and de Olmos 1983; McDonald 1984; de Olmos et al. 1985; Carlsen and Heimer 1988; McDonald 1992; Alheid et al. 1995). These structures do, however, provide inputs to the extended amygdala and basal ganglia, as do other cortical areas. The extended amygdala will be discussed in detail in the next chapter. 3.8. AMYGDALOID BODY The amygdaloid body (K1-B 6-12) which lies within the temporal lobe is functionally intimately linked to the basal forebrain. Since the central and medial amygdaloid nuclei are parts of the extended amygdala, the term amygdaloid body can be used in a restricted sense to denote the cortical and laterobasal group of nuclei. This is consistent with the usage proposed by several of the pioneering neuroanatomists in the early part of this century (e.g., 'amygdaleum proprium' by Brockhaus 1938; see following chapter). Detailed cytoarchitectonics and histochemistry permit subdivision of the amygdaloid body into multiple subnuclei. In general, there is good agreement about the major subdivisions, but unanimity is lacking concerning the nomenclature of the smaller ones. Only major subdivisions are indicated in the mini-atlas. Finer distinctions will be tackled in the following chapter. 3.9. SMALL-CELLED ISLANDS Numerous compact, island-like clusters of small neurons are widely dispersed in the basal forebrain. They are often located where distinctive major nuclear structures abut one another, lying for example between the ventral claustrum and the nucleus accumbens, between the accumbens and the diagonal band, and where ventral pallidum is intimately related to the ventral striatum. These cell islands are also prominent features of the extended amygdala. As many as twenty-five of these islands may be present in coronal sections passing through the level of the anterior perforated substance. The nomenclature and nature of these islands will be discussed in the next chapter.

4. CORONAL SECTIONS THROUGH THE BASAL FOREBRAIN

The sections that constitute the atlas presented on pp 15-56, as well as the majority of those used for the following chapter, were prepared by Dr. Noboru Sakamoto. 4.1. MATERIALS AND METHODS Three adult human brains from patients without neurological disease, aged 15, 25 and 4It should be noted that an alternative summary term applied to the laterobasal complex is the 'basolateral complex'. In our earlier discussions of these areas, we have generally used the latter designation, but have decided to alter this practice here. As we discuss in the subsequent chapter, the earliest designations of this area recognized the lateral nucleus but included the basomedial nucleus within a 'basal nucleus' that also included the large-celled basolateral nucleus of our present usage. Combined, this made up the basal + lateral complex, or basolateral complex. Most authors now agree that the basomedial nucleus is a separate nucleus from the 'basal or basolateral' on histochemical, connectional, and functional grounds. It therefore seems preferable to modify the aggregate term to laterobasal. This avoids using a term that is too readily confused with a subdivision of the larger complex, or which connotes some unwarranted preeminence for the basolateral subdivision.

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60 years were obtained within 4 and 5 hours of death respectively. The sections in this atlas were prepared from the last-mentioned brain. The brains were immediately flushed via carotid and vertebral arteries with 0.5 1 of 0.9% sodium chloride at a pressure of 100 cm H20. Fixation was initiated by perfusion at the same pressure, with 0.5 1 of 4% paraformaldehyde in 0.1 M phosphate buffer at pH 7.4. After 30 min the hardened tissue was cut into 10-mm slabs, embedded in egg yolk, and immersed in formaldehyde for 15 days at 2 ~ After fixation, slabs were immersed in 30% sucrose and 0.2% sodium azide at 4 ~ until they sank, and then stored in this solution in the refrigerator. Sections of tissues frozen on dry ice were cut on a cryotome set at 50 lam and sections were immediately picked up onto glass slides from a solution of 0.8% gelatin and 0.2% sodium azide. These were stained with the Klfiver-Barrera method (Klfiver and Barrera 1953) or the acetylcholinesterase procedure. For immunohistochemistry, free-floating sections were stained using a modification of the Sternberger PAP method in which non-specific sites were first blocked with human serum, incubated with dilute antibodies (1:3000- 1:5000) for up to four days at 4 ~ and very thoroughly rinsed between subsequent steps with secondary and bridging antibodies. In each incubation solution except that used for the peroxidase reaction, 0.1% sodium azide was included to suppress endogenous peroxidase. The final color was rendered blue-black by addition of 1.2% nickel ammonium sulfate to the final incubation mixture of diaminobenzidine and hydrogen peroxide. As controls for staining, diluted antibodies were adsorbed against the appropriate peptides where possible, after which no staining occurred. Neither was any staining seen when non-immune sera were used. For the immunostaining displayed in both the mini-atlas and the following chapter, well-characterized antibodies were generously provided by their originators: Monoelonal: Antibody against substance P (Dr. A. C. Cuello). Polyelonal: antibodies against: leu-enkephalin, substance P, somatostatin and neurotensin (Dr. M. Tohyama); tyrosine hydroxylase (Dr. M. Goldstein); glutamic acid decarboxylase (Dr. W. Oertel); met-enkephalin (Dr. S. Inagaki); and secretoneurin (Dr. R. Fisher-Colbrie). In addition, antibodies to cholecystokinin-8 were purchased from Amersham, Cambridge Research Biochemicals, and Immunonuclear Corporation. The antibodies gave staining patterns which were consistent and distinctive for the substances against which they were directed. They Selectively identified many neuronal groups which were appropriately analogous to those seen in lower animals and indicated the presence of stained structures in high frequency in areas of the human brain which had been peviously biochemically shown to contain high concentrations of the appropriate antigenic substrate. Thus it appears highly probable that the immunocytochemical results indicate the appropriate anatomic localizations of these antigens. Previous studies have shown good stability of peptides and catecholamine synthesizing enzymes within the first 24 hours after death. All the tissues used were obtained with postmortem intervals of 5 hours or less, well within the periods reported for suitable postmortem preservation of neuropeptides and enzyme protein antigens.

5. ACKNOWLEDGEMENTS This work was supported by USPHS Grant NS-17743 (L.H. and G.F.A.), and by 12

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Consejo Nacional de Investigaciones Cientificas y Tdcnicas of Argentina (J.S.O.). The Judith R. Ossoff Memorial Laboratory at New York Medical Center was funded via the Dysautonomia Foundation. We would like to thank Dr. Reiji Kishida for valuable help. The authors would also like to thank Dr. Michael Forbes and Ms. Debra Swanson for their patient and superb production of digital images from our histology and Ms. Vickie Loeser for excellent secretarial assistance.

6. REFERENCES

The citations for this section are provided with the following companion chapter.

13

Mini-Atlas of Coronal Sections through the Basal Forebrain (pp. 15-56)

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CHAPTER II

The human basal forebrain. Part II L. HEIMER, J.S. DE OLMOS, G.F. ALHEID, J. PEARSON, N. SAKAMOTO, K. SHINODA, J. MARKSTEINER AND R.C. SWITZER III

1. INTRODUCTION The basal forebrain, long considered so forbiddingly indecipherable as to be inappropriately referred to as a 'substantia innominata', a sort of neurological equivalent of the geographer's 'terra incognita' is in fact a fascinating region in which the confluence and interaction of multiple well-recognized systems provide a rich field of exploration for physiologists, neuropsychiatrists, pharmacologists and anatomists. This anatomic review will demonstrate that basal forebrain contains not only the superficially obvious continuations of the olfactory system but also associated cortical and amygdaloid areas, as well as major extensions of the striatum and globus pallidus. To these are added the basal forebrain magnocellular complex (basal nucleus of Meynert and diagonal band nuclei), ventral claustrum and extensions of the centromedial amygdala that links it via subpallidal cell columns and cell groups along the arch of the stria terminalis (Fig. 1) to the bed nucleus of the stria terminalis. In short, all parts of the basal forebrain are now well recognized as intrinsic nuclei or extensions of adjacent tissues, most notably the basal ganglia (Fig. 2). The chemical and functional anatomy of this basal region is likely to provide important insights into the basic physiology of the entire forebrain. This morphological review, which presents evidence for the anatomical composition of the human basal forebrain as it is portrayed schematically in Figs. 1 and 2, is intended as a foundation for further anatomic refinement and as a tool for those investigating the normal and pathologic functions of a region which plays profound roles in behaviors ranging from basic drives and emotions to cognition and memory. After some introductory remarks, we will first describe the anatomy of the ventral striatopallidal system and the extended amygdala which have received relatively little attention in the human brain. This will be followed by a review of the olfactory system and we will conclude the chapter with a discussion of the superficial amygdala and laterobasal amygdaloid complex, which together constitute what some anatomists referred to as the 'amygdaleum proprium' in the past (e.g., Brockhaus 1958). The human basal forebrain has a long history of anatomical descriptions (e.g. Reil 1809; Meynert 1872; Calleja 1893; Cajal 1911; Beccari 1910, 1911; Johnston 1923; Kodama 1926; Hilpert 1928; Papez and Aronson 1934; Kappers et al. 1936; Brockhaus 1938; Crosby and Humphrey 1941 ; Brockhaus 1942a,b; Allison 1954; Macchi 1951; Sanides 1957a,b; Klingler and Gloor 1960). Many of its components, including the septum, diagonal band of Broca, basal nucleus of Meynert and amygdala, as well as structures included in the olfactory system, have been described and Handbook of Chemical Neuroanatomy, Vol. 15. The Primate Nervous System, Part III F.E. Bloom, A. Bj6rklund and T. H6kfelt, editors 9 1999 Elsevier Science B.V. All rights reserved.

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Fig. 1: The extended amygdala (in color) shown in isolation from the rest of the brain, with the extensions of the central (Ce) and medial (Me) amygdaloid nuclei alongside the stria terminalis (st) and through the sublenticular region to the bed nucleus of stria terminalis (BST). The central division of extended amygdala is color-coded in yellow and the medial division in green. The supracapsular part of the bed nucleus of stria terminalis (BSTS) is depicted as a continuum, although the neuronal cell bodies of especially the medial division (green) do not form a continuous column (see text). Associated dendrites and neuropil, however, are likely to form a continuous columnar structure within the stria terminalis. Note that the laterobasal complex of the amygdala (lateral, basolateral, basomedial and paralaminar amygdaloid nuclei) and cortical amygdaloid nuclei are not included as part of the extended amygdala. (Art by Medical and Scientific Illustration, Crozet, Virginia.)

r e v i e w e d in c o n s i d e r a b l e detail (e.g. A n d y a n d S t e p h a n 1968; N a u t a a n d H a y m a k e r 1969; S t e p h a n 1975; H e i m e r et al. 1977; H e d r e e n et al. 1984; M e s u l a m a n d G e u l a 1988; A l h e i d a n d H e i m e r 1988; T a k a g i 1989; P i o r o et al. 1990; Price 1990; A l h e i d et 58

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Fig. 2: Schematic drawings showing the human basal forebrain in a series of coronal sections starting rostrally at the level of accumbens (A) and ending at the level of the caudal amygdala (D). Striatum (caudate = Cd, putamen - Pu and ventral striatum - VS) is indicated in blue color, globus pallidus (GP) and ventral pallidum (VP) in pink, basal nucleus of Meynert (B) in brown, olfactory bulb projection areas in magenta, and extended amygdala in yellow and green colors. (Art by Medical and Scientific Illustration, Crozet, Virginia.)

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al. 1990; de Olmos 1990; Saper 1990; Aggleton 1992; Arendt et al. 1995; DeLacalle and Saper 1997; Gloor 1997). 1.1. 'BASALIS' REGION The basal forebrain consists largely of intermingling extensions of structures that are adjacent to it and, as a consequence, it displays no distinct boundaries where it merges with surrounding brain. A diverse and sometimes bewildering terminology has historically tended to impede descriptive analysis of the region. A richly varied region of the human basal forebrain, located lateral to the anterior hypothalamus, has often been designated as the substantia innominata 1 or simply 'basalis' (e.g. Schaltenbrand and Bailey 1959; Klingler and Gloor 1960); in many descriptions it has become more or less synonymous with the basal nucleus of Meynert (see below). The 'basalis' region extends laterally underneath the anterior commissure and the globus pallidus into the dorsal aspect of the amygdaloid body. The region was tentatively delineated by Schaltenbrand and Bailey (1959); [see white line in the two coronal sections through the level of the anterior and middle hypothalamus (Figs. 3A and B)]. In most other illustrations or atlases, however, it either is not labeled (e.g. Reichert 1859-1861) or is designated by the term 'substantia innominata,' usually without any attempt to indicate boundaries. The lack of clear-cut anatomical margins, together with the difficulties of identifying the various cell groups which create this mosaic has, until recently, conspired against a satisfactory characterization of this part of the human brain. 1.1.1. 'Basalkerncomplex' of Brockhaus In an important series of papers, Brockhaus (1938; 1940; 1942a,b) undertook a detailed analysis of the anatomy of the human basal forebrain and provided important material for stereotaxic atlases published by Schaltenbrand and his colleagues (Schaltenbrand and Bailey 1959; Schaltenbrand and Wahren 1977). Of special interest is Brockhaus' description of the 'Basalkerncomplex', in which he included not only the basal nucleus of Meynert and scattered neurons of similar character, but also nuclear groups related to the diagonal band of Broca and other adjacent neuronal cell groups. He referred to the latter collectively as the 'tubercul~ire Gruppe' because of their close topographic relation to the olfactory tubercle, which he considered to be largely equivalent to the anterior perforated space (see below; compare Fig. 3B with Fig. 4, which is adapted from Saper 1990). Brockhaus referred to large aggregations of hyperchromatic cells (as seen in Niss| stains) as the 'compact part of the basal nucleus of Meynert' and collectively designated nonaggregated hyperchromatic cells scattered in nearby groups of generally smaller cells (e.g. Haber 1987) as the 'diffuse part of the basal nucleus of Meynert'. Brockhaus, who published in the late 1930s and early 1940s, was primarily restricted to the study of cyto- and myeloarchitecture. With the development of modern tracer ~The term 'substantia innominata', never properly defined, has been used in so many different ways as to render it useless as an anatomical term (Anthoney 1994, p. 520; Alheid and Heimer 1988; Heimer et al. 1997b). Even its origin is obscure. Because Reichert (1859-1861) left this part of the basal forebrain unnamed in his atlas of the human brain it is most often referred to as the substantia innominata of Reichert (e.g. Papez and Aronson 1934; Roussy and Mosinger 1934; Crosby and Humphrey 1941; Klingler and Gloor 1960; Nauta and Haymaker 1969). The German anatomist Johann Christian Reil (1809) referred to the area as 'die ungenannte Marksubstanz' because its functional organization was at that time indecipherable (see Alheid and Heimer 1988). The term substantia innominata of Reil was used more than one hundred years ago by the illustrious neuroanatomist Theodore Meynert (1872), and is probably a more accurate reflection of the term's origin.

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Fig. 3: Coronal myelin-stained sections of the human brain at the levels of the subcommissural (A) and sublenticular (B) parts of the basal forebrain to indicate the location of the basalis region (B). Note that the label B in these figures is not synonymous with the basal nucleus of Meynert. Modified from Schaltenbrand and Bailey (1959).

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methods and various histochemical techniques, many of the components he described have now been identified as belonging to specific functional-anatomical systems. In short, the rostral part of the 'basalis' region (Fig. 3A), referred to as the subcommissural substantia innominata (Miodonski 1967), is largely comprised of ventral parts of the basal ganglia (ventral striatum and ventral pallidum) and the basal nucleus of Meynert (compare Fig. 2 with K1-B 7 in the mini-atlas at the end of the previous chapter). The idea that the striatum reaches the ventral surface of the primate brain in the region of the 'substantia perforata anterior' was developed by some anatomists in the early part of this century (e.g. Beccari 1910, 1911 ; Economo and Koskinas 1925). Much later it" became apparent that the pallidum is also part of this region, not only in macrosmatic mammals but also in primates, and that it, together with striatum, extends towards the ventral brain surface (Heimer and Wilson 1975; Heimer 1978; Switzer et al. 1982; Heimer et al. 1982; Haber and Nauta 1983). This situation has since been demonstrated in many species, including the human (Alheid and Heimer 1988; Haber and Watson 1985; Sakamoto et al. 1988; Alheid et al. 1990; Martin et al. 199 l a). The ventral striatopallidal system will be described in Section 2 of this chapter. At a more caudal sublenticular level (Fig. 2C and 3B) the basal nucleus of Meynert is readily identified as large neurons forming aggregates among the other cell columns and groups that, with their accompanying neuropil, form bridges in the basal forebrain between the medially located bed nucleus of the stria terminalis and the central and medial amygdaloid nuclei in the temporal lobe (compare Fig. 2C with K1-B 9 in the mini-atlas). These sublenticular neuronal ensembles, identified first in the rat (de O1mos 1969, 1972), and subsequently in the rabbit (Schwaber et al. 1982), are part of a large continuum which includes, in addition to the bed nucleus of stria terminalis and the centromedial amygdaloid complex, groups of perikarya accompanying the stria terminalis (Johnston 1923; Sanides 1957a,b; Klingler and Gloor 1960; de Olmos 1972; de Olmos and Ingram 1972; Strenge et al. 1977; de Olmos et al. 1985; Alheid et al. 1994; 1995). This continuum has been referred to as the extended amygdala (Alheid and Heimer 1988) and both its subpallidal (or sublenticular) part and its dorsal (supracapsular) part are clearly identifiable in the human (Johnston 1923; Strenge et al. 1978; Alheid and Heimer 1988; Lesur 1989; Alheid et al. 1990; de Olmos 1990; Martin et al. 1991b). The extended amygdala as a functionally relevant anatomical macrostructure that incorporates central and medial amygdaloid nuclei will be presented in Section 3. This leaves the superficial (cortical) amygdala and the deep (laterobasal) group of amygdaloid nuclei to be discussed in Section 5 following a review of the olfactory system (Section 4). As demonstrated in this chapter, and elsewhere (e.g. de Olmos et al. 1985; Alheid and Heimer 1988; Alheid et al. 1990; 1995; de Olmos 1990; Heimer et al. 1991; 1997a, b) the distinction of the centromedial amygdala from the amygdaloid body is justified both by historic precedent (e.g. see discussion in Koikegami, 1963) and by contemporary anatomical studies (see Section 3). Analysis of the 'basalis' region was delayed by persistent attempts to deal with the area as a single unit. Although it is now clear that multiple systems intermingle in the region, it has taken almost two centuries to achieve a reasonable comprehension of its various components. In the meantime the term 'substantia innominata' seems to have taken on a life of its own (e.g. de Olmos et al. 1985; Alheid and Heimer 1988; de Olmos 1990; Anthoney 1994; Heimer et al. 1997b), and is still advocated in some quarters, as a term for the entire 'basalis' region in brain atlases of both primates (e.g. Martin and Bowden 1996) and non-primates (Swanson 1992; Kruger et al. 1995). Nonetheless, since it is now generally accepted that the striatum and the pallidum 62

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Fig. 4: Schematic drawing of a coronal section through the sublenticular region showing acetylcholinesterase-stained neurons, w h i c h - in large part at this level signify cholinergic neurons. (Courtesy of Dr. C.B. Saper. Modified from Saper, 1990. Cholinergic System, In: G. Paxinos (ed.): The Human Nervous System, Academic Press.)

of the basal ganglia reach the ventral surface of the brain in this region in the human and many other species, and because we believe that 'chemical neuroanatomy' corroborates anatomical evidence for the extended amygdala in the human as well as the rat (e.g. Alheid et al. 1995), it seems high time to relegate the term substantia innominata to the graveyard of anatomic anachronisms. In effect this has been done in a recent atlas of the human brain by Mai et al. (1997). 1.1.2. Basal nucleus of Meynert

The basal nucleus of Meynert is an extensively studied, but volumetrically relatively minor, component of the 'basalis' region. It consists of a widely dispersed, more or less continuous collection of aggregated and nonaggregated, predominantly large, hyperchromatic projection neurons, and stretches obliquely from the septum-diagonal band area in the rostral part of the basal forebrain to the level of the caudal part of the amygdaloid body. The collection of cells belonging to the basal nucleus of Meynert and the diagonal band has also been referred to as the 'basal forebrain magnocellular complex' (e.g. Divac 1975; Koliatsos et al. 1990) or the 'magnocellular basal complex' (e.g. Saper 1990). The extent of this complex is best appreciated in three-dimensional reconstructions (e.g. Halliday et al. 1993) in horizontal sections (e.g. Fig. 4 in Jones et al. 1976; Fig. 1 in Tagliavini 1987; Fig. 19.32 in Alheid et al. 1990). The basal nucleus of Meynert projects to the cerebral cortex (Shute and Lewis 1967; Divac 1975; Kievit and Kuypers 1975) and the large majority of its corticopetal neurons are cholinergic (Shute and Lewis 1967; Mesulam and van Hoesen 1976; Mesulam et al. 1983). It also projects to other regions that include the basal ganglia, amygdaloid body and thalamus (see reviews by Koliatsos et al. 1990; Mesulam 1995). The basal nucleus of Meynert, including its non-cholinergic components and other issues, was reviewed 63

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by DeLacalle and Saper (1997) in Part 1 of this series on the Primate Nervous System. DeLacalle and Saper also discussed problems related to nomenclature (see also Butcher and Semba 1989). While its comprehensive functional significance is not yet known (Reiner and Fibiger 1995), the basal nucleus is generally considered to be important for cortical arousal and related processes of learning and memory (e.g. Bartus et al. 1982; Butcher and Woolf 1986; Steriade and Buzsaki 1990; Mesulam 1995). Recent work has specifically emphasized its importance in attentional mechanisms (e.g. Robbins et al. 1989; Dunnett et al. 1991; Muir et al. 1994). The basal nucleus of Meynert apparently reaches its highest degree of development in the human (e.g. Kryspin-Exner 1922; Brockhaus 1942a). The report of cortical cholinergic deficit in Alzheimer patients (Davies and Maloney 1976) and the implication of the basal nucleus of Meynert as the major source of cholinergic afferents to cortex (e.g. Whitehouse et al. 1981; Etienne et al. 1986; Jacobs and Butcher 1986; Bigl et al. 1990; Giacobini 1990; Saper 1990) provided an added incentive for the current interest in the basal forebrain. The concentration of research on the basal nucleus of Meynert has led to relative neglect of other important cell groups in the 'basalis' region.

2. VENTRAL STRIATOPALLIDAL SYSTEM The rostral subcommissural part of the basalis region (Fig. 3A) is made up of ventral parts of the basal ganglia, i.e. the ventral striatum and ventral pallidum, which reach the undersurface of the human brain in the region of the anterior perforated space (Fig. 2B). The terms ventral striatum and ventral pallidum were first used in the rat (Heimer and Wilson 1975) when it became apparent that allocortex (olfactory cortex and hippocampus formation) have cortico-subcortical connections similar to the rest of the cortical mantle. Prior to that time, the prevailing notion was that allocortex and neocortex were characterized by differences rather than similarities in their subcortical connections. We showed that cytoarchitectural, connectional and histochemical data indicate that allocortex, like neocortex, is closely linked to basal ganglia structures via cortico-striatopallido-thalamic circuits 2. The corticosubcortical re-entrant circuits involving the ventral striatopallidal system relay allocortical, periallocortical and proisocortical afferents primarily via the mediodorsal thalamus to the prefrontal cortex. These circuits are analogous to those by which the dorsal parts of the basal ganglia relay neocortical afferents via the ventral-lateral thalamic complex to the premotor cortex. Re-entrant circuits involving the ventral parts of the basal ganglia have especially attracted attention because of their potential involvement in emotional and motivational behavior. The delineation of the

2The concept that different parts of the cortical mantle, in this case allocortex and neocortex, are subserved by separate cortico-striatopallidothalamic reentrant circuits (Heimer and Wilson 1975; Heimer 1978), was further pursued by DeLong and his colleagues (DeLong and Georgopoulos 1981; DeLong et al. 1983; Alexander et al. 1986; 1990) who identified several functionally distinct and segregated (parallel) corticostriatopallido-thalamocortical circuits. The notion that various cortical regions are subserved by functionally segregated cortico-subcortical reentrant loops which eventually terminate in different parts of the frontal lobe has received considerable attention among basic and clinical neuroscientists who have capitalized on the discoveries related especially to the circuits through the ventral parts of the basal ganglia to explain various symptoms of neuropsychiatric disorders (e.g. Modell et al. 1989; Swerdlow and Koob 1987; Cummings 1993; Deutch et al. 1993; Groenewegen and Berendse 1994; Mega and Cummings 1994; Salloway and Cummings 1994; Haber et al. 1995; Groenewegen 1996; Price et al. 1996; Middleton and Strick 1996). It is worth emphasizing that the nature of these corticosubcortical reentrant circuits, i.e. the extent to which they are 'closed' (parallel and independent of each other) or 'open' (interrelated with each other), is still being debated (Selemon and Goldman-Rakic 1990, 1991; Chevalier and Deniau 1990; Alexander and Crutcher 1991 ; Zahm and Brog 1992; Joel and Weiner 1994; Groenewegen 1996; see also review by Heimer et al. 1995).

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ventral striatum and ventral pallidum in the human and other primates is therefore particularly relevant to those interestea in the functional imaging or neuropathology of individuals with neuropsychiatric disorders. Studies in the rat (McGeorge and Faull 1989) demonstrate that striatal projection areas for allocortex and mesocortex (periallocortex and proisocortex) overlap significantly with striatal areas receiving input from neocortex. Primates also lack a distinct border between the ventral and dorsal parts of the basal ganglia (e.g. Kunishi6 and Haber 1994; Haber et al. 1995; Eblen and Graybiel 1995). Therefore, it is unlikely that sharp functional distinctions can be made on the basis of a strict dorsal-ventral topography in the striatal complex (e.g. Gerfen 1992). In the following discussions of ventral striatopallidal system and of the extended amygdala (Section 3) we will refer frequently to the mini-atlas presented in the previous chapter which features Kltiver-Barrera, enkephalin, substance P and acetylcholinesterase-stained coronal sections through the basal forebrain. 2.1. VENTRAL STRIATUM The ventral striatum in the rat includes the accumbens, ventromedial caudate-putamen and extensive (medium-celled) parts of the olfactory tubercle (see review by Heimer et al. 1995); all these structures project to the ventral pallidum, which, with the ventral striatum extends in a rostroventral direction into the deep part of the olfactory tubercle. During the last twenty years numerous studies have confirmed and extended the original description of the ventral striatopallidal system (reviewed by Alheid and Heimer 1988; Alheid et al. 1990; Heimer et al. 1995). The nature of the accumbens, which is the most prominent part of the ventral striatum, has been the focus of considerable interest in recent years (see review by Heimer et al. 1997a). The accumbens and neighboring parts of the ventral striatal complex have distinctive features which set them apart from the dorsal parts of the striatum. In general, the ventral striatum tends to have somewhat smaller and more tightly packed cells (Brockhaus 1942a; Namba 1957) and to have considerably more specialized cell islands (Sanides 1957a; Meyer et al. 1989; Alheid et al. 1990; HartzSchfitt and Mai 1991) than the dorsal striatum. Furthermore, compared to dorsal striatal structures, the accumbens is more often invaded by pallidal elements especially in the primate (Haber and Elde 1982; Haber and Nauta 1983). As emphasized below, this intermingling of striatal and pallidal elements is particularly pronounced in the human nucleus accumbens. The characteristic striosome-matrix organization that is found in the dorsal caudateputamen (Graybiel and Ragsdale 1983; Herkenham et al. 1984) is not readily applied to the ventral striatum where the relationship between the different neurochemical markers is considerably more complex (Groenewegen et al. 1989; Voorn et al. 1989; Zahm and Brog 1992; Meredith et al. 1993; Pennartz et al. 1994; Heimer et al. 1997a). The specialized and histochemically highly diverse nature of the ventral striatum is well established in the primate (e.g. Haber and Elde 1982; Alheid and Heimer 1988; Alheid et al. 1990; Martin et al. 1991a; Ikemoto et al. 1995) including the human (e.g. Nastuk and Graybiel 1988; Zezula et al. 1988; Berendse and Richfield 1993; Kowall et al. 1993; Hurd and Herkenham 1995; Voorn et al. 1995; Holt et al. 1996). The accumbens in .the monkey merges imperceptibly with the rostroventral parts of the caudate nucleus and putamen which may also be considered as components of the ventral striatum (Fig. 5A; see also Haber et al. 1990). 65

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Fig. 5: A. Schematic representation of the 'functional' map of the striatum based on cortical input. Levels of overlap are indicated by intermediate shades of gray. Light gray: input from allo-, periallo-, proiso- and some isocortical orbitofrontal and temporal regions. (All of these areas are sometimes referred to as 'limbicrelated cortex'). Medium gray: input from a wide range of association cortices. Dark gray: input from sensorimotor cortex and supplementary motor areas. B. Composite drawing of the midbrain projection to the striatum in two rostrocaudal views. The dorsal tier of dopaminergic neurons projects to the ventral striatum, whereas the densocellular part of the ventral tier projects throughout the striatum. (A and B, courtesy of Dr. Suzanne Haber. From Heimer et al. 1997. The Accumbens; Beyond the Core-Shell Dichotomy. J. Neuropsychiat., 9(3), pp. 354-381, 1997; with permission from American Psychiatric Press).

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In earlier discussions (de Olmos et al. 1985, p. 226; Heimer et al. 1985, p. 62; Alheid and Heimer 1988) we have revisited one of J.B. Johnston's (1923) original ideas, suggesting that the nucleus accumbens is the rostral end of the extended amygdala. Based on histochemical and hodological evidence we have adopted this proposition in a modified form, i.e., that elements of amygdala are intermingled with striatal components in the caudomedial part of the accumbens, which merges imperceptibly with the bed nucleus of stria terminalis (see also section 3.5.). The accumbens is certainly a ventral extension of the striatal complex, but is not so homogenous as its dorsal consort. The ventral striatum receives its dopaminergic innervation from the dorsal tier of mesencephalic dopamine neurons (Fig. 5B), i.e. dopamine cells of the dorsal part of substantia nigra, pars compacta, and the contiguous ventral tegmental area (Haber et al. 1995). This distribution in the monkey corresponds in general to the ventral striatum in the human, as defined by Voorn et al. (1996) on the basis of the distribution of la opioid receptor binding. Thus delineated, the ventral striatum in the human is represented predominantly by the accumbens plus the ventral part of the putamen and a ventral 'transition zone' of the head of the caudate where it borders on the accumbens. The ventral part of the striatal complex, in large part, corresponds to the fundus striati 3 of Brockhaus (1942a) who drew attention to its many specialized cytoarchitectonic features and, on this basis, divided it into several subterritories (Fig. 6). With regard to our proposition of a gradual transition between the caudomedial part of the accumbens and the extended amygdala, it is interesting to note that Brockhaus included the bed nucleus of stria terminalis in his definition of fundus striati. This topic, which is currently the focus of much attention, will be discussed further in Sections 2.1.3. and 3.5. 2.1.1. The heterogeneity of ventral striatum

Ventral striatum, including accumbens, continues to be a focal point for those interested in drug abuse and neuropsychiatric disorders, particularly schizophrenia. Consequently, reports describing the distribution of various neurochemical markers and receptors in the human accumbens or ventral striatum are appearing at an increasing rate. The ventral striatum appears at a rostral level shown in K1-B 1 (see atlas in previous chapter), where the head of the caudate first establishes direct continuity with the putamen. Despite a considerable intermingling with pallidal components, which becomes more pronounced posteriorly (see below), the ventral striatum can be identified as a more or less continuous area as far caudally as the level displayed in K1-B 7 and S P 7 (see atlas in previous chapter; see also Fig. 17 in this chapter). The cytoarchitecture of ventral striatum is more heterogeneous than that of the rest of the caudate nucleus or putamen. Many ventral striatal neurons are somewhat smaller (12-14 gm) and more intensively Nissl-stained than their dorsal counterparts (15-18 lam) and, as in the rat (e.g. Herkenham et al. 1984), have a greater tendency to

3Brockhaus (1942a) introduced the term 'fundus striati' (as an abbreviation of 'nucleus fundamentalis striati') for the nucleus accumbens and neighboring part of ventral putamen. It should be noted, however, that Brockhaus also included what we refer to as bed nucleus of stria terminalis in his definition of fundus striati (Fig. 59). He did not, however, include the clusters of granular cells and other parvicellular islands which, together with intermingling larger neurons, form a more or less continuous arch underneath Brockhaus' fundus striati, i.e. from the medial part of accumbens (including the large medial island of Calleja) through its ventral part to the border between ventral parts of putamen and claustrum, where many of the islands are closely related to the external capsule fibers. This 'archipelago' of cell islands (Sanides 1957b), which we include in ventral striatum, was referred to as 'Insulae olfactoriae striatales' by Brockhaus, who thought they were directly related to the olfactory system.

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Fig. 6: A. Human coronal brain section showing the distribution of prominent glutamate decarboxylate (GAD)-immunoreactivity in the accumbens (Acb) and neighboring parts of the basal ganglia. The hyphenated line indicates the approximate boundary between the ventral and dorsal striatum as discussed in the text. Note that bed nucleus of stria terminalis (BST) is not included in our definition of ventral striatum. B. Diagram of 'fundus striati' by Brockhaus (1942a); the bed nucleus of stria terminalis was included in his concept of 'fundus striati'.

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display irregular clumping (Brockhaus 1942a; Namba 1957). The cytoarchitectonic heterogeneity of the dorsal striatum is of lesser magnitude (e.g. Goldman-Rakic 1982). The heterogeneity of the ventral striatum is apparent in the pattern of its cholinergic innervation (Holt et al. 1996) and in the distribution of 3,-aminobutyric acid (GABA; as demonstrated by the aid of immunohistochemistry for glutamic acid decarboxylase, GAD) and for the neuropeptides met-enkephalin (ENK) and substance P (SP). In dorsal districts of the striatum, the two neuropeptides tend to follow the striosomematrix pattern in which the striosomes are often surrounded by a densely stained annular compartment which forms so-called ringed striosomes. This feature is especially prominent in the enkephalin-stained sections included in the mini-atlas (ENK 1-9; see also Graybiel and Ragsdale 1983; Beach and McGeer 1984; Faull et al. 1989; Holt et al. 1996). In the ventral striatum, by contrast, enkephalin, substance P, and GAD exhibit a more intense level of immunoreactivity in a blotchy and heterogeneous pattern (see ENK 1-4, SP 1-4 and Fig. 6A; Graybiel and Ragsdale 1983; Manley et al. 1994; Ito et al. 1992; Ferrante et al. 1986; Pioro et al. 1990; Bouras et al. 1984). While areas of weak tyrosine-hydroxylase (TH) immunoreactivity are embedded in a more densely stained matrix throughout the striatal complex, there is in general an accentuation of immunoreactivity in the ventral striatum including a large ventromedial territory of the caudate nucleus (Fig. 7; see also Ferrante and Kowall 1987; Pearson et al. 1990; Holt et al. 1996). Ventral striatum has higher prodynorphin messenger RNA levels and in general lower g opiate receptor binding than the rest of striatum (Hurd and Herkenham 1995). Voorn et al., however, (1996) found that the most medial and ventral parts of the caudal ventral striatum are exceptionally characterized by areas of very dense opioid receptor binding (Section 2.1.3). Multiple studies, including those describing the distribution of benzodiazepine receptors (Faull and Villiger 1988; Zezula et al. 1988), adenosine receptors (Martinez-Mir et al. 1991), M1 and M2 muscarinic binding sites (Nastuk and Graybiel 1988), and D1 and D3 dopamine receptors (Besson et al. 1988; Murray et al. 1994; Joyce and Meador-Woodruff 1997; Gurevich et al. 1997) emphasize the significant neurochemical differences between the ventral region and the rest of striatum. Dopamine D3 receptors, for instance, which have been proposed as an important target for antipsychotics (Sokoloff et al. 1992; Joyce and Meador-Woodruff 1997), are especially prominent in the ventral striatum (e.g. Landwehrmeyer et al. 1993; Murray et al. 1994; Diaz et al. 1995), where they show a heterogeneous pattern. Contributing to the complexity of the human ventral striatum are clusters of granular neurons and other parvicellular neuronal islands located primarily, but not exclusively, at the borders of ventral striatum with other basal forebrain structures or systems (see Interface Islands, below). Such 'interface' islands, which are concentrated primarily in the ventral parts of accumbens and putamen (K1-B 4 and 5 and Fig. 8), correspond in part to the 'neurochemically unique domains' of Voorn et al. (1996). Interface islands also appear somewhat more dorsally in the ventral striatum, especially at its interface with the main part of ventral pallidum (see below). Another distinct feature, especially in the caudomedial part of ventral striatum, is the occurrence of large (30-50 gm) neurons which are often located in the neighborhood of the above-mentioned parvicellular islands (Fig. 8D). Although some of the large cells shown in Fig. 8D do resemble the plump basal nucleus of Meynert cells in Fig. 8E, other triangular or fusiform, less densely stained cells could conceivably represent pallidal neurons. The heterogenous morphology produced by the clumping of striatal cells and the intermingling of medium-sized striatal neurons with large 69

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Fig. 7: Tyrosine hydroxylase (TH)-immunoreactivityin the human striatum is patchy with a general accentuation of reaction in the ventral striatum including a large ventromedial territory of the caudate nucleus (Reprinted from Pearson et al. 1990. Catecholaminergic Neurons. In." G. Paxinos (ed.), The Human Nervous System. With permission from Academic Press).

neurons and interface islands is clearly evident in Nissl or Klfiver-Barrera preparations (Fig. 8A and B). Quite characteristic, furthermore, are prominent groups of large, hyperchromatic basal nucleus of Meynert-type neurons, which tend to invade the ventral striatum where it borders on the external capsule (Fig. 8E) or the core of the ventral pallidum (see Section 2.2). It is worth re-emphasizing that the complexity observed in the ventral striatum reflects not only clustering of striatal-like and small neurons, but also intermingling of pallidal components with the small neurons and medium-sized striatal neurons. Haber and her colleagues (e.g. Haber and Elde 1981, 1982; Haber and Nauta 1983; Haber and Watson 1985; Haber et al. 1990) and others (e.g. Beach and McGeer 1984) emphasized this subject many years ago, when they described how pallidal dendrites, 70

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ensheathed in a network of thin ENK- or SP-positive fibers and boutons formed socalled 'woolly fibers' (Haber and Nauta 1983). Alternatively these have been depicted as 'pipe-shaped' structures by Bouras et al. (1984) or as 'ribbon-like' processes by Haber and Elde (1982) and Candy et al. (1985). In the monkey, they have a tendency to invade nearby structures, including ventral striatum. This tendency is pronounced in the human where groups of pallidal neurons give rise to prominent dendrites that are ensheathed by beaded enkephalin- (Figs. 9B and C) and substance P- (Fig. 10) immunoreactive fibers, referred to as peptidergic 'tubular profiles' by Mai et al. (1986). They are disposed in the ventral striatum both at the approximate level shown in Fig. 8A (e.g. Figs. 9B and 10) as well as in the subcommissural region rostral to the main part of ventral pallidum (Fig. 9C; see also Section 2.2). Much of the caudal part of ventral striatum is thus a patchy, indistinctly delineated, admixture of striatum and pallidum. Nevertheless, striatal cells by far outnumber collections of pallidal neuronal components at least as far caudally as the level represented in K1-B 6. The pallidal components, as indicated earlier, often appear closely related to the interface islands (Fig. 11C), which are widely dispersed in the ventral striatum. The presence of pallidal neurons in this region (Fig. l lB) is revealed by collections of a large number of peptidergic tubular profiles (Fig. 11C). Although it is certain that many of the peptidergic tubular profiles in this part of the CNS represent pallidal dendrites covered with striatofugal immunoreactive terminals (Fig. 12)4, it is important to recognize that the rostral portion of extended amygdala is an alternative source of dendrites with dense peptidergic innervation, especially within the caudomedial accumbens (e.g. Fig. 25H, inset). These profiles are not identical, however, and the differentiation between pallidal and extended amygdaloid tubular profiles are likely to be more problematic in regard to enkephalinergic, rather than substance P-positive profiles, since the former are abundant in both areas. The nature and nomenclature of the human ventral striatum. The extension of ventral striatum to the basal surface of the human brain in the region of the anterior perforated space (K1-B 5-7; ENK 4, 5-6 and SP 4 and 5; see atlas in previous chapter) was appreciated by classical neuroanatomists and is amply confirmed by 'striatal' markers such as acetylcholinesterase (e.g. Saper and Chelimsky 1984; Alheid and Heimer 1988; Alheid et al. 1990; Saper 1990; see also AChE 3), choline-acetyltransferase (e.g. Holt et al. 1996 1997) and tyrosine hydroxylase (Fig. 13A). Staining for glutamic acid decarboxylase (GAD; Fig. 13B) helps to identify both striatal and pallidal elements at the ventral surface on the medial side of the olfactory allocortex (PirF in Fig. 13B). Martinez-Mir et al. (1991) reported that the staining for adenosine 2 receptors, which is only found in striatum and external segment of globus pallidus, extends to the

4That the immunoreactive tubular profiles shown in Figs. 9 and l0 represent dendrites covered with peptidergic terminal fibers was suggested by Haber and Elde (1982) and Switzer et al. (1982), and the same conclusion was reached by Gaspar et al. (1987) in regard to the somatostatinergic innervation of dendrites in the bed nucleus of stria terminalis. This proposition has been firmly established. Especially revealing light-microscopic pictures of peridendritic patterns of immunoreactivity have been presented by Beach and McGeer (1984, Fig. 11) and by Haber et al. (1990, Figs. 1, 3, 4) in the primate. An electron microscopic picture of a ventral pallidal dendrite from the rat covered with GAD-positive boutons is shown in Fig. 12 (see also Fox et al. 1974, p. 15, and Heimer and Wilson 1975, Fig. 10). In this instance, one might refer to a GABAergic tubular profile, although in most cases GABAergic terminals in basal forebrain will also demonstrate neuropeptide immunoreactivity. As indicated by Martin et al. (1991b; see also Candy et al. 1985 and Gaspar et al. 1987), it is important to realize that the occurrence of peptidergic tubular profiles is not limited to striatopallidal connections. When comparing the 'tubular' profiles in globus pallidus with those in the ventral pallidum at this level, there is a difference in appearance. The dendritic plexi in globus pallidus (Fig. 9A) form continuous sheaths of terminals around the unlabeled dendrite (compare Fig. 12), which gives the dendrites a pipe-like appearance. The dendritic plexi in the ventral pallidum have a more granular appearance (Figs. 9B and C, and 10), presumably because of a lesser packing density of the immunoreactive terminals. A similar observation was made by Lesur et al. (1989) in regard to somatostatinergic terminal plexi in the bed nucleus of stria terminals (see Section 4.1.1.).

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Fig. 8: A, B

ventral surface of the human brain to include what they refer to as the olfactory tubercle. In a recent cytoarchitectonic study of the human accumbens, Lauer and Heinsen 72

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Fig. 8: Microphotographs of neurons in ventral striatum from one of the Kliiver-Barrera sections (K1-B 4) in the mini-atlas at the end of the previous chapter. A and B demonstrate the location of the various types of neurons shown in C, D and E. Two of the rectangles in A indicate the position of interface islands illustrated in Figs. 15 and 16. Although Kliiver-Barrera sections are not optimally suited for cytoarchitectural studies, they do provide a clear picture of the various cell types which intermingle with striatal neurons ((7) in the accumbens. Cells belonging to granular (gran) and parvicellular (parv) interface islands are shown in D and E. A group of large neurons are shown in the upper right corner in D. Note that some of the cells to the left in this group (arrows) are superimposed upon other neurons making it difficult to appreciate their size and configuration. A group of plump, densely stained basal nucleus of Meynert cells are illustrated in E.

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Fig. 9: Enkephalinergic tubular profiles in the external globus pallidus (A), and in ventral pallidal 'pockets' within accumbens (B and C). The areas for the tubular profiles in B and C are indicated in ENK 4 and ENK 5-6 in the mini-atlas in the previous chapter.

(1996) address the subject of the h u m a n ventral striatum but limit it to the nucleus accumbens. A more realistic definition of ventral striatum based on its connectivity within corticosubcortical re-entrant circuits suggests that ventrally located parts of the putamen and caudate should be included. The subpial region of this part of the h u m a n basal forebrain, i.e., the anterior 74

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Fig. 10: Substance P tubular profiles in the accumbens at the level shown in SP 5 in the mini-atlas.

perforated space, has been unjustifiably designated as the homologue of the nonprimate 'olfactory tubercle'. That this area should be regarded as a specialized component of the striatum rather than a dedicated olfactory structure, will be discussed in Section 4. It should be appreciated, however, that extensive further study will be needed to finally characterize the hodology and physiology of this complex zone. Lauer and Heinsen (1996) define the human olfactory tubercle as a series of superficial cell islands (their 'insulae terminales olfactoriae laterales') located in close rela75

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Fig. 11. A. Coronal section through the caudal part of the accumbens, which forms part of the ventral brain

surface, between the frontal piriform cortex (PirF) to the left and the subcallosal area to the right (see KI-B 5 in the mini-atlas). The area outlined by the rectangle is shown in higher magnification in B. The presence of pallidal neurons is revealed by the dense accumulation of substance-P tubular profiles demonstrated in a neighboring section (see arrows in C). Granular and parvicellular interface islands are as frequent at this level (see insets) as they are in the more rostral section illustrated in Fig. 8. Asterisk in B and C demonstrates corresponding regions.

tion to the olfactory tract as it proceeds in a lateral direction on the anterolateral aspect of the anterior perforated space. By comparing their pictures (Figs. 12-17, Lauer and Heinsen 1996) with Figs. 8A, 11A and 14, it appears that most of the cell islands (characterized as containing a mixture of granule and pyramidal-like cells) are located in the thinning, poorly laminated caudal orbital part of olfactory allocortex (PirF) where it blends with the ventromedial extensions of the claustrum (Fig. 11A) and other ventral striatal components (Figs. 13 and 14). This rudimentary part of olfactory cortex (which in part is separated from the underlying putamen by an attenuated external capsule or by fiber bundles which are continuous with it (Figs. 8 and 11) is distinguished more by its content of cell islands (presumably corresponding in large part to the 'insulae terminales olfactoriae laterales' of Lauer and Heinsen (1996)) than by coherent laminae (e.g. Economo and Koskinas 1925). The most striking aspect of the islands of cells is that most, if not all of them are located lateral to the area where the basal ganglia, i.e. ventral striatum and ventral pallidum, reach the ventral surface of the brain (Fig. 13; see also A C h E 5-6). As suggested by Lauer 76

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Fig. 11. B-C.

and Heinsen, it appears that these cell islands are in position to receive input directly from the olfactory bulb (K1-B 4-6). That part of the human brain labeled as olfactory tubercle by Lauer and Heinsen (1996) corresponds to what Brockhaus called tuber or trigonum olfactorium (T.o. in Fig. 6B). It is best conceived of as part of the olfactory allocortex, even though it exhibits a poorly developed laminar organization where it gradually merges with the ventral parts of the basal ganglia. This area of transition is best illustrated in Fig. 14 (compare with Lauer and Heinsen 1996, Fig. 15, in which the anterior commissure and the basal nucleus of Meynert are good landmarks). Although some of the superficial cell-islands on the lateral side of the blood vessel (marked by an asterisk in Figs. 14F 77

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Fig. 12: An electron micrograph of a ventral pallidal dendrite covered with glutamic acid decarboxylate

(GAD)-immunoreactive terminals from a rat brain (Courtesy of Dr. D.S. Zahm).

and G) could conceivably belong to the insulae terminales olfactoriae laterales of Lauer and Heinsen, the two superficially located cell islands immediately medial to the blood vessel, one of them granular (Fig. 14B), the other parvicellular (Fig. 14C) in nature, can hardly be part of their lateral group of olfactory islands. Nevertheless, they may be within reach of olfactory bulb projections (K1-B 6 and Fig. 14H) and they are clearly within the boundaries of the ventral part of the basal ganglia based on immunohistochemical criteria (Fig. 14F). It is likely that only this area, the olfactory recipient part of ventral striatum, is the primate/human homologue of the olfactory tubercle of macrosmatic mammals (e.g. see also Heimer et al. 1977; Price 1990, p. 985). Hartz-Schfitt and Mai (1991) used acetylcholinesterase histochemistry and the selective pseudocholinesterase inhibitor tetra-isopropylpyrophosphoramide (iso-OMPA) to delineate a broad, superficially located, cholinesterase-poor zone in the floor of the ventral striatum and considered it to be a non-striatal olfactory tubercle. This superficial zone is, however, one of the most choline acetyltransferase-rich regions of the basal ganglia complex (compare Fig. 3f in Hartz-Schfitt and Mai 1991, with Fig. 6A in Holt et al. 1996), and dense choline acetyltransferase immunoreactivity appears to be a reliable striatal marker in this part of the brain. For the present, the finding of HartzSchfitt and Mai might be considered as only one of several distinctive features of the human ventral striatum, rather than as a means of distinguishing the human olfactory tubercle. It should be appreciated that the use of iso-OMPA as a pseudocholinesterase inhibitor does not result in a histochemical distinction between the acetylcholinesterase staining of the olfactory tubercle and the remainder of ventral striatum in animals such 78

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Fig. 13: Coronal human brain sections at the subcommissural level, immunostained for tyrosine hydroxylase (A) and glutamic acid decarboxylate (B) to show the extension of the ventral striatum (VS) to the surface of the brain on the medial side of the frontal piriform cortex (PirF). The dense immunoreaction in B demonstrates the extent of the ventral pallidum (VP) at this level.

as the rat or mouse in which experimental tracing permits confident designation of primary olfactory projections. Nevertheless, we must concede that this superficial part of the ventral striatum has some cytoarchitectonically distinctive features, which make it difficult to directly compare it with the rest of the striatal complex. The extreme ventral part of the human striatum is a specialized subterritory that deserves extensive investigation. The previous discussion illuminates some of the difficulties in defining an 'olfactory tubercle' in the human brain, where a surface elevation is not usually detectable. As indicated earlier, the olfactory tubercle of macrosmatic mammals is part of the ventral striatopallidal system. It appears that input directly from the olfactory bulb to this part of the ventral striatum is rather limited, both in the monkey (Carmichael et al. 1994) and the human (K1-B 6 and 7, and Fig. 14H). For further discussion of the 79

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Fig. 14: A. Coronal section at approximately the same level shown in Fig. 13, but stained with the KlfiverBarrera method to show the distribution of granular (B) and parvicellular (C) cell islands in this area of transition between ventral striatum and olfactory cortex (PirF). Note the concentration of pallidal cells (D) and the large medially located granular island (E). Parvicellular (arrowheads) and granular (arrows) interface islands are also prominent features in the lateral bed nucleus of the stria terminalis (BSTL). The area of transition between the piriform cortex (Pir) and ventral striato-pallidal region is shown in higher magnification in F, which represents a section at approximately the same level as K1-B 6 (in G) but which is stained for both substance P and acetylcholinesterase to show the extension of ventral striatum to the ventral brain surface. The color-coded drawing in H illustrates the various components in this part of the brain (blue = striatal tissue, light blue = parvicellular islands; pink = ventral pallidum; brown = accumulations of basal nucleus of Meynert cells; black = granular cell islands; magenta = presumed olfactory bulb projection area; yellow = bed nucleus of stria terminalis). 80

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problems related to the definition of an olfactory tubercle in the human brain, the reader is referred to Stephan (1975, pp. 319-324), as well as to Heimer et al. (1977) and Price (1990). 2.1.2. Interface islands

In their studies of heterogeneous opiate receptor distribution, Voorn and his colleagues (Voorn et al. 1994; 1996; Vonkeman et al. 1996) have drawn attention to one of the most characteristic morphological features that distinguishes the human ventral striatum from the rest of the striatal complex, i.e. the number of cellular islands. We will use 'interface island' (a term originated by Drs. Sakamoto and Pearson) as a descriptor for these numerous, more or less distinct compact clusters of basal forebrain cells that are particularly prominent where the ventral striatum abuts structures which include the septum-diagonal band area, external capsule and ventral pallidum. We insert this novel term with some reluctance, but these clusters in the human brain do not all resemble the 'islands of Calleja' in macrosmatic mammals, nor can we assume them to be functional end zones as implied by the name 'terminal islands' used by Sanides (1957b). As further detailed in Sections 3 and 4, interface islands are by no means limited to ventral striatal areas, but occur throughout much of the basal forebrain and especially in relation to the extended amygdala (Section 3). Granular cell islands. One type of interface island is comprised of granule cell clusters which consist of small, round, tightly packed neurons (5-6 ~tm in diameter; Figs. 11B, and 14B and E; see also Fig. 14H in which granular cell islands are shown in black). Similar islands are well-known from studies in macrosmatic mammals in which they are known as 'islands of Calleja' and where they are confined primarily to the olfactory tubercle and the 'insula magna of Calleja' in the medial part of the accumbens. An insula magna is found at the medial border of the accumbens in all species studied (e.g. Meyer et al. 1989) including the human (Fig. 15). However, only the more diminutive cell island (marked with an arrow in Fig. 15A) contains a majority of granular or 'glia-like' cells which are typical for the 'islands of Calleja' in macrosmatic mammals. In the large elongated island (insula magna), which extends far ventrally alongside the diagonal band fibers, there is a mixture of granule cells and somewhat larger cells, with the larger cells in clear majority. We include such islands in the 'parvicellular' category (see below). Fallon and his collaborators (Fallon et al. 1983a,b) observed that many granular cell islands, including the insula magna in the rat, contain luteinizing hormone-releasing hormone (LHRH) and estrogen binding sites. They suggested that the islands might be targets for circulating hormones, but the function of these cell clusters, which were discovered more than a century ago, remains to be fully characterized. In the present era of chemical neuroanatomy renewed interest in these unusual structures might be promoted by the fact that in the rat they are the site of the most dense immunoreactivity for substances such as epidermal growth factor (Fallon et al. 1984), and display some of the most dense accumulations of D3 dopamine receptors (Sokoloff et al. 1992; see also Gurevich et al. 1997; and below). The latter are candidates for genetic alterations in schizophrenia (Griffon et al. 1996). Finally, as suggested by their relation to LHRH and estrogen receptors, some evidence indicates that these structures are sexually dimorphic, at least at the neurohistochemical level (e.g. Hill and Switzer 1984). Meynert (1872) was aware of these islands and Ganser (1882) drew attention to their presence in the olfactory tubercle of the rabbit, comparing them to 82

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the granular cells in the olfactory bulb. Interestingly, when Calleja (1893) described cell-islands in the olfactory tubercle of the rabbit a few years later, he apparently did not refer to the granule cell islands which now generally bear his name, but rather to collections of 'pyramidal' cells in the tubercle, or to so-called 'dwarf' cells which lie in the cap regions of the dense cell layer (Sanides 1957a, Millhouse 1987). As suggested by Millhouse (1987), Calleja neither described nor depicted the 'islands of Calleja'. This case of 'mistaken identity' has led to some confusion in the literature. Golgi studies in the human (Meyer et al. 1989) and in several macrosmatic animals (e.g. Fallon et al. 1978; Meyer and Wahle 1986, Millhouse and Heimer 1984; Millhouse 1987; Meyer et al. 1989) tend to show that the granule cells have a variable but generally rather undifferentiated morphology. Both unipolar and bipolar neurons have been demonstrated with dendrites that are thin and usually poorly branched. Some granule cell dendrites have spines but others are smooth. Axons tend to be very short and confined to the islands. Meyer et al. (1989) emphasize that different kinds of granule cells (which in our definition also include parvicellular neurons) coexist in the same cell cluster, and they raised the question of whether transformations from one form to another might take place postnatally. Several granule cell islands, like the one in Fig. 15, exhibit weak ENK staining but relatively strong or moderate SP- and apparently moderate AChE staining. Some have strong AChE activity but weak peptidergic innervation, whereas still others have minimal activity in all three markers. Talbot et al. (1988) and Meyer et al. (1989) have described granule cell islands in various animals. It is clear from these and other studies that such islands are not predominantly related to olfactory structures, even though some of them may be in a position to receive input directly from the olfactory bulb. Furthermore, clusters of granule cells are present in anosmatic animals like the dolphin (Jacobs et al. 1971), and insular clusters of deeply stained small 'glia-like' neurons are more numerous and more widely distributed in the microsmatic human basal forebrain than in any other species (e.g. Brockhaus 1938; 1942a,b; Crosby and Humphrey 1941; Sanides 1957a,b; 1958; Strenge et al. 1977; Meyer et al. 1989). The location of granular cell islands is subject to great variations, although two medially placed large granular islands in the ventral striatum close to the surface are constant features of all human brains, according to Meyer et al. (1989). One of these is displayed in Figs. 14A and E. Because the granule cell clusters are different from the aggregations of cells that Calleja described in the rabbit, we will simply refer to them as 'granular cell islands'. This nomenclature is further justified by the fact that most investigators now associate islands of Calleja with the olfactory tubercle, an association that is inappropriate in the human where granular cell islands are widely dispersed (shaded in black in Fig. 14H) and a homologue for the tubercle is indistinct or absent. Sanides (1957b), who mapped and described the granule cell islands of the human in great detail, included them in his definition of '71 insulae terminales'. Since these granule cell clusters, like the 'parvicellular cell islands' to be described below, are in general located between major neuronal systems and in relation to major fiber bundles which interlace to form the human basal forebrain, we include them as a subset of the collection of 'interface islands'. As we shall discuss in Section 3, interface islands are also characteristic components of the extended amygdala. In the amygdaloid body, where practically all islands are of the parvicellular variety, they are known as intercalated islands, which, like the term interface islands, is appropriate since they are located almost without exception between the extended amygdala and the rest of the amygdaloid body or else between components of the extended amygdala. 83

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Fig. 15: Interface islands at the medial border of the accumbens at the level represented by K1-B 4 (see also Fig. 8A). Only the small island marked with an arrow in A and C contains a majority of granular cells typical for islands of Calleja in macrosmatic mammals. The majority of the cells in the large island (asterisk) are parvicellular. The granule cell island is substance P-positive (arrow in C) but shows only a weak reaction in the enkephalin-stained section (B). A peripheral rim of the large parvicellular island shows moderate activity in both enkephalin (B) and substance P (C) preparations, and part of it is strongly acetylcholinesterase-positive (D).

Parvicellular islands. The human basal forebrain contains numerous examples of islands populated by neurons that are somewhat larger than those in the granular cell clusters and that are round or oval, with scanty cytoplasm and moderately stained nuclei (Figs. 8D and E, l lB). Like others before us (e.g. Brockhaus 1942a; Sanides 1957b; Meyer et al. 1989), we have found many subtle gradations and admixtures of different size cells in these islands. Some contain predominantly small (< 10 ~tm diameter) neurons and a varying minority of slightly larger cells ranging up to 14 lain in diameter that resemble small striatal-type neurons. Other islands contain a majority of the somewhat larger neurons. The first type of parvicellular island would seem to correspond to Sanides' 72 terminal island, whereas the second type, with its predominantly larger neurons, would correspo.nd to his 73 island. One example of this cellular variability is provided by the elongated island in Fig. 15; a medially located narrow rim close to the diagonal band (db) corresponds in all likelihood to Sanides' 72 type island, whereas the rest of the island fits better into his 73 type. Considering the many variations in regard to the relative contribution of small (< 10 lam) and somewhat larger (> 10 lain) cells we will collectively refer to these cell aggregates as 'parvicellular islands'. The neurons which populate the parvicellular islands generally have densely spined dendrites and clearly visible axonal arborizations and thus resemble components of the striatum (Meyer et al. 1989). Since the parvicellular islands containing these striatallike cells are usually surrounded by pallidal-like neurons having dendrites covered with peptidergic-tubular profiles, they may function as miniature striatopallidal units. The neurochemical composition of the islands and their surroundings supports this proposition. Sanides (1957b) postulated that the admixture of granular and parvicellular neurons reflects a type of arrested development of small striatal-type cells. In addition to being especially pronounced in the human brain, 'interface islands' are subject to great individual variations. Granule cells and clusters of parvicellular cells are present in the human basal forebrain at all ages. Since they appear to be more numerous in early life (Sanides 1957b; Meyer et al. 1989), Sanides suggested that these might be neural progenitor cells arrested in development (hence, terminal islands or 'insulae terminales'). Their location, moreover, would suggest that continued postnatal development might lead to transformation into other striatal (or amygdaloid) elements (Meyer et al. 1989). While generally it has been taken for granted that the population of neurons in the adult brain is relatively stable with only a slow attrition with age, recent evidence suggests that cells in the vicinity of the lateral ventricle might be induced by neuronal growth factors to differentiate into mature neurons, and even to migrate to positions in striatum or cortex (Weiss et al. 1996). The relevance of these observations to the earlier postulates of Sanides or Meyer and colleagues is, as yet, unclear. The 'neurochemically unique domain'. A large number of interface islands are concentrated in the ventral part of the accumbens (Sanides 1957b) where they appear to 85

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form an 'archipelago' extending from the dorsomedial accumbens alongside its border towards the septum-diagonal band area and further laterally into the ventral putamen at its border with the external capsule (Fig. 16; area outlined in Fig. 8). Walter et al. (1990) pointed out that the parvicellular islands in this chain are characterized by fibers and cell bodies immunoreactive for neuropeptide Y (NPY) which, in the neonate brain, can be seen to establish continuity with NPY-positive regions in the lateral bed nucleus of stria terminalis. Many of the islands seem to be special targets for axons that contain cholecystokinin (CCK) or somatostatin (SOM), possibly from the central amygdaloid nucleus as suggested by Mufson and his collaborators (Mufson et al. 1988). Other likely places of origin would be the laterobasal amygdaloid complex (see review by Heimer et al. 1995) or the lateral bed nucleus of the stria terminalis (e.g. Brog et al. 1993; Heimer et al. 1997b). This elongated, arc-like chain of interface islands corresponds in general to the 'neurochemically unique domains in the accumbens and putamen' (NUDAP) 5 which Voorn and his colleagues (Voorn et al. 1996) have identified on the basis of their distinct neurohistochemical characteristics that includes a high density of la opioid receptors. This characterization, exemplary of the importance of comparing histochemical data with cytoarchitecture, has permitted correlation of the areas of highest binding density with the chain of granular and small-celled islands identified by Sanides (1957b) along the ventral curvature of accumbens and ventral putamen. A recent study (Gurevich et al. 1997) of the ventral striatum of a patient with schizophrenia, who was not receiving antipsychotic drugs at the time of death, includes an illustration (Fig. 4, top right) that appears to show the 'neurochemically unique domain' of Voorn et al. (1996) to be prominently represented within the area of the highest increment of D3 receptor binding as compared to a normal control. In addition to those in the archipelago-like unique domain, other parvicellular islands are scattered in more caudal parts of ventral striatum, especially at the level where its components are gradually replaced by large numbers of ventral pallidal cells (Figs. 14 and 17), by components of the basal nucleus of Meynert and by the extended amygdala. The intermingling of interface islands with ventral striatal and ventral pallidal cells, as well as with hyperchromatic basal nucleus of Meynert cells, is particularly pronounced at these levels, making this subcommissural part of the basal forebrain one of the most complex regions of the human brain. Our immunocytochemical studies indicate that many of the parvicellular islands, like the clusters of granule cells, show a moderate to strong AChE reactivity (Fig. 16). Since the islands do not possess intrinsic cholinergic neurons, the AChE marker is presumably contained in fibers and terminals, and thus resemble granule cell islands in macrosmatic mammals (e.g. Phelps and Vaughn 1986; Wahle and Meyer 1986; Talbot et al. 1988). Although many interface islands exhibit a stronger AChE activity than surrounding striatal areas, cholinesterase-poor islands are sometimes encountered both in the monkey and the human (asterisk in Figs. 16A and B; see also Alheid et al. 1990, Figs. 19.20 19.21 and 19.22). Sometimes, the AChE-reactivity varies within a single island, resulting in patchy staining as, for example, in the large medial parvicellular island (insula magna) in the accumbens (Fig. 15; see also Hartz-Schfitt and Mai 1991). Many parvicellular islands have moderate to strong SP-immunoreactive processes and

5This archipelago of interface islands is not unique to the human. Similar arc-like chains of small-celled islands appear in other mammals, including the rat (Zahm and Heimer 1988, Fig. 4, Alheid et al. 1995, Fig. 18B), in which they tend to be located at the ventral, rostral, and lateral borders of ventral striatum, including the accumbens.

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Fig. 16: Interface islands alongside the ventral putamen at its border with the external capsule (the location of the area represented by these sections is indicated by a rectangle in Fig. 8A). Many of the parvicellular islands (indicated by arrows in A) show a moderate to strong reactivity both in the acetylcholinesterase (B) and substance P (C) preparations but weak enkephalin-immunoreactivity (D). Note that the parvicellular island marked with an asterisk in A is negative for all three stains.

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Fig. 17: Kltiver-Barrera (A) and substance P (C) stained sections from the subcommissural region where the ventral striatum intermingles in a labyrinthine fashion with the strongly substance P-positive ventral pallidum. B is a color-coded schematic based on information available from the two histologic sections (blue = ventral striatum; light blue = parvicellular islands; pink = ventral pallidum; brown = basal nucleus of Meynert; black = granular islands; magenta = presumed olfactory bulb projection area).

perikarya and weak ENK-immunoreactivity (Fig. 16C and D), but some have weak SP and moderate ENK immunoreactivity (upper right arrow in Figs. 16C and D; see also asterisk in Fig. 11B and C). Other islands, e.g. the medially located elongated island in Fig. 15, are poorly stained for both SP and ENK. Still others, like the one marked with an asterisk in Fig. 16, are negative for all three markers. Some 'islands' may be extensions of nearby territories. In addition to the islands described above, collections of medium-sized, oblong or stellate neurons with prominent cytoplasmic processes and weakly or moderately stained nuclei often appear in the form of compact clusters, especially at more posterior levels (Fig. 17). Since these 'islands' are comprised of neurons similar to those of both the ventral striatum and extended amygdala, and are neither granular nor parvicellular, we do not include them with the other small-celled aggregates. The packing density of these clusters may be higher than usual for striatum or extended amygdala, but without examining more extensive serial sections it is difficult to say whether they are truly isolated, or are peninsulae from nearby major compartments of striatum or extended amygdala. The presence of the morphologically ambiguous areas raises the possibility that there may be some structural and even functional gradations between distinctive islands and components of systems such as the striatum and extended amygdala. 2.1.3. Core and shell subdivisions of the accumbens

An important feature which distinguishes the ventral striatum from the rest of the striatal complex is the so-called 'core-shell dichotomy' of the accumbens. The distinction between a central core and a shell surrounding its medial, ventral and lateral sides was first suggested on the basis of staining for cholecystokinin and acetylcholinesterase in the rat accumbens (Zfiborszky et al. 1985). The concept has been amply confirmed in a number of anatomical and histochemical studies (see reviews by Zahm and Brog 1992; Groenewegen et al. 1996 and Heimer et al. 1993; 1997a). The functional significance of the core-shell dichotomy is reflected in the important observation that projections from accumbens to the hypothalamus, extended amygdala and midbrain tegmentum (all of which are atypical for a striatal structure) originate in the shell rather than in the core of the accumbens (Groenewegen and Russchen 1984; Zahm and Heimer 1990; Heimer et al. 1991). In the rat, important distinctions between core and shell have been demonstrated in regard to dopaminergic mechanisms and to putative differential roles in drug abuse (e.g. Pontieri et al. 1994; Sorg et al. 1995; Carlezon and Wise 1996a,b; Koob and Nestler 1997; Koob and Le Moal 1997). The shell rather than the core contains the majority of the neurons expressing dopamine D3 receptors (Diaz et al. 1995) and it also seems to be a significant target for the actions of antipsychotic drugs (Deutch and Cameron 1992; Graybiel et al. 1990; Merchant and Dorsa 1993; O'Donnell and Grace 1993). The urgent task of defining the core-shell subdivision in the human brain has proven difficult (e.g. Holt et al. 1997). Nevertheless, Meredith and Voorn and their colleagues have cogently argued that in the human the accumbens shell exhibits the same low 89

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calbindin immunohistochemistry relative to the accumbens core and dorsal striatum (Meredith et al. 1996) as it does in the rat. The shell also has moderate and dense opioid receptor binding (Voorn et al. 1994; 1996; Vonkeman et al. 1996) in its medial and ventral parts, in contrast to the core and neighboring transition areas in putamen and caudate nucleus, all of which exhibit lower opioid receptor binding than the rest of striatum. Differential substance P-immunoreactivity in the human accumbens (SP 4) echoes to some extent the situation in the core-shell region of the rat (Fig. 18). It is noteworthy that some of the features that distinguish the shell (particularly its caudomedial part) from the core of the accumbens and the rest of the striatum, are also characteristic of the extended amygdala, especially the central division of the latter, which is directly continuous with the posteromedial accumbens (Fig. 2A). The large forebrain continuum formed by the shell of the accumbens and the extended amygdala appears especially relevant in the context of neuropsychiatric disorders and drug abuse (Alheid and Heimer 1988; Heimer et al. 1997; Koob and Le Moal 1997). The issue of transition areas between striatum and extended amygdala will be discussed in Section 3.5. 2.2. VENTRAL PALLIDUM Ventral pallidal components in the form of peptidergic tubular profiles intermingle with ventral striatal tissue as far anterior as the levels shown in ENK 4 and SP 5 (see higher magnification images in Figs. 9, 10 and 11C). Clusters of pallidal cells become increasingly more common in caudal parts of ventral striatum (e.g. Fig. 14D). Both

Fig. 18: Coronal section through the rat brain stained for substance P to show the distinction between core and shell of the accumbens. (Courtesy of Dr. D. S. Zahm.)

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enkephalinergic (Fig. 9B) and SP-positive tubular profiles (Fig. 10) are present rostrally. The SP-ensheathed pallidal dendrites become far more numerous at the subcommissural level where the ventral striatum intermingles with the ventral pallidum in a labyrinthine manner (Fig. 17). Here, striatal and pallidal components reach the ventral brain surface and partly intermingle with the basal nucleus of Meynert and slightly further back with parts of the extended amygdala to form a highly intricate pattern. The extension of the ventral pallidum from the subcommissural part of globus pallidus in an SP-stained human coronal section (Fig. 17C) is very similar to the picture of SP-immunostaining shown by Mai et al. (1986; Fig. 9e; see also Beach and McGeer 1984; Haber and Watson 1985 and Alheid and Heimer 1988, Fig. 8B). Sections through the subcommissural region (from a different brain from the one shown in Fig. 17A) stained for TH (Fig. 13A) and GAD (Fig. 13B) reaffirm that ventral pallidum extends almost to the ventral surface of the human brain in the region of the anterior perforated space. An even more striking picture of the ventral extension of the primate pallidal complex is seen in sagittal sections stained for 'pallidal' markers such as ENK, SP and GAD (Fig. 13 in Mai et al. 1986; Figs. 19.26 and 19.27 in Alheid et al. 1990). Endogenous iron (revealed by the diaminobenzidine-intensified Perl's reaction) is also an excellent marker for the pallidal complex, especially since it densely labels both its medial and lateral segments but leaves nearby striatal or extended amygdaloid components relatively unstained. We have capitalized on this feature in earlier papers (Alheid and Heimer 1988; Alheid et al. 1990) to illustrate the surprisingly large subcommissural ventral pallidal complex in the monkey and human (Figs. 29.28-29.30 in Alheid et al. 1990). The fingerlike extensions of ventral pallidum into the ventral striatum are particularly clear in iron-stained sagittal sections of the human brain (Fig. 19A). These peninsulae correspond to what appear to be islands of ventral pallidal components when viewed in the coronal sections in Figs. 11C and 14D (see also Fig. 14 F). The compact part of the basal nucleus of Meynert is recognizable by its large hyperchromic cells, and its position just caudal to ventral pallidum is shown in a higher magnification detail (Fig. 19B) of the iron-stained preparation counterstained with thionin. It is important to reiterate that ventral pallidal components (especially pallidal dendrites entwined by substance P- and enkephalin-positive axons and terminals) intermingle with striatal neurons in the posterior parts of ventral striatum (Section 2.1.1.). Added to these are similar (but not identical) dendrites in caudomedial accumbens representing forward elements of the extended amygdala (Sections 3.1. and 3.2.), also enmeshed in peptide terminals (e.g. enkephalin and VIP-rich terminations). Therefore, much of the caudal part of the ventral striatum in the human is actually a mixture of striatal and pallidal, and to some extent, extended amygdaloid components. Ventral pallidum, like dorsal pallidum, is not distinctly stratified. The distribution of ENK- and SP-immunoreactive (IR) tubular profiles in the human globus pallidus has been described by several authors (e.g. Beach and McGeer 1984; Haber and Watson 1985; Mai et al. 1986). In general, ENK-IR tubular profiles are packed throughout the external (lateral) segment of globus pallidus (ENK 3-12), but are relatively infrequent for its internal (medial) segment (ENK 10-12). An exception to this rule is found in a small anterior portion of the internal pallidum (ENK 9). SP-IR tubular profiles, on the other hand, are especially dense in the internal pallidal segment (e.g., SP 10), but are relatively sparse in the main part of the external segment, especially in its central part (SP 5-10). The rostral pole of the external pallidal segment, however, has a more 91

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Fig. 19: A. Diaminobenzidine-intensified Perl's reaction for endogenous iron illustrates the ventral pallidum (VP) as it extends ventrally underneath the anterior commissure (ac) and behind the accumbens in a sagittal section of the human brain. Note the finger-like extensions of the ventral pallidum into the caudal regions of the accumbens. The preparation was counterstained with thionine to reveal the basal nucleus of Meynert cells (B; in 19B) behind the ventral extension of the ventral pallidum. Arrows in 19B point to groups of large hyperchromic basal nucleus of Meynert cells. For orientation a low-magnification photograph of a nearby iron-stained preparation is shown in C. Note the continuous iron-rich territory extending from globus pallidus through the cerebral peduncle into the substantia nigra (SN). 92

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prominent accumulation of SP-immunoreactive tubules compared to the more caudal portions (SP 3-5). Further subcompartments are evident in the two segments of globus pallidus. For instance, the periphery of the external segment has somewhat less densely packed ENK-immunoreactive tubular profiles than its central part (e.g. ENK 8), but has more SP-IR tubular profiles (e.g. SP 6 and 8). Thus, the globus pallidus shares with the striatum the characteristic of a complex chemoarchitectonic subterritorial organization. The border between ventral and dorsal pallidum is as elusive as the border between the dorsal and ventral parts of the striatal complex. Since ventral pallidum is, by definition the area which receives input from ventral striatum, its borders are in effect dependent on the location of the ventral striatum. This problem has been addressed by Haber et al. (1990), who compared the relationship between ventral striatal efferents and the distribution of peptidergic tubular profiles in the forebrain of the monkey. Since the relative distribution of peptide-containing fibers in the monkey appears very like that in the human we will, in part, follow Haber and her colleagues in describing our ENK- and SP-stained sections as they relate to the ventral pallidum. The human ventral pallidum, like the dorsal pallidum (globus pallidus) can be subdivided chemoarchitectonically into regions by the relative richness of their ENK- and SP-innervation (Haber and Watson 1985). A direct ventral extension of the external pallidal segment directly under the temporal limb of the anterior commissure is strongly ENK-positive (ENK 3-8) but it also contains SP-positive profiles (SP 4-7). A strongly SP-positive subcommissural area (SP 5 and 7) extending further medially than the strongly ENK-positive area (compare ENK 5-8 with SP 7) also seems to be directly continuous with the external pallidal segment (compare ENK 5-6 with SP-5). Note that part of the medially located ENK-positive area in ENK 8 belongs to the extended amygdala rather than the pallidal complex (see Section 3.2.). Continuity between the internal pallidal segment and ventral pallidum is difficult to visualize in coronal (SP 7, 8 and 9) or sagittal sections (Mai et al. 1986, Fig. 12a) of the human, although such a direct continuity appears to occur at coronal levels caudal to the anterior commissure (K1-B 8) and is apparent in marmoset monkey (Alheid et al. 1990, Fig. 19.26). These illustrations and the previously mentioned intermingling of peptidergic tubular profiles with ventral striatal components indicate that SP and ENK are at least as incompletely segregated in the ventral pallidum as they are in the internal and external segments of the globus pallidus. The ventral striatum is defined on the basis of its input from allocortex, mesocortex and some isocortical association areas in orbitofrontal and inferior temporal regions (Section 2.1.). Haber et al. (1990) indicated that in the monkey ventral pallidum, defined in terms of these corticostriatal relays, includes areas underneath the temporal limb of the anterior commissure (ENK 4-8 and SP 4-8) and in the ventral part of the rostral pole of the pallidal complex (ENK 3 and SP 3).

3. EXTENDED AMYGDALA The extended amygdala is diagrammatically shown in yellow to represent its central division and green to denote its medial division in K1-B 5-12. It is now well documented that the bed nucleus of stria terminalis and the centromedial amygdaloid nuclei are in continuity with each other both through sublenticular cell islands in the basal forebrain and through attenuated columns of cells or cell islands that also 93

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accompany the stria terminalis in its semicircular course behind and above the thalamus (K1-B 10-12; see also Fig. 1). The concept of the contiguous system that we have called the extended amygdala originated with the pioneering comparative and developmental studies by Johnston (1923) who delineated the close relationship between the bed nucleus of stria terminalis and the centromedial amygdala through continuous cell columns in the stria terminalis. Johnston also included the accumbens with the bed nucleus as well as the centromedial amygdala in his concept of a large forebrain continuum which he recognized in lower vertebrates and even in human embryos. As we discussed briefly in Section 2.1.3. the shell of the accumbens, especially its caudomedial part, has a number of characteristics typical for the central division of the extended amygdala but, since it is also part of the cortico-subcortical basal ganglia circuitry, we currently regard the caudomedial shell of the accumbens as a transition area between extended amygdala and the striatopallidal system (Section 3.5.). A sublenticular continuum between the central amygdala and the bed nucleus of stria terminalis was hinted at by Brodal (1947; see also von Bonin 1959), when he observed that the cells of the central amygdaloid nucleus in the rat 'make a gradual transition between the bed nucleus of stria terminalis and the anterior amygdaloid area'. A quarter of a century later, de Olmos (1969 1972), aided by the cupric silver method, identified a histochemically distinct sublenticular cell column between the central amygdaloid nucleus and the bed nucleus of stria terminalis. During the last 15 years, the original idea of a continuum between the bed nucleus of stria terminalis and centromedial amygdala has been reinforced and expanded by the results obtained in several normal anatomical and experimental studies, primarily in the rat (see review by de Olmos et al. 1985; Alheid and Heimer 1988; Alheid et al. 1995), but also in the cat (Holstege et al. 1985; Hopkins and Holstege 1978), rabbit (Schwaber et al. 1982) and hamster (Gomez and Winans-Newman 1992). Modern developmental studies based on migratory neurogenesis and expression of specific genes by Song and Harlan (1994a,b) and others (reviewed in Heimer et al. 1997b) are supportive of the concept of the extended amygdala, although there is not complete agreement in this regard (Canteras et al. 1995). The functional concept of the extended amygdala has been embraced especially by those interested in the neurobiology of drug addiction (e.g. Koob et al. 1993b; Koob and Nestler 1997), but deserves recognition by all who are interested in emotional disorders (e.g. Alheid and Heimer 1988; Heimer et al. 1997b). The extended amygdala in the human is fundamentally like that in other primates and non-primate mammals studied to date (Alheid and Heimer 1988; de Olmos 1990; Martin et al. 1991b; Walter et al. 1991; Marksteiner et al. 1993; Kaufmann et al. 1997). The extended amygdala has two major subdivisions. The extended amygdala has a central division involving its namesake, the central amygdaloid nucleus, and its rostral consort, the lateral bed nucleus of the stria terminalis. There is also a medial division of extended amygdala that is named after the medial amygdaloid nucleus and its rostral partner, the medial bed nucleus of the stria terminalis. As indicated in the color-coded illustrations (K1-B 5-12), the two divisions can be distinguished not only in the bed nucleus of stria terminalis and centromedial amygdala but also in the supracapsular and sublenticular regions (e.g. de Olmos et al. 1985; Grove 1988a,b; Alheid et al. 1998). The two major divisions of the extended amygdala in the rat have smaller sub-components within the bed nucleus of stria terminalis and the centromedial amygdala (Alheid et al. 1995). Not all of these may be represented in the 94

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sublenticular and supracapsular corridors but where they are not continuous from rostral to caudal parts of extended amygdala, they most often appear as rostro-caudal pairs of subnuclei (e.g. see Alheid et al. 1995). Although various subcompartments of the human extended amygdala have been noted (de Olmos 1990; Martin et al. 1991b; Walter et al. 1991; Kaufmann et al. 1997), their delineation has not progressed to the same degree as in the rodent. That the two divisions of the extended amygdala are important functional-anatomical units in the human basal forebrain is supported by the presence of many homologous elements (with the rat) of these two divisions combined with supporting chemoanatomic evidence in a growing number of reports on the human forebrain (e.g. Strenge et al. 1977; Candy et al. 1985; Bennett-Clarke and Joseph 1986; Gaspar et al. 1985; 1987; Lesur et al. 1989; Mufson et al. 1988; Pioro et al. 1990; Walter et al. 1991). The following discussion will focus attention primarily on some of the cyto- and chemoarchitectural distinctions of the two major divisions of the human extended amygdala. Although there are some likely interactions between the two divisions of the primate extended amygdala, as reflected by the presence of interconnections between the central and medial amygdaloid nuclei (Amaral et al. 1992), evidence from experimental anatomical, pharmacological and physiological studies in the rat suggest that they may be better analyzed as separate functional-anatomical systems (see reviews by McDonald 1992; Alheid et al. 1995; Heimer et al. 1993; 1997b). The extended amygdala forms a ring around the internal capsule. As we shall describe below, the bed nucleus of stria terminalis and the centromedial amygdala are in cellular continuity with each other both along the stria terminalis and in the sublenticular region. The extended amygdala, therefore, forms a ring around the internal capsule and thalamus (Fig. 1). The supracapsular part of the extended amygdala forms partly interrupted arching columns of gray matter which loop up from the bed nucleus of stria terminalis and then descend posteriorally into the central and medial amygdaloid nuclei. This arrangement was originally observed by Johnston (1923) in the monkey and the human fetal brain and confirmed in greater detail by Strenge and colleagues (1977) in the human and by Alheid et al. (1998) in the rat. The sublenticular part of the extended amygdala is shown to be composed of continuous columns by a variety of staining techniques in the rat (de Olmos 1972; Fig. 21) and the monkey (Fig. 20; see also Alheid and Heimer 1988, Fig. 12; Amaral et al. 1989, Fig. 6 and Martin et al. 1991b, Fig. 25). In the human the sublenticular part of the extended amygdala appears as fingers or cell islands (K1-B 8-10). In the coronal sections presented here these have the appearance of partially interrupted columns but, based on serial sections of the human extended amygdala, Martin et al. (1991b) proposed that there is a cellular continuum in the human as well. A similar conclusion is suggested by the work of Walter et al. (1991). Earlier, Novotny (1977) described a sublenticular connection between the bed nucleus of stria terminalis and the amygdaloid complex in the monkey consisting of bundles of very fine myelinated axons. Although he did not draw attention to any cellular continuity between the bed nucleus and the amygdala, or the existence of neuropil related to these fiber bundles, it is certainly easy to discern its existence in his Fig. 20 and in many other preparations of the monkey brain published during the last several years (e.g. Fig. 12 in Alheid and Heimer 1988; Fig. 6 in Amaral et al. 1989; Kohler et al. 1989; Christopoulos et al. 1995; C6t6 et al. 1996). The entire extended amygdala is shown in isolation from the rest of the brain as a schematic drawing in Figure 1. We have conservatively presented the sublenticular 95

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Fig. 20: Extended amygdala in Tamarin monkey demonstrated by immunostaining for secretoneurin (SECR) in A and B and with Timm's stain in C and D. The central (Ce) and medial (Me) amygdaloid nuclei as well as various components of the bed nucleus of stria terminalis (BST) are positive in both stains. The sublenticular part of the extended amygdala (SLEA) is also displayed as a continuum between the bed nucleus and the centromedial amygdala in both stains (B and D). Note that the posteromedial part of the accumbens shell is also stained in these preparations.

extended amygdala as two partly interrupted columns of cells. As depicted by Price et al. (1987; Fig. 11) the shape of this system reflects the two amygdaloid pathways, i.e. the stria terminalis and the ventral amygdalofugal pathway, which have been 'split 96

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apart' by the massive internal capsule in development. The schematic in Fig. 1 emphasizes three additional points. First, it illustrates how stria terminalis is accompanied by a doublet of continuous or nearly continuous cell columns that loop alongside the body and tail of the caudate nucleus above and behind the thalamus and the internal 97

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capsule. Second, it shows the two sublenticular cell columns which complete the ring of the extended amygdala around the internal capsule and the basal ganglia. Third, it emphasizes the fact that the cortical amygdaloid nuclei and the large laterobasal amygdaloid complex are not included within the operational definition of the extended amygdala, although they provide important inputs to its two divisions. The extended amygdala is characterized by long associative connections and has prominent projections to autonomic and somatomotor centers in lateral hypothalamus and brainstem (central division) and to endocrine-related medial hypothalamus (medial division). Thus, it represents a strategically placed ring formation capable of coordinating activities of multiple forebrain regions for the development of coherent behavioral responses through the above-mentioned output channels. 3.1. BED NUCLEUS OF STRIA TERMINALIS The bed nucleus of stria terminalis (BST), which exhibits its maximal development in primates and humans (Andy and Stephan 1968, 1976) is subject to a plethora of nomenclatures (Table 1 in Appendix). We advocate a system (de Olmos 1990) based on a classic 'zonal medial-lateral organization' (e.g. Brockhaus 1942b; Andy and Stephan 1968; Strenge et al. 1977; Gaspar et al. 1985; Walter et al. 1991). In contrast to Walter and his colleagues or Lesur et al. (1989), who recognized three major divisions (lateral, central and medial), we regard the bed nucleus as being comprised of just two basic divisions, lateral and medial (BSTL and BSTM). This bifurcation of the bed nucleus is supported by the developmental studies of Bayer and Altman (1987), and is consistent with the inclusion of the medial bed nucleus and lateral bed nucleus within medial and central divisions (respectively) of the extended amygdala. The medial division of Gaspar and Walter and their colleagues largely coincides with the medial bed nucleus of stria terminalis (BSTM) of de Olmos, whereas their central and lateral divisions are encompassed by his lateral bed nucleus (BSTL). The subdivisions of the human bed nucleus recognized by de Olmos (1990) were adopted (with slight modification) by Martin et al. (1991b) for their cytoarchitectonic study in the rhesus monkey and subsequently applied to their human material. In this chapter we also subscribe to the plan proposed by de Olmos for the additional subdivision within the medial and lateral bed nucleus of the stria terminalis. We will mainly describe the cyto- and chemoarchitecture (notably ENK, SP and ACHE) of the two major divisions of the bed nucleus to illustrate how cell columns related to them continue in a ventrolateral direction into the sublenticular area as well as in a posterodorsal direction into the stria terminalis. Where appropriate, further bed nucleus subdivisions are discussed or indicated in the figures. Where useful, additional histochemical markers such as neurotensin (NT), cholecystokinin (CCK), somatostatin (SOM) and secretoneurin (SECR) are depicted in figures and briefly discussed. For the most detailed description of the subdivisions possible for the bed nucleus, the reader should consult de Olmos (1990; see also table in the Appendix). 3.1.1. Lateral division of bed nucleus

The rostral end of the lateral bed nucleus (BSTL) is already apparent at the level shown in K1-B, 5 (e.g. Mufson et al. 1988, Fig. 5D, see also description in the monkey by Martin et al. 1991b, Fig. 2A). Walter et al. (1991, Fig. l a) suggest that it is the small-celled medial division of the bed nucleus that is the first to appear in a rostro98

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caudal series of coronal sections. Our examination of human horizontal sections, however, suggests that it is the lateral part of the bed nucleus rather than its medial subdivision which reaches far rostrally and establishes an area of transition with the posteromedial accumbens. In coronal sections, however, it is especially difficult to appreciate the way in which the BSTL merges rostrally with the posteromedial accumbens. More caudally, both the ventral border of the BSTL with ventral pallidum and the border along the anterior commissure are populated by a series of interface islands (indicated by arrowheads for parvicellular and arrows for granular cell islands in Fig. 14A). At its medial border, a thick subependymal cell layer, the lamina cornea, separates the BSTL from the lateral ventricle. The cytoarchitecture in the rostral part of the BSTL is heterogeneous, its various areas being dominated by small to medium-sized neurons of different shape, i.e., round, oval, triangular or fusiform. The last type is especially common in the dorsomedial part of the nucleus, deep to the lamina cornea, where many of the cells appear to align themselves between stria terminalis fibers. Large cells are loosely dispersed, single or in clusters, throughout most of the nucleus. Lateral division of bed nucleus." dorsal component. A characteristic element of the lateral bed nucleus is the presence of apparent islets of rather loosely arranged medium-sized neurons (round, triangular, fusiform) against a translucent background due to the paucity of glial cells found within the neuropil of these zones (Fig. 22B). The largest o f these 'translucent' islands is oval (or tear-drop) in shape and is present throughout most of the supracommissural region of the lateral bed nucleus (Figs 21 and 22). Consistent with the homologous area in the rat (e.g. Alheid et al. 1995) the central part of this oval 'encapsulated island' is designated as the central subdivision of the dorsal part of the lateral bed nucleus, i.e., BSTLDcn. The surrounding, cell-poor area that forms the boundary of BSTLcn is designated the capsular subdivision of the dorsal part of the lateral bed nucleus, i.e., BSTLDc. BSTLD is a characteristic feature of the bed nucleus in most mammals. It is referred to as the central sector or subdivision of the human BST by Lesur et al. (1989) and by Walter et al. (1991) who emphasize its conspicuous content of a variety of peptides and other neurochemical markers (see below). Compartments of lightly stained medium-sized neurons (like those mentioned below in relation to the rostral part of lateral bed nucleus at the level shown in ENK, 5-6) are usually very similar to the large oval-shaped zone illustrated in Fig. 22 (de Olmos 1990), and are profitably considered as peninsulae of this structure, or possibly in some cases, as detached islets. In contrast to BSTLDcn, the capsular subdivision of the laterodorsal bed nucleus, i.e. the BSTLDc contains considerably fewer but somewhat larger, often fusiform, neurons. Among the rostral areas of the BSTL, loosely packed collections of lightly stained medium-sized neurons are evident. These cells are usually oval (though sometimes round or triangular) against a clear background with few glia cells. They are readily appreciated in a variety of histochemical preparations and are contained by a distinct cell-poor capsule. Many of the regions surrounding these 'islands' are densely populated by glial cells; they also contain more intensely Nissl-stained neurons, many of which are elongated and aligned in a capsular area surrounding the oval islets. The remaining cells are intermingled with the fibers of the stria terminalis. In the enkephalin-stained preparation (ENK, 5-6), representing a level in between K1-B 5 and 6, there appears an enkephalin-positive cell 'island' flanked by a capsule containing enkephalin-positive granular tubular profiles (see arrow in ENK 5-6). 99

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Fig. 21: All pictures (A-D) show the characteristic oval shape of the central subdivision of the dorsal part of the lateral bed nucleus (BSTLDcn) surrounded by a capsular subdivision (BSTLDc) which is especially prominent because of its strong reaction for enkephalin (B) and negative reaction for acetylcholinesterase (D). (See text for further discussion of the chemoarchitecture of the bed nucleus.) The arrowhead in A points to a parvicellular cell island while the arrows point to granular islands. B in Fig. 21A points to a group of large hyperchromatic basal nuclei of Meynert cells.

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Encapsulated cellular compartments, which are typical for the dorsal part of the lateral bed nucleus (BSTLD), can also be appreciated at more caudal levels (K1-B 7 and 8, ENK 7-8) where the lateral bed nucleus reaches its maximal mediolateral extent and where its cyto- and chemoarchitectonic subdivisions can be easily appreciated (see Fig. 22, showing the BST at the level represented in K1-B 8). At this level the dorsal component (BSTLD), abutting laterally on the internal capsule, is evident, as is the posterior part of the lateral bed nucleus of the stria terminalis (BSTLP) which extends further ventroposteriorally than BSTLD (K1-B, 8 and 9 in the mini-atlas). The juxtacapsular part of the lateral bed nucleus (BSTLJ) 6 is located between the internal capsule and the central and capsular parts of the lateral bed nucleus (Fig. 21B), and contains smaller and more darkly stained cells, which tend to form clusters (Fig. 22E). Interface islands in the form of granular and parvicellular aggregates are typically located between the various parts of the lateral bed nucleus (Fig. 22F) as well as in other parts of the nucleus (Fig. 21A; arrows = granular islands, arrowhead = parvicellular island; see also Fig. 22). The string of cell islands which can be seen between the central part of the dorsolateral bed nucleus (BSTLDcn) and its juxtacapsular part (BSTLJ) even at low magnification (arrowheads in Fig. 22A) are mostly of the parvicellular type although many of them also contain a varying number of granule cells. The central and capsular parts of the dorsolateral bed nucleus (BSTLDcn and BSTLDc) and the juxtacapsular part of the lateral bed nucleus (BSTLJ) are easily appreciated in stains for met-enkephalin and acetylcholinesterase. The central division is positive with both stains (Figs. 21B and D and 22H and L). The capsular part is strongly enkephalin-positive (Figs. 21B and 22H) but also stands out because of its lack of staining with acetylcholinesterase (Figs. 21D and 22L). The strongly enkephalinergic capsular subdivision of the dorsolateral bed nucleus (BSTLDc) features varicose fibers and peridendritic varicosities (Fig. 22I) reminiscent of the tubular profiles described in the ventral pallidum (Section 2.2.). The central division of the dorsolateral bed nucleus (BSTLDcn) contains ENK-positive puncta and varicose fibers in addition to a significant number of ENK-positive cell bodies (Fig. 22J). Most of the dorsolateral bed nucleus is moderately stained for substance P (Figs. 21C and 22K), exceptions being small areas in the juxtacapsular part. The juxtacapsular part of the lateral bed nucleus is moderately stained for ENK (Figs. 21B and 22H) but shows strong ACHEactivity (Figs. 21D and 22L). Staining for tyrosine hydroxylase (TH) is moderately strong in the dorsolateral bed nucleus but not in its capsular part (Lesur et al. 1989) and is especially pronounced in some of the parts surrounding its central subdivision including the juxtacapsular part as well as in part of the medial bed nucleus (Gaspar et al. 1985; Lesur et al. 1989). Immunostaining for dopamine-hydroxylase (DBH) is present in both divisions but is especially strong in the medial bed nucleus (Gaspar et al. 1985). Interestingly, DBH immunoreactivity also invades the caudomedial accumbens, both in the human (Gaspar et al. 1985) and in the rat (Berridge et al. 1997). The central part of the dorsolateral bed nucleus (BSTLDcn) contains multiple neurochemical markers (especially peptides), and has a distinct capsule (BSTLDc), fea-

6juxtacapsular here refers to the fact that this group of neurons abuts the medial wall of the internal capsule as it does in the rat brain where this term was originally applied. BSTLJ should not be confused with the capsular part of the dorsal lateral bed nucleus of the stria terminalis (BSTLDc), which refers to the border area (capsule) that is relatively cell-poor, and which surrounds a central core (BSTLDcn) that is more densely populated by neurons. The capsular part of the dorsolateral bed nucleus is much more evident in the human brain, compared to the homologous area in the rat which is only suggested by its chemical neuroanatomy rather than by a clear-cut cytoarchitecture (e.g. Alheid et al. 1995).

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Fig. 22: A. Bed nucleus of the stria terminalis at the level of the crossing of the anterior commissure (see K1B 8 in mini-atlas). The insets (B-E) show the cytoarchitecture of some of the cell groups and subdivisions present at this level (see text). Arrowheads in A point to parvicellular interface islands. H, K and L are nearly matching sections stained for enkephalin (H), substance P (K) and acetylcholinesterase (L). Varicose enkephalinergic fibers and peridendritic varicosities are characteristic features of the capsular subdivision of the dorsolateral bed nucleus (/), whereas enkephalin-positive puncta, varicose fibers and neurons are prominent in the central part of the dorsolateral bed nucleus (J).

tures t h a t c o m b i n e to indicate t h a t it is a specialized c o m p a r t m e n t . S o m a t o s t a t i n , a n e u r o p e p t i d e t h a t attracts special interest because o f its n e u r o e n d o c r i n e significance, b u t which also has an implied role in A l z h e i m e r ' s disease a n d o t h e r n e u r o l o g i c disorders, has been described by m a n y a u t h o r s to be present in b o t h terminals a n d n e u r o n s in the central division o f the d o r s o l a t e r a l bed nucleus (e.g. C a n d y et al. 102

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1985; Bennett-Clarke and Joseph 1986: Gaspar et al. 1987; Mufson et al. 1988; Lesur et al. 1989; Walter et al. 1991). Other peptides such as cholecystokinin, galanin, and neurotensin are prominent in the central division and have potential relevance in neuropsychiatric disorders including schizophrenia and Alzheimer's disease (e.g. Nemeroff 1980; Chan-Palay 1988b; K6hler and Chan-Palay 1990; Levant et al. 1990; Mufson et al. 1993; Abelson 1995; Diaz et al. 1995). Walter et al. (1991) and Martin et 103

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al. (1991 b) indicate that neurotensin terminals and cell bodies are especially prominent in the lateral bed nucleus. Like enkephalin and other peptides, neurotensin is present in the form of varicose fibers and puncta, but it does not form tubular profiles. From the pictures published by Martin et al. (1991b, Figs. 17A and 18B) it is evident that the concentration of neurotensin-immunoreactivity is stronger in the posterior part of the lateral bed nucleus than in its dorsal part, whereas neurotensin-positive cell bodies apparently are present in both areas. Cholecystokinin (CCK)-immunoreactive terminals are dense in the dorsolateral bed nucleus (BSTLD), especially its central part (Fig. 23; arrow in B points to a varicose fiber) and tend to form tubular profiles in the capsular subdivision (Fig. 23C). Only an occasional cholecystokinin-positive neuronal cell body is present in the bed nucleus in our material. As emphasized by Walter et al. (1991), the central compartment of BSTLD contains significant concentrations of many other markers, including glutamic acid decarboxylate (GAD; Fig. 13B), vasoactive intestinal peptide (VIP), synaptophysin (SYN), chromogranin-A (CHR-A) and calbindin (CAB).

Fig. 23: Dorsolateral bed nucleus in a cholecystokinin (CCK)-immunoreacted section showing CCK terminals in its central subdivision (B) and tubular profiles in the capsular subdivision (C).

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Lateral division of bed nucleus." posterior compartment. This nucleus can be differentiated from the dorsolateral bed nucleus on the basis of its more heterogenous population of densely stained neurons and more numerous glial cells (Fig. 24A). Many of the neurons are somewhat smaller than those in the dorsolateral bed nucleus but there are also a significant number of large neurons. The posterior part of the lateral division (BSTLP) has a relatively larger number of myelinated stria terminalis fibers than does the dorsal part of the lateral division (BSTLD); these give it a distinct background-staining in Klfiver-Barrera sections. The posterior part of the BSTL is also less densely stained for AChE than most of the other divisions except the posterior part of the medial bed nucleus at the level shown in Fig. 24D. Immunoreactivity for substance P is in general somewhat denser in the posterior than in the dorsal part of the BSTL, but is not as dense as in the medial bed nucleus at the level shown in Fig. 22K. Staining for enkephalin is moderate but becomes increasingly weak in more ventral parts of the subdivision. 3.1.2. Medial division of bed nucleus

At the level shown in Fig. 22 (see also Figs. K1-B 7 and 8) the medial division of the bed nucleus (BSTM) is represented by its anterior component (BSTMA). It contains small and rather densely packed neurons and a few that are larger, darkly stained, often triangular in shape, and widely scattered (Fig. 22D). At a more caudal, postcommissural level (Fig. 24), the posterior part of the medial bed nucleus (BSTMP) can be divided into at least three different subcomponents (medial, intermediate and lateral with gradually increasing size of the neurons laterally). The medial part facing the lateral ventricle contains relatively densely packed and smaller neurons and more glial cells than the more voluminous intermediate portion, which contains more loosely arranged and lightly stained neurons. A large-celled lateral component is limited to the mid-section of the BSTMP and contains a heterogenous population of neurons, many of which are larger than in other parts of the medial bed nucleus. Most of the posterior (Fig. 24D) and anterior (Figs 21D and 22L) subsections of the medial bed nucleus exhibit very little acetylcholinesterase activity, especially dorsally. The staining for enkephalin is modest or very light in the anterior subregion of the medial bed nucleus (Figs. 21B and 22H), while immunostaining for substance P gradually increases in strength medially in the anterior part of the medial bed nucleus (Figs. 21C and 22K). This pattern in regard to these two peptides is not as readily apparent in the posterior part of the medial bed nucleus, especially in the supracommissural part, where both peptides have a rather heterogenous staining pattern (Figs. 24B and C). 3.2. SUBLENTICULAR COMPONENTS OF EXTENDED A M Y G D A L A The sublenticular components of the extended amygdala are illustrated in K1-B 8-10 where, apparently in the form of partly interrupted cell columns or islands, they bridge the gap between the medial and lateral divisions of bed nucleus of stria terminalis and the central and medial nuclei of the amygdala in the basal forebrain. It was suggested by de Olmos (1990) that it might be difficult or even impossible to illustrate the human sublenticular extended amygdala as a continuum in preparations which show only its neuronal cell bodies but, as described below and by others (e.g. Martin et al. 1991; Walter et al. 1991), continuity is indicated by stains for peptidergic fibers and terminals that are typical for the bed nucleus of stria terminalis and the centromedial amygdala. 105

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Fig. 24: Bed nucleus of stria terminalis at the post-commissural level showing the posterior parts of the lateral and medial division of the bed nucleus (BSTLP and BSTMP). The hyphenated line indicates the approximate border between the two divisions.

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3.2.1 Central division of the sublenticular extended amygdala (SLEAC) The central division of the sublenticular extended amygdala (SLEAC) connects the lateral division of the bed nucleus of the stria terminalis with the central nucleus of the amygdala. Cell columns corresponding to both the dorsal and posterior parts of the lateral bed nucleus appear to be located in the sublenticular region at the levels illustrated in K1-B 8 and 9. (Similar 'islands' can be seen at the level shown in K1-B 7, but because of their similarities to striatal cell clusters, and our lack of a nearby section stained with a marker typical for the central division of the extended amygdala we have not positively identified them.) The cell columns indicated underneath the internal capsule and ventral pallidum in K1-B 8 were stained in nearby sections for enkephalin (ENK 8), substance P (SP 8) and acetylcholinesterase (ACHE 8) and exhibit features typical for the BSTLD. At a slightly more caudal level (K1-B 9), the central division of the extended amygdala is more easily appreciated in the form of ventrolaterally directed sublenticular finger-like extensions of the BSTL and some sublenticular islands containing small to medium-sized cells often with typical fusiform appearance where they align themselves between the fiber bundles bridging the gap between the bed nucleus and the amygdala (Novotny 1977; the same fibers described by Novotny are often identified as part of ansa lenticularis or sometimes ansa peduncularis, e.g. Gaspar et al. 1987). In a nearby section stained for enkephalin, some of the extended amygdaloid islands correspond to immunoreactive patches, with peptidergic tubular profiles and puncta (see SLEA in ENK 9) reminiscent of the situation in the lateral bed nucleus. Martin et al. (199 lb) and Walter et al. (1991) have also demonstrated finger-like extensions into the sublenticular region from the lateral bed nucleus in the human, and especially convincing pictures of such finger-like extensions into the sublenticular region are illustrated in sections stained for cholecystokinin (CCK), neurotensin (NT), and vasoactive intestinal peptide (VIP) in Fig. 25. In an effort to demonstrate continuous columns of the sublenticular extended amygdala these sections were cut at a slight angle to the transverse plane. The CCK-immunoreactive extension (SLEA in Fig. 25A) contains immunoreactive puncta and tubular profiles typical for parts of the lateral bed nucleus of stria terminalis (Fig. 23). The corresponding NT-immunoreactive sublenticular columns display a wealth of immunoreactive puncta and varicose fibers, but no tubular profiles (Fig. 25D), corresponding to the situation in the bed nucleus. A nearby section stained with Heidenhain's technique (Fig. 25E) demonstrates a prominent cell column, continuous with the lateral bed nucleus and containing interface islands (the arrowhead points to a parvicellular island and the arrow to a granular cell island) which are typical components of the extended amygdala (see below). To complete the comparison, it should be mentioned that regions in this finger-like extension demonstrate a cytoarchitecture (Fig. 25G) which is very similar to that of the lateral bed nucleus. Compared to the surrounding dorsal and ventral striatopallidal areas, vasoactive intestinal peptide (VIP) is a specific marker for the dorsolateral bed nucleus of stria. This is evident in the VIP-stained section in Fig. 25H which also offers a convincing demonstration of the ventrolaterally directed continuum from the lateral bed nucleus into the sublenticular region. Depicted in Fig. 25I is the dense VIP immunoreactivity for the central division of the lateral part of the central amygdala (see section 3.3.1.) which is the counterpart in the temporal lobe of BSTLDcn. Neither the medial bed nucleus nor the medial amygdaloid nucleus is stained, suggesting VIP is preferentially 107

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Fig. 25: A-D. Central division of the sublenticular extended amygdala (SLEA) demonstrated by immunostaining for cholecystokinin (A) and neurotensin (B). Note that cholecystokinin has a tendency to appear in the form of tubular profiles (C) whereas neurotensin primarily appears as immunoreactive puncta and varicose fibers (D). involved with the central subdivision of extended a m y g d a l a rather t h a n with its medial corridor. VIP i m m u n o r e a c t i v i t y in these areas has a characteristic tendency to a p p e a r 108

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Fig. 25: E-G. A nearby section stained with Heidenhain's technique demonstrates the prominent sublenticular cell column which forms the immunopositive extensions in A and B. Interface islands are typical components of the extended amygdala. The arrow in F points to a granular interface island, whereas the arrowhead indicates a parvicellular island.

in the form of perisomatic and peridendritic profiles (see 25J and inset in 25H). Interestingly, the dorsolateral bed nucleus of the stria terminalis has been found to 109

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Fig. 25: H-J. Vasoactive intestinal polypeptide (VIP) is an excellent marker for the central division of the extended amygdala as reflected in the specific staining of the lateral bed nucleus (H) and the central amygdaloid nucleus (/) and sublenticular cell islands (arrows in H). Dense perisomatic and peridendritic immunoreactivity (insets in H and J) are typical for this peptide within these areas. Note that the VIP immunoreactivity also involves the caudal accumbens (H).

be sexually d i m o r p h i c in that it is m o r e than 60% larger in males than females (Swaab 1997). The brain used to depict the B S T L D in this presentation (Fig. 25H) belonged to a 16-year-old male. Additional, similar pictures o f sublenticular cell c o n g l o m e r a t e s can be o b t a i n e d in sections stained for s o m a t o s t a t i n (SOM), a n d secretoneurin ( S E C R ; Fig. 26). Soma110

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tostatin-positive neurons and terminals which are especially pronounced in the dorsolateral bed nucleus are arranged as a more or less continuous string of sublenticular island-like clusters (white arrowheads in Fig. 26A) in apparent continuity with the lateral bed nucleus of the stria terminalis (BSTL). Such islands have been described earlier by many authors (e.g. Candy et al. 1985; Bennett-Clarke and Joseph 1986; Gaspar et al. 1987; Mufson et al. 1988; Lesur et al. 1989; Walter et al. 1991). One of the illustrations in the paper by Mufson et al. (1989, Fig. 2A) beautifully demonstrates the string of sublenticular somatostatin-positive clusters and their continuity with the lateral BST. Another convincing picture of the sublenticular continuum between the central amygdaloid nucleus and the lateral bed nucleus in a coronal somatostatinstained section of the monkey has been published by Amaral et al. (1989; Fig. 6). Strings of immunoreactive patches in the sublenticular region are also apparent in material stained for secretoneurin, and since all subdivisions of the bed nucleus display a prominent immunostaining for secretoneurin (Kaufmann et al. 1997), it is reasonable to expect strings of islands both in the deep parts of the sublenticular region and in a more superficial position (i.e. close to the ventral brain surface) as illustrated in Fig. 26B. As discussed below, it is reasonable to suggest that this superficial string of immunoreactive patches represents the medial division of the sublenticular extended amygdala. An area surrounding the lateral margin of the anterior commissure and which, in the past, would usually be included as part of the putamen, is also densely stained for somatostatin in the above-mentioned picture by Mufson et al. In our own material this area (arrow in Fig. 26A), like several other sublenticular somatostatinergic 'islands', contains both somatostatin-positive neurons and terminals which form granular tubular profiles (see also Candy et al. 1985, Fig. 2B). One of the most intriguing features of this last-mentioned somatostatin-positive conglomerate is its location, i.e. in close relation to the posterior limb of the anterior commissure in a region generally recognized as the ventral part of the striatum. A secretoneurin-positive island is also present in this general region (arrow in Fig. 26B) which appears to correspond to the area which in the rat is called the interstitial nucleus of the posterior limb of the anterior commissure (IPAC) (de Olmos 1972; Alheid et al. 1995), and which has close relations to the central division of the extended amygdala (Alheid et al. 1995; Heimer et al. 1997a,b). The important subject of overlap between the extended amygdala and regions generally considered part of the striatum will be considered further in Section 3.5. Further laterally, where the sublenticular part of the extended amygdala approaches the temporal lobe (K1-B, 9 and 10), it is difficult to identify it in Nissl or KltiverBarrera sections and the areas color-coded with yellow and green are tentative in these two figures. Enkephalin, on the other hand, which is a good marker for the central division of the extended amygdala, illustrates the sublenticular continuity towards the central amygdaloid nucleus (SLEA in ENK 9, 10 and 10-11; see also Section 3.3.1.). Martin et al. (199 lb) illustrated this lateral part of the sublenticular extended amygdala with the aid of neurotensin, enkephalin and somatostatin. We have chosen to illustrate it with sections stained for cholecystokinin (CCK) and neurotensin (NT) (see arrows in Fig. 27A). Neurotensin is especially effective since it illustrates both fibers and cell bodies in the extended amygdala. (Note that the sections in K1-B, 9 and 10 belong to a different brain than the one in Fig. 27, which is the same as in Fig. 25, being cut at a slight angle to the transverse axis in order to obtain as much as possible of the extended amygdala continuum in one plane.) It is evident from the sections 111

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Fig. 26: Sublenticular extended amygdala appears in the form of isolated sublenticular clusters (white arrowheads) in these sections stained for somatostatin (A) and secretoneurin (B). The coronal sections of this human brain are cut at a different angle from those displayed in the previous figure. Note the immunopositive areas (arrows) in close relation to the anterior commissure.

illustrated in Figs. 23 and 27A and B, that C C K , like N T , stains b o t h divisions of the extended amygdala, a l t h o u g h the central division is m o r e densely stained than the 112

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Fig. 27: The lateral part of the sublenticular extended amygdala illustrated with immunostaining for cholecystokinin (A) and neurotensin (B). Neurotensin is an especially effective marker since it labels fibers and cell bodies in both the central (C) and the medial (E) divisions of the extended amygdala.

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medial. These pictures, like those in K1-B 9 and 10, also demonstrate that significant parts of the anterior amygdaloid area (AAA) are in effect integral parts of the extended amygdala (see Section 5 for further discussions of the AAA). Figs. 27C, D and E demonstrate both NT-terminals and NT-positive neurons, often small to medium in size and fusiform, where they accommodate themselves between the fiber-bundles of the so-called ventral amygdalofugal pathway. The NT-positive cell bodies at the level shown in Fig. 27C do not generally mingle with the cell groups belonging to the basal nucleus of Meynert. Neurotensin does not colocalize with choline acetyltranferase in basal nucleus of Meynert neurons (De Lacalle and Saper 1997). This datum together with the fact that the relatively small size and fusiform shape of the neurotensin neurons are distinctly different from the large basal nucleus of Meynert neurons do support the idea that these cells are indeed part of the extended amygdala rather than the magnocellular basal complex. 3.2.2. Medial division of sublenticular extended amygdala

The medial division of the sublenticular extended amygdala links the medial nucleus of the amygdala with medial division of the bed nucleus of the stria terminalis. It is easy to recognize the medially located, descending part of the medial sublenticular extended amygdala (K1-B, 9), where it is directly continuous with the posterior part of the medial bed nucleus (BSTMP). Further laterally, sections stained for both CCK (Fig. 27A) and NT (Fig. 27B) provide unmistakable evidence of partly interrupted sublenticular columns close to the ventral brain surface (see also superficially located secretoneurin-immunoreactive patches in Fig. 26B). The NT-positive islands contain neurotensinergic terminals as well as typical medium-sized fusiform neuronal cell bodies (Fig. 27E) and are part of a string of NT-positive islands, which can be seen in more rostral sections to form a continuous arc in apparent continuity with the posterolateral part of the medial bed nucleus. As indicated above, secretoneurin (SECR) is also a useful overall marker for the extended amygdala (Kaufmann et al. 1997) in the sense that it labels both the central and medial divisions. This is reflected in distinct and prominent secretoneurin staining of the centromedial amygdala (Fig. 28B) leaving the rest of the amygdala unstained save for light labeling in its superficial part. Nevertheless, secretoneurin is less specific than CCK and NT since it also labels ventromedial parts of the striatopallidal system (e.g. compare human, (Fig. 28A, B), with monkey (Fig. 20A, B) secretoneurin sections). This creates some problems of interpretation especially in the sublenticular region where pallidal areas tend to adjoin the extended amygdala. The basal nucleus of Meynert, on the other hand, is not stained and long continuous finger-like columns representing both divisions of the extended amygdala can therefore be identified in the sublenticular region (arrows in Fig. 28A), provided the plane of sectioning is optimal. 3.3. CENTROMEDIAL AMYGDALA Starting with V61sch (1906, 1910) and Johnston (1923), several scientists have parcellated the amygdala into centromedial and cortical-basolateral groups of nuclei. This essential splitting of the amygdaloid complex into two adjacently linked but separate systems is becoming increasingly relevant with the growing acceptance of the concept of the extended amygdala. In fact, as should already be evident from the previous discussion, the central and medial amygdaloid nuclei cannot be adequately understood 114

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Fig. 28: Sublenticular parts of central and medial divisions of the extended amygdala are displayed with immunostaining for secretoneurin in A (white arrows). The section in B illustrates the prominent secretoneurin staining of the centromedial amygdala and part of the anterior amygdaloid area. Note that the ventral part of putamen (Pu) and the area surrounding the ascending part of stria terminalis (st) including the amygdalostriatal transition area (AStr) are also secretoneurin-positive.

unless they are described with the nuclei of the stria terminalis as integral parts of the extended amygdala. This fundamental viewpoint was to some extent p r o m o t e d by Brockhaus (1938) in his classic study of the h u m a n amygdaloid region. A l t h o u g h Brockhaus did not describe extensions of the central and medial nuclei as recognized in the concept of the extended amygdala, he designated the centromedial nuclei of the amygdala and related parts of the anterior amygdaloid area as the 'supra-amygdaloid' division in order to separate them from the cortical-basolateral group of nuclei which

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he considered to be the true amygdala in the classic sense ('das Amygdaleum proprium').

3.3.1. Central amygdaloid nucleus The continuity from the sublenticular part of the central extended amygdala towards the central amygdaloid nucleus is clearly illustrated by stains for cholecystokinin and neurotensin (Fig. 27). Enkephalin is another excellent marker for the central extended amygdala (Fig. 29; see also Martin et al. 199 l b, Fig. 18H). The dorsomedially directed sublenticular continuation of the central amygdaloid nucleus (arrow in Fig. 29A; see ENK 10-11 in the mini-atlas for an overview of the location) is rich in granular-type tubular peptidergic profiles and immunoreactive puncta (Fig. 29C). Most contemporary scientists divide the central nucleus into lateral and medial divisions (see Tables in appendix) which can be easily distinguished by their different reactions for enkephalin. The components of the lateral division (CeL) are characterized by strong or moderately strong enkephalin reactions like those in the dorsal region of the lateral bed nucleus (BSTLD in Fig. 21B). As previously indicated by Martin et al. (1991b), the correspondence between the lateral part of the central nucleus and the dorsal component of the lateral bed nucleus is specific in the sense that some of the subsections of the dorsolateral bed nucleus have counterparts in the lateral division of the central amygdaloid nucleus. This is especially the case for the central and capsular parts of the dorsolateral bed nucleus which exhibit enkephalinergic reactions similar to those in the central core and capsular parts of the lateral central nucleus. To be specific, the central part (including both the core and the apical part in de Olmos' 1990 terminology) of the lateral division of the central nucleus (CeLcn) contains a large number of enkephalin-immunoreactive puncta and varicose fibers in addition to some enkephalin-positive neurons (Fig. 29B; compare with the central part of the dorsolateral bed nucleus in Fig. 22J), whereas the capsular part (CeLc) is characterized by granular-type tubular profiles and puncta (compare Fig. 29C with 22I). In VIP-stained sections this correspondence is more striking since the VIP reactivity favors the dorsolateral bed nucleus (central and capsular parts, Fig. 25H) and the lateral central nucleus (central and capsular parts; Fig. 25I) with little or no reactivity in the remaining portions of the bed nucleus or central amygdala. Adjacent pallidal and striatal areas (with the exception of caudomedial accumbens) are similarly unlabeled. Symmetry between parts of the lateral and medial bed nuclei of stria terminalis and parts of the central and medial amygdaloid nuclei has been prominently demonstrated in the rat brain (Alheid et al. 1995) and provides convincing support for the extended amygdaloid concept. As we shall see below, this type of substructural symmetry between the bed nucleus of stria terminalis and the centromedial amygdala components of the human extended amygdala includes cytoarchitecture as well as chemoarchitecture. The lateral division of the central nucleus, in addition to its main central part mentioned above, has a paracapsular part (CeLpc) which is located dorsolaterally, and a periparacapsular part (CeLppc) located dorsally. These accessory parts of the lateral central nucleus are, like the main part, surrounded by fiber-rich capsules characterized by tubular profiles in enkephalin-stained sections (Fig. 29A). As indicated by de Olmos (1990), the neuron-poor capsular parts of the periparacapsular, and dorsal paracapsular divisions seem to form one continuous sheet which is a prominent feature 116

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Fig. 29: The central amygdaloid nucleus and its dorsolaterally directed continuity (arrow in A) into the lateral sublenticular area in an enkephalin (ENK) immunostained preparation. Whereas the central part of the lateral division of the central nucleus (CeLcn) contains a large number of ENK-immunoreactive puncta and varicose fibers and an occasional immunoreactive neuron (B), the sublenticular extension of the lateral division of the central nucleus is characterized by enkephalinergic tubular profiles (C). The apical part of the main lateral division is marked by an asterisk in A.

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in enkephalin preparations (Fig. 29). Even the apical part of the main lateral division (indicated with an asterisk in Figs. 29A and 30F) appears to be surrounded by this capsular unit (de Olmos 1990). The medial division of the central nucleus (CeM) shows a moderately strong reaction to enkephalin (Fig. 29) similar to that in the posterior division of the lateral bed nucleus of stria terminalis (BSTLP in Fig. 24B). Cytoarchitectonically, the central and medial amygdaloid nuclei can be clearly distinguished from the rest of the amygdala on the basis of their generally smaller neurons. This is easily appreciated in cell-stains (Fig. 30; compare the large neurons in basomedial nucleus, BM [panel C], with the small ones in various parts of the centromedial amygdala [panels B, D, and E]). This cytoarchitectonic characteristic prompted several classic neuroanatomists (e.g. V61sch 1906; Hilpert 1928; Brockhaus 1938) to exclude the centromedial nuclear group from what they considered to be the amygdaloid body in a strict sense. The medium-sized, lightly stained cells of the central part of the lateral division (CeLcn, Fig. 29B) are similar to cells in the central part of

Fig. 30: The Klfiver-Barrera stained section in A (see KI-B 11 in the mini-atlas at the end of the previous

chapter for orientation) demonstrates the striking difference in cell size between the small to medium-sized cells in the centromedial amygdala (panels B, D and E) and the rest of the amygdaloid body, especially the laterobasal complex with its larger cells (panel C). The various subdivisions of the central nucleus, however, are more easily appreciated in the histochemical preparations in F (enkephalin), G (substance P) and H (acetylcholinesterase). See text for further discussion of the various subdivisions. 118

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Fig. 30" F-H.

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the dorsolateral bed nucleus (BSTLDcn, Fig. 22B); they usually appear as well defined or sharply outlined round, fusiform or triangular against a translucent background having few glial cells. The capsular part of the central nucleus of the amygdala is populated by loosely arranged, more darkly stained, usually fusiform neurons which accommodate themselves between the fibers in the capsule, similar to the situation in the capsular part of the dorsolateral bed nucleus (BSTLDc). The neurons in the paracapsular part, are, in general, smaller and more densely packed than in the central part of the lateral division. Although the basic cell morphology might suggest that the paracapsular and periparacapsular parts of the lateral subdivision corresponds to the juxtacapsular part of the lateral bed nucleus, the chemoarchitecture does not support such a proposition. The medial part of the central amygdaloid nucleus division (CeM in Fig. 30D) has a more heterogenous population of neurons and in general more glial cells than the central part of the lateral division of the bed nucleus of stria terminalis and thus would seem to resemble more closely the area of BSTL shown in panel C in Fig. 22. For a more detailed discussion of the various subdivisions of the human central amygdaloid nucleus and their cytoarchitecture see de Olmos (1990). Suffice it to say that the chemoarchitecture as revealed in sections matching the Klfiver-Barrera-stained section in Fig. 30A are coherent with his parcellation of this nucleus. The central core, apical (asterisk) and capsular parts of the lateral division are easily appreciated in the enkephalin-stained section shown in Figs. 29 and 30F, as are the paracapsular and periparacapsular parts. The medial subdivision (CeM), which encircles the dorsomedial aspect of the capsular part, can also be clearly identified because of its more modest content of enkephalin. Whereas most of the lateral division is lightly stained for substance P, the medial subdivision is somewhat more darkly stained (Fig. 30G). The acetylcholinesterase-stained preparation (Fig. 30H) reinforces the distinction between the central and capsular parts of the lateral division and provides a nice demonstration of the more or less continuous acetylcholinesterase-negative sheet encapsulating the central part of the lateral division. Additional support for the parcellation of the lateral division of the central nucleus of the amygdala is provided by sections stained for cholecystokinin (Fig. 31) and neurotensin (Fig. 32). As in the central and capsular parts of the dorsal division of the lateral bed nucleus of the stria terminalis (Fig. 23) there is a concentration of cholecystokinin-immunoreactive puncta and varicose fibers in the central part of the lateral division of central amygdaloid nucleus and a tendency for the labeling of peridendritic terminals to appear as tubular profiles (Fig. 31C), especially in the more dorsally located capsular part. Varicose fibers and immunoreactive terminals, sometimes in typical peridendritic pattern, also characterize the para- and periparacapsular parts of the lateral central nucleus. Peridendritic labeling is also apparent in the sublenticular part of the central extended amygdala (Fig. 31D). Although there are some cholecystokinin-positive neurons in the medial amygdaloid nucleus (and even more in basolateral and cortical parts of the amygdala), the central amygdaloid nucleus does not contain neuronal cell bodies stained for cholecystokinin in our material even though there is dense terminal staining. Neurotensin-immunoreactive puncta and varicose fibers are present both in the lateral and medial divisions of the central nucleus, although the intensity of the staining is considerably higher in the medial division (Fig. 32). In regard to the labeling of fibers and terminals, this is consistent with the findings in the human by Martin et al. (199 lb; Fig. 18b). Since Martin and his collaborators also found the posterior division 120

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Fig. 31: Sections stained for cholecystokinin demonstrate strong reactivity especially in the central part of the lateral division of the central nucleus, which is filled with immunoreactive puncta, varicose fibers and some tubular profiles. Other parts of the centromedial complex show a more moderate immunoreactivity. The immunoreactive fibers in the CCK-positive sublenticular patch (arrow in A and inset D) are reminiscent of those in the central amygdaloid nucleus (inset C). On the other hand, some CCK-immunoreactive neurons are present in the medial amygdaloid nucleus (E) and in the sublenticular patch (D), but not in the central part of the lateral division of the central amygdaloid nucleus in the material shown here. 121

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of the lateral bed nucleus to be more heavily populated with neurotensin-immunoreactive terminals than the dorsal division (see Martin et al. 1991b, Fig. 17A) the staining for neurotensin tends to confirm the symmetry between the lateral division of the central amygdala and the dorsolateral bed nucleus, as well as between the medial division of the central amygdala and the posterolateral bed nucleus. In regard to the distribution of neurotensin-containing perikarya, our material indicates that the majority of such neurons are located in the medial division of the central amygdaloid nucleus rather than in the central part of its lateral division. This is somewhat at odds with the description by Martin et al. (1991b), and reaffirms our contention that additional, detailed cytoarchitectonic and chemoanatomical studies of the various subdivisions and compartments of the human extended amygdala are needed before definitive statements can be made with regard to all its components and the degree to which 'paired symmetry' exists between the bed nucleus of stria terminalis and the centromedial amygdala.

3.3.2. Medial amygdaloid nucleus Whereas the rostral part of medial nucleus is located superficially in the region of the fundus of the endorhinal sulcus at the coronal level somewhere between K1-B 10 and 11, the main part of the medial nucleus is covered on its medial side by the optic tract (K1-B 11 and 12). After Brockhaus (1938), de Olmos (1990) has provided the most detailed description of the medial nucleus in the human and has divided it into a rostral and a caudal subdivision with the latter having dorsal and ventral parts (MePD and MePV). There is a tendency for the neurons of the medial nucleus to form layers, especially superficially, de Olmos identified these as a cell-poor molecular layer, a superficial dense cell-layer and a deep layer with somewhat less densely distributed neurons. Although the heterogeneous population of small- to medium-sized, relatively lightly stained neurons and a significant number of glial cells in the medial nucleus of the amygdala (Fig. 30E) is somewhat reminiscent of the situation in parts of the medial bed nucleus of the stria terminalis it is not, at present, possible to closely correlate various parts of the medial amygdaloid nucleus and the medial bed nucleus on the basis of cytoarchitecture alone for the human brain. Nor does the histochemistry for enkephalin, substance P and acetylcholinesterase offer much help in that regard (compare Figs. 30F, G and H with Figs. 21, 22 and 24). Nevertheless, the generally weak reaction for enkephalin and acetylcholinesterase combined with stronger reaction for substance P is consistent with the overall concept of the medial division of the extended amygdala, which is based on the premise of a general correspondence between the medial amygdaloid nucleus and the medial bed nucleus of stria terminalis. A more convincing argument for the existence of a medial division of the extended amygdala as defined on the basis of such a correspondence can be made with the aid of immunohistochemistry for cholecystokinin (Figs. 27A and 31A), secretoneurin (Fig. 28) and, especially, neurotensin which is located in both terminals and neuronal cell bodies in the medial amygdaloid nucleus (Fig. 32D). As mentioned in Section 3.2.2., neurotensin-immunoreactive fibers and terminals, intermingled with immunoreactive cell bodies, form a continuous column from the medial amygdaloid nucleus through the superficial anterior amygdaloid area and further medially towards the neurotensin-positive islands shown in Fig. 27E close to the lateral edge of the optic tract (opt).

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Fig. 32: The pattern of neurotensin-staining in the central amygdaloid nucleus (A) is in large part complementary to the CCK-immunoreactive pattern shown in the previous figure in the sense that the intensity of NT-staining is considerably higher in the medial division than in the lateral division. The neurotensin immunoreactivity is also relatively dense in the medial amygdaloid nucleus, which, like the central nucleus (C), contains both neurotensinergic fibers and puncta as well as cell bodies (D).

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3.4. STRIA TERMINALIS COMPONENTS OF THE EXTENDED A M Y G D A L A The stria terminalis, which makes a dorsally convex detour behind and above the thalamus, can be identified in the floor of the lateral ventricle where it accompanies the thalamostriate vein in the groove which separates the thalamus from the caudate nucleus (see BSTS/st in KI-B 12). The extreme lateral end of the stria terminalis is more or less tucked away underneath the ventromedial aspect of the caudate tail. Cell groups along the arch of the stria terminalis, referred to as the supracapsular bed nucleus of stria terminalis (BSTS) provide important evidence ' for the extended amygdaloid concept. Although such cell groups were identified over a century ago (e.g. Ziehen 1897; V61sch 1906, 1910), it was J. B. Johnston (1923) who advanced the theory that cells accompanying the arching stria terminalis might represent remnants of cell columns which in early development formed more prominent continuities between the lateral and medial bed nuclei and the central and medial amygdaloid nuclei, respectively. As demonstrated in Section 3.2., cell columns also bridge the sublenticular gap between these structures. In this section we will analyze the cell groups in the supracapsular part of the stria terminalis, with the purpose of demonstrating that the extended amygdala can be conceived of as two more or less parallel ring formations surrounding the internal capsule (as indicated in Fig. 1) in close association with the caudate nucleus and thalamus. The neuronal components of the stria terminalis have been the focus of only a few investigations (Sanides 1957b; Strenge et al. 1977; Alheid et al. 1998). The first two papers describe the groups of neurons which can be seen alongside and within the fiber bundles of the human stria terminalis from its point of continuity with the bed nucleus of stria terminalis at the level of the crossing of the anterior commissure (K1-B 8) to its continuity with the centromedial amygdaloid nuclei in the temporal lobe. Taken together, the two papers provide a detailed picture of the major cell groups related to this remarkable fiber bundle, and they form a necessary basis for the thesis to be elaborated below, i.e. that the cell groups within the stria terminalis in the human, like in the rat (Alheid et al. 1998) are integral parts of the central and medial extended amygdala. Sanides (1957b) in a classic study, classified and mapped the small-celled islands ('Insulae terminales') in the human forebrain. Such islands (referred to by us as 'interface islands'; see Section 2.1.2.) are located in varying constellations throughout most of the stria terminalis. One interface island, in particular, distinguishes itself by being generally larger than the others and is often partly or completely encapsulated by myelinated fibers. It is located between the stria terminalis and the caudate nucleus. Strenge et al. (1977) used a selective stain for intracellular lipofuscin granules on thick sections (400-800 lam) suitable for low-power examination with the stereomicroscope. They described the existence of two columns of cells, which they refer to as 'pars paracaudata' and 'pars medialis'. As mentioned by Strenge et al. their smallcelled 'pars paracaudata' corresponds undoubtedly to the large interface island described by Sanides at the ventromedial border of the arch of the caudate. Sanides did not describe the group of medium-sized neurons which Strenge and his collaborators labeled 'pars medialis'. In order to avoid confusion especially when comparing the situation in the human to that in the rat (see below) it is important to realize that the 'pars medialis' of Strenge et al. is located, like their 'pars paracaudata', in the lateral aspect of the stria terminalis (Strenge et al. 1977; Fig. 5a-d). In a recent combined light- and electron microscopic study of the supracapsular part 124

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of the bed nucleus of stria terminalis in the rat (Alheid et al. 1998) we described the presence of a relatively large laterally located column of cells (BSTSL) which is directly continuous with the lateral bed nucleus of stria terminalis and which extends to the central amygdaloid nucleus. A considerably smaller medial subdivision of the supracapsular bed nucleus (BSTSM) in the rat appears to be continuous with the medial bed nucleus. The medial column of cells, which is located in the medial corner of the stria terminalis, tapers off in the caudal direction so that in the retrocapsular part of the stria terminalis it is represented only by interrupted small clusters of cells. A neuronal cell group corresponding to the pars paracaudata in the human was not identified in the rat where it was sometimes impossible, especially in rostral sections, to distinguish the lateral cell group in the stria from the caudate-putamen because the two cellular compartments were in direct continuity and contained similar types of medium-sized cells. Except for the additional presence of a pars paracaudata the situation in the human is reminiscent of that in the rat in the sense that both a lateral and a medial cell group (a lateral and medial supracapsular bed nucleus of the stria terminalis [BSTSL and BSTSM], for convenience referred to here as lateral and medial 'pockets') can be identified in many coronal sections, with the 'lateral pocket' being considerably more pronounced than the medial one. 3.4.1. Supracapsular part of the stria terminalis

The continuity between the rostral, voluminous part of bed nucleus of stria terminalis (K1-B 8) and the cell columns along the supracapsular (suprathalamic) part of the stria terminalis is easily appreciated in K1-B 10. The relevant part of this section is shown in higher magnification in Fig. 33. The cellular continuity is unmistakable. Both the substance P-positive, small-celled posteromedial part of the medial bed nucleus (Fig. 33, C and D) and the posterolateral part with generally larger cells (Fig. 33E) can be followed without interruption into the 'supracapsular' part of stria terminalis (above the 'knee' marked with an arrowhead in Fig. 33B). It is difficult at this level, however, to distinguish cellular areas that are continuous with the lateral part of the posterior part of the medial bed nucleus from those that are continuous with the lateral division of the bed nucleus. It appears, however, that the medium-sized cells located in the gliapoor 'pocket' (F in the dorsal part of Fig. 33A) do have the morphological features (i.e., mixture of round, triangular and fusiform) corresponding to those of the central part of the dorsolateral bed nucleus of stria terminalis (Fig. 22B). Unfortunately, we do not have, at this level, a matching section stained with a marker for the dorsolateral bed nucleus (e.g. enkephalin), but the appearance of a relatively lightly stained 'pocket' in a nearby SP-stained section (arrow in Fig. 33B) would be consistent with this proposition. At a somewhat more caudal level (corresponding approximately to K1-B 11) two pockets of cells are clearly seen even under low magnification (Fig. 34). The larger lateral pocket contains medium-sized round, triangular or fusiform cells which are distinctly outlined against a relatively glia-poor translucent background (Fig. 34C) similar to the situation in the central part of the dorsolateral bed nucleus (Fig. 22B) and the central part of the lateral division of the central amygdaloid nucleus (Fig. 30B). The adjacent medial part of the caudate nucleus (Fig. 34B) contains distinctly smaller cells, reminiscent of a paracaudate interface island (see below). The smaller 'medial' or ventromedially located pocket features a mixture of small and medium-

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Fig. 33: Photomicrographs of Klfiver-Barrera (A) and substance P-stained (B) coronal section to show the cellular continuity between the rostral voluminous part of the bed nucleus of stria terminalis and the cell columns in the supracapsular part of the stria. Both the small-celled posteromedial part of the medial bed nucleus (panel C) and the posterolateral part with larger cells (panel E) can be followed into the supracapsular part (panels D and F) of stria terminalis. The black arrowhead shows the 'knee' referred to in the text. The arrow points to a relatively lightly stained substance P pocket.

sized, often fusiform n e u r o n s (arrow in Fig. 34D) against a considerably m o r e glia-rich background. It is i m p o r t a n t to realize that the distribution and cytoarchitecture o f n e u r o n s within the stria terminalis can change rather dramatically from level to level. In Fig. 35, which is close to the level shown in Fig. 34, a medially located substance P-positive pocket ( a r r o w h e a d in F i g . 35A a n d B; SP terminals in E) with a mixture o f small- a n d medium-sized n e u r o n s in a glia-rich b a c k g r o u n d can still be identified, but the laterally located cell g r o u p c o r r e s p o n d i n g in position to the lateral pocket shown in the previous 126

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Fig. 34: Coronal Kliiver-Barrera stained section through the supracapsular stria terminalis to show the supracapsular parts (pockets) of the lateral (BSTSL) and medial (BSTSM) bed nucleus of stria terminalis, which represent the two divisions of the supracapsular extended amygdala. The cell picture in the lateral pocket (C) is reminiscent of that in the dorsolateral bed nucleus (see text). Note that the adjacent part of the caudate nucleus (B) contains distinctly smaller cells resembling those in parvicellular interface islands or paracaudate island (see Fig. 37). The white arrow in D points to one of the neurons in the medial pocket.

figure, contains a mixture of primarily parvicellular and granular neurons (Fig. 35C) rather than the distinctive medium-sized neurons seen in Fig. 34C. When comparing the size of the cells in this parvicellular island with those in the nearby part of the caudate nucleus shown in the previous figure (Fig. 34B), the similarities are striking; the ventromedial part of caudate nucleus, like the small-celled island embedded among the fibers of the stria terminalis, contains primarily small cells rather than mediumsized neurons typical for the rest of striatum. We shall return to this important organizational issue in our discussion of the paracaudate interface island below. In yet another nearby section (Fig. 36) the lateral pocket is quite large and populated by medium-sized, differently shaped (triangular, fusiform, round) neurons distinctly outlined against a translucent background, similar to the situation in the central part of the dorsolateral bed nucleus of stria terminalis (Figs. 22B and 33F). The correspondence between this lateral pocket in the stria terminalis and the dorsolateral bed 127

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Fig. 35: This cross-section through the stria terminalis is rather close to that shown in Fig. 34. Nonetheless, the cytoarchitecture in the lateral pocket shown in C (granular cell island surrounded by small cells) is different from that in the lateral pocket in the previous figure. The medial 'pocket' (arrowhead in A and B), which would correspond to the medial bed nucleus of the stria terminalis, is considerably more substance Ppositive than the lateral pocket (arrow in A). A couple of neurons in the medial pocket are indicated by arrows in D. Substance-P-containing fibers and terminals within the medial pocket are shown in E.

n u c l e u s is e v i d e n t also in c h e m o a n a t o m i c a l p r e p a r a t i o n s . T h e cells in the l a t e r a l p o c k e t are s u r r o u n d e d by a s t r o n g l y e n k e p h a l i n e r g i c n e u r o p i l c h a r a c t e r i z e d by p r o m i n e n t v a r i c o s e fibers a n d a c o m b i n a t i o n o f c o a r s e g r a n u l e s a n d small p u n c t a very different f r o m the m o r e ' d u s t - l i k e ' e n k e p h a l i n e r g i c p a t t e r n seen in the n e a r b y c a u d a t e nucleus. 128

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Fig. 36: A. Kliiver-Barrera stained section close to that in Fig. 35 reveals a large lateral pocket with a cell picture (inset in A) very similar to the situation in the central part of the dorsolateral bed nucleus. The correspondence between this lateral pocket and the dorsolateral bed nucleus is evident also in the enkephalin (B) and acetylcholinesterase (C) preparations.

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The lateral pocket is also somewhat less densely stained for acetylcholinesterase than the caudate nucleus (Fig. 36C). Considering the characteristics described above for the lateral pocket, it can hardly be doubted that this roundish, encapsulated cell group corresponds to the dorsolateral part of the bed nucleus of stria terminalis and to the central part of the lateral division of the central amygdaloid nucleus. The lateral pocket can readily be identified in several of the more caudally located sections of the supracapsular stria terminalis (see below) but sometimes it is represented by only a few scattered medium-sized neurons. Strenge et al. (1977), who used a pigment stain on very thick sections, could identify a cell group which they called 'pars medialis', but which is located in the lateral part of stria terminalis. Although the smaller medially located pocket does have some characteristics reminiscent of the medial bed nucleus and medial amygdaloid nucleus, the correspondence in this case is more tenuous. The difficulty becomes even more pronounced further posteriorally and inferiorally where, in most coronal sections of the stria terminalis only scattered neurons can be identified in its medial half. It is important to reiterate that Strenge and his collaborators (1977) referred to the lateral cell group as 'pars medialis' in order to separate it from a laterally adjoining more prominent interface island, the 'pars paracaudata', which had earlier been identified by Sanides (1957b) as a large 'terminal island' on the ventromedial side of the caudate nucleus. Their 'pars medialis' would also seem to be an inappropriate designation giveia the correspondence between its cells and those of the lateral bed nucleus and the lateral part of the central amygdaloid nucleus. The paracaudate (interface) island. The prominent small-celled 'island' at the border between the stria terminalis and caudate nucleus deserves special recognition in the context of the extended amygdaloid concept. From the descriptions by Sanides (1957b) and Strenge et al. (1977), it appears that the paracaudate cell island is present alongside the entire course of stria terminalis but varies in shape and cellular composition (at some levels the cells are smaller than at others). This largest of the islands related to the stria terminalis is named for its shape in cross section but it almost certainly has the three-dimensional form of a distinct, continuous cellular column of variable diameter at the interface between the caudate nucleus and the stria terminalis. The paracaudate cell island appears encapsulated in most sections and is therefore easily identifiable in Klfiver-Barrera preparations (Fig. 37A and E; mid-thalamic level). Its neurons (Fig. 37C) are smaller than those in nearby caudate nucleus (Fig. 37B; note that the magnification in panels B-D is twice as large as in many of the other panels showing cells in this series of figures). The acetycholinesterase activity of the island changes gradually from being comparable to that of the rest of striatum ventrolaterally to almost zero in its dorsomedial part (Fig. 37F). The extent of encapsulation of the paracaudate island varies. In some sections a capsule can hardly be recognized and it is almost impossible to distinguish the island from the rest of the caudate nucleus, save for the smaller size of its neurons (as demonstrated in Fig. 34). Cholecystokinin- and neurotensin-immunoreactivity, which proved valuable for the illustration of the sublenticular part of the extended amygdala, have been used as well

Fig. 37: A. KliJver-Barrera stained section showing the general location of the supracapsular stria terminalis which is shown in higher magnification in E. This shows a large paracaudate, partly encapsulated, interface island with smaller cells (C) than in the adjoining part of caudate (B). The arrow in D points to a neuron in the medial pocket. The major part of the paracaudate island is acetylcholinesterase-positive (F).

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Fig. 37: B-F.

to complement the cytoarchitecture of the supracapsular extended amygdala and to reveal some of the features of the paracaudate island. The results obtained confirm the presence of lateral and medial pockets. They also tend to show that the paracaudate island has characteristics at least as closely related to the extended amygdala as to the striatopallidal system. Fig. 38 represents a CCK-stained section cut through the rostral part of stria terminalis (but at a slightly different angle than the brain in the mini-atlas at the end of the previous chapter). It demonstrates a large bundle of CCK-positive fibers and coarse granules reminiscent of terminals, in the 'lateral pocket' (arrow in B; the 'pocket' contains a number of medium-sized cells as is evident in a matching section stained with Heidenhain's method). A smaller, dorsolaterally-located island containing immunoreactive terminals and cell bodies is also present close to the cau132

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Fig. 38: Coronal section through the rostral part of the stria terminalis stained for cholecystokinin (CCK) demonstrates a CCK-positive large pocket (arrow in B) and a small island containing immunoreactive terminals and medium-sized cell bodies (C).

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date nucleus (Fig. 38C). Considering the presence and the size of the CCK-positive neurons, this island appears to be representative of the lateral division of the supracapsular bed nucleus of the stria terminalis (BSTSL) rather than a small-celled paracaudate island. Figs. 39 and 40 feature matching cholecystokinin and Heidenhain's sections from levels through mid-thalamus and posterior thalamus respectively of the same brain as shown in Fig. 38. The overview figures (Figs. 39A and 40A) provide a guide to the supra- and subcapsular locations of the stria terminalis (compare the

Fig. 39: A. Coronal cholecystokinin-stained section through the middle part of the thalamus (Th) to show the general location of the stria terminalis which is shown in higher magnification in B. Medial (arrowhead) and lateral (arrow) CCK-positive pockets as well as a CCK-positive paracaudate island (asterisk) can be identified. The paracaudate island has smaller cells than the lateral pocket (see insets in C). Lateral (arrow) and medial (arrowhead) pockets can be identified even at low magnification in Heidenhain's stain (C).

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Fig. 39: B-C.

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l o c a t i o n o f optic t r a c t a n d lateral geniculate nucleus in the two figures). They also indicate the presence o f ' l a t e r a l ' a n d m e d i a l ' p o c k e t s ' in a d d i t i o n to a p r o m i n e n t p a r a c a u d a t e island; this is especially the case in r e g a r d to the s u p r a c a p s u l a r c o m p o nents (Figs. 39B a n d 40B). In this b r a i n it is possible to identify a lateral a n d sometimes a m e d i a l p o c k e t even at low m a g n i f i c a t i o n in the s u p r a c a p s u l a r stria terminalis o f several H e i d e n h a i n - s t a i n e d sections (see a r r o w a n d a r r o w h e a d in 39C a n d 40C). This is especially a p p a r e n t when the sections are m a t c h e d with sections stained for c h o l e c y s t o k i n i n showing t e r m i n a l fields (Figs. 39B a n d 40B). A c o m b i n e d cell-fiber stain like H e i d e n h a i n ' s o r the K l t i v e r - B a r r e r a m e t h o d is especially well suited for this p u r p o s e . The" p a r a c a u d a t e island is also c h o l e c y s t o k i n i n - p o s i t i v e in c o n t r a s t to the rest o f the c a u d a t e nucleus. This is p a r t i c u l a r l y evident at the level s h o w n in Fig. 40B. T h e

Fig. 40: A. Coronal section (from a somewhat more caudal level than that shown in Fig. 39), stained for

cholecystokinin, shows the position of the stria terminalis displayed in higher magnification in B and in a nearby section stained with Heidenhain's technique (C). The paracaudate island is strongly positive (asterisks in B) as are the lateral (arrows) and medial (arrowhead) pockets. The cells in the paracaudate island are considerably smaller than in the nearby part of striatum (inset in C). Note that lateral (arrow) and medial (arrowhead) pockets can be identified with Heidenhain's stain even at low magnification (C). 136

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lateral pocket is typically populated by medium-sized cells rather than by the small cells characteristic of the paracaudate interface island (see insets in Fig. 39C and 40C; note that the magnification in 39C, like that in 37B-D is about twice that in many of 137

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the other panels showing neurons in this series of pictures). The CCK-immunoreactivity in the lateral pocket features both cell bodies and terminals (inset in Fig. 39B) whereas the paracaudate interface island (asterisk) has only an occasional CCK-positive cell within the CCK immunoreactive terminal field. To emphasize the apparent relations between the paracaudate interface island or column and the extended amygdala we present a neurotensin-stained section of the stria terminalis (Fig. 41) from the same brain as that in Fig. 39 but from a somewhat different level. The terminal staining is typically confined to the paracaudate island (asterisk) and to a lesser extent to the lateral and medial pockets (arrow and arrowhead). 3.4.2. Subcapsular part of the stria terminalis The caudal supracapsular part of the stria terminalis makes a descending, curving sweep and then, ventrally located, passes forward to lie underneath the sublenticular part of the internal capsule which it has encircled. It is here lodged between the tail of the caudate (TCd), laterally, and the lateral geniculate nucleus (LG) medially (Fig. 40A). The stria terminalis forms a compact bundle on the ventral surface of the internal capsule facing the temporal horn of the lateral ventricle (LV in Fig. 42). It is difficult to positively identify lateral and medial pockets at this level. Two small CCK-positive interface 'islands' with typically small- to medium-sized cells can be recognized in a paracaudate position (asterisk in Fig. 42). Between these interface islands is another region which contains loosely arranged, medium-sized cells and which, like the dorsomedial rim of the main part of the tail of the caudate, contains CCK-positive terminals (arrow in Fig. 42A). At a slightly more rostral level (Figs 39 and 43) the tail of the caudate is much reduced, being represented only by a thin wedge of tissue ventral to the sublenticular part of the internal capsule. It continues to display CCK-positive terminals (Fig. 43A). This thin wedge of tissue may, much like the parvicellular paracaudate island, serve as a transition between the extended amygdala and the striatum (see Section 3.5.). The stria terminalis (st) at this level breaks up into bundles on the superior wall of the inferior horn of the lateral ventricle. Further rostrally still (Fig. 44) the stria terminalis bundles approach the central and medial amygdaloid nuclei and the rest of the amygdala from behind and below. A cell layer of variable thickness separates the temporal horn of the lateral ventricle from these strial bundles which more or less surround several parvicellular interface islands (asterisks in Fig. 44) as they proceed through this heterogenous caudal part of the amygdala. At a somewhat more rostral level (Fig. 45) the various subdivisions of the amygdala can be clearly recognized. Individual variation in regard to the stria terminalis and to interface islands in this part of the human brain as well as variations in section level and orientation may contribute to the differences in morphology, number and location when comparing the pictures in this review with those presented by Sanides (1957b). The breaking up of the stria terminalis into fiber bundles which proceed dorsally between the various cell groups of the basolateral amygdala is displayed in Fig. 45G. The Kltiver-Barrera section in Fig. 45A also displays a number of interface islands related to the stria terminalis system and an encapsulated island (marked C in Fig. 45A) of medium-sized cells close to the surface of the inferior horn. This cell island has features including characteristic enkephalin-immunoreactivity (Fig. 45B) similar to 138

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Fig. 41: Neurotensin-stained section close to the level shown in Fig. 39. The terminal labeling is confined mainly to the paracaudate island and less prominently to the lateral (arrow) and medial (arrowhead) pockets. The black granules in the dorsal half of the stria terminalis are artifacts.

those of the lateral pocket in the supracapsular part of the stria terminalis, suggesting that it is representative of the cell column related to the central parts of the dorsolateral bed nucleus and the central amygdaloid nucleus (compare Figs 45C and E with D and F). The other regions surrounding the ascending stria terminalis bundles in Fig. 139

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Fig. 42: Subcapsular part of stria terminalis at the level shown in Fig. 40. Two CCK-positive parvicellular

interface islands are indicated by an asterisk. The dorsomedial rim of the tail of the caudate, as well as the medially located area indicated by an arrow in A, contains a moderate number of CCK-positive terminals.

45A are populated by a rather heterogenous population of medium-sized and small neurons, which in m a n y way resembles components of the bed nucleus of the stria terminalis and centromedial amygdala. The adjoining, rather extensive, region lateral to the prominent stria bundles on the lateral aspect of the amygdaloid body (Fig. 45A and K1-B 11 in the mini-atlas) is referred to as the amygdalostriatal transition area by de Olmos (1990) or striatum accessorium by Brockhaus (1938). The neurochemical composition of this region (strong E N K and weak SP and A C h E - I R ) which gradually merges with ventral putamen laterally suggests that it is representative of that part of the stria terminalis component of the central extended amygdala which gradually merges with striatal tissue. The further delineation of the subcapsular parts of the extended amygdala, especially at the level of the caudal amygdala, deserves careful attention. Whereas vestiges of a medially located cell column, apparently representative of a medial supracapsular bed nucleus of the stria terminalis (BSTSM) have been demonstrated in the more rostral parts of the stria terminalis, the presence in more caudal sections of a few neurons in a medial location is not altogether convincing evidence for continuity. Nevertheless, histochemical demonstration (e.g. Figs. 39 and 40) of a pronounced medial pocket in the h u m a n which resembles that in the rat (Alheid et al. 1998) in having a dense collection of synaptic complexes like that of the medial amygdaloid nucleus is strongly suggestive of a continuum. 140

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Fig. 4 3 : CCK and Heidenhain’s sections (see Fig. 39A for location) showing the subcapsular part of the stria terminalis at a slightly more rostra1 level than in Fig. 42. The tail of the caudate has all but disappeared, and the wedge-like striatal region between the internal capsule and the lateral ventricle is moderately CCKpositive. Asterisks indicate CCK-positive islands.

Based on the material included in this study (see also Strenge et al. 1977) it is clear that the lateral (central) division of the extended amygdala is more prominently represented than the medial division both in the supracapsular and subcapsular parts of the stria terminalis. Features with characteristics in common with central part of the dorsolateral bed nucleus and the central amygdaloid nucleus can be easily recognized both in the supra- and subcapsular segments of the stria terminalis. Unlike the situation in the rat, however, the human possesses an additional prominent stria terminalis component, i.e. the paracaudate interface island or column which, at least in part, seems to serve as an area of transition between the extended amygdala and the striatum.

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Fig. 44: Coronal section (see overview picture in Fig. 37) at the level where stria terminalis approaches the amygdala from behind. Asterisks indicate parvicellular interface islands. The arrow points to a mediumcelled island which has a cytoarchitecture similar to the central part of the lateral division of the central amygdaloid nucleus (see Fig. 45D).

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Fig. 45: Coronal sections through the caudal part of the amygdaloid body stained with Klfiver-Barrera (A) and for enkephalin (B), substance P (G) and acetylcholinesterase (H). (For general location of this area see K1-B 12 in the mini-atlas.) The cell island marked with C in A has a cell picture (see panel C) and enkephalin-immunoreactive pattern (panel E) reminiscent of that in the central part of the lateral division of the central nucleus (panels D and F). Note that the amygdalostriatal transition area, labeled Astr in G, has a staining pattern which differs from the adjoining parts of ventral putamen in enkephalin (B), substance P (OD and acetylcholinesterase (H) stained preparations. 143

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Fig. 45: G-H.

3.5. TRANSITION AREAS BETWEEN EXTENDED AMYGDALA AND THE STRIATOPALLIDAL SYSTEM

While we have generally focused our discussion on the ways in which elements of the extended amygdala in the human might be discriminated from the neural elements belonging to the adjacent striatopallidal system, it is also true that in some instances this border may be impossible to depict with a single line. This is certainly the case with the bed nucleus of the stria terminalis and the caudal accumbens. In the modern era of chemical neuroanatomy, many observers have noted the dense acetylcholines144

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terase staining within the nucleus accumbens and have used this as a boundary marker towards the lateral and medial bed nucleus of the stria terminalis, which are less densely stained. For other transmitter markers, however, this division is not so clear. In fact, it is often the case that histochemical staining or receptor binding tends to blur the distinction between the bed nucleus of the stria terminalis and the accumbens (e.g. CCK, Zfiborszky et al. 1985; angiotensin II, Lind et al. 1985; Lind and Ganten 1990; Alheid and Heimer 1988, Fig. l lA; calcitonin receptors, Skofitsch and Jacobowitz 1985, 1992; amylin receptors, Sexton et al. 1994; vasopressin and oxytocin receptors, Veinante and Freund-Mercier 1997; secretoneurin, Marksteiner et al. 1995). The likelihood that these variations in chemical neuroanatomical measures also reflect unique afferents or intrinsic components has been borne out in comparative studies of the connectivity of the accumbens. While our early efforts and those of others documented the similarities of the ventral and dorsal striatum in the rat (see section 2), it became clear that some projections were difficult to encompass in a model of striatopallidal circuitry. These include projections to lateral hypothalamus, amygdala, and brainstem (Nauta et al. 1978; Groenewegen and Russchen 1984). The accumbens' projection to the amygdala, which is to some extent reciprocated, targets the extended amygdala, and especially its central division, with projections to the lateral bed nucleus of the stria terminalis, sublenticular extended amygdala, and to a lesser extent the central amygdaloid nucleus in the rat (Heimer et al.; Brog et al. 1993). A partial resolution of this issue was the observation that the more unique projections of accumbens seemed to originate from the shell area (Heimer et al. 1991) so that at least part of the accumbens, its central core, could be analyzed as a more uniform representative of striatopallidal circuitry. The projections from the accumbens shell, however, also engage part of the striatopallidal circuit, with projections to the medial part of ventral pallidum and a subsequent relay to mediodorsal thalamus. Faced with the histochemical similarity between the caudal shell areas of accumbens and adjacent areas of extended amygdala, and with their common projections to lateral hypothalamus and rostral brainstem targets, in addition to reciprocal connections with the central division of extended amygdala, we concluded that there may well be elements of the extended amygdala that are embedded within the caudal shell area of accumbens. In other words the caudomedial shell of accumbens may represent a 'transition area' between the ventral striatum and extended amygdala (e.g. Alheid and Heimer 1988). The likelihood that this argument is also true for the primate brain is supported by the histochemical features of the accumbens zones that are the apparent homologue of the accumbens shell of the rat (e.g. see Figs. 20A, 25H; also Gaspar et al. 1985; Walter et al. 1990), and which by and large seem to possess a similar network of projections, including efferents typical of the striatopallidal system, but also of extended amygdala, including projections to lateral hypothalamus and brainstem, as well as reciprocal projections with extended amygdala (e.g. see Haber et al. 1990a,b; Price and Amaral 1981). Beyond the close relation of the caudomedial accumbens with extended amygdala, we have over the past decade identified other potential transition areas between the ventral striatum and the extended amygdala in the rat. These include an area along the posterior limb of the anterior commissure that is continuous with the caudomedial accumbens, and shares the histochemistry and close connections with the central division of extended amygdala (Alheid and Heimer 1988, 1996; Alheid et al. 1994, 1995; Heimer et al. 1997a,b; Veinante and Freund-Mercier 1997). At the present time it is not possible to specify with any precision the homologous area of the primate or 145

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human brain. As indicated in section 3.2.1., however, some histochemical evidence suggests that portions of the ventral striatum that are nearby to the temporal limb of the anterior commissure are differentiated from the overlying striatum and stain in a similar fashion to the ventrally adjacent elements of the extended amygdala (arrows in Figs. 26A and B; see also Fig. 28B). Further progress in specifying the homologous area in the human brain might be expected when specific chemical markers for this lateral zone are recognized and applied to this problem. For the rat a relatively specific indicator of the dopaminerich transition area along posterior limb of the anterior commissure appears to be immunohistochemistry for the tyrosine kinase, c-lyn (Chen et al. 1996). As discussed in the previous section (3.4.), the large paracaudate interface island appears to represent another important transition area between the extended amygdala and the striatum throughout the course of the stria terminalis in the human. In fact, this elongated transition area appears to be directly continuous with a zone that has generally been designated as the amygdalo-striatal transition area in the temporal lobe and we have retained this terminology (see AStr in K1-B 11 and 12 in the mini-atlas; see also section 5). The amygdalostriatal transition area and the caudal approach of the stria terminalis (with accompanying neurons) to the amygdala are best illustrated in Figs 42-45. In this material the distinction between the ventral putamen and the adjacent amygdalostriatal transition area is quite clear (Fig. 45), and there is even additional dorsalventral specialization within the amygdalostriatal area in terms of peptide immunohistochemistry (Fig. 45B). What is not clear, however, is whether this temporal amygdalostriatal transition area is the homologue of the caudal amygdalostriatal zone of the rat brain, which has a predominantly striato-pallidal type projection (Gray et al. 1989; Alheid, unpublished observations) or whether it involves elements resembling more rostral zones of transition alongside the temporal limb of the anterior commissure which seem to preferentially target the amygdala (Alheid et al. 1996). The amygdalostriatal transition zone, incidentally, may be a subcortical site with dense dopamine D3 receptor expression (Murray et al. 1994), a receptor subtype that is postulated to be a potential site of genetic polymorphisms related to the increased susceptibility to schizophrenia (Griffon et al. 1996).

4. OLFACTORY SYSTEM Although functionally important, the primary olfactory structures and pathways constitute a relatively small part of the human brain. Most of them lie on the ventral surface of the forebrain. The projections originating in the olfactory bulb form a compact bundle in the olfactory peduncle (or stalk) including the olfactory tract (olf, also referred to as lateral olfactory tract). As discussed in the previous chapter, the olfactory tract proceeds in a posterolateral direction on the orbital surface of the frontal lobe in front of the anterior perforated space (K1-B 4). Fibers from the olfactory peduncle or stalk have their main areas of termination in the anterior olfactory nucleus (AO, K1-B 1-3) and primary olfactory cortex (Pir, K1-B 3-6). The olfactory tract makes a sharp, medially-directed bend in the region of the limen insulae (white arrowhead in Figs. 1 and 2 in previous chapter), where the frontal part of the primary olfactory cortex

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(PirF) is directly continuous with the temporal olfactory cortex (PirT) on the dorsomedial surface of the parahippocampal gyrus (K1-B 4 and 5). The main terminal areas of the olfactory projection fibers in the primate, described by Meyer and Allison (1949) and by Allison (1954), have been confirmed in part by modern tracer techniques (Turner et al. 1978; Carmichael et al. 1994). In short, the olfactory bulb projection fibers come together to form one large olfactory tract which proceeds in a caudal direction. Along the way, axons, often in the form of collaterals (Cajal 1911; Allison 1953; Luskin and Price 1982; Devor 1976), deviate to terminate in the various cortical and cortical-like olfactory projection areas alongside the olfactory tract as well as passing in a caudomedial direction to nearby parts of the ventral striatum deep to the anterior perforated space. It is unlikely that the situation in the human is radically different from that in other primates. In humans, there is no compact collection of bulbofugal fibers which can properly be referred to as a medial olfactory tract (Allison 1954). To be sure, some olfactory bulb fibers in the monkey and human (K1-B 2-4) do turn medially at the point where the stalk attaches to the ventral surface of the brain in order to reach medially located subdivisions of the anterior olfactory nucleus (retrobulbar area) but they are scattered and do not form a tract. None of them have been shown to reach the septal area, although some apparently reach the rostral hippocampus (ventral taenia tecta) in the monkey (Carmichael et al. 1994). The rostral hippocampus is quite rudimentary in the human brain (e.g. Rose 1927b, p. 380). 4.1. PRIMARY NON-AMYGDALOID OLFACTORY BULB PROJECTION AREAS The target regions of the olfactory bulb projection fibers in the basat forebrain (colored magenta in the Kltiver-Barrera atlas of the previous chapter) are somewhat speculative, since they are based largely on extrapolations from experimental data in the monkey (Meyer and Allison 1949; Turner et al. 1978; Carmichael et al. 1994) and on a 'degeneration' study in the human brain (Allison 1954). The staining of the superficial myelinated olfactory bulb fibers in the Kltiver-Barrera (K1-B) sections and the presence of a distinct 'subpial glia zone' related to paleocortex (e.g. Economo and Koskinas 1925; Sanides and Sas 1970; Price 1973; Stephan 1975) also provide some guidance in identifying the course and distribution of these fibers in the human brain. These features (see inserts in K1-B 2 and 5) are clearly evident in the sections presented in the mini-atlas at the end of the previous chapter (K1-B 1-10). Lacking a unique 'olfactory histochemical marker', it is obviously difficult to determine exactly how far the olfactory bulb projection fibers extend in the various parts of the human basal forebrain. The areas shaded in magenta in K1-B 1-10 should provide a reasonably good, if deliberately conservative estimate of the primary olfactory areas in the human brain. That there is difficulty in estimating the extent of the olfactory bulb projections in the regions where the myelinated olfactory tract fibers gradually disappear is indicated in the figures by a fading color.

4.1.1. Anterior olfactory nucleus (retrobulbar area) The gray substance behind the olfactory bulb (i.e. both in the free-standing olfactory peduncle and further back where it becomes attached to the orbital surface, K1-B 1 and 2) is considered to be subcortical by some investigators but others consider it to be 147

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cortical or cortical-like. Herrick (1910) introduced the term 'anterior olfactory nucleus', which is most commonly used by Anglo-American authors (e.g. Gurdjian 1925; Young 1936; Crosby and Humphrey 1939, 1941; Lohman 1963; Pigache 1970; Turner et al. 1978; de Olmos et al. 1978; Carmichael et al. 1994). Others have preferred the term 'regio retrobulbaris' or retrobulbar area because of structural similarities of the region to cortex (e.g. Rose 1927a,b; Popoff and Popoff 1929; Krieg 1946; Vaz Ferreira 1951; White 1965; Stephan 1975). As discussed in some detail by Stephan (1975), the peduncular gray in macrosmatic mammals does have a laminated appearance which would justify its inclusion in the paleocortex. The situation is somewhat different in the human, in which the structure does not exhibit a consistent lamination. Nonetheless, as noted recently by Zilles (1990), it seems reasonable to include the human retrobulbar area in the paleocortex because it is equivalent to the peduncular gray in macrosmatic mammals and is directly continuous with the rest of the paleocortex, i.e. the primary olfactory cortex. Cellular elements located in the rostral part of the olfactory stalk or peduncle, and even to some extent within the olfactory bulb itself, are referred to as the bulbar (rostral) part of the anterior olfactory nucleus or as the retrobulbar area (Crosby and Humphrey 1941; Stephan 1975). At the point where the peduncle merges with the orbital surface, the peduncular gray becomes more voluminous (AO in K1-B 1). Different parcellations have been recognized in humans (e.g. Crosby and Humphrey 1941; Stephan 1975). Nevertheless, as indicated by Zilles (1990, p.760), it is often difficult to perceive subdivisions comparable to those in macrosmatic mammals and individual variations may make such an effort fruitless. Further back, at the level where the peduncle has disappeared and an olfactory tract is clearly identifiable on the orbital surface (K1-B 2), subdivisions can be recognized both deep to the tract and on its medial and lateral aspects. They can reasonably be compared to the caudal, medial and lateral parts of the AO recognized at this level by Stephan (1975, Figs. 205-207). Carmichael et al. (1994) have identified a small cell group in the monkey, located partly within the olfactory tract itself, which they believe to be equivalent to the external part of the anterior olfactory nucleus in macrosmatic mammals. They made this suggestion partly on the basis of their retrograde tracing experiments which indicated a prominent projection from this cell group to the contralateral olfactory bulb. This is reminiscent of the situation in the rat (e.g. de Olmos et al. 1978; Alheid et al. 1984; Shipley et al. 1995). It is not known if an external subdivision of the anterior olfactory nucleus exists in the human.

4.1.2. Primary olfactory cortex ('piriform cortex') The retrobulbar gray substance gradually establishes continuity with the primary olfactory cortex (piriform or prepiriform cortex 7) laterally, and also with some periallocortical formations in the caudal orbitofrontal region. The primary olfactory cortex, which we have labeled Pir (piriform cortex) in K1-B 4-6, is closely related to the olfactory tract as it proceeds laterally towards the limen insulae. It has a three-layered 7The terms 'piriform' and 'prepiriform' cortex are often used interchangeably for the major cortical termination areas of olfactory bulb projection fibers in both macrosmatic and microsmatic mammals. As discussed by Stephan (1975), neither is satisfactory. The entorhinal area is traditionally included in the piriform lobe (Smith 1895; for definition of piriform lobe, see also Stephan 1975, p. 865) but it is usually not included in the term 'piriform cortex', which is ofien used for the area we prefer to call 'primary olfactory cortex'. Olfactory cortex, therefore, is not 'prepiriform', and Price and his colleagues (Haberly and Price 1978; Carmichael et al. 1994), following the lead of Powell et al. (1965), dropped the prefix 'pre'. As a concession to uniformity, we have labeled primary olfactory cortex 'Pit' as used by Price and his colleagues as well as in the widely used atlases by Paxinos and coauthors (e.g., Paxinos and Watson 1986; 1997; Franklin and Paxinos 1997; Mai et al. 1997).

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appearance typical of paleocortex (insert in K1-B 5) and is most easily identified by a prominent superficial, densely populated pyramidal cell layer (layer II) which also contains many polymorphic neurons (see also review by Pigache 1970). In the human, there is a tendency for the superficial cell layer to form islands or clusters (Cajal 1911; 1955) in both the frontal (K1-B 4 and 5) and in the more extensive temporal part of the primary olfactory cortex. This clustering gives the superficial cell layer an undulating appearance (K1-B 4-6). In accordance with O'Leary (1937) and Pigache (1970), we prefer the term 'primary olfactory cortex' instead of piriform or prepiriform cortex although we have labeled it Pir in the figures in order to remain consistent with the widely adopted nomenclature used by Paxinos and his collaborators (Paxinos and Watson 1986; Mai et al. 1997). With the term 'primary' we emphasize the fact that this paleocortical area receives significant input from the olfactory bulb in all species, a characteristic shared with the anterior olfactory nucleus in the retrobulbar gray. Primary olfactory cortex has boundaries that can be reasonably well defined in most species (Pigache 1970) but, in humans, some of its boundaries are transitional in nature. These produce poorly-defined margins, especially at the border towards ventral striatum in the region of the anterior perforated space (K1-B 6 and 7; see also Section 2.1.1). It is important to realize that the boundaries of the primary olfactory cortex do not indicate the limit for the spread of olfactory bulb projection fibers in the brain. Besides the anterior olfactory nucleus, which is a prime target in all species, insular and temporal periallocortical regions, olfactory tubercle, amygdala and entorhinal area also receive bulbofugal fibers. The extent of their innervation shows species variation. For instance, in the monkey (e.g. Carmichael et al. 1994), only part of the olfactory tubercle receives input from the bulb, and a similar situation exists in regard to other structures, e.g. the superficial amygdala and the entorhinal area (see below). The olfactory tubercle, superficial amygdaloid areas and the entorhinal cortex should not be considered as 'primary olfactory cortex'. Following olfactory bulb removal, they, as well as the anterior olfactory nucleus, are spared from the rapidly developing transneuronal degeneration that occurs in the true primary olfactory cortex (Price 1976; Heimer and Kalil 1978; Carlsen et al. 1982). These atrophic changes, limited to the area which we, in accordance with the observations of O'Leary (1937) and Pigache (1970), have labeled primary olfactory cortex, have been described in many mammals, including the human (e.g. Winkler 1918; Uyematsu 1921; Allison 1953, 1954). These circumscribed degenerative changes indicate that the primary olfactory cortex is trophically dependent on incoming olfactory impulses to a greater degree than are other olfactory bulb projection areas. The cytoarchitecture and intrinsic organization of the primary olfactory cortex of macrosmatic animals have been the focus of a number of detailed studies and excellent reviews (e.g. Calleja 1893; Cajal 1911, 1955; Haberly 1990; Herrick 1924; O'Leary 1937; Valverde 1965; Stevens 1969, Pigache 1970; Stephan 1975; Price 1990; Shipley et al. 1995, 1996). Several of these authors have paid special attention to connections and transmitter histochemistry (e.g. Haberly 1990; Shipley et al. 1995, 1996). Comparable data from the human olfactory cortex are extremely sparse. Endopiriform nucleus. The term 'endopiriform nucleus', also known as the 'ventral prepiriform claustrum' (Macchi 1951) was originally introduced by Loo (1931) to denote a group of cells which, in the opossum, are located deep to the primary olfactory cortex and are in direct continuity with the claustrum dorsally. Loo's (1931) original proposal that the endopiriform nucleus is a structure separate from 149

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the dorsally located claustrum receives some support from the developmental studies in the rat by Bayer and Altman (1991) who discovered that the two structures originate in different types of cortical primordia and are characterized by different developmental patterns. On comparative grounds (Striedter et al. 1997) it has also been argued that the endopiriform nucleus and the claustrum have different origin. Likewise, Krettek and Price (1978), who were the first to use the term 'endopiriform nucleus' in the rat, suggested that it might be conceived of as the deep layer of the primary olfactory cortex. They widened the use of the term in the rat to a ventromedial extension (labeled Epv on section 29 in the atlas by Swanson 1992) that has traditionally been considered part of the basolateral amygdaloid complex (see area labeled BLV in Fig. 29 in Paxinos and Watson 1986). Although we have retained the term endopiriform nucleus for the heterogenous collection of neurons deep to the primary olfactory cortex in the rat, we refrain from including the above-mentioned part of the basolateral amygdaloid complex (Alheid et al. 1995). In the human, as in the rat, it is difficult, in places, to identify a border between the endopiriform nucleus and the claustrum (which becomes especially voluminous in the temporal lobe where it attaches to the rest of the brain behind the limen insulae see VC1 in K1-B 5-9). In his review of the human olfactory system, Price (1990, Fig. 29.8) combines the claustrum and endopiriform nucleus into a single complex, labeled En! C1. The endopiriform nucleus, an integral part of the 'Regio claustralis allocorticalis' of Brockhaus' (1938) terminology for the human, was included in the 'ventral claustrum' by Macchi (1951). Claustral areas bordering on the rostral parts of the amygdaloid nuclei (ACA in K1-B 8) have been referred to as the 'amygdaloclaustral area' by Macchi (1951) and as 'claustrum preamygdaleum' by Brockhaus (1938). As described below in section 4.3.2., part of claustrum has been included in the anterior amygdaloid area by some authors. Bulbopetal fibers originating in the basal forebrain. The monkey basal forebrain areas which receive projections from the olfactory bulb also project back to the olfactory bulb (Carmichael et al. 1994). The majority of these bulbopetal fibers originate in the orbitofrontal olfactory structures, i.e., the anterior olfactory nucleus and frontal part of the primary olfactory cortex, rather than in temporal olfactory structures (Carmichael et al. 1994). Many cells in the ventral agranular part of the insula are prominently labeled following injection of retrograde tracer in the bulb (Fig. 5C in Carmichael et al. 1994) underscoring the strong association between the ventral insula and the olfactory system (see below). It is important to realize, however, that the gray substance in the anterior perforated space, labeled olfactory tubercle (TOL) by Carmichael and his collaborators, does not give origin to bulbopetal projections. Likewise, the 'olfactory tubercle' a term to which our objections have been previously stated, see Section 2.1.1., does not project to nearby primary olfactory cortex, although it receives significant input from the primary olfactory cortex (e.g. Haberly and Price 1978). Taken together, these facts would appear to reaffirm our previously stated position, that the 'olfactory tubercle' should not be considered as a medial extension of the olfactory cortex, but rather as an integral part of the striatal complex (Heimer 1978). Finally, it should be mentioned that the olfactory bulb in the rodent receives centrifugal projections from 'non-olfactory' parts of the basal forebrain, including in particular cholinergic and GABA-ergic input from the horizontal limb of the nucleus of the diagonal band (e.g. Price and Powell 1970; de Olmos et al. 1978; Zfiborszky et al. 1986). The situation regarding input to the olfactory bulb from the horizontal limb

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of the nucleus of the diagonal band appears to be the same in the primate (Mesulam et al. 1983). 4.1.3. Insular and temporopolar periallocortical areas

At the region of the limen insulae, where the insula becomes continuous with the temporal lobe, the primary olfactory cortex of the monkey 'trifurcates', to borrow an expression from Mesulam and Mufson (1982a) who state, 'One limb remains in an orbital position, a second limb extends into the insula, and a third limb covers the medial aspect of the temporal pole' (in the region of the parahippocampal gyrus). This situation is clearly demonstrated in the Old World monkey (Fig. 5 in the MesulamMufson paper). Olfactory bulb fibers accompany the 'insular limb' of the primary olfactory cortex into the ventral part of the insula in the monkey (see Fig. 6 in Turner et al. 1978), as they do in other mammals (e.g. Switzer et al. 1985; Shipley and Geinisman 1984; Shipley et al. 1990). Although Carmichael et al. (1994) do not mention the existence of olfactory bulb projections to the ventral insula in the monkey, their retrograde tracing studies indicate that the primary olfactory cortex extends laterally to include the ventral insula. In the human, the existence of a characteristic superficial glia zone accompanying the myelinated olfactory bulb fibers suggests a projection area in the ventral agranular insula (Ia) indicated in magenta color in K1-B 1-5. This is reminiscent of the picture shown by Mesulam and Mufson (1982a) and Turner et al. (1978) in the monkey. In a fortuitous CCK-section (Fig. 46) corresponding to the level shown in K1-B 3, myelinated fiber bundles can be seen to radiate from the lateral olfactory tract towards the ventral part of insula. There the tract gradually tapers off in both dorsal and ventral directions. The presence of direct olfactory input to the ventral agranular insular area which joins the insular gustatory area (e.g. Pritchard et al. 1986; Yaxley et al. 1990) provides the opportunity for integration between olfaction and taste, and resembles the situation in the rat (Shipley et al. 1995). It is important to recall that both insular and orbitofrontal periallocortical regions (Ia and OFa in K1-B 2 and 3) receive projections from the anterior olfactory nucleus and the primary olfactory cortex (see below). Just rostral to the level of the limen insulae (K1-B 2) the distribution of myelinated olfactory tract fibers and accompanying subpial glia zone suggest that olfactory bulb projection fibers might reach a surprisingly large part of the temporopolar periallocortex (TPpall in K1-B 1-4), a region that has been delineated by several authors (e.g. Mesulam and Mufson 1982a; Moran et al. 1987 and Gower 1989). This myelinated fiber tract, which can be appreciated already at low magnification (see rectangle and inset in K1-B 2), is directly continuous with the main part of the olfactory tract as it turns the corner at the limen insulae (K1-B 3). It gradually diminishes in thickness and finally disappears at the level just rostral to that shown in K1-B 1 as well as in the two gyri immediately lateral and medial to the gyrus with the rectangle in K1-B 2. It is recognized that Carmichael et al. (1994) established that secondary olfactory projection fibers originate in the primary olfactory cortex of the monkey and tend to distribute their terminals in layer one in adjacent orbitofrontal areas. Nevertheless, a prominent myelinated fiber layer cannot be identified in the human posterior orbital and insular areas (Ia in K1-B 2 and OFa in K1-B 3) which, judging from the studies of Carmichael et al. (1994) in the monkey, would be the most likely candidates to receive such secondary projection fibers. Nor is any myelinated fiber layer deep to a subpial 151

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Fig. 46: Coronal section at the level of the limen insulae (see K1-B 3 for approximate location of this region)

stained for cholecystokinin. Note how myelinated fiber bundles radiate from the lateral olfactory tract (olf) towards the ventral part of the agranular insula (Ia).

glia lamina present in any other parts of insula or temporopolar cortex in the human brain. While the most likely explanation for the prominent myelinated fiber tract illustrated in the insert in K1-B 2 is that it represents the peripheral distribution of olfactory bulb fibers, we are not in a position to indicate definitive discovery of projections to this part of the primate temporopolar cortex. Nevertheless, by coloring the region magenta we have indicated our strong bias toward considering it as part of the olfactory bulb projection area.

4.1.4. Ventral striatum

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tubercle, we suggest that this layer and its counterpart in the rat (Heimer 1978) should be regarded as striatal in nature (see Section 2.1.1.). In the monkey, Turner et al. (1978) and Carmichael et al. (1994) have demonstrated that olfactory bulb projection fibers do reach part of this region. Based on the distribution of myelinated fibers peeling off from the olfactory tract and the presence of a subpial layer, there is reason to think that the situation is similar in the human. In other words, part of the striatal complex, which extends to the ventral surface in the region of the anterior perforated space, does in all likelihood receive input directly from the olfactory bulb as indicated in K1-B 6 and 7. 4.2. OLFACTORY ASSOCIATION AREAS IN THE ORBITOFRONTAL CORTEX The agranular orbitofrontal cortex (OFa) and the ventromedial extension of agranular insular cortex (Ia) represent transitions between allocortex (represented here by primary olfactory cortex) and granular type isocortex. This form of transitional cortex or periallocortex is termed paralimbic by Mesulam and Mufson (1982a) and, with the neighboring orbitofrontal regions, has been parcellated in great detail in the macaque monkey on the basis of cytoarchitectonic and histochemical characteristics (Carmichael and Price 1994). Regional connections have been studied in the monkey by experimental-anatomical methods (e.g. Potter and Nauta 1979; Porrino et al. 1981; van Hoesen 1981; Mufson and Mesulam 1982; Mesulam and Mufson 1982b; Goldman-Rakic and Porrino 1985; Russchen et al. 1987; Barbas and Pandya 1989; Barbas and de Olmos 1990; Carmichael et al. 1994; Barbas and Blatt 1995; Haber et al. 1995; Carmichael and Price 1995a,b). Many of these connections have been summarized recently in reviews by Amaral et al. (1992) and by Price et al. (1996). The general consensus from all of these tracing studies is that the various areas in the basal orbitofrontal region, including the orbital and insular periallocortical regions displayed in K1-B 2-4, are closely interrelated by way of a highly organized system of short association fibers. For instance, the agranular insular and orbitofrontal transition areas, which border on the primary olfactory areas (i.e. anterior olfactory nucleus and primary olfactory cortex), are closely and reciprocally related to 'primary' olfactory regions (Carmichael et al. 1994). In fact, as mentioned earlier in regard to the insula, it appears that olfactory bulb projection fibers do reach some of these periallocortical areas in the orbitofrontal regions where they border on the primary olfactory cortex (K1-B 2 and 3). Such 'spilling over' of olfactory bulb projection fibers into periallocortical areas also occurs in macrosmatic mammals (e.g. Switzer et al. 1985, rat; Shipley and Adamek 1984, mouse) Systematic tracing studies in the monkey by Carmichael et al. (1994) confirm the existence of olfactory association areas in the orbitofrontal cortex, as had been suggested on the basis of electrophysiological studies in the dog by Allen (1943). Other parts of the posterior orbitofrontal cortex in the human receive input from sensory cortical or thalamic regions representing non-olfactory modalities (visual, gustatory, somatosensory and visceral). In other words, all sensory modalities are represented in posterior orbitofrontal regions. Price and his colleagues (Price et al. 1996) have recently reviewed the neuronal circuits that these orbitofrontal regions establish with other parts of forebrain, Van Hoesen and his colleagues (Van Hoesen et al. 1993; Morecraft and Van Hoesen 1998) have emphasized their close relations to the anterior cingulate cortex, and Haber and her associates (Haber et al. 1995; Chikama et al. 153

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1997) have traced their output channels through the ventral parts of the basal ganglia in the monkey. Considering the various functional affiliations of the posterior orbitofrontal cortical regions and their overall connections, it is hardly surprising that lesions involving this part of the brain tend to have far-reaching effects. These are especially reflected by the inappropriate behavior which is an important part of the so-called orbitomedial frontal syndrome (e.g. Tranel and Damasio 1993; Malloy et al. 1993; Rolls 1995). 4.3. OLFACTORY AMYGDALA The olfactory bulb projection fibers which reach the anterior part of the parahippocampal gyrus in the temporal lobe terminate most prominently in the temporal part of the primary olfactory cortex (PirT, K1-B 9). The superficial part of the amygdaloid complex and part of the entorhinal cortex also receive olfactory bulb input, although the primate terminations (Turner et al. 1978; Carmichael et al. 1994) are not everywhere so prominent as those in the rat (e.g. Shipley et al. 1995, 1996) and other macrosmatic animals. Although extensive superficial parts of the amygdala are characterized by input from the olfactory system, the primate medial amygdaloid nucleus (Me, K1-B 11 and 12) does not appear to receive direct input from the olfactory bulb (Turner et al. 1978; Carmichael et al. 1994). (The medial amygdaloid nucleus was discussed in the context of the extended amygdala in Section 3.2.2.) Amygdalopiriform transition area. Most of the amygdalopiriform transition area, comparable to the subfields PACo, PACs, PAC1 and PAC2 of Price et al. 1987, appears to receive input from the olfactory bulb in the human (K1-B 5-7), as it does in the monkey (Carmichael et al. 1994). A possible exception is the most caudal part of the posteromedial amygdalopiriform transition area (See Section 5.2.3.). Anterior amygdaloid area. Considering the definition of the anterior amygdaloid area in this and many other publications (Section 5.2.3.), it appears reasonable, as suggested by Stephan (1975) and de Olmos (1990), that the superficial part of the anterior amygdaloid area is the recipient of olfactory bulb input (K1-B 8) as in other primates and macrosmatic mammals such as the rat (e.g. Heimer 1978). How far medially the olfactory tract fibers reach into the superficial part of the human AAA and beyond is difficult to say. Olfactory bulb projections to the lateral part of the horizontal limb of the diagonal band do seem to exist in the monkey (Carmichael et al. 1994, Fig. 1G and H). A subpial glia zone in this area in the human, however, does not necessarily indicate an olfactory bulb projection area (Sanides and Sas 1970). The cortical amygdaloid nuclei. The region that was originally referred to as the cortical nucleus in the human (Johnston 1923; Hilpert 1928; Crosby and Humphrey 1941) occupies most of the superficial part of the amygdala located in the semilunar gyrus (SLG, K1-B 10). Most of this region in the monkey receives direct input from the olfactory bulb (Turner et al. 1978; Carmichael et al. 1994). The situation is likely to be similar in the human (K1-B 8-10). Judging from diminution of the distinct subpial glia zone this input becomes less pronounced in more ventral and caudal parts of the semilunar gyrus. The presence of olfactory bulb projection fibers is especially prominent in the region of the anterior cortical nucleus (K1-B 8-10). This nucleus is located in the fundus and lower lip of the endorhinal sulcus, just behind the primary olfactory cortex. A nearby region, which occupies most of the semilunar gyrus ventral to the anterior cortical nucleus, is referred to as the ventral cortical nucleus. Most of this region in the 154

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monkey (Turner et al. 1978; Carmichael et al. 1994), and probably in the human, (K1B 8-10; see also Price 1990) receives olfactory bulb projection fibers. As discussed in Section 5.2.3., it is unlikely that an olfactory-related posterior cortical nucleus can be identified in the human. 4.4. OLFACTORY ENTORHINAL FIELD The question of whether the entorhinal cortex, which serves as an important gateway to the hippocampus, receives direct projections from the bulb, was long a matter of debate. It was only with the aid of more sensitive silver methods that this question could be affirmatively answered in the rat (White 1965; Heimer 1968) and the rabbit (Scalia 1966). Olfactory bulb projections to the entorhinal area have now been confirmed in a number of species including the monkey (Turner et al. 1978; Amaral et al. 1987; Price 1990; Carmichael et al. 1994). Such projections reach a major part of the entorhinal cortex in macrosmatic mammals (e.g. Kosel et al. 1981; Room et al. 1984), but their distribution is more restricted in the monkey (Turner et al. 1978; Carmichael et al. 1994). In the absence of a reliable method for labeling olfactory bulb projection fibers in the human, no hard data are available. Estimates can, however, be made by extrapolation from the monkey, and from the distribution of olfactory tract fibers and concomitant subpial glial zone in Klfiver-Barrera sections from human brains. Based on earlier studies, especially those by Price (1990) and Insausti et al. (1995), the olfactory bulb projections to the human entorhinal cortex would seem to be limited primarily to what they, and others (Amaral et al. 1987), have referred to as the olfactory field (OE in K1-B 6-7). The olfactory part of the entorhinal area includes the superficial part of the region named ambiens gyrus (AG in K1-B, 8 and 10) which forms a more or less pronounced prominence below the semiannular sulcus. The ambiens gyrus is usually demarcated ventrally by an indentation (inferior rhinal sulcus of Retzius 1896; intrarhinal sulcus of Amaral and Insausti 1990). This 'sulcus' is barely apparent in the brain we have used for the introductory series of KltiverBarrera-stained coronal sections, or in the brain shown in Fig. 47A, but is pronounced in Fig. 47B, taken from another brain. The reason for this variation, according to Van Hoesen and his colleagues (Arnold et al. 1991; Van Hoesen 1997) is that the 'sulcus' is artificial in the sense that it represents the impression made by the edge of the tentorium. This indentation provides for a more or less prominent 'landmark' on the ventral surface of the parahippocampal gyrus in about 70% of human brains (Corsellis 1958). Pathology related to this abnormality is clearly evident in the brain displayed in Fig. 48. When this indentation is exaggerated for whatever reason (e.g. increased intracranial pressure, head injury, etc.) it might, according to Van Hoesen (1997), lead to cytoarchitectural abnormalities (see inset in Fig. 48) with subsequent neuropsychological symptoms. This abnormality appears in the anteromedial 'uncal' part of the entorhinal area, which is that part of the hippocampal formation most closely related to the two major functional-anatomical systems discussed earlier in this chapter, i.e. the ventral striatopallidal system and extended amygdala (see Heimer et al. 1997b for further discussion of the relation between the anterior hippocampal formation and the mediobasal forebrain and its importance in the context of neuropsychiatric disorders).

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Fig. 47: The 'intrarhinal sulcus' (arrows) is an artifact (see text) produced by the impression of the edge of the tentorium. It is barely visible in the brain illustrated in A, but quite pronounced in the brain shown in B.

5. S U P E R F I C I A L AMYGDALA AND T H E L A T E R O B A S A L C O M P L E X 5.1. G E N E R A L S T R U C T U R E OF T H E A M Y G D A L A Major subdivisions. Humphrey (1936) and Crosby and Humphrey (1941) divided the amygdaloid complex into a superficial corticomedial and a deeply located basolateral group of nuclei. This approach was based primarily on J.B. Johnston's (1923) subdivision into a phylogenetically 'older' corticomedial group (including also the central nucleus) and a 'younger' basolateral group of nuclei 8. With minor variations Johnston's subdivision is generally adhered to by most contemporary scientists (e.g. Aggleton 1985; Price et al. 1987; Amaral et al. 1992; Kordower et al. 1992; McDonald et al. 1995; Sorvari et al. 1995; Stefanacci et al. 1996; Emre et al. 1993). J.B. Johnston's pioneering comparative and developmental studies of different species, including the human, also resulted in an additional, and as it now appears, fundamental insight regarding forebrain anatomical organization, i.e. that the developmentally distinct central and medial amygdaloid nuclei extend into the medial part

8Although Johnston (1923) expresses this view on the basis of origin and age of the amygdaloid nuclei (p. 456 in his paper), he notes (pp. 472-473) that the morphological evolution of the amygdaloid complex suggests that the medial and the central nuclei constitute an old part to which the basolateral and cortical nuclei are newly added (see Koikegami 1963; Stephan 1975, for further discussion of this subject).

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Fig. 48: The pathology including deformed neurons and subpial gliosis in the region of the 'intrarhinal sulcus' is clearly evident in this coronal Kliiver-Barrera stained section through the uncal part of the entorhinal area. The asterisk in the inset points to a zone of gliosis characterized primarily by oligodendroglia proliferation.

of the basal forebrain to form what we have referred to as the extended amygdala (Figs. 1 and 2C and D; also K1-B 6-12 in chapter I). This important discovery points to a dichotomy between the centromedial group (including to some extent the anterior amygdaloid area) and a cortical-basolateral group of nuclei in a manner alluded to in earlier studies by V61sch (1906, 1910). Many others since V61sch and Johnston (e.g. Hilpert 1928; Brockhaus 1940; Macchi 1951; Stephan 1975; Stephan and Andy 1977; Stephan et al. 1987; ten Donkelaar et al. 1979) have emphasized a subdivision between 157

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the centromedial and the cortical-basolateral group of nuclei. Hilpert (1928), for instance, suggested that the small-celled centromedial part belonged to the substantia innominata, which in his opinion was clearly demarcated from what he considered to be the amygdaloid body. Brockhaus (1938), in his classic study of the human amygdala, also makes a special point of this fundamental subdivision by referring to the centromedial complex and the anterior amygdaloid area as the supraamygdaloid division ('Supraamygdaleum') in order to separate it from what he considered to be the amygdaloid nucleus in the strict sense ('Amygdaleum proprium'), i.e. the corticalbasolateral subdivision. Although our preferred terminology is different from that of Brockhaus, we endorse his and Hilpert's fundamental subdivision by including the centromedial amygdaloid complex in the extended amygdala. The concept of the extended amygdala, incidentally, is clearly foreshadowed in the descriptions of the human brain by these pioneering neuroanatomists. [The boundary between the extended amygdala, represented by the centromedial nuclear group, and the amygdaloid body in this more restricted, classical sense is indicated by a dashed line in Figs. 53-55.] Rotations of the amygdala in primate evolution. Some of the difficulties that confront the study of the primate amygdala in a comparative-anatomical context relate to the marked expansion of the temporal neocortex in the course of primate evolution, and the concomitant displacements and rotations within the temporal lobe (Figs. 49 and 50). These rotational changes (e.g. Johnston 1923; Macchi 1951; Spatz 1966; Humphrey 1968; Sidman and Rakic 1982; Gloor 1997) can, for didactic purposes, be imagined to occur in two directions. Rotation and displacement of the ventral part of the temporal lobe in a medial and upward direction explains why the amygdaloid body, which is located on the ventral temporal surface in the rat (Fig. 49), is located in the medial and dorsal part of the temporal lobe in the human (Fig. 50, see also K1-B 11). The other rotation, which takes place more or less around a transverse axis, explains why the entorhinal area, which is located behind the amygdaloid body in the rat (Fig. 49A), has shifted to a more rostral and medial position in the human (Fig. 50). Although analogous amygdaloid nuclei are generally present in all mammals, their positions in the primate, especially in the human, are significantly changed when compared to macrosmatic species (Johnston 1923). One example is provided by the medial, basomedial, basolateral and lateral amygdaloid nuclei, which, in the rat, are located from ventromedial to dorsolateral (Fig. 49B), but which, in the human, are rotated 90 ~ to place the medial nucleus dorsomedially and the lateral nucleus ventrolaterally (Fig. 50B). This rotation also explains why, in human and other primates, the anterior cortical nucleus is located deep to the endorhinal sulcus (hemispheric sulcus) but rostral to the medial amygdaloid nucleus, whereas in the rat it is located on the ventral surface and lies lateral and anterior to the medial nucleus. Despite rotation the relative positions between the individual nuclei are retained in the human (Johnston 1923). An unfortunate consequence of this rotation is that in the human a literal interpretation of the names of the amygdaloid nuclei can sometimes be misleading; for example, the medial nucleus is no longer the most medial part of the amygdala, nor is the anterior amygdaloid area the most anterior part of the human amygdala (e.g. see Fig. 51). This latter situation seems to have been the occasion for some confusion in identification of this area (see section 5.2.3.). The recognition of the effects of developmental rotation in primates is important in identifying homologous amygdaloid nuclei among species of the amygdala. Incidentally, it is also important in understand-

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Fig 49: The general arrangement of the various amygdaloid nuclei in the rat is depicted in B, which represents a coronal section through the amygdala. The approximate level for the coronal section is indicated by the bar superimposed on the schematic sagittal section of the rat brain depicted in A. The arrow in B may be compared with a similar axis shown in Fig. 50B for the human brain.

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<

Fig. 50: The arrangement of the various subdivisions of the amygdala in the human brain is shown in a schematic coronal section in B. The approximate level of the coronal section is indicated by the white bar in A, which represents a sagittally-oriented diagram of the human brain. In B the arrow running from the optic tract to the lateral nucleus allows comparison with a similar axis drawn for the rat brain in the preceding figure (49B). Note that just within the coronal plane, the nuclei are rotated nearly 90~ from the equivalent position in the rat. It should be noted that in the sagittal plane, a second vector of rotation causes the lateral nucleus to begin rostral and ventral to the centromedial amygdala, whereas in the rat the lateral nucleus starts caudolateral to the centromedial nuclei.

ing the form and position of the primate stria terminalis and hippocampus, as well as the dorsal and, especially, the ventral striatum system. There is a dramatic phylogenetic increase in the size of the laterobasal amygdaloid complex (BM, BL and La). As indicated above, the laterobasal amygdala is closely and reciprocally connected to neocortex. With the expansion of the neocortex in the primate, there is a concomitant increase in the size of the laterobasal complex relative to that of the centromedial part. 5.2. S U P E R F I C I A L A M Y G D A L A 5.2.1. Is the superficial amygdala a cortical or subcortical structure?

The concept of the 'olfactory amygdala' emphasizes the fact that input from the olfactory bulb is a characteristic feature of most of the superficial gray matter of the amygdaloid complex in mammals, including primates (e.g. Meyer and Allison 1949; Turner et al. 1978; Price 1990; Carmichael et al. 1994). The superficial part of the amygdaloid complex, however, is quite heterogeneous, especially in the primate, and the extent to which olfactory bulb fibers involve its different parts in the human is not known. The studies mentioned in one of the previous sections (4.3.) indicate that the olfactory bulb input to some of the areas in the superficial amygdala in the monkey is sparse or even absent (see also K1-B 9-12 in the mini-atlas in the previous chapter). There is no consensus as to whether the heterogeneous superficial gray areas of the amygdala should be considered cortical or subcortical in nature. This ambiguous situation, resembling that related to the definition of some of the other olfactory bulb projection areas near the basal surface of the brain, such as the anterior olfactory nucleus (retrobulbar area), has been discussed at length by both Pigache (1970) and Stephan (1975) who came to different conclusions as to whether the superficial gray matter of the amygdaloid body represents a cortical structure, or at least a semicortical one. Pigache (1970), like Johnston (1923) and many others, contends that the superficial amygdaloid gray substance should not be considered to be cortical. An important argument in favor of Pigache's position is the absence of an external capsule which, if present, would clearly differentiate the superficial parts of the amygdala from its deeper regions. This circumstance, together with a poorly developed deep cell layer that lacks any radial organization, prevented Pigache from considering the superficial amygdala as a cortical or semicortical structure. Recent developmental studies of the amygdala (e.g. ten Donkelaar et al. 1979; Bayer 1980) appear to show that the superficial amygdaloid gray follows a pattern reminiscent of that seen in the rest of the amygdala, rather than that of the cerebral cortex. On these grounds, it seems reasonable to conceive of the superficial amygdala as a subcortical structure. 161

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Others consider that the superficial amygdaloid gray can be better understood as a cortical, or at least a semicortical or 'corticoid' structure (e.g. Sanides 1958; Jacobs et al. 1971; Stephan 1975; McDonald 1992; Alheid et al. 1995). Brockhaus (1938) was a prominent advocate of this position. His subdivisions are of particular interest in the context of this review, since the superficial amygdala is especially heterogeneous in the human. As part of his systematic approach to the analysis of the amygdala, Brockhaus restricted his definition of the superficial, semicortical amygdaloid region to the two first layers, the molecular layer and the superficial cell layer (layer II), and did not include deeper parts of what is now generally referred to as the cortical amygdala. Brockhaus' detailed and richly illustrated cytoarchitectonic studies may become increasingly useful as histochemical data on the human accumulate. De Olmos (1990) has compared his subdivisions to those named by Brockhaus. On the basis of detailed comparative-anatomical studies, Stephan (1975) provided his own nomenclature, which in many ways represents a simplified version of Brockhaus' subdivisions. The subcortical classification which was forcefully promoted by Pigache (1970), has been used in the past by most Anglo-American scientists, whereas the second system, which was meticulously developed by Brockhaus in the human (1938), and later modified and applied across a number of species by Stephan (1975), has been adopted with certain modifications primarily by the Japanese school of scientists (e.g. Fukuchi 1952; Mikami 1952; Koikegami 1963), and by Turner et al. (1978). The choice between the two systems of classification of a region that is especially heterogeneous in the human brain is not easy. De Olmos (1990), in his broadly based analysis of the superficial or 'olfactory' amygdala, arrives at a classification system which in substance is basically similar to the subdivisions recognized so presciently by Brockhaus. The terms used by de Olmos to label these subdivisions, on the other hand, which are also applied to the olfactory amygdala in the current chapter (see Section 4.3.), generally honor the Anglo-American tradition (i.e. Johnston 1923; Crosby and Humphrey 1941). These terms, suggested by Johnston and Crosby and Humphrey, are widely used, especially in non-primates, but also in primates. Using similar terms for homologous structures is necessary when extrapolating the results of experiments in other species to the human brain. 5.2.2. Superficial amygdala: a plethora of terms The tables in the Appendix at the end of this chapter compare our own and other currently used terminologies with those developed by Brockhaus and Stephan. They contain a surprisingly large number of different terms and one would be inclined to agree with Pigache (1970), who said: 'It is ludicrous that workers fresh to this field should find the language of anatomists more difficult to master than the facts of anatomy themselves'. As examination of the coronal sections through the amygdala (Figs. 51-55) makes clear, the superficial structures, in general, have a laminated structure. Deep to a distinct molecular layer (layer I) the neuron-rich zone can usually be divided into two layers (layers II and III). For Stephan (1975) this provided sufficient evidence to include the superficial amygdala in paleocortex. Like Rose (1927a,b) before him, he referred to the superficial structures of the amygdala as periamygdaloid semicortex, and used the abbreviation Pam (see Appendix). The periamygdaloid cortex (Pare) of Stephan (1975). Stephan's PamA (A for anteromedial), which is divided into three parts, denotes the superficial gray regions. In his view these are the superficial part of the anterior amygdaloid area (PamAa), the 162

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Figs. 51-55: An atlas of the human amygdala for coronal sections is shown in this series of photographs and their matching line drawings. Parvicellular neuronal groups (interface islands) within each level are filled in with gray. Some of these groups with more heterogenous cell populations are generally found in association with the paralaminar nucleus (PL), and have been termed glomerular clusters (G) by Brockhaus (1938). Other more homogenous parvicellular cell clusters are found near or adjacent to the centromedial nuclei and have been termed the intercalated cell masses (I). Arrowheads on the medial surface of the temporal lobe mark the borders between the various superficial amygdaloid nuclei. Asterisks in Fig. 55 mark a heterogeneous population of neurons which in many ways resemble the neurons of the bed nucleus of the stria terminalis (see text). In Fig. 54 a hole in the lateral amygdala resulted when cutting this section close to the surface of the block. The boundaries of the lateral nucleus within the boundaries of the hole (indicated by the dotted line) were estimated from a similar level from a separate brain.

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nucleus of the lateral olfactory tract (PamAo), and the medial amygdaloid nucleus (PamAm). Stephan's superficial part of the anterior amygdaloid area corresponds to de Olmos' superficial anterior amygdaloid area labeled AAAsf in K1-B 8 and Fig. 53B. In the older nomenclature developed by Johnston (1923) and Crosby and Humphrey (1941), the medial amygdaloid nucleus was considered to appear just caudal to the primary olfactory cortex (PirT in K1-B 6 and Fig. 51B) in the region of the fundus of the endorhinal sulcus (ers in K1-B 8-10 and Fig. 51). It is now generally recognized that the medial amygdaloid nucleus lies further caudal in the fundus of the endorhinal sulcus (Me in K1-B 11 and 12 and Figs. 54 and 55) and that the corresponding region in the rostrat half of the amygdala (K1-B 10 and Figs. 52 and 53) is occupied by the anterior cortical nucleus (ACo). The question of whether a nucleus of the lateral olfactory tract can be recognized in the human is open to question (Section 5.2.3.). The other part of the periamygdaloid semicortex, which Stephan called PamC (C for cortical), occupies most of the superficial amygdala in the semilunar gyrus (SLG in K1B 10 and Figs. 52A and 53A), and like PamA, has three subdivisions. PamCs (s for semiannular sulcus = sas, also referred to as amygdaloid fissure) is a zone located in the fundus and lower lip of the semiannular sulcus (sas in K1-B 10), where it forms a transition area (APir in Figs. 52-54) between the amygdala and neighboring entorhinal cortex. The medial boundary is usually indicated by a slight sulcus referred to as the accessory amygdaloid fissure (Crosby and Humphrey 1941; Fig. 11-02). In general PamCs corresponds to the region traditionally referred to as the cortico-amygdaloid transition area (Crosby and Humphrey 1941). Stephan's PamCh (h for hippocampus) or 'area parahippocampalis' is located in the caudal amygdala where it borders on the hippocampus formation (K1-B 12 and Fig. 55). Most of the region, which has been termed the amygdalohippocampal area (AHi in Fig. 55; see also Humphrey 1968; Price et al. 1987; de Olmos 1990) would be included in Stephan's 'area parahippocampalis'. PamCp (p for principalis) occupies most of the semilunar gyrus and corresponds in general to the superficial parts of the cortical nucleus in the nomenclature of Johnston (1923) and Crosby and Humphrey (1941). As we shall see below, the terminology is in a state of flux for several of the subdivisions of the superficial amygdala in the primate, especially those corresponding to Stephan's PamC. The periamygdaloid cortex (PAC) of Krettek and Price (1978). Krettek and Price (1978) and Berman and Jones (1982) have suggested that the superficial amygdala be conceived of partly as non-cortical and partly as cortical. They adopted Rose's term periamygdaloid cortex (but changed the abbreviation from Pam to PAC). Krettek and Price, studying the rat, and Berman and Jones (the cat), pointed out that this area (which in other naming conventions includes both the posterolateral cortical nucleus and the transition area bordering on the primary olfactory cortex [piriform cortex] rostrally, as well as the amygdalo-hippocampal area caudally), has a well-defined three-layered structure with a distinctive pyramidal cell layer and should therefore be referred to as cortex, i.e. periamygdaloid cortex (PAC). As acknowledged by Berman and Jones (1982), however, the multiform or third layer is poorly defined and merges imperceptibly with the deeper parts of the amygdala. In Nissl preparations, the second, 'pyramidal' cell layer in the region labeled PAC (Fig. 9 in Krettek and Price 1978 and Fig. F-97 in Berman and Jones 1982) resembles the second layer in neighboring primary olfactory cortex. The situation is different in Golgi-stained material, at least in the rat (Pigache 1970) where the so-called pyramidal cells in the second layer of PAC 'lack the orientation of the apical dendrites' typical of primary olfactory cortex. In 1984, Amaral and Price introduced the PAC nomenclature in the primate brain. 168

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The heterogeneity of the superficial amygdala (Price et al. 1987) led to the subdivision of PAC into five subregions (PAC1, PAC2, PAC3, PACo and PACs). PAC2 of Price (Fig. 29.8; 1990) has not been recognized in the human by Sorvari et al. (1995). Two of the other PAC subregions (PACs and PACo) which border on the entorhinal cortex are transitional in nature, and represent generally, though not exactly, what has been called the cortico-amygdaloid transition area (Apir in Figs. 51-54) since the time of Crosby and Humphrey (1941). In 1989 Amaral and Bassett, studying the distribution of ChAT immunoreactivity in the monkey, combined PAC1 and PACs into one region, for which they retained the term PACs. That left one PAC region, i.e. PAC3, constituting most of the free surface of the semilunar gyrus (Fig. 6A in Amaral and Bassett 1989). This generally corresponds to what was traditionally considered to be the cortical nucleus in the human (ventral cortical nucleus, VCo, in Figs. 52-54). The PAC-nomenclature implies that periamygdaloid cortex is a cortical extension and therefore basically different in structure from medial or anterior cortical amygdaloid nuclei, which is questionable (see also Bayer 1980). In preference to the PAC-nomenclature (see also discussion in Alheid et al. 1995, p. 558) we will adhere to the term 'cortical amygdaloid nucleus', originally suggested by Johnston (1923) and Crosby and Humphrey (1941). We have modified it, however, as required by more recent information (see below). With the term 'cortical' nucleus, Johnston implied a superficial location of tissue which has some 'cortical-like' features but which is not ranked in the same category as nearby cortical areas, (e.g. entorhinal cortex or primary olfactory cortex, piriform cortex). Another problem concerning homologies between olfactory amygdaloid areas in the human and those in macrosmatic mammals is the uncertainty in regard to the presence of a human accessory olfactory bulb with accompanying accessory bulb terminal fields within portions of the 'olfactory amygdala' (see below). 5.2.3. Review of superficial amygdaloid structures

An appreciation of the extent and topographic relations of the superficial amygdaloid areas can be obtained by comparing the coronal sections (Figs. 51-55) with the map in Fig. 56, in which the superficial amygdaloid regions have been reconstructed on the dorsomedial surface of the uncus of the parahippocampal gyrus. In general, we will use the terminology suggested by de Olmos (1990) for the human amygdala which, wherever practical, was designed both to reflect homology with non-primate amygdala and to adhere to historical precedent. As discussed in the introduction to this section, the medial amygdaloid nucleus, part of which faces the medial brain surface (Fig. 54), was described in the context of the extended amygdala in the previous section, rather than as one of the superficial amygdaloid structures. Amygdalopiriform transition area. The amygdalopiriform transition area (APir) is an extensive contiguous region. Its most anterior part (anterolateral APir) borders on the temporal part of the primary olfactory cortex (PirT) dorsolaterally, and on the temporopolar periallocortex rostrally and entorhinal cortex ventrally (Ent, Fig. 51), whereas its caudal part (posteromedial APir) is interposed between the ventral cortical nuclei (VCo) of the amygdala and the entorhinal cortex/subiculum (Figs. 51-54). Anterior amygdaloid area (AAA). The anterior amygdaloid area, poorly defined according to Crosby and Humphrey (1941), is that portion of the dorso-rostral amygdala which is located 'at the cephalic pole of the amygdaloid region', which '...has not differentiated into specific nuclear masses', and contains a heterogeneous population of 169

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Fig. 56: A. Approximate location of the superficial amygdaloid nuclei superimposed on the medial surface of the temporal lobe. The arrangement of the individual superficial amygdaloid nuclei on the medial surface of the temporal lobe is shown in figure B. The diagram in B is redrawn from a similar figure in Brockhaus (1942), created by reconstruction of the surface from serial sections.

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neurons, lightly stained in Nissl, which have been described as small to medium-sized in many species including the human (e.g. Brockhaus 1938; Crosby and Humphrey 1941; de Olmos 1990). The vaguenesses of these statements are reflected by widely divergent published descriptions of the anterior amygdaloid area. Jimenez-Castellanos (1949), who made an effort to reconcile the Crosby-Humphrey (1941) terminology with that designed by Brockhaus (1938), included in the anterior amygdaloid area, rostral and caudal parts corresponding generally to Brockhaus' 'claustrum preamygdaleum' (ClprA) and 'supraamygdaleum profundum ventrale' (Sapv). His caudal area in all likelihood includes the medial part of the central nucleus of the amygdala (CeM in Fig. 54). The rostrally located region underlies the amygdalopiriform transition area and corresponds to the preamygdaloid claustrum of Brockhaus, considered by us to be the endopiriform nucleus (En, Fig. 51). Gloor (1997) restricts the anterior amygdaloid area to the rostrally located preamygdaloid claustrum of Brockhaus (Gloor 1997, p. 629) but he indicates that it consists of small and lightly stained cells. Gloor distinguished the anterior amygdaloid area from what he considered to be the laterally located endopiriform nucleus (En) underlying the primary olfactory cortex and which he and Brockhaus described as having larger and more deeply staining cells. This description is appropriate to a section at the level of the caudal end of the anterolateral Apir and would correspond to our definition of the AAA (Fig. 52). More rostrally (Fig. 51), we consider that the AAA is replaced by the medially directed temporal limb of the endopiriform nucleus which is characterized by larger and more deeply stained cells. One reason for the current confusion may be related to the fact that Brockhaus' claustrum insulae, which corresponds to a major portion of the endopiriform/claustral area of Price (1990, Fig. 28.8), was labeled 'claustrum preamygdalae' (ClprA) in the well-known atlas of Schaltenbrand and Bailey (1959). A problem with Gloor's (1997) description is that his text does not match his figures 6-2 and 6-3, in which the anterior amygdaloid area (AAA) better corresponds to Brockhaus' claustrum insulare (Clili: Fig. 51 in Brockhaus 1938) or to a major portion of the endopiriform/claustral area as indicated by Price (1990; Fig. 29.8). This inconsistency is possibly the result of the fact that Gloor did not live to label the coronal sections shown in his chapter on the Amygdaloid System (see Preface to Gloor 1997). A different designation of the anterior amygdaloid area is advocated for the monkey by Amaral and Bassett (1989) and for the human by Sorvari et al. (1995). In both papers the anterior amygdaloid area is described as a circumscribed region with darkly stained cells which are somewhat larger than those in the central nucleus. From their descriptions and pictures, it appears that the region in question is an integral part of either the claustrum or amygdaloclaustral area, with which it shares weak ChAT staining. According to the interpretation given by Amaral and his colleagues, the anterior amygdaloid area stands out as a nucleus which is easily delineated deep to the surface of the brain beyond the reach of olfactory bulb input and thus differing from the area generally described in non-primates. According to Emre et al. (1993, Fig. 2A), the anterior amygdaloid area is a small circumscribed region below the fundus of the endorhinal sulcus, distinguished from surrounding ChAT-negative tissue by dint of its moderate ChAT immunostaining. A completely different picture of the human anterior amygdaloid area has been presented by Stephan (1975) and by de Olmos (1990). de Olmos distinguishes both superficial and deep parts. The superficial part corresponds in general to the area labeled perisupraamygdalea dorsalis (psAd) by Brockhaus (1938) and the area anterior 171

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of Stephan's (1975) periamygdalaris anteromedialis (PamAa). de Olmos' superficial part of the anterior amygdaloid area (AAAsf in Fig. 53) is located in the dorsal part of the fundus of the endorhinal sulcus, and reaches far caudally to the level shown in Fig. 54. In short, as part of the 'supraamygdaloid' region of Brockhaus, the anterior amygdaloid area is located between the diagonal band region dorsally and medially, the claustrum or amygdaloclaustral area laterally, and the anterodorsally located amygdaloid nuclei ventrally. In fact, the anterior amygdaloid area blends imperceptibly with the central and medial amygdaloid nuclei as it fills the space between them and the dorsal parts of the basolateral and basomedial amygdaloid nuclei (see de Olmos 1990, for further details). This description of the anterior amygdaloid area corresponds in general to the description presented in the well-known atlas of the human basal ganglia by Riley (1960). In the context of the olfactory system, it is important to realize that the superficial part of the anterior amygdaloid area is (contrary to the view of Amaral and Basset 1989) in a position to receive direct input from the olfactory bulb (see K1-B 8-10 and Figs. 52 and 53). The general location of the anterior amygdaloid area as identified by de Olmos (1990) and in the current description, has the virtue that it has essentially the same contiguous relationships with the surrounding superficial and deep amygdaloid nuclei as the homologous area in the rodent. Nucleus of the lateral olfactory tract (NLOT). A review of the literature indicates that this nucleus has not been easy to identify in the human. Some of the earlier students of the human amygdala (Crosby and Humphrey 1941; Allison 1954) identified a small group of deeply stained neurons located between the medial and the cortical amygdaloid nuclei as the NLOT. Others (e.g. Stephan 1975; de Olmos; 1990; Sims and Williams 1990; Gloor 1997) have not been able to positively identify this nucleus. Macchi (1951) and Stephan (1975), in particular, have argued convincingly for its gradual phylogenetic decline. As indicated by Stephan (1975), the nucleus of the lateral olfactory tract should not be found in the position between the medial and cortical amygdaloid nuclei indicated by Crosby and Humphrey (1941) and Allison (1954), nor should it lie between the cortical amygdaloid nucleus and the corticoamygdaloid transition area as labelled in Fig. 6-6 in Gloor's book (1997) [despite the fact that the text states that a human nucleus of the lateral olfactory tract can not be identified]. Carmichael et al. (1994) found that retrograde labeling from the olfactory bulb to what they refer to as nucleus of the lateral olfactory tract is modest and is similar to the labeling in neighboring parts of cortical amygdaloid nuclei, including those parts which they refer to as periamygdaloid cortex. This contrasts with the situation in macrosmatic mammals, in which the nucleus of the lateral olfactory tract is very heavily labelled following injection of a retrograde tracer in the olfactory bulb (e.g. de Olmos et al. 1978), and is distinguished from the adjacent amygdaloid areas by its projections to the contralateral olfactory bulb. In recent papers on the amygdala of monkey (e.g. Price et al. 1987; Amaral and Bassett 1989; Stefanacci et al. 1996) and human (Sorvari et al. 1995) the nucleus of the lateral olfactory tract has been designated as a prominent structure, to the point where, in the monkey, it extends for 'much of the rostrocaudal extent of the amygdala' (Amaral and Bassett 1989). Amaral and Bassett also emphasize the fact that CHATimmunoreactive fibers in this extensive region form pericellular plexuses, which according to the literature are typical for the nucleus of the lateral olfactory tract. Much of the extensive ChAT-positive area which they consider part of the nucleus of the

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lateral olfactory tract (Amaral and Bassett 1989) was previously included as part of their periamygdaloid cortex, PAC3 (Price et al. 1987). It is difficult to escape the conclusion that the apparent phylogenetic enlargement of the nucleus of the lateral olfactory tract as proposed by Amaral and Bassett stems from inappropriately renaming part of the cortical amygdaloid nucleus (PAC in the terminology of Price (1981), and Amaral and Price (1984)) as the lateral nucleus of the olfactory tract. Emre et al. (1993), on a comparative-anatomical basis, expected the nucleus to be AChE-positive and NADPH-negative, and could not identify the nucleus in humans. Sorvari et al. who, like Price et al. (1987) and Amaral and Bassett (1989) in the monkey, describe a rather large area beneath the anterior cortical nucleus in the human as the nucleus of the lateral olfactory tract, indicate a low AChE staining intensity. They suggest that diminished staining may in part be attributed to postmortem degradation of enzymatic activity, but their description is not consistent with the situation in macrosmatic mammals. The location suggested by Amaral and Bassett (1989) and Sorvari et al. (1995) for the nucleus of the lateral olfactory tract, i.e. between the anterior cortical amygdaloid nucleus on one hand, and their periamygdaloid cortex and accessory basal nucleus (basomedial nucleus of de Olmos 1990) on the other, would be highly unusual from a comparative-anatomical point of view (see Stephan 1975, for further discussion of this subject). The structure that Sorvari et al. (1995, Fig. 1A) claim to represent the nucleus of the lateral olfactory tract includes the ventral part of what we consider to be the anterior cortical nucleus (de Olmos 1990). The cortical amygdaloid nuclei. The anterior cortical nucleus, which is the prime amygdaloid recipient of olfactory input in the human, has been described in great detail by de Olmos (1990) who, like Brockhaus, has divided it into dorsal and ventral parts based on topographical and cytoarchitectonic criteria. There are minor disagreements about the boundaries of the anterior cortical nucleus (e.g., as indicated above, part of the region labeled NLOT in Sorvari et al. 1995, Fig. 1A, is included in the ventral part of the anterior cortical nucleus by de Olmos 1990). Nevertheless, a consensus seems to have developed regarding its general location in the anterior part of fundus of the endorhinal sulcus just behind the primary olfactory cortex (Figs. 52 and 53). The anterior cortical nucleus was earlier designated the anterior part of the medial amygdaloid nucleus by Johnston (1923) and Crosby and Humphrey (1941). Some authors still designate it as part of the medial amygdaloid nucleus (e.g., Sims and Williams 1990; Emre et al. 1993; Insausti, in Gloor 1997). A nearby region, which occupies a considerable part of the semilunar gyrus ventral to the anterior cortical nucleus, was previously known as the cortical nucleus. Pigache (1970) suggested the term 'superficial amygdaloid nucleus', and this was in turn adopted by Turner et al. (1978). De Olmos chose to name the region ventral cortical nucleus (VCo) in order to separate it from the distinctly different anterior cortical nucleus (de Olmos 1990). Basically, de Olmos recognizes a rostral and a caudal part of the ventral cortical nucleus, each of which he then subdivides into superior, intermediate and inferior segments (Figs. 53 and 54). A similar pattern of subdivisions was also described by Brockhaus (1938). The human ventral cortical nucleus appears to be the homologue of the posterolateral cortical nucleus of the rat brain. The problems of identifying a posterior cortical nucleus in humans. A posterior cortical nucleus (PCo) has been introduced in several recent publications (Amaral and Bassett 1989; Pitkfinen and Amaral 1991; 1993; Emre et al. 1993; Sorvari et al. 1995). Such a nucleus (sometimes referred to as posteromedial cortical nucleus) has been 173

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clearly identified as belonging to the accessory olfactory bulb projection system in macrosmatic mammals (Scalia and Winans 1975). Even though an accessory olfactory bulb is difficult to identify in the Old World monkey and the human (but see Moran et al. 1995), it was expected that a posterior cortical nucleus would be present in all primates. Thus, a posterior cortical nucleus was identified in the Old World monkey (Maeaca fascicularis) by Price et al. (1987), and in the human by de Olmos (1990). Although it is difficult to say if the human posterior cortical nucleus corresponds exactly to the posterior cortical nucleus in the monkey (COp in Price et al. 1987; Amaral and Basset 1989), its location in the caudal amygdala between the posterior part of the medial amygdaloid nucleus and the amygdalohippocampal area is congruent (Figs. 6 and 7 in Sorvari et al. 1995). The posterior cortical amygdaloid nucleus identified by Sorvari et al. at the approximate level shown in Fig. 57 (compare Fig. 5 in Sorvari et al. 1995) is AChE-negative in its superficial molecular layer and we have included this area as part of the ventral cortical nucleus (VCo). The absence of AChE in the superficial layer of VCo (Fig. 57B) stands in contrast to the amygdalohippocampal area (Fig. 57A), all of which, including its superficial molecular layer, is characterized by moderately strong AChE staining. The monkey posterior cortical nucleus (Price et al. 1987) was originally indicated as being 'ventral to the medial nucleus'. In a later publication (Price 1990, Fig. 29-2, last section), PAC 3 is interposed between the posterior cortical nucleus and the medial nucleus. At this rostral level, all of the surface area of the semilunar gyrus had previously been labeled PAC 3 by Price et al. (1987). Figures 7 and 8 in Pitk~inen and Amaral (1991) show the posterior cortical nucleus in a position which corresponds in general to the original description by Price et al. (1987). In the human (Sorvari et al. 1995, Figs. 3, 5 and 7) the posterior cortical nucleus is shown expanded to the point where it occupies the main superficial region of the semilunar gyrus, located caudal to what they identify as the nucleus of the lateral olfactory tract and lying between the anterior cortical nucleus dorsally and the amygdalohippocampal area and PAC 3. According to Sorvari et al. the posterior nucleus extends further caudally than even the amygdalohippocampal area. As reflected in these recent publications, the identification of the posterior cortical nucleus in the human and in the monkey is difficult. Part of the problem stems from uncertainty regarding the presence of an accessory olfactory terminal field in the monkey and the human. Since in the human the posterior cortical nucleus would be expected to correspond to an amygdaloid component in receipt of accessory olfactory bulb input, the purported homology of this nucleus (i.e. to the posteromedial cortical nucleus in macrosmatic animals such as the rat, see Price et al. 1987) is not assured. The only cholinesterase-positive part of the rat posterior cortical nucleus (posteromedial cortical nucleus in the classic terminology) is the superficial molecular layer. This is the inverse of the situation in the purportedly homologous nucleus of the monkey (Figs. 1F and G in Price et al. 1987) and the human (Figs. l lC and 12G in Sims and Williams 1990; see also Fig. 57B), where the nucleus proposed as the posterior cortical nucleus (COp) is cholinergic, with the exception of its superficial layer. Different parts of the region identified by Sorvari et al. (1995) as COp exhibit distinct patterns not only in AChE-stained sections, but with several other histochemical markers, including somatostatin (Figs. 57C and D) and secretoneurin (Figs. 57E and F). On the basis of what has been said above, we now believe that the caudally located region named COp in Fig. 7 by Sorvari et al. (1995) should rather be included in the amygdalohippocampal area (Figs. 55 and 57A, C and E) as originally described by 174

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Fig. 57: Comparison of three different neurochemical markers (acetylcholinesterase, ACHE; somatostatin, SOM; or secretoneurin, SECR) in coronal sections through the amygdalohippocampal area (A, C, and E) and posterior part of the ventral cortical nucleus (B, D, and E). Note the histochemical distinction between the amygdalohippocampal transition area and the ventral cortical nucleus.

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Crosby and Humphrey (1940), Humphrey (1972) and Stephan (1975; area parahippocampalis, PamCh, p. 358) whereas the region labeled COp in Fig. 5 in Sorvari et al. corresponds in general to the ventral cortical nucleus (VCo in Figs. 54 and 57B, D and F). Moreover, the rostral prolongation of the COp, labeled in Fig. 3 in Sorvari et al. (1995) in the human, would seem to be within reach of main olfactory bulb projection fibers (K1-B, 10; see also Turner et al. 1978; Carmichael et al. 1994), and for that reason it is questionable if it should be considered equivalent to the posteromedial nucleus in nonprimates. It is interesting to note that one source of information about this problem remains untapped. This is the fact that New World monkeys such as the squirrel monkey and marmoset do have an identifiable accessory olfactory bulb, but to our knowledge no experiment has been reported that uses modern tract tracing methods to trace its central projections in the primate. 5.3. LATEROBASAL AMYGDALOID COMPLEX The laterobasal amygdaloid complex is the largest part of the human amygdaloid body. It is also less controversial with regard to its subdivisions and nomenclature than the superficial amygdaloid nuclei. In fact, even if there are minor differences in the terminology to consider (see appendix), there is general agreement about its anatomical organization and major nuclear boundaries. Most authors recognize four major nuclei: lateral, basolateral (or basal), basomedial (or accessory basal), and paralaminar. Taken in this sequence, they are also ordered from largest to smallest in the human brain. As indicated in the introduction to this section, the laterobasal nuclear complex is clearly demarcated from the centromedial nuclear group, not only because of its generally larger neurons and other cytoarchitectonic characteristics, but also because of its many chemoarchitectural and connectional differences. The 'cortical' nature of the large laterobasal amygdaloid complex has been emphasized by many investigators (e.g. Johnston 1923; Crosby and Humphrey 1941, Lauer 1945; Hall 1972a; Herzog 1982; Braak and Braak 1983; Millhouse and de Olmos 1983; McDonald 1984; 1992; de Olmos et al. 1985; Alheid and Heimer 1988; Carlsen and Heimer 1988; Alheid et al. 1990; 1995). Cerebral cortex contains two basic cell types, spiny and aspiny neurons. The spiny (projection) neurons are generally considered to be excitatory in nature whereas the neurons with aspiny dendrites (smooth neurons) are believed to be inhibitory, often using T-aminobutyric acid (sometimes in combination with one or several neuropeptides) as their transmitter. These two major neuronal types characterize the laterobasal amygdaloid complex as well (see preceding references). As shown by Braak and Braak (1983), however, within these two groups there are a number of variations with regard to size and morphology. In general, the largest cells are located dorsally with a gradual decrease in cell size in the ventral direction. According to Stephan and colleagues (Stephan and Andy 1977; Stephan et al. 1987), the lateral nucleus and the small-celled ventrally located subdivisions of the basolateral nucleus are the most progressive portions of the amygdaloid nuclei in primate evolution. When comparing the laterobasal amygdaloid complex with the cerebral cortex, it is important to acknowledge that the former lacks the obvious laminar organization that is typical of the latter. Nonetheless, there are many similarities between the laterobasal amygdaloid complex and the cerebral cortex. These have been noted since the earliest discussions of the functional significance of the laterobasal complex to the rest of the 176

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basal forebrain (e.g. Johnston 1923; Crosby and Humphrey 1941). Important similarities include its chemical neuroanatomy which resembles that of the cortex. The laterobasal complex also has widespread connections with cortex. The basic cyto- and chemoarchitecture of the different subdivisions of the laterobasal amygdaloid complex will be reviewed below. Their manifold projections, however, will not be discussed; they are reviewed in many recent publications (e.g. Herzog and Van Hoesen 1976; Turner et al. 1980; Price et al. 1987; Aggleton et al. 1987; Barbas and de Olmos 1990; de Olmos 1990; Turner and Herkenham 1991 ; Amaral et al. 1992; Gloor 1997; Haber and Fudge 1997). Suffice it to say that the laterobasal complex is closely interconnected with a number of cortical regions especially in the frontal and temporal lobes and in the hippocampal formation. These connections are in large part reciprocal (e.g. de Olmos 1990; Amaral et al. 1992). Like various parts of the cerebral cortex, the laterobasal complex also serves as an important staging area for impulses to the basal forebrain, in particular to the ventral striatopallidal system and extended amygdala. We have retained the nomenclature recently outlined by de Olmos (1990) which is similar to that originally proposed for this complex by Johnston (1923), while the cytoarchitectonic divisions most closely follow those recognized by Brockhaus (1942) and Koikegami (1963). Johnston divided the laterobasal complex into lateral and basal nuclei, with the basal nucleus further divided into a large-celled lateral part (hence basal lateral or basolateral) and a small-celled medial part (e.g. basal medial or basomedial). It is clear that the last part included the zone designated as 'T' by V61sch (1910), which is similar to the basomedial nucleus of the present and earlier account (de Olmos 1990). It is also homologous to the same area that had earlier been designated as the basomedial (or basal medial) nucleus in the brains of rodents and other non-primates (e.g. see Koikegami 1963). In the primate brain, however, the term accessory basal has long been applied to the area we term the basomedial nucleus. This presumably arose from the papers by Humphrey (1936, bat) and Crosby and Humphrey (1941, human), and the later publication of Lauer (1945, monkey). In their paper Crosby and Humphrey apparently misapplied the term basal medial to the ventral part of Johnston's basal lateral nucleus. Since (as we mentioned above), there is a gradient from dorsal to ventral within the basolateral nucleus, they were correct in identifying the ventral part of the basal lateral nucleus as small-celled compared to the dorsal large-celled part of this nucleus. This, however, was not the area implied by Johnston's small-celled, basal medial nucleus (e.g. see Fig. 43 in Johnston 1923). Since they had used the term basal medial for the ventral part of the basal lateral nucleus, they turned to the term basal accessory nucleus to describe the more medial and dorsal, small-celled nucleus that we refer to as the basomedial nucleus in the rat (de Olmos et al. 1985, Alheid et al. 1995), primate (Barbas and de Olmos 1992), and human brains (de Olmos 1990; and present account; see also Franklin and Paxinos 1997, mouse; Paxinos and Watson 1997, rat; Mai et al. 1997, human). The term 'accessory basal nucleus' was applied by Johnston to a small nucleus found in the caudal lateral zone of the opossum amygdala, but which he could not discriminate in the brain of other mammals. The existence of this small cell group has not been well supported in subsequent comparative investigations, and it has been supposed that it may have been related, for example, to a caudal island of the basolateral nucleus (e.g. Koikegami 1963, i.e. his intermediate principal nucleus). It is most unlikely, however, that what Johnston labeled as the accessory nucleus in the opossum is related to the area that we currently refer to as the basomedial nucleus in other mammals. 177

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Many contemporary authors publishing on the primate and human brain, have continued to apply the term basal accessory nucleus to refer to this structure. The harm in continuing this practice comes if one fails to appreciate that the homologous area in the rat and other species is more frequently termed the basomedial nucleus. In an attempt to remedy this situation, Price and his colleagues (1987; see also Amaral et al. 1992; Sovari et al. 1995) suggested renaming the basomedial (or basal medial) nucleus in the rat and cat as the accessory basal nucleus. Except for the continued use of the term accessory basal in the primate, their suggestion has been largely ignored in comparative experiments. At the present time the suggestion by de Olmos (1990; see also Barbas and de Olmos 1992), i.e., to revise the nomenclature of the primate basomedial nucleus to reflect its earlier roots, and to restore a common term to this nucleus for comparative studies, has not been overwhelmingly accepted by those whose research is centered in the primate amygdala. A recent atlas of the human brain, however, has incorporated this simplification (Mai et al. 1997).

5.3.1. Lateral amygdaloid nucleus (La) In the human this nucleus (Figs. 51-55) is the largest of the amygdaloid nuclei both as compared by direct measurements and by allometric procedure (Stephan and Andy 1977; Stephan et al. 1987). It consists mostly of medium-sized to large neurons, but also includes smaller ones that are more numerous ventromedially as one gets close to the inferior horn of the lateral ventricle. By contrast, the glial cells are more numerous rostrodorsally, which parallels an increase in the density of myelinated nerve fibers. The neuronal population in the lateral amygdaloid nucleus is very heterogeneous, and most experts have subdivided the nucleus into at least 4 different parts. Koikegami (1963) in a detailed review of comparative research from his laboratory, including earlier reports presented by Mikami (1952) and Sasagawa (1960a,b; 1961), emphasized the cytoarchitectural complexity of the lateral nucleus and suggested that some subdivisions recognized in the human amygdala may not be present in the monkey. On the basis of fiber- and cytoarchitectonic criteria and topographical landmarks, de Olmos (1990) has divided the main body of the lateral nucleus into five subnuclei: ventrolateral (LaVL), ventromedial (LaVM), dorsolateral (LaDL), dorsomedial (LaDM), and intermediate (LaI). A multilobulated rostrolateral extension of the dorsolateral subdivision just medial to the claustrum (Fig. 52) was referred to as the limitans subdivision by Brockhaus (1938). Its comb-like appearance is derived from the many fiber bundles that invade the nucleus from the external capsule. These ectopic portions of the lateral nucleus, however, should not be confused with the larger, more darkly staining cells in the adjacent ventral claustrum which are also divided by the fascicles of the external capsule. The various subdivisions of the lateral nucleus, all of which can be easily recognized in Fig. 53, are characterized by different size neurons; the intermediate division contains medium-sized cells, the dorsolateral division somewhat larger cells and the ventromedial division smaller cells; the dorsomedial subdivision is primarily recognized because of the compact arrangement of its small cells whereas the ventrolateral subdivision is more heterogeneous. Although Sorvari and colleagues in a broadly based chemoarchitectonic study of the human amygdala (Sorvari et al. 1995; 1996) recognized the existence of the above-mentioned cellular zones, they subsequently urged a simple subdivision of the lateral nucleus into a large lateral and narrow medial compartment based in part on the distribution of

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parvalbumin-immunoreactive neurons, a parcellation reflecting the nomenclature suggested by Price et al. (1987) and Amaral et al. (1992) for the monkey. As demonstrated in the earlier sections of this chapter, the three chemical markers (enkephalin, substance P and acetylcholinesterase) used in the atlas at the end of the previous chapter are very helpful in delimiting the topography of the extended amygdala and basal ganglia including the ventral striatopallidal system, but except for acetylcholinesterase, they are less useful in the context of the laterobasal complex. The silver deposits from the acetylcholinesterase histochemical reaction are especially prominent in the basolateral amygdaloid nucleus (BL in AChE 9-12). Several authors (e.g. Svendsen and Bird 1985; Sims and Williams 1990, de Olmos 1992, and Nakamura et al. 1992) have emphasized that the generally weak AChE-reaction in the lateral amygdaloid nucleus contrasts sharply with the dense reaction in the adjacent basolateral amygdaloid nucleus. Nitecka and Narkiewicz (1976), however, argued that the acetylcholinesterase activity in the lateral amygdaloid nucleus is regionally variable with the intensity of the reaction decreasing distinctly in anteroposterior direction. Emre et al. (1993) have since indicated that the distribution of choline acetyltransferase (CHAT) in the amygdala is nearly identical to that of acetylcholinesterase. Compared to the other parts of the laterobasal complex, the lateral nucleus has a relatively low density of ChAT-positive fibers, with the overall density being somewhat higher in the posterior part of the lateral nucleus. The content of acetylcholinesterase and choline acetyltransferase within the amygdala has attracted considerable interest in the context of Alzheimer's disease, and Emre et al. (1993) indicate that the lateral nucleus displays a more severe loss of ChAT-positive profiles than most other amygdaloid nuclei in this disease. Nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d)-containing neurons have received considerable attention in recent years in part because they are resistant to neurotoxic drugs (e.g. Beal et al. 1986; 1990; Ferriero et al. 1990) and are apparently preserved in striatum in Huntington's patients (e.g. Ferrante et al. 1985). In the context of the. amygdaloid body and other cortical areas, a reasonable case can be made that neurons containing NADPH-diaphorase are more resistant to the changes during aging than those without the enzyme. Several authors have accordingly made the effort to provide a map of NADPH-d stained profiles in the amygdala of the human (e.g. Sims and Williams 1990; Brady et al. 1992; Unger and Lange 1992). These papers have provided data in regard to different morphological types of NADPH-diaphorase-positive neurons. In general they have the morphological characteristics of interneurons, and there is also an apparent tendency for NADPH-d to coexist with somatostatin and neuropeptide Y. NADPH-d neurons and fibers are heterogenously distributed throughout the amygdala but generally with the densest accumulation of intensively Golgi-like staining of local circuit neurons in the lateral nucleus and the dorsal regions of the basolateral and basomedial amygdaloid nuclei, as well as in the paralaminar nucleus (Brady et al. 1992). Sorvari and collaborators (Sorvari et al. 1995; 1996) have paid special attention to the distribution of inhibitory neurons and concomitant calcium-binding proteins that colocalize with GABA in the amygdaloid body. They found that the lateral nucleus contains the highest density of parvalbumin-positive neurons, followed by the dorsal and intermediate subdivisions of the basolateral nucleus. Based on their cytoarchitectonic studies and considering the prominent accumulation of parvalbumin-positive neurons into a large lateral segment of the lateral nucleus, Sorvari et al. subdivided the lateral nucleus in a large lateral and a narrow medial part. However, it is difficult 179

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to reconcile their subdivision of the lateral nucleus with the subdivisions which are based primarily on cyto- and fiber architecture in this chapter and in the earlier accounts of Brockhaus (1938) and Koikegami (1963). In general, the density of parvalbumin-positive fibers parallels that of parvalbumin-immunoreactive neurons. Calretinin-immunoreactive neurons and fibers are considerably more prevalent than the parvalbumin-containing neurons (Sorvari et al. 1996), and are present in large numbers throughout the laterobasal complex and the superficial amygdaloid nuclei but with a considerably lower density in the centromedial amygdala. With regard to the distribution of calretinin-immunoreactive neurons in the lateral nucleus, Sorvari et al. reported that the density of neurons is considerably higher in the medial division than in the lateral. This situation, however, is not easily appreciated by reviewing their diagrams. Sorvari and colleagues have capitalized on the fact that immunostaining for the above-mentioned calcium-binding proteins does tend to produce a Golgi-like staining of the immunoreactive neurons, and they came to the conclusion that the overwhelming majority of the immunostained neurons belong to various subtypes of the class II and III aspiny or sparsely spined cells described by Braak and Braak (1983) and suggested to be local circuit neurons by these latter authors. Based on differences in distribution and morphological characteristics, they also concluded that parvalbumin and calretinin are located in different subpopulations of inhibitory neurons. Neurotensin-immunoreactive neurons and terminals, which are plentiful and very useful in the identification of the centromedial amygdala and the rest of the extended amygdala (Section 3), are less prominent in the laterobasal complex (Mai et al. 1987; Benzing et al. 1992). In fact, besides the central and medial amygdaloid nuclei, only the intercalated islands and what Benzing et al. (1992) call 'lateral capsular nuclei' contain neurotensin cell bodies. Neurotensin fibers, on the other hand, are present both in the basolateral and paralaminar nuclei. In their study of the monkey amygdala, Amaral and Bassett (1989) illustrated the lateral capsular nuclei as patches of 'small, tightly packed neurons, located along the lateral limit of the lateral nucleus'. As described in considerable detail in Sections 2 and 3, we include these parvicellular islands in our definition of 'interface islands'. According to the description of the 'lateral capsular nuclei' by Benzing et al. (1992), they seem to correspond to some of the interface islands alongside the ascending fibers of the stria terminalis (on the lateral side of the lateral amygdaloid nucleus; Fig. 54) which are related to the extended amygdala. They, together with the centromedial complex, belong to the most neurotensinergic structures in the amygdala. A high density of neurotensin receptors is also evident in dorsal parts of the basomedial nucleus and in the paralaminar nucleus, while a relatively low receptor density occurs in the lateral and dorsal part of the basolateral nucleus. Fibers containing corticotropin-like intermediate lobe peptide (ACTH) immunoreactivity form dense networks throughout most of the laterobasal amygdaloid complex (e.g. Zaphiropoulos et al. 1991). Several other neurochemical markers, including cholecystokinin mRNA (Savasta et al. 1990), benzodiazepine receptors (Niehoff and Whitehouse 1983; Zezula et al. 1988) and adenosine A1 receptors (Fastbom et al. 1987) have a special affinity for the lateral nucleus whereas others, like muscarinic receptors (Cortes et al. 1987), and galanin receptors (K6hler and Chan-Palay 1990) are noted for their low level of activity in the lateral nucleus. The laterobasal complex in general contains an intermediate density of somatostatin receptors (e.g. Reubi et al. 1986) with the dorsal part of the basolateral, ventromedial subdivision of the lateral 180

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nucleus and the paralaminar nucleus showing a somewhat higher density of somatostatin receptors than the other parts of the complex.

5.3.2. Basolateral amygdaloid nucleus (BL) The basolateral nucleus can be divided into four subdivisions: a large-celled dorsal (BLD), a medium-celled intermediate (BLI), and two small-celled subdivisions, the ventrolateral (BLVL) and ventromedial (BLVM). The extreme dorsolateral part of the basolateral nucleus is, at mid-coronal levels, separated from the rest of the nucleus and appears in coronal sections as an encapsulated oval 'island' which has been referred to as the dorsolateral (DL) part by de Olmos (1990, Fig. 20.5a). A dosolateral cap-region is not evident in the Kltiver-Barrera section in Fig. 53, but can be appreciated in the acetylcholinesterase-stained preparation (ACHE 9) in the mini-atlas at the end of the previous chapter. Since this cap-region can be recognized only at midcoronal levels where it is fortuitously separated from the main body of the basolateral nucleus by the longitudinal association bundle, and since its cytoarchitecture is indistinguishable from the rest of the dorsal subdivision, it is questionable whether it should be awarded the status of a separate subdivision. The basolateral nucleus can be easily distinguished from neighboring central, lateral and basomedial nuclei both in Nissl and fiber preparations because its cells are larger and because it is separated from nearby nuclei by myelinated fibers forming the lateral medullary lamina on its ventrolateral side (facing the lateral nucleus) and intermediate medullary lamina on its border towards the basomedial nucleus. These distinctions are particularly easy to make in regard to the dorsal subdivision, which contains the largest cells within the amygdala (Figs. 52-54), but even the intermediate subdivision (BLI) can be reasonably well-identified on the basis of these criteria in the abovementioned Kltiver-Barrera sections. Clear-cut delineations of the basolateral and other amygdaloid nuclei can be made by studying thick sections stained for intracellular lipofuscin granules (Braak and Braak 1983), or by viewing wet unstained fixed sections in transmitted light, which accentuates the medullary laminae between the main divisions of the laterobasal complex (Fig. 20.2-20.5 in de Olmos 1990). The lateral border of the ventrolateral subdivision of the basolateral nucleus (BLVL) can also be clearly defined in regular Nissl or fiber preparations, but it may be more difficult to distinguish the medial border of the ventromedial subdivision (BLVM), unless a special technique is applied (e.g. observation of myelinated fiber bundles in fixed, unstained sections using transmitted light; see Fig. 20.7b in de Olmos 1990). The basolateral amygdaloid nucleus is particularly well-delineated by cholinergic markers like acetylcholinesterase (e.g. Nitecka and Narkiewicz 1976; Svendsen and Bird 1985; de Olmos 1990; Sims and Williams 1990; Benzing et al. 1992 and Nakamura et al. 1992; see AChE 9-12 in mini-atlas in previous chapter) and choline acetyltransferase (Emre et al. 1993). The staining, which is located primarily in the neuropil, is most dense in the magnocellular dorsal subdivision of the basolateral nucleus and gradually decreases in intensity in ventral direction through the intermediate subdivision towards the small-celled ventrolateral and ventromedial subdivisions. Both of these latter areas still contain a moderate number of cholinergic fibers according to Emre et al. (1993). This is reminiscent of the situation in the lateral nucleus mentioned earlier (note that Emre et al. use the nomenclature proposed by Crosby and Humphrey in 1941, which means that the deep part of their basomedial nucleus corresponds to the ventrolateral (BLVL) and ventromedial (BLVM) subdivisions of 181

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the basolateral nucleus in Fig. 53, whereas their superficial part of the basomedial nucleus corresponds to the paralaminar nucleus of the current account). Emre et al. (1993) emphasize that all parts of the laterobasal complex receive cholinergic input. Since, according to these authors, there are few if any cholinergic neurons within the human amygdala, cholinergic afferents must arise from extrinsic sources, presumably in large part from the ventral portions of the basal nucleus of Meynert at the level shown in K1-B 8-9 (Mesulam et al. 1983; Kordower et al. 1989). It is worth re-emphasizing that the cholinergic innervation of the amygdala is some of the densest in the forebrain, and the large majority of the cholinergic input is concentrated in the basolateral nucleus. In fact, all parts of the laterobasal complex receive a denser cholinergic innervation than any of the cortical regions (Emre et al. 1993). In spite of the considerable variations in the amount of cholinergic input to various parts of the amygdala, it is interesting to realize that muscarinic cholinergic receptors (primarily of the M~ type) are rather uniformly distributed in intermediate density throughout the amygdala (Cort6s et al. 1987). Brady et al. (1992) have shown that the distribution of NADPH-diaphorase neurons are heterogenously distributed in the basolateral nucleus but with a tendency for intensely stained ('Golgi-like') predominantly aspiny, multipolar neurons to concentrate primarily, but not exclusively in the dorsal magnocellular subdivision, and for the lightly stained neurons to be more frequent in the ventral parvicellular parts of the nucleus. In regard to NADPH-diaphorase fiber staining, there is considerable diversity in the current literature, especially in relation to the basolateral nucleus. According to Sims and Williams (1990), the neuropil in the parvicellular ventral parts of the basolateral nucleus (ventrolateral and ventromedial subdivisions in our nomenclature) in addition to the paralaminar nucleus (PL) is intensely NADPH-d positive, whereas the rest of the basolateral nucleus is negative. This contradicts the description by Brady et al. (1992), who found that, in addition to the dorsal half of the lateral nucleus, the magnocellular dorsal subdivision of the dorsolateral nucleus exhibited the greatest density of NADPH-d reactive fibers and puncta compared to a moderately dense plexus in the ventrally located small-celled subdivisions. The distribution of parvalbumin- and calretinin-immunoreactive neurons (Sorvari et al. 1995; 1996) in the laterobasal complex was briefly discussed in the previous section on the lateral amygdaloid nucleus. The laterobasal complex is a critically important forebrain structure in the context of behavior; it receives a variety of sensory inputs and in turn sends projections to the ventral striatopallidal system and extended amygdala, i.e., two major forebrain telencephalic effector systems relevant to mechanisms of emotional and motivational behavior. The inhibitory neuronal processes in the laterobasal complex presumably modulate excitatory (glutamate) projections from the laterobasal complex to the ventral striatum and extended amygdala. The studies by Sorvari et al. provide basic information relevant to inhibitory processes in the amygdala and should be consulted for further details on inhibitory neurons in this important part of the human brain. We indicated earlier that the laterobasal complex is conspicuous for its generally weak staining for neurotensin in comparison with the centromedial amygdala and the rest of the extended amygdala. This situation is especially well-demonstrated in the low-power photograph published by Benzing et al. (1992; Fig. 8). The basolateral nucleus, however, does contain a moderate amount of neurotensin-immunoreactive fibers (as does the paralaminar nucleus), the majority of which are located in the dorsal magnocellular subdivision and in the ventrally located small-celled components 182

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of the basolateral nucleus (Benzing et al. 1992). They also described a distinct anteroposterior gradient of increased immunostaining in the more posterior regions of the basolateral and paralaminar nuclei. Benzing et al. (1990) have also reported a strong reduction of neurotensin-immunoreactivity in the basolateral nucleus in addition to the cortical amygdaloid nuclei (but not in the centromedial amygdaloid complex) in Alzheimer's disease. When the distribution of neurotensin immunoreactive profiles in the amygdala is compared with the distribution of neurotensin receptors in the amygdala (Sarrieau et al. 1985; Lantos et al. 1996), it appears that the well-known 'mismatch-problem' (Kuhar 1985; Herkenham 1987) is as relevant for neurotensin as it is for many other peptides in the brain. 'Most strikingly'-- in the words of Lantos et al. 1996 'the dorsal part of the accessory basal nucleus' (basomedial nucleus in our terminology), 'where one of the highest densities of NT-binding sites was observed, almost lacks NT immunoreactivity' (Benzing et al. 1992). In regard to other neurochemical markers in the basolateral amygdaloid nucleus, it should be mentioned that Walter et al. (1990) reported the presence of many neuropeptide Y-immunoreactive cells primarily in the dorsal subdivision, whereas the density of NPY-ir fibers and terminals is denser in the ventrolateral subdivision than in the other parts of the basolateral nucleus. The concentration of cholecystokinin mRNA-containing neurons is lower in the basolateral nucleus than in the lateral and basomedial nuclei (Savasta et al. 1990). Powers et al. (1987) reported a sparse population of corticotropin-releasing factor (CRF) immunoreactive neurons in the laterobasal complex together with a rather nonhomogeneous distribution of CRF-ir fibers, with a dense concentration especially in the ventral part of the lateral amygdaloid nucleus. Whereas the amygdala in general contains low levels of angiotensin converting enzyme, the basolateral nucleus and in particular its parvicellular parts have a moderate amount (Chai et al. 1990).

5.3.3. The basomedial amygdaloid nucleus (BM) Our reasons for using the term basomedial nucleus instead of accessory basal nucleus was discussed earlier (Section 5.3.). The basomedial nucleus 9, like the basolateral nucleus, is more or less surrounded by myelinated fiber systems, and can therefore be easily identified in classic Nissl- and fiber-preparations (Figs. 53-55) with the exception of its rostral pole, which first appears slightly more caudal than the basolateral nucleus and which is initially difficult to distinguish from the superficial cortical amygdaloid nuclei (Fig. 52), even when the medullary laminae are accentuated by using specialized techniques such as in the papers by Braak and Braak (1983, Fig. 1) and de Olmos (1990, Fig. 20.3). The medial medullary lamina separates the basomedial nucleus from the superficial cortical amygdaloid nuclei and an intermediate lamina marks its boundary with the basolateral nucleus (Figs. 53-55). De Olmos divided the nucleus

9While it appears to be most practical to consider the basomedial amygdaloid nucleus in the context of the laterobasal complex, it is perhaps the portion of this complex that is most closely related to the centromedial amygdala and its extension into the forebrain (i.e. extended amygdala). Depending somewhat upon the topographical location within this nucleus, projections originate to the medial and central division of extended amygdala and include hypothalamic projections as well. The close physiological relations of the basomedial nucleus to the centromedial amygdala prompted Koikegami (1963) to suggest that the dividing line between the 'classical' medial and lateral components of the amygdala should run between the basomedial and basolateral nuclei. In an earlier account of the rat amygdala (de Olmos et al. 1985) we also included the basomedial nucleus within the extended amygdala. We later excluded the basomedial nucleus on the grounds that the operational definition of the extended amygdala would be more useful if it were restricted to those elements that seemed to be 'paired' about the axis dividing the extended amygdala in the rostral forebrain from the portion found within the temporal lobe (Alheid et al. 1995). In this context, the basomedial nucleus can be viewed as one of the specialized quasi-cortical areas that provide conditioned information to extended amygdala (e.g. McDonald 1992; Alheid et al. 1995).

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on cytoarchitectonic grounds into 5 parts: dorsomedial large-celled part (BMDM), dorsolateral mixed-celled part (BMDL), ventromedial medium-celled part (BMVM), ventrolateral small-celled part (BMVL) and caudomedial large-celled (BMCM) parts. The parvicellular parts, including particularly the ventromedial subdivision (BMVM), reach further in a rostral direction, and may be the only subdivision represented at the level shown in Fig. 52. Difficulties are also apparent when comparisons are made in regard to subdivisions proposed by various authors. The medium-celled ventromedial subdivision in de O1mos' nomenclature (e.g. Fig. 53, BMVM) corresponds in large part to the parvicellular division by Sorvari et al. (1995), whereas Sorvari's ventromedial division appears to involve only a small medial part in a relatively narrow midsection of the nucleus. The part labeled the ventromedial subdivision of the accessory basal nucleus by Sorvari et al. (1995, Fig. 3A, ABvm) may correspond to neurons of the intramedullary grisea of de Olmos (see section 5.4.). The basomedial nucleus, like the lateral amygdaloid nucleus, can be easily distinguished from the basolateral nucleus in acetylcholinesterase and choline acetyltransferase preparations because of the intense reaction in the latter (e.g. Nitecka and Narkiewicz 1976; Svendsen and Bird 1985; de Olmos 1992; Benzing et al. 1992; Nakamura et al. 1992; Emre et al. 1993; Sorvari et al. 1995). In general, however, the basomedial nucleus, especially its dorsal part, has a more intense reactivity for cholinergic markers than the lateral nucleus, although a ventrolateral region, which in general corresponds to our ventrolateral subdivision (BMVL) displays a rather weak reactivity similar to that in the lateral nucleus. As indicated earlier, in the study by Emre et al. (1993) it was argued that there are no ChAT-immunoreactive cell bodies in the human amygdala. The staining, therefore, is confined to axons (including terminals) usually in thin and varicose and occasionally thick and non-varicose fibers. They identified a rather large collection of ChAT-immunoreactive fibers at the junction of the basomedial nucleus with the cortical amygdaloid nucleus and the ventromedial subdivision of the basolateral nucleus (referred to as the deep part of the basomedial nucleus by Emre and collaborators) which they identified as an intercalated island (Emre et al. 1993; Figs. 8A, IC). Another possibility is that this cholinergic island corresponds to an expanded part of intramedullary grisea in this region as illustrated in Fig. 54 (IMG). The density of parvalbumin-immunoreactive cells in the basomedial nucleus is lower than in the neighboring basolateral nucleus, and most of them are located in the dorsal magnocellular part (Sorvari et al. 1995). The situation is reversed in regard to calretinin-immunoreactive neurons, which are somewhat more numerous in the ventral part of the basomedial nucleus, especially in more rostral regions (Sorvari et al. 1996). Like in other parts of the laterodorsal complex, NADPH-diaphorase neurons are heterogenously distributed in the basomedial nucleus (e.g. Brady et al. 1992). According to these authors the magnocellular part of the dorsolateral nucleus contains predominantly intensely stained Golgi-like neurons, whereas the lightly stained neurons are more common in the basomedial nucleus. Most of the intensely stained NADPHdiaphorase neurons in the basomedial nucleus are located alongside the border towards the basolateral nucleus. The basomedial nucleus contains a somewhat larger number of corticotropin-releasing factor (CRF)-containing neurons than the lateral and basolateral nuclei (Powers et al. 1987) with the majority concentrated in its middle sector. The density of cholecystokinin-mRNA-labeled cells in the basomedial nucleus is the highest after that in the 184

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lateral nucleus (Savasta et al. 1990). Together with the lateral and paralaminar nuclei, the basomedial nucleus also has one of the highest concentrations of benzodiazepine receptor sites in the amygdala (Niehoff and Whitehouse 1983; Zezula et al. 1988).

5.3.4. The paralaminar amygdaloid nucleus (PL) In the past, de Olmos (1990, p. 589) included the ventrally located paralaminar part of the amygdala as a subdivision of the basolateral nucleus. Many authors, however, have in the past promoted this part as a separate nucleus (e.g., Hilpert 1928; Brockhaus 1940; Mikami 1952; Sasagawa 1960a, b 1961; Sanides 1957b; Koikegami 1963) and this tendency is also apparent in more recent publications (e.g., Braak and Braak 1983; Price et al. 1987; Amaral et al. 1992; Sorvari et al. 1995; Gloor 1997). For the purpose of uniformity, we have decided to do the same, since there are no compelling reasons to consider it a subdivision of the basolateral nucleus except perhaps for the fact that its main part, the paralaminar proper, covers the ventral aspect of the two small-celled parts of the basolateral nucleus, i.e., the ventromedial and ventrolateral subdivisions (BLVM and BLVL) throughout their rostrocaudal extent (Figs. 52-55). It may be difficult in some places to identify a distinct border between the paralaminar nucleus and the small-celled subdivisions of the basolateral nucleus, although the cells in the paralaminar nucleus are smaller and more densely packed than in its dorsally adjacent neighbors. This border is also more evident in wet, fixed unstained sections viewed with transmitted light (de Olmos 1990). The special status of the paralaminar nucleus is evident in other ways. It covers not only the ventral aspect of the basolateral nucleus but also the ventromedial aspects of the lateral amygdaloid nucleus, where it has a pronounced tendency to form islands, and has therefore been referred to as the glomerular part by Brockhaus (1938). Such glomeruli (G) cover the ventral surface of the lateral nucleus from the rostral pole (Fig. 51) to the more caudal aspects of the amygdala (Figs. 1, 3 and 5 in Sorvari et al. 1995). One of the most convincing arguments for the special status of the paralaminar nucleus has been presented by Braak and Braak (1983), who demonstrated that the small spiny neurons in the paralaminar nucleus (granular nucleus in their terminology) contain a special type of lipofuscin pigment, different from that in other spiny neurons in the laterobasal complex. In fact, the small spiny neurons in the paralaminar nucleus have a Golgi-appearance and a pigment pattern reminiscent of those in the intercalated islands (Braak and Braak 1983; Millhouse 1986). Another relevant finding in this context was recently published by Amaral and Insausti (1992), who identified the paralaminar nucleus, together with the lateral nucleus, as one of the most prominent sources of a presumably excitatory pathway to the dorsal magnocellular subdivision of the basolateral nucleus (named basal nucleus by Amaral and Insausti). The paralaminar nucleus is not dramatically labeled by any of the commonly used histochemical stains, but seems to have a slightly higher concentration of peptide fibers (substance P or enkephalin) than the overlying mass of the laterobasal complex. Staining with a cholinergic marker such as ChAT (Emre et al. 1993) reveals a moderate immunoreactivity in fibers reminiscent of the situation in nearby ventrolateral and ventromedial subdivisions of the basolateral nucleus, although in the ACHEstained preparations by Sorvari et al. (1995; Fig. 6A) the paralaminar nucleus is somewhat more intensely stained than the neighboring small-celled parts of the basolateral and lateral amygdaloid nuclei. As indicated earlier, the density of muscarinic 185

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cholinergic receptors is rather homogenously distributed in the amygdala (Cort6s et al. 1987), but it is interesting to note that small-celled masses along the ventrolateral surface of the lateral nucleus (which in all likelihood correspond to the glomeruli of the paralaminar nucleus) and laterally to the dorsal pole of basolateral nucleus do exhibit a higher density of muscarinic (M1) receptors than other parts of the amygdala. These small-celled masses were considered by Cort6s et al. (1987) to represent intercalated masses. As mentioned earlier, the small cells of the paralaminar nucleus are in many ways similar to the cells of the intercalated islands. Another interesting correlation between intercalated islands and the paralaminar nucleus exists in regard to the content of benzodiazepine receptors (Niehoff and Whitehouse 1983; Zezula et al. 1988), which are especially prevalent in these two parts of the amygdala and in the lateral nucleus. The paralaminar nucleus, finally, is characteristically devoid of parvalbumin-containing neurons (Sorvari et al. 1995) and contains the lowest density of calretininimmunoreactive neurons in the laterobasal complex (Sorvari et al. 1996). 5.4. I N T R A M E D U L L A R Y GRAY SUBSTANCE AND INTERCALATED (INTERFACE) ISLANDS Neurons of various size and shape are interspersed among the fibers of the medullary laminae, and considering their large number and extensive distribution especially in the human brain, they have been designated by de Olmos (1990) as components of the intramedullary grisea (IMG). These cells, which vary in size and shape, are larger than those in the intercalated islands, and their main cell body axes are in general oriented parallel to the course of the fiber bundles. Often the cells form strings of clusters, sometimes they appear isolated among the fiber bundles, but they are present everywhere among the medullary laminae. These are prominent and extensive corridors inasmuch as they separate the various nuclei in the laterobasal complex from each other as well as from the other components of the amygdala, i.e. the centromedial and cortical amygdaloid nuclei. A prominent part of the intramedullary gray is located in the medial medullary lamina, which forms a wedge between the basomedial nucleus and the cortical amygdaloid nuclei (Figs. 53 and 54). An especially large collection of IMG cells is located at the lower end of this lamina where it breaks up into different fiber strands as it meets some of the fiber bundles in the ventral part of the intermediate medullary lamina (see Figs. 20.6a and 20.7a in de Olmos 1990). As indicated in the previous section, the part labeled ABvm in Sorvari et al. (1995; Fig. 3) may well be part of this extensive intramedullary grisea. Amygdaloid intercalated cell masses, which are populated by a rather homogeneous collection of parvicellular neurons, are almost without exception related to components of the extended amygdala as they are located primarily between the central amygdaloid nucleus and its neighbors and alongside stria terminalis fibers bundles as they ascend within and alongside the lateral margin of the lateral amygdaloid nucleus (Figs. 53-55). As discussed earlier in Sections 2 and 3, we include the intercalated islands in our concept of the interface islands, which are prominent features of both ventral striatum and extended amygdala.

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6. C O N C L U D I N G REMARKS

The intimate topographical relations demonstrated here between the basal ganglia, amygdala, and magnocellular forebrain complex argues cogently that obtaining better understanding of the interconnections and consequent functional interdependence of these important basal forebrain structures should remain a high priority. The basal forebrain appears to be crucially involved in a wide range of functions from physiological and behavioral homeostasis to higher cognitive functions, and includes a critical role in the most basic social behaviors, as well as in the organization of emotions and their physical manifestations. While the ventral striatopallidal system is often analyzed in terms of its relations to rewarding or motivated behavior, it is well to remember, that as a ventral extension of the basal ganglia, this part of the brain is also functionally relevant to neurological disorders such as Parkinson's disease where activation of the motor systems of the forebrain is suppressed. It may be recalled that many rewarding effects, for example from drugs of abuse, are accompanied by increased locomotor activity thought to originate in ventral striatum. In this chapter, we have not exhaustively reviewed the connections of basal forebrain. Such an analysis is best handled in the context of a comparative examination of basal forebrain neuroanatomy, since this topic depends heavily on results in animal experiments for interpreting the neurohistochemical patterns evident in the human brain. Rather, we have focused on the cyto- and chemoarchitecture of basal forebrain based almost entirely on human brain sections. This was done to provide a coherent picture of this crucial area in the human, without the necessary ancillary discussions of real or potential species differences (e.g., Chan-Palay 1988; Ulfig et al. 1990; Chang and Kuo 1991; Walker et al. 1991; Benzing et al. 1993), that must be included when compiling a comparative narrative of basal forebrain anatomy. One hope for the future of human chemical neuroanatomy is for chemical markers to be increasingly identified that have a unique relationship to specific systems and their connections with the rest of the brain. These may be essential for understanding the circuits underlying the integrative systems suggested by functional imaging in normal and abnormal human brains. Among these systems, some of the most interesting are likely to be those which traverse the basal forebrain.

7. A P P E N D I X : C O M P A R I S O N OF N O M E N C L A T U R E FOR THE H U M A N AMYGDALA

7.1. PREFACE In the ensuing six tables we have compared the terms we have advocated for the nuclei of the human amygdala (de Olmos 1990 and preceding chapter, Heimer et al.) with those used in other papers published in the past century. The tables are arranged in a rough chronological order, starting with more recent papers, except that some regrouping was used in order to place schemes with similar subdivisions together. We did not attempt to include all the various papers that document the amygdala in the monkey rather than in the human since we intended to maintain the focus on the human brain as we have in the preceding sections. Nonetheless, the papers of Price et al. (1987) and Amaral et al. (1992) which describe the nuclei of the macaque amygdala are included since they provide the basis for the subsequent paper by Sovari et al. 187

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(1995) on the human amygdala. In addition, we have not included a recent mapping of the human amygdala and extended amygdala contained within the atlas of the human brain prepared by Mai et al. (1997). The amygdala parcellation contained therein is loosely based on de Olmos (1990), although there are significant deviations from the designations suggested by de Olmos especially in the area of the cortical nuclei. For all the tables the first column is essentially the same and represents the combined scheme for the amygdala based on the preceding chapter and that of de Olmos (1990). The first column of Table 1 includes a more or less comprehensive listing of the terminology based on the combined descriptions in de Olmos (1990) and the preceding chapter. In order to save space, however, we have not included all these subdivisions within all the tables after Table 1; only those terms that are necessary for the comparison with the particular group of authors are shown. For comparative purposes, the last column in Table 1 includes the terminology for the amygdala and 'extended amygdala' that we have advocated for the rat (de Olmos et al. 1985; Alheid et al. 1995). This is to help bridge the gap between the detailed functional-anatomical studies in the rat (as well as in other small mammals) and the human neuro-imaging or neuropathological studies that are limited either by the current spatial resolution of live imaging techniques or by the large tissue mass that must be preserved and processed in order to adequately sample the smallest subdivisions in the human forebrain. The importance of comparative neuroanatomy in establishing reasonable subdivisions for the human basal forebrain should be emphasized; experience with experimental and histochemical preparations from a variety of species, but particularly the rat, have informed our choices for subdivisions in the amygdala. Among the other authors that have provided a comparative assessment of amygdala in recent times, the article of Price et al. (1987) is particularly relevant, while among the classical papers, those of Koikegami (1963), Johnston (1923) and V61sch (1906, 1910) remain valuable. 7.2. FOOTNOTES TO TABLES Areas filled with dark gray ( ~ ) indicate nuclei or subdivisions not discussed by the particular author(s). Terms highlighted with light gray ( ) in Table 1, designate subdivisions in the rat amygdala where we did not feel that it was useful to attempt a one-to-one-match with the corresponding subdivision in the human amygdala. 1 In the rat we initially described an intermediate nucleus (BSTLI) consisting of large cells interposed between the lateral and medial subdivisions of the bed nucleus of the stria terminalis (de Olmos et al. 1985). In the human this only appeared to be represented by a thin lamina of large neurons between these two divisions (de Olmos, 1990), however, this description was mistyped as 'a thin lamina of large neurons interposed between the intermediate and medial BST' (de Olmos, 1990, p. 598). Subsequently, in the rat, we observed that in pre-adolescent rats at least some of these large cells express tyrosine hydroxylase and send projections to targets shared by the lateral bed nucleus of the stria terminalis but not to areas targeted by the medial bed nucleus of the stria terminalis. Accordingly, we (Alheid et al. 1995) renamed this nucleus the 'intermediate part of the lateral bed nucleus of the stria terminalis' (BSTLI), to reflect its close relationship to the lateral, rather than the medial bed nucleus. 2 The designations for the posterior medial bed nucleus of the stria terminalis in the table have been modified somewhat from that presented in the 1985 or 1995 descrip188

The human basal forebrain. Part H

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tion of this area in order to correct an error that was introduced in the 1995 paper. In the rat, we initially subdivided the neuronal columns of the posterior medial bed nucleus into a medial small-celled part, an intermediate medium-celled part, and a lateral large-celled part, with the last two divisions only incompletely separated (de Olmos et al. 1985). When we revisited the topic of the bed nucleus in 1995 (Alheid et al.), we chose to further subdivide the small-celled part of the posterior bed nucleus of the stria terminalis, based on histochemical evidence; however, by an oversight, we neglected to correct the cytoarchitectural description in the text to reflect four subdivisions rather than three. To correct this problem for the terms applied to the posterior medial bed nucleus of the stria terminalis in the rat (in Table 1) we have used the medial to lateral designation for these cell columns, combined with the cell size (see table). In order to be consistent with the use of these terms in the figures for the 1995 paper and in the third edition of the Paxinos and Watson atlas of the rat brain, we have added the term 'lateral ventral (large celled) part of the posterior medial bed nucleus of the stria terminalis' or BSTMPLV. This latter term reflects the fact that the larger cells that suggest this subdivision extend ventrally from a horizontal level that is at or near the level of the anterior commissure. They, therefore, are found more ventral as a whole, than the other subdivisions of the posterior medial bed nucleus. This subdivision was not designated either in the figures for the 1995 paper or the third edition of the Paxinos and Watson atlas. 3 We have argued (see text, part 2) that the location of the nucleus of the lateral olfactory tract depicted by Crosby and Humphrey (1941) and by Price and colleagues for the human is likely incorrect, and that there is, at present, no convincing evidence for its existence in the human brain. Similarly, the apparent lack of an accessory olfactory bulb in old world primates argues against the existence of a nucleus of the accessory olfactory tract, which is evident in the rat. 4 In this instance, we have noted that Gloor in his text (p. 600) stated that the nucleus of the lateral olfactory tract 'is not demonstrable in humans' while the NLOT is labeled in Figure 6-6. Insofar as Dr. Gloor's death prevented him from labeling these figures himself, we have retained his verbal description in our table. 5 V61sch uses D' to identify the nucleus of the lateral olfactory tract (his 'Kern des sagittalen L/ingsbtindels der Stria terminalis') in non-primates. In the primate, however, he misapplies this designation to the area we identify with the anterior part of the medial amygdala nucleus or possibly part of the anterior amygdaloid area. Hilpert suggests that the nucleus D I identified by V61sch (see note 3) may be included within the substantia innominata. Since Hilpert was only examining the human brain, he is likely referring to the area designated D I in the primate by V61sch (see above) rather than the homologue of the nucleus of the lateral olfactory tract that V61sch correctly designated with D ~ in non-primates. 6 Although in comparative material from non-primate mammals, Johnston applies the term nucleus of the lateral olfactory tract to the same nucleus that modern authors recognize by the same name, in the monkey and human brain he does not clearly identify this nucleus. In the macaque, he says that a distinct cell group is not evident, but presumes that the nucleus is within the aggregate of cells at the rostral end of the fiber fascicles that he (mistakenly) identifies with the commissural component of the stria terminalis. In the human, he suggests the location of the nucleus of the lateral olfactory tract mainly on a topographical basis in the fetal human brain.

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7 'Cell complex beneath temporal limb of anterior commissure' = Y; V61sch considers this area as a part of striatum (e.g. see V61sch 1910, Fig. 28). 8 Initially, in his examination of the hedgehog and mouse, V61sch designated by the letter 'K' small-celled masses ('Kleinzellige Kernmassen') the intercalated neuronal masses of modern terminology (see text part 2). Later after examining the ferret, lemur, and monkey he mistakenly concluded that these were glial cell groups and changed the name associated with the letter K to reflect this view (e.g. Gliazellanh~iufungen). 9 Designations are freely translated from German terms that V61sch assigned to letter designations in his figures (e.g. B = 'Rindenanteil des Mandelkerns' for cortical part of the amygdala).

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8. A C K N O W L E D G E M E N T S We like to thank Drs Joseph L. Price and Gary Van Hoesen for helpful comments on portions of this manuscript. We also like to acknowledge NeuroScience Associates (Knoxville, TN) for the preparation and contribution of iron-stained human sections used in this chapter, as well as for additional Nissl- and fiber-stained sagittal and horizontal human brain sections used to supplement our analysis of basal forebrain. We would also like to thank Dr. Michael Forbes and Ms. Debra Swanson for their tireless efforts in the labeling, composition, and scanning of the histological sections used to create the digital images in this chapter, and Ms. Vickie Loeser for excellent and patient secretarial assistance. This work was supported by USPHS Grant NS-17743 (L.H. and G.F.A.), by Consejo Nacional de Investigaciones Cientificas y T6cnicas of Argentina (J.S.O.), by the Dysautonomia Foundation (J.P., N.S. and K.S.), and by the Austrian Science Foundation, G r a n t No. SFB F 00206.

9. A B B R E V I A T I O N S

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Chemical architecture of the basal ganglia ANN M. GRAYBIEL AND JOHN B. PENNEY t

1. INTRODUCTION The basal ganglia have long been singled out for studies of the chemical neuroanatomy of the brain because of the rich variety of neurotransmitter, neuropeptide and aminergic substances expressed there. The basal ganglia comprise a distributed set of forebrain structures that are tightly interconnected with the cerebral cortex and thalamus, on the one hand, and with certain parts of the limbic system on the other. Already by the 1980s, it had become evident that certain of the major neural pathways intrinsic to the basal ganglia were 'chemically coded' in the sense of expressing particular neuropeptides and other neuroactive compounds (Graybiel and Ragsdale 1983). It is now known that most of the neurotransmitters, receptors and regulatory molecules in the basal ganglia are differentially distributed with respect to the major functional subdivisions of the basal ganglia, including their input-output pathways, their macroscopic compartments, and their individual cell types. There is striking evidence that some of these neurochemically-coded subdivisions of the basal ganglia are differentially affected in the clinical syndromes associated with basal ganglia disease. The earliest documentation of such differential vulnerability was for the dopamine-containing nigrostriatal tract, which undergoes degeneration in idiopathic Parkinson's disease and related parkinsonian disorders (Ehringer and Hornykiewicz 1960). The discovery of toxin-induced parkinsonism, in which the loss of dopamine-containing fibers of the nigrostriatal system is also the principal etiologic manifestation, has allowed the experimental study of dopamine deficiency states (Breese and Traylor 1971; Langston et al. 1983). It much more recently has been discovered that in Huntington's disease, there is differential loss of expression of neuropeptides in efferent neurons of the striatum and differential loss of certain neurochemically specialized striatal interneurons as well (Reiner et al. 1988; Sapp et al. 1995; Cicchetti and Parent 1996). Also in Huntington's disease, there is increasing evidence for differential effects on the two major neurochemical compartments of the striatum, the striosomes and extrastriosomal matrix (Ferrante et al. 1987; Hedreen and Folstein 1995). Even in neuropsychiatric disorders, there are hints of differential vulnerability of neural systems interrelated to the basal ganglia (Haber et al. 1986; Swerdlow and Koob 1987; Baxter et al. 1988; Swedo et al. 1989; Leckman et al. 1991 ; Baxter et al. 1992; Drevets et al. 1992; Swedo et al. 1992; Graybiel 1997). Accompanying these overt signs of differential neuropathology of basal ganglia subsystems in extrapyramidal disorders is evidence that key receptors related to functions of neurotransmitters are also differentially distributed among striatal neurons. Notably, these include glutamate and dopamine receptors corresponding to cloned Handbook of Chemical Neuroanatomy, Vol. 15: The Primate Nervous System, Part III F.E. Bloom, A. Bj6rklund and T. H6kfelt, editors 9 1999 Elsevier Science B.V. All rights reserved.

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subtypes of receptor families (Gerfen et al. 1990; Surmeier et al. 1992; Civelli et al. 1993; Gingrich and Caron 1993; Drago et al. 1994; Testa et al. 1995; Chen et al. 1996; Chesselet and Delfs 1996; Ghasemzadeh et al. 1996; Giros et al. 1996; Tallaksen-Greene and Albin 1996; Kosinski et al. 1997; Testa et al. 1998). All of these findings have had significant impact on theories of basal ganglia function and on therapeutic protocols used in treating basal ganglia disorders (Albin et al. 1989b; Chesselet and Delfs 1996; Graybiel 1996; Mink 1996; Wichmann and DeLong 1996). Increasingly, such evidence is also being used in attempts to understand the fundamental neuropathology of the basal ganglia and their subdivisions. This information also has influenced attempts to generate transgenic mice deficient in or with an excess of key molecules in these pathways, for example, dopamine receptors (Xu et al. 1994; Accili et al. 1996; Giros et al. 1996; Xu et al. 1997) and molecules potentially related to the neuropathology of basal ganglia diseases (Duyao et al. 1995; Nasir et al. 1995; Mangiarini et al. 1996; Davies et al. 1997; DiFiglia et al. 1997; Rocha et al. 1998). For all of these reasons, understanding the chemical architecture of the basal ganglia has become a central focus for much work in the field of forebrain control of behavior. In this chapter, we will focus on functional approaches to understanding the primate basal ganglia and their chemically specialized subsystems. We will not, however, present a survey of all the new and current information about these neurotransmitterrelated characteristics of the basal ganglia. For example, much work is being carried out on the development of the basal ganglia, and we will not pursue this issue. Other parts of the system are treated in other chapters. There is a detailed treatment of the dopamine-containing systems of the brain presented elsewhere in this Series (Lewis and Sesack 1997). Finally, it is important to mention at the outset that much new information has been gathered on the basal ganglia in rodents and other non-primate species, rather than in primates themselves. We will refer only occasionally to this literature.

2. SYSTEMS APPROACH TO THE BASAL GANGLIA 2.1 THE BASAL GANGLIA PROPER AND THEIR ALLIED NUCLEI The basal ganglia and their allied nuclei together include many of the large subcortical structures of the forebrain (Figs 1, 2). The largest of these is the striatum (properly, the corpus striatum), itself made up of the caudate nucleus and the putamen and a differentiated ventral part that includes the nucleus accumbens septi and contiguous gray matter. The globus pallidus (pallidum) is the principal target of striatal outflow and forms a core structure of the basal ganglia. The pallidum is divided into two functionally distinct parts, an external segment (external pallidum) and an internal segment (internal pallidum) that itself can be further subdivided into inner and outer parts. Just as there are dorsal and ventral parts of the striatum, so there are dorsal and ventral parts of the pallidum. The ventral pallidum, which receives input mainly from the nucleus accumbens, is the part of the striatum most tightly linked to the limbic system (see Heimer and de Olmos, this volume). The dorsal pallidum is almost universally known simply as the pallidum or globus pallidus. In terms of information flow through the basal ganglia, the striatum is the largest input structure of the whole

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Fig. 1. Schematic diagram of the basal ganglia: the striatum (the caudate nucleus, CN, and the putamen, P), the globus pallidus (the external segment, GPe, and the internal segment, GPi). Also shown are the other allied nuclei: the subthalamic nucleus (SthN), the substantia nigra, itself made up of the dopamine-containing pars compacta (SNpc) and the pars reticulata (SNpr), and the thalamus (Thal).

system, and the striatum projects most massively to the pallidum and to the substantia nigra, the main output structures of the system. The substantia nigra, although not properly a part of the basal ganglia because it is situated in the midbrain, is a key structure in this interconnected network. The substantia nigra actually is a complex of different nuclei. The so-called pars reticulata of the substantia nigra is similar to the pallidum in many of its anatomical and neurochemical characteristics. Functionally, also, the pallidum and nigral pars reticulata are similar in being principal output nuclei of the basal ganglia, but the targets of their efferent fiber systems are different. The pars compacta of the substantia nigra contains neurons that synthesize dopamine. These neurons give rise to the nigrostriatal tract. Just medial to the substantia nigra, pars compacta, and continuous with it, is another major dopamine-containing midbrain cell group, the ventral tegmental area. The third major dopamifie-containing cell group of the midbrain, the retrorubral area, lies just dorsal and caudal to the nigral pars compacta. These three dopamine-containing cell groups have been assigned letter and number designations according to the general categorization of aminergic cell groups of the midbrain introduced for the rat brain by Dahlstr6m and Fuxe (1964). The substantia nigra, pars compacta corresponds to cell group A9, the ventral tegmental area to cell group A10, and the retrorubral region to cell group A8 (for a recent treatment of this complex in the human brain, see Damier et al. 1999a and b). Two other critical elements in the basal ganglia system are the subthalamic nucleus and the pedunculopontine nucleus (formally, the nucleus tegmenti pedunculopontinus, pars compacta). The almond-shaped subthalamic nucleus lies in the diencephalon, within the subthalamic region. It now is known to be a critical controlling nucleus for much of the neural processing that goes on in the pallidum and substantia nigra (Kitai and Kita 1987; Bergman et al. 1990; Parent and Hazrati 1995b; Chesselet and Delfs 1996; Joel and Weiner 1997) and is a key target for neurosurgery to relieve 229

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Parkinson's disease (Baron et al. 1996; Lang et al. 1997). The pedunculopontine nucleus lies in the midbrain. It also is closely related to the basal ganglia proper by interconnecting pathways, but much less is known about its functional significance

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Fig. 2. Autoradiograms of ligand binding to neurotransmitter receptors in the brain of a 22-year-old woman who died in a motor vehicle accident. The postmortem delay was 21 hours before half the brain was blocked and frozen in dry ice. The plane of section is near-coronal, except that the medial part of the section is somewhat caudal to the lateral part. This results in the substantia nigra, pars reticulata and subthalamic nucleus being in the same plane of section as the internal segment of the globus pallidus. (A), 95 nmol [3H]muscimol binding to (largely) 13subunits of GABAA receptors. (B), 21 nM [3H]-flunitrazepam binding to c~ units of GABAA receptors. (C), 14 nM [3H] (D)-ala-(D)-leu-enkephalin binding to 8 opiate receptors, (D), 3 nM [3H]-naloxone binding to ~ opiate receptors. (E), 1 nM [3H]-spiperone binding to dopamine D2 receptors. (F), 1.4 nM [3H]-quinuclidinylbenzilate binding to muscarinic cholinergic receptors. Abbreviations: A, amygdala; C, caudate nucleus" C1, claustrum; Cx, cortex; E, external segment of globus patlidus" I, internal segment of globus pallidus" N, substantia nigra, pars reticulata; P, putamen, S, subthalamic nucleus; T, thalamus. (Garcia-Rill 1986; Ohye 1987; Garcia-Rill 1991; F u t a m i et al. 1995; K o j i m a et al. 1997). In the account that follows, we will briefly review the circuit d i a g r a m o f the basal ganglia a n d some of the n e u r o t r a n s m i t t e r - r e l a t e d c o m p o u n d s , particularly receptors, associated with particular subcircuits. W e will then relate these to functional concepts a b o u t the basal ganglia in relation to the p a t h o p h y s i o l o g y o f m o v e m e n t disorders and, where possible, to neuropsychiatric disorders. 2.2. T H E C O N N E C T I O N S

OF THE BASAL GANGLIA"

AN OVERVIEW

A schematic s u m m a r y of some of the connections of the basal ganglia is shown in Figs 3-5. A m a j o r set of input p a t h w a y s to the system originate in the neocortex a n d enter basal ganglia circuitry at the level o f the striatum. F r o m the striatum, three m a j o r p a t h w a y s (or sets of pathways) emerge: the direct p a t h w a y , the indirect p a t h w a y , and the striosomal o u t p u t pathway. 231

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2.2.1. The direct pathway The direct pathway is the largest single outflow channel of the basal ganglia (Figs 3-5). It exits the caudate nucleus and putamen and leads to the internal pallidal segment (GPi) and to the substantia nigra, pars reticulata. From these two nuclei, pathways lead to the ventral nuclear (VA-VL) complex of the thalamus and also to the thalamic centre median-parafascicular complex. The VA-VL complex projects densely to the premotor, supplementary motor and motor cortex. Those parts of the complex influenced by the substantia nigra, pars reticulata pathway also reach regions of the prefrontal cortex as well as part of the temporal cortex (see Flaherty and Graybiel 1994a; Joel and Weiner 1994; Haber et al. 1995; Parent and Hazrati 1995a,b; Middleton and Strick 1996; Levy et al. 1997). The circuit linking the neocortex, striatum, internal pallidum, thalamus and frontal cortex has classically been considered the 'main circuit' of the basal ganglia. However, there are also downstream output connections of the basal ganglia. These include a pathway from the pars reticulata of the substantia nigra, which is a critical oculomotor control circuit for saccadic eye movements (Graybiel 1978; Hikosaka and Wurtz 1983a,b,c; Chevalier and Deniau 1990).

2.2.2. The indirect pathway There are extremely important side loops that modify and regulate the direct pathway circuits. Of these, the best known is the so-called indirect pathway. This takes its starting point from the caudate nucleus and putamen, and leads to the external seg-

Fig. 3. Diagram of the main connections of the basal ganglia. Putative excitatory and inhibitory connections are shown by plus and minus signs, based on current views of the excitatory effects of glutamate and the inhibitory effects of GABA (but see, e.g., Fiorillo and Williams 1998). Am, amygdala; CM-Pf, centre median-parafascicular nuclear complex of the thalamus; SNpc, substantia nigra, pars compacta; GPi, internal pallidum; SNpr, substantia nigra, pars reticulata; GPe, external pallidum; Sth N, subthalamic nucleus; Thal, thalamus; S Coll, superior colliculus; PPN, pedunculopontine tegmental nucleus. Modified from Graybiel 1996. 232

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Fig. 4. Diagram of basal ganglia circuits. The primary flow of cortical information through the system is shown with thick arrows. Cx, cortex; PTO, parietotemporo-occipital cortex; Ci, cingulate cortex; S, striosome; M, matrix; GPe and GPi, external and internal segments of the globus pallidus; Sth N, subthalamic nucleus; VA-VL and MD, ventroanterior-ventrolateral and mediodorsal nuclei of the thalamus; CM-Pf, centre median-parafascicular complex of the thalamus; SNpc and SNpr, pars compacta (pc) and pars reticulata (pr) of the substantia nigra; S Coll, superior colliculus; PPN, pedunculopontine nucleus; Am (bl), basolateral nucleus of amygdala. Modified from Flaherty and Graybiel 1994a.

ment of the globus pallidus (GPe) and from there on to the subthalamic nucleus (Figs. 3-5). The subthalamic nucleus, in turn, projects back to the pallidum. This pathway is thought to be one of the most important regulators of pallidal activity, and it is a major target for neurosurgical intervention in Parkinson's disease (Svennilson et al. 1960; Laitinen et al. 1992a; Ceballos-Baumann et al. 1994; Iacono et al. 1994; Dogali et al. 1995; Lozano et al. 1995; Baron et al. 1996; Wichmann and DeLong 1996, 1998; Benazzouz et al. 1996; Chesselet and Delfs 1996; Lang et al. 1997). It is important to note that the subthalamic nucleus itself receives input not only from the external pallidum, but also from the cerebral cortex (Parent and Hazrati 1995b; N a m b u et al. 1996; Joel and Weiner 1997) and from the centre median-parafascicular complex (Feger et al. 1994). The indirect and direct pathways are linked by powerful connections from the external pallidum to the internal pallidum and a somewhat weaker return pathway from the internal to external pallidum (Shink et al. 1996). In addition, there are return pathways from pallidum to striatum (Staines and Fibiger 1984; Takada et al. 1986). The indirect pathway (subthalamic loop) not only involves the pallidum, but also 233

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Fig. 5. Schematic circuit diagram of the basal ganglia and associated input-output connections. The bold arrows show the main circuits of the system which include an excitatory (glutamatergic) projection from the neocortex to the striatum (caudate nucleus and putamen, left) and an inhibitory (GABAergic) striatal path (the 'direct path') to the internal pallidum (GPi) and substantia nigra, pars reticulata (SNpr). These nuclei give rise to a set of inhibitory (GABAergic) projections to the thalamus and the brainstem. Brainstem targets include the superior colliculus (S Coll) and pedunculopontine nucleus (PPN). The * indicates that most of these brainstem projections originate in SNpr. The main thalamic target of this basic circuit (VA-VL) projects to frontal cortex including parts of the premotor (and supplementary motor) cortex and to the motor cortex (right in diagram). Also shown are the through-projections via the mediodorsal nucleus (MD) to the prefrontal cortex. This basic circuit is modulated by side loops, of which representative examples are shown here. The dopamine (DA)-containing substantia nigra, pars compacta (SNpc) innervates the striatum (and other targets, not shown). The SNpc receives input from parts of the limbic system and limbic-related cortex (far left), which also project to the striatum, particularly to striosomes (S). The subthalamic loop includes projections from the striatum to the external pallidum (GPe), and then to the subthalamic nucleus (Sth N), which in turn projects to GPe, SNpr/GPi, and to SNpc. This GPe-mediated circuitry is called the 'indirect pathway'. There are also interconnections between GPe and SNpr/GPi. Other motor-related connections shown include projections from prefrontal/premotor/motor cortex to the Sth N and to nuclei of the thalamus. The centre median-parafascicular complex of the thalamus (CM-Pf) closes another loop by projecting back to the striatum. The nucleus reticularis of the thalamus (NRT) also interacts with the circuitry. Not shown are connections of brainstem regions such as PPN and connections related to the ventral striatum. Glu, glutamate, SP, substance P, Dyn, dynorphin, Enk, enkephalin. Modified from Graybiel 1993.

the s u b s t a n t i a nigra, p a r s r e t i c u l a t a , w h i c h , like t h e i n t e r n a l p a l l i d u m , receives i n p u t b o t h f r o m the e x t e r n a l p a l l i d u m a n d f r o m t h e s u b t h a l a m i c n u c l e u s . F u r t h e r m o r e , t h e e x t e r n a l p a l l i d u m n o t o n l y p a r t i c i p a t e s in t h e i n d i r e c t p a t h w a y , b u t also h a s a s t r o n g p r o j e c t i o n to s o m e o t h e r r e g i o n s ( P a r e n t a n d H a z r a t i 1995b; S a t o et al. 1997). T h u s , a l t h o u g h the i n d i r e c t p a t h w a y is p r i n c i p a l l y v i e w e d as a m o d u l a t o r o f t h e direct p a t h way, it c a n influence s t r u c t u r e s o u t s i d e o f t h e b a s a l g a n g l i a p r o p e r . A s we discuss 234

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below, this has become a controversial but critical issue in terms of neurosurgical approaches to therapy of basal ganglia disorders. 2.2.3. The striosomal output pathway

Within the caudate nucleus and putamen of human and non-human primates (and many other mammalian species as well), there are prominent neurochemically distinct tissue compartments called striosomes (Fig. 6), which lie scattered within the much larger surrounding tissue, the striatal matrix (Graybiel and Ragsdale 1978). These neurochemical compartments were discovered long after the classical subdivisions of the striatum (the caudate nucleus and the putamen), but they appear to represent functional subsystems within the basal ganglia. First, striosomes and matrix have received much attention because their neurochemical properties suggest that they differ from one another in their relative expressions of mostly all of the known neurotransmitter-related molecules in the striatum, from neurotransmitters and neuromodulators to receptors, uptake sites and enzymes (see Graybiel 1990; Gerfen 1992b; Holt et al. 1997). Examples of these neurochemical differences between striosomes and matrix are shown in Figs. 6-9. It is now clear that striosome and matrix compartments have different input-output connections, so that when we speak of pathways leading into or out of the striatum, it is necessary to specify the compartment they are related to. The direct and indirect pathways mainly (or even exclusively) arise in the large matrix compartment (Gim6nez-Amaya and Graybiel 1990, 1991). It is also the matrix that receives most of the cortical inputs to the striatum that arise in sensory and motor cortex and considerable parts of association cortex (Flaherty and Graybiel 1994b). The striosomal compartment seems to be specialized for dealing with information related to limbic system function. In monkeys, parts of the posterior orbital frontal cortex and anterior cingulate very strongly project to striosomes (Fig. 10), as does a medial part of the substantia nigra, pars compacta (Fig. 11). Striosomes also receive a nigrostriatal input that is distinct from that of the matrix (Fig. 11). Striosomes, in turn, project to the compacta region of the substantia nigra (perhaps to the dopamine-containing neurons, but this is not certain), and some striosomal neurons project to the ventral pallidum, the limbic part of the pallidum. There is serious interest in the possibility that the striosomal output pathway deals with 'evaluator functions' as contrasted with the sensorimotor 'executive functions' of the direct and indirect pathways (Graybiel and Kimura 1995; Houk 1995; Graybiel 1997). 2.2.4. General modular architecture of the striatum: striosomes and matrisomes

An increasing body of evidence suggests that, in addition to the division of the striaturn into striosomes and matrix, the large matrix compartment itself has a modular design. This suggestion has been made on the basis of tract-tracing and gene-induction experiments in primates demonstrating that corticostriatal afferents originating in localized sites in the neocortex (for example, sites in the somatosensory cortex (Flaherty and Graybiel 1993a,b; 1994b; 1995; Parthasarathy and Graybiel 1997), the frontal cortical eyefields (Parthasarathy et al. 1992) and the prefrontal cortex (Eblen and Graybiel 1995) terminate in patchy zones ('matrisomes') in the matrix (Figs. 12 and 13). The afferent input patches in the matrix have been identified not only with classical fiber-tracing methods, but also by stimulation of local sites in the cortex, 235

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Fig. 6. Striosomal organization of the human striatum. Acetylcholinesterase (ACHE) staining in a transverse section through the adult human striatum (CN, caudate nucleus; P, putamen; NAc, nucleus accumbens; IC, internal capsule) shows compartments of low AChE staining (one marked by asterisk) called striosomes, surrounded by an AChE-rich matrix. Scale bar, 2 ram. From Graybiel 1984.

which induces the expression of immediate-early genes in patchy zones in the matrix corresponding to afferent-fiber patches (Fig. 13). The striatopallidal output neurons of the primate caudate nucleus and p u t a m e n are also distributed in clumpy arrangements (Gim6nez-Amaya and Graybiel 1990; 1991). 236

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In some instances, the input and output matrisomes overlap (Fig. 14). This suggests that there may be a divergent-reconvergent architecture for some sets of corticostriatal inputs and striatopallidal outputs (Flaherty and Graybiel 1994b; Graybiel et al. 1994). Neurochemical correlates of this compartmental organization of the matrix have not yet been identified, but inhomogeneities in many neuronal markers have been noted in the matrix (Holt et al. 1997).

2.2.5. Loop systems of the basal ganglia The indirect pathway and the striosomal output pathway are both, in part, loop systems of the basal ganglia in that they involve strong internal connectivity among striatal, pallidal and nigral subdivisions of the basal ganglia. They have strong inputs from outside the basal ganglia, however, and are not fully closed on their output sides, either. Other well established loop circuits modulate the basal ganglia as well. These include (1) the centre median-parafascicular (CM-Pf) loop, in which the striatum projects to the internal pallidum, the internal pallidum to the CM-Pf complex of the thalamus, and the CM-Pf complex back to the striatum; and (2) the pedunculopontine loop, in which the striatum projects to the internal pallidum, which projects to the pedunculopontine nucleus, which in turn sends projections back to the pallidum as well as to the subthalamic nucleus and the substantia nigra, pars compacta. These internal loops of the basal ganglia are both modulated by cortical input. For example, some areas of the frontal cortex project massively to the CM-Pf complex (Parent and Hazrati 1995a). This means that the neocortex has the potential to influence the basal ganglia at multiple stages, even though the largest volume of cortical input to the system is directed toward the striatum. Other 'internal connectivity' of the basal gang-

Fig. 7. Striosomes express low levels of choline acetyltransferase (CHAT). Adjoining sections through the caudate nucleus (CN) and putamen (P) of a rhesus monkey illustrating correspondence of staining patterns seen with ChAT immunohistochemistry and AChE histochemistry. Broad gradients of ChAT and acetylcholinesterase staining are also similar in that the staining is stronger dorsolaterally than ventromedially. IC, internal capsule. Scale bar, 2 mm. Modified from Graybiel et al. 1986. 237

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Fig. 8. Striosomal organization of enkephalin immunostaining in the human brain. Cross section through the striatum of a human brain illustrating Met-enkephalin-like immunoreactivity in the caudate nucleus (CN), putamen (P) and ventral striatum (VS). Note striosomes (example at asterisk) and marked dorsoventral gradient in intensity of the immunostaining. IC, internal capsule. Scale bar, 2 mm. Modified from Graybiel 1986. See also Holt et al. 1997. lia includes a considerable return connection from the pallidum to the striatum (Staines and Fibiger 1984; H a b e r et al. 1993; Spooren et al. 1996). Finally, there are other afferents to the basal ganglia which, a l t h o u g h smaller in m a g n i t u d e than those f r o m the cerebral cortex and thalamus, are nevertheless prob238

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ably critical in functional terms. The amygdaloid complex projects strongly to the ventral striatum and also to parts of the dorsal striatum (Ragsdale and Graybiel 1988; Kita and Kitai 1990; Percheron et al. 1992 and personal communication). The hippocampal formation projects densely to the nucleus accumbens, principally to the most medial 'shell' subdivision of the nucleus (see Heimer and de Olmos, this volume). There are strong inputs from the motor cortex (and some other cortical areas) to the subthalamic nucleus (Nambu et al. 1996) and to the CM-Pf complex (Parent and Hazrati 1995a). From even this brief summary, it is clear that there are multiple connections within the basal ganglia nuclei proper that interrelate them to the cortex, to the thalamus, and to the brainstem. The direct pathways to the pallidum and the substantia nigra are viewed as the main ways out of the system, leading toward the thalamus and such structures as the superior colliculus. This entire circuitry is modulated by ascending aminergic fibers from the substantia nigra, pars compacta and from the serotonergic

Fig. 9. Neurons in striosomes express low levels of enkephalin-like immunoreactivity in the primate. Patches of low enkephalin immunostaining (pale zones; example at asterisk, shown at higher magnification in inset) detected in the striatum of squirrel monkey by a protocol demonstrating perikaryal enkephalin-like immunoreactivity. CN, caudate nucleus; P, putamen; IC, internal capsule. Scale bar, 1 mm. Modified from Graybiel and Chesselet 1984. 239

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Fig. 10. Orbital and anterior cingulate-medial prefrontal sites projecting to striosomes. Lateral, medial and ventral views of a macaque monkey brain, showing locations in which injections of anterograde tracer labeled corticostriatal projections to striosomes (darker stipple) and to matrix (lighter stipple). Modified from Eblen and Graybiel 1995.

dorsal raphe nucleus (Charara and Parent 1994). Not considered here are ventral striatal-ventral pallidal circuits, tied to the limbic system. These are considered in detail elsewhere in this volume (Heimer and de Olmos). It should be remembered, however, that even in the dorsal striatal circuitry, striosomes (and probably some regions of the matrix) also link basal ganglia circuitry to the limbic system. In the rodent, direct interaction between these limbic ventral striatal and pallidal structures and classic (dorsal, sensorimotor) basal ganglia nuclei have been discovered (Bevan et al. 1997). It is not yet known whether such interconnectivity also exists in the basal ganglia in primates, but studies on the substantia nigra already suggest this to be true (Haber 1993; Haber et al. 1993). The anatomy of the primate striatum indicates that such interactions also could occur across striosome-matrix boundaries (Walker et al. 1993; Walker and Graybiel 1993). 2.3. TRANSMITTER-RELATED COMPOUNDS ASSOCIATED WITH BASAL GANGLIA PATHWAYS If we now look at the circuit diagram of the basal ganglia in terms of the neurotransmitters and neuromodulators expressed in the pathways (Fig. 3), there are two striking points to note immediately. First, the main inputs to the striatum from the neocortex (and probably those from the thalamus and amygdala) are thought to use excitatory amino acids, principally glutamate (Young et al. 1983; Herrling 1985; Calabresi et al. 1996). This means that the principal extrinsic inputs to the basal ganglia may principally excite the system. The cortical projections to other nuclei of the circuitry, includ240

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ing the subthalamic nucleus, the pedunculopontine nucleus, and the C M - P f complex are also thought to be glutamatergic. In sharp contrast, the internal connectivity of the basal ganglia and the outputs of the system are predominantly GABAergic. This is true both for the striatal outputs to the external and internal pallidum and the substantia nigra, pars reticulata, and for the projections from these structures to their target structures in the thalamus and brainstem (Chevalier and Deniau 1990). Thus, although there are many circuits related to the basal ganglia, in terms of their principal classical neurotransmitters, the circuits at first glance are quite simple: the input paths are mainly excitatory and the output paths are inhibitory (but see Fiorillo and Williams 1998). Despite the strong excitation of the striatum by its extrinsic afferents, however, striatal projection neurons are normally held at a resting voltage that is well below their threshold for firing action potentials (Nisenbaum et al. 1994). They are held in a 'down state'. When they are sufficiently excited, their membrane potential shifts to just below their threshold, or 'up state', and any further excitatory input at this point can provoke them to fire a brief burst of action potentials (Nisenbaum et al. 1994). In contrast to striatal neurons, pallidal neurons and neurons of the substantia nigra, pars reticulata have high tonic firing rates. They thus should tonically inhibit the thalamus

Fig. 11. Nigrostriatal innervation of striosomes and matrix arise in distinguishable parts of the A8-A9 complex. (A), Autoradiogram through the striatum of a squirrel monkey in which anterograde tracer was injected into the substantia nigra, pars compacta so as to involve mainly the lateral part of the main horizontal band and associated ventrally-extending fingers of dopamine-containing neurons. There is predominant labeling of striosomes (examples marked by asterisks) in the caudate nucleus and medial putamen, with much weaker labeling of the matrix. (B), Autoradiogram through the striatum in another squirrel monkey in which a deposit of anterograde tracer involved cell group A8 and the pars mixta. There is predominant labeling of the extrastriosomal matrix, so that striosomes in the field of terminal labeling (examples marked by asterisks) appear weakly labeled. CN, caudate nucleus; P, putamen; VS, ventral striatum, IC, internal capsule; AC, anterior commissure. Scale bar, 2 mm. Modified from Langer and Graybiel 1989. 241

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Fig. 12. The supplementary motor area (SMA) projects predominantly to the matrix compartment of the primate putamen. Photographs of adjacent sections through the striatum of a macaque monkey processed for corticostriatal tracer labeling (A) and for enkephalin-like immunoreactivity (B) demonstrating that the experimentally labeled SMA fibers avoid striosomes in the putamen (reverse contrast photography). Where striatal labeling is heaviest in the caudate nucleus, striosomal avoids are less obvious. Asterisks indicate the location of corresponding striosomes in the pair of sections. AC, anterior commissure; CN, caudate nucleus; GPe, globus pallidus external segment; IC, internal capsule; P, putamen. Scale bar, 2 mm. Modified from Parthasarathy et al. 1992. (Mitchell et al. 1987; Wichmann et al. 1994a). A brief burst of firing by GABAergic direct pathway neurons should therefore temporarily relieve a small part of the pallidorecipient thalamus from its tonic inhibition. Thus, the net effects of the striatopallido-thalamic and striato-nigrothalamic pathways, considered most simply, are thought to be disinhibitory. The subthalamic nucleus controls this circuit. Its neurons fire at a high rate (Kitai and Deniau 1981), use glutamate as their neurotransmitter (Albin et al. 1989a; Brotchie and Crossman 1991), and receive a strong excitatory glutamatergic input from the neocortex. But a pivotal point about the sulSthalamic nucleus is that it receives a GABAergic input from the external pallidum. It is thought that when neurons in the subthalamic nucleus are excited by the neocortex and fire, they are quickly inhibited by the external pallidum (Kitai and Deniau 1981; Kita et al. 1983). Activation of the GABAergic indirect pathway projection neurons in the striatum, by reducing activity in the external pallidum, should thus disinhibit the subthalamic nucleus. Thus, although the direct pathway leads to disinhibition of the thalamus and such brainstem targets as the superior colliculus, by a GABA-GABA double inhibition, the indirect pathway (subthalamic loop) produces inhibition of the thalamus and superior colliculus by exciting the internal pallidum and substantia nigra, pars reticulata. There is also a short-cut pathway from the external pallidum to the internal pallidum that can have a similar effect. It has been proposed that activity in the direct striatal output pathway produces the focused disinhibition (release) of appropriate action commands at the level of the thalamus while activation of the indirect pathway produces a surround inhibition of inappropriate action commands at the thalamic level (Mink 1996). Physiological stud-

242

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Fig. 13. Electrical stimulation of the cutaneous foot digit representation in area SI induces Fos in multiple patches in the primate striatum that correspond to the afferent patches labeled by injection of anterograde tracer in the 3b foot digit representation. Rectangle in (A) shows a region shown at higher magnification in C-E. (B), Map of sites in cortical area SI identified by neuronal recording. A, ankle; D, digit; F, foot; LL, lower leg; P, foot pad. Approximate borders between areas 3a and 3b, and areas 3b and 1, are shown by the dotted lines. Darker circle indicates the reconstructed tracer ([35S] methionine) injection site. The lighter concentric circle indicates the less intensely labeled marginal zone of the injection site. Stimulation was applied across areas 3b and 1. Stimulation sites shown at asterisks indicate positions of bipolar electrodes. The fields of afferent fibers labeled from the injection site and immediate-early gene expression induced by the electrical stimulation in the rectangular region outlined are shown in C-E in high-magnification photomicrographs of serially adjacent transverse sections. (C), Patches of [35S] methionine-labeled corticostriatal fibers viewed under dark field illumination. (D), Patches of Fos-positive nuclei. (E), Patches of Jun B-positive nuclei, v, blood vessels used as fiducial points. Scale bar, 0.5 mm. From Parthasarathy and Graybiel 1997.

ies o f eye m o v e m e n t control, exerted by the nigrotectal p a t h w a y s u p p o r t this general view ( H i k o s a k a a n d W u r t z 1983a-d; Chevalier a n d D e n i a u 1990). T h e centre m e d i a n - p a r a f a s c i c u l a r l o o p similarly has two i n h i b i t o r y p a t h w a y s in series, f r o m the s t r i a t u m to the p a l l i d u m a n d f r o m the p a l l i d u m to the t h a l a m u s ; b u t the final stage of the loop, f r o m the C M - P f c o m p l e x to the striatum, is t h o u g h t 243

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to be excitatory. Thus, just as the subthalamic loop excites the pallidum, the centre median-parafascicular loop excites the striatum. Very little is yet known about the physiology of this pathway, but in sheer volume the thalamic input from the CM-Pf complex is second only to that from the neocortex, and understanding of this loop may be key to understanding of the functions of the basal ganglia as a whole. The neurotransmitter circuit diagram just described has had a profound effect in guiding therapeutic approaches to basal ganglia disorders. In particular, for the hyperkinetic disorders, the reasoning is that there is abnormal 'release' of acts that would otherwise be suppressed due to too little inhibition of the thalamus. For hypokinetic parkinsonian states, the neurotransmitter circuit considerations have led to therapeutic approaches to relieve excess inhibition of the thalamus by lesions of the motor sector of the internal pallidum or the subthalamic nucleus itself (Svennilson et al. 1960; Laitinen et al. 1992a; Iacono et al. 1994; Ceballos-Baumann et al. 1994; Dogali et al. 1995; Graybiel 1996; Lang et al. 1997). Promising efforts are underway to inhibit these structures reversibly through application of high frequency electrical stimulation via chronically indwelling electrodes (Benabid et al. 1991; Siegfried and Lippitz 1994; Lirnousin et al. 1995). Such a logical circuit analysis did not underpin the original L-DOPA therapy for parkinsonian disorders. The dopamine replacement therapy originated many years before these pathways and their transmitters were clearly delineated. The powerful effect of L-DOPA in ameliorating parkinsonian signs, however, testifies to the strong

Fig. 14. Correspondence of input matrisomes and output matrisomes in the monkey striatum. (A), Dark field photomicrograph of a coronal section through the putamen of a squirrel monkey, with input matrisomes anterogradely labeled by an injection of WGA-HRP in the foot region of the motor cortex. (B), Serial section from the same brain showing output matrisomes retrogradely labeled by an injection of reterograde label in the GPi. Borders of the putamen are outlined in white. IC, internal capsule; P, putamen. Scale bar, 1 mm. Modified from Flaherty and Graybiel 1994b. 244

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influence of dopamine on the system. All of the subcortical circuits of the basal ganglia now are thought to be modulated to a greater or lesser extent by the biogenic amines. The strongest modulation known is by the dopaminergic fibers of the midbrain that project to the striatum, but the pallidum also receives dopamine-containing afferents in the primate, and the subthalamic nucleus receives a weak input as well (Chesselet and Delfs 1996). The leading current view of the actions of dopamine on the system is that dopamine acts in the caudate nucleus and putamen through two principal mechanisms, an excitatory one directed toward the D 1-dopamine-associated direct pathway neurons, and a second, inhibitory one, directed toward the D2-class bearing striatal neurons of origin of the indirect path (Gerfen 1992a; Wichmann and DeLong 1996). L-DOPA therapy in this way could be seen as bolstering disinhibition of the thalamus via the direct pathway while at the same time diminishing the inhibition produced by the indirect pathway. There is not complete agreement on this simple scheme (Surmeier et al. 1992, 1993). The development of new reagents, including receptor-specific antibodies should soon bring new evidence to bear on receptor selectivity in the primate striatum (Hersch et al. 1994). Aside from dopamine's effects on the striatum, there is considerable interest in the possibility that dopamine, and consequently L-DOPA, exert some of their effects directly on the substantia nigra, pars compacta, where dopamine D 1-class and D2class receptors are also present and are thought in part to control the efficacy of striatal inputs to the substantia nigra (Robertson and Robertson 1989). In the ventral striatum, special effects are considered likely because of the uniquely high concentrations there of D3-class dopamine receptors (Sokoloff et al. 1990; Landwehrmeyer et al. 1993) which likely are activated by dopamine released from mesolimbic tract fibers originating in the ventral tegmental area. The effects of serotonin on the basal ganglia are not well understood, but serotonincontaining fibers are densely distributed in basal ganglia circuits at many levels from the substantia nigra, pars compacta to the striatum and pallidum (Charara and Parent 1994). Noradrenergic influences are also to be expected, especially for the ventral striatum-ventral pallidal system. However, evidence suggests that there are only very low levels of noradrenergic innervation of the dorsal striatum-dorsal pallidal system. 2.4. NEUROPEPTIDES IN BASAL GANGLIA PATHWAYS A dramatic set of findings made in the 1980s showed that the simple outline just given, in which nearly all the pathways internal to the basal ganglia circuits are GABAergic, is an oversimplified view of these pathways. In fact, the cells of origin of all three major pathways leaving the striatum the direct and indirect pathways and the striosomal output pathway express different neuropeptides that coexist with the classic inhibitory neurotransmitter GABA. Direct pathway GABAergic neurons coexpress substance P and dynorphin. Indirect pathway GABAergic neurons coexpress enkephalin (for review, see Graybiel 1990; Gerfen 1992b; Graybiel 1996). Neurons in striosomes mainly express substance P and dynorphin, but some neurons express enkephalin (Graybiel and Chesselet 1984; Besson et al. 1990; Martin et al. 1991; Holt et al. 1997). The functions of these neuropeptides are still poorly understood, but there is increasing interest in the possibility that the neuropeptides are key players in the functioning of the basal ganglia. Evidence suggests that they may influence excitability of striatal neurons and control the release of classical neurotrans245

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mitters from striatal neurons. For example, in slice preparations of the rodent striaturn, substance P and enkephalin have been found to influence the firing rates of cholinergic interneurons, suggesting that the peptides may control input and output flow through the striatum (Aosaki 1995; Aosaki and Kawaguchi 1995, 1996; Kawaguchi et al. 1997). Other evidence suggests that enkephalin expressed in the indirect pathway neurons can control the release of GABA in the pallidum (Maneuf et al. 1994). This finding suggests that neuropeptide control of transmitter release in basal ganglia pathways could have fundamental importance for the activity levels of basal ganglia output nuclei. The presence of dense concentrations of neuropeptide receptors in these nuclei (including opiate receptors and tachykinin receptors, see below) supports this view. Whatever the functional effects of these coexpressed neuropeptides, from the point of view of neuropathology, the differential distribution of the neuropeptides in direct and indirect pathway neurons and striosomal neurons or neuropil has provided a reliable basis for detecting these pathways in postmortem specimens (Graybiel 1986; Albin et al. 1991; Holt et al. 1997). Immunohistochemically detected neuropeptides are excellent markers for corresponding subdivisions of the pallidum and substantia nigra (Fig. 15). Substance P and dynorphin are at high levels in the direct pathway output nuclei, the internal pallidum and substantia nigra, pars reticulata. Enkephalin-like immunoreactivity is densely distributed in the external pallidum. These distributions, as noted below, are altered differentially in Huntington's disease (Reiner et al. 1988; Albin et al. 1991 ; Sapp et al. 1995). Neuropeptides are not the only neuroactive substances co-expressed in striatal pro-

Fig. 15. Neurochemical specializations of the human pallidum. Transverse sections through the globus pallidus of the adult human brain stained for acetylcholinesterase (ACHE), enkephalin-like immunoreactivity (ENK) and substance P-like immunoreactivity (SP). High levels of AChE mark the adjoining putamen (P). Within the globus pallidus, the external segment (GPe) and the internal segment (GPi) are characterized by different peptide immunoreactivities: enkephalin-like immunoreactivity is dense in GPe and moderate in the medial part of GPi, whereas SP-like immunoreactivity is dense in GPi. Scale bar, 3 mm. From Graybiel 1984. 246

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jection neurons (see Graybiel 1990 for review). A full account cannot be given here, but an example is the calcium binding protein, calbindin DZSK, which is preferentially expressed in matrix neurons except in the sensorimotor sector of the striatum (Gerfen et al. 1985; Martin et al. 1991; Francois et al. 1994; Holt et al. 1997). There are also many neurotransmitter-related substances readily visible in the neuropil of the striatum, and among these are not only neuropeptides and GABA produced by projection neurons, but also substances contained in the striatal interneurons. 2.5. NEUROTRANSMITTER-RELATED COMPOUNDS IN STRIATAL INTERNEURONS So far, we have only touched on the main long-axon connections of the basal ganglia. In the striatum, however, interneurons are thought to exert powerful effects on the neurons giving rise to the direct and indirect pathways (Kawaguchi et al. 1995) and to the striosomal output pathway (Aosaki et al. 1995). There are at least four main classes of interneuron in the striatum, and interestingly, at least two (and perhaps three) of these types use GABA as their principal neurotransmitter. Their distributions are shown in Fig. 16. These interneurons differ from the projection neurons in expressing the 67 kDa rather than the 65 kDa isoform of the GABA synthesizing enzyme, glutamic acid decarboxylase (Gonzales et al. 1991). The best documented GABAergic interneurons are the fast-spiking interneurons that coexpress parvalbumin, and the interneurons that coexpress the calcium-binding protein calretinin. A third type of striatal interneuron, which expresses at least low levels of GABA, coexpresses two neuropeptides, somatostatin and neuropeptide Y, and in addition nitric oxide synthase. These interneurons are attracting special interest because of the possible functions of nitric oxide in cell death and neuroplasticity. Finally, a rare but conspicuous class of very large interneurons use acetylcholine as their neurotransmitter. These neurons, although sparsely distributed, are a main source of the acetylcholine in the striatum. They are thought to correspond to the physiologically identified tonically active neurons (TANs) of the striatum (Aosaki et al. 1995). Striatal interneurons are thought to make up a relatively small proportion of the total neurons in the striatum, perhaps 20-25% in the primate (Fox et al. 1971; Kemp and Powell 1971; Graveland and DiFiglia 1985). They are numerous enough, however, to influence very large numbers of other neurons and thus could control intrinsic striatal function (e.g. Graybiel et al. 1994; Kawaguchi et al. 1995; Parthasarathy and Graybiel 1997). They contribute great neurochemical diversity to striatal circuits, and thus to basal ganglia circuits in general. Finally, striatal interneurons appear to have a special status in at least one basal ganglia disorder, Huntington's disease: they are selectively spared (DiFiglia 1990).

3. FUNCTIONAL CONCEPTS ABOUT THE BASAL GANGLIA 3.1. MOVEMENT DISORDERS In this chapter we will concentrate on four prototypic diseases in which disordered movement with preservation of strength is a major symptom, and in which the pathologies are largely confined to the basal ganglia. There are a number of other diseases that have disordered movement as part of their symptomatology, and that involve 247

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9

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Fig. 16. Charts illustrating the distribution of four major types of striatal interneurons: choline acetyltransferase (CHAT) immunoreactive, NADPH diaphorase (NADPHd)-positive, parvalbumin-positive and calretinin-positive. The neurons were plotted in sections from a normal adult squirrel monkey. Fine outlines show striosomes, determined by reference to adjacent sections stained for enkephalin-like immunoreactivity. The bundles of the internal capsule (IC) are denoted with thicker outlines in a string of connected forms separating the caudate nucleus (CN) from the putamen (P). Scale bar, 1 mm. From Aosaki et al. 1995. destruction of parts of the basal ganglia as part of their pathology, such as Wilson's disease, multisystem atrophy, and progressive supranuclear palsy. There are also a n u m b e r of disease states involving m o v e m e n t disorders in which basal ganglia dysfunction has been inferred, but for which no pathology has yet been definitively established, such as Gilles de la Tourette's syndrome. We will not deal with these disorders, because of the current lack of convincing clinicopathology. We suspect, however, that it soon will be possible to include these in a review such as ours.

3.1.1. Ballism The first of the basal ganglia disorders we will emphasize is hemiballismus, in which there is the abrupt onset of largely proximal, flinging movements of the limbs on one side of the body. The movements may be of such a violent nature that the patient 248

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becomes unable to keep up with the caloric requirements of his movements and may die of exhaustion. Usually, however, the amplitude of the movements diminishes with time, and over weeks to months the patient may return to a nearly normal state. During this recovery phase, the patient may continue to have vigorous adventitious movements but at the same time may exhibit a great deal of control over voluntary movements. We have seen a patient eat peas with a fork held in his right hand while at the same time having large amplitude, adventitious right shoulder movements! Somehow, the patient was able to compensate for the constantly changing position of his shoulder with corrective movements of his wrist and elbow. The pathology of hemiballismus usually consists of an infarct in one subthalamic nucleus induced by occlusion of a perforating branch of the posterior cerebral artery. The same symptoms can be produced in primates with lesions of the subthalamic nucleus (Carpenter et al. 1950). If we recall the fact that the subthalamic nucleus gives rise to an excitatory, glutamatergic projection to the internal pallidum (Figs. 2-4), one interpretation of this syndrome is that excitation of the inhibitory pallidothalamic pathway has been lost with the subthalamic infarct. Ironically, as we discuss below, subthalamic lesions or blocking microstimulation is now a leading neurosurgical approach to Parkinson's disease (Svennilson et al. 1960; Bergman et al. 1990; Benabid et al. 1991; Laitinen et al. 1992a,b; Ceballos-Baumann et al. 1994; Siegfried and Lippitz 1994; Wichmann et al. 1994b; Iacono et al. 1994; Dogali et al. 1995; Graybiel 1995; Limousin et al. 1995; Lozano et al. 1995; Baron et al. 1996; Wichmann and DeLong 1998). 3.1.2. Parkinson's disease

The second of the prototypic basal ganglia disorders is Parkinson's disease. First described by James Parkinson in 1817, the disease ('idiopathic' Parkinson's disease) typically begins with the insidious onset of decreased amounts of spontaneous movement, a slowness of those movements that are performed, and usually, a 4-5 Hz tremor that is present when the limb is at rest or holding a fixed posture, but that is suppressed during movement. The symptoms usually begin in one arm and spread gradually to involve the ipsilateral leg, then the neck and trunk muscles, and then the other side of the body. The side on which the disease began almost invariably remains the more involved side. As the disease progresses, patients develop a difficulty in swallowing, and a stooped posture and impairment of postural reflexes so that falls become a constant danger. The gait becomes festinating (a progressive shortening of the stride length as the patient walks, so that strides become shorter and shorter and quicker and quicker), and the patient develops great difficulty initiating any changes in the current state of motion, so that initiating movement of any kind is difficult and changing direction while moving is also difficult. There are other, inconstant, features of the disease, such as depression and dementia. There is considerable controversy about the degree to which these more cognitive signs are associated with lesions outside of the basal ganglia. The most constant pathologic finding in Parkinson's disease is loss of dopaminecontaining neurons in the midbrain, with neuronal loss in the substantia nigra, pars compacta (cell group A9) being the most prominent, cell loss in the retrorubral area (A8) being the next most visible, and cell loss in the ventral tegmental area being least prominent (Hirsch et al. 1988; Damier et al. 1996). As a consequence of the degeneration of dopamine-containing neurons, there is loss of dopaminergic markers in the 249

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striatum, particularly in the caudal and mid-anteroposterior regions of the putamen and caudate nucleus (Kish et al. 1988) (Fig. 17). The histopathologic hallmark of Parkinson's disease is the Lewy body, an eosinophilic, intracytoplasmic inclusion that consists of a tangle of neurofilament proteins, ~t-synuclein, ubiquitin and many other largely uncharacterized proteins. These are common in the surviving neurons of the substantia nigra, pars compacta, but can occur elsewhere as well. Most cases of Parkinson's disease appear to be sporadic, but the incidence of the disease in first degree relatives of someone with Parkinson's disease is several times that of the general population (Lazzarini et al. 1994). Moreover, several large families have been identified in which the disease is clearly inherited in an autosomal dominant fashion (Duvoisin and Golbe 1995). In two of these families the genetic abnormality has been found to be point mutations in the gene for a-synuclein, a protein normally found at the synapse (Polymeropoulos et al. 1997; Kruger et al. 1998). a-synuclein has since been found to be one of the components of Lewy bodies (Spillantini et al. 1997; Irizarry et al. 1998). Abnormalities in a second gene, Parkin, have also been described in familial Parkinson's disease (Kitada et al. 1998). These genetic abnormalities may not account for most cases of Parkinson's disease (Chan et al. 1998a,b), but the finding of a-synuclein has again directed researchers' attention to the Lewy body as having a key function in the pathogenesis of Parkinson's disease. The situation may be analo-

Fig. 17. Loss of tyrosine hydroxylase-positive fibers in the striatum in idiopathic Parkinson's disease. (A) shows the striatum from a control brain. (B) shows the striatum from a patient who suffered idiopathic Parkinson's disease. Note the striosomal organization of the TH-positive neuropil in the control brain, with weaker TH-like immunoreactivity appearing in striosomes (see asterisks). TH-poor striosomes are much easier to detect in the caudate nucleus than in the putamen. A similar pattern of TH-poor striosomes in a TH-rich matrix is evident ventrally in the Parkinson's brain. Note that the loss of TH-like immunoreactivity in the striatum appears to follow a dorsolateral-to-ventromedial gradient; both the caudate nucleus (CN) and putamen (P) are affected. IC, internal capsule. Scale bar, 2 mm. From Graybiel, et al. 1990. 250

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gous to Alzheimer's disease, in which f3-amyloid plays such a key role, but only a tiny number of patients appear to have abnormalities in the amyloid precursor protein itself. Poverty of movement, reminiscent of humans with Parkinson's disease, and sometimes tremor, can be produced in humans and in non-human primates by exposure to the selective dopamine neurotoxin, 1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) (Burns et al. 1983; Langston et al. 1983). This compound crosses the blood brain barrier and is metabolized by the enzyme monoamine oxidase B to 1-methyl-4phenylpyridine (MPP +) (Heikkila et al. 1984). MPP + is a substrate for the high affinity dopamine transporter that is located only on dopamine-containing neurons. MPP + is, therefore, concentrated to at least 1,000 fold within dopamine-containing neurons (Javitch and Synder 1984). MPP + is an inhibitor of complex 1 of the mitochondrial respiratory chain (Kindt et al. 1986). Thus, it impairs respiration once taken up into dopaminergic neurons. High enough concentrations of MPP + will kill other neurons, but the high affinity of the compound for the dopamine transporter means that dopamine-containing neurons expressing the transporter are vulnerable to even low systemic concentrations of MPTP. In MPTP-induced experimental parkinsonism in the monkey, the loss of dopamine is greater in the dorsal striatum than in the ventral striatum (Moratalla et al. 1992). It has been shown in the monkey that the ventral striatum expresses much lower levels of the dopamine transporter than do the caudate nucleus and putamen (Graybiel and Moratalla 1989), which may contribute to the greater vulnerability of the dopaminergic innervation of these nuclei. Interestingly, experiments also suggest differential vulnerability of striosome and matrix subdivision of the nigrostriatal innervation (Moratalla et al. 1992). As we will see below, differential vulnerability of these compartments also characterizes the striatum in Huntington's disease. The fact that MPTP (and MPTP-like compounds) can lead to a parkinsonian state has strongly encouraged efforts to identify environmental neurotoxins that can induce parkinsonism and, perhaps, idiopathic Parkinson's disease. A number of epidemiologic studies hint at such an environmental toxin. In North America, the disease is more common in rural areas with high concentrations of pesticides and a tendency to drink well water (Rajput et al. 1986; Barbeau et al. 1987; Koller et al. 1990). Glucose metabolism in the basal ganglia has been studied with the autoradiographic 2-deoxyglucose method in primates and with positron emission tomography (PET) scanning in living humans (Kuhl et al. 1984; Crossman et al. 1985) Normally glucose metabolism is quite high in the primate caudate nucleus, putamen, nucleus accumbens and in the subthalamic nucleus, but there is considerably lower glucose metabolism in the globus pallidus and substantia nigra. The globus pallidus, substantia nigra and subthalamic nucleus cannot be resolved reliably in human PET scans, but they can be seen by tissue processing for radiolabeled 2-deoxyglucose in monkeys. In monkeys that are rendered parkinsonian with MPTP, there is an increased glucose metabolism in the caudate nucleus, putamen and GPe, with decreased activity in the subthalamic nucleus (Crossman et al. 1985). Treatment of such animals with dopamine receptor agonists produces a significant decrease in the activity of the GPe and a marked increase in the activity of the subthalamic nucleus, particularly its most ventral and medial tip, and in the GPi (Clarke et al. 1987). The glucose metabolic activity probably reflects activity in nerve terminals, so that the increased activity in the external pallidum in the treated parkinsonian animals probably reflects increased activity in the indirect pathway. The increase in activity in the subthalamic 251

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nucleus in the treated animals, particularly those that are dyskinetic or dystonic after the treatment, suggests that there is release of external pallidal neurons from striatal inhibition after the treatment with dopamine agonist drugs. Further support for this interpretation comes from experiments in which Crossman and colleagues injected bicuculline (a GABAA receptor antagonist) into the external pallidum (GPe) of monkeys and induced dyskinesias, including chorea and myoclonus (Jackson and Crossman 1984). This finding is consistent with the idea that lack of GABAergic innervation of GPe produces a choreiform movement due to overactivity of external pallidal neurons and subsequent inhibition of the subthalamic nucleus and the internal pallidal segment. Further evidence for overactivity of the indirect pathway in parkinsonism is provided by [3H]-flunitrazepam autoradiography carried out on the brains of parkinsonian monkeys (Robertson et al. 1989). These studies show decreased benzodiazepine receptor binding in the GPe of untreated parkinsonian monkeys, suggesting that the number of GABAA/benzodiazepine receptors has been down-regulated in this nucleus due to overactivity of the indirect pathway. Early PET studies of humans with Parkinson's disease did not demonstrate any abnormality of glucose metabolism. However, work with more sophisticated techniques has since shown a relative increase in activity in medial parts of the lentiform nucleus, consistent with overactivity of the indirect pathway (Eidelberg et al. 1995).

3.1.3. Huntington's disease The third of the prototypic basal ganglia diseases we will cover is Huntington's disease. This disease is inherited in an autosomal dominant fashion. Symptoms usually begin in middle life with personality change including apathy, irritability and depression. The patients then develop chorea (brief adventitious movements that are more prominent distally than proximally and that are characterized by normal reciprocal inhibition of agonist and antagonist muscles). Neurologic exams of patients with this stage of the disease also reveal that they have slowness in making rapid alternating movements and difficulty in initiating saccadic eye movements. These abnormalities on neurological examination are often present before the development of chorea. As the disease progresses, the amplitude of the chorea increases, often becoming large enough and proximal enough to be classified as ballistic. There is also cognitive decline and the development of a rigidity similar to that seen in Parkinson's disease and in dystonia. Difficulty in swallowing and caring for oneself become major problems; the patients usually die of aspiration. There is a wide range in age of onset of the disease, with differences in the symptoms that largely correlate with the onset age. Patients with elderly (over age 60) onset typically have prominent chorea without much cognitive impairment or rigidity. On the other hand, patients with juvenile (under age 20) onset generally have parkinsonian rigidity and slowness of movement without chorea. Such patients often have an action tremor as opposed to a rest tremor. Extremely young onset patients (under age 10) often present with dystonia more than rigidity and chorea. The pathology of Huntington's disease involves generalized loss of brain substance, but the most prominent pathology is in the basal ganglia. PET studies of glucose metabolism in Huntington's disease have shown that striatal glucose metabolism is markedly decreased in the disease, especially in the caudate nucleus (Kuhl et al. 1982). The degree of decline in glucose metabolism correlates well with the severity of the symptoms of the disease (Young et al. 1986a). There is even some evidence that 252

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glucose metabolism may decrease before the onset of clear symptoms (Hayden et al. 1986; Mazziotta et al. 1987). Gross atrophy begins in the tail of the caudate nucleus and spreads forward from there to involve the body and then the head of the caudate nucleus (Vonsattel et al. 1985). From there, the atrophy spreads laterally and ventrally to involve the putamen, but the nucleus accumbens is spared until late in the disease. Histopathologically, the disease is characterized by loss of striatal projection neurons with relative sparing of striatal interneurons and, perhaps, absolute sparing of the nitric oxide synthase/somatostatin-containing striatal interneurons (Ferrante et al. 1987). Among the three major output pathways of the striatum, the enkephalin-containing indirect pathway projecting to the external pallidum is involved earlier and more prominently than the substance P/dynorphin-containing direct pathway to the internal pallidum (Reiner et al. 1988; Sapp et al. 1995). This difference suggests that the indirect pathway is more vulnerable in Huntington's disease. However, the substance P/dynorphin direct pathway to the substantia nigra, pars reticulata appears to be affected as early as the enkephalinergic indirect pathway to the GPe. Thus the disease does not simply hit the indirect pathway: both the direct and the indirect pathways are affected, but differentially according to their targets. Recent neuropathologic evidence suggests that the striosomal compartment of the striatum may be the first part of the striatum to be involved in the disease process, even before the extrastriosomal matrix (Hedreen and Folstein 1995). This would suggest relative sparing of the striosomal output pathway. Not all investigators agree on this point, however. Ferrante et al. (1997) suggest an opposite compartmental vulnerability. These conflicting findings may represent inconsistencies from case to case (Faull et al. 1997). The differential involvement of striosomes and the surrounding matrix also remains controversial (see the location of the huntingtin protein below, Fig. 18). The first studies to reveal these differential vulnerabilities among striatal projection neurons were immunohistochemical. They focused on loss of enkephalin and substance P immunostaining of striatal efferent terminals in the globus pallidus (Reiner et al. 1988; Sapp et al. 1995). More recent studies have shown that expression of enkephalin in surviving striatal neurons is affected very early in the disease, whereas expression of substance P is relatively normal and declines gradually over the course of the disease (Richfield et al. 1995). In the brains of some persons who carried the Huntington's disease gene but did not yet have symptoms at the time of death, there is loss of enkephalin immunoreactive terminals in the globus pallidus and enkephalin gene expression in the striatum in the absence of classical histopathologic abnormality (Albin et al. 1990, 1991). Such brains may also have selective striosomal loss (Hedreen and Folstein 1995). Clear hypotheses have been raised to relate the early loss of enkephalinergic indirect pathway neurons in the disease to the symptomatology of Huntington's disease (Penney and Young 1986). Loss of the indirect path to the GPe with relative sparing of the direct path could result in imbalance of these pallidal control circuits favoring unopposed release of the motor thalamus by actions of the direct pathway with loss of surround inhibition generated by the indirect pathway. The result could be the appearance of inappropriate, but otherwise normal, movements: chorea. It is not yet clear how the probable preferential early damage to striosomes relates to the evolving symptomatology of Huntington's disease, although one possibility is that this pathology relates to cognitive-affected aspects of the disorder. An interesting hypothesis raised by Hedreen and Folstein (1995) is that the early loss of striosomes would 253

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Fig. 18. Photographs of thin sections through the striatum of two humans who suffered from Huntington's disease. (A) shows a Grade 2 case and (B) a Grade 3 case (Vonsattel et al. 1985). The dark regions show the location of acetylcholinesterase staining. In Huntington's disease, the striatum decreases markedly in size as a result of massive cell death. Even in the Grade 2 case, zones of especially weak staining are visible (example at asterisk). These seem to be akin to the very prominent striosomes in normal human brain and in the brains of higher primates. CN, caudate nucleus; P, putamen; IC, internal capsule. denervate nigral dopaminergic neurons of a GABAergic innervation, resulting in hyperactivity. Overactivity of these dopamine-containing neurons should result in overactivity of the direct striatal output pathway via activation of excitatory D 1-class receptors and underactivity of the indirect striatal pathway by activation of the inhibitory D2-class receptors. These changes in activity could, in turn, lead to the differential loss of enkephalin as compared to substance-P in the striatal output pathways. The genetic abnormality that results in Huntington's disease has been found to be an expansion of a section of D N A in which the codon C A G is repeated. The normal number of CAG repeats is about 20, and more than 38 repeats produces disease (Duyao et al. 1993; Huntington's Disease Collaborative Research Group 1993; Penney et al. 1997). This expansion produces an abnormally long string of glutamine moieties in the amino terminal end of a previously unknown protein (huntingtin). The normal role of huntingtin is unknown, but it is vital for normal development, as mice in which this gene has been eliminated do not develop beyond the sixth day of embryogenesis (Duyao et al. 1995; Nasir et al. 1995). How does this defect relate to the pathogenesis of the disease? Huntingtin appears to be expressed at a significant level by all or nearly all neurons (Li et al. 1993; Strong et al. 1993; Landwehrmeyer et al. 1995a). The distribution of huntingtin in the human striatum is unclear. One study found the protein concentrated in the neuropil of the matrix and not in the somata of interneurons (Ferrante et al. 1997), but a study with a 254

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different antibody found huntingtin to be concentrated in striosomal neuropil (Gutekunst et al. 1995). A recent study in the rat (Kosinski et al. 1997) reports that some striosomal neurons have a high concentration of huntingtin in their somata. Perhaps it is these neurons that are the most susceptible to the disease process. Mutant huntingtin has a similar distribution, except that it is also found in neuronal intranuclear inclusions where it may effect gene transcription (Davies et al. 1997; DiFiglia et al. 1997). Recently, a huntingtin-associated protein has been described whose levels of expression are higher in basal ganglia structures than in other brain regions (Li et al. 1996). This protein appears to bind more tightly to the abnormal huntingtin protein found in the disease with its expanded polyglutamine repeat than to the normal huntingtin protein (Li et al. 1995). It is not known how this huntingtin-associated protein, the tendency for huntingtin to be a substrate for apopain (Goldberg et al. 1996) or the tendency for huntingtin to stick to glycerol-6-phosphate dehydrogenase (Burke et al. 1996) may contribute to the pathogenesis of the disease. Excellent animal models of Huntington's disease can be produced in both rodents and primates by intrastriatal injection of N-methyl-D-aspartate (NMDA) receptor agonists. Such injections produce excitotoxic lesions of the striatal projection neurons and leave the interneurons (particularly the somatostatin/nitric oxide synthase-containing neurons) undamaged. Similar selective damage can be produced by ischemia (Gonzales et al. 1992) or by intrastriatal injections of mitochondrial respiratory chain complex 2 inhibitors such as malonate and 3-nitroproprionic acid (3-NP). Furthermore, systemic injection or ingestion of the appropriate amount of 3-NP produces lesions that are selective for the striatum and that spare the somatostatin/nitric oxide synthase-containing interneurons (Brouillet et al. 1995). Contamination of sugar cane by this toxin in China has produced a clinical syndrome of striatal necrosis accompanied by dystonia similar to that seen in extreme cases of juvenile Huntington's disease. That a systemic, mitochondrial toxin can produce lesions confined to the striatum suggests that there is unique vulnerability of striatal neurons that may account for how a widely expressed protein such as huntingtin produces pathology largely confined to the caudate nucleus and putamen.

3.1.4. Dystonia The fourth of the diseases we will consider here is dystonia. In this clinical syndrome, limbs or trunk or face assume abnormal sustained postures. Electromyographic (EMG) studies of dystonic contractures reveal that the postures are produced by simultaneous contraction of both agonist and antagonist muscles acting on a joint (Cohen and Hallett 1988). These contractures are mediated by the cerebral cortex, as magnetic stimulation of cortex can alter dystonic contractions and cortical readiness potentials are abnormal in dystonics (Reilly et al. 1992; Ikoma et al. 1996). Positron emission tomographic (PET) studies of cerebral metabolism show a pattern of increased metabolism in the lentiform nucleus (particularly in the putamen), and also in the pons, the midbrain and the lateral frontal and paracentral cortices (Chase et al. 1988; Eidelberg et al. 1995). Cases of idiopathic dystonia do not have detectable cell loss in the brain. However, dystonia can often be a secondary symptom in other basal ganglia diseases. Infarcts, infections, tumors and metabolic derangements relating to the putamen have all led to dystonia. Wilson's disease (an abnormality of cellular copper metabolism in which copper is deposited in and destroys the putamen) frequently has dystonia as one of its cerebral manifestations (Starosta-Rubinstein et al. 255

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1987). There are also drug-induced dystonias that are almost always caused by derangements in dopamine function. The neuroleptic drugs that act by blocking dopamine D2-class receptors sometimes cause acute dystonic reactions (Klawans 1988). Some patients with Parkinson's disease endure biphasic dyskinesias, in which brief periods of dystonia are produced at the beginning and the end of the patient's response to the dopamine precursor, levodopa (Klawans 1988). Among the generalized inherited dystonias are several well defined syndromes. The best understood of these is the dopa-responsive dystonia first described by Segawa et al. (1976). This dominantly or recessively inherited disease is characterized by deficiency of the enzyme GTP-cyclohydrolase, which results in an inability of the patient to synthesize tetrahydrobiopterin, a necessary co-factor for tyrosine hydroxylase, the rate-limiting enzyme in the synthesis of dopamine (Ichinose et al. 1994). Other cases of dystonia have been described as being due to a deficiency in tyrosine hydroxylase itself (Ludecke et al. 1995). The most common and severe of the early-onset, inherited dystonias is dystonia musculorum deformans (DMD). Symptoms usually begin in an arm or a leg at about age 12 and spread to involve other limbs within 5 years. The disease is present in all ethnic populations, but its highest prevalence is in the Ashkenazic Jews as a result of a founder mutation. D M D is an autosomal dominant disease with penetrance of 30-40% (Bressman et al. 1989). Recent studies have identified the genetic abnormality in this disease as the deletion of a single glutamine near the carboxy terminus of a novel gene (Ozelius et al. 1997). The putative protein (torsin A) coded for by this gene has a probable leader sequence suggesting targeting to an organelle or membrane (Boyd and Beckwith 1990) and an ATP binding domain (Walker et al. 1982), and has many analogies to the heat shock protein (HSP) 100/Clp family of proteins (Schirmer et al. 1996) that had not previously been identified in humans. The gene is expressed prominently by the dopamine-containing neurons of the substantia nigra as well as by granule cells of the cerebellar cortex and dentate gyrus and pyramidal cells of the CA3 region of hippocampus (Augood et al. 1998). The paradox raised by these new findings about early onset dystonia is that a dopamine deficiency in adulthood leads to the syndrome of parkinsonism, and yet the genetic abnormality in D M D is also mainly expressed in dopamine-containing neurons of the substantia nigra. This may mean that there is an important age effect on the manifestations of basal ganglia abnormalities. An analogous situation is evident for Huntington's disease, in which adult onset cases are manifested by chorea, cases with onset in the teens are manifested by a parkinsonian state, and cases with onset under age 10 are manifested by prominent dystonia (Young et al. 1986b). Lubag, an X-linked dystonia-parkinsonism syndrome found in the Philippines, is characterized by decreased fluorodopa uptake on PET scans, indicative of decreased L-aromatic amino acid decarboxylase activity (Waters et al. 1993). Another possible resolution of this dopamine deficiency parkinsonism/dystonia paradox will be offered in section 5.1 of this chapter. 3.2. NEUROPSYCHIATRIC DISORDERS Depression and other changes in affect and condition occur to varying degrees in patients with the classic 'movement disorders' of the basal ganglia, including Parkinson's disease and Huntington's disease. No invariant histopathologic changes in the basal ganglia have yet been found in neuropsychiatric disorders such as major depres256

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sion, manic-depressive disorder, or schizophrenia. However, many lines of evidence suggest that disordered signaling in the basal ganglia may be implicated in such disorders. The fact that the basal ganglia (and especially the striatum) have the densest dopaminergic innervation in the brain, and that neuroleptics effective in treating schizophrenia act strongly at dopamine receptors, was an early clue (Iversen et al. 1983). The strong expression of dopamine receptors in the neocortex (including the cloned D3 and D4 receptor subtypes) suggests that disordered dopamine function in the cortex may account for some or most of these effects (Sokoloff et al. 1990; Van Tol et al. 1991). There still is a considerable body of evidence indirectly suggesting dysfunction of the striatum or pallidum in this disease complex. Interestingly, immunohistological work on postmortem brains from schizophrenic patients suggests that there may be sporadic loss of striatal cholinergic neurons in at least some schizophrenics (Holt et al. 1994; Holt et al. 1999, submitted, and references therein). Given that the basal ganglia are tightly linked to the frontal lobes, involvement of these subcortical nuclei would not be surprising. Neuropathologic, neuroimaging and neurochemical studies have suggested a basal ganglia defect in Gilles de la Tourette syndrome, characterized both by motor tics and by neuropsychiatric signs (Singer et al. 1991; Peterson et al. 1993; Malison et al. 1995; Wolf et al. 1996). Recent work suggests that Tourette's syndrome has strong genetic determinants but is also constrained by environmental factors (see Pauls and Leckman 1988; Hyde and Weinberger 1995). Abnormal dopaminergic function, particularly in the striatum, has repeatedly been suggested to occur in Tourette's patients (Singer et al. 1991; Malison et al. 1995; Wolf et al. 1996). In a case study, abnormal dynorphin levels in the internal segment of the globus pallidus were found (Haber et al. 1986). A core histopathologic defect has not yet, however, been identified. The development of scanning methods has been instrumental in documenting basal ganglia abnormalities in obsessive-compulsive disorder (Baxter et al. 1987, 1988, 1992, Swedo et al. 1989, 1992; Benkelfat et al. 1990; Sawle et al. 1991; Rubin et al. 1992). Metabolic abnormalities have been found in the caudate nucleus of patients with this neuropsychiatric disorder, and these have been coupled to abnormalities in the orbital frontal and anterior cingulate cortex, and have been shown to be reversible with either pharmacologic or behavioral treatment (Schwartz et al. 1996). It is not known what pathology the metabolic abnormalities reflect.

4. CHEMICALLY SPECIFIED SUBSYSTEMS: RECEPTOR SYSTEMS IN THE

BASAL GANGLIA We have now completed a brief sketch of the major nuclei and pathways of the basal ganglia, prototypical basal ganglia disorders affecting these pathways, and the main neurotransmitters and neuromodulators associated with them. These molecules exert their functional effects through specific classes of receptors. We turn next to the relative distributions of these receptors. We again will have a selective coverage of this topic, partly because information about receptor distributions still lags information about the localization of the neurotransmitters and neuromodulators. Antibodies to receptor subtypes are being developed at a rapid rate, however, and these should help to pinpoint receptor location at the cellular and subcellular levels required to understand circuit function. At present, especially in primates, we mainly can point to regional distributions. 257

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4.1. RECEPTORS ASSOCIATED WITH BASAL GANGLIA AFFERENTS 4.1.1. Glutamate receptors Glutamic acid is the major excitatory neurotransmitter in the basal ganglia, as it is in other parts of the central nervous system. Glutamic acid is the neurotransmitter used by the corticostriatal pathway (Kim et al. 1977; Young et al. 1983), by subthalamic nucleus neurons (Albin et al. 1989a; Brotchie and Crossman 1991), and probably by the thalamic and amygdaloid neurons projecting to the basal ganglia. Glutamate interacts with at least four different types of receptors. Fast-acting, rapidly desensitizing excitatory neurotransmission is conveyed by the a-amino-3-hydroxy5-methylisoxazole-4-propionic acid (AMPA) receptor. It has a monovalent cation (i.e. sodium) channel that probably consists of four subunits forming a pore. Like other ionotropic receptors, of which the nicotinic cholinergic receptor is the prototypic example, each receptor subunit has four intramembranous regions with the walls of the pore being formed by the second intramembranous region of the subunit. Unlike other ionotropic receptors, however, the second intramembranous region of glutamate receptors does not go all the way through the membrane, but instead goes most of the way through the membrane and then returns to the internal side of the membrane (Hollmann and Heinemann 1994; Stern-Bach et al. 1994). Thus, while other types of ionotropic receptors have their N- and C-terminals on the outside of the cell membrane, glutamate receptors have their C-terminals on the inside of the membrane. Impermeability to divalent cations is conveyed by the GluR2 subunit that contains a glutamine moiety in the second membrane-spanning region that forms the walls of the ion pore. This glutamine moiety is present because of messenger RNA editing which substitutes the code for glutamine for the code for arginine (Sommer et al. 1991). NonmRNA edited GluR2 subunits will allow the passage of calcium and other divalent cations into neurons through AMPA receptors. There are moderate numbers of AMPA receptors located in the caudate nucleus and putamen and in the subthalamic nucleus with lower numbers present in the globus pallidus and the substantia nigra (Albin et al. 1992; Dure et al. 1992) (Fig. 19A). There is evidence that some of the striatal AMPA receptors are located on nigrostriatal terminals (Wullner et al. 1994). Striatal AMPA receptor loss in Huntington's disease parallels striatal cell loss (Dure et al. 1991). Glutamate receptors of the kainate type are slower-acting, non-desensitizing receptors that also pass monovalent cations. There is a low density of these receptors in the caudate nucleus and putamen (Fig. 19B), with somewhat higher numbers being present in striosomes in primates but not in rodents (Dure et al. 1992). The particular cell type on which this higher number of striosomal kainate receptors is located has not been determined. There are few kainate receptors in the globus paUidus, the subthalamic nucleus, and the substantia nigra. In presymptomatic Huntington's disease, there is loss of these striosomal patches of increased kainate binding (Dure, Young and Penney; unpublished). The third class of glutamate receptor is the N-methyl-D-aspartate (NMDA) receptor (Fig. 19C). These receptors are only distantly related to the other ion channel receptor families (Moriyoshi et al. 1991; Nakanishi 1992). NMDA receptors have binding sites for glutamate and glycine and are regulated by polyamines. These receptors open a voltage-gated divalent cation channel. This channel cannot be opened at normal resting potentials because it is blocked by a magnesium ion, but at low membrane poten258

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Fig. 19. Autoradiograms of ligand binding to neurotransmitter receptors and transporters in coronal sections from the basal ganglia of a 73-year-old man who died of a myocardial infarction. The postmortem delay was 7 hours before half of the brain was blocked and frozen in liquid nitrogen vapors. (A), 10 nM [3H] r 3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) binding to the AMPA subtype of ionotropic glutamate receptors. (B), 60 nM [3H] kainic acid binding to the kainate subtype of ionotropic glutamate receptors. (C), 65 nM [3H] glutamate binding to the N-methyl-D-aspartate (NMDA) subtype of ionotropic glutamate receptors. (D), 100 nM [3H] glutamate binding to both type 1 (mGluR1 and mGluR5) and type 2 (mGluR2 and mGluR3) metabotropic glutamate receptors. (E), i00 nM [3H] glutamate binding to type 2 metabotropic receptors. (Type 1 metabotropic binding can be calculated by subtracting values in E from those in D. (F), 6 nM [3H] mazindol binding to synaptic dopamine transporters. (G), 500 pM [3HI SCH23390 binding to dopamine D1 receptors. (H), 250 pM [3H]-spiperone binding to dopamine D2 receptors. (/), 10 nM [3H] flunitrazepam binding to tz subunits of GABAA receptors. (J), 1 nM [3H] quinuclidinylbenzilate binding to muscarinic cholinergic receptors. Abbreviations: C1, claustrum; Cx, insular cortex; E, external segment of globus pallidus; I, internal segment of globus pallidus; P, putamen. 259

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tials the magnesium ion leaves the channel, and extracellular glutamate is able to activate the receptor and open the channel (Nowak et al. 1984). It is thought that this receptor plays an important role in the neuroplasticity underlying learning because a 'double hit' is required (both lowering the membrane potential and presenting glutamate to the N M D A receptor at the same time) so that calcium can flood into the cell. This same receptor is also responsible for a number of excitotoxic mechanisms because of its ability to pass calcium. N M D A receptors are composed of subunits from two separate gene families. One is the NMDAR1 gene, which comes in several splice variants. NMDAR1 is required for N M D A receptor function. It is expressed in all neurons of the caudate nucleus and putamen, and perhaps in all neurons. In striatal projection neurons of rodents, the subunit lacks the amino terminal insert splice and contains both carboxy terminal splice variants (Standaert et al. 1994). The same splice variants are found in low concentrations in the globus pallidus. The subthalamic nucleus, on the other hand, contains a moderate number of receptors that contain the amino terminal insert. There are N M D A receptors on dopamine-containing neurons of the substantia nigra, pars compacta (Counihan et al. 1998). The NMDAR1 receptor is usually coupled with one or two members of the NMDAR2 family. There are four known members of the NMDAR2 subfamily. NMDAR2A and 2B are commonly found in striatal projection neurons, whereas NMDAR2D is found in cholinergic and nitric oxide synthase-containing interneurons (Landwehrmeyer et al. 1995b; Kosinski et al. 1998). The globus pallidus and the substantia nigra also have N M D A R 2 D as their major NMDAR2 subunit. The neurons of the substantia nigra, pars compacta have NMDAR2C, 2D, and a few NMDAR2B receptors in primates (Counihan et al. 1998), whereas rodent nigral neurons contain only NMDAR2C and 2D. Whether the presence of specific NMDAR2 subunits on basal ganglia neurons (particularly the 2B subunits on striatal projection neurons and substantia nigra dopamine neurons) contributes to their susceptibility in neurodegenerative disease remains to be determined. There is loss of substantia nigra, pars compacta N M D A receptors in Parkinson's disease (Difazio et al. 1992) and prominent and early loss of these receptors in Huntington's disease (Young et al. 1988; Dure et al. 1991). These findings have led to the speculation that N M D A receptor activation may play an important role in the pathophysiology of these diseases. Blockade of N M D A receptors can prevent both the parkinsonism induced by MPTP (Brouillet and Beal 1993) and the Huntington's disease-like syndrome induced by 3-NP (Brouillet et al. 1995). The fourth class of glutamate receptors are the G-protein coupled metabotropic receptors. There are at least eight different metabotropic receptor genes. Their coded proteins are grouped into three pharmacological classes of receptor. Pharmacological type 1 metabotropic receptors stimulate phosphatidylinositol metabolism and are located near the postsynaptic density, where they may play a role in neuroplasticity underlying learning (Bortolotto and Collingridge 1992) and in excitotoxicity (Orlando et al. 1995). This pharmacological type is conveyed by the mGluR1 and mGluR5 genes. The MGluR1 receptor is expressed by substantia nigra, pars compacta neurons and to a lesser extent by pallidal, subthalamic and striatal projection neurons, and at very low levels by striatal interneurons (Fig. 19D). The MGluR5 receptor is intensely expressed by projection neurons of the caudate nucleus and putamen, moderately expressed by subthalamic neurons, and is expressed at a low level by pallidal and

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nigral neurons. Of the striatal interneurons, only the calretinin-containing neurons express mGluR5 (Testa et al. 1994, 1995, 1998). The second and third pharmacological classes of metabotropic receptor are linked to cyclic AMP inhibition and are mostly located on presynaptic terminals, where their activation inhibits neurotransmitter release. The second pharmacological class consists of receptors expressed by the mGluR2 and mGluR3 genes. The MGluR2 receptor is highly expressed by the cholinergic interneurons and to a lesser extent by the parvalbumin-containing neurons of the caudate nucleus and putamen, as well as by subthalamic neurons (Testa et al. 1995; Kerner et al. 1997) (Fig. 19E). The MGluR2 receptor is also highly expressed by cortical neurons that project to the striatum, where its location on axon terminals near the synapse plays a role in glutamate release (Testa et al. 1998). The MGluR3 receptor is expressed at moderate levels by striatal, pallidal and subthalamic projection neurons, and at low levels by striatal parvalbumin-positive and somatostatin-containing interneurons but not by cholinergic interneurons. It is also expressed at high levels by thalamic reticular nucleus neurons as well as by glia throughout the brain (Testa et al. 1994; Kerner et al. 1997). There are moderate numbers of metabotropic type 2 binding sites present throughout the basal ganglia, including in the caudate nucleus and putamen. Metabotropic type 2 receptor binding sites are lost early in the course of Huntington's disease (Greenamyre et al. 1985; Catania et al. 1993). Pharmacologic type 3 metabotropic receptors are composed of subunits expressed by the mGluR4, 6, 7 and 8 genes. These receptors are located adjacent to the active release zone at the synapse, where they are ideally situated to control transmitter release (Ottersen and Landsend 1997). The MGluR6 receptor is expressed only in the retina and mGluR8 has very little expression in the basal ganglia. The MGluR4 receptor is expressed at moderate levels by thalamic neurons, at low levels in striatal enkephalin and cholinergic neurons, at very low levels by striatal substance P-containing neurons (making it the only glutamate receptor that is expressed differentially by direct and indirect pathway neurons), and not at all in other basal ganglia structures (Testa et al. 1994; Kerner et al. 1997). The MGluR7 receptor is robustly expressed by striatal projection neurons and at low levels by all the interneurons (Kerner et al. 1997).

4.1.2. Dopamine receptors Dopamine released from dopamine-containing afferents can interact with two pharmacological classes of dopamine receptors, both of which are G-protein coupled. Receptors with dopamine D1 pharmacology are positively linked to cyclic AMP. They are produced by the expression of d l and d5 receptor genes. D 1-class receptors are highly expressed by neurons in the caudate nucleus and putamen that express substance P and dynorphin and that project to the internal segment of the globus pallidus and to the substantia nigra, pars reticulata (Gerfen et al. 1990; Harrington et al. 1995). These receptors are present not only on the dendrites of these neurons, but also on their axon terminals (Richfield et al. 1987; Beckstead et al. 1988) (Fig. 19G). There is a patchy distribution of these receptors, with somewhat higher binding being present in striosomes than in matrix (Besson et al. 1988). Dopamine D2-class receptors are linked to the inhibition of cyclic AMP and to the stimulation of the phosphoinositol pathway. These receptors are present at high levels in the enkephalinergic striatal neurons that project to the external segment of the globus pallidus (Gerfen et al. 1990; 261

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Harrington et al. 1995) (Figs. 2E, 19H). D2-class receptors are also present in the large cholinergic interneurons of the striatum (DeBoer and Abercrombie 1996), and they are present as autoreceptors on neurons of the substantia nigra, pars compacta (Tepper et al. 1997). The degree of co-localization of D 1-class and D2-class receptors remains somewhat controversial, with some studies finding almost complete segregation of the two classes of receptors (Gerfen et al. 1990), others finding considerable overlap of the two (Meador-Woodruff et al. 1991), and still others finding almost complete overlap of the two classes of receptors, considering the different subtypes within each class (Surmeier et al. 1992, 1996). D3-class receptors are largely located in the ventral striatum and the nucleus accumbens (Freedman et al. 1994; Potenza et al. 1994), but their expression in the dorsal striatum is sharply elevated following damage to the dopamine-containing afferents to the striatum (Bordet et al. 1997). D4 receptors are expressed at relatively low levels in the caudate nucleus and putamen, but at quite high levels in the neocortex (Murray et al. 1995; Matsumoto et al. 1996). Early studies of dopamine receptor binding in Parkinson disease brains suggested that there was supersensitivity of dopamine receptors (specifically pharmacological D2 receptors) in the striatum (Lee et al. 1978). The original study was carried out on postmortem samples of brains from patients who had not been treated with dopamine receptor agonist drugs. Subsequent postmortem studies have not been able to confirm this supersensitivity, and some studies indicate that there is a loss of dopamine D1class receptors with advanced Parkinson's disease (Rinne et al. 1985). PET studies of dopamine receptors in early untreated Parkinson's disease patients have shown an increase in the number of D2-class receptors in striatum with no change in the number of D 1-class receptors (Laihinen et al. 1994; Rinne et al. 1995). Studies in treated patients have shown normalization of the number of D2-class receptors (Rinne et al. 1990). Dopamine receptors of both the D1 and D2 classes are clearly lost in Huntington's disease, along with the loss of striatal neurons (Reisine et al. 1977; Whitehouse et al. 1985).

4.1.3. Serotoninergic receptors All serotonergic pathways in the forebrain originate in the raphe nuclei, which are situated in the midline of the brainstem. There is significant serotonergic input to the basal ganglia, particularly to the substantia nigra, including its pars compacta, and to the globus pallidus (Charara and Parent 1994). There is also a strong projection to the striatum, preferentially innervating the matrix compartment (Lavoie and Parent 1990). There are three pharmacological classes of serotonin receptors (Julius 1991). The ion channel-linked 5-HT3 receptors are found only in the periphery, whereas the G-protein-coupled 5-HT1 and 5-HT2 receptors are found in the brain. 5-HT1 receptors are linked to cyclic AMP inhibition and many of them are presynaptic including autoreceptors on the terminals of neurons of the raphe nuclei. 5-HT1A receptors are present at relatively low levels throughout the basal ganglia (Hoyer et al. 1986a; Pazos et al. 1987a). 5-HT1B receptors are located in the substantia nigra and the globus pallidus, where they are preferentially present on the terminals of striatal output neurons (Pazos et al. 1987a). Their behavioral importance has been highlighted in gene deletion experiments in mice (Saudou et al. 1994; Rocha et al. 1998). 5-HT2 receptors are linked to stimulation of the phosphatidylinositol pathway. These receptors have high binding affinity for lysergic acid diethylamide (LSD). There are a large number of these receptors in the cerebral cortex, and lower numbers in the basal 262

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ganglia. In the striatum, they are enriched in striosomes (Hoyer et al. 1986b; Pazos et al. 1987b; Waeber and Palacios 1994). 5-HT2C receptors are present in moderate numbers throughout the basal ganglia and are expressed in extremely high numbers in the dopamine-containing neurons of the pars compacta (Pazos et al. 1987b; EberleWang et al. 1997).

4.1.4. Adrenergic receptors Norepinephrine receptors are all G-protein coupled and have two pharmacological subtypes, a and [3. a receptors are linked to the inositol phosphate system and to the inhibition of cyclic AMP, whereas 13 receptors are linked t o t h e stimulation of cyclic AMP. Alpha-1 receptors are located postsynaptically throughout the brain and have moderate concentrations in the basal ganglia (Nicholas et al. 1993). a-2 receptors, on the other hand, are located both postsynaptically and presynaptically as autoreceptors on the synaptic terminals of norepinephrine-containing neurons where they regulate norepinephrine release (Nicholas et al. 1993). 13receptors are located throughout the brain. There are significant numbers of these receptors in the globus pallidus, and they are moderately concentrated in the caudate nucleus and putamen (Reznikoff et al. 1986). There is a gradient in receptor numbers in the striatum, with receptors being denser ventrally than dorsally, similar to the known serotonergic pattern of innervation (Waeber et al. 1991). The beta adrenergic receptors in the caudate nucleus and putamen are decreased in Huntington's disease, suggesting that they are located on intrinsic striatal neurons (Waeber et al. 1991).

4.1.5. Glycine receptors The amino acid glycine interacts with two types of binding sites in the central nervous system. The first to be described is the classical inhibitory ion channel/receptor complex that is inhibited by strychnine and is found post-synaptic to glycinergic neurons (Young and Snyder 1973). Glycine is the major inhibitory neurotransmitter of the anterior horn of the spinal cord and of brainstem motor nuclei. There are no inhibitory glycine receptors in caudate nucleus, putamen or globus pallidus. There are, however, a few glycine receptors present in the substantia nigra (de Montis et al. 1982), and there is some evidence for glycinergic innervation of neurons of the pars reticulata of the substantia nigra (Mercuri et al. 1995). The excitatory glycine binding site was discussed above in conjunction with the N M D A receptor on which it is located. 4.2. RECEPTORS ASSOCIATED WITH INTRINSIC BASAL GANGLIA PATHWAYS

4.2.1. GABA receptors The major rapidly acting neurotransmitter of intrinsic basal ganglia pathways is 3'aminobutyric acid (GABA). GABA interacts at postsynaptic sites with two different classes of GABA receptor. The first, the GABAA receptor, is a typical postsynaptic, ligand-gated ion channel (Seeburg et al. 1990; Macdonald and Olsen 1994). The GABAA receptor is a member of the ligand-gated ion channel superfamily of receptors best characterized by the nicotinic acetylcholine receptor found at the neuromuscular 263

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junction. That is, each GABAA receptor is thought to be made up of five protein subunits. Each subunit has four membrane-spanning domains, with the ligand binding site being located near the amino terminal end and outside the plasma membrane. The second membrane-spanning domain of the five subunits is thought to form the ion channel pore. An individual GABAA receptor typically has several different types of subunit proteins as members of the functional receptor, consisting usually of two a, two 13, and one ~, or ~5 receptor (Tretter et al. 1997). The ~ subunits also contain a binding site for benzodiazepine drugs such as diazepam, alprazolam, and clonazepam. However, benzodiazepine binding is often not demonstrated by receptors unless there is a ~, subunit present in the receptor complex. There are two main classes of benzodiazepine binding sites. The class of these binding sites is governed by the type of tt subunit that is present, a-1 subunits convey benzodiazepine type 1 pharmacology, and ~-2, 3, 4, or 5 subunits convey benzodiazepine type 2 binding, a-1 subunits are typically coupled in receptor complexes with 132 subunits. Within the basal ganglia, a-l, [3-2 receptors are heavily expressed by globus pallidus and substantia nigra, pars reticulata neurons, conveying an exclusively benzodiazepine type 1 pharmacology on these regions (Wisden et al. 1992). ~-1,13-2 subunits and benzodiazepine type 1 pharmacology are also moderately expressed in the subthalamic nucleus, the caudate nucleus and the putamen (Wisden et al. 1992). The caudate nucleus and putamen also express ~-3 subunits, which convey benzodiazepine type 2 pharmacology on the caudate nucleus and putamen (Wisden et al. 1992). Similarly, ct-2 subunits are expressed by substantia nigra, pars compacta neurons (Wisden et al. 1992). Overall, within the basal ganglia, GABAA receptors are present most densely in the caudate nucleus and putamen. Lower amounts are present in the globus pallidus, the subthalamic nucleus, and the substantia nigra (Penney and Pan 1986) (Figs. 2A,B; 19I). In Huntington's disease and in animals in which a striatal lesion has been made, there is local loss of GABA and benzodiazepine receptors in the caudate nucleus and putamen. On the other hand, there is an increase in GABA and benzodiazepine binding in the globus pallidus and the substantia nigra, pars reticulata. In adult onset Huntington's cases, this increase in binding is much more prominent in the external segment of the globus pallidus (particularly along its outer rim) than in the internal segment of the g|obus pallidus (Penney and Young 1982). In juvenile onset Huntington's disease cases, there is equal upregulation of GABA receptors in both external and internal segments of the globus pallidus (Penney and Pan 1986). This finding is consistent with the preferential loss of the striato-external pallidal pathway in choreic, adult Huntington's disease, whereas there is equal loss of both the striato-external pallidal and striato-internal pallidal GABAergic pathways in juvenile Huntington's disease. Patients with very early symptomatic Huntington's disease have upregulation of external pallidal GABAA receptors even at points in the disease process in which there is no gross atrophy of the striatum (Walker et al. 1984). GABAB receptors are G-protein coupled receptors that have been shown to function in neurotransmitter release. They bind the muscle relaxant drug, baclofen. Genes for these receptors have been cloned and shown to have a high degree of homology to the metabotropic glutamate receptors (Kaupmann et al. 1997). There is a moderately dense distribution in these receptors in the caudate nucleus and putamen, but low binding in the globus pallidus, the subthalamic nucleus, and the substantia nigra (Bowery et al. 1987).

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4.2.2. Cholinergic receptors Muscarinic acetylcholine receptors are denser in the caudate nucleus and putamen than any place else in the brain (Fig. 19J). These are G-protein coupled receptors that are produced by the expression of four different genes. Studies in rodents (Hersch et al. 1994) have shown that striatal projection neurons express the M1 subtype of muscarinic receptor and that these receptors are enriched in their spiny dendrites. M2 receptors are expressed by the large cholinergic interneurons. This distribution of M2 receptors as autoreceptors is typical of their distribution throughout the brain. There are very few M3 receptors present in the striatum. M4 receptors are present on about half the striatal spiny neurons. There are low levels of muscarinic receptors present in the internal segment of the globus pallidus and the substantia nigra, pars reticulata. These receptors may be on the terminals of striatal efferent neurons, given that these receptors are lost in Huntington's disease (Penney and Young 1982). There are also nicotinic cholinergic receptors present in the basal ganglia. These are the prototypic ionotropic receptor type, and they are largely located as autoreceptors on cholinergic striatal interneurons (Wada et al. 1989). These receptors and muscarinic cholinergic receptors are decreased in Parkinson's disease, suggesting that there is loss or dysfunction of cholinergic interneurons in this disease (Perry et al. 1987; Lange et al. 1993). I

4.2.3. Adenosine receptors Adenosine has recently been demonstrated to function as a neuromodulator in the central nervous system. There are two subtypes of adenosine receptor present. One of them, the adenosine A1 receptor, is present throughout the brain. It is present in high concentrations in the caudate nucleus and GPe. There are low concentrations in GPi and in the substantia nigra. The adenosine A2a receptor has a remarkably localized distribution in the brain. It is predominantly found in neurons of the striatum. There are lower levels of A2a receptors in the external globus pallidus. At a cellular level, the A2a receptor is co-localized in the cell bodies, dendrites and terminals of enkephalinimmunoreactive neurons, which also contain dopamine D2 receptors (Schiffmann et al. 1991; Peterfreund et al. 1996; Faull et al. 1997). The action of adenosine at these receptors antagonizes the effect of dopamine on D2 receptors in the same neurons (Ferre et al. 1993). Being located on striatopallidal neurons, these receptors are lost early in the course of Huntington's disease (Faull et al. 1997).

4.2.4. Opiate receptors There are three major classes of opiate receptor, named p, ~, and ~c. Despite the high concentrations of enkephalin and dynorphin in the basal ganglia, particularly enkephalin in the external segment of the globus pallidus and dynorphin in the pars reticulata substantia nigra, there are relatively low numbers of opiate receptors in these regions. This 'mismatch' of transmitter and receptor concentrations is common for peptide neurotransmitter receptors, and the reason for it is unknown (Herkenham 1987). Hypotheses for this mismatch include that the receptors are present in places to which the peptides can diffuse over long distances, that the peptides are paradoxically present in great concentrations at places where they have no functional role, and that

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the presence of high concentrations of peptides elicits down-regulation of the receptors that would otherwise be present. Moderate numbers of bt and 8 opiate receptors are expressed by striatal neurons (Young and Kuhar 1979; Mansour et al. 1994). In rodents, ~ opiate receptors have an extremely patchy distribution within the striatum (Young and Kuhar 1979). This patchy distribution is present, but is less prominent, in the human brain. There are also some ~c-containing striatal neurons, but in addition, ~ receptors are expressed by the dopamine neurons of the substantia nigra, pars compacta (Mansour et al. 1994). There is very little or no opiate receptor expression by neurons of the globus pallidus. The opiate receptors that are present in globus pallidus are present on the terminals of striatopallidal afferents (Abou-Khalil et al. 1984), where they may regulate GABA release (Maneuf et al. 1994). These pallidal receptors are mainly of the la and 8 types. They are lost in Huntington's disease, thus confirming their presynaptic localization (Penney et al. 1984). PET studies of opiate receptors with l lC-diprenorphine have shown no change in opiate receptor numbers in Parkinson's disease, but there are decreases in the number of opiate receptors in striatonigral degeneration and in progressive supranuclear palsy (PSP) (Burn et al. 1995). These results suggest that in humans, the majority of striatal opiate receptors are located on intrinsic striatal neurons, which are spared in Parkinson's disease but are affected in striatonigral degeneration and PSP. 4.2.5. Tachykinin receptors The NK1 receptor is relatively specific as a binding site for substance P (Nakanishi 1991). It is highly expressed in the caudate nucleus and putamen. Many NK1 receptors are on the cholinergic striatal interneurons (Arenas et al. 1991; Gerfen 1991). There are low levels of expression of NK1 receptors in the internal segment of globus pallidus and the substantia nigra, pars reticulata, however, where there are high concentrations of substance P (Maeno et al. 1993; Stoessl 1994; Parent et al. 1995). There are very few NK2 (tachykinin A) or NK3 (neuromedin 3) (Ding et al. 1996) receptors expressed by basal ganglia neurons except for NK3 receptors, which are on dopaminecontaining neurons of the substantia nigra, pars compacta (Stoessl et al. 1991; Keegan et al. 1992; Whitty et al. 1997).

4.2.6. Cannabinoid receptors There are strikingly high densities of cannabinoid (marijuana) receptors on the terminals of striatal projection neurons in globus pallidus and substantia nigra, pars reticulata, together with lower densities on the cell bodies and dendrites of striatal projection neurons (Herkenham et al. 1991). These receptors regulate the release of GABA from striatal efferent terminals (Glass et al. 1997). They are lost in the external segment of the globus pallidus early in the course of Huntington's disease and later in the internal pallidal segment and the substantia nigra (Richfield and Herkenham 1994; Faull et al. 1997). This finding confirms the results from immunohistochemical studies, suggesting that it is the striatopallidal neurons projecting to the external pallidal segment that degenerate first in Huntington's disease.

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4.2.7. Somatostatin receptors There is abundant binding of ligands to somatostatin receptors in the human caudate nucleus and putamen (Reubi et al. 1986), and the number of these binding sites is decreased in Huntington's disease (Palacios et al. 1990). These studies were interpreted as indicating that striatal somatostatin receptors were located on intrinsic striatal neurons. However, five different somatostatin receptor genes have now been cloned from human brain (Bell and Reisine 1993; Hoyer et al. 1995), and none of them is expressed by striatal neurons (Thoss et al. 1996). There is significant expression of the somatostatin 1 receptor gene by neurons of the substantia nigra, pars compacta and of somatostatin receptor genes 1, 2 and 3 by cortical neurons (Thoss et al. 1996). Thus, the somatostatin binding sites in the striatum are likely to be on afferent terminals, at least some of which are on corticostriatal terminals that degenerate during the course of Huntington's disease.

5. FUTURE DIRECTIONS 5.1 F U N C T I O N A L CONSIDERATIONS: THE INVOLVEMENT OF BASAL G A N G L I A D Y S F U N C T I O N IN THE P R O D U C T I O N OF DISORDERED MOVEMENT A number of lines of evidence suggest that decreased activity in either the indirect striatal output pathway or in the subthalamic nucleus produce the hyperkinetic disorders of chorea, drug-induced dyskinesias, and ballism. Chorea is an early manifestation of Huntington's disease, in which the indirect striatopallidal pathway degenerates before the direct striatal output pathway (Young et al. 1986b; Albin et al. 1995). Injection of GABA antagonists into the external pallidal segment produces chorea (Crossman et al. 1988). Ballism can be produced by destruction or inactivation of the subthalamic nucleus (Carpenter et al. 1950; Wichmann et al. 1994b). Over-activity of the indirect striatal output pathway, the subthalamic nucleus, and the internal segment of the globus pallidus seems to produce parkinsonian symptoms, as evidenced by increased external pallidal glucose metabolism (Mitchell et al. 1989) and decreased GABA/benzodiazepine receptors in parkinsonian monkeys (Robertson et al. 1989). However, the parkinsonian rigidity that is seen late in the course of Huntington's disease is most easily interpreted as being the result of decreased activity in the direct striatal output pathway. Such underactivity would also lead to decreased inhibition, and thus over-activity, of the internal pallidal segment. Further evidence implicating increased subthalamic and internal pallidal activity in the generation of parkinsonian symptoms has been provided by pallidotomies in monkeys with experimental parkinsonism disease (Bergman et al. 1990) and in humans with typical Parkinson's disease (Laitinen et al. 1992a; Lang et al. 1997). These operations are capable of relieving much of the rigidity, slowness of movement, akinesia, and some of the tremor seen in these patients. However, the operations do not improve the postural instability or frequent episodes of inability to generate an appropriate motor response (freezing) seen in this disease, particularly in patients who have onset of the disease at an elderly age (Lang et al. 1997). In this scheme, dystonia can be thought of as a consequence of failure of both striatal output pathways. Focal putamenal lesions produce focal dystonia. Generalized 267

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destruction of the putamen, such as that seen in Wilson's disease, produces generalized dystonia. The dystonia in partial dopamine deficiency syndromes such as Segawa's disease, beginning and ending dose dyskinesias in Parkinson's disease patients with fluctuating responses to levodopa, and, presumably, early onset torsion dystonia may result from a partial dopamine deficiency state. In the basal ganglia, dopamine acting through dopamine Dl-class receptors activates the direct striatal output pathway, but acting through D2 receptors, dopamine inhibits the indirect striatal output pathway (Albin et al. 1989b; Gerfen et al. 1990). Dl-class and D2-class receptors exist in both high and low affinity states. Under ordinary circumstances, about three-quarters of D 1-class receptors are in the low affinity state and three-quarters of D2-class receptors are in the high affinity state (Richfield et al. 1989). At the appropriate concentration ( ~ 10-7 M), dopamine should stimulate D2-class receptors, resulting in inhibition of the indirect pathway, without stimulating D 1-class receptors to activate the direct pathway. Thus, neither output pathway would be active, resulting in a functional state that would be like a striatal infarct. There are, however, a number of responses in patients that are inconsistent with this simple interpretation that (A) underactivity of the indirect output pathway produces chorea and dyskinesia, (B) overactivity of this pathway (or underactivity of the direct output pathway) produces parkinsonism and (C) underactivity of both pathways produces dystonia (Marsden et al. 1985; Augood et al. 1998). The most obvious difficulty is that pallidotomy relieves not only the parkinsonian symptoms, but also the druginduced dyskinesias that are seen in Parkinson's disease patients (Laitinen et al. 1992a; Lang et al. 1997). Theoretically, such lesions should increase rather than decrease dyskinesias. One alternative is that dyskinesias are produced by overactivity of the direct pathway rather than by underactivity of the indirect pathway (Trugman 1995). This possibility, however, would not account for the fact that pallidotomies have been used on several occasions to relieve ballism produced by subthalamic nucleus infarcts in patients (Suarez et al. 1997). Furthermore, diseases that lead to degeneration of the external pallidal segment would be expected to produce parkinsonian symptoms and such patients can have chorea. In addition, diseases that affect the internal pallidal segment, such as PSP, would be expected to produce dyskinesias, when they in fact produce a parkinsonian syndrome. Interpretations of basal ganglia function based on PSP pathology must be made very cautiously, however, because so many other regions of the brain are involved in this disease. Yet, if destruction of the main basal ganglia output pathway relieves all the symptoms of basal ganglia diseases, then the question arises: 'What are the basal ganglia normally doing?' 'Preventing movement disorders', does not seem to be an adequate answer! There is a growing body of evidence that a core function of the basal ganglia is a learning function involving the building up of habits (see Hirsh 1974; Mishkin et al. 1984; Graybiel 1995; Salmon and Butters 1995; Knowlton et al. 1996; White 1997; Graybiel 1998). This learning and memory function may, in turn, depend on rewardrelated signals from the substantia nigra, pars compacta (Schultz 1997; Schultz et al. 1997) and elsewhere (Graybiel 1998). One idea relating such reward-based learning and memory functions of the basal ganglia to the control of movement that we have emphasized in discussing movement disorders is that normal basal ganglia function may be necessary to produce behavioral sequences that have been put together into 'chunks' through experiential learning (Graybiel 1998). The patient with Parkinson's disease, for example, has difficulty standing up when his doctor asks him to rise from a

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sitting position. Yet the individual movements involved in rising are easily within his performance capacity. Another outstanding question about the basal ganglia is the extent of their involvement in 'higher' aspects of behavior such as cognitive planning. There is a tempting analogy, for example, between a habit of thought and a motor habit, and between the over- or under-production of behavior or thoughts in syndromes ranging from depression to obsessive-compulsive disorder, Gilles de la Tourette's disease and even schizophrenia, and the over- and under-production of movements with the hyperkinetic and hypokinetic disorders that we have discussed (Swerdlow and Koob 1987; Graybiel 1997). There is, in fact, increasing evidence for basal ganglia dysfunction in such disorders (Haber et al. 1986; Swerdlow and Koob 1987; Baxter et al. 1988; Swedo et al. 1989, 1992; Leckman et al. 1991; Baxter et al. 1992; Drevets et al. 1992). For the motor functions of the basal ganglia, no less than for their potential functions in cognitive behaviors, we still lack critical neurobiological information. For example, with respect to the relationship between the two pallidal segments and the subthalamic nucleus, even in animal studies there is confusion. Parent and Hazrati (1995b) report that they fail to find evidence for a key part of the circuitry on which much current thinking is based. They suggest that the parts of the subthalamic nucleus that project to the internal pallidum do not receive input from the external pallidum, in contradiction to the assumptions of the functional model of the indirect pathway. On the other hand, Smith and colleagues (Smith et al. 1994) report that the subthalamic regions that project to the internal pallidum do receive input from external pallidal cells that also project to the same region of the internal pallidum to which the subthalamic nucleus region projects. Their data, in contrast to that of Parent and Hazrati, suggests that the two pallidal segments do have connections with the same parts of the subthalamic nucleus. Further studies of the details of the pallidosubthalamic relationship are needed. Another major issue to be resolved is whether or not the cortical and other inputs to the direct and indirect pathways are equivalent. Based on anatomical data, cortical inputs reach the striatal cells of origin of both pathways (Dube et al. 1988; Hersch et al. 1995; Kincaid and Wilson 1996). Both in the macaque monkey and in the rat, however, stimulation of the sensorimotor cortex elicits immediate-early gene induction mainly in the indirect pathway neurons (Berretta et al. 1997; Parthasarathy and Graybiel 1997). Even if both direct and indirect pathway neurons receive cortical inputs, in other words, these may not be functionally equivalent. This could mean that the model of direct/indirect pathway control of basal ganglia function needs significant modification. For example, different cortical areas may have different inputs to the two pathways. Additional information is also needed about the relationship between striatal direct and indirect output pathway cells. Do these cells directly influence each other? What is the relationship between these cells and the clusters of striatal dye-coupled neurons that have been found (Onn and Grace 1994)? Finally, what is the role of the striatal interneurons in governing the relative output of the two projection pathways? And of potentially great significance, what are the functions of the 'non-motor' parts of the basal ganglia? Although a great deal has been learned about the chemical neuroanatomy and function of the basal ganglia in the last twenty years, there is still much that remains to be known.

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6. A C K N O W L E D G E M E N T T h e a u t h o r s a c k n o w l e d g e the s u p p o r t o f Javits A w a r d N S 2 5 5 2 9 , g r a n t N S 3 1 5 7 9 a n d grant NS38372 from the N a t i o n a l Institute of Neurological Disorders and Stroke.

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Chemical neuroanatomy of the hippocampal formation and the perirhinal and parahippocampal cortices YASUSHI KOBAYASHI AND DAVID G. AMARAL

1. INTRODUCTION The hippocampal formation is unique in many respects. While the evidence is not all in, it appears that the hippocampal formation plays a fundamental role in producing autobiographical or episodic memories (Squire and Zola-Morgan 1991; Vargha-Khadem et al. 1997). Bilateral damage to even a single field of the human hippocampus results in a profound and long-lasting inability to store newly acquired information into long term memory (Zola-Morgan et al. 1986).The processes through which this transformation occurs are not known but one candidate physiological substrate for plastic change, long term potentiation, has been most intensively analyzed in the hippocampal formation (Bliss and Collingridge 1993). Even if the hippocampal formation had not been linked to such an important function as memory, its highly organized cytoarchitectonic and connectional neuroanatomy would have proven irresistible to neuroscientists, There is an enormous amount of information available on the cell types of the hippocampus, on their intrinsic connections and on its various extrinsic inputs and outputs. The highly laminar organization of its constituent neurons and of many of their inputs has made the hippocampus a seductive model system for understanding the brain. While the hippocampal formation is often touted as a 'simplified' cortical region (as if it was a model for a 'real' cortex), it is now clear that the neuroanatomical uniqueness of the hippocampal formation predestines it for carrying out the building of relationships between different sources of sensory information leading to episodic memory. But it is not the normal function of the hippocampal formation alone that makes it unique. Unfortunately, the hippocampal formation is one of the most vulnerable brain regions to disease and trauma. One often gets the impression that the price paid by the hippocampal formation for the ability to rapidly encode new information into memory is a recta-stable existence where the slightest shift in its chemical or electrical milieu may lead to disaster. One example of this is that the hippocampal formation, and particularly the hippocampus, is often damaged in temporal lobe epilepsy (Corsellis and Bruton 1983; Babb et al. 1984). Interestingly, it remains contentious whether the hippocampal damage is a cause or an effect of epileptic seizures. The hippocampus is also extraordinarily vulnerable to ischemia. Near complete loss of certain hippocampal fields can result from Handbook of Chemical Neuroanatomy, Vol. 15." The Primate Nervous System, Part III F.E. Bloom, A. Bj6rklund and T. H6kfelt, editors 9 1999 Elsevier Science B.V. All rights reserved.

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transient ischemic episodes in the context of virtually complete sparing of other cortical regions (Zola-Morgan et al. 1986). And the hippocampal formation appears to be highly vulnerable to the ravages of Alzheimer's disease. In this case, it is the entorhinal cortex that is an early and devastated victim of the disease process (Van Hoesen et al. 1991). Thus, an understanding of the chemical neuroanatomy of the primate hippocampal formation will contribute not only to an understanding of the mechanisms involved in normal memory and perhaps in its enhancement, but may also contribute to therapeutic efforts to prevent damage resulting from ischemia and other traumas to the brain. 1.1. WHY THE HIPPOCAMPAL FORMATION? Whatever the hippocampal formation does, and however it does it, the neuroanatomy of the hippocampal formation virtually mandates that it be considered an integrated functional system. More than 80% of the synaptic input to the dentate gyrus, for example, is derived from the entorhinal cortex. Thus, thinking of the dentate gyrus as an independent functional unit devoid of entorhinal input would seem to ignore the neuroanatomical hint that these two structures are intimately associated with each other. Looking at this from the entorhinal point of view, the layer II cells of the entorhinal cortex project only to themselves, to the dentate gyrus and to the CA3 field of the hippocampus. The layer III cells of the entorhinal cortex project mainly, if not exclusively, to CA1 and the subiculum. So, if the dentate gyrus, hippocampus and subiculum were removed, the entorhinal cortex might still receive much of its sensory input from other cortical areas, such as the perirhinal and parahippocampal cortices, but it would have only meager opportunity to communicate with other brain regions. Because of the unique and essential quality of the connections between the dentate gyrus, hippocampus, subiculum, presubiculum, parasubiculum and entorhinal cortex, we believe that it is justified to group these structures as a functional system under the term hippocampal formation. It should also be noted, however, that the unique neuroanatomy of the components of the hippocampal formation would suggest that they are each carrying out distinctly different functions. And one would predict that the building of an episodic memory would entail the unique contribution of all portions of the hippocampal formation. 1.2. WHY INCLUDE THE PERIRHINAL AND PARAHIPPOCAMPAL CORTICES? The perirhinal and parahippocampal cortices lie adjacent to the hippocampal formation in the temporal lobe. The first hint that they might be different from the rest of the temporal neocortex came from the analysis by Jones and Powell (1970) of the corticocortical connections of various sensory systems. They demonstrated that both the perirhinal and parahippocampal cortices were areas of convergence of projections arising from several sensory systems. Electrophysiological studies ultimately demonstrated that single neurons in these regions are responsive to multimodal stimulation (Desimone and Gross 1979) Studies from our own laboratory, conducted during the last 10 years, have shown that the perirhinal and parahippocampal cortices not only have unique cytoarchitectonic features but also have unique patterns of connections. One defining feature of the perirhinal and parahippocampal cortices is that they 286

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Fig. 1 (A-D)." Low-power photomicrographs of Nissl-stained coronal sections through the Macacafascicularis monkey temporal lobe. Sections are arranged from rostral (A) to caudal (D). Note that the rostral portion of the entorhinal cortex (E) is located ventromedial to the amygdaloid complex. Note also in (A) that the deep layers of areas 35/36 ascend in a position located medial to the periamygdaloid cortex as the perirhinal cortex follows the rhinal sulcus to its termination at the limen insulae. Calibration bar in (A) applies to all panels.

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project to the entorhinal cortex (Insausti et al. 1987) whereas the adjacent temporal neocortex does not. In fact, the macaque monkey perirhinal and parahippocampal cortices provide about two-thirds of the neocortical input to the entorhinal cortex. The perirhinal and parahippocampal cortices themselves receive unique complements of inputs from a variety of unimodal and polymodal cortical areas (Suzuki and Amaral 1994a). In addition to the neuroanatomical uniqueness of these cortical areas, a growing number of lesion studies in the monkey has demonstrated that, as might be predicted from their close association with the hippocampal formation, they play a prominent role in certain forms of memory. In fact, many of the memory impairments previously thought to be due to damage of the amygdala or hippocampal formation (Mishkin 1978) now appear to be due to damage of the perirhinal cortex (Mishkin and Murray 1994). The hippocampal formation is not essential, for example, for mediating certain forms of object recognition memory and one possibility is that the perirhinal cortex can carry out this function independently of the hippocampal formation. Because of the close neuroanatomical and functional association of the perirhinal and parahippocampal cortices with the hippocampal formation, it seemed appropriate to include these regions in this chapter. Unfortunately, there is only scant information on the specific chemoanatomical organization of these cortical areas. One goal of this chapter is to highlight the gaping holes in our knowledge of the chemical neuroanatomy of these cortical areas in order to encourage further study. One final comment on the perirhinal region concerns the use of the term 'rhinal'. This term has been adopted by Mishkin and Murray (1994) and colleagues to refer collectively to the entorhinal and perirhinal cortices. We believe that this is a mistake. Clearly, the entorhinal and perirhinal cortices have entirely different cytoarchitectonic organization and entirely different patterns of connectivity. While it may be facile to use this term to describe the extent of medial temporal lobe lesions, it does a disservice to a sophisticated systems neuroscience approach to this region which will undoubtedly find that the entorhinal and perirhinal cortices carry out distinctly different functions. The term rhinal would seem to take a step back in the representation of this area of the brain, as if we were to begin referring to areas V1, MT and TE simply as 'visual' cortex. 1.3. ORGANIZATION OF THE CHAPTER The chapter begins with an overview of the cytoarchitectonic organization of the various fields of the hippocampal formation and perirhinal and parahippocampal cortices. We have prepared a series of low power and somewhat higher magnification photomicrographs that hopefully clearly indicate the boundaries and laminar organization of these regions. We then give a very brief overview of the intrinsic and extrinsic connectivity of the hippocampal formation. More detailed reviews of the connectivity of the hippocampal formation are available (Swanson et al. 1987; Amaral and Insausti 1990). We then begin with the dentate gyrus (and proceed to each division of the hippocampal formation and into the perirhinal and parahippocampal cortices) and describe the organization of various intrinsic and extrinsic chemically identified candidate transmitter systems, the distribution of several peptide systems, the organization of neurons and fibers containing calcium-binding proteins, the distribution of hormone binding sites and enzymes and finally the distribution of trophic factors and their receptors. In preparing this chapter, we struggled with the issue of whether to confine our 288

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Fig. 2 (A-H): Photomicrographs of the Macacafascicularis medial temporal lobe showing the major divisions of the hippocampal formation and the perirhinal and parahippocampal cortices. (A). Note that area 36 (36d and 36r) makes up much of the medial half of the temporal polar cortex. (C) and (D). Note the less laminated appearance of the rostral divisions of the entorhinal cortex in (C) compared to the intermediate division illustrated in (D). The rostral pole of the intraventricular portion of the hippocampal formation is seen at this level. It consists primarily of neurons of the subiculum (S). At this rostral limit of the temporal horn of the lateral ventricle (V), the hippocampal formation flexes medially and then caudally. In (E), the dentate gyrus and hippocampus have the 'mirror image' appearance that is typical of the uncal portion of the hippocampal formation. Note that the layers of the entorhinal cortex are indicated with Roman numerals in panel D. In (E), the various layers of the dentate gyrus and hippocampus have been indicated. This level is near the caudal pole of the entorhinal cortex. In panel F, the entorhinal cortex has ended and has been replaced by areas TH and TF of the parahippocampal cortex. Panels G and H are near the caudal pole of the hippocampal formation. The laminae of the hippocampus are again indicated in panel G. Note in panel H that the presubiculum and parasubiculum have been replaced by the most ventromedial components of the retrosplenial cortex (areas 29m and 291). Note also at these levels that the sulcus lying lateral to the hippocampal formation has changed from the anterior middle temporal sulcus, seen rostrally, to the occipital temporal sulcus. Calibration bar in panel A applies to all panels.

survey to data only from the n o n h u m a n and h u m a n primate brains or whether to include data from the rat brain, particularly when nothing was available for the primate brain. We decided to restrict our presentation to data derived almost entirely from the m o n k e y and h u m a n brains. This avoids the problem of extrapolating from the rat to the m o n k e y brain and also serves to emphasize the areas of chemical n e u r o a n a t o m y research that are in particular need of attention in the primate brain. The distributions of all of these chemically identified systems are summarized in a general way on standardized line drawings that represent the entorhinal cortex and two levels t h r o u g h the remainder of the hippocampal formation (Fig. 10). There are so few data available for the c h e m o a n a t o m y of the perirhinal and p a r a h i p p o c a m p a l cortices that it is not necessary to have an additional series of plates to illustrate data for them.

2. OVERVIEW OF THE C O M P O N E N T S OF THE MEDIAL TEMPORAL LOBE The hippocampal formation and the perirhinal and p a r a h i p p o c a m p a l cortices make up a substantial portion of the medial temporal lobe. These structures can be seen in the context of other temporal lobe regions in the low power p h o t o m i c r o g r a p h s that make up Fig. 1. At caudal levels (Fig. 1D; 2H), several c o m p o n e n t s of the hippocampal formation, including the dentate gyrus, h i p p o c a m p u s and subiculum) are visible in the floor of the temporal horn of the lateral ventricle. Medial to the hippocampal formation at these caudal levels is the temporal portion of the retrosplenial cortex, which is bordered even more medially by visual association cortex. At this caudal level, there is little or no remaining p a r a h i p p o c a m p a l gyrus and there is no entorhinal cortex, parasubiculum or presubiculum. At a level t h r o u g h the caudal portion of the lateral geniculate nucleus (Fig. 1C; 2 FG), the presubiculum and parasubiculum are now present but the entorhinal cortex is not apparent. The caudal border of the entorhinal cortex occurs at a level within the rostral half of the L G N . The p a r a h i p p o c a m p a l cortex borders the hippocampal formation ventromedially and both areas T H and T F are apparent at this level. Panel B of Fig. 1 makes a big j u m p rostrally, t h o u g h intervening levels through the hippocampal formation are illustrated in Fig. 2. The only field of the hippocampal formation 293

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Fig. 3" Sagittal section through the medial temporal lobe of a Macaca fascicularis monkey. The tight juxtaposition of the amygdaloid complex (A) with the hippocampal formation is evident from this picture. The main purpose for this illustration is to demonstrate the continuity of cytoarchitectonic features in the perirhinal cortex from caudal levels (36c) to the most rostrodorsal levels (36d). Note in particular the clusters of darkly-stained cells located at the superficial margin of layer II.

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Fig. 4 (A-D).. (A). Coronal section through the rostral half of the Macacafascicularis hippocampal formation processed for the immunohistochemical localization of calretinin. Note the particularly dense immunoreactivity in the dentate gyrus and presubiculum. (B). Adjacent section stained by the Nissl method for comparison with (A). (C). Higher magnification photomicrograph of the section shown in A to illustrate the distinctive pattern of immunoreactivity in the dentate gyrus. (D). Photomicrograph of the adjacent Nisslstained section for comparison with (C). By comparing panels C and D it is apparent that there is a dense band of immunoreactivity in the inner portion of the molecular layer (iml). This is in the zone occupied by axons and terminals of the associational projection that arises from cells in the polymorphic cell layer. There is a high density of immunoreactive neurons in the polymorphic layer (pl) that may give rise to the labeling in the molecular layer. While there has been substantial controversy concerning the boundary between the polymorphic layer of the dentate gyrus and the CA3 field of the hippocampus, these calretinin preparations provide a sharp boundary between the two areas. This illustration also demonstrates that layer II of the presubiculum can be differentiated into a lightly stained superficial band and a darkly labeled deep band. The calibration bar in panel B applies to panel A and the one in panel D also applies to panel C. that remains in Fig. 1B is the entorhinal cortex. Here, it lies ventromedial to the amygdaloid complex. In fact, approximately half of the rostrocaudal extent of the entorhinal cortex is ventral to the amygdala rather than the hippocampus. At this level, the rhinal sulcus is prominent and it separates the entorhinal cortex medially from the perirhinal cortex laterally. The lateral border of the perirhinal cortex is somewhat variable from animal to animal but is located approximately two thirds of the distance from the rhinal to the anterior middle temporal sulci. As the amygdaloid complex ends rostrally, it is replaced by the deep layers of the perirhinal cortex (Figs 1A; 2C) and by the periamygdaloid cortex. At the rostral pole of the temporal lobe, the rhinal sulcus follows a rostrodorsal trajectory and ends at the limen insulae i.e. at the border between the temporal and frontal lobes. The perirhinal cortex follows the rhinal sulcus to its dorsal termination. The continuity of the temporal polar cortex with the perirhinal cortex is best appreciated in sagittal sections such as the one shown in Fig. 3. Here it is clear that area 36 of the perirhinal cortex extends rostrally and dorsally from a position ventral to the rostral portion of the hippocampus to end adjacent to the piriform cortex. Our analyses of the perirhinal region indicate that the medial surface of the temporal pole has Strong cytoarchitectonic and connectional similarities with the remainder of the perirhinaI cortex, And, as illustrated in Fig. 3, we have included this region as perirhinal cortex.

3. C Y T O A R C H I T E C T O N I C O R G A N I Z A T I O N OF T H E H I P P O C A M P A L FORMATION In order to summarize the distribution of various neuroactive substances in the hippocampal formation, it will first be necessary to give a short overview of the cytoarchitectonic organization and boundaries of the various fields of the hippocampal formation. In the term hippocampal formation we include the dentate gyrus, hippocampus, subiculum, presubiculum, parasubiculum and entorhinal cortex. The various fields are illustrated in the series of photomicrographs of Nissl-stained sections shown in Fig. 2; additional immunohistochemical data for proposed boundaries are illustrated in Figs 4-6. The dentate gyrus is comprised of 3 layers: a cell-dense granule cell layer, a relatively cell-free molecular layer which lies superficial to the granule cell layer and extends to the hippocampal fissure or ventricle, and a rather narrow polymorphic layer located subjacent to the granule cell layer (Fig. 2E; 4D). Historically, there has been 297

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Fig. 5 (A-D): (A) Photomicrograph of a coronal section through the hippocampal formation of a Macaca fascicularis monkey stained immunohistochemically for the identification of nonphosphorylated neurofilament protein using antibody SMI-32. (B) A photomicrograph of a Nissl-stained section adjacent to panel A. In panel A, the SMI-32 antibody labels cells in the CA3 and CA2 fields, but not in the CA1 field. Dense SMI-32 immunoreactivity reappears in the subiculum and remains high in the presubiculum. (C) and (D). These panels illustrate SMI-32 staining and Nissl staining, respectively, of the border region between the unstained CA1 region of the hippocampus and the heavily stained subiculum. Dashed lines in panel (D) indicates the oblique border between the two fields. The SMI-32 marker provides a clear-cut marker for the cell bodies and apical dendrites of subicular pyramidal cells. At the border of CA1 and the subiculum, unstained CA1 pyramidal cells overlap the stained subicular pyramidal cells. Calibration bar in B applies to pane| A and the calibration bar in D applies to panel C.

substantia! difficulty in setting the border between the polymorphic cell layer of the dentate gyrus and the pyramidal cell layer of the hippocampus. This is particularly true in the monkey and human brains where the hippocampal pyramidal cell layer inserts deeply into the limbs of the dentate gyrus and bends back on itself to form a more diffuse arrangement of neurons. The problem of setting the border is obviated by the use of histochemical or irnmunohistochemical techniques. A standard histochemical technique is the Timm's method that demonstrates the heavy metal staining in the mossy fiber plexus that delimits the polymorphic layer. An equally distinctive method in the macaque monkey is to stain the tissue for the presence of calretinin (Fig. 4A and C). The polymorphic layer contains a dense plexus of calretinin immunoreactive fibers and cell bodies that clearly delimits it from the adjacent CA3 region. Many of the labeled cell bodies appear to be the so-called mossy cells that provide the major excitatory input to the inner third of the molecular layer (see below) which is also densely immunoreactive (Fig. 4B). The hippocampus is divided into three distinct fields: CA3, CA2, and CA1. CA3 and CA2 are characterized by large pyramidal cells which are located in a relatively compact principal cell layer. CA2 is differentiated from CA3 by the lack of a mossy fiber input. CA1 has smaller pyramidal cells in its principal cell layer, which is substantially thicker than in CA2 and CA3. The hippocampus is further subdivided into several laminae that run parallel to the pyramidal cell layer (Fig. 2E and G). In all hippocarnpal fields, the term 'superficial' means towards the pia (or hippocampal fissure), and the term 'deep' is used to indicate the opposite direction. Deep to the pyramidal layer is the cell-sparse stratum oriens and deep to this is the fiber-containing alveus. Superficial to the pyramidal cell layer in CA3 is stratum lucidum in which some of the mossy fibers travel. In CA2 and CA1, the region just superficial to the pyramidal cell layer (and in CA3 superficial to the stratum lucidum) is the stratum radiatum; the stratum lacunosum-moleculare is superficial to stratum radiatum. The border of CA1 with the subiculum has been another area of controversy. Something is clearly different at this border zone. There is a slightly higher density of small cells here and the density of staining for a variety of substances including cholinergic markers is denser here than either in CA1 or the subiculum (Alonso and Amaral 1995). Rosene and colleagues (Rosene and van Hoesen 1987) have concluded that this region is so distinct as to be deserving of a different name and have followed the lead of Lorente de N6 (1934) and called it the 'prosubiculum'. Other than the cytoarchitectonic and chemoanatomic differences, however, they have not demonstrated that this region has distinct intrinsic or extrinsic connectivity. While we have agreed that this region is different from the main portions of CA1 or the subiculum, we have proposed that this difference is accounted for mainly by the fact that the 300

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Fig. 6 (A-D): Photomicrographs of coronal sections through the rostral portion of the Macacafascicularis monkey hippocampal formation. Panels A and B show SMI-32 and Nissl-stained, respectively, adjacent sections and panels C and D show higher magnification photomicrographs of the entorhinal cortex of the same sections. Note in panel A, that the medially situated subiculum is heavily labeled with SMI-32 whereas the laterally situated CA1 region is not. This level of the hippocampal formation is notoriously difficult to differentiate into cytoarchitectonic field based solely on Nissl-stained material. Panel C demonstrates that the cell islands of layer II of the entorhinal cortex (bold arrow) stain intensely for SMI-32 whereas the vast majority of cells in layer III are SMI-32 negative. Moderately intense labeling is seen in some cells located in layer V and more cells in layer VI. The calibration bar in panel B applies to panel A and the one in panel D applies to panel C. pyramidal cell layers of CA1 and the subiculum are actually overlapped in this region. The boundary is thus quite oblique and is sometimes marked either by a narrow cellfree zone or a zone with a slightly increased number of small neurons. The obliquity of the border between CA1 and the subiculum is perhaps best demonstrated immunohistochemically with an antibody to nonphosphorylated neurofilament (SMI-32). As illustrated in Fig. 5, the cell bodies and dendrites of many of the subicular pyramidal cells are heavily immunoreactive for SMI-32. Close inspection of these preparations (Fig. 5B) indicates that there are subicular-like neurons beneath the distal portion of the CA1 pyramidal cell layer and that this type of neuron becomes progressively more numerous as one moves medially into the main portion of the subiculum. This gradual change in the number and density of subicular neurons clearly marks the oblique border between the two fields. In addition to this distinctive marker, we have observed that the entire CA1 field, including this terminal region, receives Schaffer collateral connections from CA3 and all of the CA1 cells (including those intermixed with the subicular cells) give rise to projections to the subiculum. We feel justified, therefore, in not applying an additional term to the border region between CA1 and the subiculum and thus the term prosubiculum will not be used. The stratum radiatum of the hippocampus ends at the CA1/subiculum border and the relatively cell-free zone superficial to the pyramidal cell layer in the subiculum is called the molecular layer. The continuation of stratum oriens beneath the subiculum is not typically given a distinct name. We have previously referred to this layer of small cells as layer III (Bakst et al. 1985) and will use this term for this layer in this chapter. The presubiculum and parasubiculum have a cell-free layer I and a densely cellular layer II. Layer II of the presubiculum can be differentiated into a thinner superficial and thicker deep sublaminae on the basis of a number of histochemical and immunohistochemical staining procedures (Fig. 4 C and D). There is a thin band of large cells located deep to layer II of the presubiculum and parasubiculum (Figs 2E; 4B) and scattered cells deep to the thin layer. These cells are often included as deep layers of these regions. It is unclear in the monkey, however, whether these cells are associated with the presubiculum and parasubiculum or are instead an extension of the deep layers of the entorhinal cortex (Amaral et al. 1987). We shall simply to refer to the cells in this region as deep to layer II. The monkey entorhinal cortex is divided into 7 cytoarchitectonically distinct divisions (Amaral et al. 1987). These are illustrated in Figs 2C-E and include: Eo, olfactory division; ER, rostral division; ELR rostral portion of lateral division; ELc, caudal portion of lateral division; El, intermediate division; Ec, caudal division; and EcL, caudal limiting division. The entorhinal cortex is further divided into six layers (Figs 2D; 6). These include: layer I, a cell-poor layer beneath the pia; layer II, a thin layer of darkly stained multipolar cells that are sometimes grouped into islands; layer III, a broad, densely cellular layer in which the cells tend to be organized in patches rostrally 303

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but are more columnar caudally; layer IV, a narrow cell-free layer (the lamina dissecans) that is only clearly visible in El; layer V, a band of large pyramidal cells that can be subdivided into two superficial laminae (Va and Vb) with cells of different sizes and a deeper, largely acellular layer (layer Vc), and layer VI, which is a relatively broad cellular layer that at caudal levels has the appearance of coiled rows of cells. The entorhinal cortex is distinctive in many regards. Unlike most areas in the neocortex, it completely lacks an internal granule cell layer. Perhaps the most distinctive feature of the entorhinal cortex, however, is layer II (Fig. 6 A-D). This layer contains primarily stellate or modified pyramidal cells in the primate and human brains which (as will be described more fully below) give rise to the major input to the dentate gyrus and the CA3 field of the hippocampus. Interestingly, the layer II cells also demonstrate unique histochemical and immunohistochemical staining characteristics (Beall and Lewis 1992). As illustrated in Fig. 6 (A and B), virtually all of the neurons in layer II stain intensely for the presence of nonphosphorylated neurofilament protein. For further information on the cytoarchitectonic organization of the human entorhinal cortex, the reader is referred to the papers by Insausti et al. (1995) and by Solodkin and Van Hoesen (1996). The latter paper, in particular, provides a comprehensive analysis of the modular nature of the human entorhinal cortex using both classical methods and well as chemical neuroanatomical approaches.

4. REGIONAL AND CYTOARCHITECTONIC FEATURES OF THE PERIRHINAL AND PARAHIPPOCAMPAL CORTICES The perirhinal cortex occupies the rostral third of the medial temporal lobe. It is made up of a smaller medially situated area 35 and a larger laterally situated area 36 (Fig. 2 C and D). For most of its rostrocaudal extent, area 35 is confined to the fundus and lateral bank of the rhinal sulcus; only at the extreme rostral pole of the entorhinal cortex does area 35 extend slightly onto the medial bank of the rhinal sulcus. Area 35 is an agranular cortex that is characterized by a densely populated layer V made up of large, darkly staining cells. Area 35 also has a sparsely cellular layer III which often merges with an irregular layer II. Area 36 is located just lateral to area 35. Five subdivisions of area 36 have been recognized (Suzuki and Amaral 1994a,b) although there is little chemoanatomical data that differentiates one from the other. At the most rostrodorsal extent of the perirhinal cortex is area 36d (the dorsal subdivision of area 36), which makes up approximately the dorsal one-third of what is typically referred to as the temporal pole. This area shares many of the same cytoarchitectonic characteristics with the other subdivisions of area 36, but tends to be less organized and less laminated than the other subdivisions. Caudally and ventrally adjacent to area 36d is area 36r (the rostral subdivision). We have further subdivided area 36r into 36rm (rostromedial subdivision of area 36) and area 36rl (rostrolateral subdivision of area 36) on the basis of subtle cytoarchitectonic differences. Area 36rm is a rather narrow cortical area that is situated lateral to area 35, and medial to the full rostrocaudal extent of area 36rl. It is characterized by prominent clumps of darkly staining small cells in layer II, large lightly staining roundish cells in layer III, and large, darkly staining fusiform-shaped cells in the deep layers. Area 36rl is the largest of the subdivisions of area 36. At its most rostral and dorsal extent, it makes up approximately the ventral two-thirds of what is typically referred to as the temporal pole, or area TG 304

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Fig. 7: The major excitatory intrinsic connections of the hippocampal formation are portrayed on line drawings of a coronal section through the monkey hippocampal formation. Origins or projections are indicated by large circles and terminations are indicated by small circles. See text for details.

of von Bonin and Bailey (1947). It is bounded laterally by the unimodal visual area TE. More ventrally, area 36rl is adjacent to approximately the rostral half of the entorhinal cortex. Area 36 can be distinguished from the laterally adjacent area TE because the latter has a clear separation between layers V and VI, and layer II is thicker and lacks the patches of darkly stained cells that are c o m m o n in area 36. The cortex of area TE also has a more columnar organization. The caudal extreme of the perirhinal cortex is called area 36c (the caudal subdivision). Like area 36r, we have further subdivided this area into area 36cm (caudomedial subdivision) and area 36cl (caudolateral subdivision). Areas 36cm and 36cl are located medially adjacent to the 305

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intermediate and caudal divisions of the entorhinal cortex and are typically bounded laterally by the most rostral portion of area TF of the parahippocampal cortex. In general, these subdivisions are the most laminated and differentiated of all the subdivisions of the perirhinal cortex. Layer IV tends to be thicker in these subdivisions and the cortex has a more radial organization. The parahippocampal cortex is located caudal to the perirhinal cortex and is made up of a smaller, medially situated area TH and a larger, laterally situated area TF (Fig. 2F). Area TH is an agranular cortex with a distinctive deep cell layer made up of large and darkly staining cells in layers V/VI. Layers II and III of area TH are also merged and form an outer layer of smaller cells. Area TF is larger than area TH and is laterally adjacent to it. We have subdivided area TF into medial (TFm) and lateral (TF1) subdivisions. In general, area TF is a dysgranular cortex that is distinguished by large, darkly staining cells in layers V and VI. Area TF1 can be distinguished from the laterally adjacent areas TE or TEO because the deep cells of area TE are smaller, the cortex is much more radially organized, and layer IV becomes more prominent in area TE.

5. AN OVERVIEW OF THE CONNECTIVITY OF THE H I P P O C A M P A L FORMATION

In order to provide the context for discussions of the distributions of the various neurochemically defined systems in the hippocampal formation, we will first provide a brief overview of the major excitatory pathways within the hippocampal formation. More detailed coverage of the intrinsic and extrinsic connections of the hippocampal formation are to be found in recent reviews (Swanson et al. 1987; Amaral and Witter 1989; Amaral and Insausti 1990). The intrinsic inhibitory pathways in the hippocampal formation will be described in the sections on GABAergic cells and fibers. An authoritative review on this topic has been published by Freund and Buzsf.ki (1996). 5.1. INTRINSIC CONNECTIONS OF THE HIPPOCAMPAL F O R M A T I O N The major intrinsic connections of the hippocampal formation are illustrated in Fig. 7. Since most of the sensory information to the hippocampal formation enters via the entorhinal cortex, we begin our survey at this starting point. The entorhinal cortex projects via the perforant path to the dentate gyrus, hippocampus and subiculum. The projections to the dentate gyrus and CA3 field of the hippocampus originate mainly from cells in layer II. The projections to CA1 and the subiculum, in contrast, originate mainly from cells in layer III. The layer II projection has a laminated terminal pattern. Projections arising from rostral levels of the entorhinal cortex terminate in the outer portion of the molecular layer of the dentate gyrus and the most superficial portion of stratum lacunosum-moleculare of CA3. Perforant path projections arising from more caudal levels, in contrast, terminate in the mid portion of the molecular layer of the dentate gyrus and in the deeper portion of stratum lacunosum-moleculare of CA3. The layer III projection is organized differently. Fibers arising from all portions of the entorhinal cortex terminate throughout the full width of stratum lacunosum-moleculare. Fibers originating rostrally in the entorhinal cortex terminate close to the CAll subiculum border whereas those that originate progressively more caudally terminate in positions in CA1 progressively closer to CA3 and in the subiculum at positions 306

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progressively closer to the presubiculum. Neither the dentate gyrus nor CA3 project back to the entorhinal cortex but both CA1 and the subiculum project to the deep layers of the entorhinal cortex. The dentate gyrus gives rise to only one major connection within the hippocampal formation. Axons of the granule cells, the mossy fibers, project throughout the CA3 region in the stratum lucidum and terminate on the proximal dendrites of the pyramidal cells. The mossy fibers also give off collaterals which terminate on cells within the polymorphic layer of the dentate gyrus. These synapse on a variety of neuronal cell types including the mossy cells which give rise to an associational connection back to the granule cells. These axons terminate almost exclusively within the inner third of the molecular layer. Interestingly, the associational connection is extensive along the long axis of the dentate gyrus. The projection is rather light to the rostrocaudal level at which the cell bodies are located. It thus appears that this projections provides a summary of granule cell activity at one level of the dentate gyrus to other distant levels of the dentate gyrus. The granule cell axons also terminate on GABAergic interneurons located in the polymorphic cell layer and these cells give rise to projections both to the granule cell layer and to the outer portion of the molecular layer (not pictured in Fig. 7). Projections arising from the CA3 pyramidal cells include collaterals to other CA3 pyramidal cells (the associational connections) as well as the major projection to CA1 (the Schaffer collateral projection). Both of these connections terminate throughout stratum oriens (on the basal dendrites of the pyramidal cells) and in stratum radiatum

Fig. 8: This circuit diagram presents a summary of cortical inputs to the hippocampal formation via the entorhinal, perirhinal and parahippocampal cortices. The thickness of connecting lines indicates the relative magnitude of projections. Adapted from Suzuki and Amaral (1994a). 307

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(on the proximal apical dendrites of the pyramidal cells). These projections are topographically organized such that certain CA3 pyramidal cells are much more likely to interact with certain CA1 pyramidal cells (Ishizuka et al. 1995). The CA3 projections are also very extensive in the rostrocaudal axis of the hippocampus; projections from one particular level of CA3 innervate CA1 cells along as much as 75% of the entire rostrocaudal extent of the field. The CA1 field projects both to the subiculum and to the deep layers of the entorhinal cortex. The projection to the subiculum is organized in a columnar fashion. CA1 cells located close to the CA3 field project to the most distal portion of the subiculum, i.e. the portion close to the presubiculum. CA1 cells located close to the subiculum, in contrast, project just across the border into the subiculum. And CA1 cells located in the middle of the field project to the middle of the subiculum. Unlike the CA3 field, there are few associational connections within CA1. As the CA1 axons extend towards the subiculum, some contacts are made on the basal dendrites of other CA1 cells. However, the extensive system of associational connections observed in CA3 is almost entirely lacking in CA1. 308

Fig. 10: The following series of line drawings summarizes the distribution of various neuroactive substances or receptor systems. The three panels shown above provide a template of the major subdivisions of the macaque monkey hippocampal formation. Similar templates are used i n the following line drawings. The references that are located in the left panels are listed in an order that reflects the extent to which data were used in producing the illustration. It should be noted that some of these illustrations are based on fragmentary and sometimes contradictory information. In these cases, we have made a judgment as to the best summary of current information. See text for further information and references. In the line drawings depicting the distribution of receptors it is usually impossible to distinguish labeling of cell bodies from that of neuropil. When there are substantial data derived from immunohistochemistry, cell body labeling and neuropil labeling are illustrated on separate panels. N/A: not analyzed. Template for cytoarchitectonic divisions of the hippocampal formation.

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The subiculum gives rise to a majority of the subcortically directed projections of the hippocampal formation. In addition, it projects both to the pre- and parasubiculum and to the entorhinal cortex, primarily layer V. The connections of the pre- and parasubiculum are not as well studied as some of the other hippocampal connections. The presubiculum is known to give rise to a major projection to layer III of the caudal entorhinal cortex. The parasubiculum gives rise to a projection to layer II of the entorhinal cortex. Since the presubiculum, in particular, is in receipt of a substantial input from the anterior thalamic nuclei, the projection from the presubiculum to the entorhinal cortex provides a mechanism for thalamic influence of CA1 and the subiculum. In the rat, there is a light projection from the pre- and parasubiculum directly to the dentate gyrus but this has not yet been confirmed in the monkey. 5.2. CONNECTIONS BETWEEN THE PERIRHINAL AND PARAHIPPOCAMPAL CORTICES AND THE HIPPOCAMPAL FORMATION Fig. 8 provides a summary of the cortical inputs to the hippocampal formation and to the perirhinal and parahippocampal cortices. This figure summarizes data derived from Insausti et al. (1987) and Suzuki and Amaral (1994a,b). The major neocortical input (approximately two-thirds of all inputs) to the entorhinal cortex originates in the perirhinal and parahippocampal cortices. The other major cortical input originates in the retrosplenial cortex. The perirhinal cortex terminates throughout the rostral half of the entorhinal cortex whereas the parahippocampal cortex projects in a slightly more topographic fashion to the caudal half of the entorhinal cortex (Suzuki and Amaral 1994b).These projections are reciprocal and the entorhinal cortex projects heavily both to the perirhinal and parahippocampal cortices. The perirhinal and parahippocampal cortices receive quite distinctive complements of cortical inputs from unimodal and polymodal associational areas. The perirhinal cortex, for example, receives its major input from area TE, the laterally adjacent unimodal visual association area. The parahippocampal cortex, in contrast, receives its major visual input from area V4. And, in contrast to the perirhinal cortex which receives little or no 'dorsal stream' visual input, area TF receives substantial inputs from the visuospatial integrative regions of the posterior parietal cortex. Interestingly, the parahippocampal cortex also receives a substantial input from the retrosplenial cortex. 5.3. OTHER EXTRINSIC CONNECTIONS OF THE HIPPOCAMPAL FORMATION The hippocampal formation is connected with a variety of brain regions in addition to those summarized in Fig. 8; many of these are indicated in Fig. 9. Some of the subcortical inputs, such as the noradrenergic input from the locus coeruleus, will be covered in more detail in the following sections. The vast majority of the outputs of the hippocampus arise from pyramidal cells in the hippocampus and subiculum and are presumed to use the excitatory neurotransmitter glutamate. Data from the rat indicate that some of the 'intrinsic' GABAergic neurons may also project subcortically, at least to the septal complex (T6th and Freund 1992); this has not been confirmed in the primate. Fig. 9 also makes the point that cortical interconnections are not exclusively directed to the entorhinal cortex. The subiculum and CA1, for example, are reciprocally inter336

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connected with the perirhinal and parahippocampal cortices (Suzuki and Amaral 1990). The presubiculum receives direct inputs from a number of cortical regions including the retrosplenial cortex, posterior parietal cortex, superior temporal gyrus and frontal lobe (Seltzer and Pandya, 1984).

6. DENTATE GYRUS The dentate gyrus receives much of its input either from the entorhinal cortex (which contributes approximately 85% of the excitatory inputs to the outer portion of the molecular layer (Nafstad 1967)) or from the associational connection which originates from cells in the polymorphic layer and again provides the vast majority of excitatory inputs to the inner third of the molecular layer. Of the remaining, quantitatively more meager inputs, many are derived from GABAergic fibers of both intrinsic and extrinsic origin and the remainder arise from a variety of neurochemically identified subcortical systems. 6.1. GLUTAMATE SYSTEM Glutamate acts as an excitatory neurotransmitter in the major intrinsic pathways of the hippocampal formation. Layer II and III neurons in the entorhinal cortex, which give rise to the perforant path, the granule cells of the dentate gyrus and the pyramidal cells in the hippocampus are all glutamatergic (Storm-Mathisen 1981). Glutamate receptors are densely distributed in the terminal fields of these neurons. 6.1.1. Glutamate

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In the dentate gyrus of the baboon, most of the granule cells are stained with an antibody against glutamate (Ottersen and Storm-Mathisen 1985). The polymorphic layer also contains occasional glutamate-immunoreactive cell bodies; the large 'mossy cells' of the polymorphic layer are also glutamatergic (Soriano and Frotscher 1994). Very few neurons in the molecular layer are immunoreactive for glutamate. 6.1.2. Glutamate receptors

Localization of the full spectrum of glutamate receptors has been analyzed by receptor autoradiography using [3H]L-glutamate. In the marmoset dentate gyrus (Kraemer et al. 1995), glutamate binding sites are densest in the molecular layer. Glutamate receptors are subdivided into two main types: ionotropic receptors that are linked to ion channels and metabotropic receptors that are linked to second messenger systems (see review by Hollmann and Heinemann (1994)). The ionotropic receptors are further subdivided into N-methyl-o-aspartate (NMDA), a-amino-3-hydroxy-5-methyl-4-isoxazole (AMPA) and kainate receptors. 6.1.3. NMDA receptors

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NMDA receptors have three different binding sites for various ligands: a transmitter recognition site, a modulatory site and the surface of the channel. L-glutamate NMDA and [(+)2-carboxypiperazine-4-yl] propyl-l-phosphonic acid (CPP) bind to the trans337

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mitter recognition sites, while glycine shows strychnine-insensitive binding to the modulatory sites. Phencyclidine, 1-(1-thienyl-cyclohexyl)' piperidine (TCP) and MK801 are specific channel ligands systems (see reviews by Cotman and Iversen (1987) and by Hollman and Heinemann (1994)). Both in the monkey (Kraemer et al. 1995) and the human (Geddes et al~ 1986; Maragos et al. 1987; Monaghan et al. 1987; Jansen et al. 1989a; Jansen et al. 1989b; Johnson et al. 1989; Ulas et al. 1992), the N M D A receptors are densest in the molecular layer. The polymorphic layer demonstrates a moderate level of N M D A receptor density, while the receptors are relatively sparse in the granule cell layer. Within the molecular layer, the inner one third shows the highest density and the outer one third the lowest. Immunohistochemistry in the macaque monkey and the human (Siegel et al. 1994, 1995; Hof et al. 1996) show that the granule cell bodies and their dendrites, as well as mossy fibers and terminals, are intensely stained with a monoclonal antibody directed against the N M D A receptor subunit 1 (NMDAR1). Messenger RNA of NMDAR1 is also detected in human granule cell bodies (B6ckers et al. 1994).

6.1.4. AMPA/kainate receptors

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Molecular cloning has so far identified nine AMPA/kainate receptor subunits in the rat brain. Of these subunits, GluR1-4 are AMPA-selective, and GluR5-7 and KA1-2 are kainate-selective. In the human dentate gyrus, AMPA binding sites are most numerous in the inner one third of the molecular layer, moderately dense in the outer two thirds of the layer and quite sparse in the polymorphic layer (Geddes et al. 1992). The density of kainate binding sites is highest in the inner one third of the molecular layer and relatively low in the outer two thirds of the molecular layer and in the polymorphic layer (Geddes and Cotman 1986; Geddes et al. 1992). Immunohistochemical and in situ hybridization studies in the human (Hyman et al. 1994; Day et al. 1995; Ikonomovic et al. 1995a,b; Breese et al. 1996) show that GluR1-7 receptor subunits are all detected on granule cells and some cells in the polymorphic layer. GluR1 subunits are more often located on the dendrites of granule cells than on the cell bodies, whereas GIuR2/3/4 are more frequently observed on the cell bodies. In situ hybridization studies in the human dentate gyrus indicate that AMPA/kainate receptor messenger RNA is concentrated in the granule cell layer (Harrison et al. 1990; Porter et al. 1997). In the macaque monkey, antibodies against GluR2/4 show dense labeling of granule cells (Siegel et al. 1995; Hof et al. 1996), whereas in the African green monkey, an antibody against GluR2/3 fails to label granule cell bodies (Leranth et al. 1996). Immunohistochemistry for GluR5-7 in the macaque monkey (Good et al. 1993) labels granule cell bodies, some cell bodies and dendrites in the polymorphic layer, and neuropil in the inner part of the molecular layer.

6.1.5. Metabotropic glutamate receptors Molecular biological approaches are revealing an increasing number of genes for the metabotropic glutamate receptors (mGluR). Of those gene products (which currently number 8), mGluR1-5 and 7 have been sought and found in the human hippocampal formation (Blfimcke et al. 1996; Makoff et al. 1996a,b,c). In the dentate gyrus, virtually all neurons appear to be immunoreactive for mGluR1. Reaction product is associated mainly with cell bodies and their proximal 338

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dendritic segments. Granule cell bodies are also positive for mGluR5. Immunoreactivity for this receptor is also very dense in the inner portion of the molecular layer. There is also dense staining just subjacent to the granule cell layer. Immunostaining for mGluR2/3 almost exclusively labels granule cell bodies, while mGluR4a-labeling is not significant in the dentate gyrus. In situ hybridization studies also demonstrate expression of mGluR1- and mGluR3 RNA and a lack of mGluR4 expression in the granule cell layer (Makoff et al. 1996a,c; Lin et al. 1997). Thus far, there are no immunohistochemical reports of the distribution of the mGluR7 receptor. However, in situ hybridization for mGluR7 (Makoff et al. 1996b) shows a high level of expression in the human granule cell layer.

6.1.6. Aspartate A second putative excitatory transmitter in the hippocampal formation is aspartate. In the baboon dentate gyrus, aspartate-immunoreactive cell bodies are chiefly located in the polymorphic layer (Ottersen and Storm-Mathisen 1985). Aspartate-immunoreactive cell bodies are also located in the molecular layer and the deepest portion of the granule cell layer. Typical granule cells are usually not aspartate-immunoreactive. Aspartate-positive fibers are diffusely distributed in all layers of the dentate gyrus. 6.2. CHOLINERGIC SYSTEM The cholinergic innervation of the dentate gyrus has been studied both in the nonhuman primate (Bakst and Amaral 1984; Kitt et al. 1987; Samson et al. 1991; Alonso and Amaral 1995) and in the human brain (Perry et al. 1980; 1992; Henke and Lang 1983; Green and Mesulam 1988; Ransmayr et al. 1992; de Lacalle et al. 1994). While staining for acetylcholinesterase (ACHE) and choline acetyltransferase (CHAT) has been carried out in both species, ChAT provides the more reliable staining of the cholinergic system. It is now quite clear that acetylcholinesterase activity is found in a variety of neuronal cell types that are not cholinergic (Bakst and Amaral 1984; Alonso and Amaral 1995). While we will emphasize the distribution of ChAT labeling, we will also point out some of the differences in the distributions of ChAT and AChE labeled fibers and cell bodies. The dentate gyrus demonstrates substantial variation in the density of ChAT immunoreactive fibers and terminals at different rostrocaudal levels. The uncal ~or most rostromedial portion of the dentate gyrus has an extremely dense network of cholinergic fibers and the density decreases in a gradual fashion at more caudal levels. The cells of origin for the cholinergic innervation of the monkey dentate gyrus are mainly located in the medial septal nucleus and in the nuclei of the diagonal band of Broca (Amaral and Cowan 1980; Mesulam et al. 1983); a more meager component of the cholinergic innervation arises in the basal nucleus of Meynert. ,,

6.2.1. Cholinergic fiber systems

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6.2.1.1. Molecular layer The molecular layer of the dentate gyrus has a light to moderate density of cholinergic fibers. The distribution of cholinergic fibers is slightly different in different species of monkeys (Alonso and Amaral 1995). In the rhesus monkey, the distribution of fibers 339

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divides the molecular layer into two approximately equal-sized sublayers. The superficial sublayer has a high density of fibers which is highest just at the border with the deeper sublayer, which has a substantially lower density of fibers. At caudal levels, cholinergic fibers are more homogeneously distributed throughout the molecular layer. In the Macaca fascicularis monkey, the pronounced sublamination of the molecular layer is only observed at the rostromedial tip of the dentate gyrus. This less laminated pattern has also been reported for the human dentate gyrus (de Lacalle et al. 1994) which nonetheless has a density of cholinergic fibers that resembles the monkey. Cholinergic fibers enter the molecular layer via four routes (Alonso and Amaral 1995). Most commonly, fibers enter directly from the fimbria. Other fibers enter the molecular layer from the stratum lacunosum-moleculare of the hippocampus either by perforating the hippocampal fissure or by entering the dorsolateral tip of the molecular layer. Some fibers enter the molecular layer after crossing the polymorphic and granule cell layers. Studies carried out in the rat (reviewed in Freund and Buzs~iki (1996)) indicate that the majority of cholinergic fibers terminate on principal neurons (not interneurons) within the dentate gyrus. Comparable electron microscopic studies have not yet been conducted in the primate. In adjacent sections through the dentate gyrus prepared for the demonstration of AChE or CHAT, there are both similarities and differences in the distribution of labeled fibers in the dentate gyrus (Alonso and Amaral 1995). In both preparations, for example, there is a diffusely distributed plexus of axons throughout the molecular layer. In AChE preparations, however, there is an additional intensely stained band of diffuse labeling that occupies about the inner one quarter to one third of the molecular layer. While there is a slight supragranular increase in the density of ChAT-labeled fibers in the molecular layer of the Macaca fascicularis monkey, there is nothing in the ChAT staining that resembles the appearance of the AChE positive band. The origin of the AChE positive, ChAT negative fibers is currently unknown.

6.2.1.2. Granule cell layer There is a relatively low level of cholinergic innervation of the granule cell layer. Interspersed among the negatively stained profiles of the granule cells, there are ChAT immunoreactive fibers that traverse the layer.

6.2.1.3. Polymorphic cell layer Cholinergic labeling of the polymorphic layer is not homogeneous. There is a narrow zone just below the granule cell layer that contains a relatively high density of cholinergic fiber and terminal labeling. The remainder of the layer demonstrates a much lower level of cholinergic fibers. A major difference in the staining of AChE and ChAT profiles in the dentate gyrus is in the distribution of positive cell bodies (Butcher and Woolf 1982; Fibiger 1982). There are numerous AChE-stained cell bodies in the polymorphic layer. These cells comprise a variety of sizes and cell shapes both in the monkey and human polymorphic cell layers (Bakst and Amaral 1984). There are no ChAT-positive cells either in the monkey (Alonso and Amaral 1995) or in the human (de Lacalle et al. 1994) dentate gyrus. This difference is not so clear in the rodent. Here, there is a population of ChAT positive neurons distributed throughout the hippocampal formation including the dentate gyrus (Levey et al. 1984). A similar situation is apparent in essentially 340

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all of the hippocampal fields. There are numerous AChE labeled cells scattered throughout the hippocampal formation with particularly dense accumulations in the stratum oriens of the hippocampus, layer III of the subiculum and throughout the entorhinal cortex (Bakst and Amaral 1984). Since there is no indication that any of these neurons are cholinergic, we will not mention this difference in any of the other sections on cholinergic innervation.

6.2.2. Cholinergic receptor systems

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The distribution of muscarinic binding sites has been analyzed in the dentate gyrus of the nonhuman primate (Mash et al. 1988; Miyoshi et al. 1989; Kraemer et al. 1995) and human (Biegon et al. 1982; Cort6s et al. 1987; Court et al. 1997) brains. In the monkey brain, the M1 receptor type is most highly concentrated in the molecular and polymorphic layers of the dentate gyrus. In the human, the density of muscarinic receptors is reported to be higher in the molecular and granule cell layers than in the polymorphic cell layer. Nicotinic receptors have not been evaluated in the nonhuman primate. In the human brain, Rubboli et al. (1994) have used in situ hybridization to show that the granule cells express both the a7 and 132 subunits of the nicotinic receptor. Granule cells also demonstrate high binding of [125I]a-bungarotoxin (Rubboli et al. 1994; Court et al. 1997). 6.3. GABAergic SYSTEM

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The primate dentate gyrus contains a heterogeneous population of GABAergic neurons and is innervated by GABAergic fibers that are both of intrinsic and extrinsic origin (Jongen-R61o et al. 1999). While earlier studies primarily used immunohistochemistry for the synthetic enzyme, glutamic acid decarboxylase (GAD) (Ribak et al. 1978), more recent studies have employed either in situ hybridization for mRNA coding for GAD or antibodies directed against GABA. The study by Babb et al. (1988) is one of the few studies that identified GABAergic neurons in the monkey hippocampal formation using immunohistochemistry to GAD and then quantified the putative GABAergic neurons. They found that the polymorphic layer of the dentate gyrus contains the highest density of GABAergic neurons in the monkey hippocampal formation. In the polymorphic cell layer, GABAergic neurons account for 65% of the total neurons; in the molecular layer the number was 89% and in the granule cell layer only 0.3%.

6.3.1. GABAergic fiber innervation GABAergic fibers are most densely distributed within the granule cell layer of the dentate gyrus (Schlander et al. 1987). A dense plexus of varicose axons and individual varicosities surround unstained granule cells (Babb et al. 1988). Electron-microscopic analysis of these varicosities in the human dentate gyrus indicates that they form symmetric contacts with dendrites, cell bodies and axon initial segments. Themolecular layer generally has a much lower density of varicose fibers; most of these are found in the outer two thirds of the layer. The polymorphic layer has a slightly denser fiber and terminal labeling than in the adjacent portion of CA3. The origin of these fiber systems has been partially established from work carried out in the rat but has 341

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not been well studied in the primate brain. The pericellular innervation of the granule cells appears to come primarily from 'basket' cells most of which are located just subjacent to the granule cell layer. The GABAergic innervation of the superficial portion of the molecular layer originates primarily from cells located in the polymorphic cell layer but also from extrinsic sources in the medial septal nucleus (Freund and BuzsS.ki 1996).

6.3.2. GABAergic cell bodies GABAergic neurons are found in all layers of the dentate gyrus with the highest density in the polymorphic layer.

Molecular layer The GABAergic neurons located in the molecular layer are of two categories. The largest GABAergic neurons have spheroidal or multipolar cell bodies. A second, less common, class of GABAergic molecular layer neurons have fusiform cell bodies and dendrites oriented parallel to the granule layer. The latter cells are typically located close to the hippocampal fissure. The distribution of the axons of these neurons has not yet been established for the primate. Granule cell layer Most of the GABAergic neurons in the granule cell layer are located at the interface between the granule cell and polymorphic layers. Among the most commonly observed GABAergic cells are the pyramidal basket cell, the fusiform basket cell and the multipolar basket cell; all of these are presumed to contribute to the basket plexus within the granule cell layer (Ribak and Seress 1983; Seress and Ribak 1983; Jongen-R~lo et al. 1999).The pyramidal basket cells have a triangular-shaped soma that inserts into the deep half of the granule cell layer with a main apical dendrite that ascends through the granule cell layer and into the molecular layer and basal dendrites that ramify in the polymorphic layer. The fusiform basket cells have cell bodies located within the lower half of the granule cell layer or just subjacent to it. Multipolar basket cell bodies are distributed throughout the granule cell layer. Some dendrites of these multipolar cells enter the molecular layer while others descend into the hilus. Another multipolar cell type is seen typically at the 'V' of the granule cell layer. This oval-shaped cell body has dendrites that extend into and through the granule cell layer to the pial surface of the molecular layer. Small spheroidal, multipolar cells are found in the lower half of the granule cell layer; these have thin radiating dendrites that remain within the granule cell layer. Polymorphic cell layer Two major types of GABAergic neurons are located in the polymorphic layer. The most prominent type is a class of multipolar cells. Some of the dendrites of these cells enter the granule cell and molecular layers. Occasionally, the dendrites of the largest multipolar cells extend into the hilar portion of CA3. The second major GABAergic cell type has a large, fusiform-shaped cell body. Two subtypes of the fusiform cells are common: one has a horizontally oriented cell body with dendrites running parallel to the granule cell layer while the other has a vertically oriented soma with dendrites extending through the granule cell layer into the molecular layer. The polymorphic layer also has a variety of less numerous GABAergic cell types. 342

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One is a large pyramidal-like neuron located just subjacent to the granule cell layer. Another GABAergic cell type has a small, spherical soma with short, thin dendrites. In the caudal dentate gyrus, in the space that forms the medial and lateral 'V' of the granule cel! layer, two unique types of GABAergic cells have been identified. These cells have two or more thick, parallel dendrites emerging from one pole of the cell body that extend into the molecular layer; the dendrites originating from the other pole remain in the polymorphic layer. These cells have a thin axon that extends into the polymorphic layer. Unfortunately, many of the recent advances in determining the input/output characteristics of GABAergic neurons in the rat dentate gyrus (Freund and Buzs/tki 1996) have not been replicated in the monkey or human brains; this provides a fertile area for future research.

6.3.3. GABAergic receptors

Figure IOC2

Receptor autoradiography and immunohistochemistry consistently demonstrate that the monkey (Kraemer et al. 1995) and human (Manchon et al. 1985; Houser et al. 1988; Young and Chu 1990) dentate gyrus has relatively high densities of both GABAA and GABAB receptors. In fact, the molecular layer demonstrates the highest density of both types of receptors of any region in the dentate gyrus or hippocampus. The GABAA immunoreactivity is mainly associated with dendrites (mainly from granule cells) that occupy the molecular layer. GABAA immunoreactivity is also distributed on the cell soma of granule cells. The polymorphic layer of the dentate gyrus also demonstrates a very dense distribution of GABAA and GABA~ receptors. A variety of sizes and shapes of neurons in the polymorphic layer are stained with antibodies to GABAA receptors; many, if not all, of these cells appear to be interneurons. 6.4. MONOAMINES Because of the similarity of the distribution of at least the noradrenergic and serotonergic fibers in the dentate gyrus, we will describe the distribution of the monoamines together in each field of the hippocampal formation. Compared to the rat, there are relatively few publications describing the distribution of these fiber systems in the primate brain.

6.4.1. Noradrenaline

Figures IODI&2

While a variety of technologies have been employed in demonstrating monoaminergic fibers, the most selective marker for noradrenergic fibers is dopamine [3-hydroxylase (DBH) immunohistochemistry. In the monkey, DBH-immunoreactive fibers are chiefly distributed to the polymorphic layer, particularly in a narrow zone just subjacent to the granule cell layer (Amaral and Campbell 1986; Samson et al. 1990). The granule cell layer itself contains only a few noradrenergic fibers. The molecular layer has a slightly higher density of labeled fibers than the granule cell layer and they tend to be oriented perpendicular to the granular cell layer. DBH fibers have been described in the human dentate gyrus (Powers et al. 1988; Gaspar et al. 1989), in the context of general surveys of cortical noradrenergic innervation; no details about laminar or regional differences are available from these studies. The origin of the noradrenergic fibers to the monkey hippocampal formation is likely to be the locus coeruleus (Amaral and Cowan 1980) although this projection has not yet been double labeled. 343

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The distribution of ctl a and ~1 b receptors has been analyzed for the monkey (Kraemer et al. 1995) and human (Biegon et al. 1982; Hoyer et al. 1990; Zilles et al. 1991) dentate gyrus using receptor autoradiography. Of the two subtypes, a lb is predominant in the molecular layer (Hoyer et al. 1990; Zilles et al. 1991). [3-adrenergic receptors, as identified with [125I]iodocyanopindolol autoradiography, generally have a high density over the dentate gyrus (Slesinger et al. 1988). 6.4.2. Adrenaline

Immunohistochemical studies using an antiserum against phenylethanolamine-Nmethyltransferase did not demonstrate labeled fibers in the hippocampal formation (Samson et al. 1990). 6.4.3. Dopamine

Figures lOD3&4

Dopamine is both a neurotransmitter and the precursor for synthesis of noradrenaline. Tyrosine is converted to dopamine via enzymatic activity of tyrosine hydroxylase, and dopamine is converted to noradrenaline with dopamine [3-hydroxylase. While antibodies to tyrosine hydroxylase might stain both dopaminergic and noradrenergic neurons, in fact, a double labeling study using antibodies against both TH and DBH showed that only 2% of DBH-immunoreactive fibers were also TH-immunoreactive in the monkey entorhinal cortex (Akil and Lewis 1993). The TH-labeled fibers appear to be exclusively dopaminergic. Thus, TH immunohistochemistry is currently the most sensitive marker for the dopaminergic system in animal studies. One caveat to this conclusion is that, in the human, the percentage of fibers that are double labeled for TH and DBH is higher ( 1 0 - 5 0 ~ depending on the cortical area) (Gaspar et al. 1989), though the overlap is on the lower end of the range in the hippocampal formation. In the macaque monkey (Amaral and Campbell 1986; Samson et al. 1990) the dentate gyrus contains a greater number of TH-immunoreactive fibers than has been reported for the rat. The pattern of distribution is also different. TH-labeled fibers are found mainly in the outer half of the molecular layer and within the polymorphic layer. The granule cell layer is traversed by only a few TH-labeled fibers. Gaspar et al. (1987; 1989) documented the occurrence of dopaminergic fibers in the human dentate gyrus but few details were provided. Three kinds of dopamine receptors (D1, D2 and D5) have been identified in the primate dentate gyrus. In the macaque monkey, Bergson et al. (1995) demonstrated staining for the presence of dopamine receptors on the granule cells (K6hler et al. 1991) and on cells located in the polymorphic layer. The vast majority of D5-positive cells also contained D 1 receptors but not all D 1-positive cells contain D5 receptors. D 1 labeling is prominent in dendritic spines, while D5 labeling is more evenly distributed along dendritic shafts. K6hler et al. (1991) and Goldsmith and Joyce (1994) evaluated the distribution of D2 receptors in the human dentate gyrus. These papers demonstrate high densities of receptors in the molecular and polymorphic layers. 6.4.4. Serotonin

Figures lOD5&6

In the macaque monkey, there is a moderately dense distribution of 5-hydroxytryptamine- (5-HT; serotonin) immunoreactive fibers in the outer half of the molecular layer and in the polymorphic layer (Amaral and Campbell 1986; Ihara et al. 1988; Wilson 344

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and Molliver 1991). The density of immunoreactive fibers in the polymorphic layer is substantially higher just below the granule cell layer. The inner half of the molecular layer and the granule cell layer contain only a few radially oriented 5-HT fibers. In the marmoset, Hornung et al. (1990) distinguished two types of serotonergic axons in the dentate gyrus: fine axons with sparse ovoid varicosities whose diameter is less than 1 gm, and thicker axons with large spheroidal varicosities up to 5 lam in diameter. In the molecular layer, the fine axons with small varicosities predominate and are much more densely distributed in the outer 2/3 than in the inner third. In the polymorphic layer, the thin axons are lightly and diffusely distributed throughout whereas the thicker axons tend to terminate close to the granule cells and are denser subjacent to the layer than superficial to it. Tract-tracing or biochemical studies following lesions of the raphe nuclei in the rat have demonstrated that these nuclei give rise to the 5-HT containing fibers that innervate the dentate gyrus (Conrad et al. 1974; Moore and Halaris 1975; Azmitia et al. 1978; K6hler and Steinbusch 1982). The raphe nuclei of the macaque monkey are also known to project to the dentate gyrus (Amaral and Cowan 1980) and it is likely (though not yet demonstrated) that this is the source of the serotonergic input in the primate brain. Serotonin receptors are currently divided::into two types, i.e., 5-HT1 and 5-HT2. The former are further subdivided into 5-HTIA, 5-HT1B, 5-HTIc and 5-HT1D receptors. 5HT1 and 5-HT2 receptors have been localized to the dentate gyrus of monkey (Kraemer et al. 1995) and human (Biegon et al. I986; Hoyer et al. 1986a, b; Pazos et al. 1987a, b). Subtypes 5-HT1A and 5-HTlc are also detected in the human dentate gyrus (Hoyer et al. 1986a, b; Pazos et al. 1987a). In none of these papers was the precise laminar or cellular distribution described. 6.5. PEPTIDES 6.5.1. Substance P

Figure I OE1

Radioimmunoassay of the monkey hippocampus and dentate gyrus indicate that they contain the highest concentration of substance P (SP) among eleven cortical areas surveyed (Hayashi and Oshima 1986). Substance P immunoreactive neurons are found in the polymorphic layer of the dentate gyrus both in the monkey (Iritani et al. 1989; Nitsch and Leranth 1994) and in the human (Del Fiacco et al. 1984; 1987; Del Fiacco and Quartu 1989). These neurons are of various sizes and shapes. Smaller substance P positive cells are oval or pear-shaped, while larger cells are multipolar. Numerous immunostained fibers are observed in the superficial part of the molecular layer and at the boundary between the molecular and granule cell layers. The latter forms a distinct supragranular plexus of immunopositive axons and terminals. A few immunoreactive fibers are also observed in the deep part of the molecular layer, granule cell layer and polymorphic layer. Immunohistochemical studies combined with tract-tracing techniques (Leranth and Nitsch 1994; Nitsch and Leranth 1994) have demonstrated the origins and synaptic organization of these fibers. Substance P immun,oreactive fibers in the superficial molecular layer establish symmetrical synapses that survive transection of the timbria-fornix (Nitsch and Leranth 1994). Labeled fibers in the supragranular plexus and polymorphic layer, in contrast, form exclusively asymmetrical synapses, and these are lost following transection of the fimbria-fornix. Both the supragranular plexus and 345

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the polymorphic layer receive projections from SP containing neurons in the supramammillary area (Leranth and Nitsch 1994). In the supragranular zone, SP-immunoreactive terminals contact a small population of basket neurons which stain positively for parvalbumin, while in the polymorphic layer, the SP terminals contact neurons that also demonstrate calbindin immunoreactivity.

6.5.2. Cholecystokinin

Figure lOE2

The only paper dealing with CCK immunoreactivity in the monkey brain (Leranth et al. 1988) investigated the types of CCK-immunoreactive synapses formed on hippocampal pyramidal cells. We will return to this study in a later section. In the human, cholecystokinin (CCK) fiber and terminal labeling produces a trilaminate pattern in the molecular layer of the dentate gyrus (Lotstra and Vanderhaeghen 1987). The outer one third of the molecular layer contains only a few thin beaded fibers. The middle one third, in contrast, contains a very dense plexus of thin, beaded axons with fine varicosities. The inner one third of the layer also has many beaded fibers although the density of CCK immunoreactivity is less than in the middle one third. Thick vertically oriented fibers traverse the three sublayers and arborize around the granule cells. Within the granule cell layer, CCK-labeled fibers are densest in the most superficial portion and contribute to the appearance of a supragranular plexus. Numerous thin beaded fibers are found in the zone just subjacent to the granule cell layer. Beaded fibers and CCK-labeled cell bodies are also observed in the polymorphic layer.

6.5.3. Vasoactive intestinal peptide To our knowledge, there is no study reporting the distribution of vasoactive intestinal peptide-immunoreactivity in the monkey or human hippocampal formation.

6.5.4. Neurotensin

Figure lOE3

A few cell bodies immunoreactive for neurotensin (NT) are observed in the granule cell layer of the human dentate gyrus (Gaspar et al. 1990). NT-labeled fibers are mainly found in the polymorphic layer

6.5.5. Somatostatin

Figure lOE4

Bakst et al. (1985), described a dense plexus of somatostatin (SS)-immunoreactive fibers that occupies the outer two thirds of the molecular layer of the dentate gyrus. Only a few SS-positive fibers are observed in the inner third of the layer or in the granule cell layer. The polymorphic layer contains many somatostatin-immunoreactive fibers and varicosities, the density of which is higher at rostral levels. Somatostatin-immunoreactive cell bodies are found mainly in the polymorphic layer and in the inner third of the molecular layer. Labeled cells in the molecular layer are mostly small and relatively few in number. Somatostatin-immunoreactive neurons located just subjacent to the granule cell layer have the appearance of GABAergic pyramidal basket cells and give rise to stained axons that originate from their apical dendrites located just above the granule cell layer. In the deeper part of the polymorphic layer, labeled neurons have a variety of shapes and sizes. Cell bodies in the polymorphic layer of the human dentate gyrus also express 346

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mRNA for somatostatin (Dournaud et al. 1994). The distribution of SS-immunoreactive fibers in the human is also very similar to the monkey (Bouras et al. 1987; ChanPalay 1987, 1989; Amaral et al. 1988). The major differences are that (1) clusters of grape-like large varicosities are distributed throughout the dentate gyrus, especially in the polymorphic layer of the dentate gyrus, and (2) the density of SS-positive fibers in the inner molecular layer is higher in the human than in the monkey (Amaral et al. 1988). While double labeling studies have not yet been carried out in the monkey, work in the rat and the similarity of the location of fiber plexuses, suggests that many of the somatostatin-immunoreactive neurons are also GABAergic.

6.5.6. Neuropeptide Y

Figure l OE5

The distribution of neuropeptide Y (NPY) is very similar to that of somatostatin. In fact, in the human dentate gyrus (Chan-Palay 1989) at least 30% of the somatostatin neurons colocalize NPY. In the monkey dentate gyrus, NPY-immunoreactive fibers form a dense plexus in the outer part of the molecular layer (K6hler et al. 1986; Nitsch and Leranth 1991). A few immunoreactive fibers are located in the polymorphic layer and some fibers run from the outer part of the molecular layer into the polymorphic layer. NPY-immunostained cell bodies are concentrated in the polymorphic layer. They are medium-sized multipolar or bipolar neurons. In the human dentate gyrus, the distribution of NPY-immunoreactive fibers and cells is similar to that in the monkey (Chan-Palay et al. 1986; Lotstra et al. 1989).

6.5.7. Opioid peptides (dynorphin, enkephalin) To our knowledge, there are no studies on the distribution of opioid peptides in the nonhuman primate hippocampal formation. In the human hippocampal formation, there are relatively few enkephalin immunoreactive neurons. In the dentate gyrus, faintly stained cell bodies and a few labeled fibers are located in the polymorphic layer (Sakamoto et al. 1987). In the human dentate gyrus, dynorphin A-immunoreactive terminals are most numerous in the polymorphic layer (Houser et al. 1990). These resemble the large synaptic expansions that occur along the mossy fiber axons. The density of these is highest near the cell bodies and proximal dendrites of neurons that seem to be mossy cells. Occasional labeling is also found in the cell bodies and neuronal processes within the granule cell layer. In normal preparations, there is little or no dynorphin-A immunoreactivity within the molecular layer. However, in pathologic conditions such as temporal lobe epilepsy, where mossy fibers have been shown to sprout into the inner portion of the molecular layer, a dense band of dynorphin-A immunoreactivity is visible in a supragranular position within the molecular layer. Thus, dynorphin-A appears to be a useful marker for the distribution of mossy fiber expansions in the human brain.

6.5.8. Galanin Data concerning galanin are very meager both in the monkey and in the human. Galanin-binding sites are found in all three layers of the monkey and human dentate gyrus (K6hler 1989; Fisone et al. 1991). In the owl monkey, galanin-immunoreactive fibers demonstrate a distribution very similar to acetylcholinesterase positive fibers (Melander and Staines 1986). Whether these two fiber systems are identical remains 347

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an open question for the nonhuman primate brain. While Gentleman et al. (1989) analyzed the distribution of galanin immunoreactivity in the human brain, they did not report any fibers in the dentate gyrus. 6.6. CALCIUM-BINDING PROTEINS There has been an enormous interest in the distribution of the calcium-binding proteins. This has been sparked, in part, by the ready supply of useful antibodies for detecting this family of calcium buffering proteins. This has been particularly important in studying the parvalbumin-positive neurons which appear to constitute a subset of GABAergic interneurons. Since antibodies to glutamic acid decarboxylase or to GABA typically do not show much dendritic detail, the calcium-binding protein antibodies, with the near Golgi-like appearance that they demonstrate, provide useful information on the dendritic organization of GABAergic neurons. In addition, since the level of calcium in the hippocampus appears to be critically important for normal synaptic transmission on the one hand as well as ischemia and other trauma-related cell death on the other, the distribution and regulation of these proteins also has important functional implications. 6.6.1. Parvalbumin

Figure IOF1

The distribution of parvalbumin-immunoreative cells and fibers in the dentate gyrus has been analysed both in the monkey (Leranth and Ribak 1991; Seress et al. 1991; Pitkfinen and Amaral 1993) and the human (Ohshima et al. 1991; Braak et al. 1991; Seress et al. 1993a; Brady and Mufson 1997) brains.

Distribution of parvalbumin fibers Based on our own studies in the macaque monkey dentate gyrus (Pitk/inen and Amaral 1993) which is consistent with other studies in the monkey (Gulyfis et al. 1991; Nitsch and Leranth 1991; Ribak et al. 1993) and human (Braak et al. 1991; Seress et al. 1993a), the highest density of parvalbumin-immunoreaetive fibers and terminals is located within the granule cell layer. In this respect, the distribution parallels the distribution of GABAergic fibers. Throughout the granule cell layer there is a dense plexus of labeled varicosities often linked by thin intervaricose axonal segments. In the macaque monkey, terminal density is higher in a narrow zone in the deepest portion of the granule cell layer. Here, conspicuous dense patches of terminals outline the dendrites or cell bodies of unstained neurons. There is also a second zone of increased terminal density at the superficial edge of the granule cell layer. This supragranular plexus extends into the overlying molecular layer for a short distance. There are remarkably few parvalbumin positive terminals in most of the molecular layer. This would indicate that the population of GABAergic/somatostatinergic cells located in the polymorphic layer that project to the outer portion of the molecular layer do not also colocalize parvalbumin. There are also very few parvalbumin fibers and terminals in the polymorphic layer. The cells of the adjacent CA3 field have relatively weak pericellular terminal labeling compared with the rest of the hippocampal pyramidal cell layer. But even this light staining is clearly more substantial than the staining in the polymorphic layer. In both the monkey (Ribak et al. 1993) and human (Seress et al. 1993a) dentate gyrus, parvalbumin terminals form symmetrical synaptic junctions with cell bodies, dendrites and axon initial segments. 348

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Distribution of parvalbum#t-positive cell bodies In the monkey dentate gyrus, parvalbumin-immunoreactive cells are located in each layer of the dentate gyrus (Pitkfinen and Amaral 1993). In the molecular layer, they are relatively rare and tend to be small, spheroidal or multipolar with seve~l thin radiating dendrites. Most of these are found in the deep two-thirds of the molecular layer (Seress et al. 1991). The dendrites of cells located in the molecular layer tend to remain within the layer but occasionally enter the granule cell and polymorphic layers. It is difficult to follow the thin, lightly stained axons of these cells but some descend into the granule cell layer and give rise to many varicose collaterals. Seress~et al. (1993a) have emphasized that there are substantially greater numbers of parvaJbuminpositive neurons in the molecular layer of the human dentate gyrus. Since they (Seress et al. 1991) had earlier found the paucity of such neurons in the monkey molecular layer that Pitkfinen and Amaral, (1993) observed, this may represent a true species difference. Certainly, Braak et al. (1991) have pictured more parvalbumin cells in the human molecular than is typically found in the nonhuman primate. Most of the parvalbumin immunoreactive neurons in the monkey dentate gyrus are located at the border between the granule cell and polymorphic layers. Cells in this region comprise a variety of morphological types ranging from large multipolar cells with dendrites extending both into the molecular layer and into the polymorphic layer (and even into CA3), to small, spherical cells with thin dendrites confined to the polymorphic layer. Many of the cells resemble the classically defined dentate pyramidal basket cell. The cell body is generally situated slightly within the granule cell layer and a single, prominent apical dendrite ascends into the molecular layer. Here the dendrite branches several times and gives rise to thinner secondary and tertiary branches. There are several other parvalbumin-positive cell types located at the same position as the basket cell. One of these has a cell body that is as large or larger than the basket cell and has several thin, nontapering dendrites originating from its cell body. Unlike the pyramidal basket cell, two or more of the primary dendrites enter the granule cell layer and ramify in the molecular layer. A variety of parvalbumin-positive cells are located in the polymorphic layer. Many of these cells are quite large and some of their dendrites enter the granule cell and molecular layers while others remain in the polymorphic layer or enter CA3. A distinctive form of parvalbumin-positive polymorphic neuron is located in the medial or lateral V's of the dentate gyrus. Cells in this position give rise to 3 or more pitch forklike dendrites that enter the granule cell and molecular layers. Dendrites from the other pole of these neurons extend through the polymorphic layer. There are also smaller cells in the polymorphic layer with round or irregular cell bodies. Since there are very few parvalbumin-immunoreactive terminals in the polymorphic layer and since cells of the polymorphic layer do not project outside of the dentate gyrus, all of the various cells in this region presumably contribute terminals to the granule cell layer plexus. Ribak et al. (1993) have carried out electron microscopic analyses of parvalbuminimmunoreactive cells in the dentate gyrus and hippocampus of African green monkeys. They noted that these cells have the nuclear infoldings and intranuclear rods that are typical of GABAergic interneurons. They also pointed out that while the dendrites of parvalbumin-immunoreactive neurons received both symmetrical and asymmetrical synapses that they also demonstrated appositions with other parvalbumin-immuno-

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reactive dendrites that resembled gap junctions. This raises the possibility that the class of parvalbumin-positive GABAergic neurons are electrotonically coupled. Brady and Mufson (1997) have noted that there is approximately 60% loss of parvalbumin-immunoreactive neurons in the dentate gyrus and adjacent portion of the hippocampus in Alzheimer's diseased brains. 6.6.2. Calbindin

Figure lOF2

The distribution of calbindin DZ8K immunoreactive fibers and cells have been studied in the monkey (Seress et al. 1991; Seress et al. 1993b; Leranth and Ribak 1991; Hornung and Celio 1992) and in the human (Sloviter et al. 1991; Seress et al. 1992; Seress et al. 1993a; Tufi6n et al. 1992). In the dentate gyrus, the granule cells are immunopositive for calbindin DzgK. The mossy fibers are also strongly stained so that preparations for calbindin DzgK resemble Timms stained sections. A population of calbindin DzsK-positive interneurons are also observed in the molecular and polymorphic layers. The cells in the polymorphic layer tend to be small, bipolar and located close to the granule cell layer. The cells in the molecular layer are also small, scattered throughout the molecular layer and at least some are located just adjacent to the hippocampal fissure. These tend to be fusiform in shape. Hornung and Celio (1992) have noted that these calbindin DzsK-immunopositive neurons, as well as those in the hippocampus, are the recipients of a selective serotonergic innervation that arises from the raphe nuclei. They point out that calbindin D28K interneurons, but not parvalbumin-containing neurons, receive these serotonergic inputs. While the distribution of calbindin DZ8K immunoreactivity appears to be similar in the human dentate gyrus (Seress et al. 1993a), the number of calbindin DzsK-positive cells in the molecular layer appears to be somewhat more numerous than in the monkey species that have been studied. 6.6.3. Calretinin

Figure lOF3

The distribution of neurons and fiber systems that stain for the calcium-binding protein calretinin has proven to be enormously variable from species to species and even within, for example, different families of old world monkeys. In both the African green monkey (Seress et al. 1993b) and the normal human (Nitsch and Ohm 1995) calretinin is reported to be located exclusively in interneurons in the polymorphic layer and to a lesser extent in the molecular layer. Calretinin-positive cells in the polymorphic layer are of two types. The most frequent type is a fusiform cell that has its dendrites oriented perpendicular to the granule cell layer. Dendrites emerging from one pole enter the granule and molecular layers whereas those from the other pole extend through the polymorphic layer towards CA3. The other type of cell tends to be smaller and roundish and resembles granule cells. There are some large and small multipolar cells in the polymorphic layer as well. In the molecular layer, calretinin-positive cells are small and either fusiform or multipolar. The dendrites of these cells tend to be very thin and distributed throughout the molecular layer. In addition to the labeled cell bodies, there is a fairly dense calretinin-positive plexus of fibers and terminals located just superficial to the granule cell layer. In the African green monkey, these fibers are mainly eliminated following fornix transection and appear to arise from the large multipolar cells of the supramammillary area (Nitsch and Leranth 1993). In the Macaca fascicularis monkey, the situation appears to be 350

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somewhat different. As illustrated in Fig. 4, the polymorphic layer of the dentate gyrus is intensely stained. This consists both of labeled fibers and labeled cell bodies (Crespo, Alonso and Amaral, unpublished observations). Based on the position and number of labeled neurons, some would appear to be the large mossy cells. This is consistent with the heavy fiber labeling in the inner third of the molecular layer which is coincident with the association projection arising from the mossy cells. Unfortunately, it is not known whether this staining is decreased after fornix transection in the Macaca fascicularis monkey. 6.7. HORMONE RECEPTOR SITES While the evidence is relatively scarce, it appears that human dentate granule cells demonstrate mRNAs for both glucocorticoid and mineralocorticoid receptors (Seckl et al. 1991). Binding of [3H]corticosterone in the tree shrew hippocampal formation is highest in the dentate gyrus, slightly lower in the hippocampus and even lower yet in the subiculum (Fltigge et al. 1988; J6hren et al. 1994). Early autoradiographic data indicate that dentate granule cells concentrate [3H]corticosterone (Gerlach et al. 1976). Uptake studies in the same paper indicate that corticosterone is 2-6 times more concentrated by cells of the hippocampus than cortisol and thus corticosterone would appear to be the predominant adrenal glucocorticoid in macaque monkeys. The human dentate gyrus contains a relatively high concentration of thyrotropin releasing hormone ( T R H - Kubek et al. 1977). TRH binding sites are densest in the molecular layer of the dentate gyrus (Eymin et al. 1993). Immunohistochemical studies have demonstrated moderate intensity of insulin-like immunoreactivity in the granule cells (Dorn et al. 1982). 6.8. ENZYMES

6.8.1. Cytochrome oxidase

Figure lOG1

Cytochrome oxidase (CO) is a useful endogenous metabolic marker for neurons, since the nervous system heavily depends on aerobic metabolism for its energy supply and cytochrome oxidase plays an essential role in mitochondrial aerobic energy metabolism (Wong-Riley 1989). In the monkey dentate gyrus, CO-activity is highest in the outer two thirds of the molecular layer and relatively low in the inner one third of the layer (Kageyama and Wong-Riley 1982; Hevner and Wong-Riley 1991; Chandrasekaran et al. 1992). CO-activity in the molecular layer is located mainly in dendrites, presumably in granule cell dendrites. This is somewhat surprising since granule cell bodies and proximal dendrites show little or no CO-activity. Basket cell bodies, in contrast, which are located in the deep portion of the granule cell layer, are highly CO reactive. In the polymorphic layer, horizontally oriented cell bodies and their dendrites show COactivity. In situ hybridization for mitochondrial DNA shows a pattern of distribution that is similar to CO-activity in the monkey dentate gyrus (Hevner and Wong-Riley 1991). There is, however, some labeling of granule cells. In contrast, messenger RNA encoding CO subunits is chiefly located within cell bodies in the granule cell layer and polymorphic layer.

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6.8.2. Nitric oxide synthase and NADPH-diaphorase

Y. Kobayashi and D.G. Amaral Figures lOG2&3

Nitric oxide has been proposed to be a putative neurotransmitter or second messenger in the nervous system (see review by Jaffrey and Snyder (1995)). Two markers for nitric oxide are currently used: immunohistochemistry for nitric oxide synthase (NOS) and histochemistry for nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d). Nitric oxide is formed from arginine by NOS. NADPH-d has NOS activity (Hope et al. 1991). NOS-immunoreactivity and NADPH-d-activity colocalize within neurons in the monkey neocortex and the entorhinal cortex (Hashikawa et al. 1994). NADPH-d-histochemistry shows more robust staining than NOS-immunoreactivity, particularly for fiber systems. Histochemistry for NADPH-d in the monkey dentate gyrus heavily labels a variety of cell types in the polymorphic layer (Mufson et al. 1990). The distribution of fibers in the monkey dentate gyrus has not been described. In the human, Rebeck et al. (1993) report high density of NADPH-d positive fibers in the outer two-thirds of the molecular layer whereas the more extensive description of Sobreviela and Mufson (1995) report that the density of these fibers is higher in the inner portion of the layer. In both human reports, the polymorphic layer is described as demonstrating a high density of fibers and NADPH-d-positive cell bodies. NOS-immunoreactivity also demonstrates cell bodies in the polymorphic layer and in fibers that are distributed diffusely in all the layers (Egberongbe et al. 1994; Doyle and Slater 1997). 6.9. TROPHIC FACTORS 6.9.1. Nerve growth factor

Figures IOHI &2

Nerve growth factor (NGF) is the prototypical neurotrophin, associated initially with the maintenance of peripheral sympathetic ganglia (Levi-Montalcini and Angeletti 1968). In recent years, both NGF and NGF receptors have been described in various regions of the brain. In the monkey brain, NGF receptor immunoreactivity has been associated with cholinergic neurons of the medial septum/diagonal band complex and the basal nucleus of Meynert (Kordower et al. 1988). More recently, immunohistochemical studies have demonstrated NGF immunoreactivity in the same populations of basal forebrain cholinergic neurons as well as in fiber systems of the hippocampal formation. In the dentate gyrus, NGF immunoreactivity is most closely associated with the large terminal expansions of the mossy fibers. NGF immunoreactivity is observed to surround the proximal dendrites of neurons within the CA3 field (Mufson et al. 1994). NGF receptor immunoreactivity is much more diffuse in the dentate gyrus. A dense fiber plexus is observed in the polymorphic cell layer with somewhat lighter staining in the molecular layer. The human hippocampal formation also demonstrates NGF receptor immunoreactivity (Kerwin et al. 1991). The distribution of NGF receptor immunoreactivity is remarkably similar to the distribution of acetylcholinesterase-positive fibers. Enzyme immunoassay analysis of the distribution of nerve growth factor in the human postmortem brain demonstrates that the hippocampus has substantially higher levels of NGF than either the putamen or frontal cortex (Bertrand et al. 1992).

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6.9.2. Ciliary neurotrophic factor (CNTF) Immunoreactivity for the alpha subunit of CNTF stains virtually all of the neurons in the granule cell layer and the polymorphic layer of the monkey brain (Kordower et al. 1997).

6.9.3. Brain-derived neurotrophic factor (BDNF) The strongest level of hybridization for BDNF cRNA probes is found in the granule cells of the human dentate gyrus (Phillips et al. 1991; Murray et al. 1994). No BDNFpositive cells are observed in the polymorphic or molecular layers. In situ hybridization for trkB, which has as its preferred ligand BDNF, demonstrates strong signal throughout the human hippocampal formation (Allen et al. 1994). The granule cells of the dentate gyrus demonstrate strong labeling with a probe for trkB. In contrast, trkA (the high affinity NGF receptor) does not demonstrate neuronal labeling in the human hippocampal formation.

7. HIPPOCAMPUS 7.1. GLUTAMATE SYSTEM

7.1.1. Glutamate

Figure IOA1

In the baboon hippocampus, glutamate-like immunoreactivity is almost exclusively confined to pyramidal cell bodies and their dendrites. Only a few neurons in the pyramidal cell layer are glutamate negative (Ottersen and Storm-Mathisen 1985) Both in the monkey and human (Sandier and Smith 1991) glutamate and GABA colocalize in mossy fiber terminals in stratum lucidum of CA3. 7.1.2. NMDA receptors

Figure l OA2

Both in the monkey (Kraemer et al. 1995) and the human (Geddes et al. 1986; Maragos et al. 1987; Monaghan et al. 1987; Jansen et al. 1989a, b; Johnson et al. 1989; Ulas et al. 1992) hippocampus, binding sites of various ligands to NMDA receptors are found to be most numerous in the pyramidal cell layer of CA1. The density of NMDA receptors is also very high in stratum radiatum of CA1, moderately high in stratum oriens, and fairly low in the other layers of CA1 and all the layers of CA3. In contrast to studies using ligands, an in situ hybridization study in the human (B6ckers et al. 1994) demonstrated more intense labeling of the pyramidal cell layer in CA3 and CA2 than in CA1. The reason for this discrepancy is unclear. In the macaque monkey and the human, pyramidal cell bodies and dendrites in CA1-3 as well as mossy fiber terminals in CA3 are intensely labeled with a monoclonal antibody against NMDA receptor subunit 1 (NMDAR1) (Siegel et al. 1994, 1995; Hof et al. 1996). Siegel et al. (1995) also showed NMDARl-labeled cell bodies in stratum oriens throughout the macaque monkey hippocampus.

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7.1.3. AMPA-kainate receptors

Y. Kobayashi and D.G. Amaral Figures 10A3&4

In the human hippocampus, AMPA binding sites are dense in the pyramidal cell layer of CA1-3, the stratum radiatum of CA1, and the stratum lacunosum-moleculare of CA1-3 (Dewar et al. 1991; Geddes et al. 1992). The density of AMPA binding sites is relatively low in other areas of the hippocampus. In contrast to AMPA binding sites, kainate binding sites are only substantial in the pyramidal cell layer and stratum lucidum of CA3 (Tremblay et al. 1985; Geddes and Cotman 1986; Dewar et al. 1991 ; Geddes et al. 1992). Immunohistochemistry and in situ hybridization reveal that GluR1-4 receptors are located on pyramidal cell bodies of CA1-3, cell bodies in stratum oriens of CA1-3, and neuronal processes throughout the hippocampus in the monkey (Good et al. 1993; Siegel et al. 1995; Leranth et al. 1996) and the human (Hyman et al. 1994; Bltimcke et al. 1995; Day et al. 1995; Ikonomovic et al. 1995a, b; Breese et al. 1996). GluR2/4positive profiles located in stratum lucidum of CA3 resemble thorny excrescences (Bltimcke et al. 1995). GluR5-7-immunoreactivity is also located on pyramidal cell bodies and dendrites of CA1-3, cell bodies in stratum oriens of CA1-3 in the macaque monkey (Good et al. 1993; Siegel et al. 1995). AMPA/kainate receptor messenger RNA is concentrated in the pyramidal cell layer (Harrison et al. 1990; Porter et al. 1997).

7.1.4. Metabotropic glutamate receptors In the human hippocampus (Bltimcke et al. 1996), almost all neuronal cell bodies and their proximal dendritic segments are immunoreactive for the mGluR1 receptor; there is no significant neuropil staining. In contrast, diffuse, neuropil staining for mGluR5 occurs preferentially in stratum lacunosum-moleculare and in the pyramidal cell layer; fine granular mGluR5 staining is also observed in many neuronal cell bodies. There is no clear difference in staining pattern among CA1, CA2 and CA3 for mGluR1 and mGluR5. Immunoreactivity for the mGluR2/3 receptor is located on pyramidal cells in the hippocampus. Pyramidal cells in CA3 are much more darkly stained than in CA1. CA2 pyramidal cells show intermediate density of mGluR2/3 immunoreactivity. Mossy fibers in stratum lucidum of CA3 also demonstrate mGluR2/3 immunostaining. Immunoreactivity for the mGluR4 receptor is heavy in stratum lucidum of CA3 and weak within the pyramidal cells. Other areas of the hippocampus show no labeling. In situ hybridization studies in the human demonstrate a high level of mGluRl-signal in the CA1-3 pyramidal cell layer (Lin et al. 1997) and also heavy signal for the mGluR7 receptor in the CA3 pyramidal cell layer (Makoff et al. 1996b).

7.1.5. Aspartate In the baboon hippocampus, aspartate-immunoreactive at the boundary between stratum oriens and the alveus 1985). Aspartate-immunoreactive cell bodies are also Aspartate-positive fibers are diffusely distributed in all dum where they are rarely found.

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cell bodies are most numerous (Ottersen and Storm-Mathisen scattered in the other layers. layers except for stratum luci-

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Ch. IV

7.2. CHOLINERGIC SYSTEM Most of the studies that examined the cholinergic innervation of the monkey (Mesulam et al. 1986; Alonso and Amaral 1995) and human (Perry et al. 1980; 1992; Henke and Lang 1983; Ransmayr et al. 1989; 1992) dentate gyrus have also examined the hippocampus. We shall again focus our comments on the ChAT immunohistochemical findings based on findings reported in Alonso and Amaral (1995).

7.2.1. Cholinergic fiber systems

Figures IOBI&2

As with the dentate gyrus, the distribution of ChAT-positive fibers and terminals varies in the macaque monkey hippocampus along rostrocaudal and transverse gradients. The highest densities of fibers are observed at rostral levels of the hippocampus, particularly in the uncal region. The lowest density of fiber labeling is observed at mid rostrocaudal levels and there is a slight increase near the caudal pole of the hippocampus. Along the transverse axis, there is a gradual but marked decrease in the density of ChAT immunoreactive fibers and terminals as one progresses from CA3 to CA2 and then to CA1. There is, however, a distinct increase in the number of cholinergic fibers at the border of CA1 with the subiculum. Thehighest density of ChAT immunoreactivity in CA3 is observed in stratum oriens. This layer demonstrates numerous cholinergic fibers that appear to be entering directly from the fimbria and alveus. Stratum oriens of CA3 and CA2 demonstrates a dense imeshwork of ChAT-positive fibers which course obliquely in the proximal portion of the field and more horizontally in the distal portion. The pyramidal cell layer formsthe superficial boundary of this fiber plexus. In CA1, the density of fibers in stratum oriens is much lower than in CA3. The plexus extends with gradually decreasing density through the wide pyramidal cell layer and into stratum radiatum. Throughout the hippocampus, the pyramidal cell layer has a meager innervation of ChAT positive fibers. The few fibers that traverse the layer are mainly very thin and varicose. Stratum lucidum has one of the lowest densities of ChAT-positive fibers and terminals in the hippocampal formation. The mossy fibers are clearly ChAT immunonegative and only scattered varicose cholinergic fibers are observed in the layer. Stratum radiatum of CA3 and CA2 demonstrates numerous cholinergic fibers, most of which enter the layer obliquely from the stratum lacunosum-moleculare. A few fibers also enter stratum radiatum from stratum oriens. The density of labeled fibers is higher in the superficial portion of stratum radiatum particularly at the border with stratum lacunosum-moleculare. Not only is the innervation of the deep half of the layer less dense, but the density continues to decrease gradually towards the pyramidal cell layer. Stratum radiatum of CA1 has far fewer labeled fibers than in CA3 though the distribution is similar. Stratum lacunosum-moleculare has a fairly high density of ChAT immunoreactive fibers. While fibers are distributed throughout the full radial extent of the layer, they tend to be densest at its superficial margin. The overall pattern of AChE staining in the hippocampus generally resembles the pattern described for ChAT labeled fibers. However, the density of AChE labeling is higher than for CHAT. This is most obvious in CA1. While ChAT labeling of fibers in CA1 is extremely sparse and contrasted clearly with the higher density of labeling in CA2 and the subiculum, there is a fairly dense plexus of AChE-labeled fibers in CA1. The density of this AChE plexus is nonetheless lower than the density of fibers in CA3/

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CA2. The origin of these AChE-positive and ChAT-negative fibers is currently unknown. In the human hippocampus, ChAT-stained fibers have been reported to have a somewhat different distribution from the macaque monkey (de Lacalle et al. 1994). The highest density of ChAT-immunoreactive fibers in the human are found in the pyramidal cell layer and in stratum radiatum. Stratum oriens, which has the highest density of labeling in the monkey, has only light to moderate innervation in the human, which is similar to the low levels observed in stratum lacunosum-moleculare.

7.2.2. Cholinergic receptors

Figure lOB3

In the monkey brain, the M1 receptor type is most highly concentrated in the pyramidal cell layer and in the layers superficial to it (Mash et al. 1988; Miyoshi et al. 1989; Kraemer et al. 1995). In the human, in contrast, the CA1 field has a higher density of muscarinic receptors than CA2 and CA3 and the receptors are located mainly in stratum oriens and the pyramidal cell layer (Cort6s et al. 1987). Nicotinic receptors have not been evaluated in the nonhuman primate hippocampus. In the human, Rubboli et al. (1994) have used in situ hybridization to show that the CA2 and CA3 pyramidal cells express both the a7 and 132 subunits of the nicotinic receptor. CA1 pyramidal cells demonstrate high binding of [125I]a-bungarotoxin (Rubboli et al. 1994; Court et al. 1997). 7.3. GABAergic SYSTEM

Figure lOCI

7.3.1. Fiber innervation The hippocampus has GABAergic fibers and terminals in all layers. In CA3, the mossy fibers are heavily GABA-immunoreactive. This is a bit surprising since the mossy fibers are presumed to provide excitatory glutamate-mediated synapses to the proximal dendrites of CA3 pyramidal cells. The pyramidal cell layer of CA3 demonstrates punctate staining of GABAergic terminals that forms a basket-like plexus around the unstained cell bodies (Braak et al. 1986; Babb et al. 1988). The CA2 field demonstrates the highest density of GAD-immunoreactive varicosities (Babb et al. 1988). Pyramidal layer terminal labeling is lower in CA1 and lower yet in CA3. High densities of GABAergic fibers and terminals are also observed in stratum lacunosummoleculare. The other layers demonstrate a relatively light distribution of GABAergic fibers. The neuropil labeling in CA2 is slightly higher than in CA1 and CA3 but otherwise the distribution is very similar. Gulyfis et al. (1991) have demonstrated that some of the GABAergic fibers that are observed in the macaque monkey hippocampus originate from neurons in the medial septal nucleus. The vast majority of terminals from this septal GABAergic projection terminate on GABAergic neurons within the hippocampus. In CA1, most labeled fibers are confined to the border between stratum lacunosummoleculare and stratum radiatum. Stratum radiatum shows a lower density of labeled fibers and terminals than stratum lacunosum-moleculare and the pyramidal cell layer. Stratum oriens contains more fibers and numerous varicosities. At the border of CA1 with the subiculum there is a conspicuous increase of the GABAergic fiber and terminal labeling.

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Ch. IV

7.3.2. GABAergic cell bodies Within CA3, the stratum lacunosum-moleculare and pyramidal cell layer contain a slightly higher density of GABAergic neurons than strata radiatum and oriens (Jongen-R61o et al. 1999). Babb et al. (1988) found that the pyramidal layer has the highest density of GAD-immunoreactive neurons which accounted for approximately 3% of the cells in the layer. They found that strata oriens and lacuosum-moleculare had a slightly higher density than stratum radiatum. In their quantitative assessments, they indicated that GAD-immunoreactive neurons make up about 7% of cells in the pyramidal cell layer, 16% of cells in stratum oriens, 28% of cells in stratum radiatum and 50% of cells in stratum lacunosum-moleculare. In CA2, the percentages are the following: pyramidal cell layer, 3%; stratum oriens 34%; stratum radiatum, 55%; and stratum lacunosum-moleculare, 34%. The density of labeled neurons in all lamina of CA3 is highest rostrally and decreases at more caudal levels. In the hilar portion of the monkey CA3, there are two peculiar types of GABAergic cells. One is a stellate/multipolar cell, found intermingled with the labeled mossy fibers. These cells have numerous, fine, slightly varicose dendrites, which remain mostly in CA3. These stellate cells are present almost exclusively in the proximal part of CA3. The second cell type is a multipolar cell with a large, diamond-shaped cell body. These multipolar cells have smooth as well as beaded dendrites that radiate in all directions. Some of these cells have long beaded dendrites that occasionally enter the polymorphic layer of the dentate gyrus. Pyramidal-shaped and modified pyramidal-shaped GABAergic cells are also occasionally seen in the proximal portion of CA3. GABAergic neurons in stratum lacunosum-moleculare have spheroidal, multipolar cell bodies with few visible dendrites. These cells are typically located deep in stratum lacunosum-moleculare. In stratum radiatum, two major types of GABAergic cells are observed. One type consists of large, vertically oriented fusiform cells with apical dendrites extending into the pyramidal cell layer and basal dendrites into the stratum lacunosum-moleculare. The other type is a multipolar cell which varies substantially in size. Typically, the large multipolar cells are located at the deeper portions of the stratum radiatum. The dendrites of these cells extend into the pyramidal cell layer. There is often a marked accumulation of large fusiform and multipolar GABAergic cells superficially in stratum radiatum, at the border with stratum lacunosum-moleculare. Several types of GABAergic neurons are found in the pyramidal cell layer. One prominent type has a pyramidal-shaped cell body with apical dendrites extending into the stratum radiatum and basal dendrites to stratum oriens. This pyramidal basket cell presumably contributes to the basket plexus of fibers and terminals within the pyramidal cell layer. Another major cell type is a class of multipolar cells with dendrites sometimes extending into the stratum radiatum. There are also horizontally oriented fusiform cells in the pyramidal cell layer, with dendrites running into the stratum oriens. GABAergic neurons located in the most superficial part of the pyramidal cell layer have dendrites that extend into and through the stratum lucidum. Modified pyramidal shaped cells are also seen in the pyramidal cell layer. In stratum oriens, the GABAergic neurons are mainly multipolar cells. The dendrites of these cells typically remain in stratum oriens or extend into the deep portions of the pyramidal cell layer. Very few if any GABAergic neurons are observed within the stratum lucidum. Occasionally a neuron is seen at the most superficial portion of

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the stratum lucidum with dendrites extending through it towards the pyramidal cell layer. These cells are mostly small, multipolar and have spheroidal cell bodies. The pyramidal cell layer of the CA2 field has the highest density of GABAergic neurons in the hippocampus. Within CA2, the highest number of GABAergic neurons is located in the pyramidal cell layer, and the lowest number is in stratum lacunosummoleculare. In stratum lacunosum-moleculare of CA2, the most prominent GABAergic cell type is a multipolar cell with a small, spherical cell body. Fusiform cells are also seen in this layer. GABAergic cell types in stratum radiatum include modified pyramidal cells and small to large multipolar cells. Many cells are seen in the deep portion of stratum radiatum which contrasts with the adjacent CA3, where few cells are found in stratum lucidum. As in CA3, there is an accumulation of large, fusiform GABAergic neurons located at the border between strata radiatum and lacunosum-moleculare. In the pyramidal cell layer of CA2, the majority of the GABAergic neurons have either pyramidal, modified pyramidal, fusiform or multipolar cell bodies. Small spheroidal cells are also present in the pyramidal cell layer. Stratum oriens of CA2 has cell types similar to those in CA3. Very few labeled cells are located in the alveus. Within CA1, all layers show approximately similar densities of GABAergic neurons. Stratum lacunosum-moleculare shows a somewhat higher density than in the other hippocampal fields. Babb et al. (1988) found that 2% of the cells in the pyramidal cell layer were GAD immunoreactive, 10% of the cells in stratum oriens and 100% of the cells in stratum radiatum and lacunosum-moleculare. The laminar distribution of GABAergic cells is slightly different in CA1 than in CA2 and CA3. In CA3 and CA2, GABAergic neurons are roughly equally dense throughout the full width of each layer. In CA1, however, most of the GABAergic neurons are concentrated at the border of stratum radiatum with stratum lacunosum-moleculare and within the deep portion of the pyramidal cell layer. There is also a higher density of GABAergic neurons in the distal portion of CA1 than in proximal parts. In stratum lacunosum-moleculare, most GABAergic cells are multipolar with a spheroidal cell body. A heterogeneous population of GABAergic neurons is observed in stratum radiatum, consisting of fusiform neurons, irregular shaped multipolar neurons, pyramidal shaped cells and spheroidal/multipolar neurons. The fusiform neurons have cell bodies that are oriented perpendicular to the pyramidal cell layer. Their long, beaded dendrites extended into the pyramidal cell layer and often enter stratum lacunosum-moleculare. Many medium size to large multipolar cells are also seen in the stratum radiatum. Pyramidal-shaped and modified pyramidal cells are also common. The multipolar cells have smooth as well as beaded dendrites, with apical dendrites that sometimes extend into stratum lacunosum-moleculare and basal dendrites that extend into the pyramidal cell layer. Large fusiform cells and large multipolar cells occur at the border of stratum radiatum and stratum lacunosum-moleculare. The population of GABAergic neurons in the pyramidal cell layer is also diverse. They include a variety of multipolar cells, pyramidal shaped cells and fusiform cells. The stellate cell resembles the chandelier cell described by Somogyi et al. (1983). There are slightly more GABAergic neurons in stratum oriens of CA1 than in CA3 and CA2. Most of these neurons are large, horizontally oriented fusiform cells that have very long dendrites oriented parallel to the alveus These neurons resemble the large somatostatin-positive fusiform neurons that have been described by Bakst et al. (1985). GABAergic neurons were very rarely seen in the alveus.

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7.3.3. GABAergic receptors

Ch. IV Figure 10 C2

The human hippocampus contains a high density of GABAA and GABAB receptors. The GABAA receptors outnumber the GABAB receptors by approximately 3 to 1. The receptors were densest in the pyramidal cell layer. With the higher spatial and cellular resolution afforded by immunohistochemistry, Houser et al. (1988) found that the GABAA receptor was distributed most heavily to the CA1 field and then progressively less densely to CA2 and CA3. Moderate densities of varicose labeling are observed in the pyramidal cell layer and in strata oriens and radiatum and was lower in stratum lacunosum-moleculare. While pyramidal cells in CA3 are not obviously labeled, pyramidal cells in CA2, CA1 and the subiculum are labeled. Interestingly, receptor immunohistochemistry reveals numerous nonpyramidal cells throughout all fields of the dentate gyrus, hippocampus and subiculum. The receptor labeling stains the cells in a Golgi-like fashion. Why these presumably GABAergic interneurons should have such a robust distribution of GABAA receptors is currently unclear. 7.4. MONOAMINES

7.4.1. Noradrenaline

Figures IODI &2

DBH-immunoreactive fibers are found in all layers of the monkey (Samson et al. 1990) and human (Powers et al. 1988) hippocampus. In the human, immunoreactive punctate fibers are most prominent in the intrahilar portion of CA3, decrease in density towards CA2 and reach their lowest levels in CA1 (Powers et al. 1988). DBH-labeled varicosities are most dense in the pyramidal cell layer where they contact the somata and proximal dendrites of pyramidal cells. In the monkey, the regional distribution of noradrenergic fibers is reported to be rather homogeneous. a l-adrenergic receptors are located throughout the human (Biegon et al. 1982) and marmoset (Kraemer et al. 1995) hippocampus. In the marmoset, the density is highest in strata lacunosum-moleculare and radiatum. In contrast to the dentate molecular layer, CA3 contains more a l A receptors than alB (Hoyer et al. 1990; Zilles et al. 1991). 13-adrenergic receptors are also observed in the baboon hippocampus (Slesinger et al. 1988). [31-receptors are predominant in CA1 while [32-receptors are more frequently found in CA3.

7.4.2. Dopamine

Figures lOD3&4

TH-immunoreactive fibers are distributed throughout the human (Gaspar et al. 1987; 1989; Torack and Morris 1990) and monkey (Samson et al. 1990) hippocampus. In the human, dopaminergic fibers are more numerous in CA3 than in CA1 (Torack and Morris 1990); this difference is not as apparent in the macaque monkey (Samson et al. 1990). The density of dopaminergic fibers is heavier in stratum lacunosum-moleculare than in other layers of both CA1 and CA3; other layers contain moderate densities of TH-labeled fibers. D1 and D5 receptors are located on hippocampal pyramidal cell bodies and dendrites in the rhesus monkey (Bergson et al. 1995). D2 receptors are also distributed throughout the hippocampus both in the monkey (K6hler et al. 1991) and in the human (Camps et al. 1989; Goldsmith and Joyce 1994).

359

Ch. I V 7.4.3. Serotonin

Y. Kobayashi and D.G. Amaral Figures 10D5&6

5-HT immunoreactive axons and terminals are found throughout the macaque monkey hippocampus (Ihara et al. 1988; Wilson and Molliver 1991). Serotonin fibers are densest in stratum lacunosum-moleculare and moderately dense in stratum radiatum. Serotonin fibers are less numerous in the pyramidal cell layer and in stratum oriens. In the marmoset, Hornung et al. (1990) observed 5-HT immunoreactive axons with sparse, small, ovoid varicosities in all layers of the CA3 field and immunoreactive axons with large spheroidal varicosities only in the pyramidal cell layer and stratum radiatum (Hornung et al. 1990). We are not aware of any studies of serotonergic fibers in the human hippocampus. Both 5-HT~ receptors and 5-HT2 receptors are distributed throughout the human (Biegon et al. 1982; Hoyer et al. 1986a, b; Pazos et al. 1987a, b) and marmoset (Kraemer et al. 1995) hippocampus. 5-HT1A receptors are much denser in CA1 than in CA3, whereas 5-HT~c receptors are equally dense in these areas (Hoyer et al. 1986a, b; Pazos et al. 1987a). 5-HTlB receptors have not beendetected in the human hippocampus (Hoyer et al. 1986a). 7.5. PEPTIDES 7.5.1. Substance P

Figure IOE1

SP-immunoreactive fibers are distributed throughout the hippocampus in the monkey (Iritani et al. 1989; Nitsch and Leranth 1994) and the human (Del Fiacco et al. 1987; Sakamoto et al. 1987; Del Fiacco and Quartu 1989). The heaviest plexuses of SPimmunoreactive fibers are located in the stratum lacunosum-moleculare of all subdivisions of the hippocampus (heavier in CA1) and in the pyramidal cell layer of CA2. SPimmunostained cell bodies are mostly confined to stratum oriens and to the deepest part of the pyramidal cell layer. Immunoreactive fibers in the human stratum lacunosum-moleculare are apparent in the fetus, whereas labeled fibers in the pyramidal cell layer only become identifiable in the neonate (Del Fiacco and Quartu 1989; Del Fiacco et al. 1990) and the density of fibers increases in the adult brain. Labeled fibers in the CA2 pyramidal cell layer establish asymmetrical synapses. These fibers originate from SP containing neurons in the supramammillary nucleus and decrease in number after a fimbria-fornix transection (Nitsch and Leranth 1994). Substance P-immunoreactive fibers also form asymmetric synapses with calbindin immunoreactive neurons in stratum lacunosum-moleculare of CA3 (Leranth and Nitsch 1994). 7.5.2. Cholecystokinin

Figure lOE2

In the human, CCK-immunoreactive nerve cells and fibers are found in all layers and subdivisions of the hippocampus (Lotstra and Vanderhaeghen 1987). In CA3/CA2, CCK-immunoreactive fibers are densest in the pyramidal cell layer and in stratum oriens. In CA1, the densest fiber plexus is observed in stratum lacunosum-moleculare and stratum radiatum. The plexus in CA1 is particularly dense at the border with the subiculum. It is difficult to determine from published data the relative densities of CCK-immunolabeled cell bodies in the different fields and layers of the hippocampus. It does appear that within stratum lacunosum-moleculare, there may be a greater number of CCK-immunoreactive neurons in CA3/CA2 than in CA1. Within the pyr360

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amidal cell layer, CCK-immunoreactive cell bodies are located mainly in its deepest part and are more numerous in CA3 and CA2 than in CA1. No pyramidal cells are CCK-immunoreactive. Using electron microscopy, Leranth et al. (1988) analysed CCK-immunoreactive terminals in the hippocampus of the rat and monkey. In both species, CCK-immunoreactive terminals establish symmetric synapses on cell bodies and dendritic shafts. In the monkey, CCK-positive terminals also form asymmetric synapses on dendritic spines, whereas such synapses are not observed in the rat. 7.5.3. Neurotensin

Figure lOE3

NT-immunoreactive fibers have been observed in CA3 of the human hippocampus (Mai et al. 1987; Gaspar et al. 1990); however, their distribution has not been thoroughly studied. 7.5.4. Somatostatin

Figure l OE4

In the monkey, SS-immunoreactivity is found in all subdivisions of the hippocampus (Bakst et al. 1985). As in the polymorphic layer of the dentate gyrus, SS-immunoreactivity is denser at rostral levels of the hippocampus than at caudal levels. Stratum lacunosum-moleculare has the highest density of SS-immunoreactive fibers. The plexus of fibers is denser in CA1 than in CA3. Stratum radiatum and the pyramidal cell layer contain relatively few immunolabeled fibers whereas there are numerous SS-immunoreactive fibers in stratum oriens. SS-immunoreactive cell bodies are most numerous in and around CA2, less numerous in CA3 and rarest in CA1. In CA3 and CA2, labeled cell bodies are located primarily in stratum oriens and within the pyramidal cell layer but some stained cell bodies are also found in other layers. In CA1, most of the stained cells are located in stratum oriens. In the human, SS-immunoreactivity shows a similar distribution to that in the monkey. Labeled fibers are densest in stratum lacunosum-moleculare (Bouras et al. 1987), while SS-positive cell bodies are preferentially distributed in stratum oriens and the pyramidal cell layer (Chan-Palay 1987; 1989; Dournaud et al. 1994). It is currently thought that there are five subtypes of somatostatin receptors (sstl-5). In situ hybridization demonstrates that some neurons in the intrahilar portion of CA3 express several of the subtypes of the somatostatin receptors (Schindler et al. 1995). 7.5.5. Neuropeptide Y

Figure lOE5

In the monkey, NPY-immunoreactive multipolar cell bodies are found in the intrahilar portion of CA3 (Nitsch and Leranth 1991) and in stratum oriens of CA3-CA1 (K6hler et al. 1986). Labeled fibers are densest in stratum lacunosum-moleculare and are moderately dense in stratum oriens. Only a few labeled fibers are found in stratum radiatum and within the pyramidal cell layer. In the human, the number of NPY-positive cell bodies is higher in CA1 than in CA2 and CA3 (Chan-Palay et al. 1986; Lotstra et al. 1989). Labeled cell bodies are chiefly located in stratum oriens and in the superficial portion of the pyramidal cell layer. A few labeled cell bodies are also found in stratum radiatum and the alveus. Immunoreactive fibers are distributed in all the layers of the hippocampus. As in the monkey, 361

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stained fibers are densest in stratum lacunosum-moleculare in CA3 and CA2. In CA1, stratum oriens shows the highest density of NPY immunoreactive fibers. NPY is colocalized in some of the SS-positive cell bodies in CA1 (Chan-Palay 1989)

7.5.6. Opioid peptides In the human hippocampus, a few enkephalin-immunoreactive cell bodies of various shapes are observed in the pyramidal cell layer and in stratum oriens of CA1 and CA2 (Sakamoto et al. 1987). As in the dentate gyrus, dynorphin A-immunohistochemistry labels the large expansions of the mossy fibers and thus the stratum lucidum is heavily dynorphin-positive (Houser et al. 1990).

7.5.7. Galanin In the human CA3 region, galanin-immunoreactive fibers are located in the pyramidal cell layer (Gentleman et al. 1989); no galanin fiber immunoreactivity has been noted for any other portion of the hippocampus. In the CA1 region of the monkey hippocampus, galanin binding sites are located chiefly in the pyramidal cell layer. CA3-1 pyramidal cells express mRNA for preprogalanin, a precursor of galanin (Evans et al. 1992). In the human hippocampus, the pyramidal cell layer demonstrates the highest density of galanin binding sites but binding is also seen in other layers (K6hler 1989; Rodriguez-Puertas et al. 1997). 7.6. CALCIUM-BINDING PROTEINS

7.6.1. Parvalbumin

Figure IOF1

The distribution of parvalbumin-immunoreative cells and fibers in the hippocampus has been analysed both in the monkey (Seress et al. 1991; Sloviter et al. 1991; Leranth and Ribak 1991; Pitk~inen and Amaral 1993) and in the human (Ohshima et al. 1991; Sloviter et al. 1991 ; Braak et al. 1991 ; Seress et al. 1993a; Brady and Mufson 1997) brains. 7. 6.1.1. Distribution of parvalbumin-positive fibers CA3 and CA2 The highest level of parvalbumin fiber and terminal labeling is observed in the pyramidal cell layer of the hippocampus. CA3 cells located deep in the hilus of the dentate gyrus demonstrate a light plexus of pericellular terminal labeling and the terminal density increases through more distal levels of CA3 and reaches a peak in CA2; CA2 consistently has the highest level of pericellular fiber and terminal labeling (Leranth and Ribak 1991 ; Pitk~inen and Amaral 1993). Leranth and Ribak (1991) have evaluated parvalbumin-immunoreactive terminals in the CA2 region of the African green monkey. They found that most of the symmetrical synapses that are formed on the CA2 pyramidal cell bodies are parvalbumin-positive. Parvalbumin-positive terminals are also observed on dendrites and axon initial segments. The terminal plexus in the pyramidal cell layer of CA3 is interrupted by bundles of mossy fibers that travel through the layer. There is also a decreased staining of the most superficial row of CA3/CA2 pyramidal cells. There is a lower level of terminal 362

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labeling within stratum oriens and very few labeled fibers or terminals are located in stratum lucidum. In stratum radiatum of CA3, and to a greater extent in CA2, a light to moderate level of terminal labeling is found mainly in the deep half of the layer. There is a marked increase in the density of parvalbumin immunoreactivity in stratum lacunosum-moleculare. This consisted both of labeled fibers and terminals as well as thin terminal dendritic branches originating from the parvalbumin-labeled cells located in the pyramidal cell layer and stratum oriens.

CA1 In CA1, the density of pericellular parvalbumin staining in the pyramidal cell layer is substantially lower than in CA3 or CA2. There is also far less staining within stratum oriens and stratum radiatum. Moreover, the conspicuous band of staining located in stratum lacunosum-moleculare of CA3 and CA2 is absent in CA1. 7.6.1.2. Distribution of parvalbumin-positive cell bodies CA3 and CA2 Parvalbumin-immunoreactive cells in the hippocampus are located primarily in stratum oriens and in the pyramidal cell layer. Cells are almost never seen in stratum radiatum or stratum lacunosum-moleculare (Seress et al. 1991; Pitk/inen and Amaral 1993). In the CA3 and CA2 fields, labeled neurons are located mainly in the pyramidal cell layer. Many of the cells have large cell bodies which are pyramidal or multipolar in shape and have prominent apical and basal dendrites. The apical dendrites extend through stratum radiatum and ramify within the stratum lacunosum-moleculare. Dendritic segments in this region are quite thin and wavy. Most of the dendrites in stratum radiatum are aspiny and beaded. The number of parvalbumin-immunoreactive cells situated in the pyramidal cell layer increases in a gradual fashion from the lowest level in the hilar portion of CA3 to the highest level in the CA2 field. There are several other types of parvalbumin-immunoreactive neurons in CA3 and CA2. Many of these are located in the deep portion of the pyramidal cell layer and in stratum oriens. They consist of various categories of neurons ranging from larger multipolar cells with long dendrites ascending into stratum radiatum and descending into stratum oriens, to fusiform cells with long dendrites more or less confined to stratum oriens, to small spherical and multipolar cells with relatively short, dendrites. The dendrites of the larger of these cells tend to be aspiny but occasional, apparently stubby spines are observed on proximal dendrites. Many of these neurons demonstrate highly beaded dendrites. CA1 There are several differences in the distribution and types of parvalbumin-immunoreactive neurons in CA1 relative to CA2 and CA3. Parvalbumin-positive neurons tend to be situated either in the deepest portion of the pyramidal cell layer or in stratum oriens rather than in the main portion of the pyramidal cell layer, as in CA2/CA3. More of the labeled cells tend to be fusiform-shaped in CA1 and to have their major dendrites confined to stratum oriens or to the deep portion of the pyramidal cell layer. Thus, there are far fewer parvalbumin-labeled dendrites located in stratum radiatum and stratum lacunosum-moleculare. Parvalbumin-positive cells are most numerous in the proximal portion of CA1 and they often form large clusters. Cells in proximal CA1 are more commonly of the 363

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pyramidal cell type and their cell bodies are scattered throughout the depth of the pyramidal cell layer. The overall density of parvalbumin-labeled cells increases in the caudal portion of the monkey hippocampus and the density of cells in the proximal portion of CA1 at these levels approximates that observed in CA2. The labeled cells in this region are large and have prominent apical and basal dendrites. The apical dendrites are generally aspiny, beaded and enter stratum radiatum and stratum lacunosum-moleculare. Most of the other parvalbumin cells in CA1 are located in stratum oriens or in the deepest portion of the pyramidal cell layer. These cells are often quite large; many are as large or larger than any other parvalbumin-positive cells in the hippocampal formation. Some of these cells are fusiform or multipolar in shape and they have varicose dendrites that extend for long distances in stratum oriens. Some of the dendrites of these cells bend sharply to cross the pyramidal cell layer and enter stratum radiatum. In addition to the large fusiform cells in stratum oriens, there are several other forms of cells either in stratum oriens or in the pyramidal cell layer. In the mid to distal portions of CA1, cells located in the pyramidal cell layer tend to be substantially smaller than in the proximal CA1. Often these cells are fusiform or stellate in shape and have several, thin, beaded dendrites that enter stratum radiatum. Small pyramidalshaped cells are also common, especially in the superficial portion of the pyramidal cell layer. The distribution of parvalbumin-immunoreactive neurons in the human hippocampus is quite similar to that described above for the macaque monkey (Brady and Mufson 1997) One potential difference is in the finding that the human stratum lacunosum-moleculare has no staining. This is in sharp contrast to the dense staining observed in the CA3/CA2 regions in several nonhuman primate species. 7.6.2. Calbindin

Figure lOF2

In the monkey, many of the pyramidal cells of CA2 and CA1 are immunopositive for calbindin D2sK whereas CA3 pyramidal cells are not (Seress et al. 1992 1993a 1994).There are also rare calbindin DZ8K positive neurons located mainly in stratum oriens. Most of the positive neurons in stratum oriens are large cells with long dendrites running parallel to the layer. Most of the cells located in other layers are small with thin, varicose dendrites. Despite the fact that the CA3 pyramidal cells are not labeled, there is a higher density of nonpyramidal cells that are positive for calbindin DzgK. Hornung and Celio (1992) have made the interesting observation that calbindin D28K positive cells in the dentate gyrus and hippocampus are preferentially innervated by serotonergic fibers that originate in the raphe nuclei. This feature distinguishes the calbindin D2aK interneurons from parvalbumin interneurons. Seress et al. (1993a) have evaluated the distribution of calbindin DZ8K cells and fibers in the human hippocampal formation and came to the conclusion that it is remarkably similar to that of the nonhuman primate. Sloviter et al. (1991) had initially claimed that unlike the rat and the baboon, the human hippocampus has a unique calbindin DZSK staining pattern. They suggested that the CA1 pyramidal neurons were not calbindin DzsK-positive and suggested that this may be one component of the greater vulnerability to ischemia of CA 1 pyramidal cells. However, Seress et al. (1991 ; 1993a) have clearly demonstrated that human CA1 pyramidal cells are indeed calbindin DzaK-positive.

364

The hippocampal formation and perirhinal and parahippocampal cortices 7.6.3. Calretinin

Ch. IV Figure l OF3

The vast majority of calretinin-positive neurons are interneurons located in strata radiatum and lacunosum-moleculare (Seress et al. 1993b; Nitsch and Ohm 1995). The cells have small, fusiform cell bodies with dendritic plumes oriented perpendicular to the pyramidal cell layer or hippocampal fissure. The population of calretinin cells in the hippocampus is remarkably homogeneous. Calretinin-positive fibers and terminals are lightly and diffusely distributed throughout all layers of the hippocampus. The density of fibers is substantially higher in the CA2 region and represents the projection that originates in the supramammillary region of the hypothalamus. 7.7. HORMONE RECEPTOR SITES The human hippocampus demonstrates mRNAs for both glucocorticoid and mineralocorticoid receptors (Seckl et al. 1991).The CA3 cells show the highest expression of RNAs for both receptors, followed by CA2, and CA1 had the lowest density. Interestingly, this is quite different from the rat hippocampus where the mineralocorticoid receptor is expressed at similar levels in all hippocampal fields and the glucocorticoid receptor is more heavily expressed in CA1. The tree shrew hippocampus also demonstrates binding of [3H]corticosterone and mRNA for the glucocorticoid receptor (Fltigge et al. 1988; J6hren et al. 1994). Autoradiographic data indicate that pyramidal cells in the rhesus monkey hippocampus concentrate [3H]corticosterone (Gerlach et al. 1976). There is virtually no evidence of TRH binding sites in any portion of the hippocampus (Eymin et al. 1993). The hippocampus of the rhesus monkey demonstrates androgen binding (Clark et al. 1988) and immunohistochemistry has detected androgen receptors in the pyramidal cell layer of the monkey hippocampus (Clancy et al. 1992). Weak insulin-like immunoreactivity is observed in pyramidal cells throughout the hippocampus and occasional labeled cells are observed close to the alveus (Dorn et al. 1982). 7.8. ENZYMES 7.8.1. Cytochrome oxidase

Figure lOG1

In the monkey hippocampus, cytochrome oxidase (CO) activity is very high in the superficial part of stratum lacunosum-moleculare of CA1-3 and in the pyramidal cell layer of CA3 (Kageyama and Wong-Riley 1982; Hevner and Wong-Riley 1991; Chandrasekaran et al. 1992). For CA3 pyramidal neurons, both cell bodies and distal apical dendrites show strong CO reactivity, while CA1 pyramidal neurons display high COactivity only in the distal part of their apical dendrites. There are also some interneurons demonstrating strong CO-activity both deep to, and superficial to, the pyramidal cell layer. In addition to the CO-enriched areas revealed by histochemistry, immunostaining also shows a dense accumulation of CO in the CA1 pyramidal cell layer (Hevner and Wong-Riley 1991). As in the dentate gyrus, mitochondrial DNA has an overlapping distribution with the CO activity, while mRNA of CO subunits is more confined to the pyramidal cell bodies of CA1-3. 365

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Ch. IV 7.8.2. Nitric oxide synthase and NADPH-diaphorase

Figures lOG2&3

In the human hippocampus, both NOS-immunoreactivity and NADPH-d activity are found in a subpopulation of the pyramidal cells (Egberongbe et al. 1994; Sobreviela and Mufson 1995; Doyle and Slater 1997). NADPH-d positive cell bodies are also located in stratum radiatum and the alveus (Mufson et al. 1990; Sobreviela and Mufson 1995). NADPH-d-reactive fibers, which are distributed in all layers, are denser in CA1 than in CA2-3. Stratum lacunosum-moleculare and the pyramidal cell layer show somewhat heavier distributions of NADPH-d-reactive fibers.

7.8.3. Other enzymes Phosphatase inhibitor 1 is located in the mossy fiber terminals in the stratum lucidum in the monkey CA3 (Barbas et al. 1993). 7.9. TROPHIC FACTORS

7.9.1. Nerve growth factor Nerve growth of the mossy appears to be resembles the

Figures I OH1 &2

factor immunoreactivity is associated with the large terminal expansions fiber axons (Mufson et al. 1994). Immunoreactivity for N G F receptor more diffusely distributed throughout stratum oriens and radiatum and distribution of cholinergic fibers (Kerwin et al. 1991).

7.9.2. Ciliary neurotrophic factor Virtually all neurons in the pyramidal cell layer of the Cebus apella monkey stain positively for CNTF. Labeled neurons are also apparent in the other hippocampal layers (Kordower et al. 1997).

7.9.3. Brain-derived neurotrophic factor Low levels of hybridization for probes to BDNF are observed in CA3 of the human brain (Murray et al. 1994). Only the most proximal portion of CA1 demonstrates any positive pyramidal cells.

8. SUBICULUM 8.1. GLUTAMATE SYSTEM

8.1.1. Glutamate While the pyramidal cells of the primate subiculum presumably use an excitatory amino acid as their primary transmitter, there is currently no experimental data in support of this. In their study of glutamate immunoreactivity in the baboon, Ottersen and Storm-Mathisen (1985) did not comment on the appearance of the subiculum. In the same paper they did report, however, that subicular neurons are immunoreactive for aspartate. 366

The hippocampal formation and perirhinal and parahippocampal cortices

8.1.2. NMDA receptors

Ch. IV Figure l OA2

In the human (Jansen et al. 1989a; Ulas et al. 1992), binding sites of ligands to NMDA receptors are moderately dense in the subiculum. In the monkey subiculum, pyramidal cell bodies are intensely labeled with a monoclonal antibody against NMDA receptor subunit 1 (Siegel et al. 1994; 1995).

8.1.3. AMPA-kainate receptors

Figures 10A3&4

In the human subiculum, both AMPA and kainate binding sites are moderately dense in the pyramidal cell layer, relatively sparse in the molecular layer and layer III (Geddes et al. 1992). In the human (Hyman et al. 1994; Ikonomovic et al. 1995a, b), GluRl-immunoreactivity is relatively low in the subiculum. Pyramidal cells are lightly immunoreactive for GluR1 and the neuropil shows weak immunoreactivity. In contrast to GluR1, subicular pyramidal cell bodies and neuropil show fairly high GluR2/3-immunoreactivity (Hyman et al. 1994; Blfimcke et al. 1995; Ikonomovic et al. 1995a, b). In situ hybridization studies indicate that AMPA/kainate receptor messenger RNA is expressed by human subicular pyramidal cells (Harrison et al. 1990).

8.1.4. Metabotropic glutamate receptors An in situ hybridization study (Lin et al. 1997) shows moderately high expression of mGluR1 mRNA in the human subiculum.

8.1.5. Aspartate Many pyramidal neurons show aspartate-immunoreactivity (Ottersen and StormMathisen 1985). They are much more darkly stained, in fact, than the weakly immunoreactive pyramidal neurons in the hippocampus. 8.2. CHOLINERGIC SYSTEM

8.2.1. Cholinergic fiber systems

Figures IOBI&2

The density of ChAT-labeled fibers in the subiculum is intermediate between the low density in CA1 and the relatively high density of the presubiculum. At the border region with CA1, there is a slight increase in the density of immunoreactive fibers and terminals. Throughout the subiculum, ChAT fiber labeling is densest in the molecular layer. This labeling is continuous with the plexus of fibers located in stratum lacunosum-moleculare of CA1. The density of this labeling is higher, however, than in CA1. There is a moderate density of ChAT-labeled fibers in the subicular pyramidal cell layer. The density of ChAT-labeled fibers increases somewhat in the region just deep to the pyramidal cell layer. The density of AChE-labeled fibers is somewhat lower in the subiculum than in CA1. However, as in ChAT preparations, AChE-stained material shows an increased staining at the border between CA1 and the subiculum. This distinctive border is much more apparent in AChE stained material than in ChAT preparations. In contrast to the ChAT preparations where no labeled cells are observed, there are numerous AChE positive cells in the subiculum, particularly just below the pyramidal cell layer. 367

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De Lacalle et al. (1994) reported that the human subiculum has very low levels of ChAT fiber staining and this increases only slightly in the presubiculum. If replicated, this would provide a substantial species difference between the macaque monkey and the human subiculum.

8.2.2. Cholinergic receptors

Figure lOB3

In the monkey, both M1 and M2 muscarinic receptors are observed in the subiculum (Mash et al. 1988; Miyoshi et al. 1989). The highest density of these receptors occurs at the border of CA1 with the subiculum and the more medial portions of the subiculum have rather low levels of muscarinic receptor. In the human, Cort6s et al. (1987) observed both M1 and M2 receptors in the subiculum. The density is lower than in CA1 of the hippocampus but higher than in the presubiculum. The human subiculum contains a very high density of nicotinic cholinergic receptors (Rubboli et al. 1994; Court et al. 1997). Labeling for et3, ct7 and 132 receptor subunits is similar in the subiculum. 8.3. GABAergic SYSTEM

Figure IOC1

8.3.1. Fiber innervation The density of labeled fibers and terminals increases markedly in the pyramidal cell layer of the subiculum relative to CA1. This change in GABAergic fiber density clearly demarcates the oblique border of CA1 with the subiculum. In the molecular layer, there is a slightly lower density of labeled fibers but the fibers are more varicose than in other layers.

8.3.2. GABAergic cell bodies The density of GABA-immunoreactive neurons in the subiculum is among the highest in the hippocampal formation. About the same density of GABAergic neurons are observed in the molecular and pyramidal cell layers. Most of the numerous GABAergic neurons in the molecular layer of the subiculum have small, spherical cell bodies and are darkly immunoreactive. In the pyramidal cell layer, GABAergic neurons are distributed in two broad, obliquely oriented bands that are located in the superficial and deep thirds. In the deep one third, a variety of immunoreactive cell types is observed including multipolar cells and fusiform cells. In the superficial third of the pyramidal cell layer, most labeled neurons have small, spherical cell bodies that are darkly stained. Occasionally, large multipolar and fusiform GABAergic neurons are seen in the superficial portion of the pyramidal cell layer. At the border of CA1 with the subiculum, many of the GABAergic neurons are large multipolar and stellate cells.

8.3.3. GABAergic receptors

Figure 10C2

Houser et al. (1988) reported that subicular pyramidal cells demonstrate a high density of GABAA immunohistochemical reaction product along their apical dendrites.

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Ch. IV

8.4. MONOAMINES 8.4.1. Noradrenaline

Figures 10D1 &2

In the subiculum of the macaque monkey, DBH-immunoreactive fibers are slightly more numerous in the molecular layer and in layer III than in the pyramidal cell layer (Samson et al. 1990). In the human subiculum, however, DBH-immunostained fibers are reported to be most densely distributed in the pyramidal cell layer (Powers et al. 1988). a l-adrenoceptors are present in the subiculum but at a much lower density than in the dentate gyrus and hippocampus (Biegon et al. 1982). 8.4.2. Dopamine

Figures lOD3&4

TH-immunoreactive fibers are found both in the monkey (Samson et al. 1990) and human (Torack and Morris 1990) subiculum. The dopamine fibers are distributed similar to noradrenergic fibers but the density in the molecular layer is higher than in layer III (Samson et al. 1990). Dopamine D2 receptors are detected in the subiculum of the monkey and human (K6hler et al. 1991; Goldsmith and Joyce 1994). Rostral levels of the subiculum demonstrate the highest density of D2 receptors of any field of the hippocampal formation (Goldsmith and Joyce 1994). 8.4.3. Serotonin

No data are available concerning the distribution of 5-HT immunoreactive fibers and terminals in the primate subiculum. 8.5. PEPTIDES 8.5.1. Substance P

Figure IOE1

Substance P-immunoreactive fibers are located mainly in the molecular layer of the subiculum in both monkey and human (Del Fiacco et al. 1987; Del Fiacco and Quartu 1989; Iritani et al. 1989). 8.5.2. Cholecystokinin

Figure lOE2

Cholecystokinin-immunoreactive thin fibers and varicosities are chiefly distributed in the superficial portion of the subicular pyramidal cell layer (Lotstra and Vanderhae' ghen 1987). Large beaded fibers run perpendicularly throughout the whole thickness of the pyramidal cell layer and are also located in layer III. CCK-immunolabeled cell bodies are located in the pyramidal cell layer. 8.5.3. Neurotensin

Figure lOE3

In the human, the majority of subicular pyramidal neurons are positive for neurotensin (NT) immunoreactivity (Sakamoto et al. 1986; Gaspar et al. 1990). The subiculum also contains a dense meshwork of NT-labeled fibers that are located chiefly in the pyramidal cell layer.

369

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8.5.4. Somatostatin

Y. Kobayashi and D.G. Amaral Figure lOE4

In the monkey (Bakst et al. 1985), the pyramidal cell layer of the subiculum essentially lacks SS-positive fibers which is in clear contrast to the border region between CA1 and the subiculum where there is heavy fiber labeling. The molecular layer an.d layer III of the subiculum shows a fairly high density of labeled fibers. Labeled cell bodies are relatively few compared to the border region between CA1 and the subiculum. SS immunoreactive cell bodies are located in the pyramidal cell layer and in the immediately subjacent layer III. An in situ hybridization study also demonstrates somatostatin mRNA containing cell bodies in the pyramidal cell layer and layer III of the human subiculum (Dournaud et al. 1994). As in CA1, some of the subicular SS-positive neurons colocalize NPY in the human (Chan-Palay 1989).

8.5.5. Neuropeptide Y

Figure lOE5

In the monkey subiculum, NPY-immunoreactive fibers are distributed in all the layers (K6hler et al. 1986). Labeled cell bodies are located in the pyramidal cell layer and layer III. The human subiculum shows a similar distribution of NPY-immunoreactivity (Chan-Palay et al. 1986, 1989; Lotstra et al. 1989). Labeled fibers are dense in the molecular layer, moderately dense in the pyramidal cell layer, and sparse in layer III.

8.5.6. Opioid peptides Enkephalin-immunoreactive cell bodies are located in the human subiculum (Sakamoto et al. 1987). Labeled neurons are heterogeneous in size and shape and are located both in the pyramidal cell layer and in layer III.

8.5.7. Galanin In the macaque monkey, in situ hybridization for the mRNA of preprogalanin demonstrates expression in subicular pyramidal cells (Evans et al. 1992). A receptor autoradiographic study shows that the human subiculum contains a fairly high density of galanin-binding sites (K6hler 1989; Rodriguez-Puertas et al. 1997), whereas the monkey subiculum shows no galanin binding sites (K6hler 1989). The reason for this discrepancy is not clear. 8.6. CALCIUM-BINDING PROTEINS

8.6.1. Parvalbumin

Figure IOF1

8. 6.1.1. Distribution of parvalbumin-positive fibers There is a striking increase both in the density of fibers and terminals and in the number of parvalbumin-immunoreactive cells in the subiculum relative to CA1. The pyramidal cell layer of the subiculum contains a moderately dense plexus of parvalbumin-immunoreactive fibers and terminals that provide a clear-cut indication of the oblique border with CA1. The border of the CA1 and subiculum show staining characteristics different from either the subiculum or CA1. In the parvalbumin preparations, this region stains even more intensely for parvalbumin fibers and terminals than 370

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Ch. IV

the rest of the subiculum. The band of more intense staining is broadest at the border of the CA1 and subiculum but continues medially within the superficial portion of the subicular pyramidal cell layer and covers the entire transverse extent of the subiculum. There are few labeled fibers and terminals in the molecular layer of the subiculum. The human subiculum appears to be characterized by a dense plexus of parvalbuminimmunoreative fibers within the pyramidal cell layer and subjacent layer III (Brady and Mufson 1997).

8. 6.1.2. Distribution of parvalbumin-positive cells The density of parvalbumin-immunoreactive neurons is substantially higher in the subiculum than in any portion of CA1. Most of the labeled neurons are scattered throughout the pyramidal cell layer though an occasional cell is located in the molecular layer. The density of labeled neurons is somewhat higher in the region of increased fiber and terminal labeling that makes up the lateral and superficial portions of the pyramidal cell layer. This is particularly apparent in the portion of the subiculum located deep to the distal CA1 pyramidal cell layer. The subiculum demonstrates a variety of parvalbumin-positive cell types. In general, the cells in the subiculum tend to be smaller, rounder and have shorter visible dendritic segments than cells in CA1. The largest pyramidal and multipolar cells are typically smaller than the largest cells in CA1 and the subicular cells generally stain somewhat more darkly. As in other portions of the hippocampal formation, the dendrites of the stained neurons either have few or no apparent spines. Many of the stained neurons have a pyramidal shape with apical and basal dendrites. Other cells are either fusiform, multipolar, triangular or spheroidal and most have thin dendrites; some of the dendrites are beady. In the proximal portion of the subiculum, the various sizes and shapes of labeled neurons are mixed together. At distal levels of the subiculum, however, the larger cells are located more superficially in the pyramidal cell layer than the smaller cells. The majority of the visible parvalbumin-immunoreactive dendrites appeared to remain within the pyramidal cell layer. This is particularly true of parvalbumin immunoreactive cells located deep in the pyramidal cell layer that are often fusiform-shaped with dendrites oriented parallel to the cell layer. Many of the cells located deep in the layer are small, spheroidal cells that have only a few, short dendrites. There are a few parvalbumin-immunoreactive cells located in the molecular layer of the subiculum. These tend to be small, round cells with a stellate dendritic plexus. 8.6.2. Calbindin

Figure l OF2

The subicular pyramidal cells are not immunopositive for calbindin D28K. Moreover, calbindin DZ8K positive interneurons are also rare in the subiculum (Seress et al. 1994). Calbindin DZ8K immunoreactive fibers and terminals are more abundant in the molecular layer than in the pyramidal cell layer (Seress et al. 1994). 8.6.3. Calretinin

Figure lOF3

Calretinin-positive neurons are observed in the subiculum. As in CA1, the cells are preferentially located in the superficial layers. The cell types are similar to those in the hippocampus, i.e., small, fusiform cells. There are occasional larger multipolar cells 371

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located in the pyramidal cell layer. Calretinin fibers and terminals are scattered diffusely throughout the subiculum. 8.7. H O R M O N E RECEPTOR SITES No information is available for adrenal steroid receptors. TRH binding is relatively high in the subiculum which provides a contrast with the hippocampus where there is little or no TRH binding (Eymin et al. 1993). Insulin-like immunoreactivity is high in the subiculum (Dorn et al. 1982). 8.8. ENZYMES

8.8.1. Cytochrome oxidase

Figure lOG1

In the monkey subiculum, CO activity, CO immunoreactivity, mitochondrial DNA, and mRNA for CO subunits are all moderately high in the pyramidal cell layer (Hevner and Wong-Riley 1991). In contrast to stratum lacunosum-moleculare of the hippocampus, the molecular layer of the subiculum shows low levels of CO-markers.

8.8.2. Nitric oxide synthase and NADPH-diaphorase

Figure lOG3

In contrast to the dense accumulation of NADPH-d-positive fibers in CA1, the subiculum shows only a diffuse network of labeled fibers (Sobreviela and Mufson 1995). Labeled cell bodies are chiefly located in the pyramidal cell layer and layer III. 8.9. TROPHIC FACTORS

8.9.1. Nerve growth factor

Figure l OH2

There is currently no published information on the distribution of NGF in the primate subiculum. Kerwin et al. (1991) report that NGF receptor immunoreactivity drops to near background levels in the subiculum.

8.9.2. Ciliary neurotrophic factor Kordower et al. (1997) report that many neurons in the subiculum are immunoreactive for CNTF.

8.9.3. Brain-derived neurotrophic factor Murray et al. (1994) report that there is no detectable level of in situ signal for BDNF mRNA in the subiculum. They note that this is different from findings reported for the rat.

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9. PRESUBICULUM AND PARASUBICULUM 9.1. GLUTAMATE SYSTEM Other than AMPA receptors there are no available data on the distribution of glutamate systems in the primate presubiculum and parasubiculum. 9.1.1. AMPA receptors

Figure lOA3

In the superficial layers of the human presubiculum, there is a dense distribution of GluR1- and GluR2/3-immunoreactive processes; this staining is dense outside the cell islands of layer II and sparse within the cell islands (Ikonomovic et al. 1995a). In the deeper layers, GluRl-positive cell bodies are sparsely distributed, whereas GluR2/3positive cell bodies tend to aggregate into clusters. 9.2. CHOLINERGIC SYSTEM 9.2.1. Cholinergic fiber systems

Figures 10B1 &2

9.2.1.1. Presubiculum The density of ChAT-positive fibers in the presubiculum is substantially higher than in the subiculum but somewhat lower than in the parasubiculum (Alonso and Amaral 1995). The density of labeled fibers is highest in layer II. Layer II can be divided into a thinner superficial region which has the higher density of ChAT-labeled fibers and a thicker, but more lightly innervated, deep region. There are only a few cholinergic fibers in layer I of the presubiculum. As in ChAT immunohistochemistry, layer II of the presubiculum demonstrates a very dense plexus of AChE-labeled fibers that forms deep and superficial sublaminae. While conspicuous patches of labeled fibers are observed in layer I in the AChE preparations, these are not observed in ChAT material. Interestingly, the cholinergic innervation of the presubiculum appears to take a nonfornical route since transection of the fimbria/fornix does not appreciably decrease the density of stained fibers.

9.2.1.2. Parasubiculum The parasubiculum demonstrates one of the highest densities of ChAT labeling in the primate hippocampal formation. All portions of layer II show a very dense and essentially homogeneous network of cholinergic fibers. As in the presubiculum, there are no marked changes in the density of labeled fibers at different rostrocaudal levels of the parasubiculum; cholinergic innervation is uniformly heavy. There are relatively few cholinergic fibers in layer I; most of these have a trajectory that is oriented parallel to the pial border. The density of AChE labeled fibers is also very high in the parasubiculum, particularly in its lateral subdivision. The human parasubiculum demonstrates slightly higher staining than in the presubiculum but no where near the intense labeling observed in the monkey parasubiculum (Alonso and Amaral 1995).

373

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9.2.2. Cholinergic receptors

Y. Kobayashi and D.G. Amaral Figure lOB3

The monkey presubiculum contains low densities of both M1 and M2 muscarinic cholinergic receptors (Mash et al. 1988; Miyoshi et al. 1989). Muscarinic receptors are also low in the human presubiculum (Cort6s et al. 1987). In contrast, the density of nicotinic receptors in the monkey and human presubiculum is very high (Mash et al. 1988; Rubboli et al. 1994; Court et al. 1997). Interestingly, the monkey parasubiculum demonstrates a high density of M2 receptors (Mash et al. 1988) though it still has a relatively low level of M1 receptor. 9.3. GABAergic SYSTEM

Figure IOC1

9.3.1. Fiber innervation The density of labeled fibers and terminals in the presubiculum is higher than in the subiculum. Layer II has a higher density of labeled fibers than layer I but layer I contains a dense, punctate labeling of the neuropil. Interestingly, Babb et al. (1988) found that the presubiculum demonstrates the highest, density of GAD-immunoreactive varicosities in the hippocampal formation. The density is substantially higher than the CA2 region which demonstrates the next highest density of varicosities. The density of labeled fibers and terminals is lower in the parasubiculum than in the presubiculum. Numerous labeled fibers are distributed throughout layers I and II; layer II has a higher density. As in the presubiculum, layer I of the parasubiculum shows a dense punctate neuropil staining. 9.3.2. GABAergic cell bodies The presubiculum, particularly layer II, demonstrates the highest density of GABAergic neurons in the hippocampal formation (Babb et al. 1988; Jongen-R~lo et al. 1999). The majority of these cells resemble the darkly stained, small spheroidal cells found in the molecular layer of the subiculum. Occasionally, large multipolar cells are seen in layer I. In the thicker, medial portion of the presubiculum where layer II is bilaminate, most of the GABAergic neurons are located in the deep half of the layer. The most commonly found GABAergic cell type in layer II is a small to medium size spheroidal, multipolar neuron. In the area deep to layer II, GABAergic cells are generally larger than those in layers I and II. Most of these cells are multipolar and the dendrites of these cells often extend into layer II. Occasionally, vertically oriented fusiform cells are observed deep to layer II. The density of GABAergic neurons in layer II of the parasubiculum was second only to the presubiculum. Within the parasubiculum, the density of labeled neurons in layer II is markedly higher than in layer I. Moreover, the density of labeled neurons in layer I is lower than in layer I of the presubiculum. The types of GABAergic neurons in the parasubiculum are similar to those in the presubiculum. Most of the GABAergic neurons in layer I have a small spherical cell body. The most common GABAergic cell type in layer II is a small, darkly stained spheroidal cell with very thin dendrites. Occasionally, fusiform and multipolar cells are seen in the deeper portions of layer II that have dendrites which extend into more superficial parts of layer II. 374

The hippocampal formation and perirhinal and parahippocampal cortices 9.3.3. GABAergic receptors

Ch. IV Figure 10 C2

The human presubiculum demonstrates a distinctive pattern of immunohistochemical staining for GABAA receptors. The distinctive islands of cells that are located in the superficial "portion of layer II and within layer I are densely immunoreactive for GABAA receptors (Houser et al. 1988). This is compatible with the very high density of GABAergic fibers and terminals observed in this region. 9.4. MONOAMINES

9.4.1. Noradrenaline No published data are available.

9.4.2. Dopamine

Figures lOD3&4

The density of dopaminergic fibers in the presubiculum is as high as in CA3; together these fields contain the highest number of TH-immunoreactive fibers and terminals in the hippocampal formation (Torack and Morris 1990). D2 receptors are distributed throughout the presubiculum (K6hler et al. 1991).

9.4.3. Serotonin No published data are available. 9.5. PEPTIDES

9.5.1. Substance P No published data are available.

9.5.2. Cholecystokinin

Figure lOE2

In the human presubiculum, fine CCK-immunoreactive puncta are observed within layer II (Lotstra and Vanderhaeghen 1987). Thick, beaded fibers are found both in layer II and in the area deep to layer II. Fine CCK-immunoreactive puncta are also densely distributed in layer II and the superficial part of the deep layers of the parasubiculum. Immunolabeled cell bodies are found both in the presubiculum and parasubiculum. They are chiefly distributed in layer II. In the macaque monkey, the presubiculum shows the highest density of CCKB receptors among structures in the hippocampal formation (Mercer et al. 1996).

9.5.3. Neurotensin

Figure lOE3

In the human presubiculum, there is a dense plexus of NT-immunoreactive fibers and terminals within layer II (Gaspar et al. 1990). The presubiculum does not contain immunoreactive cell bodies.

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9.5.4. Somatostatin

Figure lOE4

The monkey presubiculum shows a distinct laminar pattern of SS-immunoreactive fibers (Bakst et al. 1985). Throughout the rostrocaudal extent of the presubiculum, layer I contains a dense plexus of SS-positive fibers. In layer II, the superficial part has a high fiber density and the deeper part has a sparser distribution of labeled fibers. Cell bodies demonstrating SS-immunoreactivity are mainly located deep to layer II. In the parasubiculum, the molecular layer and layer II show high densities of SSpositive fibers. SS-immunoreactive neurons are observed both in and below layer II. Somatostatin and neuropeptide Y coexist in some neurons in the deep layers of the human presubiculum and parasubiculum (Chan-Palay 1989). 9.5.5. Neuropeptide Y

Figure lOE5

In the presubiculum and parasubiculum of the monkey, NPY-immunoreactive fibers are dense in the molecular layer and layer II, and sparse in the deep layers, whereas labeled cell bodies are concentrated in the deep layers (K6hler et al. 1986). 9.5.6. Opioid peptides No published data are available 9.5.7. Galanin

In situ hybridization in the macaque monkey demonstrates that the mRNA of preprogalanin is expressed by neurons located in layer II of the presubiculum (Evans et al. 1992). 9.6. CALCIUM-BINDING PROTEINS 9.6.1. Parvalbumin in the presubiculum

Figure IOF1

9. 6.1.1. Distribution of parvalbumin-immunoreactive fibers Layer II of the presubiculum demonstrates one of the highest densities of parvalbumin immunoreactive fibers and terminals in the hippocampal formation (Pitk/inen and Amaral 1993). The dense terminal plexus coincides with the borders of layer II. Parvalbumin immunoreactive varicosities surround and outline the cell bodies of labeled and unstained neurons. The parvalbumin-staining pattern in layer II differentiates it into two sublaminae. The superficial one-third of the layer has a distinctly lighter density of labeling. As in the monkey, layer II of the human presubiculum demonstrates dense parvalbumin immunoreactivity (Brady and Mufson 1997). This occurs both in the principal cell layer as well as in the circular islands of cells located within layer I.

9. 6.1.2. Distribution of parvalbumOl-immunoreactive cells There are two major parvalbumin cell types in layer II of the presubiculum. The most commonly observed cell is a small, spheroidal cell with few, if any, visible dendrites. 376

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These cells are scattered throughout all portions of the layer. The more distinctive, though less common cell, is about twice the size of the smaller cell with numerous dendrites emerging from the cell body. The soma of these cells are generally spherical or irregular and the dendrites are more numerous at one pole of the cell body giving it an octopus-like appearance. The dendrites are distributed within, above and below layer II. The presubiculum shares the distinction with the parasubiculum of having the greatest number of labeled cells in layer I. These cells are typically very small and spheroidal with a stellate plexus of thin, aspiny dendrites. Occasionally, however, larger multipolar cells are located in layer I. The larger of these cells are located just beneath the pia. Similar small and medium cells are observed mainly deep to layer II in the human presubiculum (Brady and Mufson 1997). 9.6.2. Parvalbumin in the parasubiculum

9. 6.2.1. Distribution of parvalbumin-immunoreactive fibers The density of parvalbumin immunoreactive fibers and terminals in the parasubiculum is somewhat more variable than in the presubiculum. Terminal labeling is heavier in the medial and dorsal portions of the parasubiculum than in the lateral portion. The almost complete lack of staining in the lateral portion of the parasubiculum actually produces a substantial gap that separates the presubiculum from the heavily stained medial portions of the parasubiculum; this gap is more noticeable at more caudal levels of the hippocampal formation. Within the parasubiculum, terminal labeling surrounds the unlabeled cell bodies. As in the presubiculum, there are very few terminals in layer I of the parasubiculum.

9.6.2.2. Distribution of parvalbumin-immunoreactive cells As with the fiber and terminal labeling, the number of parvalbumin labeled cells is higher in the dorsal and medial portions of layer I! of the parasubiculum. The cell types are very similar to those observed in layer II of the presubiculum. Labeled cells are much more common in layer I of the parasubiculum than of the presubiculum. Cells in layer I are typically small spherical cells with several thin, aspiny radiating dendrites. 9.6.3. Calbindin

Figure lOF2

The pyramidal cells of layer II o f the presubiculum are not immunoreactive for calbindin DZ8K. Layer II does contain, however, a fairly high density of calbindin DZ8K positive synaptic varicosities (Seress et al. 1994). The principal cells of the parasubiculum demonstrate weak immunoreactivity for calbindin DZ8K 9.6.4. Calretinin

Figure l OF3

There are calretinin-positive cells located mainly in the superficial (I, II) layers of the presubiculum (Seress et al. 1993b). These tend to be small, fusiform (bipolar) cells with two or more main dendrites. Dendrites tend to be smooth, thin, varicose and usually 377

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very short. There is a dense bundle of calretinin-immunoreactive fibers in layer I of the presubiculum that is similar in density to staining in the molecular layer of the dentate gyrus or in CA2 of the hippocampus. Since the supramammillary nucleus does not appear to project heavily, if at all, to the presubiculum, the source of these fibers is currently unknown. 9.7. H O R M O N E RECEPTOR SITES No information is available for adrenal steroids. TRH binding sites are dense in the human presubiculum. They appear to be focused over the cell islands of layers I/II (Eymin et al. 1993). Interestingly, while TRH binding in other regions such as the dentate gyrus is seen both in infants and in mature humans, the presubiculum demonstrates binding only in the mature brain. Insulin-like immunoreactivity is high in the pre- and parasubiculum (Dorn et al. 1982). 9.8. ENZYMES

9.8.1. Cytochrome oxidase

Figure lOG1

In the monkey presubiculum, layer II shows a dense accumulation of CO-activity, COimmunoreactivity, mitochondrial DNA and mRNA of CO, whereas the density of these markers is relatively low in deeper layers (Hevner and Wong-Riley 1991).

9.8.2. Nitric oxide synthase and NADPH-diaphorase

Figure lOG3

Both in the monkey (Mufson et al. 1990) and human (Sobreviela and Mufson 1995), NADPH-d reactivity is scarce in the presubiculum. The parasubiculum, in contrast, shows the heaviest innervation of NADPH-d-positive fibers of the subiculum, presubiculum and parasubiculum. Moderately stained cell bodies are distributed in all layers of the pre- and parasubiculum, while darkly stained cell bodies are concentrated in the deeper layers and within the white matter subjacent to it. 9.9. TROPHIC FACTORS No published data are available.

10. ENTORHINAL CORTEX 10.1. GLUTAMATE SYSTEM Other than AMPA-kainate receptors, there are no available data on the distribution of glutamate systems in the primate entorhinal cortex.

10.1.1. AMPA-kainate receptors

Figure lOA3

In the human entorhinal cortex, GluRl-immunoreactive cell bodies are located in layers V and VI, while GluR2/3-immunoreactive cell bodies are located in layers IIIII and V-VI (Armstrong et al. 1994; Longson et al. 1997). The dendrites of neurons in 378

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the entorhinal cortex of the macaque monkey that project to the superior temporal gyrus are immunoreactive for GluR5/6/7 (Good and Morrison 1995). 10.2. CHOLINERGIC SYSTEM

10.2.1. Cholinergic fiber systems

Figures IOBI&2

The density of labeled fibers in the entorhinal cortex varies both in the transverse and radial axes. Overall, the density of ChAT labeling is much lower than in the parasubiculum but higher than in the hippocampus and dentate gyrus. It is also higher than in the adjacent perirhinal cortex so that the boundary between these cortices is fairly easy to detect in ChAT preparations. The highest density of fiber labeling is found in the superficial layers (I-III). The boundary between the superficial and deep zones is quite distinct due to the substantially lower density of fibers in the deep layers (layers V-VI). Unlike the other hippocampal fields, there is no obvious difference in the density of ChAT-labeled fibers at different rostrocaudal levels of the entorhinal cortex. There are differences, however, related to the transverse position within the entorhinal cortex. In general, the highest density of ChAT labeling is found medially regardless of the rostrocaudal level. Thus, at rostral levels, the densest labeling is observed in Eo, decreases as one progresses laterally through ER, and is lowest closer to the rhinal fissure (ELR). This transverse gradient is most clearly observed in layers III and V and is less evident in layers I and II. The cholinergic innervation varies considerably in the different layers of the entorhinal cortex. Layer I contains a fairly dense plexus of fibers that are mostly oriented parallel to the pial surface. The density of ChAT-positive fibers in layer I increases along the transverse and rostrocaudal axes. ChAT-positive fibers are prevalent throughout the width of layer I. In contrast to the pattern of ChAT fiber labeling, AChE staining of layer I is much more heterogeneous along both rostrocaudal and transverse extents. A distinctive aspect of the AChE staining in layer I is the presence of tooth-like zones of dense staining located superficial to the cell free zones of layer II. At caudal levels of the entorhinal cortex, the zones of higher density of AChE labeled fibers become circular and occasionally extend into portions of layer II. This pattern of AChE staining is observed in the human entorhinal cortex as well (Solodkin and Van Hoesen 1996). The density of cholinergic fibers is much higher in layer II than layer I. The cell islands of layer II demonstrate a lower density of ChAT-immunoreactive fibers than the intervening cell-sparse zones. Plexuses of cholinergic fibers surround the deep half of the layer II cell islands. Labeling in the cell sparse spaces between the layer II islands is not homogeneous but contains patches and fascicles of ChAT-positive fibers. As noted above, the tooth-like staining of AChE in layer I extends into the cell-sparse regions of layer II. These distinctive labeling patterns are not observed in the ChAT preparations. Layer III demonstrates a high density of ChAT-positive fibers throughout the entorhinal cortex. The density of immunoreactive fibers in layer III is generally highest superficially and decreases deeper within the layer. Layer IV has slightly fewer cholinergic fibers than the deep part of layer III. The deep layers of the entorhinal cortex (layers V and VI) generally have a lower density of cholinergic innervation than the superficial layers. The pattern of ChAT labeling in layer VI is less organized and the fibers are arranged in more irregular 379

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trajectories. In comparison with layer V, the density of ChAT-positive fibers of layer VI is slightly lower in Er and EI, and slightly higher in ER. The staining in layer VI of ELR and ELC is reduced to a sparse plexus of fibers. Consistent with the ChAT labeling, the density of AChE labeled fibers in layer VI is weak in comparison with the labeling in more superficial layers. The density of AChE-positive fibers increases in the subcortical white matter deep to the cell dense strands that constitute layer VI. This subcortical white matter also demonstrates a higher number of ChAT-positive fibers than layers V and VI. The cholinergic innervation of the human entorhinal cortex has both similarities and differences with the monkey entorhinal cortex (de Lacalle et al. 1994). The laminar organization is similar with the superficial layers receiving a denser cholinergic innervation than the deep layers. However, the reported regional differences in cholinergic innervation are strikingly different. In the human, for example, the most rostral and medial entorhinal field, Eo, receives the heaviest innervation in the monkey and the lightest innervation in the human. While there was not much rostrocaudal difference in the innervation of the monkey entorhinal cortex, the human entorhinal cortex demonstrates a much higher innervation at caudal levels than at rostral entorhinal levels. It is not clear whether these differences reflect a true species difference or the aged population (mean age 72 years) that was studied by de Lacalle et al. (1994). It would be of interest to determine whether there are age-related changes in the cholinergic innervation of the monkey entorhinal cortex since technical considerations such as health status of the subject and histological preparation of the brain material could be better controlled.

10.2.2. Cholinergic receptors

Figure lOB3

10.2.2.1. Muscarinic receptors

Miyoshi et al. (1989) found high levels of the M1 receptor in the macaque monkey entorhinal cortex. No laminar or regional description was provided. Mash et al. (1988) observed that the highest density of M2 receptor was located in deep layer III and layer V of the lateral part of the macaque monkey entorhinal cortex. They also found high densities of M1 receptors, particularly in the superficial layers. In the human, Cort6s et al. (1987) found high density of M 1 receptors in the human entorhinal cortex and a somewhat less dense distribution of M2 receptors. 10.2.2.2. Nicotinic receptors

Human entorhinal cortex shows a relatively high density of [3H]nicotine binding (Court et al. 1997). Rubboli et al. (1994) have reported that the human entorhinal cortex demonstrates moderate densities of the a7 and 132 subunits and light densities of the ~3 subunit of the nicotinic receptor. In contrast to the human, Mash et al. (1988) demonstrated relatively low levels of [3H]nicotine binding sites in the rhesus monkey entorhinal cortex.

380

The hippocampal formation and perirhinal and parahippocampal cortices 10.3. GABAergic SYSTEM

Ch. IV Figure 10 C1

10.3.1. Fiber innervation

The distribution of GABAergic fibers and terminals in the monkey entorhinal cortex shows marked regional and laminar differences. Throughout the whole rostrocaudal extent of the entorhinal cortex, layer I shows the highest density of varicosities while the highest density of labeled fibers is found in layers II and III. In layer II, a dense terminal plexus surrounds the unlabeled pyramidal cells. In layer III, labeled fibers are often associated with clusters of labeled cells, giving a patchy appearance to the distribution of GABAergic neuropil staining. There are very few labeled fibers and terminals in the lamina dissecans (layer IV). Layer V has lower levels of labeled fibers and terminals than the superficial layers with varicosities surrounding the unlabeled pyramidal cell bodies. Layer VI demonstrates the lowest levels of GABAergic neuropil staining. 10.3.2. GABAergic cell bodies The macaque monkey entorhinal cortex demonstrates a fairly high density of GABAimmunoreactive neurons and the density of cells does not differ much at different rostrocaudal levels. At any particular rostrocaudal level, however, there is a higher density of GABAergic neurons in layer I laterally than medially. No lateromedial gradients are observed in other layers. Throughout the entire rostrocaudal extent of the entorhinal cortex, the density of labeled cells is higher in layers II/III than in layers V and VI. GABAergic neurons in layer I are mainly small, spheroidal/multipolar cells which have short dendrites distributed in a stellate fashion. There are also a few small, fusiform cells and multipolar cells. The predominant GABAergic cell types in layer II are multipolar and fusiform neurons. These neurons are commonly found within the cell islands of layer II and their dendrites extend into layer III. Some islands, however, do not have any GABAergic neurons. Occasionally, fusiform and multipolar GABAergic neurons are observed between the cell islands. Smaller, multipolar and fusiform neurons are also seen in layer II. The dendrites of the fusiform cells are typically oriented parallel to the pial surface. Layer III has a diverse group of GABAergic neurons. The most common type is the multipolar cell. Some GABAergic cells located deep in layer III have long dendrites that extend into layer II. GABAergic pyramidal-shaped cells with apical dendrites extending into the superficial layers are also found in layer III. Small spheroidal cells and fusiform GABAergic cells are also seen in layer Ill. There are very few GABAergic neurons in layer IV. In layer V, the most prominent cell type has a fusiformshaped cell body, with apical dendrites extending into layer III and basal dendrites into deeper layers. There are also small spheroidal, multipolar and pyramidal-shaped GABAergic cells in layer V. GABAergic neurons in layer VI are generally larger than those in the other layers of the entorhinal cortex. The most common type is a fusiform cell. The apical dendrites of the fusiform cells extend into the superficial layers and the basal dendrites descend into the subcortical white matter. The deeper portion of layer VI contains small, spheroidal and small fusiform GABAergic cells. Longson et al. (1997) have evaluated the distribution of GABAergic neurons in the human entorhinal cortex using in situ hybridization with a probe to GAD67 mRNA. 381

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While GAD-positive neurons were distributed throughout all layers (except perhaps layer I) there were both regional and laminar differences to their distribution. The largest number and the largest neurons were found in layer III of El. Layers V and VI also had many, although, less GAD-positive cells. In ER, there were labeled cells associated with the cell islands of layer II and these could be differentiated from labeled cells in layer III. In El, labeled cells in layer II merged imperceptibly with others in layer III. Longson et al (1997) also evaluated the distribution of GABAA receptor subunits. These tended not to be exclusively associated with neuronal cell bodies and were not restricted to certain laminae. The cells of layer II, however, were conspicuously labeled for a l, 3'2, and 132 receptor subunits. Beyond this heavy labeling in layer II, cells in layer III, particularly the superficial part of the layer, were also heavily labeled for these GABA receptor subunits. Solodkin and Van Hoesen (1996) point out that the human entorhinal cortex has a very high density of GAD-positive fibers and that these are particularly dense within the cell islands of layer II. GAD-positive cell bodies, in contrast, are observed either below or between the cell island but rarely within them. They observed that the highest densities of GAD-immunoreactive neurons are located in layers III and V. 10.4. MONOAMINES

10.4.1. Noradrenaline

Figure IOD1

In the human entorhinal cortex, DBH-immunoreactive fibers are observed throughout the thickness of the cortex (Powers et al. 1988) with no distinct laminar organization. Fetal and neonatal monkeys show a similar diffuse distribution of DBH labeled fibers in the entorhinal cortex (Berger and Alvarez 1994).

10.4.2. Dopamine

Figures lOD3&4

Lewis and colleagues have carried out detailed analyses of the distribution of dopaminergic fibers in the macaque monkey (Akil and Lewis 1993) and human (Akil and Lewis 1994) entorhinal cortex. They have noted both regional and laminar differences in the distribution of TH-immunoreactive fibers in the macaque monkey entorhinal cortex. TH-immunoreactive fibers tend to be much denser in the rostral portions (Eo and ER) of the entorhinal cortex compared to more caudal divisions (El and Ec). At rostral levels, there is also an increasing medial to lateral gradient of TH-immunoreactive fiber density. TH fibers are denser in Eo, for example, than in ER. And the medial part of ER has a higher density of fibers than the lateral portion. TH-immunoreactive fibers are distributed to all layers of the entorhinal cortex. Throughout the entorhinal cortex, the highest density of fibers is in layer I. In Eo, layers II and III also demonstrate very dense fiber plexuses, deeper layers are slightly less dense. In ER, all layers deep to layer I demonstrate a fairly heavy plexus of TH-immunoreative fibers. In El, deeper layers have a TH plexus that is less dense than in ER and in Er all layers other than layer I have a very light TH plexus. In the human entorhinal cortex, Akil and Lewis (1994) also observed a rostr0caudal density gradient of TH-immunoreactive fibers. They pointed out that the mediolateral density gradient is more apparent in the human entorhinal cortex than in the monkey. In the human, however, the gradient is reversed. Lateral portions of the entorhinal cortex, regardless of division, demonstrates the heaviest density of TH-immunoreactive 382

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fibers. As for the laminar organization, and similar to the macaque monkey, layers I and superficial II have the highest density of TH-immunoreactive fibers. However, the differential between layer I and the deeper layers is less apparent in the human than in the monkey. The entorhinal cortex generally contains low levels of D2 receptors. The only exception is in its most lateral portions at rostral levels. Here, D2 receptors are densest in layers I-II, moderately dense in layers V-VI, and sparse in layers Ill-IV (Goldsmith and Joyce 1994). This trilaminar pattern of receptor distribution continues into the perirhinal cortex. K6hler et al. (1991) also investigated the distribution of D2 receptors in the human entorhinal cortex but reported a higher density of receptors in the deep layers. The cause of this discrepancy is not clear. K6hler et al. (1991) reported that the density of D2 receptors in the macaque monkey entorhinal cortex is fairly homogeneous across layers with a higher density in layer IV. Dopamine- and adenosine 3':5' monophosphate-regulated phosphoprotein of molecular weight 32 kDa (DARPP-32) acts as a phosphatase 1 inhibitor and is regulated by dopamine and cyclic AMP (Hemmings et al. 1984). In other brain regions such as the neostriatum, DARPP-32 is present in a subclass of dopaminoreceptive neurons which contain D1 receptors (Ouimet et al. 1984). In fetal and neonatal animals only, DARPP-32 immunoreactivity is found in the entorhinal and perirhinal cortices (Hemmings and Greengard 1986; Berger et al. 1990; Ouimet et al. 1992; Barbas et al. 1993; Berger and Alvarez 1994). The functional significance of this transient expression of DARPP-32 is currently unclear. 10.4.3. Serotonin

Figures lOD5&6

In the entorhinal cortex of the marmoset, 5-HT immunoreactive axons with small ovoid varicosities are more densely distributed in layers I-III than IV-VI, and labeled axons with large spheroidal varicosities are confined to layers I-III (Hornung et al. 1990). In fetal and neonatal rhesus monkeys, all layers contain numerous 5-HT immunoreactive fibers (Berger and Alvarez 1994). In the neonates, labeled fibers are denser in ER and EI than in Ec. In ER, serotonergic fibers surround cell clusters in layer II, whereas in EI, fibers are located both in and above the cell clusters. In the human entorhinal cortex, 5-HT1 and 5-HT2 receptors are distributed in all the layers except for lamina dissecans (Pazos et al. 1987a, b). At rostral levels of the entorhinal cortex, 5-HT1A receptors are dense both in layers I-II and layers V-VI, whereas at middle and caudal levels, they are more concentrated in layers I-II. 10.5. PEPTIDES 10.5.1. Substance P

Figure IOE1

Data concerning the distribution of SP immunoreactivity in the monkey and human entorhinal cortex are meager. In the rhesus monkey, a few labeled neurons are found in layers III, V and VI while stained fibers are more diffusely distributed (Carboni et al. 1990). Labeled cells are bipolar or bitufted and oriented vertically or horizontally. In layer II of the human entorhinal cortex, SP-immunoreactive fibers are densely distributed within the cell clusters of layer II (Mai et al. 1986).

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Ch. IV 10.5.2. Cholecystokinin

Y. Kobayashi and D.G. Amaral Figure lOE2

Cholecystokinin-immunoreactive fibers and varicosities are distributed chiefly in layers II, IV and VI of the human entorhinal cortex (Lotstra and Vanderhaeghen 1987). In layer II, they are confined to the cell dense clusters. Large beaded fibers are found in all layers. CCK-immunoreactive cell bodies are only observed in layers II and III.

10.5.3. Neurotensin

Figure lOE3

The entorhinal cortex does not have cell bodies that are NT-immunoreactive though immunostained fibers are densely distributed in the entorhinal cortex (Mai et al. 1987; Gaspar et al. 1990; Berger and Alvarez 1994). In the neonatal rhesus monkey, the laminar distribution of NT-labeled fibers shows regional differences (Berger and A1varez 1994). In the rostral and intermediate fields of the entorhinal cortex, labeled fibers are more densely distributed in layers I-III than in the deeper layers. At caudal levels of the entorhinal cortex, however, labeled fibers are predominant in layers I-II and V-VI. In layer II, immunostained fibers are most heavily distributed between the cell islands. [125I]neurotensin binding sites are densest in layer II and moderately dense in layers V-VI in the human entorhinal cortex (Wolf et al. 1994).

10.5.4. Somatostatin

Figure lOE4

The distribution of SS-immunoreactivity has been extensively analyzed both in the monkey (Bakst et al. 1985; Carboni et al. 1990) and human (Chan-Palay 1987; Friederich-Ecsy et al. 1988; Solodkin and Van Hoesen 1996). At all rostrocaudal levels of the entorhinal cortex, the densities of SS-immunoreactive cell bodies and fibers are higher in the medial half than in the lateral half. Numerous SS-positive cells are found throughout the entorhinal cortex. They are generally small and most numerous in layer VI and in the white matter just subjacent to it. Among the other layers, layer III has a higher density than layer V, and layer II contains only a few labeled cell bodies. Whether the labeled layer II cells contribute to the perforant path projection to the dentate gyrus has not yet been determined but the labeled neurons actually look quite different from the typical stellate neurons that give rise to the perforant path. Layer I of the monkey entorhinal cortex contains a dense plexus of SS-positive fibers. The density decreases towards the rhinal sulcus and the lower density at the most lateral part of the entorhinal cortex presents a distinct border with the heavily labeled layer I of the perirhinal cortex. In layer II of Eo, fiber labeling is associated with the thin band of small cells that forms this layer. In ER, E1 and EL, however, SSpositive fibers are located between the cell islands. In layer II of Ec and EcL, immunostained fibers form distinct patches that are associated with SS-positive cell bodies. At rostral levels, layer III contains a dense plexus of SS-immunoreactive fibers that are grouped into large fascicles. Caudally, the density of immunoreactive fibers decreases and exhibits a distinct radial orientation that is reminiscent of the adjacent neocortex. The most lateral part of layer III has only a few labeled fibers so that this low density shows a clear boundary with the densely labeled perirhinal cortex. Layer IV in EI has a higher density of SS-immunoreactive fibers than the adjacent layers. At all rostrocaudal levels, layer V shows dense SS-immunoreactive fibers especially in the relatively acellular layer Vc. Layer VI has few labeled fibers at all levels. Some SS-immunore384

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active neurons in the deep layers of the entorhinal cortex are also NPY-positive (ChanPalay 1989).

10.5.5. Neuropeptide Y

Figure lOE5

In the monkey entorhinal cortex, NPY-immunoreactive cell bodies are located mainly in layers IV-VI though occasional positive cell bodies are also found in layer II. I~PYimmunoreactive fibers are distributed throughout all layers (K6hler et al. 1986). The density of NPY-positive fibers is higher in layers I-II than in the deeper layers. In the human entorhinal cortex, NPY-positive neurons are chiefly located in layers III, V and VI (Lotstra et al. 1989). Immunostained fibers are dense in the deep part of layer II and the superficial part of layer III as well as in layer VI (Lotstra et al. 1989; ChanPalay 1989).

10.5.6. Opioid peptide No published data are available.

10.5.7. Galanin High levels of galanin-binding are observed in all layers of the human entorhinal cortex (Rodriguez-Puertas et al. 1997). In situ hybridization in the macaque monkey shows that the mRNA of preprogalanin is chiefly distributed in layers V-VI of the entorhinal cortex (Evans et al. 1992). 10.6. CALCIUM-BINDING PROTEINS

10.6.1. Parvalbumin

Figure I OF1

10.6.1.1. Distribution of parvalbumin-immunoreactive fibers The macaque monkey entorhinal cortex demonstrates striking regional and laminar differences in the density of parvalbumin fiber and terminal labeling (Pitkfinen and Amaral 1993). There are prominent rostrocaudal and transverse gradients to the density of parvalbumin immunoreactivity. In general, rostral levels of the entorhinal cortex demonstrate lower densities of parvalbumin immunoreactive fibers and terminals than caudal levels. At any particular level, however, medial portions of the field demonstrate fewer immunoreactive fibers and terminals than lateral portions of the field. The lateral divisions of the entorhinal cortex (ELR and ELC) always have higher densities of labeled fibers and terminals than the medial divisions at the same level (ER or EI). Throughout the entorhinal cortex, layer III demonstrates the highest density of fiber and terminal labeling and layer II is somewhat less densely innervated. There is little or no terminal labeling in lamina dissecans (layer IV). Layer V has a low level of fiber and terminal labeling and layer VI has very little at all. There are also very low levels of fiber and terminal labeling in layer I. This general pattern of fiber and terminal labeling has also been reported in comprehensive studies of the human entorhinal cortex (Tufi6n et al. 1992; Schmidt et al. 1993). At rostral levels of the entorhinal cortex where the cells in layer III tend to form clusters, the parvalbumin terminal immunoreactivity is associated with the patches of 385

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cells rather than with the acellular regions. Similarly, the islands of layer II cells are innervated by immunoreactive fibers and terminals but the acellular gaps have very low levels of labeling. At caudal levels of the entorhinal cortex, the transverse gradient of terminal density is not as apparent. There is a very dense plexus of immunoreactive fibers and terminals throughout the transverse extent of the field. Within layer III, however, there is a somewhat higher density of labeling in the middle third (radially) of the layer.

10.6.1.2. Distribution of parvalbumin-immunoreactive cells The distribution of parvalbumin-immunoreactive neurons in the entorhinal cortex parallels the distribution of labeled fibers and terminals (Pitk/inen and Amaral 1993). There are more labeled cells caudally than rostrally and at any particular rostrocaudal level there are more labeled cells laterally than medially. Layer III has the highest density of parvalbumin-labeled cells. Layers V and VI have a much lower density. There are relatively few parvalbumin-immunoreactive cells in layers II or I. This general distribution is again very similar in the human (Tufi6n et al. 1992; Schmidt et al. 1993; Solodkin and Van Hoesen 1996). Parvalbumin labeled cells in layer II cells are generally located in the deep portion or just beneath the cell layer and most of the dendritic tree of these cells is directed towards the pia. The axon of these cells descends, collateralizes in layer III and several collaterals are given off into this layer. The principal axon then ascends into layer II and ramifies among the cell bodies of the layer. Where layer II consists of cell islands, only one or at most two parvalbumin-labeled cells are associated with each island. Within layer II there are very small round cells with short aspiny dendrites. Layer III has the highest density of parvalbumin neurons in the entorhinal cortex. The density of labeled cells is somewhat higher in the deeper half of the layer. There are at least two types of labeled cells in layer III. Many are small stellate cells with round or irregular cell bodies. The dendrites of these cells tend to remain within the layer. There are also larger, multipolar cells that have a pyramidal or modified pyramidal shape. These cells give rise to long, nontapering dendrites that, in some cases, extend superficially into layer I and deeply into portions of layer V and layer VI. Neither the smaller nor the larger types of layer III parvalbumin cells have particularly beady dendrites although some of the descending dendrites are somewhat varicose. In layer V, there are very few parvalbumin-labeled cells in the more cellular, superficial sublaminae (Va and Vb). Most of the labeled cells are located in the relatively acellular layer Vc. Many of the cells in this layer are relatively large multipolar cells and many have long, thin dendrites that ascend into layer III. There are also small, round cells in layer V. The number of parvalbumin labeled cells is greater in layer VI than in layer V and labeled cells comprise a variety of cell types. The major cell type is fusiform shaped. These fusiform cells give rise to narrow apical and basal plexuses of very beady dendrites. The basal dendrites of these cells descend as far as the subcortical white matter and the apical dendrites ascend towards layer III. There are always a few cells located in the subcortical white matter. These tend to be rather large cells with coarse, irregular dendrites. 10.6.2. Calbindin

Figure lOF2

Pyramidal and other 'principal' cell types of the entorhinal cortex are immunopositive 386

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Ch. IV

for calbindin D28K (Seress et al. 1994). The density of these cells is greater in the layers superficial to the lamina dissecans (layer IV). The most prevalent calbindin DZSK cell types in the entorhinal cortex are small bipolar and fusiform cells that have dendrites oriented perpendicular to the pial surface. There is a diffuse distribution of calbindin DzsK-positive varicosities throughout all of the layers of the entorhinal cortex with a substantially lower density in layer I.

10.6.3. Calretinin

Figure l OF3

Calretinin-positive cells are found in all layers of the entorhinal cortex but they are most common in layers I-III. The calretinin neurons are mainly small, bitufted cells with dendrites oriented radially (Seress et al. 1993b). There are occasional multipolar calretinin labeled cells in all layers. Calretinin-immunoreactive fibers and terminals are seen throughout the entorhinal cortex with a preferential termination in the superficial layers. Many of the stained fibers are seen to be in close proximity to unlabeled cells that make up the bulk of the entorhinal cortex. 10.7. H O R M O N E RECEPTOR SITES No published data are available. 10.8. ENZYMES

10.8.1. Cytochrome oxidase

Figure lOG1

In the monkey, neuropil-like cytochrome oxidase (CO)-activity is distributed throughout the entorhinal cortex (Chandrasekaran et al. 1992). Cell bodies demonstrating high activity of CO, or mRNA of a CO subunit, are located in layers II-III and V-VI (Carboni et al. 1990; Chandrasekaran et al. 1992). In the human, CO activity is high in layers II-III and V-VI and low in layer I and lamina dissecans (Hevner and Wong-Riley 1992; Solodkin and Van Hoesen 1996). Neuropil within and above the cell islands of layer II is heavily labeled, while the interstices between cell islands show relatively low levels of CO activity.

10.8.2. Nitric oxide synthase and NADPH-diaphorase

Figures lOG2&3

In the monkey (Carboni et al. 1990; Mufson et al. 1990) and the human (Rebeck et al. 1993; Sobreviela and Mufson 1995), nerve cells highly reactive for NADPH-d are located in layer VI and the white matter subjacent to it. NOS-immunoreactivity is usually colocalized in the heavily NADPH-d-labeled cells. Although moderately NADPH-d-reactive cell bodies are found in all layers, they are more numerous in layer II and the superficial portion of layer III. NADPH-d-reactive fibers are distributed throughout the thickness of the entorhinal cortex. The density of labeled fibers is higher in the lateral portion of the entorhinal cortex where a dense plexus of NADPHd-positive fibers is located in layers III, V and VI.

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10.9. TROPHIC FACTORS

10.9.1. Nerve growth factor Kerwin et al. (1993) report the presence of NGF receptor immunoreactivity in the human entorhinal cortex but no regional or laminar description is provided.

10.9.2. Ciliary neurotrophic factor Kordower et al. (1997) report that many neurons in the entorhinal cortex are immunoreactive for CNTF.

10.9.3. Brain-derived neurotrophic factor Murray et al. (1994) report that there is no detectable level of in situ signal for BDNF mRNA in the entorhinal cortex. They note that this is different from findings reported for the rat.

11. PERIRHINAL CORTEX 11.1. GLUTAMATE SYSTEM No published data are available. 11.2. CHOLINERGIC SYSTEM There are currently no comprehensive studies of the cholinergic system of the primate perirhinal cortex. However, Voytko et al. (1992) have illustrated the distribution of ChAT immunoreactive fibers in the anterior temporal lobe of the rhesus monkey and have included the rostral and polar portions of the perirhinal cortex. The heaviest fiber and terminal labeling is located in layers I, II and superficial III. The density of ChAT staining is substantially higher in area 36 of the perirhinal cortex than in the adjacent area TE. These observations are similar to the results of ChAT assay studies carried out by Mesulam et al. (1986) that indicated very high levels of ChAT activity in the agranular portions of the temporal polar cortex. 11.3. GABAergic SYSTEM No published data are available. 11.4. MONOAMINES

11.4.1. Noradrenaline In fetal and neonatal macaque monkey, DBH immunoreactivity is reported both in area 35 and 36 (Berger and Alvarez 1994). No details on regional or laminar organization have been provided.

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11.4.2. Dopamine The distribution of dopamine D2 receptors in the human perirhinal cortex shows a trilaminar pattern similar to that in the lateral portion of the entorhinal cortex (Goldsmith and Joyce 1994, 1996). D2 receptors are most dense in superficial layers (I-II), moderately dense in deep layers (V-VI), and sparse in layers III and IV. Interestingly, autoradiograms for the distribution of D2 receptors provide a clear boundary between the entorhinal cortex and the perirhinal cortex along the medial bank of the collateral sulcus (Goldsmith and Joyce 1996). DARPP-32 labeled neurons are located in layers II-III and the upper part of layer V in the perirhinal cortex of the fetal and neonatal rhesus monkey (Berger and Alvarez 1994). 11.4.3. Serotonin No published data are available. 11.5. PEPTIDES Other than somatostatin and neuropeptide Y, there is little or no information on the distribution of peptides in the primate perirhinal cortex. 11.5.1. Somatostatin SS-immunoreactivity is abundant both in the monkey (Bakst et al. 1985) and human perirhinal cortex (Chan-Palay 1989). Labeled fibers are dense in layers I-IV and relatively sparse in layer V. SS-positive cell bodies are distributed throughout layers II-VI. 11.5.2. Neuropeptide Y In the human perirhinal cortex, NPY-immunoreactive neurons are found in layers IIVI (Chan-Palay 1989). 11.6. CALCIUM-BINDING PROTEINS 11.6.1. Parvalbumin While there has not yet been a detailed study of the distribution of parvalbumin immunoreactive cells in the perirhinal cortex, Kondo et al. (1994) reported that the ratio of parvalbumin-immunoreactive cells to all cells is lower in the perirhinal cortex than in areas V1, V4, TEO or TE. 11.7. H O R M O N E RECEPTOR SITES No published data area available.

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11.8. ENZYMES 11.8.1. Nitric oxide synthase and NADPH-diaphorase In the human (Sobreviela and Mufson 1995), NADPH-d-reactive fibers are distributed in all layers of the perirhinal cortex. In area 35, labeled fibers are denser in layers V and VI, while, in area 36, they are predominant in layer III. Heavily labeled cell bodies are chiefly located in layers V-VI and moderately labeled cell bodies are observed in layers II-III. As in the entorhinal cortex, NOS-immunoreactive cell bodies are found in layer VI. 11.9. TROPHIC FACTORS 11.9.1. Nerve growth factor While there is little information available on the normal distribution of N G F in the human perirhinal cortex, Mufson and Kordower (1992) have made the interesting observation that NGF-positive neurons are observed in the perirhinal and entorhinal regions in brains from Alzheimer's patients and in one 98-year-old nondemented subject.

12. PARAHIPPOCAMPAL CORTEX 12.1. GLUTAMATE SYSTEM/CHOLINERGIC SYSTEM/GABAergic SYSTEM/MONOAMINES No published data are available for any of these transmitter systems. 12.2. PEPTIDES Other than substance P, there are no available data on the distribution of peptide systems in the primate parahippocampal cortex. 12.2.1. Substance P In the parahippocampal cortex in the human, SP-immunoreactive cell bodies are distributed in layer VI, while immunostained fibers are chiefly distributed in layer I (Del Fiacco et al. 1987). 12.3. CALCIUM-BINDING PROTEINS No published data are available. 12.4. H O R M O N E RECEPTOR SITES No published data are available.

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12.5. ENZYMES

12.5.1. Nitric oxide synthase and NADPH-diaphorase In the human parahippocampal gyrus (Rebeck et al. 1993), NADPH-d-positive cell bodies are densest in layer VI and the white matter subjacent to it. Labeled cells are also frequently found in layer V, while they are rarely present in layers I-IV. 12.6. TROPHIC FACTORS No published data are available.

13. CONCLUDING REMARKS In this chapter, we have attempted to provide a framework for future studies on the chemical and molecular neuroanatomy of the primate hippocampal formation and perirhinal and parahippocampal regions. For this reason, we have provided criteria, or pointers to papers that provide criteria, for subdividing the various cytoarchitectonic fields of the hippocampal formation and adjacent perirhinal and parahippocampal regions. In reviewing this literature, we found that several of the apparent controversies were simply due to different terms being applied to the same brain area. In the human brain, for example, the term parahippocampal cortex or gyrus would variably refer either to the entorhinal cortex (which was sometimes called the anterior parahippocampal cortex) or to the regions that we have defined as the perirhinal and parahippocampal cortices. There is clearly a continued need for more definitive neuroanatomical and functional criteria to delimit the various portions of this fairly extensive region of the primate brain. Having limited our descriptions primarily to data from the nonhuman and human primate brains, we have still managed to produce a rather substantial manuscript. Nonetheless, there are many areas of the chemical neuroanatomy of the primate brain that are skimpy at best and others where data are entirely lacking. Even for topics as well studied in the rat as the distribution of monoamine systems, descriptions in the monkey rely on only one or two papers. Since there are repeated examples of where, when well-studied, there are differences in the distribution of neuroactive substances in the rat and monkey brains, it is perhaps foolhardy to extrapolate too freely from the rat to the monkey and human brains. The glaring holes in our knowledge of the chemical neuroanatomy of the human medial temporal lobe highlights the necessity for concerted efforts at applying modern neuroanatomical techniques to the analysis of the human brain. This brain region is involved in important cognitive functions such as the formation of episodic or autobiographical memories and is prone to a variety of serious illnesses such as Alzheimer's disease, epilepsy and schizophrenia. Undoubtedly, a deeper understanding of the specific neurochemical attributes of these brain regions will provide insight into why they are so vulnerable to these devastating disorders. While descriptive neuroanatomy is often spoken of in disparaging terms, it may be the precise description of unique features of the chemical or molecular neuroanatomy of the medial temporal lobe that will lead to insights into its normal function and to its pathology. There is clearly

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much left to be learned about the human and nonhuman primate hippocampal formation and the perirhinal and parahippocampal cortices.

14. A B B R E V I A T I O N S

A ac

AHA amts CA1, CA2, CA3 al pcl slm so sr

CD CL DG gl ml iml oml pl E ER, Eo, EI, ELR and ELC, Ec, ECL

f i I

LGN ls o ots

PAC PIR PaS PrS PV rs

RSP S STG sts

TE TEO TF TH 392

amygdala anterior commissure amygdalohippocampal area anterior medial temporal sulcus fields of the hippocampus (Lorente de N6) alveus of the hippocampus pyramidal cell layer of the hippocampus stratum lacunosum-moleculare stratum oriens of the hippocampus stratum radiatum caudate nucleus claustrum dentate gyrus granule cell layer of the dentate gyrus molecular layer of the dentate gyrus inner portion of the molecular layer of the dentate gyrus outer portion of the molecular layer of the dentate gyrus polymorphic layer of the dentate gyrus entorhinal cortex

subdivisions of the entorhinal cortex fimbria inner or deep band of layer II of the presubiculum insula lateral geniculate nucleus lateral sulcus outer or superficial band of layer II of the presubiculum occipital temporal sulcus periamygdaloid cortex piriform cortex parasubiculum presubiculum pulvinar rhinal sulcus retrosplenial cortex subiculum superior temporal gyrus superior temporal sulcus Temporal lobe area TE (Bonin and Bailey) Temporal lobe area TEO (Bonin and Bailey) Temporal lobe area TF (Bonin and Bailey) Temporal lobe area TH (Bonin and Bailey)

The h i p p o c a m p a l f o r m a t i o n a n d perirhinal and p a r a h i p p o c a m p a l cortices

V 29m, 291 35, 36 36d, 36r, 36c

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l a t e r a l ventricle s u b d i v i s i o n s o f the r e t r o s p l e n i a l c o r t e x s u b d i v i s i o n s o f the p e r i r h i n a l c o r t e x s u b d i v i s i o n s o f a r e a 36

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CHAPTER V

The primate mesocortical dopamine system P.S. GOLDMAN-RAKIC, C. BERGSON, L.S. KRIMER, M.S. LIDOW, S.M. WILLIAMS AND G.V. WILLIAMS

1. INTRODUCTION This chapter describes recent advances and insights into the organization and function of the primate mesocortical dopamine system. The review covers new detailed information about the organization of the brainstem nuclear groups that give rise to the neocortical innervation as well as the fine structure and receptor targets of afferent fibers in the cortex. Studies of the nonhuman primate brain have a special prominence in these advances, due to the progressive elaboration of the dopamine system in their development and evolution, the similarity of these systems in monkey and man, and the unique opportunities for structure-function analysis of cognitive functions in this species.

2. PRIMATE SPECIALIZATION IN THE BRAINSTEM ORIGIN AND ORGANIZATION OF THE MESOCORTICAL DOPAMINE SYSTEM

The midbrain dopamine (DA) system of neurons has traditionally been divided into cellular groupings designated as A8, A9 and A10, corresponding respectively to three cytoarchitectonically defined regions of the ventral mesencephalon: the retrorubral area (RRA or A8); the pars compacta and dorsal contiguous zones of the substantia nigra (A9); and the ventral tegmental area (A10 or VTA) (Dahlstrom and Fuxe 1964; Anden et al. 1966). In rodents, the mesocortical projection arises from two of these subdivisions, the A9 and A10 groupings (for reviews see Fallon and Loughlin 'and Moore and Bloom 1978). The prefrontal cortex of this species receives input primarily from a circumscribed midline group of ventral tegmental area neurons and it is this projection that has been traditionally associated with the mesocortical system. In primates, however, the mesocortical dopamine system is more extensive at both the terminal and brainstem levels (Fig. 1). DA afferents innervating the macaque frontal cortex originate from a widespread distribution of neurons in the dorsal aspects of all three of the mesencephalic DA cell groups (Williams and Goldman-Rakic 1998). Further, in primates, in contrast to the rodent, the A8 retrorubral area is a substantial source of dopamine afferents to regions of frontal cortex (Porrino and Goldman-Rakic 1982; Gaspar et al. 1992; Williams and Goldman-Rakic 1998). The mesocortical projections in primates also display a coarse mediolateral topographic organization. Thus, the preponderance of DA neurons innervating the dorsal frontal areas (Walker's areas 46, 8B/6M, and 4) originate primarily from the A9 cells Handbook of Chemical Neuroanatomy, Vol. 15: The Primate Nervous System, Part III F.E. Bloom, A. Bj6rklund and T. H6kfelt, editors 9 1999 Elsevier Science B.V. All rights reserved.

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Fig. 1. Origin of dopamine projection neurons to various cortical areas in the macaque brain. Drawing illustrates both the widespread nature and course topography of the mesocortical connections: (Top panel). A coronal section through the prefrontal cortex with markings reflecting the target areas of labeled cell groups in the lower two panels. (Rostral panel) The substantia nigra pars compacta (SNpc) contains densely packed DA cell bodies and a group of more loosely organized DA cells dorsal to the SNpc (A9 dorsalis; A9d) and lateral to the parabrachial pigmented nucleus (PBPG). These cell groups project to areas 9 and 46 and 12 respectively. (Caudal panel). The A8 cell group is essentially a caudal extension of A9d and is easily recognizable at the level of the decussation of the superior cerebellar peduncle (DSCP). These cells roughly correspond to the retrorubral nucleus (Rioch 1948; Berman et al. 1968) and are continuous with the A10 PBPG and laterally with the A9 neurons of the substantia nigra pars lateralis. These neurons project mainly to the medial cortex surrounding the cingulate sulcus. The most medial group of dopaminergic neurons, those in the A10 subgroup project mainly to the prelimbic cortex as indicated in the coronal section through the prefrontal cortex. In addition to the A8-A10 DA neurons, several dopaminergic cells lie in the ventral half of the periaqueductal gray in the rostral half of the midbrain (referred to as Aaq by Felton and Sladek 1983, not shown). Abbreviations." DSCP, decussation of the superior cerebellar peduncle; IF, interfascicular nucleus; IP, ML. medial lemniscus; RL, rostral linear nucleus; RN, red nucleus, RN; IIIn, third cranial nerve. 404

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dorsal to the SNpc, the retrorubral area and to a lesser extent from the midline nuclei which have typically been associated with the mesocortical DA system. In contrast, the ventromedial prelimbic area (PL) and infralimbic area (IL), receive more input from the PBPG and midline linear VTA nuclei than from the lateral groups. The anterior cingulate cortex (area 24) is innervated by a group of DA neurons primarily located between these laterally and medially concentrated populations. In parallel with the significant expansion and reorganization of the midbrain cellular origin of the cortical projecting nuclei, there has been both areal and laminar expansion of the dopaminergic innervation of the frontal cortex in primates (Levitt et al. 1984; Lewis et al. 1988; Berger et al. 1991; Oeth and Lewis 1992; Williams and Goldman-Rakic 1993). As mentioned above, the frontal innervation of the rodent is significantly more circumscribed (for review see Berger et al. 1991) and arises primarily from neurons located in the ventral tegmental area, with significantly fewer cells located in A9 (medial A9) and virtually no input from the retrorubral area (Deutch et al. 1987). Similarly, the cells of origin of the DA projections to the neocortex in cats appear to be restricted to the midline VTA nuclei (Scheibner and Tork 1987). Thus, it appears that as the dopamine innervation during primate evolution expanded into more dorsolateral areas of the macaque frontal lobe (e.g., premotor, motor and the phylogenetically newer dorsolateral prefrontal areas), as well as into the superficial layers of all frontal areas, a parallel lateral and caudal shift occurred in the midbrain cellular origin of these projections (see Gaspar et al. 1992). Recently, McRitchie et al. (1996) have demonstrated the greater number of A8 neurons in the human mesencephalon as compared to the rodent, relative to the other DA cell groups, suggesting species-specific functional specialization of the DA cell groups. This relative increase in the size of the A8 cell group may indeed reflect the expansion of the neocortex, as well as the expansion of the neocortical DA affereffts in anthropoid primate species, but may also be indicative of other aspects of midbrain DA reorganization. That is, in the rodent, the retrorubral area projects to the majority of mesolimbic structures (e.g., bed nucleus of the stria terminalis, nucleus accumbens, olfactory tubercle and amygdala), mesostriatal structures (especially the ventrolateral caudoputamen), and allocortex (piriform and entorhinal cortices) (reviewed in Bj6rklund and Lindvall 1984). Although considerably less is known about retrorubral efferents in the primate, projections to the caudate and putamen have been described (Szabo 1980). It is not clear, however, if mesolimbic structures, including the nucleus accumbens, are significantly innervated by A8 neurons (Lynd-Balta and Haber 1994; Williams and GoldmanRakic, unpublished observations). Therefore, it appears that the primate A8 region is intimately associated with the dorsal mesofrontal and dorsal striatal innervation and may not be a major source of mesolimbic dopamine (at least to the ventral striatum) in the primate. The large numbers of cortically-projecting neurons observed in the retrorubral area of the primate mesofrontal system (Porrino and Goldman-Rakic 1982; Gaspar et al. 1992) are now to be considered clearly mesofrontal DA cells (Williams and GoldmanRakic 1998). Quantitative analysis in the Gaspar et al. (1992) study of the owl monkey revealed that less than 15% of mesofrontal (motor, SMA and lateral PFC) DA cells were observed in this area, with little variability between the different frontal areas. Estimates in individual cases by Williams and Goldman-Rakic suggest that approximately 40% of DA cells projecting to dorsal frontal areas are located in A8. Although species differences between Old and New World monkeys could be responsible for this discrepancy, definitions of the A8 region may also underlie these differences. That is, 405

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as the boundaries of the retrorubral area are not precise, there is considerable variability in the definition of this region across studies, with many investigators including much of the rostral RRA as part of the parabrachial pigmented nucleus or dorsal A9. The origin of the DA innervation of the medial frontal cortex of primates is highly relevant to issues of prefrontal cortical homology between rodents and primates (Williams and Goldman-Rakic 1998). Indeed, a comprehensive review of connectional data, including an analysis of the dopamine innervation and functional studies, has led to the suggestion that rodents may lack homologues of the dorsolateral granular frontal (prefrontal) cortex of primates (Preuss and Goldman-Rakic 1991a,b; Preuss 1995). According to this model, the medial prefrontal areas of the primate (areas PL and IL) exclusive of the dorsolateral areas, are homologous to the entire rodent prefrontal cortex. Supporting this concept, it is these medial areas and not the dorsolateral PFC in the primate that receive a robust input from the VTA equivalent to the VTA innervation of the entire rodent PFC. Furthermore, these anatomical data would appear to substantiate the claim that the rodent prefrontal cortex is devoid of an area homologous to dorsolateral granular frontal cortical areas in primates.

3. QUALITATIVE ORGANIZATION OF THE DOPAMINE INNERVATION OF CEREBRAL CORTEX Views of dopamine's functions in the central nervous system have been linked in part to its anatomical distribution in target structures, and importantly, by drug-receptor interactions in diseases like parkinsonism and schizophrenia. These various avenues of investigation have led to different conceptions about the key neural structures and pharmacological mechanisms that could explain dopamine's prominent role in a multiplicity of behaviors (for reviews, see Goldman-Rakic et al. 1992; Kalivas and Nemeroff 1988; Willner and Scheel-Kruger 1991). Accordingly, dopamine has been linked to a wide variety of functions including motivation, reward, affect and movement. The neural basis of dopamine's actions in the central nervous system have reasonably been focused on the caudate nucleus and/or nucleus accumbens, where the dopamine innervation is most concentrated and the consequences of nigrostriatal and mesolimbic pathology are most severe. In consequence, however, the influence of dopamine on specific cortical functions has been much less studied and is much less understood. Nevertheless, the independent role of dopamine as a neurotransmitter in prefrontal areas has been well appreciated for decades (Thierry et al. 1977; Brown et al. 1979; Brozoski et al. 1979), and this recognition has spawned a variety of seminal pharmacological and anatomical observations on the cortical dopamine innervation. A number of studies have demonstrated differences in the laminar density of the tyrosine hydroxylase (TH)-labeled (Lewis et al. 1988) and dopamine-labeled fiber systems in the cortex (Goldman-Rakic et al. 1992; Williams and Goldman-Rakic 1993). These studies have revealed that catecholaminergic axons arborize extensively in the supragranular layers II and upper layer III and to a lesser extent in deep layers (Fig. 2). Receptor autoradiographic studies have localized the D 1 and D2 families of dopamine receptors to the precise laminae in frontal cortical areas where the innervation is most prominent (Goldman-Rakic et al. 1990; Lidow et al. 1991). Similar findings have been observed in biopsy samples from the frontal and/or temporal lobes of Parkinson patients and epilepsy patients (Smiley et al. 1992). The matching bilaminar distributions of dopa-

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Fig. 2. Schematic diagram of the distribution of dopamine axons (left) and their relationship to cortical elements (right). The triangles in the drawing represented putative DA contacts as conjectured before the in vitro findings illustrated in Fig. 3 were obtained. The model and the actual distribution are in excellent agreement; the density of contacts is actually greater on basilar than apical dendrites. Neuron E is a layer V pyramidal neuron that receives DA inputs on its distal horizontally oriented basilar dendrites and on the distal branches of its apical dendrites in layers II and upper II. B, C and G are pyramidal neurons in layers II, III and VI, respectively. A, D and F are nonpyramidal neurons which also receive DA afferents. Reprinted from Williams and Goldman-Rakic 1993.

m i n e t e r m i n a l s a n d d o p a m i n e r e c e p t o r s i m p l i e d a h i g h d e g r e e o f t a r g e t specificity a n d e n c o u r a g e d t h e s u p p o s i t i o n t h a t d o p a m i n e m a y be selective in its f u n c t i o n a l o r p h a r macological consequences.

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4. QUANTITATIVE ANALYSIS OF DOPAMINE CONTACTS ON PYRAMIDAL AND NONPYRAMIDAL NEURONS A full understanding of the action of dopamine in cortical circuits will require more complete and detailed knowledge of its connectional relationships with cortical targets. Traditional anatomical approaches have to date not provided a complete view of a given neuron's total dopaminergic (or any other) innervation; neither have they addressed whether neurons of different classes (pyramidal, nonpyramidal) or different layers are equivalent in the numerical strength of their afferentation. A recent study by Krimer et al. (1997) is the first to provide a complete three-dimensional morphometric reconstruction of cortical neurons targeted by catecholaminergic axons and to measure the total number as well as density of axonal appositions on their dendrites. Krimer et al. (1997) filled individual pyramidal and non-pyramidal cells in formalin-fixed slices of monkey prefrontal cortex with Lucifer Yellow (LY) and subsequently labeled the section containing the injected cell(s) both with an anti-LY antibody to reveal the neuron's dendritic arbor in its entirety and anti-TH antisera to reveal catecholaminergic axons in the same section of tissue. The study revealed that TH-axonal appositions on cortical pyramidal cells were distributed on the distal branches of dendrites, generally avoiding the primary basal or apical dendrites and were evenly distributed between dendritic spines and shafts with an average density of 0.7 per 100p of dendritic length (Fig. 3). An average of 90 appositions per pyramidal neuron was found for principal cells of different layers. However, some pyramidal neurons in layer II and upper layer III were exceptions as the number of appositions per unit length of their spiny dendrites was double that of any other neuron sample in the lower strata. This finding is worth mentioning only because it parallels the noticeably higher TH axonal density in this lamina (Lewis et al. 1988; Williams and Goldman-Rakic 1993). The greater dopamine innervation on the cells in these laminae may be implicated in the atrophic process which these cells exhibit in the prefrontal cortex of schizophrenic patients (Benes et al. 1991; Rajkowska et al. 1998; Selemon et al. 1998). Compared with the projection neurons of deeper cortical layers, the superficial prefrontal neurons are likely to carry out extensive associative cortical functions (Schwartz and GoldmanRakic 1984). Nevertheless, the dopaminergic innervation of each pyramidal cell constitutes but a small proportion of its total synaptic input. Thus, a volume transmission mechanism of dopaminergic modulation is a strong possibility to complement presumed synaptic action on the target cells of prefrontal cortex (Kawagoe et al. 1992; Garris and Wightman 1994; Garris et al. 1994). TH appositions are also present on the dendrites of interneurons but their density is nearly half that on pyramidal cells, comprising only 0.4+0.05 per 1001a of dendritic length. In contrast to pyramidal cells, interneurons exhibit a high variability with respect to their TH innervation. Some interneurons have only a single TH apposition while others have as many as an average pyramidal cell of layer III, probably reflecting the heterogeneity of the interneuron population in the cortex and the possibility that different subtypes of interneurons receive different numbers of TH contacts. Accurate quantitative assessments of catecholaminergic cortical innervation can now be used in comparative studies of brain development, aging or experimental pathology and may provide insight into the action of drugs at these sites in subject populations of different ages, genders, or in different conditions of disease and in different species.

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Fig. 3. 3-dimensionalreconstructed pyramidal and nonpyramidal cells with TH appositions. The pyramidal neuron was reconstructed from camera lucida drawings of appositions in six separate slices through the neuron. Nonpyramidal neurons were similarly reconstructed. A-appositions to spines; O-appositions to shafts.

5. E L E C T R O N M I C R O S C O P I C EVIDENCE OF DOPAMINE SYNAPTIC TRIADS AND D1 RECEPTOR LOCALIZATION IN SPINES Until the late eighties, the synaptic targets of dopamine axons in cortical circuitry were completely unknown and indeed there was considerable doubt as to whether dopamine axons formed synaptic specializations. Immunocytochemical electron-microscopic studies have now established the existence of classical synaptic contacts between dopamine axons and both pyramidal (Van Eden et al. 1987; Seguela et al. 1988; Goldman-Rakic et al. 1989; Verney et al. 1990) and nonpyramidal neurons in the primate prefrontal cortex (Smiley et al. 1994; Sesack et al. 1995). In monkeys, numerous dopamine axon terminals in prefrontal and other cortical areas form symmetrical synapses indistinguishable from traditional Gray Type II synaptic specializations (Goldman-Rakic et al. 1989; Smiley et al. 1992; 1994; Smiley and Goldman-Rakic 1993). The dopamine terminals in the prefrontal cortex are largely found on the distal dendrites and spines of pyramidal cells in both monkey (Goldman-Rakic et al. 1989; Smiley and Goldman-Rakic 1993) and humans (Smiley et al. 1992). In rodents, where dopamine synapses are also symmetrical, fewer of them are axospinous relative to 409

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axodendritic or axosomatic (Van Eden et al. 1987; Seguela et al. 1988; Verney et al. 1990) whereas in humans, it has been estimated that about 60% of dopamine synapses are axospinous (Smiley et al. 1992). As illustrated in Fig. 4, the spines on pyramidal neurons are invariably the targets of both dopamine afferents and another unspecified asymmetrical and presumed excitatory synapse (Goldman-Rakic et al. 1989; Smiley et al. 1992; Smiley and Goldman-Rakic 1993). This arrangement is referred to as a synaptic triad because it involves three circuit elements- two afferents and a target neuron. Similar synaptic triads are found in prefrontal, premotor and motor cortex suggesting that this anatomical arrangement may be widespread and common to many cortical areas. Dopamine triads have been observed in rat (Verney et al. 1990), monkey (Goldman-Rakic et al. 1989; Smiley and Goldman-Rakic 1993) and human (Smiley et al. 1992). Synaptic triads in which the dendritic spines of medium spiny neurons receive both a dopamine- or tyrosine hydroxylase-positive bouton and an asymmetrical synaptic specialization are also not unique to the cortex. A similar arrangement exists with the medium spiny cell in the rodent neostriatum (Freund et al. 1984). In both the cortex and striatum, the dopamine terminal endings are strategically placed within the local circuitry to alter local spine responses to excitatory inputs, and through these, to make a contribution to the overall excitability of the projection neurons in both structures. As will be described in greater detail below, the spines and distal dendrites of cortical pyramidal cells harbor D 1 receptors (Smiley et al. 1994; Bergson et al. 1995a). Many of these D1 positive spines are more often observed in contact with asymmetric excitatory terminals and less often in contact with symmetric dopaminergic afferents. These findings indicate a substantial non-synaptic mode as well as synaptic modulation at the D1 receptor.

Fig. 4. Diagram of synaptic arrangements involving the dopamine input to the cortex. A. Afferents labeled with a dopamine (DA) specific antibody terminate on the spine(s) of a pyramidal cell in the prefrontal cortex, together with an unidentified axon (UA); B. Enlargement of axospinous synapses illustrated in A showing apposition of the DA input and a presumed excitatory input (UA) that makes an asymmetrical synapse on the same dendritic (D) spine; C. Diagram of ultrastructural features of the axospinous synapses illustrated in B; the dopamine terminal (darkened profile representing DA immunoreactivity) forms a symmetrical synapse; the unidentified profile forms an asymmetrical synapse with the postsynaptic membrane. (Diagram modified from data presented in Goldman-Rakic et al. 1989.)

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6. D O P A M I N E INNERVATION OF THE MICROVASCULATURE

The dopamine innervation has to date been exclusively focused on neuronal interactions but light- and electronmicroscopic evidence has recently revealed a dopaminergic innervation of the microvasculature (Krimer et al. 1998). Dopamine and dopamine transporter immunopositive axons have been found in close apposition to blood vessels in frontal areas 6, 9 and 46 (Fig. 5). These appositions are particularly promlnent in layers I and II in accordance with the denser innervation of neurons in these cortical laminae. Ultrastructural analysis has confirmed that the direct appositions between dopamine axons and the vascular basal lamina frequently involve a thin glial process and processes of pericytes embedded in the basal lamina. Pericytes are contractile (Murphy and Wagner 1994), as they contain actin/myosin, and are involved in the regulation of perfusion and permeability in the microvasculature (Shepro and Morel 1993). Furthermore, dopamine exerts a powerful vasomotor response in small blood vessels in vitro (Krimer et al. 1998). In contrast, the well-known noradrenergic innervation of blood vessels is more prominent on pial vessels in the primate cortex. Noradrenergic appositions are much less common on the cortical microvasculature, in agreement with studies showing a low density of noradrenergic axons in the monkey prefrontal cortex (Morrison et al. 1982). Thus, there is a notable difference in the innervation of the intracortical microvasculature as compared to the extraparenchymal

Fig. 5. High-powerphotomicrographs of dopaminergic terminals associated with small cortical blood vessels. Dopaminergic axons and terminals are labeled with anti-dopamine (a-c) antibodies. They partially wrap around the vessel giving rise to several small varicosities (d, e) or to one giant (a-c) bouton closely apposed to the vessel. In Fig. 5f, a string of three terminals is apposed to a smooth muscle cell. Scale bar: 10 gm. 411

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blood vessels. The mechanisms regulating the cortical microcirculation are complex and not well understood but a direct innervation by dopamine may be one of the neurotransmitters involved in establishing a prompt and adjustable response to local metabolic demand imposed by the varied information processing functions of different cortical regions. The suggested role for dopamine neurotransmission in the regulation of local cortical blood flow is also a possible link between the mesocortical dopamine system and compromised blood in schizophrenia and Parkinson's disease (e.g., Wolfson et al. 1985; Weinberger et al. 1988).

7. DOPAMINE DI AND D2 FAMILY OF RECEPTORS IN THE CEREBRAL CORTEX

The availability of antibody probes for the D1 and D2 family of dopamine receptor proteins has permitted these subtypes of dopamine receptor to be localized at the lightand electron-microscopic level using standard immunohistochemical techniques. A summary of these immunocytochemical findings in the nonhuman primate cortex is provided below and in Table 1. 7.1. LOCALIZATION OF THE D1 FAMILY OF DA RECEPTORS IN PREFRONTAL CORTEX D l-immunoreactive neurons are present in all cortical layers of prefrontal cortex, but pyramidal neurons of layers II, III and V are particularly invested with this protein. Furthermore, the pattern of immunolabeling in perikarya, apical dendrites and neuropil in layers I-II and V-VI is in excellent agreement with the bilaminar pattern observed in autoradiographic studies of D1 binding sites (Goldman-Rakic et al. 1990; Lidow et al. 1991). Electronmicroscopic analysis has revealed that the vast TABLE 1. Location and function of dopam&e receptors & primate prefrontal cortex Receptor

Cellular localization

D1

Pyr and some NP 1'2'3

D5 D2L D2S D3 D4

Subcellular localization

Cellular functionaction on mem. fields

Sp, Den (adj to asym syn), T at mod. occupancy and some Ax 1'2'3 .L at high occ in Pyr 4 Den 1,5 see D 14 Pyr ~ NP 6 nonspec, inhibition of Pyr 4 nonspec, inhibition of Pyr 4 NP and dopamine fibers 6 nonspec, inhibition of Pyr 4 Som, Den and some Ax 7 ~. in Pyr 8 NP and some Pyr 7

Abbreviations: Pyr: pyramidal cell, NP: nonpyramidal cell, Som: soma, Den: dendritic shaft, Sp: dendritic spine, Ax: axon terminal, asym: asymmetric, and syn: synapse. ~Bergson C, Mrzljak L, Smiley JF, Pappy M, Levenson R, Goldman-Rakic PS (1995b). 2Muly EC, Szigeti K, Goldman-Rakic PS (1977). 3Muly EC, Williams GV, Szigeti K, Goldman-Rakic PS (in preparation). 4Williams GV, Goldman-Rakic PS (1995). 5Bergson C, Mrzljak L, Lidow MS, Goldman-Rakic PS, Levenson R (1995a). 6Khan Z, Mrzljak L, Gutierrez A, de la Calle A, Goldman-Rakic PS (in preparation). 7Mrzljak L, Bergson C, Pappy M, Huff R, Levenson R, Goldman-Rakic PS (1996). 8Williams GV, Rao SG, Leung H-C, Goldman-Rakic PS (1997).

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majority of D1 receptors are localized postsynaptically, and predominantly in the spines of cortical neurons (Figs 6 and 7). Indeed, it has been estimated that approximately 20% of the total number of spines in area 46 are labeled by D1 antibodies. Double labeling studies with tyrosine hydroxylase and the D1 receptor show that D1 immunoreactivity is more often in close proximity to asymmetric synapses than to THpositive axons, where it is typically slightly displaced from the asymmetric synapse or completely fills the spine head (Smiley et al. 1994). Presynaptic localization has also been observed as small patches of reaction product in axon terminals. These terminals often form asymmetric synaptic specializations and the immunoreaction product is most often found at a distance from the synaptic specialization. The D5 receptor is also expressed in pyramidal neuronal populations in the prefrontal cortex as well as all other neo-, meso- and archicortical areas of monkey brain examined. As with the D1 receptor, D5-immunoreactive neurons are visible in all cortical layers, again most prominently in layers II, III and V. The possibility that the D1 and D5 receptors are co-expressed within pyramidal neurons has been confirmed by double-label immunofluorescence microscopy (Bergson et al. 1995b). However, while the vast majority of D5-1abeled neurons also contain D1 receptors, not all D l-labeled cells appear to contain D5 receptors. Moreover, both light- and electronmicroscopic analysis has revealed that compared with D1 receptor, the D5 receptor sites are more prevalent in dendrites, and less in spines. Another difference with the D 1 receptor is that presynaptic D5 antibody labeling is observed not only in terminals, but also in the initial axonal segments of pyramidal neurons and D5 receptors are also present in axon terminals forming both symmetric and asymmetric synapses (Bergson et al. 1995b). Like the D l-labeled spines, however, D5 receptor-containing spines are nearly always targets of asymmetric synaptic input and the immunoreaction product in D5-positive spines is also either distant from the synaptic specialization or diffusely distributed in the spine. It is of interest that relatively greater D1 receptor immunoreactivity is observed in the primate prefrontal cortex compared to the rodent cortex (Levey et al. 1993; Smiley et al. 1994; Bergson et al. 1995b; Bergson et al., unpublished observations). A similar monkey-rodent difference has also been reported for D5 mRNA expression (Laurier et al. 1994). These phylogenetic differences in receptor density may correspond to those observed in the DA innervation of the cerebral cortex (reviewed in Berger et al. 1991) with primates and humans possessed of much more extensive DAergic input than rodents. The higher levels of the D1 and D5 receptor expression and DA innervation in monkey cortex compared to rodent raise the possibility that levels of DA receptor expression in cortex may be related to the levels of DA input. 7.2. LOCALIZATION OF THE D2 FAMILY OF DA RECEPTORS IN PREFRONTAL CORTEX Among all the dopamine receptors cloned to date, the D2 subtype of dopamine receptors has been the one most closely linked to the positive symptoms of schizophrenia (Reynolds 1996; Joyce and Meador-Woodruff 1997), and most often implicated in extrapyramidal side effects (Nordstrom et al. 1993; Calabresi et al. 1997). Employing subtype-specific antibodies to the D2 receptor, a recent study in this laboratory has established that the D2 receptor is present exclusively in cortical neurons with nonpyramidal morphologies (Khan et al. 1998). Double labeling with D2 antibodies and the calcium-binding protein, parvalbumin, indicate that the D2-bearing 413

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Fig. 6: Electronmicrograph of a biopsy of human cortex labeled with the D1 antibody. The photograph shows a single putative excitatory terminal forming asymmetric synapses with two spines (s), each of which is labeled with the D1 antibody. One of the spines is a continuation of the large dendrite (d).

neurons are indeed members of the interneuronal population in the primate prefrontal cortex. Two splice variants of the D2 receptor have been identified - a short form, D2S and a long form, D2L. The short form is lacking 29 amino acids in the third cytoplasmic loop (Giros et al. 1989; M o n s m a et al. 1989). Anatomical (Sesack et al. 1994; Hersch et al. 1995). Physiological studies have attributed both autoreceptor and postsynaptic functions to the D2 receptors (Garris et al. 1994; Cragg and Greenfield 1996; Mercuri et al. 1997). K h a n et al. (1998) have shown that the two isoforms are differ414

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entially compartmentalized in the cortex with the D2S predominating in the cell bodies and projection axons of the mesencephalic and hypothalamic dopaminergic cell groups, whereas the D2L is more strongly expressed by GABAergic neurons in the striatum and nucleus accumbens, structures targeted by dopaminergic fibers. The strategic localization of the D2S isoform in dopaminergic cell bodies and axons strongly suggests that this receptor predominantly serves an autoreceptor function, while the D2L isoform appears to be mainly involved in postsynaptic function. The D3nf DA receptor appears to be expressed by primates, but not rodents. In humans, D3nf presumably arises from a splicing event that deletes 98 nucleotides of the D3 receptor coding sequence and also shifts the D3 receptor's open reading frame (Schmauss et al. 1993). D3nf rabbit antiserum produced by Liu et al. (1994) prominently labels apical dendrites in all layers of the macaque prefrontal cortex (Fig. 7). In contrast to all other antibody labeling of pyramidal neurons in the prefrontal cortex, the triangular-shaped pericarya from which the D3nf immunoreactive dendrites presumably originate are only faintly labeled. The densest packing of labeled dendrites is observed in layers I-III and in layers V-VI. However, dendrites in layer IV exhibit the most intense staining and are often present in irregularly spaced bundles. Some of these boldly stained, relatively straight dendrites project across several cortical layers. In contrast, the labeled dendrites in the upper layers are shorter and more frequently branched. The subcellular localization of the D3nf polypeptide has not yet been determined nor is a D3 antibody yet available to compare with the splice variant. The role of the D3nf receptor in vivo is unclear. The primary sequence of the D3nf polypeptide is expected to be identical to that of the full length D3 receptor from its N terminus through the first five transmembrane segments and 76 amino acids of the predicted third cytoplasmic loop. Beyond this point, however, the D3 and D3nf proteins share no sequence homology. Furthermore, protein secondary structure algorithms predict that the novel C-terminal 55 amino acids of the D3nf protein are unlikely to form a sixth and seventh transmembrane segment. Studies with other members of the seven-transmembrane-segment receptor superfamily suggest that residues in these membrane-bound segments, as well as in the corresponding intracellular domains, play a role in ligand binding and/or G-protein coupling (Dahl et al. 1991; Weiss 1993; Chen et al. 1995). It is of interest that D3nf transcripts are maintained in postmortem neocortical tissues obtained from schizophrenic patients whereas those for D3 are dramatically reduced relative to the levels observed in tissue from unaffected individuals (Schmauss et al. 1993). Thus, the D3nf protein looms as a potentially intriguing link in the proposed role of DA in schizophrenia. The D4 receptor has been thought to be one of the major targets of the atypical neuroleptic, clozapine, and possibly the receptor most important for its beneficial effects on negative symptoms (Meltzer et al. 1989; Lee et al. 1994). The D4 receptor has been studied at both light- and electronmicroscopic levels with a D4 receptorspecific antibody (Mrzljak et al. 1996) and found to be prominently localized in interneurons of the macaque monkey cerebral cortex and hippocampus (Fig. 7). Unlike the D2 receptor, some immunolabeling with the D4 antibody has been found in pyramidal neurons as well and electronmicroscopic analysis shows this receptor on postsynaptic structures apposed to asymmetric synapses. The association of the D4 receptor with GABAergic neurons is particularly pronounced in subcortical structures such as the globus pallidus and the pars reticulata of the substantia nigra, where the principal GABAergic neurons in these structures are intensely labeled by D4 antibodies. 415

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Fig. 7. Diagrammatic representation of the prominent localization of the dopamine subtype specific receptors (D 1, D2, D3nf, D4 and D5) in cortical pyramidal and nonpyramidal neurons of the cortex. Diagram is based on findings reported in Smileyet al. 1994; Bergson et al. 1995a; 1995b; Liu et al. 1994; Mrzljak et al. 1996 and Khan et al. 1998.

With the exception of the D3nf isoform, the predominance of D2 family receptors in interneurons (the D2 apparently exclusively and the D4 predominantly in nonpyramidal cells) contrasts with the predominant localization of D1 family receptors in pyramidal neurons. These findings reveal an heretofore unappreciated degree of specification in the localization of receptors within cortical circuits and circuit elements and provide the first evidence for localized actions of these receptors in different compartments of the cortical neuropil.

8. R O L E OF D O P A M I N E R E C E P T O R S IN C O R T I C A L F U N C T I O N In spite of the scope of dopamine's behavioral effects, knowledge of how prefrontal cortex neuronal activity is regulated by the mesocortical dopamine system is still limited. While some authors report excitatory effects of dopamine on pyramidal and/or GABA-ergic neurons on rat prefrontal cortex (Penit-Soria et al. 1987), others have observed inhibitory effects (Law-Tho et al. 1994; Geijo-Barrientos and Pastore 416

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1995; Williams and Goldman-Rakic 1995) or differential modulatory effects depending on the strength and timing of synaptic input rather than effects of pure excitation or inhibition (Yang and Seamans 1996). Neuronal responsivity of cortical neurons in awake behaving monkey is highly sensitive to the level of dopamine stimulation of D1 receptors (Sawaguchi and Goldman-Rakic 1994; Williams and Goldman-Rakic 1995). As indicated above, this dopamine receptor subtype occupies a strategic position on the spines of pyramidal neurons, which are also a major postsynaptic target of excitatory input (Goldman-Rakic et al. 1989; Levey et al. 1993; Smiley et al. 1994; Bergson et al. 1995b). This and other evidence is accumulating to indicate that dopamine has a major role in regulating the excitability of the pyramidal neuron in prefrontal cortex and in particular its responsiveness to particular sensory input (Williams and Goldman-Rakic 1995). The synaptic triads shown in Fig. 4 have been proposed as an important morphological substrate for dopamine's specific actions in the cortex. In a triad, the same spine belonging to a pyramidal neuron is postsynaptic to both a dopamine terminal and an excitatory terminal (Goldman-Rakic et al. 1989). As pyramidal cells receive the major sensory inputs arriving at the cortex via spine synapses, this synaptic 'triad' complex allows direct dopamine modulation of the spine's response to a specific input. As the majority of the dopamine synapses appear to be formed on pyramidal neurons, dopamine axons are thus placed in direct contact with the major projection neurons of the prefrontal cortex and with the neuronal compartment of the cell where D1 receptors are most concentrated. It could be predicted from this synaptic arrangement, that stimulation of the D1 receptor would have content specific actions related to the specific nature of a spine's excitatory input. Recent studies combining single-cell recording and iontophoretic application of dopamine receptor antagonists have indeed revealed remarkable specificity in the role of the D 1 receptor in the mnemonic process carried out by prefrontal neurons (Fig. 8). This process has been shown to consist in part of neurons with 'memory fields', i.e., the propensity of prefrontal neurons to exhibit maximal firing for a preferred target in the delay period of a working memory paradigm associated with the recall of its preferred visual target (Fig. 7; Funahashi et al. 1989). In the pharmacological studies, D1 blocking (or stimulant) drugs such as SCH389166 are applied by local iontophoresis onto neurons with physiologically characterized memory fields recorded during behavioral performance of trained monkeys (Williams and Goldman-Rakic 1995). The evidence shows that a moderate level of D1 receptor stimulation optimizes the prefrontal neurons response to its preferred visual target while having remarkably little effect on the neuron's firing rate in response to nonpreferred targets. The D2 receptor antagonist, raclopride, had little effect on the neuron's responsiveness or produced a weak inhibitory action on neuronal firing. Thus, D 1 modulatory effects thus appear to localized and constrained to the prefrontal neuron's excitatory input. Such an effect can be explained by the triadic anatomical arrangement in which the D1 receptor is adjacent to a specific excitatory terminal. The importance of D1 stimulation for behavioral performance on delayed-response tasks has been examined both with intracerebral (Sawaguchi and Goldman-Rakic 1991, 1994) and systemic injections (Arnsten et al. 1994) of D1 antagonists and D1 agonists. D1 antagonism impairs delayed-response behavior in young adult monkeys independent of whether the drugs are locally applied or injected systemically. On the other hand, D1 agonists improve performance in monkeys in whom dopamine levels are experimentally depleted by reserpine treatment or in the aged monkey in whom 417

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endogenous levels of dopamine are reduced (Brown et al. 1979; Arnsten et al. 1994). These studies together with the electrophysiological results described above indicate that a moderate level of D1 stimulation is facilitatory for working memory performance and that either insufficient stimulation or overstimulation may be detrimental to performance (Murphy et al. 1996).

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In a d d i t i o n to direct action at D1 receptors p r e s u m e d to be at spine synapses, d o p a r n i n e m a y h a v e a c o n s i d e r a b l e influence on b e h a v i o r t h r o u g h n o n s y n a p t i c action. N u m e r o u s d o p a m i n e varicosities are o b s e r v e d in n o n s y n a p t i c r e l a t i o n s h i p to cortical elements (Smiley a n d G o l d m a n - R a k i c 1993; Smiley et al. 1994) a n d m a y r e p r e s e n t a m o r e pervasive m e a n s o f altering p y r a m i d a l cell activity, possibly f o r m i n g a basis o f tonic actions. M a n y D1 receptors h a v e been localized to spines o f p y r a m i d a l cells which a p p e a r to lack a d o p a m i n e synaptic t e r m i n a l a l t h o u g h these receptors are inv a r i a b l y a p p o s e d to g l u t a m a t e r g i c synapses on the same spine (Smiley et al. 1994). Thus, actions at a n y a n d all of these receptors c o u l d be d u e to n o n s y n a p t i c m e c h a nisms or at h e t e r o r e c e p t o r s . H o w such actions m i g h t be expressed a n d w h e t h e r they w o u l d differ f r o m those at triadic c o m p l e x e s r e m a i n s to be e x a m i n e d . Still a n o t h e r i m p o r t a n t m e c h a n i s m of d o p a m i n e action is an indirect one involving f e e d f o r w a r d inhibition on p y r a m i d a l n e u r o n s f r o m n o n p y r a m i d a l i n h i b i t o r y i n t e r n e u r ons. R e c e n t evidence indicates t h a t p y r a m i d a l a n d n o n p y r a m i d a l n e u r o n s interact physiologically as m o n k e y s h o l d a p a r t i c u l a r item of i n f o r m a t i o n in w o r k i n g m e m o r y . In particular, i n t e r n e u r o n s , like p y r a m i d a l n e u r o n s , express directional preferences; a n d p a t t e r n s o f activity expressed by closely a d j a c e n t p y r a m i d a l a n d n o n p y r a m i d a l n e u r o n s are often inverse, such t h a t as a n o n p y r a m i d a l n e u r o n increases its rate o f discharge, a n e a r b y p y r a m i d a l n e u r o n decreases its rate (Wilson et al. 1993; R a o et al., u n p u b l i s h e d observations). These findings p r o v i d e evidence t h a t f e e d f o r w a r d inhibi-

(

Fig. 8 A, Left: schematic sequence of events in each phase of the ODR task (aligned in time with rasters and histograms shown immediately below); Right: depiction of the eight positions of the target (plus the central fixation position, #0) to be remembered for guidance of oculomotor response. B, Effect of SCH 39166 on response of neuron W54 (rastergram above, histogram below: bin = 50 ms) for a target (position #2) in the memory field (left) and for a target (position #7) in nearly the opposite location in space (right). Top: Control recording showing significant but weak delay activity. Middle: SCH 39166 (25 nA) produces dramatic enhancement of activity during the delay period when the target is in the memory field but produces an inhibition of activity when the target is in position #7. Bottom: SKF 38393 reverses the effect of SCH 39166 and reduces delay activity to 'background' level. Note: C = cue period, D = delay period, R = response period in all figures.

Methods. In the ODR task a monkey is required to fixate a central small stimulus (approximately subtending 1~ of visual space) for 0.5 s after which a peripheral cue stimulus (13~ eccentric, 45~ separation) appears for 0.5 s in one of eight positions (see Fig.la; position randomly allocated for each trial). The monkey has to maintain its central fixation for a further 3 s during the delay period. After this time, the fixation stimulus is removed and the monkey has to make a rapid saccade to, and fixate upon, the location where the cue stimulus had been shown. Each neuron was tested for 8 peripheral target locations (as shown in Fig.lA) presented randomly over multiple trials in both control and drug conditions. Analysis of variance was used to compare neuronal responses with regard to: (i) different periods of the task (including cue, delay, response, and inter-trial interval); (ii) different drug conditions; and (iii) different target locations. The source of significant variance was then ascertained by the Tukey HSD test. All delay responses and their spatial tuning as well as all drug effects were based on significant comparisons (P < 0.05). Iontophoresis was started after sufficient numbers of trials (usually 9 or more) had been collected for each target position in the task under the control condition. Data was taken after drug had been applied for at least 10 seconds. In most cases the neuron was recorded in recovery from the drug (<45 minutes) in order to check that activity returned to approximate control levels. While drugs were not being tested, a retaining current of 1-2 nA was applied to each drug channel periodically. Iontophoretic electrodes were constructed from quad-sectioned glass tubing (Clark Electromedical, Pangbourne, UK) using 33 gm carbon fiber (Textron Inc., Lowell, MA, USA). The glass was flame-polished at the top end and the assembly was 'pulled' using a computer-driven device to produce long electrode shanks (90-100 mm) with fine tips (c35 gm) which were then silver- plated for low noise recording. The electrodes were then loaded with drugs in a concentration of 5-10 mM at pH 3.5-4.0. 419

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tion may play a role in the construction of a memory field in prefrontal neurons. The indirect action of dopamine on this circuit derives from the identification of dopamine synapses on nonpyramidal GABAergic neurons in prefrontal cortex (Sesack et al. 1995; Smiley et al. 1994) and the previously mentioned finding that both the D2 and D4 members of the D2 family of dopamine receptors are localized postsynaptically on a subset of GABA interneurons (Mrzljak et al. 1996; Khan et al. 1998). Dopamine has been shown to both stimulate and inhibit interneurons in rat cortical neurons (Thierry et al. 1977; Sheldon and Aghajanian 1990). The different effects of dopamine may depend upon the subtype of interneuron engaged and future studies may indicate whether interneuron heterogeneity is the basis for the differential modulation of nonpyramidal neurons in the cortex.

9. REGULATION OF CORTICAL DOPAMINE RECEPTORS AS TARGETS OF ANTIPSYCHOTIC DRUGS 9.1 EFFECT OF ANTIPSYCHOTIC MEDICATIONS ON THE D2 RECEPTORS IN THE PRIMATE CEREBRAL CORTEX It is widely assumed that the therapeutic action of typical neuroleptic drugs depends on their antagonistic action at D2 receptors (Seeman et al. 1975; Creese et al. 1976) and their capacity to up-regulate D2 sites, particularly in the neostriatum (Rupniak et al. 1983; Memo et al. 1987; O'Dell et al. 1990; See et al. 1990). However, recent studies in nonhuman primates have provided new evidence for a common site of antipsychotic action in the cerebral cortex, particularly association cortex (for review see Lidow et al. 1997; Lidow and Goldman-Rakic 1997; 1998). One line of evidence comes from studies on the effect of chronic treatment of monkeys with the atypical neuroleptic drug, clozapine, a drug which has strong anti-psychotic efficacy in patients with schizophrenia. Clozapine and other atypical neuroleptics do not produce the unwanted extrapyramidal side-effects associated with typical antipsychotic drugs like haloperidol. This benefit is attributed to clozapine's low affinity for most subtypes of the D2 receptor class at therapeutic doses (for review see Meltzer 1990; Coward 1992) and low levels of occupancy of the D2 receptors in the neostriatum (Farde and Nordstrom 1992; Matsubara et al. 1993; Farde et al. 1994; Scherer et al. 1994). Significantly, chronic clozapine treatment has been found to up-regulate D2 receptor protein and/or mRNAs in the primate cerebral cortex at doses which produce no effect on the striatal receptors (Janowsky et al. 1992; Lidow and Goldman-Rakic 1994; Lidow et al. 1997; Baldessarini et al. 1996; I. Creese, personal communication). Further, both the D2-1ong and D2-short isoforms of message for this receptor are up-regulated (Lidow et al. 1997). Thus, the studies of receptor regulation in the primate have shown that clozapine and typical neuroleptics appear to differ in their influence on neostriatal receptors but are highly similar to each other with respect to their effects on cortical D2 receptors. Although D2 dopamine receptor antagonism is postulated to be the key to antipsychotic efficacy in the treatment of schizophrenia, quantitative receptor binding (Lidow et al. 1989) and autoradiographic studies (Goldman-Rakic et al. 1990; Lidow et al. 1991) in primate cortex have revealed that the D 1 dopamine family of receptors are far more prevalent in the cortical areas of the brain, such as the prefrontal cortex, than are the D2 receptors which have been more commonly implicated in schizophre420

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nia. Moreover, the prefrontal cortical D1 sites and mRNAs have recently been shown to be down-regulated by chronic treatment with several commonly used antipsychotic drugs, all of which block D2 receptors (Lidow and Goldman-Rakic 1994; 1997) (Fig. 9). Remarkably, levels of D1 receptor protein (Lidow and Goldman-Rakic 1994) and both D1 and D5 mRNAs (Lidow and Goldman-Rakic 1997) are reduced in the prefrontal cortex by 30-60% compared to a vehicle control group, while mRNAs in the neostriatum are not affected, supporting other studies in the literature which show no clozapine-related effects at these sites (Ashby et al. 1989; Jiang et al. 1990). This observation indicates that a reduction in the levels of prefrontal cortical dopamine receptors of the D1 class may be an obligatory consequence of D2 receptor antagonism and, as such, another common pharmacological property of antipsychotic drugs. The down-regulatory effects of anti-psychotic drugs on D1 receptors may be pertinent to understanding the cognitive impairments which are characteristic of schizophrenia (Taylor and Abrams 1984; Goldman-Rakic 1987; 1991; Weinberger et al. 1988; King 1990) and their inconsistent, if ineffective, impact on these impairments (Berman et al. 1986; Classen and Laux 1988; Tomer and Flor-Henry 1989; King 1990; Hindmarch 1994). The level of D1 receptors has recently been reported to be lowered in drug-naive schizophrenics (Sedvall and Farde 1996; Okubo et al. 1997). If D1 sites are further reduced due to drug treatment, as the present experimental study in nonhuman primates shows, it is possible that the number of D1 sites are suboptimal for cortical function. As mentioned in Section VII, a narrow range of D1 occupancy optimizes physiological signaling in prefrontal neurons engaged by working memory while too little D1 stimulation (due to excessive blockade of the receptor) results in diminished neuronal activation (Williams and Goldman-Rakic 1995) as well as behavioral impairment (Murphy et al. 1996). The strong indication that impairment in working memory is one of the major deficits underlying the cognitive impairments of schizophrenia (Goldman-Rakic 1987; 1991) raises the possibility that antipsychotic drugs may either improve, worsen or have no effect on cognitive performance in schizophrenia depending on how they regulate the levels of prefrontal cortical D 1 sites in relation to the optimal range. Similar considerations could be raised with regard to the action of antipsychotic drugs on the negative symptoms of schizophrenia, which, according to a number of investigators (Johnstone et al. 1978; Andreasen and Olson 1982; Bilder et al. 1985; McKenna et al. 1989; Meltzer and Zureick 1989) are closely associated with cognitive abnormalities, and like cognitive deficits, do not show consistent improvement with presently-available drug treatments (Moiler 1993; Lindenmayer 1995). Furthermore, Dl-specific drugs have been reported to affect the negative symptoms without significant influence on the positive symptoms of the disease (Davidson et al. 1990; De Boer et al. 1995; Karle et al. 1995). Altogether, these findings suggest that, while the ability to down-regulate cortical D 1 receptors maybe an indirect effect associated with D2 antagonism, it nevertheless is common for all presently effective antipsychotic agents and, as such, may have important implications for their therapeutic effects. In evaluating the regulatory actions of antipsychotic treatments, greater consideration should therefore be given to changes in prefrontal cortical D1 receptors, and future antipsychotic treatments might be designed to provide optimal stimulation of cortical D1 sites as well as to antagonize D2 receptors.

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10. SUMMARY AND FUTURE DIRECTIONS Anatomical, physiological and neuropharmacological studies in n o n h u m a n primates are providing a new more detailed image of dopamine's role in cortical function. These studies of the circuit, cellular and subcellular levels of dopamine distribution and function can now be interconnected with the study of intracellular signaling pathways, on the one hand, and computational modeling on the other, to decipher the key mechanisms involved in regulation of normal function and dissolution of function in disease. It needs to be kept in mind, however, that additional mechanisms are integral to the optimal functioning of cortical cells and circuits. A m o n g these, the serotonergic afferents and their receptor substrates are of great prominence as it is 422

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now known that the 5-HT2A receptor is predominantly located more proximally to the D1 receptor sites in pyramidal neurons (Jakab and Goldman-Rakic 1996; 1998) and acts to facilitate the tuning of these neurons in working memory tasks (Williams and Goldman-Rakic 1995). Serotonin 5-HT2A receptors are also present in a subset of cortical interneurons (Morilak et al. 1993; Jakab and Goldman-Rakic 1998). Serotonin induces IPSPs in pyramidal neurons and excitatory responses in a subset of nonpyramidal neurons and both effects are blocked by the 5HTzA/5HT1c antagonist, ritanserin (Sheldon and Aghajanian 1990), and by atypical neuroleptics (Gellman and Aghajanian 1994). The presumed co-localization of D2, D4 and serotonin receptors in nonpyramidal neurons could provide a basis for a synergistic action of these monoamines on cognitive function. Given that the atypical neuroleptic, clozapine, has a high affinity for the 5-HT2 receptor (Meltzer et al. 1989; Leysen et al. 1995), such colocalization may offer another possible neural explanation for the reported improvements in negative symptoms by atypical neuroleptics (Lee et al. 1994). As both dopamine and serotonin have complex effects - modulating pyramidal cell firing directly and indirectly through control of nonpyramidal cell f i r i n g - understanding the relative impact of direct and indirect actions of these neurotransmitters on pyramidal cell firing in vivo and on the glutamate receptors involved in excitatory neurotransmission may hold the key to effective pharmacotherapy of all classes of symptoms in schizophrenia. These circuit mechanisms may also provide answers to long-standing questions about the role of the brain stem monoamines systems in maintaining optimal functioning in normal individuals. And finally, the omnipresent interactions between pyramidal neurons and interneurons and thus the critical roles of gamma-aminobutyric (GABA) receptors and glutamate receptors on excitatory transmission in local and long-tract cortical circuits need to be more fully integrated with the actions of dopamine and serotonin. Studies in primates, especially of their well developed and highly differentiated cortical circuits should contribute significantly to these issues which are so relevant to the highest functions of the human brain.

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428

Subject index

A8 retrorubral area dopamine neurons 403 A9 and A10 dopamine neurons dopamine projections 403 accessory olfactory bulb in New World monkeys 176 accumbens core and shell subdivisions 89 transition borders with 144 acetylcholinesterase reactivity in extended amygdala 98, 107 sublenticular component 107 in latero-basal amygdaloid complex 179 in ventral striatum 86 ACTH immunoreactive fibers in latero-basal amygdaloid complex 180 adenosine receptors in basal ganglia 263, 265 amygdala (see also specific nuclei and extended amygdala) nuclear subdivisions 114, 156 posterior cortical nucleus 173 amygdalofugal pathways of extended amygdala 97 AMPA-kainate receptors in basal ganglia 258 in hippocampus 354 in subiculum 367 amygdaloid body subnuclei 11 amygdaloid complex

projections to basal ganglia 239 relative to hippocampal formation 297 amygdalopiriform transition area 154 amygdalostriatal transition area 10 anterior amygdaloid area ChAT-immunoreactivity 171 in human 171 in monkey 171 within extended amygdala 114 anterior cingulate cortex dopamine afferents 405 area TF 306 area TH 306 aspartate systems in hippocampus 354 in subiculum 367 basal forebrain acetylcholinesterase reactivity 1 enkephalin immunoreactivity 1 substance P immunoreactivity 1 surface boundaries 2 surface topography 1 basal ganglia aminergic afferents to 239 and higher mental functions 269 connections of, to basal ganglia 229 connections of 231 differential vulnerability neurons 227 direct outputs 232

GABA-ergic circuits 234 glutamatergic circuits 234 indirect outputs 232 matrisomes 235 transmitters 235 matrisomes 236 immediate early gene expression in 236 neurochemically-coded subdivisions 227 neuropeptides 234, 245 normal functions challenged 268 open functional questions remain 269 other afferents to 239 pars compacta 229 dopamine containing cell groups 229 pars compacta of the substantia nigra 229 pars reticulata of the substantia nigra 229 pedunculopontine nucleus 229 striosomes 235 subnuclei 228 subthalamic nucleus 229, 233 basal ganglia diseases functional considerations 267 therapeutic approaches based on chemical neuroanatomy 244 basal nucleus of Meynert 57, 62 and Alzheimer's disease 64 cellular composition 63 neurons 70 non-cholinergic cells 63 secretoneurin 111

429

Subject index within extended amygdala 114

basolateral amygdaloid nucleus angiotensin converting enzyme in 183 calretinin- immunoreactive neurons 182 cholecystokinin mRNAcontaining neurons 183 cholinergic markers of 181 corticotropin-releasing factor 183 CRF immunoreactive neurons 183 NADPH-diaphorase neurons 182 parvalbumin neurons 182 peptide-Y immunoreactive cells 183 subdivisions 181

basomedial amygdaloid nucleus cholinergic markers 184 cholecystokinin neurons in 184 corticotropin-releasing factor 184 enkephalin 179 NADPH-diaphorase neurons in 184 neurons in 184 parvalbumin-immunoreactive cells in 184 subdivisions 184

bed nucleus of stria terminalis 62 chemoarchitecture 98 subdivisions 98 transition borders with 144

benzodiazepine receptors in basomedial nucleus of amygdala 185 in laterobasal amygdaloid complex 180 in paralaminar amygdaloid nucleus 186 neurochemical markers in 185

brain-derived neurotrophic factor in dentate gyrus 353 in entorhinal cortex 388 430

in hippocampus 366 in subiculum 372

calbindin glutamic acid decarboxylase 247 in basal ganglia 247 isoforms of, in basal ganglia 247 parvalbumin 247 in bed nucleus of stria terminalis 105 in dentate gyrus 350 in extended amygdala 98 in hippocampus 364 in perirhinal and parahippocampal cortices 37 in subiculum 371

calcium-binding proteins (see also specific proteins) in in in in in

dentate gyrus 348 entorhinal cortex 385 hippocampus 362 perirhinal cortex 389 subiculum 370

calretinin as marker of dentate polymorphic neurons 300 in dentate gyrus 350 in hippocampus 365 in perirhinal and parahippocampal cortices 377 in subiculum 371

cannabinoid receptors in basal ganglia 266

central amygdaloid nucleus cellular characteristics 120

centre median parafascicular (CM-Pf) loop 237 inhibitory pathways in 243

centre median-parafascicular complex basal ganglia connections 232 downstream output connections 232 subthalamic loop 233

centromediai amygdaloid complex 62 chandelier cell and GABA in hippocampus 358 ChAT immunoreactivity 184

in anterior amygdaloid area 171 in nucleus of lateral olfactory tract 172 in paralaminar amygdaloid nucleus 185 cholecystokinin (CCK) 180 entorhinal cortex and 384 immunoreactive fibers in latero-basal amygdaloid complex 180 in basomedial amygdaloid nucleus 184 in bed nucleus of stria terminalis 98, 103, 104 central division 103 in lateral division 104 in central amygdaloid nucleus 116, 120 in dentate gyrus 346 in entorhinal cortex 384 in extended amygdala 98, 107, 132, 138, 139 stria terminalis, supracapsular part 138, 139 supracapsular subdivision 132 sublenticular component 107 in hippocampus 360 in perirhinal and parahippocampal cortices 375 in presubiculum and parasubiculum 375 in subiculum 369 in ventral striatum 86

cholinergic interneurons in basal ganglia 247, 265

cholinergic system in in in in

entorhinal cortex 379 hippocampus 355 perirhinal cortex 388 presubiculum and parasubiculum 373 in subiculum 367

chromogranin-A in bed nucleus of stria terminalis 105

ciliary neurotrophic factor in in in in

dentate gyrus 353 entorhinal cortex 388 hippocampus 366 subiculum 372

Subject index

claustrum and boundary with endopiriform nucleus 150 components of 7 relationship to endopiriform nucleus 8 corpus striatum 228 cortical amygdaloid nuclei 154, 173 corticotropin releasing factor 184 cytochrome oxidase activity in dentate gyrus 351 cytochrome oxidase in entorhinal cortex 387 in hippocampus 365 in perirhinal and parahippocampal cortices 378 in subiculum 372 dentate gyrus and monoaminergic afterents 343 and peptidic innervation 345 cellular boundaries defined immunohistochemically 300 cholinergic system 339 GABAergic systems 341 glutamate system 337 of glutamate receptors 337 diagonal band of Broca 57 anatomic boundaries 6 anatomic components 6 disinhibition in basal ganglia 242 dopamine brainstem nuclear groups 403 in presubiculum and parasubiculum 375 dopamine afferents to extended amygdala transition zone 146 comparative evolutionary features in frontal lobe 405 primate-rodent differences 406 cortical dopamine receptor distributions 410

microvascular appositions 411 contrasts with noradrenergic innervation 411 actions of anti-psychotic medications on 420 differential effects of drugs on, D1 vs D2 receptors 421 interactions with other transmitter actions GABA 422 5-HT 422 interneuronal innervation 420 non-synaptic D1 effects 419 cortical regional and laminar patterns 406 quantitative synaptic localizations 408 synaptic triads 410, 417 ultrastructural studies 409 volume transmission concept 408 dopamine receptors changes with diseases of basal ganglia 262 context-specific actions 417 cortical distributions 412 cortical neuronal differences in 413 cortical neuronal species differences 413 cortical neuronal differences in 413 cortical subtype expression differences 415 cortical neuronal difference 416 D1 vs D2 416 cortical actions 416 D3nf and D3nF subtype 415 D4 subtype and GABA neurons 415 subtypes on basal ganglia neurons 261 dopamine-fl-hydroxylase in bed nucleus of stria terminalis 101 dorsal frontal areas dopamine afferents of 403

prefrontal projections 403 dorsal pallidum see also globus pallidus 228 see pallidum 8 dynorphin in basal ganglic striosomes 245 dystonia drug-induced syndromes 256 inherited forms 256 pathology 255 signs and symptoms 255 dystonia musculorum deformans dopamine paradox in 256 genetic abnormalities 256 in Ashkenazis 256 PET studies in 256

endopiriform nucleus 149 and boundary with claustrum 150 relationship to claustrum 8 enkephalin in basal ganglia striosomes 245 in bed nucleus stria terminalis 99 in central amygdaloid nucleus 116 in extended amygdala 98, 107, 130 in ventral pallidum 90 in ventral striatum 69, 86 lateral subdivision of 99 stria terminalis 130 sublenticular component 107 entorhinal and perirhinal cortices : cellular differences in 288 entorhinal cortex cytoarchitectonic divisions 303 immunohistochemical markers for 304 episodic memory 285 extended amygdala amygdalofugal pathways 97 components 10, 93 contiguous elements 94 431

Subject index divisions 10 encirclement of internal capsule 95 excluded amygdala nuclei 10 interface islands 124 neuronal components 124 of small-celled islands 124 overlaps with striatum 111 small-celled islands 11 stria terminfilis 124, 125 subdivisions 94 sublenticular components 105 supra-capsular subdivision 125

GABA neurons basal ganglia circuits 234, 241 down regulation in Parkinson's disease 252 in latero-basal amygdaloid complex 179 in ventral pallidum 90 in ventral striatum 69 GABA receptors and benzodiazepines 264 in Huntington's disease 264 subtypes in basal ganglia 263 subunits of 264 GABAergic systems in dentate gyrus 343 in entorhinal cortex 381 in hippocampus 356 in presubiculum and parasubiculum 374 in subiculum 368 galanin in bed nucleus stria terminalis 103 central division of 103 in dentate gyrus 348 in entorhinal cortex 385 in hippocampus 362 in presubiculum and parasubiculum 376 in subiculum 370 Gilles de la Tourette syndrome

432

basal ganglia changes in 257 globus paUidus AMPAJkainate receptors 338 glutamate receptors in dentate gyrus 337 NMDA receptors 337 glutamic acid decarboxylate in bed nucleus of stria terminalis in lateral division of 104 glutamate receptors (see also specific types) in basal ganglia 234, 240, 258 in entorhinal cortex 378 in hippocampus 353 in presubiculum and parasubiculum 373 in subiculum 366 glycine receptors in basal ganglia 263

hemiballismus subthalamic nucleus infarction 249 hippocampal formation boundaries 293 concept defined 286 projections to basal ganglia 239 hippocampus cellular layers defined 300 huntingtin in striosomes 255 huntingtin-associated protein 255 Huntington's disease basal ganglia neuronal changes in 227 cannabinoid receptors in 266 dopamine changes in 254 environmental toxins and 255 genetic mutations in 254 inheritance of 252 neuropeptides, changes in 253 pathology 252 rodent models 255 signs and symptoms 252

striosomal changes in 253 striosome loss hypothesis 253 substance P changes in 253

infralimbic area dopamine afferents 405 insulin receptors in dentate gyrus 351 insulin-like immunoreactivity in hippocampus 365 kainate receptors in basal ganglia 258 Kliiver-Barrera stain 1 laterobasal amygdaloid complex 176 neurochemical markers in 179 subnuclei of 178 lateral olfactory tract amygdala 161 change with primate evolution 158 ChAT-immunoreactivity 172 comparative morphology in mammals 158 concordant terminologies for divisions 162 nucleus 172 olfactory afferents 161 Lewy body in Parkinson's disease 250 and c~-synuclein 250 and ubiquitin 250 limbic system non-existence of 2 limen insulae 3, 151 metabotropic glutamate receptors and transmitter release in basal ganglia 261 cyclic AMP effects in basal ganglia 261 in basal ganglia 260 in hippocampus 354 in subiculum 367 on cholinergic neurons of basal ganglia 261

Subject index

1-methyl-4-phenyl-l,2,3,6tetrahydropyridine (MPTP) as dopamine neurotoxin 251

monoamines in in in in

entorhinal cortex 382 hippocampus 359 perirhinal cortex 388 subiculum 369

motor cortex projections to basal ganglia 239 multisystem atrophy 248

muscarinic receptors in entorhinal cortex 380

NADPH-diaphorase 182, 184 in latero-basal amygdaloid complex 179

nerve growth factor in in in in in

dentate gyrus 352 entorhinal cortex 388 hippocampus 366 perirhinal cortex 390 subiculum 372

neurons of polymorphic layer and GABA 342

neuropeptide Y in in in in in

basal ganglia 247 dentate gyrus 347 entorhinal cortex 385 extended amygdala 98 GABA neurons of basal ganglia 247 in hippocampus 361 in perirhinal cortex 389 in presubiculum and parasubiculum 376 in subiculum 370

neuropeptides as markers of basal ganglic subdivisions 246 in dentate gyrus 345 in entorhinal cortex 383 in hippocampus 360 in perirhinal cortex 389 in presubiculum and parasubiculum 375 in subiculum 369, 370

neuropsychiatric disorders and basal ganglia 256 basal ganglia neuronal changes in 227

neurotensin in basolateral amygdaloid nucleus 182 in bed nucleus of stria terminalis 98, 103 central division of 103 in central amygdaloid nucleus 116, 120 in dentate gyrus 346 in entorhinal cortex 384 in extended amygdala 98, 107, 132 supracapsular subdivision 132 sublenticular component of 107 in hippocampus 361 in laterobasal amygdaloid complex 180 in presubiculum and parasubiculum 375 in subiculum 369 neurotensin-immunoreactive fibers of 182

nicotinic receptors in entorhinal cortex 380

nitric oxide synthase in dentate gyrus 352 in entorhinal cortex 387 in GABA neurons of basal ganglia 247 in hippocampus 366 in parahippocampal cortex 391 in perirhinal and parahippocampal cortices 378 in perirhinal cortex 390

nitric oxide synthase and NADPH-diaphorase in subiculum 372 NMDA receptors in basal ganglia 258 in hippocampus 353 in subiculum 367 subtypes in basal ganglia 260

non-phosphorylated neurofilamerit (SMI-32) immunoreactivity for, in hippocampal neurons 303 NPY in ventral striatum 86

nucleus accumbens 2 surface extensions of 9

olfactory allocortex 77 olfactory bulb cholinergic projections to 150 efferent projections of 2 terminal projection areas of 7 olfactory trigone 6 olfactory tubercle 2 : comparative species features of, surface 3 see olfactory allocortex 77 striatal nature 5 ventral striatum, boundary with 152

opiate receptors in basal ganglia 265 subtypes of 266

opioid peptides (dynorphin, enkephalin) in dentate gyrus 347 in hippocampus 362 in presubiculum and parasubiculum 376 in subiculum 370

paleocortex appearance of 149 cytoarchitecture 149 excluded regions 149 justification for inclusion of retrobulbar olfactory projections 148

pallidum dorsal, parcellation of 8

paracaudate interface island of extended amygdala 127, 130

paralaminar amygdaloid nucleus neurochemical markers in 185

Parkinson's disease and PET studies 251 environmental toxins in 251 familial forms 250 festinating gain in 249 genetic abnormalities 250 Lewy bodies in 250 433

Subject index pathology in 249 signs and symptoms 249 surgical treatment of 267 treatments of conceptual problems in pathogenesis 268 parvalbumin fibers in CA1 363 in CA2, CA3 363 in dentate 348 in presubiculum 376 in subiculum 370 parvalbumin neurons of human dentate and Alzheimer's 350 in CA1 363 pedunculopontine loop 237 pedunculopontine nucleus CM-Pf complex 241 periallocortex transitional elements 153 periamygdaloid cortex 297 of Krettek and Price 168 of Stephan 162 perirhinal cortex area 36 305 perirhinal and parahippocampal cortices area 35 304 area 36 304 cortical areas of, 304 defining features of 286 Perl's reaction for endogenous iron in ventral pallidum 92 posterior cortical nucleus neurochemical distinctions of 174 primary olfactory cortex 149 progressive supranuclear palsy 248 pyramidal basket cell of dentate and GABA 342 RNA editing of glutamate receptors 258

Segawa's disease 268 serotonergic receptors subtypes in basal ganglia 262 serotonin

434

in presubiculum and parasubiculum 375 somatostatin enkephalin 69 GABA 69 in bed nucleus of stria terminalis 98, 102 in dentate gyrus 346 in entorhinal cortex 384 in extended amygdala 98 in hippocampus 361 in perirhinal cortex 389 in presubiculum and parasubiculum 376 in subiculum 370 in ventral striatum 86 neurochemical markers for 71 neurotransmitter patterns of 69 substance P 69 transmitter receptors in 69 tyrosine hydroxylase 69 somatostatin receptors in basal ganglia and diseases 267 steroid receptors in dentate gyrus 351 in hippocampus 365 striatal projection neurons physiological properites of 241 subcaHosal cortical area (SCA) 2 sublenticular extended amygdala and enkephalin immunoreactivity 9 and substance P immunoreactivity 9 substance P in basal ganglic striosomes 245 in dentate gyrus 345 in entorhinal cortex 383 in extended amygdala 98, 107, 126 in hippocampus 360 in medial amygdaloid nucleus 122 in presubiculum and parasubiculum 375 in subiculum 369

in ventral pallidum 90 in ventral striatum 69, 86 stria terminalis part 126 sublenticular component of 107 substantia innominata doubtful value of term 60 substantia nigra 229 subthalamic nucleus 233 physiological properties of neurons 242 synaptophysin in bed nucleus of stria terminalis 105 ct-synuclein in Lewy bodies of Parkinson's disease 250

tachykinin receptors in basal ganglia 266 temporal lobe epilepsy 285 toxin-induced parkinsonism 227 TRH receptors in dentate gyrus 351 tyrosine hydroxylase in bed nucleus of stria terminalis 101 in ventral striatum 69 ubiquitin in Lewy bodies of Parkinson's disease 250

vasoactive intestinal peptide (VIP) in bed nucleus of stria terminalis 105 in dentate gyrus 346 in extended amygdala 107 sublenticular component of 107 ventral claustrum see claustrum 8 ventral nuclear (VA-VL) complex of the thalamus basal ganglia connections 232 ventral pallidum components 9 connections 64 cytoarchitecture of 67 dopaminergic afferents 67

Subject index endogenous iron in 92 enkephalin 90 GABA-91 9O heterogeneity 67 neurochemical divisions in 93 neuropeptide distributions 90 olfactory tubercle, boundary with 152 origins of term 64 re-entrant circuits 64 substance P 89, 90 ventral putamen 9 ventral striatum

cellular islands 86

acetylcholinesterase 86 cholecystokinin 86 NPY 86 somatostatin 86 substance P 86 cellular islands of 76, 82 chemical markers, in rats 82 distinguished from 'islands of Calleja' 82 enkephalin 69 GABA 69 granule cell clusters of 82 cholinergic systems of 78 components of, in primates 65

components of, in rat 65 cytoarchitecture 67 dopaminergic afferents of 67 heterogeneity 67 origins of term 64 parvicellular islands of 69, 85 re-entrant circuits 64 ventral taenia tecta 147 ventromedial prelimbic area

dopamine afferents of 405 Wilson's disease

dystonia in 255

435

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