Mechanisms and Functions of Brain and Behavioural Asymmetries (Philosophical Transactions of the Royal Society series B)

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Mechanisms and functions of brain and behavioural asymmetries Papers of a Theme Issue compiled and edited by Luca Tommasi Introduction Mechanisms and functions of brain and behavioural asymmetries L. Tommasi

855

Articles Intraspecific competition and coordination in the evolution of lateralization S. Ghirlanda, E. Frasnelli & G. Vallortigara

861

The evolution and genetics of cerebral asymmetry M. C. Corballis

867

Why are some people left-handed? An evolutionary perspective V. Llaurens, M. Raymond & C. Faurie

881

Asymmetries of the human social brain in the visual, auditory and chemical modalities A. Brancucci, G. Lucci, A. Mazzatenta & L. Tommasi

895

Epigenesis of behavioural lateralization in humans and other animals S. M. Schaafsma, B. J. Riedstra, K. A. Pfannkuche, A. Bouma & T. G. G. Groothuis

915

929

Hand and paw preferences in relation to the lateralized brain L. J. Rogers

943

Ascending and descending mechanisms of visual lateralization in pigeons C.-E. Valencia-Alfonso, J. Verhaal & O. Güntürkün

955

Lateralization of social cognition in the domestic chicken (Gallus gallus) J. N. Daisley, E. Mascalzoni, O. Rosa-Salva, R. Rugani & L. Regolin

965

Light during embryonic development modulates patterns of lateralization strongly and similarly in both zebrafish and chick R. J. Andrew, D. Osorio & S. Budaev Zebrafish and medaka: model organisms for a comparative developmental approach of brain asymmetry I. A. Signore, N. Guerrero, F. Loosli, A. Colombo, A. Villalón, J. Wittbrodt & M. L. Concha

983 991

The habenular nuclei: a conserved asymmetric relay station in the vertebrate brain I. H. Bianco & S. W. Wilson

1005

Determining the function of zebrafish epithalamic asymmetry L. Facchin, H. A. Burgess, M. Siddiqi, M. Granato & M. E. Halpern

1021

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Mechanisms and functions of brain and behavioural asymmetries

Does testosterone affect lateralization of brain and behaviour? A meta-analysis in humans and other animal species K. A. Pfannkuche, A. Bouma & T. G. G. Groothuis

Phil. Trans. R. Soc. B | vol. 364 no. 1519 pp. 853–1032 | 12 Apr 2009

12 April 2009

ISSN 0962-8436

volume 364

number 1519

pages 853–1032

In this issue

Mechanisms and functions of brain and behavioural asymmetries Papers of a Theme Issue compiled and edited by Luca Tommasi

The world’s longest running science journal

12 April 2009

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Cover image: The domestic chick (Gallus gallus) is one of the best established models in the study of behavioural asymmetries. Preference for one eye over the other has been demonstrated in many tasks involving discrimination of fine visual details (as in the picture, in which differently coloured paper cones containing food crumbs must be pecked at). Eye preferences are closely associated with asymmetries of information processing in the chick's brain. (Photograph courtesy of D. Osorio; see pages 983–989.)

Mechanisms and functions of brain and behavioural asymmetries Papers of a Theme Issue compiled and edited by Luca Tommasi Contents

Introduction Mechanisms and functions of brain and behavioural asymmetries L. Tommasi

855

Articles Intraspecific competition and coordination in the evolution of lateralization S. Ghirlanda, E. Frasnelli and G. Vallortigara

861

The evolution and genetics of cerebral asymmetry M. C. Corballis

867

Why are some people left-handed? An evolutionary perspective V. Llaurens, M. Raymond and C. Faurie

881

Asymmetries of the human social brain in the visual, auditory and chemical modalities A. Brancucci, G. Lucci, A. Mazzatenta and L. Tommasi

895

Epigenesis of behavioural lateralization in humans and other animals S. M. Schaafsma, B. J. Riedstra, K. A. Pfannkuche, A. Bouma and T. G .G. Groothuis

915

Does testosterone affect lateralization of brain and behaviour? A meta-analysis in humans and other animal species K. A. Pfannkuche, A. Bouma and T. G .G. Groothuis

929

Hand and paw preferences in relation to the lateralized brain L. J. Rogers

943

Ascending and descending mechanisms of visual lateralization in pigeons C.-E. Valencia-Alfonso, J. Verhaal and O. Gu¨ntu¨rku¨n

955

Lateralization of social cognition in the domestic chicken (Gallus gallus ) J. N. Daisley, E. Mascalzoni, O. Rosa-Salva, R. Rugani and L. Regolin

965

Light during embryonic development modulates patterns of lateralization strongly and similarly in both zebrafish and chick R. J. Andrew, D. Osorio and S. Budaev

983

Zebrafish and medaka: model organisms for a comparative developmental approach of brain asymmetry I. A. Signore, N. Guerrero, F. Loosli, A. Colombo, A. Villalo´n, J. Wittbrodt and M. L. Concha

991

The habenular nuclei: a conserved asymmetric relay station in the vertebrate brain I. H. Bianco and S. W. Wilson

1005

Determining the function of zebrafish epithalamic asymmetry L. Facchin, H. A. Burgess, M. Siddiqi, M. Granato and M. E. Halpern

1021

853

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Phil. Trans. R. Soc. B (2009) 364, 855–859 doi:10.1098/rstb.2008.0293 Published online 4 December 2008

Introduction

Mechanisms and functions of brain and behavioural asymmetries Luca Tommasi* Department of Biomedical Sciences, Institute for Advanced Biomedical Technologies, University of Chieti, Blocco A, Via dei Vestini 29, 66013 Chieti, Italy For almost a century the field of brain and behavioural asymmetries has been dominated by studies on humans, resting on the evidence that the anatomical structures underlying language functions are asymmetrical, and that human handedness is lateralized at the population level. Today, there is not only evidence of population-level lateralization of brain and behaviour across a variety of vertebrate and invertebrate species, but also a growing consensus that the comparative analysis of the environmental and developmental factors that give origin to neural and behavioural laterality in animal models, together with theoretical analyses of their costs and benefits, will be crucial for understanding the evolutionary pathways that led to such a multifaceted phenomenon. The present theme issue provides a survey of theoretical, review and research work cutting across the biological and the cognitive sciences, focusing on various species of fishes, birds and primates (including humans) and emphasizing an integrative approach to the study of lateralization encompassing neural, behavioural, cognitive, developmental and environmental aspects. Keywords: lateralization; brain asymmetries; laterality; behavioural laterality; hemispheric asymmetries

Brain asymmetries are (and most probably will continue to be) one standard chapter in every respectable neuroscience handbook. Typically, such a chapter focuses mainly on hemispheric asymmetries in humans and one will almost certainly find it in the second half of the handbook, in between chapters on the neural bases of language and other cognitive processes. There is a historical reason justifying this tendency: some of the scientific discoveries on brain asymmetries that have been achieved in humans can be considered authentic milestones in the history of the neurosciences from their early infancy to their adulthood. Noticeably, these discoveries have involved the faculty of language and its interaction with other higher cognitive processes. The key findings that paved the way to the localization of human brain asymmetries are epitomized by the well-known case of a patient (nicknamed Tan), studied by the French neurologist Paul Pierre Broca at Biceˆtre Hospital in Paris during the second half of the nineteenth century. Broca discovered that a lesion of a circumscribed region of the left frontal lobe was responsible for Tan’s inability to produce articulate speech (Broca 1861). The link between language disorders and lesions in the left hemisphere had been proposed at least two decades before Broca by another French neurologist, Marc Dax, although his clinical investigations (titled as unequivocally as ‘Observations

aiming at proving the systematic coincidence of disturbances of speech with a lesion of the left brain hemisphere’) went basically unnoticed both before and after his death (but see Cubelli & Montagna (1994), for a historical reassessment of the relative weight of Dax and Broca). Further seminal discoveries on the relationship between the left hemisphere and language comprehension (rather than production) came later, thanks to the work of Wernicke (1874), a German psychiatrist. All of this evidence pointed clearly to a role of the human left hemisphere in the control of speech production and perception. Another moment in the history of studies on human brain asymmetries that became a classic landmark for the entire neurosciences deals with a more general idea of functional hemispheric specialization, and with the phenomenon of interhemispheric transmission: it is the work carried out by Sperry (1974) and his students on patients that had their corpus callosum surgically severed to prevent the diffusion of epileptic seizures. These patients, better known as ‘split brains’, were tested by presenting lateralized stimuli to their visual fields and asking them to perform specific motor, linguistic or purely visual tasks based on the content of the stimuli presented. As the tasks sometimes posed requests that made the transmission of information across the hemispheres necessary (such as in the case of naming a visual object presented to the left visual field, which projects to the right hemisphere), and the division of the corpus callosum prevented such transmission, the resulting inability of split-brain subjects to complete such apparently effortless tasks was astonishing even to the

*[email protected] One contribution of 14 to a Theme Issue ‘Mechanisms and functions of brain and behavioural asymmetries’.

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general public, and largely boosted interest for the study of functional hemispheric specializations of the human brain (see Gazzaniga (2005) for a current survey of split brain research). The hemispheric asymmetry underlying language processing has been considered a clear signature of the human brain, together with the hemispheric asymmetry responsible for handedness, which is a strongly asymmetrical behavioural manifestation in the human species, with a distribution of approximately 90 per cent right-handers. Despite the relevance of these aspects and their clear value to human neuropsychology, we still have a limited understanding of the general origins of morphological and functional asymmetries in the brain and of their importance for behaviour. This is in part due to the fact that adequate model systems have been lacking until quite recently, lateralization of brain and behaviour having being considered an exclusively human trait for a long time. The change of perspective was reached gradually during the last century, with evidence accumulating in the 1970s that left–right paired nerves innervating the avian syrinx have different roles in the control of song production (Nottebohm 1971; Nottebohm & Nottebohm 1976), and that the left and right hemispheres of the chicken brain have different roles in visual behaviour (Rogers & Anson 1979). Asymmetries in behaviour exhibited by birds, fishes, amphibians, rodents and primates have since provided a strong argument for functional lateralization being a universal and evolutionarily ancient trait of the vertebrate brain (Bisazza et al. 1997). In an increasing number of cases behavioural biases have been directly linked to anatomical asymmetries, and today we can count on excellent animal model systems of brain and behavioural lateralization (Halpern et al. 2005), rivalling the well-established studies of human asymmetries (Toga & Thompson 2003). Importantly, the growing empirical evidence of brain and behavioural lateralization in animals has progressed in parallel with explanations of lateralization as a natural phenomenon, from its proximate manifestations to the factors determining its evolution and widespread distribution across vertebrate and invertebrate species ( Vallortigara et al. 1999). In the last decades, thus, an increasing number of studies on non-human species have been carried out, expanding our knowledge about the universality of lateralization in behavioural processes and cognitive tasks, running in parallel with a more and more refined elucidation of the structural asymmetries that underlie these differences across the animal kingdom. Evolutionary pressures that brought the emergence of brain and behavioural lateralization have been hypothesized and the functional advantages that this general biological trait would convey have also been suggested (Andrew et al. 2000; Rogers & Andrew 2002; Vallortigara & Rogers 2005). Among a number of advantages, the specialization of the two sides of the brain has been supposed to increase neural efficiency. Despite the fact individual brain efficiency does not require the alignment of lateralization in the population, directional preferences in the use of limbs or eyes (and the underlying brain asymmetries) usually occur at the population level, Phil. Trans. R. Soc. B (2009)

with most individuals showing similar direction of bias. Only recently it has been suggested that alignment of the direction of behavioural asymmetries in a population can arise as an evolutionarily stable strategy if individually asymmetrical organisms must coordinate their behaviour with that of other asymmetrical organisms, and a model was presented that accounted for the population-level lateral biases observable in prey–predator interactions (Ghirlanda & Vallortigara 2004). The present theme issue starts with an extension of that model. In the article by Ghirlanda et al. (2009), in fact, a new game-theoretical model is presented that takes into account not only agonistic interactions but also synergistic ones, showing that population-level lateralization can be established and maintained at equilibrium by means of strategic factors emerging from purely intraspecific interactions among individuals. The improvement of the model presented by Ghirlanda et al. (2009) rests on the fact that by accommodating phenomena of intraspecific social cooperation alongside with interspecific competition, the model can explain more easily human lateralization than a model based on purely agonistic interactions. The following group of articles offers variable support to the theoretical hypothesis set forth in the model. Corballis (2009) emphasizes the fact that benefits of asymmetry might not necessarily be due to shared directionality (as the previous article assumes), but rather to the degree of expression of the trait. By showing that genes and environmental factors are inadequate to predict the distribution of two alternative asymmetrical phenotypes, and that lateralization is a trait varying along a continuum rather than a truly dichotomous variable, Corballis suggests that advantages of lateralization degree can be measured along cognitive and personality dimensions, disregarding the direction of its expression. Llaurens et al. (2009) focus on the issue of human handedness, reviewing specifically the literature concerning left-handedness and the costs and benefits that influence the conservation of its frequency in the human population. The evolutionary history and geographical variation of left-handedness, as witnessed by human palaeoanthropological and ethological data, suggest that the low frequency of left-handedness in humans can be explained both by its likely benefits (i.e. fact that it confers some advantage in fighting behaviour due to unpredictability) and by its associated costs (i.e. the fact that a number of health problems are consequent to its possession). Brancucci et al. (2009) keep the focus on human lateralization but shift the attention to functional asymmetries of the brain hemispheres. Reviewing the rich literature on social perception including visual, auditory and olfactory representations of self and other individuals, they show that the right-hemispheric lateralization pattern underlying the analysis of human faces, voices and smells (including the processing of pheromones), which is commonly revealed through both behavioural and neuroimaging research, despite the structural symmetry of the neural structures capable of supporting such representations, might be driven by other well-known types of right-hemispheric specialization.

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Introduction L. Tommasi In the following two articles, we are first offered a general overview about the relative weight of genes and the environment on the development of brain and behavioural asymmetries in humans and other animals, and then a detailed analysis of a specific environmental factor, namely the effect of prenatal exposure to testosterone on the development of asymmetries. Schaafsma et al. (2009) clearly show that pre-, periand post-natal environmental factors, such as light exposure, body posture, or the side preferentially taken by parents while cradling infants, are important in influencing the development of the degree of lateralization, despite the fact their exact mechanisms have not been fully understood. Data obtained in domestic chicks (Gallus gallus) are presented to convey the idea that social rearing can be considered another environmental factor modulating lateralization. Pfannkuche et al. (2009) carry out a meta-analysis concerning the effects of prenatal exposure to testosterone on the degree and direction of lateralization in mammals and birds, testing four hypotheses and demonstrating a partial relationship between prenatal testosterone levels and asymmetry, emphasizing a higher correlation with the extent of the asymmetry rather than the direction of its expression. Handedness has classically constituted one test bench for theories on both the development and the evolution of lateralization (MacNeilage 1991; Annett 2002). Rogers (2009) returns to the topic of handedness but she expands the scope to primates in general. Reviewing recent data on the preferential use of limbs/ paws in a number of monkey species (including prosimians) and the growing evidence of asymmetrical anatomical correlates of such side preferences, Rogers argues that lateralization patterns might depend in the first place on hemispheric asymmetries in sensory processing, and that both sensory and motor biases might correlate with more general behavioural traits, such as response to novelty, coping and temperament. These traits, finally, would be mediated by the hemispheric asymmetries underlying the regulation of aggression and the control of stress responses. Data obtained in common marmosets (Callithrix jacchus) are presented to support the hypothesis. Asymmetry in the processing of sensory information by the two brain hemispheres is also the topic of the article by Valencia-Alfonso et al. (2009), featuring the pigeon (Columba livia) as a model system of the hemispheric lateralization of visual abilities. In pigeons, as in all birds, the optic nerves almost completely decussate at the level of the chiasm, so the visual input to each eye is processed more or less entirely by the contralateral hemisphere. Moreover, the avian visual system is divided into two main subsystems (the tectofugal and the thalamofugal systems). These anatomical constraints are the basis of an empirical analysis of the functional asymmetries ascribed to the visual system of the pigeon, and it is shown that these asymmetries depend on the interplay of descending and ascending visual information streams (between telencephalic and subtelencephalic structures), whose net balance is the left-hemispheric lateralization observed in many visual discrimination tasks in pigeons. Phil. Trans. R. Soc. B (2009)

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Daisley et al. (2009) focus on the domestic chick as a model system for the study of hemispheric lateralization of social cognition, echoing some of the phenomena described in the preceding article on human social perception (Brancucci et al. 2009). Both in reviewing the literature and in describing their own research work (that take advantage of the monocular occlusion technique), the authors present solid evidence of right-hemispheric asymmetry of social representations in chicks, modulated by perinatal environmental effects such as light exposure, and social rearing, as already shown in the article by Schaafsma et al. (2009). A pivotal role is assumed by the article of Andrew et al. (2009), for it links the articles based on avian models dealing with visual perception and cognition, to those dealing with the genetics and embryology of brain and behavioural asymmetries of other increasingly important model systems: fishes. Indeed, the research presented in Andrew et al.’s article shows that environmental manipulation (i.e. exposure of the eggs to light or dark) during the pre-hatching development of chicks and zebrafish (Brachydanio rerio), determines strong similarities in lateralized visual behaviour and in ‘personality traits’ of the two species, as assessed by the timing and dynamics at which tasks involving visual exploration and response to releasers are accomplished. Genetic approaches that provided insights on the asymmetric development of the viscera (Hamada et al. 2002) are recently proving valuable for exploring left– right differences in the fish nervous system, particularly in the zebrafish—which has gained the status of top model organism for the study of developmental biology. Recent work has been carried out on the dorsal diencephalic region of the forebrain, the epithalamus, which in zebrafish is organized asymmetrically and has been correlated with lateralized visual behaviour. The last three articles provide a sort of ‘theme issue in the theme issue’, as they all specifically target epithalamic asymmetries in the zebrafish. Signore et al. (2009) compare the wellknown temporal and spatial features of asymmetrical development of epithalamic structures in the zebrafish, with the events that bring the establishment of asymmetries in the equivalent regions of another teleost fish, medaka (Oryzias latipes). Similarities in the developmental events triggered by the Nodal signalling pathway are taken as evidence of shared ancestry and as indicators of a roughly comparable bauplan for symmetry in the two species, although differences emerge when the temporal and spatial details of neurogenesis are compared at a fine level of detail. Together with testing methods for comparing neural development across species, their empirical work provides a convincing demonstration that medaka can be considered as valuable an animal model system of neural lateralization as the more used zebrafish. Bianco & Wilson (2009) review the asymmetries of the dorsal diencephalic conduction system (comprising the habenulae and related structures), its development, and its multifaceted reflections on the behaviour of vertebrates (from a role in regulating sleep and circadian rhythms to involvement in attention, learning and higher cognitive processes), with special

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reference to the zebrafish model. They present a theoretical framework for the design of asymmetrical circuitry describing multiple forms of implementation that apply to known vertebrate cases, from the realization of size asymmetry using identical elements to the realization of microstructural asymmetry based on different element types or their ratios. Finally, Facchin et al. (2009) concentrate on the behavioural consequences of epithalamic asymmetry reversal in zebrafish (obtained by targeting the southpaw gene), and show that the main effect of reversing the side of parapineal is more a matter of altered motor patterns (i.e. swimming latency and duration) rather than altered lateralized visual behaviour. This is in contrast to previous research work that put epithalamic asymmetries in a direct relationship with asymmetries in eye use, and is to be taken as a sign of the complex link between neural and behavioural lateralization. The overall message conveyed by this theme issue is that brain asymmetries and behavioural lateralization should be taken as a genuine case of successful interaction among the biological and the cognitive sciences. Bringing into play the knowledge acquired on animal model systems it will become more and more obvious that brain and behavioural asymmetries must be studied at the variety of levels as represented in the articles here presented, and the privileged focus on human brain asymmetry that has characterized the field until very recently should become complementary to a more general picture, taking into account more seriously the evolutionary and developmental dimensions of these fascinating phenomena. The author acknowledges the financial support of the Commission of the European Communities, through the project EDCBNL (Evolution and Development of Cognitive, Behavioural and Neural Lateralization—2006/2009), within the framework of the specific research and technological development programme ‘Integrating and strengthening the European Research Area’ (initiative ‘What it means to be human’). A particular acknowledgement goes to all the referees that kindly accepted to review the manuscripts.

REFERENCES Andrew, R. J., Tommasi, L. & Ford, N. 2000 Motor control by vision and the evolution of cerebral lateralization. Brain Lang. 73, 220–235. (doi:10.1006/brln.2000.2304) Andrew, R. J., Osorio, D. & Budaev, S. 2009 Light during embryonic development modulates patterns of lateralization strongly and similarly in both zebrafish and chick. Phil. Trans. R. Soc. B 364, 983–989. (doi:10.1098/rstb. 2008.0241) Annett, M. 2002 Handedness and brain asymmetry: the right shift theory. Hove, UK: Psychology Press. Bianco, I. H. & Wilson, S. W. 2009 The habenular nuclei: a conserved asymmetric relay station in the vertebrate brain. Phil. Trans. R. Soc. B 364, 1005–1020. (doi:10.1098/rstb. 2008.0213) Bisazza, A., Rogers, L. J. & Vallortigara, G. 1997 The origins of cerebral asymmetry: a review of evidence of behavioural and brain lateralization in fishes, reptiles and amphibians. Neurosci. Biobehav. Rev. 22, 411–426. (doi:10.1016/S01 49-7634(97)00050-X) Brancucci, A., Lucci, G., Mazzatenta, A. & Tommasi, L. 2009 Asymmetries of the human social brain in the visual, Phil. Trans. R. Soc. B (2009)

auditory and chemical modalities. Phil. Trans. R. Soc. B 364, 895–914. (doi:10.1098/rstb.2008.0279) Broca, P. P. 1861 Perte de la parole, ramollissement chronique, et destruction partielle du lobe ante´rieur gauche du cerveau. Bulletin de la Socie´te´ Anthropologique 2, 235–238. Corballis, M. C. 2009 The evolution and genetics of cerebral asymmetry. Phil. Trans. R. Soc. B 364, 867–879. (doi:10. 1098/rstb.2008.0232) Cubelli, R. & Montagna, C. G. 1994 A reappraisal of the controversy of Dax and Broca. J. Hist. Neurosci. 3, 215–226. Daisley, J. N., Mascalzoni, E., Rosa-Salva, O., Rugani, R. & Regolin, L. 2009 Lateralization of social cognition in the domestic chicken (Gallus gallus). Phil. Trans. R. Soc. B 364, 965–981. (doi:10.1098/rstb.2008.0229) Facchin, L., Burgess, H. A., Siddiqi, M., Granato, M. & Halpern, M. E. 2009 Determining the function of zebrafish epithalamic asymmetry. Phil. Trans. R. Soc. B 364, 1021–1032. (doi:10.1098/rstb.2008.0234) Gazzaniga, M. S. 2005 Forty-five years of split-brain research and still going strong. Nat. Rev. Neurosci. 6, 653–659. (doi:10.1038/nrn1723) Ghirlanda, S. & Vallortigara, G. 2004 The evolution of brain lateralization: a game theoretical analysis of population structure. Proc. R. Soc. B 271, 853–857. (doi:10.1098/ rspb.2003.2669) Ghirlanda, S., Frasnelli, E. & Vallortigara, G. 2009 Intraspecific competition and coordination in the evolution of lateralization. Phil. Trans. R. Soc. B 364, 861–866. (doi:10.1098/rstb.2008.0227) Halpern, M. E., Gu¨ntu¨rku¨n, O., Hopkins, W. D. & Rogers, L. J. 2005 Lateralization of the vertebrate brain: taking the side of model systems. J. Neurosci. 25, 10 351–10 357. (doi:10.1523/JNEUROSCI.3439-05.2005) Hamada, H., Meno, C., Watanabe, D. & Saijoh, Y. 2002 Establishment of vertebrate left-right asymmetry. Nat. Rev. Genet. 3, 103–113. (doi:10.1038/nrg732) Llaurens, V., Raymond, M. & Faurie, C. 2009 Why are some people left-handed? An evolutionary perspective. Phil. Trans. R. Soc. B 364, 881–894. (doi:10.1098/rstb.2008.0235) MacNeilage, P. F. 1991 The “Postural Origins” theory of primate neurobiological asymmetries. In Biological and behavioral determinants of language development (eds N. A. Krasnegor, D. M. Rumbaugh, R. L. Schiefelbusch & M. Studdert-Kennedy), pp. 165–188. Hillsdale, NJ: Lawrence Erlbaum. Nottebohm, F. 1971 Neural lateralization of vocal control in a passerine bird. J. Exp. Zool. 177, 229–261. (doi:10.1002/ jez.1401770210) Nottebohm, F. & Nottebohm, M. E. 1976 Left hypoglossal dominance in the control of canary and white-crowned sparrow song. J. Comp. Physiol. 108, 171–192. (doi:10. 1007/BF02169047) Pfannkuche, K. A., Bouma, A. & Groothuis, T. G. G. 2009 Does testosterone affect lateralization of brain and behaviour? A meta-analysis in humans and other animal species. Phil. Trans. R. Soc. B 364, 929–942. (doi:10.1098/ rstb.2008.0282) Rogers, L. J. 2009 Hand and paw preferences in relation to the lateralized brain. Phil. Trans. R. Soc. B 364, 943–954. (doi:10.1098/rstb.2008.0225) Rogers, L. J. & Andrew, R. J. 2002 Comparative vertebrate lateralization. Cambridge, UK: Cambridge University Press. Rogers, L. J. & Anson, J. M. 1979 Lateralisation of function in the chicken fore-brain. Pharmacol. Biochem. Behav. 10, 679–686. (doi:10.1016/0091-3057(79)90320-4) Schaafsma, S. M., Riedstra, B. J., Pfannkuche, K. A., Bouma, A. & Groothuis, T. G. G. 2009 Epigenesis of behavioural

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Introduction L. Tommasi lateralization in humans and other animals. Phil. Trans. R. Soc. B 364, 915–927. (doi:10.1098/rstb.2008.0244) Signore, I. A., Guerrero, N., Loosli, F., Colombo, A., Villalo´n, A., Wittbrodt, J. & Concha, M. L. 2009 Zebrafish and medaka: model organisms for a comparative developmental approach of brain asymmetry. Phil. Trans. R. Soc. B 364, 991–1003. (doi:10.1098/ rstb.2008.0260) Sperry, R. W. 1974 Lateral specialization in the surgically separated hemispheres. In Neurosciences third study program (eds F. Schmitt & F. Worden), pp. 1–12. Cambridge, MA: MIT Press. Toga, A. W. & Thompson, P. M. 2003 Mapping brain asymmetry. Nat. Rev. Neurosci. 4, 37–48. (doi:10.1038/ nrn1009)

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Valencia-Alfonso, C.-E., Verhaal, J. & Gu¨ntu¨rku¨n, O. 2009 Ascending and descending mechanisms of visual lateralization in pigeons. Phil. Trans. R. Soc. B 364, 955–963. (doi:10.1098/rstb.2008.0240) Vallortigara, G. & Rogers, L. J. 2005 Survival with an asymmetrical brain: advantages and disadvantages of cerebral lateralization. Behav. Brain Sci. 28, 575–589. (doi:10.1017/S0140525X05000105) Vallortigara, G., Rogers, L. J. & Bisazza, A. 1999 Possible evolutionary origins of cognitive brain lateralization. Brain Res. Rev. 30, 164–175. (doi:10.1016/S0165-0173(99) 00012-0) Wernicke, C. 1874 Der aphasische symptomenkomplex. Eine psychologische studie auf anatomischer basis. Breslau, Germany: M. Cohn & Weigert.

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Phil. Trans. R. Soc. B (2009) 364, 861–866 doi:10.1098/rstb.2008.0227 Published online 4 December 2008

Intraspecific competition and coordination in the evolution of lateralization Stefano Ghirlanda1,2, Elisa Frasnelli3 and Giorgio Vallortigara3,* 1

Department of Psychology, University of Bologna, 40127 Bologna, Italy Centre for the Study of Cultural Evolution, Stockholm University, 106 91 Stockholm, Sweden 3 Centre for Mind/Brain Sciences, University of Trento, Corso Bettini, 31, 38068 Rovereto (TN ), Italy 2

Recent studies have revealed a variety of left–right asymmetries among vertebrates and invertebrates. In many species, left- and right-lateralized individuals coexist, but in unequal numbers (‘populationlevel’ lateralization). It has been argued that brain lateralization increases individual efficiency (e.g. avoiding unnecessary duplication of neural circuitry and reducing interference between functions), thus counteracting the ecological disadvantages of lateral biases in behaviour (making individual behaviour more predictable to other organisms). However, individual efficiency does not require a definite proportion of left- and right-lateralized individuals. Thus, such arguments do not explain population-level lateralization. We have previously shown that, in the context of prey–predator interactions, population-level lateralization can arise as an evolutionarily stable strategy when individually asymmetrical organisms must coordinate their behaviour with that of other asymmetrical organisms. Here, we extend our model showing that populations consisting of left- and right-lateralized individuals in unequal numbers can be evolutionarily stable, based solely on strategic factors arising from the balance between antagonistic (competitive) and synergistic (cooperative) interactions. Keywords: asymmetry; brain evolution; brain lateralization; evolutionarily stable strategy; laterality; lateralization of behaviour

1. INTRODUCTION Left–right asymmetries in brain and behaviour, once believed to be uniquely human, have now been established in many vertebrates (Rogers & Andrew 2002; Vallortigara & Rogers 2005) and in invertebrates (Pascual et al. 2004; Letzkus et al. 2006, 2007; Rogers & Vallortigara 2008), suggesting that lateralization contributes significantly to biological fitness. Lateralized animals have been shown to outperform nonlateralized ones in many circumstances ( Fabre-Thorpe et al. 1993; McGrew & Marchant 1999; Gu¨ntu¨rku¨n et al. 2000; Rogers et al. 2004), and researchers agree that a lateralized brain may confer several advantages: sparing neural tissue by avoiding duplication of functions in the two hemispheres ( Levy 1977); processing information in parallel (Rogers 2002; Rogers et al. 2004); and preventing the simultaneous initiation of incompatible responses by allowing one hemisphere to have control over actions (especially in animals with laterally placed sensory organs, Andrew 1991; Vallortigara 2000). One intriguing aspect of lateralization, however, cannot be explained by arguing that lateralized brains are more efficient. The direction of lateralization, in fact, is usually aligned at the population level, with 60–90% of individuals showing the same direction of bias (depending on species and behaviour considered, see Previc (1991) and Vallortigara & Rogers (2005), for humans). Individual efficiency does not require an

alignment of lateralization at the population level, and does not explain why a minority of individuals lateralized in the other direction almost always exists (e.g. hand use in humans). One could argue that population-level lateralization is a mere by-product of genetic expression, but it has been proved that selection for the strength of lateralization does not necessarily favour one direction of lateralization over the other (e.g. Collins 1985). Two explanations (not mutually exclusive) have been proposed for the evolution of population-level asymmetries. Some genetic models of human handedness (McManus 1999; Annett 2002) posit one or more ‘directional’ (D) alleles that cause right-handedness, and one or more ‘chance’ (C) alleles that cause left- or right-handedness at random. A population with a majority of right-handers and a minority of left-handers can be maintained, in these models, if DC genotypes have higher fitness than CC and DD genotypes (heterozygotic advantage), for instance, if intermediate levels of brain asymmetry are superior to both extreme asymmetry and symmetry (Corballis 2006). Suggested disadvantages of CC and DD homozygotes include impairments in spatial, verbal and other cognitive abilities (Annett 2002; Barnett & Corballis 2002; McManus 2002). The second suggested explanation is that the population structure of lateralization may reflect, not a balance between symmetry and asymmetry, but an evolutionarily stable strategy that can arise when individually asymmetrical organisms must coordinate their behaviour with that of other asymmetrical organisms ( Vallortigara & Rogers 2005). This

* Author for correspondence ( [email protected]). One contribution of 14 to a Theme Issue ‘Mechanisms and functions of brain and behavioural asymmetries’.

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hypothesis recognizes that brain asymmetries manifest themselves in behaviour, and thus may have fitness consequences in interactions with other organisms. For instance, vigilance behaviour and escape responses elicited by predators often show lateral biases (Lippolis et al. 2002, 2005; Vallortigara & Rogers 2005). We have studied this idea in a game-theoretical model considering group-living prey subjected to predation (Ghirlanda & Vallortigara 2004; Vallortigara 2006). We assumed first that lateralization influences the direction of escape from predators. We then considered two contrasting selection pressures on lateralization. On one hand, individuals in large groups have a lesser risk of being targeted by predators (the so-called ‘dilution’ of predation risk, Foster & Treherne 1981). This favours individuals who tend to escape in the same direction as the majority, thus promoting the same direction of lateralization across the whole population. On the other hand, given that predators may learn to anticipate prey escape strategies, individuals who escape in a different direction from the majority may surprise predators and survive predation attempts more often. This tends to favour populations in which left- and right-lateralized individuals are equally common. We showed that, in this model, population-level lateralization can emerge provided that none of the two selection pressures is much stronger than the other. According to this view, the evolution of brain lateralization would have occurred in two steps: first, individuals became lateralized because of advantages from increased brain efficiency (e.g. Rogers et al. 2004); and second, individually lateralized organisms aligned the direction of their asymmetries when they started to interact to each other in ways that made their asymmetry relevant to each other’s behaviour (e.g. in fishes shoaling, Vallortigara & Bisazza 2002). Here, we investigate whether a similar scenario could hold when selection pressures on lateralization arise purely from intraspecific interactions of competition and cooperation, rather than interspecific prey– predator interactions.

2. MODEL We study the influence on lateralization of purely intraspecific interactions using a similar modelling strategy as Ghirlanda & Vallortigara (2004). We assume that individuals engage in both antagonistic (competitive) and synergistic (cooperative) interactions. An individual’s pay-off depends on its success in interactions, which is a function of how common its lateralization is in the population. Synergistic activities tend to favour individuals with the same lateralization (they can, for instance, have an easier time coordinating physical activities, use efficiently the same tools, etc.). Antagonistic activities, on the other hand, tend to favour individuals different from the majority. The reason is similar to the one mentioned above for predation: minority-type individuals will be able to surprise opponents, adopting behaviours to which opponents are less accustomed. For example, it has been argued that human left-handers may hold an advantage in fighting, or in more recent times in certain sporting activities, but only so long as they remain in Phil. Trans. R. Soc. B (2009)

1.00

fitness contribution

862

0.75

0.50

0.25

0

0.25 0.50 0.75 1.00 frequency of individuals laterlized as oneself,

Figure 1. Graph of the functions a(x) and s(x) (equations (2.2) and (2.3)), which enter fitness (equation (2.1)). Parameter values: k aZ5, k sZ1. Since k aOk sZ1, the fitness contribution of antagonistic interactions a(x) decays more quickly than the fitness contribution of synergistic interactions s(x) increases. Solid curve, antagonistic interactions, a(x); dotted curve, synergistic interactions, s(x).

the minority (Raymond et al. 1996). Thus, if only synergistic interactions were present, the population would be composed entirely of individuals with the same lateralization. If only antagonistic interactions were present, the population would be composed of left- and right-lateralized individuals in proportion of one-half. We want to study whether, when both kinds of interactions exist, it is possible to maintain a population in which left- and right-lateralized individuals coexist in a proportion different from one-half, and how such a situation is influenced by model parameters. Let x be the proportion of left-lateralized individuals in the population. We write the fitness f (x) of such an individual as the sum of a term accounting for antagonistic interactions (a) and one-term accounting for synergistic interactions (s) f ðxÞ Z aðxÞ C csðxÞ;

ð2:1Þ

where the parameter c weights the relative importance of the two kinds of interactions. We use the following forms for a(x) and s(x) aðxÞ Z expðKka xÞ;

ð2:2Þ

sðxÞ Z 1KexpðKks xÞ;

ð2:3Þ

where k a and k s are positive parameters. In keeping with our assumptions, a(x) decreases with the proportion of individuals with the same lateralization, while s(x) increases (figure 1). We have chosen an exponential shape because it is often a good approximation to actual learning curves, that is, how performance on a given task increases as a function of increasing experience with that task (Mackintosh 1974; Pearce 1997). In figure 1, parameter values are chosen so that k aOk s (in particular k aZ5, k sZ1). This means that a(x) decreases more rapidly than s(x) increases; i.e. the fitness contribution of antagonistic interactions varies more quickly with strategy frequency than the fitness contribution of synergistic interactions.

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frequency of left-lateralized individuals, x

1.0

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(b)

(a)

0.5

0 ~c –c relative importance of synergistic interactions, c

~c –c relative importance of synergistic interactions, c

Figure 2. Equilibrium frequency of left-lateralized individuals x as a function of the relative importance of antagonistic and synergist interactions (parameter c in equation (2.1)). Solid lines represent stable equilibria; dotted lines unstable equilibria. (a) The case in which frequency dependence is stronger for antagonistic than synergistic interactions (k aOk s in equations (2.3) and (2.4)). For c!~c, x
Z1/2 is the only stable solution; for cO
c, x
Z1/2 is unstable while x
Z0 and x
Z1 (populations with only right- or left-lateralized individuals) are both stable. Between c~ and c
, two values of x different from one-half are stable equilibria, corresponding to populations in which left- and right-lateralized individuals coexist but are not equally common. (b) The converse case (k sOk a). For c!~c, x
Z1/2 is stable, for cO
c, x
Z0 and x
Z1 are stable, for intermediate c values x
Z1/2, x
Z0 and x
Z1 are all stable, meaning that coexistence between left- and right-handers is not possible.

The fraction of right-lateralized individuals in the population is 1Kx. Since we are not assuming any intrinsic advantage of being left- or right- lateralized, the fitness of these individuals is f ð1KxÞ Z að1KxÞ C csð1KxÞ:

ð2:4Þ

Evolutionary equilibria, x
, are derived by equating the fitness of left- and right-lateralized individuals f ðx
Þ Z f ð1Kx
Þ:

ð2:5Þ

The evolutionary stability of an equilibrium x
is assessed by asking what happens if the proportion of left-handers deviates slightly from x
. If the equilibrium is stable, natural selection tends to restore the equilibrium proportion x
. Thus, an increase in the proportion of left-lateralized individuals from x
to x
CE should result in a situation in which their fitness falls below that of right-lateralized individuals. Formally f ðx
C E Þ! f ð1Kx
KE Þ:

ð2:6Þ

Likewise, a decrease in left-lateralized individuals should result in these individuals having a higher fitness f ðx
KE ÞO f ð1Kx
C E Þ:

ð2:7Þ

We show in the appendix that these conditions are equivalent to the following condition on the derivative f 0 (x) of f(x) f 0 ðx
Þ C f 0 ð1Kx
Þ! 0:

ð2:8Þ

Combining this condition with the equilibrium condition (2.6) we can look for evolutionary equilibria and assess their stability. We also need to check whether populations composed entirely of left- or right-lateralized individuals are stable, corresponding to the conditions, respectively f ð0ÞO f ð1Þ;

ð2:9Þ

f ð1ÞO f ð0Þ:

ð2:10Þ

Phil. Trans. R. Soc. B (2009)

We have performed this analysis by a mixture of analytical and numerical methods, as detailed in appendix A. 3. RESULTS We study the model varying the relative importance, c, of synergistic and antagonistic interactions. The nature of the equilibria depends on the relationship between the parameters k a and k s. If k aOk s the situation is similar to that found by Ghirlanda & Vallortigara (2004) in interspecific prey–predator interactions ~ below which (figure 2). There exists a value of c, c, x
Z1/2 is the only stable solution. In such a situation, synergistic interactions are too weak to cause a departure from the strategic equilibrium favoured by antagonistic interactions. Similarly, there exists a value
above which x
Z1/2 is unstable while x
Z0 and of c, c,
x Z1 are both stable, corresponding to populations with only left- or right-lateralized individuals. Here synergistic interactions dominate, determining completely the population structure of lateralization. Finally, there is a range of c-values in between c~ and c
where two values of x different from one-half are stable equilibria, corresponding to populations in which leftand right-lateralized individuals coexist but are not equally common. This is the situation we observe in humans and many other vertebrates. The range of c-values in which this situation occurs expands as k a increases with respect to k s. If k a%k s, we still have that for small c, x
Z1/2 is stable and that for large c, x
Z0 and x
Z1 are stable, but the situation for intermediate c-values is different. Coexistence between left- and right-handers is not possible; rather x
Z1/2, x
Z0 and x
Z1 are all stable. In this case, synergistic interactions are strong enough to stabilize a monomorphic population, but not strong enough to destabilize a population with 50 per cent right- and left-handers. In summary, existence of lateralized populations requires in our model that

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k aOk s, meaning that the graph of a(x) must be steeper than the graph of s(x) (figure 1; see below for interpretations).

4. DISCUSSION Our model demonstrates that populations consisting of left- and right-type individuals in unequal numbers can be evolutionary stable based solely on strategic factors arising from intraspecific interactions. The model makes several testable predictions. An important prediction is that the frequency of the minority type depends on the balance between the fitness contributions of antagonistic versus synergistic interactions. When antagonistic interactions are more important for individuals’ fitness, we expect the minority type to be more common. Likewise, when synergistic interactions are more important, we expect the minority type to be less common. To evaluate this prediction, we need data from populations that differ in the balance between antagonistic and synergistic interactions but are otherwise as similar as possible. One possibility is to compare different human groups. Faurie & Raymond (2005) provide data in agreement with our model, showing that the frequency of left-handers in eight traditional societies is strongly correlated with the rate of homicides, ranging approximately between 5 and 25 per cent as the adult homicide rate ranges between 0.01 to more than 1 per 1000 individuals per year. Another source of evidence may be comparative studies of related species. For instance, it is currently debated whether lateralization is more pronounced in humans than in non-human primates. This seems unlikely for cerebral lateralization in general ( Vallortigara et al. 1999), but it could hold for certain forms of behavioural lateralization, such as handedness (Rogers 2007; and see Andrew et al. (2000) for the general issue of lateralization of non-bilateral effectors). Wild chimpanzees show population-level handedness for tool use ( Lonsdorf & Hopkins 2005), but apparently not so strongly as humans do (Annett 2006). The fact that synergistic interactions are more important in humans (e.g. Jensen et al. 2007) may explain why we are more strongly lateralized at the population level. Another prediction concerns the fact that the model allows for population-level lateralization only when the condition k aOk s is met (see §3 and appendix A). That is, when the frequency of majority- and minority-type individuals varies, the fitness contribution of antagonistic interactions should vary more quickly than the fitness contribution of synergistic interactions. From the point of view of selective pressures, this prediction means that minority-type individuals should lose their advantage in antagonistic interactions very quickly as they become more common, more quickly than they gain an advantage in synergistic interactions. From a behavioural point of view, this corresponds to the fact that individuals should learn quickly how to contrast minority-type individuals in antagonistic interactions, while they should learn more slowly how to cooperate with them in synergistic interactions. This prediction can be put to empirical test (perhaps in experimental Phil. Trans. R. Soc. B (2009)

populations in the laboratory), but presently, we are not aware of any direct evidence in favour or against it. In conclusion, we have extended previous results on interspecific interactions to intraspecific interactions, reinforcing the view that strategic factors may have been a powerful force in the evolution of lateralization. We have considered a purely strategic model for simplicity, but future research should also consider how strategic factors interact with other potential determinants of lateralization, such as neurophysiological constraints, the genetic mechanisms of lateralization, and especially in humans, traditions and culture (Laland et al. 1995).

APPENDIX A A.1 Stability condition (equation (2.8 )) A first order Taylor expansion of equation (2.6) yields f ðx
Þ C f 0 ðx
ÞE C OðE 2 Þ! f ð1Kx
ÞKf 0 ð1Kx
ÞE C OðE 2 Þ:

ðA 1Þ

Dropping terms of higher order in E and using the equilibrium condition f (x
)Zf (1Kx
) (equation (2.5)), we obtain equation (2.8). A similar argument shows that equation (2.7) is also equivalent to equation (2.8). Given that f (x)Za(x)Ccs(x), equation (2.8) can be written as a 0 ðx
Þ C cs 0 ðx
Þ C a 0 ð1Kx
Þ C cs 0 ð1Kx
Þ! 0:

ðA 2Þ

A.2 Stability of the equilibrium x
Z1/2; (non-lateralized population) The value x
Z1/2 is always a solution of equation (2.5), hence it is always an equilibrium. Equation (A 2), evaluated for x
Z1/2, implies that this equilibrium is stable if c is smaller than c~ Z

ka e Kðka =2Þ : ks e Kðks =2Þ

ðA 3Þ

A.3 Stability of x
Z0 and x
Z1 (completely lateralized populations) Now we consider the situation where the population is composed entirely of left- or right-lateralized individuals. These situations are stable if equations (2.9) and (2.10) hold, respectively. Using expressions (2.1) and (2.2) we see that both expressions hold if c is larger than c
Z

1KeKka : 1Keks

ðA 4Þ

A.4 Existence of partially lateralized populations We have shown that a non-lateralized population (x
Z 1/2) is stable if c!~c and fully lateralized populations are stable only if cO
c. Thus, a lateralized population with
c. 0!x
!1/2 or 1/2!x
!1 can be stable only if cO~ Using expressions (A 3) and (A 4), we see that the

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The evolution of lateralization latter is equivalent to Kðka =2Þ

1Ke ke O a Kðk =2Þ ; Kk s 1Ke ks e s Kka

or sinhðka =2Þ sinhðks =2Þ O ; ka =2 ks =2

ðA 5Þ

ðA 6Þ

which in turn is equivalent to ka O ks ;

ðA 7Þ

because sinh(k)/k is monotonically increasing for kO0. When condition (A 7) holds, the interval of values between c~ and c
can be explored numerically to calculate the equilibrium value x
. We performed this calculation, for instance, to build figure 2a. We used two methods to guard against numerical instability. The first method used the fsolve function of the OCTAVE software (v. 2.9.9), designed to solve nonlinear equations. The second method looks for a solution by iterating the map   x 0 ZKln eKka ð1KxÞ C cð1KeKks ð1KxÞ ÞKcð1KeKks x Þ =ka ; ðA 8Þ obtained from equation (A 2) using equations (2.1) and (2.2). The fixed point theorem (Granas & Dugundji 2003) guarantees that a solution for this recursion exists. The two methods typically produced the same answer, but for some parameter values one or the other method would not converge to a solution. We then used the value obtained by the other method.

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Phil. Trans. R. Soc. B (2009) 364, 867–879 doi:10.1098/rstb.2008.0232 Published online 4 December 2008

Review

The evolution and genetics of cerebral asymmetry Michael C. Corballis* Department of Psychology, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand Handedness and cerebral asymmetry are commonly assumed to be uniquely human, and even defining characteristics of our species. This is increasingly refuted by the evidence of behavioural asymmetries in non-human species. Although complex manual skill and language are indeed unique to our species and are represented asymmetrically in the brain, some non-human asymmetries appear to be precursors, and others are shared between humans and non-humans. In all behavioural and cerebral asymmetries so far investigated, a minority of individuals reverse or negate the dominant asymmetry, suggesting that such asymmetries are best understood in the context of the overriding bilateral symmetry of the brain and body, and a trade-off between the relative advantages and disadvantages of symmetry and asymmetry. Genetic models of handedness, for example, typically postulate a gene with two alleles, one disposing towards right-handedness and the other imposing no directional influence. There is as yet no convincing evidence as to the location of this putative gene, suggesting that several genes may be involved, or that the gene may be monomorphic with variations due to environmental or epigenetic influences. Nevertheless, it is suggested that, in behavioural, neurological and evolutionary terms, it may be more profitable to examine the degree rather than the direction of asymmetry. Keywords: behavioural asymmetries; bilateral symmetry; cerebral asymmetry; evolution; handedness; genetics

1. INTRODUCTION The asymmetry of the brain raises something of a paradox, since, in most respects, the brains and bodies of most organisms, including humans, are strikingly bilaterally symmetrical. As Palmer (2004) put it, bilateral symmetry is the default condition. The midplane of the developing organism is defined by two axes, the anteroposterior and dorsoventral axes, but there is no left–right axis. Instead, the left and right halves of the organism are constructed from separate mediolateral axes. Since these axes are mirror images, the resulting organism will be bilaterally symmetrical, unless there is some symmetry-breaking step. Indeed, most organisms, including humans, belong to the phylum known as Bilateria, which goes back some 600 million years (Chen et al. 2004). Nevertheless, bilateral symmetry is not restricted to the Bilateria, and has arisen independently in different lineages. It may even precede the Bilateria, since it is also present in some species of the phylum Cnidaria, which is outside the Bilateria. In the sea anemone Nematostella vectensis, for example, bilateral symmetry is dependent on the expression of homologous Hox genes much as it is in the Bilateria, suggesting that bilateral symmetry arose even before the evolutionary split between the Cnidaria and the Bilateria (Finnerty et al. 2004).

For animals that move freely in the natural world, bilateral symmetry is adaptive, because symmetrically placed limbs, be they legs, wings or flippers, provide for linear movement, which is more efficient than motion in an arc. Directional motion creates a back–front asymmetry, so that eyes and mouth are placed forward, but asymmetry tends to be preserved with respect to left and right. Any sensory asymmetry would create an increased risk of predation from the weaker side. In a world in which left–right parity is largely conserved, then, bilateral symmetry is a natural adaptation. Against this strong background of bilateral symmetry, our brains and bodies exhibit some striking left–right asymmetries. Indeed, asymmetries are widespread in nature, albeit superimposed on a body plan that is fundamentally bilaterally symmetrical. Many asymmetries are so-called fluctuating asymmetries, which are random variations from symmetry, usually slight, and these are not of concern here. Rather, my focus is on cerebral and behavioural asymmetries in which the direction of asymmetry in the majority of individuals in a population is in the same direction. Such asymmetries suggest that bilateral symmetry is readily and systematically broken if asymmetry proves more adaptive. This is true of the internal organs, including the heart, lungs, stomach and liver, which are arranged asymmetrically, presumably in the interests of more efficient packaging, and perhaps also of more effective function. Automobiles, for example, have evolved to be outwardly bilaterally symmetrical, but their engines are arranged asymmetrically—a matter of

*[email protected] One contribution of 14 to a Theme Issue ‘Mechanisms and functions of brain and behavioural asymmetries’.

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efficiency in both packaging and performance. Internal organs, moreover, are relatively independent of the organism’s interactions with the spatial world, so the pressure to symmetry is eased. The brain and nervous system, on the other hand, are more directly concerned with sensorimotor activity, and are, for the most part, organized symmetrically. Superimposed on the fundamental symmetry of the brain, though, are a number of systematic asymmetries. In humans, at least, the most obvious asymmetry is handedness. In the great majority of the human population, one hand is clearly dominant in activities such as writing and throwing, and, in approximately 90 per cent of the population, the dominant hand is the right hand. This asymmetry is not at all obvious in the actual structure of the hands themselves, although there are some differences in muscle strength and bone density favouring the dominant hand; at least some of these are a consequence rather than a cause of greater use of the dominant hand (see Steele & Uomini 2005, for review). Handedness is much more obviously a matter of differential skill and activity between the hands, reflecting a cerebral asymmetry rather than a mechanical one. Since the pioneering discoveries of Broca (1861), it is well established that the left hemisphere of the brain is also dominant for language, especially those aspects of language concerned with production. It is also clear that there are complementary specializations of the right hemisphere (Sperry 1982; Corballis 1991; Mort et al. 2003). It is widely held that these asymmetries are uniquely human, and perhaps even a defining characteristic of our species. It is often suggested that handedness and cerebral asymmetry resulted from some genetic mutation at some point after the split of the hominins from the other great apes (e.g. Corballis 1991; Annett 2002; McManus 2002), and Crow (2002) has gone so far as to suggest that this mutation was the speciation event that created Homo sapiens and other putatively human characteristics such as language, theory of mind and a susceptibility to psychosis. It is probably true that some functions that are lateralized in the human brain, such as language and specialized manual functions, are unique to our species, but it is becoming increasingly clear that cerebral asymmetry itself is not. Furthermore, many of the lateralized functions documented in non-humans are probably precursors to those functions we regard as uniquely human (e.g. Rogers & Andrew 2002; Corballis 2003).

2. LATERALITY IN NON-HUMAN SPECIES (a) Handedness The illusion that cerebral asymmetry is uniquely human may stem from the fact that the most obvious manifestation is handedness. At least among mammals, humans are unique in that they are bipedal, freeing the hands from involvement in locomotion. As a consequence, humans are supremely manipulative, and manipulative actions of the hands are an outward manifestation of cerebral asymmetry. This makes human cerebral asymmetry uniquely transparent. Nevertheless, there is now some evidence for consistent handedness in other species. The work of Hopkins and Phil. Trans. R. Soc. B (2009)

colleagues has revealed a population-level preference for the right hand in captive chimpanzees, at least for certain activities such as extracting peanut butter from a glass tube (Hopkins 1996), using an anvil (Hopkins et al. 2007), gestural communication (Hopkins & Leavens 1998) and throwing (Hopkins et al. 2005). The incidence of right-handedness in chimpanzees in these studies is typically approximately 65 per cent, considerably less than the incidence of right-handedness in humans, which is approximately 90 per cent. These estimates may not be truly indicative, however, since, within each species, hand preference does vary with task, and the tasks themselves are somewhat species-specific. One activity common to tests on both species is throwing, and the proportion of chimpanzees throwing with the right hand is higher than that for other measures (Hopkins et al. 2005). In a sample of over a million humans in the USA, the incidence of right-handed throwing was 89.9 per cent for men and 92.4 per cent for women (Gilbert & Wysocki 1992), considerably higher than the values observed in a chimpanzee sample, where 53 animals were reported as right-handed, 16 as ambiguous and 23 as left-handed (Hopkins et al. 2005). Of course, even throwing may not be strictly comparable in the two species. Humans have developed throwing to a more precise and intricate level, and more than half of the chimpanzees in the sample observed by Hopkins et al. did not throw at all. Even so, it seems unlikely that the incidence of righthandedness in chimpanzees approaches that in humans. Curiously, one study of 22 bonobos, which along with common chimpanzees are our closest living nonhuman relatives, revealed no evidence for species-level handedness (Harrison & Nystrom 2008). Palmer (2002) has suggested that the findings of Hopkins and colleagues may be due to statistical artefacts, and has shown the results to be marginal when assessed using funnel plots, which show scatter plots of righthand use against sample size, although the more recent studies do reveal significant species-level right-handedness using this technique (e.g. Hopkins et al. 2005). Another difficulty is that field research suggests little or no population-level asymmetry in non-human primates, including chimpanzees. Sugiyama et al. (1993) examined handedness in chimpanzees for nut-cracking, a lateralized task in which one hand manipulates the anvil and the other the hammer, but left-handers were as frequent as right-handers. McGrew & Marchant (2001) found no evidence for handedness across a variety of activities in chimpanzees observed in the wild, and suggested that the bias in captive chimpanzees is a consequence of contact with right-handed humans. Hopkins et al. (2004) have disputed this, claiming that right-handedness occurs in three distinct populations of captive chimpanzees and is unrelated to the proportion of animals raised by humans. Yet, a recent study of well-digging in wild chimpanzees again has suggested a lack of any population bias in handedness (McGrew et al. 2007). To confound matters further, Corp & Byrne (2004) studied the dominant hand used by wild chimpanzees when eating Saba florida, and found that females were predominantly right-handed and males predominantly left-handed.

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Review. Brain asymmetry: genetics and evolution M. C. Corballis Whether there is true species-specific right-handedness in chimpanzees may remain unresolved until there is unequivocal evidence for population-level handedness in chimpanzees in the wild. Evidence from other primates is inconsistent. There have been claims that monkeys show a slight population-level preference for reaching with the left hand (MacNeilage et al. 1987), but subsequent evidence has been mixed (see commentaries to the article by MacNeilage et al. 1987), but if true, the asymmetry may reflect a right-hemispheric bias for spatial perception—as also documented in humans (for a review see Corballis 1983). At least one study has shown a slight right-hand advantage in a bimanual task in rhesus monkeys, but no bias in capuchins (Westergaard & Suomi 1996). In a sample of baboons, too, nearly 80 per cent were reported to prefer the right hand in making specific communicative gestures (Meguerditchian & Vauclair 2006). Oddly enough, the clearest case of limb asymmetry in non-human animals comes not from primates but from birds. Most species of parrot show a strong preference for the left foot in picking up objects, and the proportion of left footers is close to 90 per cent, comparable with the proportion of humans who are right-handed (Rogers 1980). Given that the bill is the main manipulative organ in the parrot, the use of the left foot as the holding device could be regarded as the equivalent of the use of the left hand by righthanded humans. This result might be taken as evidence that manual specialization arises in species, such as parrots, that use their limbs for manipulation, as proposed by Walker (1980). Consistent with this, Gu¨ntu¨rkun et al. (1988) gave pigeons, which do not use the feet in a manipulative fashion, the task of scratching a piece of tape from the bill, and found no preference for one or other foot at either the individual or species level. Rogers & Workman (1993), though, found that 31 out of 38 chicks, given the same task, chose the right foot. Chicks make use of the feet in scratching the ground for food, whereas pigeons do not, suggesting to Rogers and Workman that involvement in feeding rather than manipulation per se may be the critical factor underlying limb preference in birds. This may generalize to other species. For example, Levermann et al. (2003) reported that some 77 per cent of walruses show a preference for the right flipper when feeding. The direction of the asymmetry may vary between species, though, since Sovrano (2007) reported a left-forelimb feeding bias in toads. There may also be precursors to handedness in postural asymmetries. For example, horses tend to stand with the left foreleg in front of the right rather than vice versa, which has been taken as evidence that the right foreleg tends to be the weight-bearing one, and therefore the stronger of the two (McGreevy & Rogers 2005). Similar asymmetries are present in zebras and impalas (McGreevy et al. 2007). Horses also gallop asymmetrically, with one hindhoof striking the ground before the other. One study of two species of thoroughbred race horses, Arabians and American Quarter horses, showed that 90 per cent led with the right hoof, and only 10 per cent with the left hoof Phil. Trans. R. Soc. B (2009)

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(Williams & Norris 2007)—estimates very close to those for hand and foot dominance in humans. (b) Cerebral and behavioural asymmetries Asymmetries in non-human species are also clearly observed in behaviours other than those to do directly with hands or limbs, providing further evidence of cerebral asymmetry. Many species also show biases in overt behaviour, such as turning to escape predators or to attack prey. Faced with a barrier through which a predator was visible, some species of fishes showed population-level biases to turn left or right, while others did not (Bisazza et al. 2000). Tadpoles have a bias to turn left when escaping a predator, but a bias to turn right when turning to take in air at the surface (Rogers 2002b). Dogs tend to wag their tails to the left, implying right-hemisphere dominance, when faced with an unfamiliar, dominant dog, but wag to the right, implying left-hemisphere dominance, when faced with their owners (Quaranta et al. 2007). These findings are broadly consistent with the suggestion by Davidson (2004), based on human research, that the left hemisphere tends to be specialized for approach and the right hemisphere for avoidance. A right-hemisphere bias has also been documented for social responses in a number of species of fishes (Sovrano et al. 2001), chicks ( Vallortigara & Andrew 1994), sheep ( Peirce et al. 2000) and monkeys (Vermeire et al. 1998), and may relate to the righthemispheric involvement in social understanding in humans (e.g. Sperry et al. 1979). Chicks also show a right-hemisphere bias in processing the gaze direction of a predator (Rosa Salva et al. 2007), which is interesting because it involves both response to a predator and social cognition—the ability to respond to social cues. The right hemisphere may also be the dark side, as there is also evidence that it is the more specialized for aggressive behaviour in a number of species, including toads (e.g. Rogers 2002b), lizards (Deckel 1995), chicks (Howard et al. 1980), baboons (Casperd & Dunbar 1996) and humans (Devinsky et al. 1994). Right-handed boxers typically hold a stance in which their opponents are in their left visual fields, perhaps to ratchet up the aggression in their right hemispheres, but also, of course, to give greater momentum to the stronger right hand. Complementary to the right-hemispheric dominance for attack is a left-hemisphere dominance for feeding. Chicks ( Deng & Rogers 1997), pigeons (Gu¨ntu¨rkun 1985), zebra finches (Alonso 1998) and toads ( Vallortigara et al. 1998) look preferentially with the right eye in responding to prey or feeding matter, and we saw earlier that some species, at least, show a right-hand preference for feeding-related activities. Andrew et al. (2000) have also suggested that this asymmetry may be related to left-hemispheric control of the mouth structures, an asymmetry that may be widespread in vertebrates and may relate to the lefthemispheric control of vocalization, also documented in frogs (Bauer 1993) and canaries (Nottebohm 1977; Halle et al. 2004). Hook-Costigan & Rogers (1998) found that marmosets opened the right side of the mouth wider when making social contact calls, again implying left cerebral dominance, but the left side of

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the mouth wider when expressing fear, implying right cerebral dominance for emotion. This finding mimics that found in humans, with the right side of the mouth more prominent for speech and the left for emotional expression (e.g. Graves & Goodglass 1982; Graves & Potter 1988). These asymmetries are also evident in 5- to 12-month-old human babies, who open the right side of the mouth wider when babbling and the left side when smiling (Holowka & Petitto 2002). Asymmetries for vocalization apply to perception as well as to production. A left-hemispheric advantage for the perception of species-specific vocalizations has been demonstrated in mice (Ehert 1987), rhesus monkeys (Hauser & Anderson 1994), Japanese macaques (Heffner & Heffner 1984) and rhesus monkeys (Poremba et al. 2004). In chimpanzees, the left temporal planum is larger on the left than on the right (Gannon et al. 1998; Hopkins et al. 1998), an asymmetry that seems to be absent in rhesus monkeys and baboons ( Wada et al. 1975), but is well documented in humans (Geschwind & Levitsky 1968; Ja¨ncke & Steinmetz 1993; Foundas et al. 1996). These asymmetries may well be precursors to left cerebral dominance for language processing in humans. This review is by no means exhaustive, but shows overwhelmingly that cerebral asymmetries abound in non-human species, and at least some of these asymmetries were almost certainly precursors to handedness and left cerebral dominance for language, and to right-hemisphere specializations, in humans. Of course, language itself is widely supposed to be uniquely human (e.g. Chomsky 1966; Pinker 1994; Hauser et al. 2002), and we humans have also exploited manipulative skill to a level far beyond that evident in any other species—consider, for example, throwing, writing, playing musical instruments or even tying shoelaces. However, the mechanisms by which these accomplishments were achieved were built from the mechanisms that were probably lateralized in our forebears, and the added complexity may well have exacerbated the earlier asymmetries. Indeed, there are even glimpses of cognitive asymmetries in non-human animals in functions that might have served as precursors to the evolution of language. For example, pigeons tend to discriminate patterns projected to the left hemisphere in a categorical fashion, and those projected to the right hemisphere in a more holistic (‘coordinate’) fashion (Yamazaki et al. 2007). The same appears to be true of humans (Kosslyn et al. 1989), and may well have set the stage for language to be lateralized to the left hemisphere. This conclusion should be treated with caution, though, since there is considerable phylogenetic distance between pigeons and humans. These and other asymmetries may well have come about through convergent evolution, rather than common descent. As another example, left-hemisphere dominance in the control of vocalization has been shown in both canaries and humans, as noted above, but in canaries appears to derive from a leftward bias in the syrinx, the vocal organ itself (Halle et al. 2004), rather than in the brain, as in humans. Comparative psychologists have made extraordinary progress in documenting cerebral asymmetries in non-human species, but the challenge now is to Phil. Trans. R. Soc. B (2009)

determine which are true homologies and which mere analogies. Two of the most prolific investigators of animal asymmetries, Vallortigara & Rogers (2005), write that ‘.the overall similarities across species strongly support the hypothesis of a common origin of lateralization in vertebrates (p. 578)’, but they go on to suggest that the evolutionary pressures for lateralization are indifferent as to whether it is the product of homology or convergent evolution. The issue becomes critical, though, to the question of whether the cerebral and manual asymmetries in humans somehow set our species apart in a fundamental way from all other species (e.g. Crow 2002). The asymmetries reviewed above are in a consistent direction in the majority of the population, but there are always some individuals in which the direction is reversed, or in some cases seemingly absent. Ghirlanda & Vallortigara (2004) noted that, in animal studies, the proportion of individuals that reverse the population-level bias ranges from approximately 10 per cent, as in human handedness, to approximately 35 per cent, as in chimpanzee handedness. Both extremes are also evident within our own species. Previc (1991) has summarized evidence for what he termed ‘natural’ forms of auditory and motor asymmetries in humans, and these favour one side over the other in a ratio of 2 : 1. They include the right-ear advantage in dichotic listening, right-eye dominance, a host of postural asymmetries and a tendency, especially among newborns, to turn the head to the right. These asymmetries may relate to the fact that about two-thirds of human foetuses are confined to an asymmetrical foetal position, with the right side facing towards the mother’s front, during the final trimester. This leaves approximately 33 per cent of people with the reversed asymmetry. One possibility is that the 90 per cent bias evident in human handedness and cerebral asymmetry reflects a genetic influence superimposed on a more general bias of approximately 67 per cent (Corballis 1997). 3. GENETIC THEORIES Variations in laterality suggests the possibility of genetic influences. Genetic theories of laterality have focused on human handedness, and, as noted above, have typically incorporated the assumption that handedness is uniquely human and involved some genetic mutation since the split of the hominins from the great apes (e.g. McManus 1999; Annett 2002; Crow 2002). The ubiquity of cerebral and behavioural asymmetries calls into question the notion of some uniquely human laterality gene, but the examination of contemporary genetic theories of handedness may nevertheless provide insights into the more general nature of genetic control over lateral asymmetries, and may apply widely across species and different manifestations of asymmetry. (a) Single-gene models Approximately 36 years ago, Annett (2002) proposed that the important genetic distinction, at least with respect to handedness, was not between left- and right-handers, but between those carrying a ‘right-shift’

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Review. Brain asymmetry: genetics and evolution M. C. Corballis (RS) factor and those not carrying this factor—in more recent terminology, there is a RS allele, RSC, and an allele without directional specification, RSK. It should be emphasized, though, that, in Annett’s model, most of the variation in handedness is considered to be random, and the RSC allele shifts a normal distribution of intermanual differences to the right. For individuals homozygous for the RSC allele, designated RSCC, the shift is approximately two standard deviations to the right of neutrality, for heterozygotes, designated RSCK, the shift is approximately one standard deviation to the right, and for those homozygous for the RSK allele, designated RSKK, the distribution is centred on the point of neutrality—that is, the direction of handedness is essentially assigned at random. (Since the proportion of left-handers is slightly lower in women than in men, Annett (2002) proposed that the shifts are slightly larger in women.) The idea that genes can influence the presence versus the absence of an asymmetry, rather than the direction of the asymmetry, may be a general principle in the genetics of asymmetry (Morgan & Corballis 1978), and applies, for example, to the asymmetry of the heart and other visceral organs (Layton 1976; Supp et al. 1997). In mice, a mutation on a single gene, known as iv, can cancel a left–right gradient and the asymmetry of the heart is randomized. Half of the affected mice show situs inversus (left–right reversal of the heart and other visceral organs; Layton 1976; Supp et al. 1997). This provides a plausible precedent for the single-gene models of human handedness and cerebral asymmetry developed by Annett (2002). Nevertheless, it does not lead to the identification of the gene itself, since situs inversus in humans appears to be unrelated to handedness or cerebral dominance for language (Kennedy et al. 1999). The actual gene or genes involved must be different. The same principle is embodied in Klar’s (1996) and McManus’s (1999, 2002) genetic models of handedness. Similar to Annett, McManus proposed a two-allele gene, with a dextral (D) allele specifying right-handedness and a chance (C) allele that does not specify the direction of handedness, but leaves it to chance. Unlike Annett, McManus proposed that handedness is fundamentally dichotomous, so that all DD individuals are right-handed, 75 per cent of CD individuals are right-handed and 25 per cent lefthanded, and CC individuals are equally divided between left- and right-handers. Annett’s and McManus’s models provide essentially indistinguishable fits to the data on the inheritance of handedness. Table 1 shows how McManus’s version fits the data accumulated by McManus & Bryden (1992), with the proportion p(D) of D alleles in the population estimated at 0.76. This estimate might seem high, but perhaps reflects a largely literate society in which dextrality, or left cerebral dominance, has greater adaptive fitness than the lack of consistent handedness or cerebral dominance. Variations in this parameter might explain cultural differences in handedness. In more recent formulations of her model, Annett (e.g. 2002) has proposed that the bias is cerebral rather than manual, so that right-handedness implies a dominance of the left hemisphere. (In these terms, the Phil. Trans. R. Soc. B (2009)

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Table 1. Percentage of left-handed offspring by parental combination based on the data summarized by McManus & Bryden (1992) and prediction from McManus’s model. parental handedness R–R

R–L

L–L

per cent left-handed off- 9.5 spring predicted by McManus’s 9.45 model with p(D)Z0.76

19.5

26.1

20.24

28.87

Table 2. Expected numbers of right- and left-handed individuals with left and right cerebral dominance for language in a hypothetical population of 100, according to McManus’s model of handednessa. language-dominant hemisphere

right-handers left-handers

left

right

83 7

7 3

a The numbers are based on p(D)Z0.8. DD individuals are assumed to be right-handed and left-cerebrally dominant for language. In DC individuals, the proportions of right-handed and left-cerebrally dominant individuals are both 0.75, and are assumed to be uncorrelated. CC individuals are assumed to be equally divided among all combinations of right- and left-handedness and left and right cerebral dominance.

right shift is better described as a left shift.) There is also a weak correlation between handedness and the lateralized representation of language in the human brain. Studies based on the Wada test (Rasmussen & Milner 1977), electroconvulsive therapy (Warrington & Pratt 1973) and brain imaging (Pujol et al. 1999; Knecht et al. 2000) are reasonably consistent in showing that over 90 per cent of right-handers are left-cerebrally dominant for language, compared with approximately 70 per cent of left-handers. These estimates can be matched by McManus’s model with p(D)Z0.8, on the assumption that handedness and cerebral dominance for language are subject to the same biases in the three genotypes, but that the biases are applied independently (table 2). It may therefore be reasonable to suppose that a single twoallele gene may underlie variations in both handedness and cerebral dominance for language, and perhaps other asymmetries, both human and non-human, as well. (b) Where is the gene? Genetic models are unlikely to be widely accepted until the putative gene is located. The evidence so far is not especially convincing. One specific claim is that of Crow (2002), who has argued that the laterality gene is located in the Xq21.3/Yp11.2 region of homology on the X and Y chromosomes, and suggested protocadherin XY as a likely candidate. These claims are based largely on evidence that individuals with Turner’s syndrome, who lack an X-chromosome, have deficits in performance associated with the right hemisphere, while those with an extra X chromosome (XXY, as in Klinefelter’s syndrome, or XXX syndrome) have relative deficits in verbal IQ, suggesting a left-hemisphere deficiency. Further evidence comes from a study

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showing a higher concordance of handedness in siblings of the same sex than in opposite-sex siblings, as expected from linkage to homologous X–Y loci (Corballis et al. 1996), but the effect was weak. One argument against this theory is that polymorphisms are unstable on the Y chromosome (Corballis 1997), yet variations in handedness seem to have been fairly constant for at least 5000 years (Coren & Porac 1977) and probably longer. Evidence from the prehistoric record is necessarily indirect, but in a careful analysis of skeletal evidence and material cultural markers, Steele & Uomini (2005) suggested that the predominance of right-handedness was probably present in early species of our own genus, Homo, approximately 2 Myr ago. Following McKeever (2000), I have suggested that the gene may be on the X chromosome alone (Corballis 2001; see also Jones & Martin 2000). However, a genome-wide search for the handedness gene has since offered little support for X-linkage, and suggests that the region 2p11.2-12 on chromosome 2 may be a more likely candidate (Francks et al. 2002). Although this failed to replicate in an independent sample, a further analysis has revealed significant paternal linkage within this site (Francks et al. 2003), suggesting that imprinting may play a role. Further investigation has narrowed the locus to the leucine-rich repeat transmembrane neuronal 1 (LRRTM1) gene on chromosome 2p12, a maternally suppressed gene that appears to be associated paternally with handedness and schizophrenia (Francks et al. 2007). The effect was observed in a sample of dyslexic siblings but not in a set of twins, and the same haplotype was over-transmitted paternally in a large sample of individuals with schizophrenic and schizoaffective disorders, which are, in turn, known to be related to the anomalies of handedness and cerebral asymmetry. Paternal inheritance is something of a puzzle, since surveys on phenotypic handedness have suggested a stronger maternal than paternal influence (e.g. Annett 2002). It seems unlikely, then, that LRRTM1 is the only gene involved in handedness and cerebral asymmetry—indeed, it may have more to do with conditions such as dyslexia or schizophrenia, with only an indirect influence on laterality. There are other reasons to suppose that several genes may be involved, perhaps with additive effects. Besides suggesting 2p12 as a likely candidate, linkage analyses have pointed to other regions of interest, including17p11-q23 ( Francks et al. 2003), 10q26 (Van Agtmael et al. 2002) and 12q21-23 ( Warren et al. 2006). Inconsistencies between these reports might be due to the differences in the way handedness is defined, differences in populations, or the vagaries of statistical analysis. Furthermore, if the models proposed by Annett and McManus are correct in the assumption that chance plays a major role, especially in the determination of left-handedness, the gene or genes will be difficult to detect using linkage analyses. It has also been suggested, though, that handedness is a facultative trait, with no genetic variation. Laland et al. (1995) have shown how a model incorporating a single dextral gene can explain the data on inheritance of right handedness, on the assumption that facultative right-handedness can be negated or reversed by Phil. Trans. R. Soc. B (2009)

parental and cultural influences. For example, the advantage of being in a left-handed minority in fighting or in sport might be maintained through non-genetic parental inheritance; the successful left-handed warrior might train his sons also to be left-handed. Laland and colleagues. also suggested that handedness can be transmitted from parent to infant through imitation or through the tendency of the parent to place objects in the hand corresponding to their own hand preference. An alternative possibility is that the action of the dextral gene is itself silenced by an epigenetic event, such as methylation (Klar 2004). Such events can even be transmitted between generations, but they do not involve mutations, and so would not be evident in the genome (Bird 2007). Models in which variation is non-genetic might after all be consistent with Crow’s (2002) claim that the laterality gene is located in a homologous region of the X and Y chromosomes.

4. EVOLUTIONARY THEORIES (a) Why asymmetry? As a general rule, although there are noteworthy exceptions, the advantages of symmetry seem to apply more strongly to motor output than to sensory input (for a review see Corballis 1998). As an example, Watson & Kimura (1989) showed that right-handers were much better able to throw with the right hand, but equally adept with either hand at intercepting rapidly moving targets. In sports such as cricket, fielders can typically throw much further and more accurately with the dominant hand, but there is relatively little difference between the hands in catching a ball. Studies of patients following commissurotomy indicate that the production of speech typically depends exclusively on the left hemisphere, but that both hemispheres are capable of comprehending speech—although the left is usually superior (Sperry 1982). In general, then, there may be a stronger evolutionary imperative to preserve at least a degree of symmetry in reactions to the environment, which can impinge on either side, than in actions on the environment, where the organism is free to reposition itself to take advantage of any asymmetry (Corballis & Beale 1976). Complex motor patterns, such as speech or skilled manual performance, are generated within the brain and are relatively impervious to environmental input, so bilateral symmetry can be relaxed. There may also be adaptive advantages to unilateral control. One suggestion is that bilateral control would be constrained by the relatively slow conduction time between hemispheres, so that unilateral computations can be carried out with greater speed (Ringo et al. 1994). Another advantage of hemispheric specialization is that it avoids duplication, and this may be especially important in complex functions, such as language, which require extensive neural circuitry. Duplication may therefore be wasteful of neural space, and complementary specialization in the two hemispheres results in a gain in overall computational efficiency. The left-hemispheric dominance for language, for example, is matched by a righthemispheric dominance for spatial attention (Mort et al. 2003). Duplication of programming in the two

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Review. Brain asymmetry: genetics and evolution M. C. Corballis hemispheres might also lead to interhemispheric conflict (Corballis 1991). Stuttering, for example, has been associated with anomalies in cerebral dominance (Foundas et al. 2003). These arguments, though, do not explain cases in which direction of asymmetry is the same in the majority of the population. One possibility is that there are group pressures for conformity in lateralized functions. In human societies, manufactured objects are often intrinsically asymmetrical and constructed for the convenience of right-handers and inconvenience of left-handers—these include scissors, books, magazines, musical instruments and even the placement of door handles. Convention demands that we shake hands and salute with the right hand. Of course, these asymmetries may be the consequence rather than the cause of right-hand dominance, and conformity in lateralized behaviour need not depend on biological asymmetry, except perhaps in the sense that asymmetry is a necessary requirement for the ability to tell left from right (Corballis & Beale 1970). In driving, for example, our very survival demands that we keep to the appropriate side of the road, but, in some countries, this is the left side and some the right. If conformity does play a role in the shaping of directional asymmetries, we might expect asymmetries to be more pronounced in gregarious species than in those in which individuals are relatively isolated. There is some evidence that this may be so. In fishes, shoaling is a means of protection, and it is adaptive if all fishes in a shoal turn in the same direction when confronted with a predator, particularly if the predator is directly in front and turning in either direction would be equally effective. Bisazza et al. (2000) found that, among species of shoaling fishes, all six demonstrated a turning bias at the population level, whereas, among 10 species of non-shoaling fishes, six did not show a populationlevel bias, although all showed a bias at the individual level. Other pertinent evidence is difficult to find, and Vallortigara & Rogers (2005) pointed out that the gregariousness may change over time, and the conditions that led to population-level lateralization in the first place may no longer apply to extant species. It is also possible that population-level asymmetries are based on some underlying property of living matter, such as the helical coiling of amino acids. For some speculation along these lines, see the final chapter of McManus (2002). (b) Why the variation in lateralization? If cerebral asymmetry were clearly adaptive, one might ask why it varies between individuals, and is sometimes even reversed. We have seen that the variation, in humans at least, may be best described in terms of the presence versus the absence of a population-level lateralizing influence, such as the RSC or D allele, rather than in terms of opposite directions of asymmetry. If asymmetry were the sole consideration, then one might expect the entire population to show the same direction of asymmetry (e.g. all people righthanded and left-cerebrally dominant for language), or perhaps equal numbers of individuals showing opposite directions of asymmetry (e.g. half the population lefthanded and half right-handed). This state of affairs has Phil. Trans. R. Soc. B (2009)

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been called antisymmetry and applies to the asymmetry of the claws in male fiddler crabs—one claw is larger than the other, but the larger one is as likely to be on the left as on the right. But the behavioural and cerebral asymmetries evident in both humans and non-human species apply only to a majority, with a significant minority showing either reversed asymmetry or a lack of asymmetry. Regardless of whether these variations in the direction of asymmetry are of genetic or non-genetic origin, it is of interest to speculate that variation itself might be adaptive. Vallortigara & Rogers (2005) have suggested that directional asymmetries may have been subjected to frequency-based selection, such that there is an adaptive advantage to being in a reversed minority only if it remains a minority. Suppose, for example, that members of a group tend to stick together to avoid predation, and run off to the left when a predator threatens. By being one of many, each individual is less likely to be singled out by the predator. The predator may nevertheless choose to attack the mob rather than the strays, since the chances of catching at least one victim is maximized. Some individuals may therefore benefit from belonging to a minority that veers off to the right—a strategy that works only if this group remains a minority. This may have resulted in a subtle selection dynamic that held left- and right-turning in balance (see also Ghirlanda & Vallortigara 2004), but with left-turning, implying a right-hemisphere dominance for this behaviour, maintained for the majority. One might argue similarly that left-handers hold an advantage in fighting, but only so long as they are in the minority (Raymond et al. 1996). In genetic terms, this theory implies an allele that reverses the prevalent asymmetry, but it is also consistent with a model, such as that of Annett (2002) or McManus (2002), in which one allele cancels, rather than reverses, the asymmetrical influence of the other. A more general possibility is that of a trade-off between bilateral symmetry and asymmetry—perhaps too much symmetry leads to difficulties in the neural programming of complex action, and too much asymmetry leads to a vulnerability in an even-handed world where impediments, such as attack from predators, may occur on either side of the organism. The balance may be achieved simply by developmental mechanisms in which tendencies to asymmetry are held in check by those conforming to the basic bilateral symmetry of the body plan. In this case, variations might be attributed simply to environmental influences. But balance may also be accomplished through genetic influences. In terms of single-gene models, for example, balance may be accomplished through a heterozygotic advantage (Annett 2002); that is, RSCK individuals may have slightly greater biological fitness than either RSCC or RSKK individuals. This ensures that both alleles are preserved in the population. Annett herself has documented evidence that, in the human population, left-handers may be especially susceptible to reading disorders, while extreme right-handers may be relatively disadvantaged in spatial or some sporting activities. She also noted a preponderance of lefthanders among surgeons.

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The more interesting and relevant comparisons, though, may be between the presence and absence of asymmetry rather than between opposite directions of asymmetry. A study of 12 770 eleven-year-olds in the UK suggests that those without clear handedness performed worse than either left- or right-handers on tests of verbal ability, non-verbal ability, reading comprehension and mathematical ability (Crow et al. 1998). This suggests that those lacking the directional allele (RSC or D) may run the risk of what Crow et al. called ‘hemispheric indecision’, to the detriment of certain intellectual activities. Of course, chance influences will ensure that some of these individuals will be left-handed and some right-handed, so the overall risk of falling into the susceptible group is small. Crow and colleagues result was not replicated in a sample of 530 younger boys (Mayringer & Wimmer 2002), but similar deficits associated with ambidexterity in adults have been reported by Peters et al. (2006) and Corballis et al. (2008). The disadvantages of cerebral symmetry may apply also to non-human species. In chicks, cerebral asymmetry is determined by asymmetrical exposure to light prior to hatching, and chicks raised without this pre-hatching asymmetry are at a disadvantage relative to lateralized birds in a situation where they monitor a hovering predator while, at the same time, discriminating grain from non-edible grit ( Rogers 2002a). A similar result has been obtained in pigeons. As with chickens, pigeons show a right-eye advantage in discriminating grain from grit, and Gu¨ntu¨rkun et al. (2000) reported a positive correlation between the degree of asymmetry, as determined under monocular viewing, and the discrimination performance under binocular conditions, suggesting that visual foraging is accomplished more effectively if mediated by a single hemisphere. Given the advantages of an asymmetrical brain, the question arises as to why asymmetry has not become fixed in the population. One possibility, suggested earlier, is that reversed asymmetry may be advantageous so long as it is a minority condition. Reversed asymmetry may result from the lack of any genetically induced bias, and its advantages may offset any penalty owing to the risk of a lack of asymmetry. Alternatively, there may be compensatory advantages more directly associated with the lack of asymmetry. These may have to do with the more general benefits that drove the evolution of bilateral symmetry in the first place, resulting in a more balanced awareness and disposition to movement. Sexual selection may also have played a role; symmetry is seen as more attractive than lopsidedness, and people judge symmetrical faces to be more attractive than asymmetrical ones (e.g. Gangestad et al. 1994; Rhodes & Zebrowitz 2002). (c) Symmetrical oddity? It is of interest to speculate, though, that cerebral symmetry, or a relative lack of consistent lateralization, might have cognitive consequences that are adaptive, but only if a minority condition, creating kinds of cognitive oddity that may lead to creativity or enhanced charisma. In what may appear as an unpromising lead, Phil. Trans. R. Soc. B (2009)

Barnett & Corballis (2002) found that mixed-handers were more prone to magical ideation, characterized by mild paranoia and superstition, than either left- or right-handers—a function that was essentially the inverse of the relationship between academic achievement and handedness reported by Crow et al. (1998). A similar result was reported by Nicholls et al. (2005), although Jaspers-Fayer & Peters (2005) found no relationship between handedness and magical ideation, which was nevertheless more prevalent in females with a tendency to left–right confusion, perhaps suggestive of cerebral symmetry. In a similar vein, there is evidence that mixed-handedness is associated with a greater sensitivity to sensory illusions ( Niebauer et al. 2002) and a higher risk of schizophrenia (Claridge et al. 1998; Upadhyay et al. 2004), and strong belief in the paranormal seems to be associated with symmetrical brain activity (Pizzagalli et al. 2000). Jaynes (1976) speculated that cerebral asymmetry emerged in the second millennium BC, in response to assorted catastrophes, such as floods, invasions, etc. Prior to this, people were governed by hallucinations, invoking the Gods, but cerebral asymmetry allowed the left hemisphere to create a sense of self, so that people took responsibility for their own actions. Jaynes’s theory makes little evolutionary sense, since handedness and cerebral asymmetry probably go back at least 2 million years, and perhaps even earlier, in hominid evolution (Corballis 1997; Steele & Uomini 2005). Nevertheless, there may well be some truth to the idea that cerebral asymmetry underlies rational thought, and that a lack of asymmetry may well lead to more delusional and perhaps hallucinatory thought processes. Although magical thinking may seem counterproductive in terms of biological fitness, it may be related to creativity, with positive implications for science and mathematics. Leonhard & Brugger (1988) noted a link between paranormal thought, delusional thought and creativity, and suggested that these characteristics relate to heightened righthemispheric activation and relatively coarse semantic activation in that hemisphere. This, in turn, results in a loosening of associations and enhanced creativity. Although Leonhard and Brugger’s account focuses on the right hemisphere, it is possible that the profile has to do with the lack of cerebral dominance rather than any specialization of the right hemisphere itself. Despite the evidence that mixed-handers show some deficit in arithmetic ability (Crow et al. 1998; Corballis et al. 2008), Singh & O’Boyle (2004) reported that mathematically gifted adolescents show no hemispheric asymmetry on tasks involving global–local judgements and matching letters, whereas average-ability adolescents and college students show a left-hemispheric advantage, suggesting that the mathematically gifted may lack consistent cerebral asymmetry. Although Singh and O’Boyle selected right-handers for this study, they also characterize the mathematically gifted as ‘typically male, left-handed, and myopic’ (p. 371). At present, then, it remains unclear precisely what advantages accrue to cerebral symmetry rather than the asymmetry observed in most human brains. There are hints that symmetry may lead to enhanced creativity, but this needs further investigation. There is a popular

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Review. Brain asymmetry: genetics and evolution M. C. Corballis view that left-handers are overly represented among creative artists or scientists,1 but this is based more on the idea that the right hemisphere, which controls the left hand, is the more creative of the two sides of the brain, itself a dubious proposition (Zangwill 1976; Corballis 2007). But left-handedness itself may be indicative of the lack of consistent cerebral asymmetry, and any associations with creativity may be a reflection of that rather than of left-handedness per se. To my knowledge, there is no comparable evidence from non-human species suggesting that there may be advantages associated with the lack of asymmetry in an otherwise asymmetrical population. Human societies have often revered the oddball, especially if associated with mystical or even hallucinatory behaviour, and there is at least some evidence that these characteristics may be associated with the lack of consistent asymmetry, as documented above. A symmetrical brain may well provide avenues of thought that do not conform to academic expectations, but may nonetheless provide the impetus for significant discovery and leadership.

5. CONCLUSIONS Recent research has made it abundantly clear that handedness and cerebral asymmetry are not unique to humans. Nevertheless, activities that are uniquely human, such as language, or that are more highly developed in human than in other species, such as manual skill (dexterity), may well have exploited asymmetry in ways not evident in non-human species. Asymmetries are too ubiquitous to be attributed simply to environmental influences, but their genetic bases remain elusive. Single-gene models can provide good fits to phenotypic data, but the location of the putative gene is not known. A paradoxical feature of the various behavioural and cerebral asymmetries reviewed above is that they do not apply to all members of the species. This suggests that there is some adaptive advantage in maintaining variations in laterality, along with advantages to asymmetry itself. In this respect, these asymmetries contrast with the characteristic asymmetry of the heart and other visceral organs, where reversals and other variations are extremely rare and usually attributed to pathology. In this paper, I have sketched a number of hypotheses as to why variation of lateralization might itself be adaptive. These are not necessarily mutually incompatible, although they do suggest a number of issues that might guide further inquiry. One is whether the genetic component is fixed, and variations arise simply from environmental or epigenetic influences, or whether the variation itself is genetic in origin. If the latter, the question is whether the balance of asymmetries is maintained through frequency-based selection, or through a mechanism such as heterozygotic advantage. At present, it seems more likely that the balance is one between asymmetry and symmetry, rather than between symmetry and antisymmetry. First, in Bilateria—the phylum to which we and most other animals belong— symmetry is the default condition, and the advantages of Phil. Trans. R. Soc. B (2009)

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asymmetry must be weighed against the long-standing adaptiveness of symmetry in a world lacking systematic left–right biases. Second, genetic models and genetic evidence suggests that genes rarely determine the direction of asymmetry, but influence instead whether or not an asymmetry will be expressed. In research on lateralization in humans, it has been traditional to compare individuals of opposite laterality, as in comparing left- and right-handers or left and right cerebral hemispheres, but, from both evolutionary and genetic perspectives, it may be more fruitful to compare degrees rather than directions of lateralization. We have seen that those without consistent handedness, for example, may differ from both the left- and right-handers in terms of both intellectual abilities and personality characteristics such as magical ideation, delusional behaviour and possibly creativity. This is one avenue, I suggest, that it might be useful to explore further. I have benefited from discussion and correspondence with Kylie Barnett, Richard Byrne, Timothy Crow, Clyde Francks, Bill Hopkins, Kevin Laland, Chris McManus, Leslie Rogers and Giorgio Vallortigara, who do not necessarily agree with the ideas expressed in this paper. Two unnamed referees were also extremely helpful.

ENDNOTE 1

This has even led to false claims of left-handedness. For example, Wikipedia lists Albert Einstein, Benjamin Franklin, Pablo Picasso and Leonardo da Vinci among famous scientists and artists who were left-handed. As McManus (2002) documented, the first three were almost certainly right-handed. Wikipedia is right about Leonardo.

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Review. Brain asymmetry: genetics and evolution

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Phil. Trans. R. Soc. B (2009) 364, 881–894 doi:10.1098/rstb.2008.0235 Published online 5 December 2008

Review

Why are some people left-handed? An evolutionary perspective V. Llaurens1,*, M. Raymond1 and C. Faurie1,2 1

Institut des Sciences de l’Evolution de Montpellier (UMR CNRS 5554 ), Universite´ de Montpellier II, C.C. 065, 34095 Montpellier Cedex 5, France 2 Department of Animal and Plant Sciences, University of Sheffield, Sheffield S10 2TN, UK

Since prehistoric times, left-handed individuals have been ubiquitous in human populations, exhibiting geographical frequency variations. Evolutionary explanations have been proposed for the persistence of the handedness polymorphism. Left-handedness could be favoured by negative frequency-dependent selection. Data have suggested that left-handedness, as the rare hand preference, could represent an important strategic advantage in fighting interactions. However, the fact that left-handedness occurs at a low frequency indicates that some evolutionary costs could be associated with left-handedness. Overall, the evolutionary dynamics of this polymorphism are not fully understood. Here, we review the abundant literature available regarding the possible mechanisms and consequences of left-handedness. We point out that hand preference is heritable, and report how hand preference is influenced by genetic, hormonal, developmental and cultural factors. We review the available information on potential fitness costs and benefits acting as selective forces on the proportion of left-handers. Thus, evolutionary perspectives on the persistence of this polymorphism in humans are gathered for the first time, highlighting the necessity for an assessment of fitness differences between right- and left-handers. Keywords: handedness; polymorphism; human

1. INTRODUCTION The aim of this review is to identify the evolutionary forces involved in human handedness. Two main questions are critical to improve our understanding of the evolution of human handedness: (i) why is hand use asymmetric (i.e. why do individuals show a preference for one hand in most manual tasks)? and (ii) why is hand use asymmetry polymorphic (i.e. why do some individuals prefer the left hand and some the right for a similar task)? Most research on handedness has focused on the intersection of these two questions, namely, why are humans right-handed? As a consequence, the debate on the origin and understanding of handedness has been partially obscured, as left-handedness was historically considered as an anomalous or pathological case, thus ignoring the relatively high proportion of left-handers within human populations. Previously, asymmetric hand use has been studied extensively. Corballis (2003) suggested that the evolution of human speech implied an association between speech and gesture, and thus brain lateralization for speech may be responsible for asymmetric hand use. This evolutionary explanation was further elaborated by Vallortigara & Rogers (2005) who evaluated

the costs and benefits of brain asymmetry. The aim of the present review is to clarify the question of the asymmetric hand use polymorphism in humans. Many diverse studies on left-handedness have been conducted by researchers from various fields such as medicine, neurology and psychology. Although some data remain controversial, several hormonal, cultural and developmental factors have been found to be associated with handedness. Here, we attempt to review the information available on both proximal and ultimate aspects of handedness in humans to identify the evolutionary mechanism of the persistence of left-handers. 2. RIGHT AND LEFT HAND USE IN HUMAN POPULATIONS To understand the evolutionary processes implied in handedness, it is first necessary to have a clear idea of the historical and geographical variation of this trait. (a) Hand preference assessment Handedness measures are based on hand use preference or hand performance ( McManus 1996). However, there are no two clear categories such as left- and right-handers. For a given manual action, each individual shows a preference for the use of one hand, and it is not always the same hand for two different actions (Salmaso & Longoni 1985). This suggests that right- or left-handers are not general

* Author for correspondence ([email protected]). One contribution of 14 to a Theme Issue ‘Mechanisms and functions of brain and behavioural asymmetries’.

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categories, but rather are defined as a function of the tasks. When the tasks considered are highly skilled and complex, and the individuals tested are specialized in these tasks, there is a very strong correlation between the different tasks (Bryden 1977; Wood & Aggleton 1989; Connolly & Bishop 1992; Marchant et al. 1995; Marchant & McGrew 1998). To study handedness variations in humans, it is important to choose tasks that are typical tasks among human populations from different cultures. Thus, some tasks commonly used in Western societies to measure handedness, such as writing or teeth brushing, are meaningless in other cultures. Hand preference for some tasks could also be modified by social or religious influence. For example, Teng et al. (1976) observed in China a strong social pressure for right-handed writing and eating, which has drastically decreased the proportion of left-handers for these tasks compared with other tasks. Thus, the tasks chosen to measure handedness should be logically related to the biological hypothesis tested. For example, if one wants to assess handedness in the context of the hypothesis of a frequencydependent advantage of left-handers in fights, tasks should be related to fighting actions. If the aim is to examine brain lateralization related to language, writing handedness is more relevant. Therefore, despite the complexity of the phenomenon, the biological causes for left- and right-handers still make sense under some circumstances. (b) Handedness in the past Handedness in ancient humans has been inferred by analysis of archaeological samples from skeletons, stone tools and various other artefacts (see Steele & Uomini (2005) for a review). By studying arm bone length, Trinkaus et al. (1994) observed a prevalence of right hand dominance in Neanderthal skeleton samples (dating from approx. 35 000 BP). For some tools, modern replication has shown that handedness conditioned the pattern of knapping scatters and that it is thus possible to infer the laterality of the tool maker by studying ancient tools (Rugg & Mullane 2001). A handedness polymorphism, with a majority of righthanders, has been inferred from tools dating from 300 000 to 400 000 BP. Data from tool shape or wear, which both reflect tool use, also allowed inferences on ancient human handedness. Phillipson (1997) reconstructed grip types on hand axes and cleavers dating from approximately 1 Myr ago, and also observed a majority of right users. However, it is a possibility that these estimations could have been modified by the use of these same tools by different individuals. Dental marks have also been used to infer hand use for cutting food with a stone tool. These data suggest that the handedness polymorphism existed in Neanderthals (Bermu`dez de Castro et al. 1988; Fox & Frayer 1997). Again, for this task, right-handers outnumbered left-handers. However, these could be biased by dietary or post-mortem marks. Negative hands painted in caves during the Upper Palaeolithic in Western Europe, or more recently elsewhere in the world, could also be informative on the handedness of the painter. In all cases, both right and left hands are found, with a higher Phil. Trans. R. Soc. B (2009)

prevalence of left hands, indicating a higher proportion of right-handers for this task (for a review see Steele & Uomini 2005). Human representations in artistic samples were also used to track the handedness of artists, or the handedness of individuals depicted by artists. For the handedness of artists, Perello (1970) showed that representations differ between right- and left-handers and by studying painting from prehistoric caves (e.g. Altamira Cave, 14 000–18 500 BP), he inferred that handedness should be polymorphic. These methods could be reliable if the characteristic left-hander’s marks on painting or engraving were formally tested on modern humans. Another approach consists of studying the handedness of the individual’s depicted (e.g. Spennemann 1984). However, these methods are more problematic, as it has not been shown that handedness frequency in art reflects reality. In addition, there are known biases in the depiction of handedness, at the cultural, religious and aesthetic levels (Needham 1973; Faurie & Raymond 2004). Thus, the use of these data requires further study. However, all the above-described studies clearly show a polymorphism of hand use in Hominid populations during prehistoric and historic times, with an overall dominance of right-handers. The polymorphism thus seems to have persisted over significant evolutionary time, suggesting that selection may play an important role in the persistence of this diversity. Another indication of selection pressures is provided by the study of the variation of the frequencies of right- and left-handers throughout the world. (c) Geographical variation The diversity of the tasks used to test handedness introduced complications in comparing hand preference across populations. When only one task is considered, there is still substantial geographical variation. Raymond & Pontier (2004) reviewed 81 studies on handedness that examined throwing or hammering in 14 countries in America, Africa, Europe, Asia and Australia and found a range of 5–25.9%, suggesting an important geographical variation in hand preference. Such geographical variations have also been observed for writing hand preference: in a survey of 12 000 subjects from 17 countries, 2.5–12.8% were left-handed for writing (Perelle & Ehrman 1994), and among seven ethnic groups based on 255 100 answers to a BBC internet study 7–11.8% were left-handed (Peters et al. 2006). Studies on traditional societies tend to show a similar range of variations. Faurie et al. (2005b) found a range of left-hander frequencies between 3.3 and 26.9% across eight societies. The frequency of left-handedness thus seems to be variable among human populations, left-handers being always at a lower frequency than right-handers. Moreover, in most populations studied, the proportion of left-handers among women was lower than in men (reviewed in Raymond & Pontier 2004), suggesting an important influence of sex in the determinism of hand preference. This polymorphism is thus present in every human population studied, suggesting that evolutionary mechanisms should be involved in its persistence.

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Review. Polymorphism of handedness in humans However, for selection to take place, hand laterality should be a heritable trait. Thus, in the following sections, we review the determinism and transmission of hand preference in humans. The exact mechanisms have not yet been clearly characterized, but several influential factors have been identified.

3. GENETIC FACTORS (a) Handedness in families The study of handedness in families is a first attempt to characterize the mechanism involved, since it allows assessment of the transmission of this trait across generations. Tables 1 and 2 show a clear familial effect upon handedness. Two right-handed parents produce fewer left-handed offspring than parents with any other handedness combination and two left-handed parents produce the highest proportion of left-handed children, i.e. approximately 30–40% (McManus 1991; McKeever 2000). This suggests that hand preference could be transmitted by parents to their children, either at a genetic or learning level. There is a higher prevalence of left-handedness in children of right-handed men and left-handed women (RxL mating) than left-handed men and right-handed women (LxR matings) (Annett 1973; Ashton 1982; Spiegler & Yeni-Komshian 1983; Risch & Pringle 1985; McManus 1991), thus suggesting stronger maternal effects on offspring handedness. Such a finding could result from a sex-linked genetic effect, or from a greater social influence likely to be exerted by the mother on the child. Note that McKeever (2000) observed this maternal effect only for sons, not daughters and also observed a paternal effect for daughters, but not sons. This would be consistent with an X-linked genetic determinism of handedness. Published heritability estimates for handedness range from 0.23 to 0.66 ( Hicks & Kinsbourne 1976; Longstreth 1980; Porac & Coren 1981; Annett 1985; Risch & Pringle 1985; McManus & Bryden 1991; McKeever 2000; Warren et al. 2006). Some results of sex-specific heritability estimates are presented in table 3. The fact that handedness runs in families is not convincing evidence of a genetic component, since parents also transmit a particular environment to their offspring. The transmission of genes can be distinguished from the transmission of environment by means of adoption studies. Unfortunately, there have been few such studies of handedness, where adoption had taken place early enough (before the age at which the direction of children’s handedness is established). Carter-Saltzman (1980) showed that handedness of adopted children has no similarity with their adoptive parents, whereas the handedness of a control group showed a significant correlation with their biological parents. The same pattern was observed by Saudino & McManus (1998), although the sample size was again too small to distinguish properly between genetic and environmental components of variance. The study of twins could clarify the relative contribution of genetic and environmental factors. Monozygotic twin pairs are significantly more likely to be concordant for handedness than dizygotic pairs Phil. Trans. R. Soc. B (2009)

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Table 1. Frequency of left-handers in families, according to maternal/paternal handedness and the sex of the offspring. (Combined results, adapted from McManus (1991). Numbers in parentheses indicate sample sizes (total 64 582). L, left; R, right.) parental handedness

left-handed offspring

father

mother

sons

R R L L

R L R L

10.4% 22.1% 18.2% 27.0%

daughters (30 268) (1815) (2308) (215)

8.5% (26 020) 21.7% (1688) 15.3% (2100) 21.4% (168)

Table 2. Frequency of left-handed writers in families, according to maternal/paternal handedness and the sex of the offspring. (Adapted from McKeever (2000). Numbers in parentheses indicate sample sizes (total 2632). L, left; R, right.) parental handedness

left-handed offspring

father

mother

sons

R R L L

R L R L

16.97% 25.29% 15.45% 37.14%

daughters (3329) (340) (382) (35)

16.39% 21.52% 20.51% 44.83%

(3666) (395) (429) (29)

(Sicotte et al. 1999). Table 4 shows that dizygotic twins do not differ from binomial expectations in their hand preference, whereas monozygotic twins show more concordance than would be expected by chance. These data therefore suggest that there is a genetic contribution to handedness. However, discordance of handedness among monozygotic twins also raises the question of cultural influence on hand preference. Even if the genetic and cultural contributions to transmission of hand preference are not fully determined, these results provide convincing evidence for a significant heritability, allowing the action of natural selection on this trait. (b) Genetic models of handedness Some authors have developed completely non-genetic theories for the determinism of side preferences (e.g. Morgan & Corballis 1978; Provins 1997). However, there is extensive evidence against these theories. These theories are beyond the scope of this review. Several authors have tried to build genetic models to account for the transmission patterns observed. Three major problems have arisen for determining a genetic aetiology of handedness: (i) cultural biases influence the practice of hand usage, (ii) despite identical genotypes, approximately 18 per cent of monozygotic twins are discordant for handedness and (iii) only 30–40% of children from LxL couples are left-handed. Models of handedness generally assume a genetic basis to both laterality and hemispheric asymmetry (Levy & Nagylaki 1972; Annett 1985; McManus 1991). Conventional Mendelian genetic models fail to fit the data. An important and influential study modified the conception of asymmetrical development: by breeding inbred strains of mice, Layton (1976) showed

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Table 3. Sex-specific estimates of handedness heritability in three studies on UK university students. (Hull University (studies 1 and 2) and Open University (study 3). Left-handedness criterion: writing hand (studies 1 and 3) left hand preference for any one out of the 12 items (study 2). Data from Annett (1973, 1978).) parent

father

mother

sex of offspring male study h2 (%)

1 17.4

female 2 16.8

3 —

1 3.5

male 2 31.9

Table 4. Number of different handedness combinations in monozygotic and same sex dizygotic twins. (Combined results, adapted from McManus (1991). L, left; R, right.) handedness

monozygotic

dizygotic

R–R R–L L–L observed/expected discordant pairs (%)

2184 629 87 90.1

1951 585 53 99.3

that in mice carrying a recessive allele known as the iv mutation in homozygous form, exactly half of the mice presented situs inversus, i.e. a reverse disposal of organs within the body. The iv mutation was thus responsible for a random right–left disposal of organs. This random genetic factor had a strong influence on subsequent models of genetic determinism of handedness. Causal models involving a single gene with major effects have been proposed, most influentially Annett’s ‘right shift theory’ and McManus’ model, which are based on a single hypothesized gene with two alleles. Such models have to include a significant role for chance factors during development, setting a 50 per cent threshold on the possible prevalence of lefthandedness in any population, to explain the low rates of left-handedness in the children of two left-handed parents and to solve the problem of the occurrence of monozygotic twins discordant for handedness. A few other simple genetic models have been proposed such as the X-linked three alleles model (McKeever 2004) or the random-recessive model (Klar 2003). Nevertheless, there are a number of observed associations that are difficult to accommodate within any simple genetic model. Segregation analysis of hand preference and hand use on 1818 nuclear Hawaii families failed to fit any fully genetic model of handedness determinism and suggested that handedness phenotypic variation could be 10–20% explained by genetic causes and 80–90% environmental (Ashton 1980). The failure of these simple genetic models to fit the data indicates that the genetic determinism of handedness is not simple and may imply several genes or other unidentified factors. (c) Molecular studies Genome-wide approaches have identified a few regions that could possibly be implied in handedness. Using 14 markers distributed on the X chromosome in 180 pairs of left-handed brothers, Laval et al. (1998) suggested linkage between one marker on the X chromosome (Xq21) and relative hand skill measured by questionnaire and the Annett Peg board test (Annett 1994). Phil. Trans. R. Soc. B (2009)

3 —

1 56.6

female 2 42.3

3 79.2

1 51.1

2 58.3

3 46.5

The first genome-wide screen was performed by Francks et al. (2002) who carried out a study on 195 reading-disabled sibling pairs by using 401 markers. They identified two putative quantitative trait loci (QTLs) for relative hand skill (Peg board test) on chromosome regions 2p11.2–12 and 17p11–q23. The QTL located at 2p12–q11 was further confirmed in a study of left-handed brothers (Francks et al. 2003a) and showed a parent-of-origin effect ( Francks et al. 2003b). In a study of 25 Australian nuclear families, Van Agtmael et al. (2003) found genetic linkage for handedness on chromosome region 10q26 using a laterality quotient computed from questionnaires. In 584 Mexican–Americans, Warren et al. (2006) identified a linkage signal for drawing and writing handedness, assessed by questionnaire, within chromosome region 12q21–23. Genomic regions identified to be linked to handedness differed among studies, probably due to differences in the measurement of handedness. This suggests that several genes could influence handedness. Therefore, large studies with better genome coverage are needed to clearly identify the genes implied in relative hand skills and hand preferences. Empirical studies, as well as family studies, have thus shown that hand preference has an important genetic component. To further identify the selection pressures involved in this trait, we have also focused on the environmental factors that have been shown to have a substantial influence on handedness.

4. DEVELOPMENTAL FACTORS There are several developmental factors implied in handedness in humans. The existence of associations between left-handedness and various health problems have often led to a distinction being made between pathological left-handedness, which would arise from developmental stresses and familial left-handedness, which would be due to genotype (Harris & Carlson 1988). This hypothesis considered that some people are left-handed because they have suffered different types of pathology. The explanation of Satz et al. (1985) for the increased (often twofold) frequency of lefthanders in clinical populations with central nervous system disorders (e.g. schizophrenia, epilepsy, mental retardation or learning disabilities) was based on the claim that early brain insult may cause the individual to switch to the opposite hand for unimanual activities. Thereby, markers of any stressor or pathological factor disrupting normal development and inducing a switch in hand preference, regardless of mechanism, would be

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Review. Polymorphism of handedness in humans expected to show itself in a higher percentage of lefthandedness (Coren & Halpern 1991). (a) In utero environment Lateralized behaviour seemed to be expressed in early developmental stage and could thus be influenced by the in utero environment. At 9–10 weeks, the foetus begins to exhibit single arm movements: a majority (75%, nZ72) exhibited a greater number of right arm movements, 12.5 per cent a greater number of left arm movements, and 12.5 per cent an equal number of left and right arm movements (Hepper et al. 1998). Similar results were also observed for foetuses from 12 to 27 weeks (McCartney & Hepper 1999). From 15 weeks of gestation, the foetus exhibits a preference for sucking its right thumb (Hepper et al. 1991) and the sucking behaviour at foetal state is related to hand preference at a later age (10–12 years; Hepper et al. 2005). From 38 weeks of gestation, the foetus shows a preference for having its head turned to the right relative to its body ( Ververs et al. 1994). Hormonal factors associated with the intrauterine environment are a proposed source of development of left-handedness (Geschwind & Galaburda 1985a–c). This theory is based on the assumption that prenatal sex hormones exert powerful influences on the central nervous system of the developing foetus. Specifically, high levels of testosterone during foetal development or heightened sensitivity to these prenatal hormones will disrupt neural development, causing a number of physiological changes, and also result in an increased likelihood of anomalous dominance, i.e. left-handedness and/or weak lateralization (Geschwind & Behan 1982; McManus & Bryden 1991). It has been hypothesized that the left hemisphere matures later than the right, so that it is at risk for a longer period of time, and therefore more likely to be affected by an adverse environment. High levels of prenatal testosterone would slow neuronal growth in the left hemisphere, hence weakening its relative control. This theory does not exclude genetic hypotheses, as testosterone levels in utero have a genetic component (Manning et al. 2000a). According to the Geschwind–Behan–Galaburda theory, dyslexia, immune disorders and left-handedness are thought to share a common underlying factor: an elevated level of prenatal testosterone, which acts independently on both the thymus and the brain in the embryo. It also favours compensatory mechanisms, which may explain specific high talents associated with left-handedness (McManus & Bryden 1991). Testosterone retards the growth of structures involved in immunity, such as the bursa of Fabricius in the chick embryo and post-natally, the thymus gland in the rat (McManus & Bryden 1991). Retardation of the immune system increases susceptibility to immune disorders, such as atopic disorders of childhood (asthma, eczema, hay fever). Numerous case control studies were performed to test the association between handedness and immune disorders. Populations of patients affected by an immune disorder (such as immune thyroid or gastrointestinal tract disorder, type I diabetes, Crohn’s disease, ulcerative colitis, allergy, etc.) were compared with a control population for their handedness, which was affected with a related disorder Phil. Trans. R. Soc. B (2009)

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of non-immune origin. High testosterone levels also seem to be associated with birth complications and birth stress (McManus & Bryden 1991). The correlations between left-handedness and various diseases are unclear, as positive (Searleman & Fugagli 1987; Smith 1987; Tonnessen et al. 1993) and negative (Pennington et al. 1987) results were both published. Studies in the general population also have led to contradictory results. The Geschwind and Galaburda model therefore remains controversial. It is difficult to directly test for the effect of prenatal testosterone in humans. However, Manning et al. (1998) have shown that the ratio of the length of the second and fourth digits (2D and 4D) in right hands is negatively correlated with adult testosterone levels in men. As digit ratios are fixed in utero it may be that the 2D : 4D ratio is associated with prenatal testosterone. Manning et al. (2000b) also examined the relationship between relative hand skill (left hand skill–right hand skill) and the 2D : 4D ratio in children. The difference in 2D : 4D ratio between the two hands (left hand ratio–right hand ratio) showed a strong relationship with relative hand skill: a high ratio for the left hand together with a low ratio for the right hand correlated with a higher left hand performance. Furthermore, Medland et al. (2005) showed that the number of CAG repeats in an androgen receptor located on the X-chromosome explained 24 per cent of the genetic variance of handedness (i.e. 6 and 10% of the total variance for females and males, respectively). This suggested that sensitivity to androgen hormonal sensitivity to could be involved in handedness. The influence of the in utero environment could thus result from heritable factors such as maternal or foetal hormonal secretion or sensitivity. (b) Developmental instability in early foetal development Based on polygenetic inheritance of factors that influence development, another approach suggesting that developmental instability underlies variation in handedness has been considered. Yeo & Gangestad (1993) presented two studies in which they observed an increased incidence of minor physical anomalies and fluctuating asymmetries (classic markers of developmental instability) in both left-handers and extreme right-handers. They reported evidence that the minimum developmental instability is near the median of the distribution for relative hand skill. They also successfully predicted that extreme right-handers are more apt to have left-handed parents than moderate right-handers, because they possess genotypes predisposed to developmental instability (Gangestad & Yeo 1997). They suggested that deviation from moderate right-handedness reflects imprecise expression of the developmental design due to developmental instability. Consistent with this, Galaburda (1991) noted that left-handers show greater brain symmetry and more reversed asymmetry than right-handers. Yeo & Gangestad (1993) suggested that individuals vary only in the genes that determine the precision with which a design for moderate right-handedness is expressed. No brain damage is hypothesized, only regional variations in foetal growth rates. Moreover,

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their observations suggest that polygenic homozygosity, some particular human leukocyte antigen alleles, and the lack of pathogen resistance may be important factors underlying developmental instability. This developmental instability could thus have a genetic basis. Left-handedness has been reported to be common in a variety of disorders that presumably reflect developmental abnormality. These include neural tube defects, autism (Dane & Balci 2007), psychopathy, cleft palate syndrome, stuttering (Dellatolas et al. 1990) and schizophrenia ( Yeo & Gangestad 1993). However, it should be noted that negative results have also been reported (Bishop 1990). Coren & Searleman (1987) suggested that if an individual has been subjected to a birth stressor or an atypical intrauterine environment, and if the stressor is mild enough, left-handedness might just be a behavioural marker linked to a syndrome caused by minor abnormalities in neurological development. (c) Birth stress According to Bakan (1971), left-handedness results from perinatal left hemisphere neurological damage, due to an oxygen deficiency induced by birth stress (e.g. premature birth, prolonged labour, Rhesus incompatibility, breech delivery, multiple birth, respiratory distress syndrome, primiparity, maternal age). He argues that the change in hand preference may be a residual effect of birth trauma. He presents evidence that hypoxia is more common in difficult births and that the left hemisphere is more vulnerable to the effects of hypoxia than the right (Bakan et al. 1973). Indeed, there is an excess of left-handers in babies with a history of birth stress (Schwartz 1988; Williams et al. 1992), and in individuals with neurological impairments of diverse kinds. However, several reports failed to support this hypothesis (Hicks & Beveridge 1978; Hicks et al. 1978, 1979; Annett & Ockwell 1980; Coren & Porac 1980; Dusek & Hicks 1980; McManus 1981; Ashton 1982; Searleman et al. 1989). Coren & Porac (1980) found a higher average age for the mothers of left-handed children and Smart et al. (1980) observed more left-handed than right-handed children for primiparous mothers aged 39 years or older. However, negative findings were also reported concerning maternal age (McManus 1981; Ashton 1982; Peters & Perry 1991). Twins, regardless of zygosity, have an elevated rate of left-handedness compared with singletons (Sicotte et al. 1999; Williams et al. 1992). This could be due to particular in utero conditions encountered in multiple birth pregnancies. (d) Birth weight It has been proposed that birth weight and its consequences may be the unifying causal factor of ‘pathological left-handedness’ (D. Nettle 2003, unpublished data, Newcastle University). Low birth weight is associated with perinatal complications, neurological problems and a number of adult pathologies. There is evidence for an excess of lefthandedness among extremely low birth weight babies (O’Callaghan et al. 1987; Powls et al. 1996). Low birth weight could play a key role in the health problems associated with left-handedness. The Phil. Trans. R. Soc. B (2009)

mechanism that has been proposed most frequently to explain an association between left-handedness and low birth weight involves early brain damage. Indeed low birth weight greatly increases the risk of early brain damage (Stewart et al. 1999). An alternative possibility is that foetal brain development is interrupted by birth (O’Callaghan et al. 1987). Thus, small or premature babies would have reached a different stage of cortical growth than heavier or full-term ones. Specifically, posterior left hemisphere structures such as the planum temporale tend to be larger than their counterparts on the right in right-handers, whereas in left-handers, these posterior asymmetries are more often absent (Habib et al. 1995). Structural asymmetries of the brain appear in utero (Chi et al. 1977), and are statistically related to hand preference (Beaton 1997), although this relationship between brain asymmetries and handedness is not strict. If there really are two distinct groups of left-handers, one of pathological origin due to low birth weight, and another of familial origin, then there should be a tendency for bimodality in the birth weight distribution of left-handers. This predicts a lower overall birth weight for left-handers and a greater variance in birth weight for left-handed as opposed to right-handed individuals that should be investigated. Although developmental and perinatal problems can be partly due to environmental conditions, they are significantly heritable (e.g. Cai et al. (2007) for birth weight or Moller & Thornhill (1997) for developmental instability), indicating a genetic contribution. Their link with left-handedness therefore represents a negative selection pressure.

5. CULTURAL INFLUENCE Environmental factors could also exert selection forces on left-handers. Laland et al. (1995) criticized the fact that none of the most often cited models of handedness incorporate cultural influences on handedness, despite widespread evidence of their importance. Attitudes towards left-handedness vary from one culture to another (Needham 1973; Teng et al. 1976; Harris 1992; Bryden et al. 1993; Mandal et al. 1999). Cultural and environmental factors could change hand preference in three ways, which correspond to different degrees and types of pressure by: (i) changing the hand used for some activities (e.g. writing, eating), with no change for other unimanual activities, (ii) reducing the degree of hand preference, when weak pressure applies to all hand actions, or (iii) changing the overall preferred hand, when strong pressure applies to all hand actions. (i) Dellatolas et al. (1988) observed an increase in the frequency of left hand use for writing in France (‘generation’ effect), showing clearly that the educational attitude towards left hand writing has significantly changed in France during the second half of the twentieth century. The same phenomenon has been observed in other countries (e.g. Italy: Salmaso & Longoni 1985; Brazil: Berdel Martin & Barbosa Freitas 2003). Studies of school children in China and

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Review. Polymorphism of handedness in humans Taiwan have found that only 3.5 and 0.7% used their left hand for writing (Teng et al. 1976). This contrasts with a 6.5 per cent figure for Asian school children living in the United States, where cultural pressures have been reduced (Hardyck et al. 1976). In two African countries (Ivory Coast and Sudan), the target activity against left hand use was eating and there remains strong cultural pressure for this activity (De Agostini et al. 1997). In Japan, the proportion using the left hand for writing and eating are only 0.7 and 1.7%, respectively (Shimizu & Endo 1983), again suggesting strong cultural pressures. Coren (1992) reported a reduction of the degree of hand preference as a consequence of environmental influences: subjects who reported attempts to change handedness (by parents, teachers) could switch their hand preference for the targeted tasks. However, he also noted that this cultural influence on one particular task (e.g. writing or eating) did not condition hand preference for other tasks. (ii) De Agostini et al. (1997) showed that the proportion of subjects with weak handedness is higher among those who reported earlier injuries causing a temporary shift of hand use. Bryden et al. (1993) also observed that positive reinforcement for right hand use can modify patterns of handedness, and alter the relationships among different handedness tasks. (iii) Bryden et al. (1993) suggested that the Tucano of Amazonia successfully modify preference at an early age through positive reinforcement, and that this switched preference is manifested in all unimanual activities. Mikheev et al. (2002) have found that highly qualified right-handed judo wrestlers more frequently preferred to perform certain judo movements with the left hand than right-handed controls. They suggest that during motor skill acquisitions (long-term judo training), lateral preferences are modified though neuroplastic development. However, an alternative hypothesis to consider is that less asymmetry is advantageous in judo and so that individuals with low asymmetry are more likely to become qualified judo wrestlers. Genetic, developmental and environmental components have been identified be involved in hand preference determinism. Hand preference has been shown to be heritable and variable across populations, suggesting that evolutionary processes are acting on this trait.

6. EVOLUTIONARY FORCES ACTING ON THE POLYMORPHISM OF HANDEDNESS The variation in morph frequencies for a given trait is essential to characterize the selective forces involved. A polymorphism maintained in all populations of a given species is a rare case. It can happen for a neutral trait, but is easily lost by genetic drift, so that at least some populations lose the polymorphism. The fact that the polymorphism of handedness is maintained in all Phil. Trans. R. Soc. B (2009)

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human populations suggests that handedness is not a neutral trait, and that some selective forces are maintaining this diversity. Directional selection, if acting alone, would lead to the fixation of the advantageous morph, and eliminate the polymorphism. The ancient and ubiquitous polymorphism observed for handedness is thus a signal of balancing selection acting on this trait. This balancing selection could result from a situation-dependent benefit. Hence, we tried to identify, in the existing publications, the deleterious and advantageous traits associated with left-handedness, as they could, respectively, represent fitness costs and benefits playing a relevant evolutionary role. (a) Left-handedness as a costly trait The frequency of left-handers has been reported to vary according to age classes (Porac et al. 1980; Gilbert & Wysocki 1992). This could be interpreted as due to changing patterns of social norms (Hugdahl et al. 1993): for example, writing handedness was submitted to more social pressures in the past than in the present (Dellatolas et al. 1988). As a consequence, studies using hand preference for writing as the marker of handedness will find that mean age at death is lower for left-handers, even if the longevity of left- and righthanders was actually the same. Nevertheless, even when hand preference assessment was based on other tasks, longevity has been shown to be reduced in lefthanders, from a few months to a few years (Halpern & Coren 1988, 1991; Coren & Halpern 1991; Aggleton et al. 1993), but some contradictory evidence also exists (Wood 1988; Anderson 1989; Harris 1993; Hicks et al. 1994; Berdel Martin & Barbosa Freitas 2003). Three factors may explain the reduced longevity of left-handers: (i) prenatal and perinatal birth stressors, more probable in left-handers, (ii) genetic effects and intrauterine hormones may have reduced the effectiveness of the immune system of left-handers, and (iii) left-handers may have more lethal accidents. However, fitness costs have not been directly measured yet, so we are still unable to properly evaluate its evolutionary significance. Concerning the accidental mortality, a higher risk of accidents for left-handers has been observed in Western societies (Halpern & Coren 1991; Daniel & Yeo 1994), probably due to the industrialized environment designed for a right-handed majority (Porac & Coren 1981; Coren & Halpern 1991). As shown by Aggleton et al. (1993), an important part of the difference in lifespan between left- and right-handers is due to accidental death and death in warfare. According to Aggleton et al. (1993), the most likely explanation for the increase in accidental death among left-handed men concerns their need to cope in a world full of righthanded tools, machines and instruments. The fact that a difference still remained, after removal from the sample of the known cases of accidental death, suggests, however, that some other factor may produce a left-handed disadvantage. However, it is also possible that the sources used did not mention all the cases of unnatural death. Interestingly, De Agostini et al. (1997) suggested that injury on upper limbs that made a person unable to use the preferred hand could lead to

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mixed handedness and create an association between accident frequency and mixed handedness. In a study on 556 dead Brazilians, Berdel Martin & Barbosa Freitas (2003) pointed out that dextral and not sinistral individuals manifested an increased vulnerability to accidental death. Further investigations on these aspects are thus needed with reliable information on death causes and birth cohort. The importance of survival before and during the reproductive period of life for the fitness of an individual is clear. Moreover, there is now clear evidence that survival beyond menopause is of great importance for women’s reproductive value (Lahdenpera¨ et al. 2004). Unfortunately, the link between life expectancy and handedness has as yet only been reliably investigated for men. The impact of longevity on human fitness is not fully characterized. The importance of reduced longevity in left-handedness evolution is thus still unclear. Another cost for left-handers resides in the lower body size observed for left-handers (Coren 1989b; Fudin et al. 1994). This could have fitness consequences as body size is an important component of selective value in humans (Gue´gan et al. 2000; Nettle 2002b; Silventoinen et al. 2003). For males, it is clearly established that height is correlated with reproductive success (Pawlowski et al. 2000; Mueller & Mazur 2001; Nettle 2002a). Coren et al. (1986) also showed that an association between delay in physical maturation (based on the onset of secondary sexual characteristic, age of menarche and relative body size) and lefthandedness (see Eaton et al. (1996) for contradictory results). A delay in sexual maturity could also have an influence on reproductive success and thus lead to some fitness cost for left-handers. Further investigations are needed to quantify the influence of this factor. The frequency of left-handers among homosexual men seemed to be higher than in the general population: in their meta-analysis, Lalumiere et al. (2000) reported 39 per cent greater chance of being non-right-handed. As reproductive success has been shown to be lower for homosexual men, this could introduce some fitness bias (Berman 2003). However, the association between handedness and sexual orientation is still being discussed (Bogaert et al. 2007), and the proportion of homosexual men in the general population is low: from 2 to 6 per cent of males in the general population, depending on the study (Kinsey et al. 1948; Sandfort 1998; Berman 2003). Therefore, the effect of this association has probably a low influence on the evolution of handedness frequencies. Some potential fitness costs are thus suggested by the literature, but proper estimation of the actual consequences on fitness are not yet identified, limiting the evolutionary significance of these results. (b) Left-handedness as a beneficial trait It was shown that left-handers could have greater intermanual coordination (Gorynia & Egenter 2000; Judge & Stirling 2003). Left-handers have indeed smaller asymmetries in hand skills than right-handers (Peters 1989; Curt et al. 1992; Judge & Stirling 2003) and are less lateralized in language dominance (Steinmetz et al. 1991). Smaller right–left differences as well as higher intermanual coordination in left-handers Phil. Trans. R. Soc. B (2009)

may be due to greater control of both hemispheres. There are contradictory results but some studies point to better interhemispheric transfer in non-righthanders (Gorynia & Egenter 2000; Christman & Propper 2001). A larger corpus callosum has been detected in non-right-handers ( Witelson 1985), but the precise implications for interhemispheric interaction are unclear. Moreover, there is considerable controversy about the relation to handedness: the degree of hand lateralization rather than its direction may be related to callosal morphology (Beaton 1997). This is supported by the finding that left-handers, who are less lateralized show significantly higher values than right-handers in intermanual coordination, a performance thought to be more demanding in terms of bihemispheric control, and that may be due to a more efficient exchange of information transmitted by callosal pathways (Gorynia & Egenter 2000). A larger corpus callosum has also been reported to be associated with superior verbal fluency (Hines et al. 1992) or to confer advantages in some forms of memory (Christman & Propper 2001); two advantages from which left-handers could benefit. Creativity has also been reported to be linked with left-handedness ( Newland 1981), more specifically in men (Coren 1995). The proportion of left-handers also appeared to be greater in gifted children (IQO131) than in non-gifted children (Hicks & Dusek 1980), but the importance of this effect at the population level remains to be quantified, owing to the low proportion of gifted children. A few studies have considered that left-handers could have special talents that could lead to benefits, such as enhanced musical (Aggleton et al. 1994; Kopiez et al. 2006) or mathematical capacities (Casey et al. 1992; Crow et al. 1998), although this last fact seems controversial (Peters 1991). All these advantages may play a significant role in the social status of left-handers. Some studies concerning socio-economic status and cognitive abilities have tried to estimate differences in social status between right- and left-handers (see Faurie et al. (2008) for a review). Left-handers are supposed to have particular cognitive capacities that could lead them to particular kinds of professional activities. Faurie et al. (2008) highlighted that lefthanders could have some particular socio-economic positions, which could lead to a socio-economic advantage. A few studies have compared the earnings of right- and left-handers. Denny & O’Sullivan (2007) revealed that the hourly earning of left-handed men was greater (approx. 4%) and observed an opposite result for right-handed women. Ruebeck et al. (2007) also found a significant increase of wage for left-handed men in the group with high levels of education and did not observe any effect of handedness on wages for women. The differences between right- and lefthanders socio-economic statuses could be related to their reproductive success, though the importance of socio-economic status in human mate choice directly benefits the offspring. Another important benefit of left-handedness could be represented by a strategic advantage of left-handers in sports: a number of studies have noted an excess of left-handers at the top levels of sports such as tennis,

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Review. Polymorphism of handedness in humans baseball and fencing (Annett 1985; Voracek et al. 2006). The left-handed advantage in many sports can be explained tactically without any hypothetical additional neurological advantage ( Wood & Aggleton 1989). As right-handers are more frequent, an individual is always more likely to be confronted by a right-handed opponent, so right-handers are not used to the different gestures of left-handers, whereas lefthanders are used to the right-handers way of playing. Thus, left-handers have a surprise advantage, which increases when their frequency is lower (Raymond et al. 1996). Left-handedness frequencies in interactive sports (such as fencing, boxing, tennis, baseball, cricket), offering a strategic advantage to the rarer left-hander, appear to be very high, when compared with non-interactive sports (gymnastics, swimming, bowling), where the frequencies are no different from those of the general population (Aggleton & Wood 1990; Goldstein & Young 1996; Raymond et al. 1996; Grouios et al. 2000; Brooks et al. 2003). This strategic advantage of left-handers in interactive sports could be a marker of a strong selective advantage during fights. This advantage in fights could indeed lead to direct benefit through increased survival during fighting interaction or indirect benefit through acquisition of higher social status, facilitating access of partners. It is negatively frequency dependent because it is higher when the left-handers are rarer. Theoretical approaches have confirmed that the maintenance of two opposite asymmetrical morphs by frequencydependent selection could be an evolutionary stable strategy (Ghirlanda & Vallortigara 2004; Faurie et al. 2005a). The frequency-dependent strategic advantage of left-handers in fights could be the source of balancing selection involved in the persistence of the handedness polymorphism in the general population.

7. DISCUSSION The existence of frequency-dependent selection acting on handedness has been suggested by the correlation observed between the frequency of left-handers and the rate of homicide, indicating a frequency-dependent advantage of left-handers in violent interactions (Faurie & Raymond 2005). However, in the absence of any cost, a frequency-dependent advantage would lead to a frequency of 50 per cent at equilibrium. The fact that the frequency of left-handedness never reaches 50 per cent in any human population investigated so far (Faurie et al. 2005b; Raymond & Pontier 2004) indicates that some costs associated with left-handedness must exist. The costs associated with left-handedness have mainly been studied in Western societies, and have often been attributed to the technological environment with asymmetrical artefacts being dangerous for lefthanders (Coren 1989a; Aggleton et al. 1993; Daniel & Yeo 1994). However, the frequency of left-handers does not exceed 30 per cent in any traditional society, suggesting the existence of costs in non-industrialized environments as well ( Faurie & Raymond 2005). There seem to be increased heath risks and problems among left-handers. It still remains to be established whether these are characteristic of all left-handers, or of a subgroup whose left-handedness is of the pathological Phil. Trans. R. Soc. B (2009)

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type. The problem is that ‘pathological’ and ‘familial’ left-handers, if these two categories exist, cannot in fact be distinguished, since no gene of major effect has been identified, whose presence could be tested for. The alleles in single-gene models are postulated from an ad hoc assumption, rather than on the basis of empirical genetic data. An indication of the probable heterogeneity of left-handers is the lateralization of language. Although 97 per cent of right-handers demonstrate predominant left hemisphere language localization, only 60 per cent of left-handers demonstrate left hemisphere language dominance, 30 per cent show bihemispheric language and approximately 10 per cent show right hemisphere language (Geschwind 1970; Annett 1985). Precise characterization of categories of left-hander should help the understanding of the evolution of handedness. To be able to identify the evolutionary forces acting on handedness, data on left-handedness frequency dynamics over time are critical. Writing handedness has been shown to vary during the twentieth century, due to cultural influences. For hand preference in other tasks, there are surprisingly few studies addressing this question. Comparison of arm waving in Victorian England films (1897 and 1913) and in a modern population, from Google images, suggested that left-handers frequency has increased in England during the last century (McManus & Hartigan 2007). However, the reliability of these data are questionable, especially because arm waving is not a complex task needing hand specialization. Further investigation of left-handedness frequency across generations is needed to establish if the left-handed polymorphism is variable or at equilibrium. If the polymorphism of handedness is nearly stable, it would be very unlikely to empirically detect variations of fitness estimates because differences between left- and right fitness are expected to be low near the equilibrium value. In fact, at the equilibrium value, the fitness of right- and left-handers is equal (although this does not mean that all fitness components are necessarily equal). In such a case, some advantages for one trait could be found for one handedness category, and other advantages for other traits for another handedness category. This could explain many discrepancies in handedness studies. What is currently lacking is a way to clearly identify the left-hander categories in order to better estimate fitness costs and benefits associated with each category. It is also pivotal to further investigate the possible current evolution of left-handedness frequencies, and to examine, in different environments, the type of selection, particularly frequency dependent, acting on handedness. The authors would like to thank Luca Tommasi and two anonymous reviewers for their helpful comments on the manuscript, and the European Commission programme Specific Targeted Research Project (STREP) Evolution and Development of Cognitive, Behavioural and Neural Lateralisation (EDCBNL) for funding. Contribution 2008-063 of the Institute of Evolutionary Sciences of Montpellier (ISEM).

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Phil. Trans. R. Soc. B (2009) 364, 895–914 doi:10.1098/rstb.2008.0279 Published online 4 December 2008

Review

Asymmetries of the human social brain in the visual, auditory and chemical modalities Alfredo Brancucci, Giuliana Lucci, Andrea Mazzatenta and Luca Tommasi* Department of Biomedical Sciences, Institute for Advanced Biomedical Technologies, University of Chieti, Blocco A, Via dei Vestini 29, 66013 Chieti, Italy Structural and functional asymmetries are present in many regions of the human brain responsible for motor control, sensory and cognitive functions and communication. Here, we focus on hemispheric asymmetries underlying the domain of social perception, broadly conceived as the analysis of information about other individuals based on acoustic, visual and chemical signals. By means of these cues the brain establishes the border between ‘self ’ and ‘other’, and interprets the surrounding social world in terms of the physical and behavioural characteristics of conspecifics essential for impression formation and for creating bonds and relationships. We show that, considered from the standpoint of single- and multi-modal sensory analysis, the neural substrates of the perception of voices, faces, gestures, smells and pheromones, as evidenced by modern neuroimaging techniques, are characterized by a general pattern of right-hemispheric functional asymmetry that might benefit from other aspects of hemispheric lateralization rather than constituting a true specialization for social information. Keywords: hemispheric asymmetries; social perception; lateralization; brain hemispheres; social neuroscience

1. INTRODUCTION The new field of human social neuroscience is investigating the neural correlates of social perception and cognition at an incredibly fast pace (Cacioppo & Berntson 2002; Adolphs 2003; Heatherton et al. 2004). Studying the brain mechanisms that underlie the perception and representation of others has become one of the most intriguing topics at the border of psychology and the neurosciences, due not only to the fact that it has become easier to apply modern imaging techniques to stimuli related to the social dimension, but also because it is of crucial relevance to study how the brain manages the rich and complex information provided by the social environment. Many cues are exploited to decode the identity and characteristics of other individuals, in order to interact with them on the spot or to store them in memory, in view of future interactions. These cues are principally conveyed by the visual, auditory and olfactory modalities. Moreover, there is ample evidence that visual, auditory and olfactory cues interact cross modally, forming integrated person perceptions (Kova´cs et al. 2004; Platek et al. 2004; Campanella & Belin 2007). Touch could be listed as another source of social information, but despite its non-irrelevant involvement in social perception and interaction, it has received comparatively less attention (but see Bufalari et al. (2007) and Dunbar

(in press) for recent theoretical and empirical work). Even more dramatically, the mere idea of gustatory inputs to social perception might be rejected for it contravenes human moral principles connected to contamination (Rozin et al. 1994). Both touch and taste are in fact modalities that clearly need the closest of contacts to the source of stimulation, whereas vision, hearing and smell demand a lesser degree of personal contact and are thus more ubiquitous in everyday social interaction. The range of cues conveyed by the visual modality is very wide, and at a first stage this involves the decoding of characteristics that are present in the physical features of faces and bodies, important to decide about others’ sex, age, ethnicity, health state, attractiveness and of course individual identity. At a subsequent stage, postures, gestures, facial expressions, gaze and behavioural patterns at various time-scales permit a person to decode others’ psychological states, emotions, direction of attention and behavioural intentions. Voice can also be very informative about others’ characteristics. Although it is difficult to sharply separate the information content of spoken language from its surface level, voice can convey social cues comparable with those that we can gather through the visual modality. Finally, personal odours and pheromones are bodily produced, airborne substances acting through the olfactory system in ways that influence individuals’ responses to other individuals. Despite the controversies concerning the nature of pheromone physiology and its genuine relationship to olfaction, it

* Author for correspondence ([email protected]). One contribution of 14 to a Theme Issue ‘Mechanisms and functions of brain and behavioural asymmetries’.

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can be safely maintained that pheromones are, together with visual and vocal features, important carriers of information about other individuals. The other character of this review, hemispheric lateralization, in some sense has always had to do with the social dimension. Language, which is structurally and functionally a left-hemispheric function in the great majority of right-handers, can be considered the foremost social function in humans. Undoubtedly, Broca’s and Wernicke’s areas (the two main cortical areas responsible for processing language) are asymmetrical (at both the macro- and microscopic level of their anatomical organization, as well as functionally) and their discovery sharply marks the beginning of the history of scientific studies on brain asymmetries. Even though a function attributable to the right hemisphere has never been demonstrated with as undisputed clarity as in the case of the attribution of language to the left hemisphere, spatial cognition and the processing of emotions can be considered the two most robust right-hemispheric functions demonstrated so far. It appears clear that social perception based on non-verbal cues would depend mostly on the right hemisphere, as the left is immediately ruled out of the story due to its major implication in linguistic processing. However, given that language is the instrument of social exchange among individuals, the brain in its entirety can be considered a ‘social engine’, mediating verbal and non-verbal signals by means of the interaction among the two hemispheres. Explanations of hemispheric asymmetries have also been proposed based on the computational advantages that follow from an asymmetric subdivision of tasks, disregarding the specific attribution of one or another function to the hemispheres. Tests of computational efficiency, based on the assumption that inter-hemispheric communication is slower and more costly than intra-hemispheric communication (due to the necessary transmission through the fibres of the corpus callosum), among other things, have concluded that stimulus complexity, as well as task concurrency, are two likely factors that favoured the evolution of segregated specialization in the two hemispheres. Social information (for instance the categorization of sex as assessed by the perception of facial features, vocal pitch and contour and smell) is in a way a puzzling domain, because at first sight it is a complex type of information (it is certainly so in the everyday glossary of the neuroscientist), if compared with the simplified stimuli generally used to assess computational efficiency of the hemispheres, which have consisted of digits, letters or simple spatial patterns (e.g. Banich 2003). However, the ease and the speed at which individual recognition or social judgement takes place, which are of course justified by the relevance of these activities for social interaction, seem to imply that this type of information must be accessed with high priority by the human brain. From this simple assumption stems the hypothesis that, although demanding a high degree of inter-hemispheric exchange in order to relay linguistic information, social information would not benefit so much if it were localized only in one hemisphere, rather it seems that either a bihemispheric or a distributed network for social perception would be the most advantageous solution. Phil. Trans. R. Soc. B (2009)

Here, we provide a non-exhaustive, but tentatively extensive, review of the literature concerning the issue of hemispheric lateralization of social perception. Of course, there is more research on social perception and lateralization as independent fields than any single review could ever accommodate (and there are good reviews of both fields), but we felt that the intersection among these two topics is a relatively empty domain demanding closer attention. We believe that starting with the lateralization of voice perception is a way to acknowledge the fact that the human voice can hardly undergo processes of artificial transformation (as in the case of visual appearance with clothing/make-up or olfactory presence with perfumes) and can thus be considered the most honest of human social signals; the visual modality will be reviewed for what concerns the specific issues of perception of faces, gaze, biological motion and gestures; lateralization of olfaction, and in particular of the brain substrates of pheromone processing, will conclude the review.

2. AUDITORY MODALITY: LATERALIZATION OF VOICE PERCEPTION Voices are probably the most important social sounds of the human auditory scene. Humans may spend more time listening to voices than to any other sound, and their ability to analyse information contained in voice sounds is of basic importance in social interactions. It has been shown that many regions of the auditory cortex exhibit a greater response to vocal compared with non-vocal sounds, whereas no part of the same cortex shows the reverse pattern (Belin et al. 2000). Human voice is the carrier of speech, which appeared relatively recently in the evolutionary history of primates as a particularly composite use of voice by humans (Hauser 1996; Fitch 2000). However, vocalizations were present in the auditory environment of vertebrates for very long time before speech emerged, and perceiving (non-verbal) information contained in vocalizations in an appropriate way has been since then of crucial importance for survival. Thus, voices carry additional information other than speech, and humans, such as many other species, are capable of extracting that information from voices. When speech cues are not contained in a voice, such as in a laugh, in a cry, in a tune or because the vocal information is distorted or damaged, we are still able to extract information about the sex, the age and the affective state of the subject and even about her/his personal identity (Belin et al. 2004). The abilities involved in perceiving non-linguistic information in voices have been far less investigated than speech perception, and little is known about their neural bases. Recent findings, however, suggest that there are voice-specific areas in the human (Belin et al. 2000) and macaque (Poremba 2006; Petkov et al. 2008) brain and that these areas are organized in an asymmetrical way. The different types of vocal information are processed in partially dissociated functional pathways and the parameters of voice, such as pitch, loudness, spectral content, amplitude envelope, formants, prosody, and accent seem to have specific neural modules dedicated to their analysis which are often lateralized. Functional lateralization of

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Review. Asymmetries of the human social brain A. Brancucci et al. voice or vocalization perception has been indexed by some behavioural and neuroimaging studies in both human and non-human primates. It should be considered that some of these studies have been carried out under the major hypothesis that investigating neural mechanisms underlying voice perception might provide useful information concerning the evolutionary history of language. Thus, the role of voice has often remained in the background. With the aim of investigating ear preferences in the perception of calls, Petersen et al. (1978) trained Japanese macaques (Macaca fuscata, an Old World monkey) to discriminate between conspecific calls. When communicatively relevant information was the key feature to be discriminated, authors found that the five Japanese macaques they tested showed a better performance when the stimuli were presented to the right when compared with the left ear. This result was not replicated in a control experiment, in which calls had to be discriminated by animals from other monkey species. Conversely, when Japanese macaques were trained to perform the discrimination on the basis of acoustical features of the stimuli, such as pitch, they showed either no advantage or even a left-ear advantage. The fact that in this study no right-ear advantage was observed when the same sounds were discriminated by pitch, could be interpreted as suggesting that only the communicatively relevant features of the call might engage lateralized processes. Alternatively, different features of the same call could be processed using partially distinct, differentially lateralized neural networks, as seems to be the case in humans. One following study from the same group confirmed the presence of a right-ear advantage in the discrimination of intraspecific but not interspecific calls (Petersen et al. 1984). The lack of lateralization in a control primate species in these studies is particularly interesting, and would suggest that these lateralized processes are observed only for conspecific calls. Another method used to measure functional asymmetries in non-human primates involves unilateral cortical lesions. Heffner & Heffner (1984, 1986) performed unilateral lesions in the superior temporal gyrus of macaques (entailing primary as well as secondary auditory cortices) and measured the effects of the lesions on performance in call discrimination according to whether the lesion had been performed in the left hemisphere (five animals) or right hemisphere (five animals). A striking pattern of lateralization emerged: the animals having received a lesion in the right hemisphere showed no noticeable deficit within one week from the lesion, whereas the animals with a lesion in the left hemisphere showed a marked initial deficit followed by a progressive recovery over the successive days. A second lesion to the remaining auditory cortex of the other hemisphere then completely abolished the ability to discriminate the calls. More recently, Gil-da-Costa & Hauser (2006) conducted an experiment on vervet monkeys (Cercopithecus aethiops, an Old World monkey) using a head-orienting procedure, and found a strong left ear bias for both familiar and unfamiliar conspecific vocalizations, whereas no asymmetry was found for Phil. Trans. R. Soc. B (2009)

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other primate vocalizations or non-biological sounds. This finding raises significant questions about how ontogenetic and evolutionary forces have impacted on primate brain evolution, and suggests that although auditory asymmetries for processing species-specific vocalizations are a common feature of the primate brain, the direction of this asymmetry may be relatively plastic. Further head-orienting experiments in field studies yielded additional useful information on the cerebral lateralization of the processing of calls in nonhuman primates. Hauser & Andersson (1994) monitored the orienting response to conspecific calls in a large number of rhesus macaques. The majority of adult macaques were found to orient to the sound source by turning their head to the right, thus seeking to increase sound amplitude in the right ear, preferentially connected to the left hemisphere. Conversely, they tended to present the left ear to the source when a familiar, but heterospecific (i.e. from another species) alarm call was played. Infants tested using the same paradigm failed to show any head-turning preference. The authors interpreted this finding as evidence for left-biased cerebral lateralization for processing conspecific calls in the rhesus macaque, as for human speech, but only once a certain stage of maturation is reached. Further studies using the same paradigm but acoustically modified calls showed that temporal modifications such as expansion or contraction (Hauser et al. 1998) or temporal inversion (Ghazanfar et al. 2001) could eliminate or reverse the right-ear advantage. In humans, speech processing engages left-lateralized networks in most right-handed subjects (Broca 1861; Price 2000), but processing of pitch timbre or identity from the same vocal input can reverse this pattern and yields a right-hemispheric advantage (Zatorre et al. 1992a; Brancucci & San Martini 1999, 2003; Von Kriegstein et al. 2003; Brancucci et al. 2005). Koeda et al. (2006), aiming at clarifying the role of voice perception in language dominance for lexical and semantic processing, scanned 30 healthy righthanded subjects by functional magnetic resonance imaging (fMRI ) while listening to sentences, reversed sentences and identifiable non-vocal sounds. They found a right-lateralized activation in the anterior temporal cortices in the contrast ‘reversed sentences minus non-vocal sounds’. Conversely, both contrasts, ‘sentences minus non-vocal sounds’ and ‘sentences minus reversed sentences’ showed left-lateralized activation in the inferior and middle frontal gyrus and middle temporal gyrus. Of note, the contrast ‘sentences minus reversed sentences’ without the influence of human voice perception showed no activation in the right temporal hemisphere. These results suggest that the influence of human voice perception should be adequately taken into account when language dominance is determined and point to the presence of a prominent right-lateralized activation for human voice perception. In a further fMRI study the same group (Koeda et al. 2007) demonstrated that, within righthanders, the degree of handedness does not influence the magnitude of the right-hemispheric bias for voice perception. Lattner et al. (2005) examined the neural processing of voice information by using event-related

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fMRI. They controlled the role of the major acoustic parameters as well as of the sex of both listeners and speakers. Male and female, natural and manipulated voices were presented to 16 young adults who were asked to judge the naturalness of each voice. The activations were generally stronger in response to female voices as well as to manipulated voice signals, whereas the influence of listener’s sex was negligible. The results showed that voice pitch is processed in regions close and anterior to the Heschl’s gyrus, with a bias towards the right hemisphere. Voice spectral information was observed to be processed in the posterior parts of the superior temporal gyrus and in the areas surrounding the planum parietale bilaterally. Finally, a prominent role of the anterior parts of the right superior temporal gyrus was observed for the processing of voice naturalness. This study demonstrates again the fundamental role of the human right hemisphere in voice processing. Belin et al. (2000) used fMRI to measure brain activity during passive stimulation with a large variety of natural sounds grouped in blocks of either vocal or non-vocal sounds. The cortical regions showing the highest selectivity for voice were consistently located along the superior bank of the superior temporal sulcus (STS) with a prevalence for right-sided activation. Moreover, with stimuli degraded by frequency filtering, the activity of those areas reflected subjects’ behavioural performance. Authors suggest that the voice-selective areas in the upper bank of the STS may represent the counterpart of the faceselective areas in human visual cortex, pointing to the existence of cortical regions selective to voice sounds that would be similar to the known face-specific areas. In a study using dichotic listening to measure lateralization of voice recognition abilities in normal subjects (Kreiman & Van Lancker 1988), listeners had to identify both the speaker (a famous male) and the word pronounced on each trial. The voice identification task resulted in a zero ear advantage, which differed significantly from the right-ear advantage found for word identification. This result suggests that voice and word information, although carried in the same auditory signal, engage different cerebral mechanisms and different degrees of lateralization. A further dichotic study aimed at investigating ear asymmetries in the recognition of unfamiliar voices (Riley & Sackeim 1982), extended evidence of the right-hemispheric superiority to this type of stimulus. Fewer studies have used neuroimaging techniques to investigate the perception of affective information contained in voice. In these works, brain activity was measured during stimulation with speech stimuli in which prosody was manipulated in order to generate various emotional states. Studies using positron emission tomography (PET; George et al. 1996) or fMRI ( Wildgruber et al. 2002; Mitchell et al. 2003) generally emphasized the greater activation of the right temporal lobe and right inferior prefrontal cortex when attention was directed to emotional prosody, confirming earlier clinical work (Ross 1981; Heilman et al. 1984). More recently, the neural bases of emotional perception in voice have been studied outside the context of speech by using affective non-verbal vocalizations such as laughs, cries, groans and other Phil. Trans. R. Soc. B (2009)

more primitive vocal expressions of emotion. Until now, PET (Phillips et al. 1998; Morris et al. 1999) and fMRI (Sander & Scheich 2001) studies did not show consistent asymmetries in the perception of pure (non-verbal) emotional processing. Relatively little is known about the neuronal bases of speaker identity perception and recognition. Some clinical studies have documented cases of brainlesioned patients with a deficit in speaker discrimination or recognition (Van Lancker & Kreiman 1987; Peretz et al. 1994). These studies generally show that deficits in discriminating unfamiliar speakers or deficits in the recognition of familiar speakers (‘phonagnosia’) can be dissociated, but both seem to occur more often after lesions in the right hemisphere. Importantly, a double dissociation between speech perception and speaker recognition has been demonstrated by cases of preserved speech perception but impaired speaker recognition, as well as cases of aphasia with normal voice recognition (Assal et al. 1981). This supports a model of the organization of voice processing in which speech and identity information are processed in partially dissociated cortical regions. Francis & Driscoll (2006) trained their subjects to use voice onset time (VOT) to cue speaker identity. Successful learners showed shorter response times for stimuli presented only to the left ear than for those presented only to the right. The development of a right hemisphere specialization for processing a prototypically phonetic cue such as VOT supports a lateralization model in which the functional demand drives the side of processing in addition to stimulus properties (Simos et al. 1997). Again, only few neuroimaging studies have investigated the perception of identity information. Imaizumi et al. (1997) were the first to use PET to examine patterns of cerebral activity induced by speaker identification. Subjects were scanned while performing a forced-choice identification of either the speaker or the emotion in non-emotional words pronounced by four actors with four different emotional tones. They found that, in both hemispheres, the anterior temporal lobes were more active during speaker identification than during emotion identification. In a subsequent study (Nakamura et al. 2001), the same group scanned normal volunteers with PET while they performed a familiar/unfamiliar decision task on voices from unknown persons and from their friends and relatives. A comparison task consisted of deciding whether the first phoneme of sentences pronounced by unfamiliar speakers was a vowel or a consonant. The results showed that several cortical regions, including the enthorinal cortex and the anterior part of the right temporal lobe, were more active during the voice familiarity task. Interestingly, the amount of activity in the right anterior temporal pole was found to correlate positively with the subjects’ performance at a speaker identification task administered just after scanning. Von Kriegstein et al. (2003) used fMRI to measure brain activation during identification tasks directed to either the speaker’s voice or the verbal content of sentences in German. They found that the right anterior STS and a part of the right precuneus were principally active when the identification task was focused on speaker’s identity, whereas left middle

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Review. Asymmetries of the human social brain A. Brancucci et al. temporal regions showed enhanced activity more related to verbal/semantic processing. Thus, even if the vocal stimuli were similar in the two conditions, directing attention to vocal identity or speech content was found to modulate lateralized activity in the STS regions. A convergent finding was obtained by Belin & Zatorre (2003) in a fMRI study with an opposite design. In this experiment, two conditions shared a common passive listening task but blocks of vocal stimulation were composed either of the same syllable spoken by 12 different speakers, or of 12 syllables spoken by the same speaker—thus repeating either speaker or syllable. Only one region of the auditory cortex, in the right anterior STS, showed reduced activity when different syllables were pronounced by the same voice when compared with different voices pronouncing the same syllable. This reduced response to the same voice was interpreted as an adaptation response by neuronal populations sensitive to idiosyncratic acoustic features of a speaker’s voice. Thus, there is clear converging evidence for an important role of anterior temporal lobe regions of the right hemisphere, particularly right anterior STS regions, in processing information related to speaker identity. This is consistent with recent models of the organization of the primate auditory cortex (Kaas & Hackett 1999; Rauschecker & Tian 2000) in which a ventral ‘what’ stream, homologous to the similar pathway in the visual system ( Ungerleider & Haxby 1994), would be specialized in the recognition of auditory objects, and in particular of individual voices. Note that the STS is a long heterogeneous structure: cytoarchitectonic and connectivity studies in the rhesus monkey have demonstrated a division of this area into several unior polymodal areas organized in a precise sequence of connections with one another and with other regions of the cortex (Seltzer & Pandya 1989). Thus, the various STS activations observed in neuroimaging studies on different cognitive processes probably correspond to several functionally distinct regions. Recent electroencephalography (EEG) and magnetoencephalography (MEG) studies also addressed the question of voice selectivity. Levy et al. (2001, 2003) used event-related potentials (ERPs) to compare the response evoked by sung voices and tones played by different musical instruments. No difference between the voices and instruments was observed for the N1 component (i.e. the first negative response recorded with the EEG or MEG 100 ms after the onset of the sensory stimulus, reflecting early cortical processing)—a result that was replicated with MEG (Gunji et al. 2003). Conversely, in the cited EEG (but not MEG) studies, a ‘voice-specific response’ could be observed peaking at approximately 320 ms after stimulus onset and stronger on the right side. They suggested that this component, different from the ‘novelty P300’ (i.e. a positive response recorded with the EEG approximately 300 ms after the onset of the sensory stimulus, reflecting middle–late cortical processing), might reflect allocation of attention related to the salience of voice stimuli. Finally, lateralization of the processes underlying one’s own voice perception has also been investigated. One recent study consisting of a series of three experiments (Rosa et al. 2008), investigated functional Phil. Trans. R. Soc. B (2009)

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asymmetries related to self-recognition in the domain of voices. Participants were presented with self, familiar or unknown voices as well as with morphed voices and were asked to perform a forced-choice decision on speaker identity with either the left or the right hand. In accordance with a previous intracranial recording study showing that neuronal responses to the subject’s own voice in the dominant and non-dominant temporal lobe were about equally affected by overt speech (Creutzfeldt et al. 1989), this study did not reveal strong laterality effects—except a slight right bias for selfrecognition, similar to that observed in the visual domain for the recognition of one’s own face. To summarize, available results on lateralization for the processing of purely vocal information, i.e. deprived of linguistic cues, show that the brain areas involved in such analysis are located mainly in the upper part of the temporal lobes (STS), and that the balance between the two sides of the brain leans towards right. This claim is based on behavioural studies in non-human and human primates as well as in neuroimaging studies on humans. The competition between the left and right hemisphere in the processing of voice can be viewed as a parallel process in which individual neural populations are devoted to the analysis of single physical aspects of voice. This perspective is based on the current view of hemispheric specialization that is structured in a parameter-specific rather than a domain-specific fashion (Zatorre et al. 2002). According to the parameter-specific hypothesis, the classical domain-related dichotomy (speech left versus non-speech right) changed to a physical dichotomy which assigns a better temporal resolution to the left auditory cortex and a better spectral resolution to the right auditory cortex (Zatorre 2003; Tallal & Gaab 2006; Hickok & Poeppel 2007; Brancucci et al. 2008). Concerning the perception of voice, the physical dichotomy would mean that those cues contained in natural voices which need high temporal resolution to be properly analysed (i.e. principally language) are mainly processed in lefthemispherical areas, whereas those cues which do not need a high temporal resolution or which need a fine spectral resolution to be properly analysed are processed mainly in right-hemispheric areas.

3. VISUAL MODALITY: LATERALIZATION OF FACE AND GAZE PERCEPTION Faces are certainly the most relevant ‘social objects’ in the visual domain: it would not be an overstatement to say that faces are the most important objects of social perception altogether. By perceiving faces we assign individuals precise characteristics that define their individuality, from the inclusion into classes and categories (male or female, old or young, black or white) to the assessment of their attractiveness, fitness, mood and emotional tone. Sometimes this process brings a long-term encoding of characteristics of a given face in memory and to association with a name for future retrieval. Faces are thus a special domain in our social world, and the brain mechanisms underlying their perception and representation reflects such special status.

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Structurally, faces are stimuli that resemble one another for their ‘faceness’: discounting the enormous variance between faces, and extracting the attributes common across all possible faces is necessary to categorize a face as such and not as a mobile phone or a spider. A basic configuration of facial fundamental features and their spatial relationships has to be necessarily present in the brain if rapid categorization is to be carried out to discriminate faces from other biological and non-biological objects (Tsao & Livingstone 2008). This is typically shown by the demonstration that face recognition is made almost impossible when faces are presented upside down, the so-called ‘face inversion effect’ (Yin 1969). Further aspects of shape and microstructure in the face space must be extracted for rapid categorization of sex, ethnicity, age, attractiveness, emotion and even subtler cues such as health state as revealed by texture of skin, eyes and lips (Bruce & Young 1986; Brown & Perrett 1993; Rhodes 2006). These are characteristics that can be shared by large subsets of faces, although their constancy might vary in time from very stable even in the range of a lifetime (such as sex and ethnicity), to extremely variable even in the range of fractions of a second (such as emotional expressions). The temporal stability of features revealing age, for instance, holds on a time-scale long enough to allow for a stable interpretation of identity during months or years. Other characteristics, such health state or attractiveness might vary at an intermediate temporal scale, depending on season (and susceptibility to illness), metabolism and oestrous in the case of women. Even more crucially, individual recognition must be based upon the precise encoding of absolute features present on a given face, because approximate or fuzzy encoding would make undesirable recognition errors possible. Accurate individual recognition, moreover, must discount the enormous variability present within the single face at different moments in time and from different points of view in space. The history of studies on face perception and its neural substrates is long and still very lively. Faces are objects of experience for which dedicated neural machinery exists, are processed automatically, and are preferentially looked at rather than any other category of objects since very early in development (Tsao & Livingstone 2008). Demonstrations that face perception is a matter of right-hemispheric specialization came relatively long ago from studies using chimeric faces (stimuli obtained juxtaposing the left and right halves of different faces), from studies using the divided visual field technique, from neuropsychological evidence on brain-lesioned patients with selective impairments in face recognition (prosopagnosia), and from work on split brain patients. Among the first demonstrations of asymmetries in face perception are the investigations of Wolff (1933) who observed that the right half of a face, more than the left half, carries the impression conveyed by the full face: to come to this conclusion he compared the impression evoked by chimeric faces created adjoining the left (or right) halves of faces to their mirror images, noticing that RCR chimeras resembled more the original faces than LCL chimeras. The right side of a face falls to the left of its observer, and the possibility that this effect was not due to structural differences in Phil. Trans. R. Soc. B (2009)

the two halves of faces, but rather to differences between the two halves of the perceptual space of observers was later demonstrated by Gilbert & Bakan (1973). Rhodes (1985) proposed a model of hemispheric lateralization for face perception that distinguished between right hemisphere contribution, relevant for early categorization and representation, assigning to the left hemisphere a role in face-name association and retrieval of semantic information associated with faces. Leftward perceptual asymmetries for the recognition of face attributes, supporting such right-hemispheric involvement, have been confirmed in many studies using chimeric faces: for instance, Burt & Perrett (1997) showed that the left bias is present for judgements on sex, age and attractiveness, but not for the recognition of phonemes associated with lip movements. Other studies confirmed and extended these results for not only sex (Luh et al. 1994; Butler et al. 2005; Parente & Tommasi 2008) but also attractiveness and health (Zaidel et al. 1995; Reis & Zaidel 2001), with the possible exception of another attribute, trustworthiness (Zaidel et al. 2003). Chimeric faces can be presented in free vision in order to observe such left-sided (right-hemispheric) bias. Experiments making use of the divided visual field technique, instead, consist in the very brief (tachistoscopic) presentation of stimuli accurately confined to the left or the right visual hemifield, ensuring that the stimuli are processed by the hemisphere contralateral to the side of presentation. Using this technique with faces as stimuli in a variety of tasks, a right-hemispheric superiority for facial recognition has been substantially confirmed by various researchers during many decades (Rizzolatti et al. 1971; Leehey et al. 1978; Grega et al. 1988; Rhodes & Wooding 1989; Dutta & Mandal 2002). In this scenario of converging evidence, a factor that has been shown to modulate lateralization is the attribute of familiarity, as different investigations led to conflicting results when the hemispheric asymmetry for the recognition of familiar or famous (versus unknown) faces was tested, some evidence suggesting a lefthemispheric superiority (Marzi & Berlucchi 1977), other studies a right-hemispheric superiority (Levine & Koch-Weser 1982), and others no difference between the hemispheres (Kampf et al. 2002), or interactions between laterality and angle of view (Laeng & Rouw 2001). Clearly, the perception of familiarity of known faces is associated with the retrieval of semantic (including linguistic) information (i.e. the name associated with a given face) that might call for lefthemispheric cooperation beyond the right-hemispheric involvement generally evidenced by much evidence on face perception. Chimeric faces and divided visual field presentations have also largely been exploited to investigate lateralized processing of facial expressions of emotion. The amount of literature is more than abundant on this aspect and two main models have been proposed to explain emotional lateralization (see Demaree et al. (2005) for a comprehensive review). The right hemisphere hypothesis posits a right-hemispheric superiority in production and perception of all emotional expressions (Campbell 1978; Ley & Bryden 1979; Levy et al. 1983; Tucker et al. 1995), whereas the valence hypothesis assumes a left-hemispheric superiority

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Review. Asymmetries of the human social brain A. Brancucci et al. for the processing of positive emotions and a righthemispheric superiority for the processing of negative emotions (Reuter-Lorenz & Davidson 1981; Borod et al. 1997). The latter model is also in line with another influential model of hemispheric lateralization, the ‘approach–withdrawal’ model, positing that from the standpoint of motivation, the left hemisphere would be more strongly associated with approaching rewards and the right hemisphere to withdrawing from punishments (Davidson 1993). Recent accounts have partially reconciled these two hypotheses, as it seems that the right hemisphere hypothesis could hold true for emotion perception, whereas the valence hypothesis could hold true for the production of expressions and for the conscious experience of emotions (Canli 1999; Gainotti 2000), with a possible higher involvement of the right hemisphere in the perception of basic (when compared with socially complex) emotions (Prodan et al. 2001; Shamay-Tsoory et al. 2008). Another source of information on asymmetries of face processing comes from neuropsychological studies of prosopagnosia, a pathological condition in which the patient fails to recognize others’ faces even when they belong to people encountered frequently (being unimpaired in the recognition of other categories of visual objects). Prosopagnosia is usually associated with bilateral damage in the temporal lobes (Damasio et al. 1982), but unilateral damage to the right hemisphere can suffice to induce the pathology (Kolb et al. 1983; De Renzi 1986; De Renzi et al. 1994). Finally, evidence from split brain patients already present in the pioneering work of the Nobel laureate Roger Sperry, showed that interrupting communication across the hemispheres due to the resection of the corpus callosum, did not prevent the identification of others’ faces and self-recognition (Sperry et al. 1979). This special case, the recognition of one’s own face, has resurrected more recently as a topic of interest in the study of split brain patients and normal subjects, providing conflicting evidence on the hemispheric biases of self-recognition, much resembling the contradictory results obtained in the case of face familiarity: some studies have reported a right-hemispheric lateralization (Preilowski 1977; Keenan et al. 2001, 2003), other studies a left-hemispheric lateralization (Turk et al. 2002; Brady et al. 2004) and others no asymmetry (Uddin et al. 2005). Neuropsychological data on both prosopagnosic and split brain patients have also concerned the specific issue of perception of emotion expression, and the overall pattern of evidence, taken together with that derived from behavioural studies in normal subjects, confirms that the identification and recognition of facial affect and emotion expression is separate from identity recognition, and might be more strongly lateralized in favour of the right hemisphere (Bowers et al. 1985; Stone et al. 1996; Adolphs et al. 2001; Coolican et al. 2008). The story turned out to be more complicated with the advent of neuroimaging techniques, as the evidence for right-hemispheric superiority in the perception of faces became less clear-cut than previous research making use of purely behavioural paradigms seemed to suggest. Research has firmly established that the analysis of faces in the human brain depends on a Phil. Trans. R. Soc. B (2009)

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distributed cortical network involving a number of regions in both hemispheres (Haxby et al. 2000; Rossion et al. 2003; Ishai et al. 2005; Ishai 2008). Recent work in non-human primates (both single cell electrophysiology in behaving monkeys and neuroimaging), moreover, is generating evidence supporting the existence of such network (Pinsk et al. 2005; Tsao et al. 2006; Rolls 2007; Gross 2008). It is, however, quite undisputed from neurophysiological work on primates that some aspects of face processing are lateralized, more often in the direction of a stronger involvement of the right hemisphere (Perrett et al. 1988; Zangenehpour & Chaudhuri 2005; Tsao & Livingstone 2008), a result that has been found even in the non-primate brain (sheep: Peirce & Kendrick 2002). The primate brain regions involved in the perception of face identity are areas receiving their input from the occipital cortex, and are located along the occipito-temporal stream in the visual pathway (Ungerleider & Haxby 1994). Neuroimaging studies of face perception have clearly shown that the main stations along this stream are the inferior occipital gyrus (IOG; also known as occipital face area); the fusiform gyrus (FG; also known as face fusiform area, FFA), the STS and the anterior inferotemporal cortex (aIT). The relative contribution of these regions as assessed by fMRI during a number of passive and active tasks on various types of facial stimuli, appears to be differential, some regions being more involved in the analysis of ‘stable’ features necessary to recognize identity, and other regions more involved in the analysis of ‘variable’ features necessary to process intentions and visual cues to communication (i.e. gaze direction and lip movements). Despite this the network is assumed to be largely bilateral, work on IOG, FFA and aIT (a role of STS in gaze selectivity will be dealt with later) has often evidenced a major involvement of the right hemisphere during identification and recognition of faces (Kanwisher et al. 1997; Halgren et al. 2000; Ishai et al. 2000; Grill-Spector et al. 2004; Rotshtein et al. 2005; Kanwisher & Yovel 2006; Kriegeskorte et al. 2007), and it has been suggested that the corresponding areas in the left hemisphere might subserve a more general process of object recognition, in a less face-selective fashion. Other evidence point instead to an asymmetrical subdivision of competences assigning a primacy for global analysis of faces to the right FG and for local or feature-based face analysis to the left FG (Rossion et al. 2000; Harris & Aguirre 2008), a result suggested by previous behavioural and electroencephalographic studies of asymmetries in the processing of inverted faces and objects (Leehey et al. 1978; Levine et al. 1988; Hillger & Koenig 1991; Rossion et al. 1999), and grounded on a more general theoretical framework that hypothesizes that the left hemisphere is specialized for processing high visual frequencies and the right hemisphere is specialized for processing low visual frequencies (Sergent 1983). IOG, FFA and STS constitute the main centres of a neural network for face processing, and are heavily connected to other areas where further processing takes place. Most notably, connections to the amygdala, insula, basal ganglia, orbitofrontal cortex (OFC) and

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other regions in the frontal cortex seem to subserve the processing of emotional expression, the assessment of reward content inherent or associated with faces (i.e. attractiveness, status), and self-perception. For instance, Krendl et al. (2006) showed activation of the insula and the amygdala during evaluation of faces associated with negative judgements (stigmatization). Stronger activation of these two regions was shown during observation of faces with physical imperfections (obesity, unattractiveness, and facial piercings). The amygdala is considered a major centre for the processing and integration of emotion and cognition, and it is not chance that emotional expression as perceived on faces strongly evokes activation in this region, as shown by a large number of imaging studies (see Adolphs & Spezio (2006) for a review). Importantly, the activation of the amygdala associated with perception of emotional faces (but also other categories of emotional stimuli) is most often bilateral or lateralized to the left hemisphere: in a meta-analysis about amygdala activation across a large number of PET and fMRI studies (Baas et al. 2004), lateralization was almost invariably found in favour of the left hemisphere when the stimuli involved were emotional faces (see Noesselt et al. (2005) for opposite results). Recently, however, it has been argued (Sergerie et al. 2008) that this pattern of asymmetry might be due to the differential time course of activation decay of the left (slower) and right (faster) amygdalae and its interaction with the fMRI experimental design (block versus event). The anterior insula and the adjacent frontal operculum have been associated more tightly with the perception of the specific emotion of disgust (disregarding input modality, gustatory or visual), but lateralized activation of this region appears most of the time to be non-significant (Calder et al. 2001; Jabbi et al. 2007) or leaning towards the right hemisphere (Phillips et al. 1997). Thus, behavioural evidence in normal subjects, clinical data and neuroimaging studies strongly support the idea that face processing depends more on righthemispheric activity, although the asymmetry in itself appears to be largely functional, assuming that a bilateral circuitry for face representation has been ascertained. Importantly, in a recent study (Yovel et al. 2008) a strong correlation was found between the left visual field bias as observed in a chimeric face task, and the asymmetrical activation of the FFA in the right hemisphere during fMRI scans, crucial evidence linking behavioural and neuroimaging work and restoring confidence in the tenability of purely behavioural paradigms. Gaze plays a central role in social interactions, informing individuals about others’ attention, goals and intentions. Perception and interpretation of gaze direction are automatic and effortless processes in normal individuals, while they are altered in autistic subjects and in schizophrenic patients (Pinkham et al. 2008). For studying gaze processing, attention orienting paradigms are usually used (Posner 1980). In such paradigms, a face is first presented centrally with gaze directed towards the subject or invisible because masked, it is followed by the same face with the eyes looking to the left or right. Finally, a target is presented to the left or right, congruently or incongruently with Phil. Trans. R. Soc. B (2009)

the gaze cue: chronometric differences in the recorded reaction times between conditions can reveal the effects on attention allocation due to the presence or absence of the gaze and its direction. Given the importance of perceiving others’ gaze, one might expect that it receives specialized processing in the brain. Studies investigating the neural substrates of gaze direction processing have found that the vision of moving eyes activates the STS. As reviewed by Allison et al. (2000), much evidence suggests that the STS plays a central role in the perception of gaze, together with the FG (Kanwisher et al. 1997; Puce et al. 1998; Wicker et al. 1998; Hoffman & Haxby 2000; Haxby et al. 2002; Hooker et al. 2003) and the amygdala (Kawashima et al. 1999; Adolphs et al. 2005; Benuzzi et al. 2007). Some evidence is also suggestive of hemispheric asymmetries in the neural substrates of gaze perception, and behavioural research on domestic chicks show that these might be relatively conserved phylogenetically (Rosa Salva et al. 2007). Data on humans come from Ricciardelli et al. (2002) who showed that eye gaze is processed better when presented in the left visual field, as opposed to when it is presented in the right visual field, supporting the idea of a right-hemispheric specialization for eye gaze perception. Moreover, Calder et al. (2007), using fMRI, demonstrated that clusters of neurons of STS selectively sensitive to eye gaze direction are primarily present in the right hemisphere. A similar result was also found for the right inferior parietal lobule. In an experiment (Conty et al. 2007), in which EEG activity was recorded during the presentation of faces suddenly turning their gaze towards the subject or away from her/him, a negative peak emerged at 170 ms ( N170) after stimulus presentation, markedly enhanced in the condition of direct gaze when compared with averted gaze. The source analysis revealed a complex network of sources, composed of four clusters of activation: two in dorsomedial prefrontal regions, one in the OFC and the fourth in the right STS. Grosbras et al. (2005) performed a wide metaanalysis of brain-imaging studies, finding that the networks responsible for gaze perception are more similar to those involved in reflexive than to those involved in voluntary shifts of attention and eye movements. The analysis indicated that gaze perception, reflexive shifts of covert attention and visually guided eye movements all activate the temporoparietal junction in proximity of the ascending branch of the STS in the right hemisphere. Some lateralization has also been found in the amygdala: Wicker et al. (1998) found a strong activation of the right amygdala during gaze perception. Right-hemispheric lateralization in the processing of gaze perception is also suggested by neuropsychological evidence obtained in patients suffering from brain damage. Akiyama et al. (2006a,b) described a patient with a right superior temporal gyrus lesion, impaired at determining the direction of observed gaze, who was able to interpret arrow cues, in agreement with the results of Hietanen et al. (2006), suggesting that orienting of attention by gaze cues and orienting of attention by arrow cues are not supported by the same cortical network.

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Review. Asymmetries of the human social brain A. Brancucci et al. 4. VISUAL MODALITY: LATERALIZATION OF BIOLOGICAL MOTION PERCEPTION Biological motion perception has an important adaptive role; it allows animals to predict future actions of prey, predators and mates, and to decide whether to move towards or away from them (Regolin et al. 2000). Social animals, such as humans, behave largely on the basis of their interpretations and predictions about the actions of others (Blakemore & Decety 2001), and given the evolutionary importance of detecting biological motion, it would be logical to expect neural machinery dedicated to its perception. Brain-imaging studies, in which investigators usually contrasted brain activation produced when observers viewed animations of point lights following the trajectories of joints, limbs and other relevant body parts (PL animations) with activations produced when viewing scrambled versions of the same animations, have attempted to investigate whether the perception of biological motion is subserved by a specific neural network in humans. A large number of brain areas are involved in biological motion perception: the motion sensitive area MT/V5C, the posterior superior temporal gyrus (pSTG), the posterior superior temporal sulcus (pSTS), the ventral temporal cortex ( Thompson et al. 2005), the ventral FG ( Vaina et al. 2001; Grossman & Blake 2002), the posterior FG (or fusiform body area; Peelen & Downing 2005), the so-called ‘extrastriate body area’ corresponding to the posterior inferior temporal sulcus (Downing et al. 2001; Astafiev et al. 2004), and the parietal, premotor and inferior frontal regions involved in action recognition and execution (Rizzolatti et al. 2001; Saygin et al. 2004). A central role in this large network is played by the pSTS in the right hemisphere. The STS represents a relay for the dorsal and ventral visual streams (Felleman & Van Essen 1991), in which form and motion information arising from the same person are integrated (Shiffrar 1994; Oram & Perrett 1994). Although STS neurons are largely visual, their activity can be modulated by the motor system (Hietanen & Perrett 1996) and by the amygdala (Aggleton et al. 1980). Using PET, Bonda et al. (1996) identified regions along the posterior portions of the STS (pSTS) that were activated when people viewed coherent, but not scrambled point light actions. This activation was stronger in the left hemisphere during observation of hand movements, and in the right pSTS when subjects observed body motion. Using fMRI, Grossman et al. (2000) found more activation sites in the right pSTS than in the left, and more strongly in response to upright human motion than upside down animations (the ‘body inversion effect’; Grossman & Blake 2001). In a recent study, Peuskens et al. (2005) found that it has been primarily the pSTS in the right hemisphere that responds strongly to human motion, a trend apparent also in the results of other works (Beauchamp et al. 2003). The pSTS is also robustly activated when one views whole-body motions rather than PL sequences (Pelphrey et al. 2003), as well as when one views motion confined to specific limbs or to the eyes, hand and mouth (Calvert et al. 1997; Puce et al. 1998; Gre`zes et al. 2001). Interestingly, brain areas including the pSTS in the right hemisphere also respond robustly Phil. Trans. R. Soc. B (2009)

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when people view humanly impossible movements (Costantini et al. 2005). Santi et al. (2003) used fMRI to dissociate brain areas responsive to whole-body actions portrayed in PL animations from brain areas responsive to visible speech rendered using PL animations. While there were a few overlapping activation areas, the speech animations selectively activated the left pSTS, portions of auditory cortex, and a network of motor regions including Broca’s area; the whole-body PL animations, besides activating the pSTS in the right hemisphere, selectively activated the FG bilaterally and a network of more rostrally located cortical areas that Santi et al. believe are involved in the mirror neuron system. In their fMRI study, Wheaton et al. (2004) found that face, hand and leg motion activate the STS, MT/V5C, anterior intraparietal cortex (aIP) and ventral premotor cortex, predominantly in the right hemisphere. Saygin (2007) examined biological motion perception in 60 unilateral stroke patients, and found no evidence in the neuroanatomical data suggesting either left or right hemisphere dominance for biological motion perception. Saygin supposed that the right lateralization of biological motion perception in previous studies may be explained by the ‘social’ aspects elicited by human motion rather than by body movement per se. The central role of the right temporal cortex is instead supported by other neuropsychological data: Vaina & Gross (2004) described four patients with right temporal lesion, who failed to recognize biological motion, while able to report correctly the global direction of the point lights in the display, indicating that they were not ‘motion blind’. A particular type of human movements consists of gestures. During human interactions, gestures assume many meanings and the perception and recognition of gestures are cognitive abilities that allow us to interpret, and even predict, the actions of others (Meltzoff & Decety 2003; Rizzolatti & Craighero 2004). Gestures can be transitive, if the action involves the use of a tool and/or an object, and intransitive (usually hand action with a symbolic connotation). Some authors (i.e. Kendon 2004) think that gestures, which palaeoneurologists suppose to be derived from tool use (Frey 2008), belong to the linguistic system. It has also been suggested that language evolved from manual gestures: the relationship between hand and mouth begun as ingestive movements, progressively adapted for communication (Gentilucci & Corballis 2006). Others posit that gesture and speech are two different communication systems, depending upon different brain structures (Levelt et al. 1985; Hadar et al. 1998). The localization evidence obtained so far points to a bilateral brain network underlying gesture perception, that however includes many of the known structures in the right hemisphere that have been shown to support the perception of biological motion per se: for instance, an fMRI study by Villarreal et al. (2008) demonstrated an extensive, common network underlying the recognition of gestures consisting of the right pre-supplementary motor area, the right STS/ STG, the left inferior posterior parietal cortex, and bilateral superior posterior parietal cortex (PPc), precuneus, fusiform gyri, occipitotemporal regions

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and visual cortices. Aziz-Zadeh et al. (2006), studying the lateralization of the mirror neuron system, found that the visuomotor regions of the system engaged during action observation and imitation (when compared with mere execution) are largely bilateral, suggesting an evolutionary independence of the language (left-lateralized) system from gestural and visual inputs. To further understand the differences and commonalities of language and gesture, it is useful to consider in short the case of sign language. In subjects that communicate using sign language bilateral cerebral activation has often been observed. This could be explained by the fact that in sign language speakers both hemispheres mediate different kinds of information: damage to the right hemisphere in American Sign Language produces deficits in processing the spatial topography associated with the relative positioning of arms and hands, whereas damage to the left hemisphere reduces the expression of grammatical relationships conveyed by signs. MacSweeney et al. (2004) compared the neural correlates of viewing a gestural language and a manual-brachial code (Tic Tac) relative to a low level baseline task, and found activation in an extensive frontal-posterior network in response to both types of stimuli. The superior temporal cortex, including the planum temporale, was activated bilaterally in response to both types of gestures. In signers, a greater activation for sign language than for Tic Tac was observed in the left posterior STS and STG, extending into the supramarginal gyrus. This suggests that the left posterior perisylvian cortex is of fundamental importance to language processing, regardless of the modality in which it is conveyed. Furthermore, Sakai et al. (2005) used fMRI to examine hemispheric dominance during both the processing of signed and spoken sentences in normal and deaf subjects. They found left-dominant activations involving frontal and temporoparietal regions: the ventral part of the inferior frontal gyrus, the precentral sulcus, the superior frontal gyrus, the middle temporal gyrus, the angular gyrus and the inferior parietal gyrus. Finally, perception of fingerspelling (in which different hand configurations are used to produce the different letters of the alphabet) determines activation in both the left and the right mid-FG (Waters et al. 2007). Biological motion as a visual input for social perception appears thus to be largely dependent on a neural network lateralized in the right hemisphere, but cooperation of left-hemispheric structures is demanded for processing the content of those biological motions that convey meaning, i.e. gestures.

5. LATERALIZATION OF THE OLFACTORY MODALITY AND PHEROMONES The social systems of many species rely upon chemical signals passed between individuals and carrying information about reproductive and health status, and individual identity that have important influences on adaptive processes (Brennan & Kendrick 2006; Shepherd 2006). Chemical communication is based on a peculiar class of signals that differ from stimuli such as light, Phil. Trans. R. Soc. B (2009)

sound and pressure, well described by systematic variations in wavelength, frequency or other physical dimensions. Chemical stimuli have no equivalent metric because they can be described only using a multidimensional space (Haddad et al. 2008). The general idea is that chemical signals can be no longer classified as volatile (odorants) and not volatile, but should be grouped primarily based on different behavioural and physiological effects (Sbarbati & Osculati 2006): semiochemical (i.e. a food smell—substances eliciting a conscious perception and carrying information categorized as attractive, repulsive, stimulating, deterrent, etc.), allelochemical (substances produced by members of one species influencing the behaviour of members of another species, eliciting conscious perception, typical of prey–predator relationship and symbiosis), pheromones (substances eliciting an unconscious perception and triggering a behavioural response in another member of the same species, often activating a neuroendocrine response) and vasana (social chemosignals that are neither classifiable as odours nor as pheromones, that are not consciously detectable as odours, and do affect psychological state yet not triggering a unique set of behavioural, neural or endocrine responses). Also in humans, the chemical environment is perceived starting from the detection of these classes of stimuli in the known chemosensory systems (olfactory system, trigeminal system, vomeronasal organ) and ascending to several higher brain areas. In particular, pheromones stimulate olfactory as well as vomeronasal sensory neurons (Zufall & Leinders-Zufall 2007). For instance, a class of pheromones, major histocompatibility complex class I peptides, have been shown to activate both olfactory receptors involved in mate choice (Boehm & Zufall 2005) and vomeronasal sensory neurons required for the Bruce effect (the exteroceptive block of pregnancy; Bruce 1959), as shown by Spehr et al. (2006). The traditional distinction that common odours are perceived through the olfactory pathway and pheromones through the vomeronasal pathway appears incorrect or too simplistic. Furthermore, bypassing the discussion on humans lacking a functional vomeronasal system, it has been demonstrated by functional imaging that sex pheromones activate several regions of the human brain (Savic et al. 2001). One key aspect is the fact that the anatomical pathways of chemical senses are organized ipsilaterally whereas vision and hearing are organized contralaterally. Olfactory inputs emerging from the main olfactory and/or vomeronasal systems are processed by the ipsilateral primary olfactory cortex (including the piriform cortex and entorhinal cortex) and subsequently at the level of the OFC, insula and amygdala, the latter playing a major role in the learning and recognition of social chemosignals as well as being a hub for visual and acoustic emotion-related information. The cross-modal integration of information processed by chemosensory systems with that processed by the visual and auditory systems, provide interesting evidences of asymmetries that extend our current view on the lateralization of the human social brain. One basic fact that sets the stage for olfactory lateralization is the evidence that the maximum nasal airflow rate is congruent with handedness: cycles of

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Review. Asymmetries of the human social brain A. Brancucci et al. breathing during which one nostril dominates alternate, however, the right nostril is used more frequently by right-handers and the left nostril is used more frequently by left-handers (Searleman et al. 2005). Despite the ipsilateral organization of the main neuroanatomical pathways, behavioural and imaging evidence indicate that olfactory stimuli are processed both by the ipsilateral and the contralateral hemisphere (Savic & Gulyas 2000). However, many studies show that the right hemisphere appears to be involved more than the left in the recognition and evaluation of olfactory stimuli disregarding the side of nostril stimulation (Zucco & Tressoldi 1988; Zatorre & Jones-Gotman 1990; Zatorre et al. 1992b; Zald & Pardo 2000; Dijksterhuis et al. 2002), and the right OFC seems to have a special role in this circuitry. However, there are many aspects of olfactory lateralization that seem to strongly depend on the task accomplished or the stimuli used (Brand et al. 2001; Royet & Plailly 2004): when subjects are exposed to strongly aversive stimuli, the activity of the OFC is stronger in the left hemisphere and a bilateral activation of the amygdala is observed (Zald & Pardo 1997; Anderson et al. 2003). Quite in disagreement with the right hemisphere hypothesis mentioned above, it has been suggested that activation of the OFC would be lateralized in the left or the right hemisphere according respectively to the emotional aspects (i.e. detecting the pleasantness or the edibility of a stimulus) or familiarity (i.e. the recognition of a known stimulus; Royet & Plailly 2004). More intriguingly, differential patterns of asymmetric activation of the OFC emerge depending on the level of pleasantness of stimuli: as mentioned, it was reported that a higher lefthemispheric activity (in the OFC) can be observed during exposure to aversive stimuli (Zald & Pardo 1997; Anderson et al. 2003). However, when a subject is exposed to a pleasant smell, the asymmetry reverses and a higher activity of the right hemisphere is observed in the OFC and the piriform cortex (Zatorre et al. 2000; Gottfried et al. 2002), an asymmetry that had been suggested also by psychophysical evidence based on unilateral presentation (Herz et al. 1999; Dijksterhuis et al. 2002). These results are also in disagreement with the mentioned valence hypothesis, so it appears that data on olfactory lateralization are not easily reconciled with models of emotional lateralization. One factor that to our knowledge has never been stressed in discussion on olfactory lateralization measured by means of behavioural tests, however, is the possible confound due to the fact that unilateral nostril breathing, which is necessarily used in lateralized presentation of odorants, has been shown to modulate the performance of verbal and spatial tasks in a manner that is consistent with the functions of the hemisphere contralateral to the open nostril (Schiff & Rump 1995). Little is known on the laterality of what could be considered the most obvious manifestation of olfactory social perception: personal body odour. In a PET study carried out on female subjects, Lundstro¨m et al. (2008) have recently shown that brain activation induced when smelling body odours was topographically different from activation induced by non-body odours. Interestingly, body odours activated a circuit including more non-olfactory Phil. Trans. R. Soc. B (2009)

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than olfactory regions, an example being robust righthemispheric activation in the occipital and angular gyri. The familiarity of body odours (i.e. personal odour, odour of a friend, odour of a stranger) induced further topographical differentiation, with a higher left-hemispheric activation (including insula and amygdala) following exposure to a personal odour never smelt before, and higher right-hemispheric activation following exposure to personally familiar body odours. Many studies indicate that putative human sexual pheromones are androstadienone (4,16-androstadien3-one, AND), androstenol (5a-androst-16-en-3a-ol), androstenone (5a-androst-16-en-4-one) and estratetraenol (1,3,5(10),16-estratetraen-3-ol, EST). Strong evidence of the effect of pheromones on behaviour and physiology in humans ranges from effects on the synchronization of menstrual cycle ( McClintock 1971; Graham 1992; Weller & Weller 1993) to avoidance or preference for sitting on a chair sprayed with putative male pheromone (Cowley et al. 1977; Kirk-Smith et al. 1978). Male pheromones act on females during the ovulatory period, inducing a stronger sexual selection of symmetric male faces (Thornhill & Gangestad 1999), and around ovulation women perceive the male pheromone as less aversive compared with other cycle phases (Grammer 1993). Interestingly, the large amount of behavioural research on pheromones has neglected possible links to hemispheric lateralization: only recently neuroimaging work has been started to provide data on brain activity underlying pheromone processing, and asymmetries have started to emerge. In females, it has been shown that AND activates the anterior ventral hypothalamus, mostly in the preoptic and ventromedial nuclei, but not the olfactory regions (piriform, orbitofrontal and insular cortex) and the amygdala, which are instead activated (mostly in the right hemisphere) when EST is smelt (Savic et al. 2001). On the other hand, the hypothalamus (especially the paraventricular and dorsomedial nuclei) but not olfactory regions is activated in males when smelling EST. When males smell AND, the amygdala, piriform cortex, cerebellum and postcentral gyrus appear to activate, predominantly in the right hemisphere. This sex-dependent pattern of activation, apart from revealing a physiological substrate for a differentiated sexual response in humans, is thus accompanied by lateralization patterns when subjects are exposed to pheromone-like substances. These results were confirmed and expanded in further studies in which the brain activation of homosexual individuals was compared with that of heterosexual subjects when exposed to EST or AND (Savic et al. 2005; Berglund et al. 2006). Of note, when homosexual men smelled EST the left amygdala and piriform cortex were primarily recruited (although with inclusion of a minor portion of the anterior hypothalamus), whereas asymmetries in activation when smelling AND were comparably weaker in lesbian women. Savic & Lindstro¨m (2008) have recently analysed in more detail the hemispheric asymmetries of homo- and heterosexual subjects. Magnetic resonance volumetry and PET measurements of regional cerebral blood flow were carried out in heterosexual and homosexual men and women, to investigate respectively structural

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asymmetries and functional connectivity of the amygdala. Heterosexual men and homosexual women showed larger right hemispheres, whereas volumes of the cerebral hemispheres were symmetrical in homosexual men and heterosexual women. Homosexual subjects, however, showed sex-atypical connections to the amygdala. In both homosexual men and heterosexual women, the connections were more widespread from the left amygdala, whereas in heterosexual men and homosexual women, from the right amygdala. This result echoes the recent discovery that a greater functional connectivity of the right amygdala at rest is present in males but not in females, whereas a greater functional connectivity of the left amygdala is observed in females but not in males (Kilpatrick et al. 2006). The overall pattern of lateralization underlying pheromone processing appears thus to be strongly dependent on sex: it is predominantly right hemispheric in males and less so in females.

6. CONCLUSIONS Recognizing others and keeping track of their identity in memory is a function necessary to assign appropriate roles to agents in the social environment. Functions of social perception require special attention because of their role for survival beyond individual recognition and identification, such as in judgements needed for kin selection, mating, cooperation and competition, and in the understanding of others’ mental and affective states necessary for interacting. Finally, the tight coupling between sensory and motor processes underlying the execution of one’s own actions and the observation of others’ actions, due to its importance for social regulation (i.e. in empathy, imitation, communication), gives an idea of how much the functions of the nervous system are adapted to the interactive nature of human sociality. The study of single- and multi-modal cues to social perception has revealed that there are strong reciprocal influences between auditory, visual and chemical inputs (Kova´cs et al. 2004; Platek et al. 2004; Campanella & Belin 2007), and in this review we have attempted to summarize the current knowledge on their neural bases, with a focus on hemispheric asymmetries. It is, however, hard to draw clear-cut conclusions from the amount of evidence here presented on the lateralization of these cues and their interaction in social perception, of which this review can be considered simply the tip of the iceberg. Even more embarrassing is the fact that many crucial aspects have been completely or partly left out of the review, sex differences and handedness being probably the most crucial given their relevance for both social perception and brain asymmetry. However, it is not impossible to formulate some remarks on emerging aspects that might be valuable for better understanding the role of brain asymmetries in social neuroscience. In all of the three modalities considered, the assignment of a dominant role to the right hemisphere in social perception would appear well deserved. For many of the functions reviewed, stronger involvement of the right hemisphere in coding some aspects of person perception seems to be the rule, whereas involvement Phil. Trans. R. Soc. B (2009)

of the left hemisphere appears to sometimes be a shared role, and only exceptionally a main role. Before neuroimaging, purely behavioural investigations and clinical studies on unilateral lesions in patients provided strong and suggestive evidence of righthemispheric lateralization for social perception. Taking the ‘face processing circuit’ as an example (Ishai 2008; Tsao & Livingstone 2008), neuroimaging and electrophysiology allowed us to get a clearer and more detailed description of the neural topography and chronometry than could be obtained using behavioural techniques and lesion data, and the discovery of the substantial bilaterality of brain structures dedicated to representing faces, in spite of much evidence on left visual field advantages in face and emotion perception, pops out as a topic for discussion. Generalizing what has been discovered about the neural bases of face processing, both hemispheres appear structurally endowed for processing cues of social perception, and the asymmetry is evident in the net balance of right-hemispheric activation, both when social perception is superficial and transient (Haxby et al. 2001) and when it is focused on specific social cues such as sex, if sex is relevant for social judgement ( Yovel et al. 2008). The same seems to be true for more complex domains of social representation, such as theory of mind (ToM), the ability to attribute mental states to other individuals. ToM is in fact believed to involve a bilateral neural network (Gallagher & Frith 2003), but the activity of this circuit depends also on the right-lateralized contribution specifically involving the orienting of attention to emotional cues that are present in faces (Narumoto et al. 2001). Right-hemispheric asymmetries found ubiquitously in social neuroscience might thus depend on the existence of an asymmetrical triggering mechanism in one or more basic functions outside the recently discovered neural correlates of social perception. Spatial attention is one first candidate, as the orienting of attention necessary to establish a first person perspective in space strongly depends on right-lateralized structures ( Vogeley & Fink 2003), and the automaticity in attending spatial locations is also believed to depend on the right hemisphere (Corbetta & Shulman 2002). In order to perceive others as separate from ourselves, it is of fundamental importance that a solid spatial framework centred on the observer is maintained and updated. Spatial mapping and the addressing of attention to locations in space are two functions needed to this aim, and they engage a neural network with a crucial role of the PPc in the right hemisphere. Spatial attention might thus be a right-hemispheric function driving the activation of ipsilateral neural structures specialized for person perception, and an obvious advantage coming with this guiding function is that relative spatial positions of ‘self’ and ‘other’ would be available automatically before any further processing takes place. As spatial information (distance, orientation, etc.) is essential for social perception, it would not be implausible to suppose that the right social brain is ‘primed’ by the right spatial brain. Another function that might have a driving effect for the lateralization of social perception could be the major role in avoidance behaviour attributed to the

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Review. Asymmetries of the human social brain A. Brancucci et al. right hemisphere, in opposition to the left hemisphere having a major role in approach behaviour (Davidson 1993, 2003). This RH-avoidance/LH-approach system might reasonably have its default mode in the most conservative of the two dispositions (avoidance), whose effects are immobility and freezing, attentive scrutiny of novelties, and energy conservation (Braun 2007), all behavioural aspects that might have conferred an evolutionary advantage over an uncontrolled approach. Avoidance can be a winning default strategy but it cannot be the only strategy. Past the first phases of interpersonal knowledge, when humans become acquainted with each other, affiliative behaviour is demanded. The attribute of familiarity certainly has a key role in social perception, and it appears to be the most controversial factor in modulating the lateralization of the social brain. A mixed pattern of zero-, leftand right-asymmetric lateralization emerges from studies on the neural substrates underlying the processing of the familiarity of faces, voices and personal odours and it is not clear how the approach/ avoidance hemispheric subdivision could explain the discordant results obtained across these different modalities. Actually, right-hemispheric lateralization has been found more frequently in familiarity tasks, but the presence of counterevidence is puzzling, and calls into question aspects of the familiarity attribute that bring us to the final considerations, concerning the dependence of the social brain upon the brain regions responsible for language processing. A large amount of evidence (Banich 1998, 2003; Weissman & Banich 1999) shows that interhemispheric communication is strongly beneficial for allocating resources to demanding tasks, but that distracting factors (such as the Stroop effect) can also produce interference across the hemispheres (Compton et al. 2000). Compton (2002) extended the idea of the interhemispheric cooperation advantage to the domain of faces, showing that identity and emotion comparisons are best carried out across the hemispheres. This demonstration lends support to the fact that both hemispheres are capable of processing social information, and that the net lateralization of social perception might be a consequence of other determinants. Recently, it has been demonstrated that interhemispheric transfer of social information (faces) can be influenced by verbal information (words) in the other hemisphere when the tasks to be accomplished on the two types of information differ (dual task; Bergert et al. 2006). Importantly, the direction of the interhemispheric transfer necessary to accomplish the tasks (left to right or right to left) had no effect, supporting the idea of an equally distributed representation of social information across the hemispheres. Surprisingly, Hirnstein et al. (2008) showed that the strength of hemispheric lateralization measured in subjects before carrying out a dual task demanding interhemispheric transfer (of faces and words), was inversely correlated with the success in managing the tasks, further confirming that equal hemispheric resources are preferable and pay more than lateralized resources. If the social brain is structurally bilateral but functionally right-sided, as results from much empirical evidence, the complementary left-sidedness of the Phil. Trans. R. Soc. B (2009)

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language function might have favoured inter- over intrahemispheric communication for all those situations in which non-verbal and linguistic verbal information must interact, such as in associating semantic information (i.e. names) to perceptual appearance, or more commonly in linguistic interactions. Moreover, interhemispheric cooperation has been shown to facilitate familiarity encoding through repeated experience (Mohr et al. 2002). Given the strength and stability of the left-hemispheric asymmetry of language processing, the advantages apparently conferred by interhemispheric transfer might have further supported the right-hemispheric asymmetry in social perception, together with the bootstrap effect of spatial attention, and the influence of an avoidant (conservative) default state. Lateralization of the social brain might thus be the net result of several forces, ultimately relevant for sociality and interaction that act concurrently on the right hemisphere. The authors acknowledge the financial support of the Commission of the European Communities, through the project EDCBNL (Evolution and Development of Cognitive, Behavioural and Neural Lateralization—2006/2009), within the framework of the specific research and technological development programme ‘Integrating and strengthening the European Research Area’ (initiative ‘What it means to be human’).

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Phil. Trans. R. Soc. B (2009) 364, 915–927 doi:10.1098/rstb.2008.0244 Published online 4 December 2008

Review

Epigenesis of behavioural lateralization in humans and other animals S. M. Schaafsma1, B. J. Riedstra1, K. A. Pfannkuche1, A. Bouma2 and T. G. G. Groothuis1,* 1

Department of Behavioural Biology, University of Groningen, PO Box 14, 9750 AA Haren, The Netherlands 2 Department of Clinical and Developmental Psychology, University of Groningen, Grote Kruisstraat 2-1, 9712 TS Groningen, The Netherlands Despite several decades of research, the epigenesis of behavioural and brain lateralization is still elusive, although its knowledge is important in understanding developmental plasticity, function and evolution of lateralization, and its relationship with developmental disorders. Over the last decades, it has become clear that behavioural lateralization is not restricted to humans, but a fundamental principle in the organization of behaviour in vertebrates. This has opened the possibility of extending descriptive studies on human lateralization with descriptive and experimental studies on other vertebrate species. In this review, we therefore explore the evidence for the role of genes and environment on behavioural lateralization in humans and other animals. First, we discuss the predominant genetic models for human handedness, and conclude that their explanatory power alone is not sufficient, leaving, together with ambiguous results from adoption studies and selection experiments in animals, ample opportunity for a role of environmental factors. Next, we discuss the potential influence of such factors, including perinatal asymmetrical perception induced by asymmetrical head position or parental care, and social modulation, both in humans and other vertebrates, presenting some evidence from our own work on the domestic chick. We conclude that both perinatal asymmetrical perception and later social modulation are likely candidates in influencing the degree or strength of lateralization in both humans and other vertebrates. However, in most cases unequivocal evidence for this is lacking and we will point out further avenues for research. Keywords: cerebral asymmetry; behavioural lateralization; development; handedness; plasticity; genetic models

1. INTRODUCTION Lateralization of brain and behaviour refers to the fact that the hemispheres of the brain differentially control behaviour. It is also known as hemispheric or cerebral asymmetry/specialization ( Vallortigara & Rogers 2005). At the behavioural level, it is often expressed in side biases for motor output, perception and information processing. For a long time, lateralization was considered unique to humans, but recently it has become clear that lateralization is a fundamental characteristic of the organization of brain and behaviour in vertebrates ( Vallortigara & Rogers 2005). Animal models open new and exciting perspectives for understanding the function and evolution and provide the opportunity to experimentally study the causes and consequences of lateralization. It is highly likely that such a fundamental aspect of brain and behaviour is under the control of genetic encoding. However, this does not exclude an important

role for environmental factors in the development and expression of lateralization. The debate whether behavioural and brain lateralization is caused by genetic or environmental factors has been long-standing (Annett 1978b; Laland et al. 1995; Provins 1997; Bishop 2001). Insight into the epigenesis of lateralization is highly relevant to understand both its evolution and possible constraints on plasticity as well as its adaptive flexibility and pathologies. By describing correlations between genetic information, environmental factors and the development or expression of lateralization, or by manipulating genetic and environmental factors using animal models, such insights can be acquired. Especially in the psychological literature, there is some consensus about the genetic heritability of lateralization. This is mainly based on the distribution and genetic modelling of handedness in humans. Handedness is heritable as it runs in families. Only 7.6 per cent of the children of two right-handed parents are left-handed. This percentage increases to 19.5 per cent if one of the parents is left-handed and to 54.5 per cent if both the parents are left-handed (Rife 1940). Heritability estimates vary between 0.23

* Author for correspondence ([email protected]). One contribution of 14 to a Theme Issue ‘Mechanisms and functions of brain and behavioural asymmetries’.

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and 0.66 (Denny & O’ Sullivan 2007). However, these data are no hard evidence for a genetic basis for the degree or direction of lateralization in itself. Traits may run in families owing to exposure to environmental factors that are more similar within than between families and other forms of non-genomic inheritance. Furthermore, heritability estimates can be influenced by these factors too, and can differ greatly depending on the environment in which the data were obtained. In this paper, we review the evidence for genetic and environmental influences on brain and especially behavioural lateralization in humans and other animal species. We focus on handedness since this might be more sensitive to (especially post-natal) environmental factors than lateralization of cognitive functions. We will first discuss the explanatory power of the existing genetic models for human handedness, including their strengths and weaknesses followed by what is known of genetic influences on lateralization in other animal species. Next, we will focus on environmental influences and review evidence for humans and other vertebrate species. Section 4 summarizes and synthesizes both sections and offers suggestions for future research. 2. EXPLANATORY POWER OF GENETIC MODELS One of the most common ways to investigate lateralization in humans is measuring handedness in combination with cerebral dominance for speech for which several genetic theories have been proposed. We will briefly describe the features of the main genetic models and the findings that challenge the hypothesis that handedness is determined genetically. For each of these potential problems, we will explore to what extent environmental factors may be an alternative to the genetic explanation. (a) Models of genetic transmission of handedness Although offspring of left-handed parents are more likely to be left-handed than offspring of right-handed parents, right-handed offspring can be produced by two left-handed parents (Rife 1940; McManus & Bryden 1992). The classical Mendelian approach incorporating a recessive allele for left-handedness (Jordan 1911) was therefore discarded. Subsequently, several other single-locus models were proposed. These models do not propose the existence of genes encoding for right- or left-handedness, but alleles for right-handedness (in combination with left-hemispheric dominance for language), and handedness (and language) becoming left- or rightlateralized by chance (Annett 1972, 1985, 2002; McManus 1985a, 1999; Klar 1996). This is to account for the finding that left-handers can be lateralized for language in either direction. In Annett’s theory, a normal distribution (arising from environmental influences) of the difference in skill between the two hands exists. A ‘right’ allele, which encodes for left-cerebral dominance for speech, shifts this distribution to the right (increasing right- over left-hand skills; figure 1a). An individual with low left-hand skills and high righthand skills is therefore likely to become right-handed (but not necessarily so if environmental factors, such as social pressures are high). By contrast, the right allele in Phil. Trans. R. Soc. B (2009)

(a)

LH = RH

LH > RH (b)

RH > LH (c)

3

2

3

2 1

1

1

1

2

LH

RH

LH

RH

Figure 1. Distribution of lateralization of handedness in proportion of individuals with a certain allele combination, according to three genetic models: (a) Annett’s model for hand skill, (b) McManus’ model and (c) Klar’s model, both for hand preference. 1, homozygote chance; 2, heterozygote; 3, homozygote for right allele. For details see text.

McManus’ and Klar’s models encodes directly for right-hand preference and left-cerebral dominance (figure 1b,c, respectively). In these two models, homozygous individuals for the ‘chance’ allele (no right allele present) will be left- or right-handed with language left- or right-lateralized all with equal probabilities, whereas in Annett’s model the skill distribution is centred around zero with approximately 50 per cent of these individuals better skilled with the right hand and 50 per cent with the left hand. Depending on the theory, heterozygotes become either right-handed (Klar 1996) or have an increased chance of becoming right-handed (Annett 1972, 1975; McManus 1985a, 1999). Homozygotes for the right allele will be right-handed according to McManus (1985a, 1999) and Klar (1996); in Annett’s model (1972, 1975), these individuals can still be left-handers, owing to the fact that the model describes a shift in the distribution of skill between the hands that still extends, albeit at low frequency, into the better left-hand skilled range. In contrast to the single-locus models, Levy & Nagylaki (1972) proposed a two-loci, four-allele model. One locus encodes for cerebral dominance for speech, the other for either contralateral or ipsilateral hand control relative to the dominant hemisphere. Yeo & Gangestad (1993) proposed that there is little or no direct genetic effect on handedness. A deviation from the moderate right-handed population mean is assumed to be caused by early polygenetic homozygosity causing developmental instability and extreme rightor left-handedness. (b) Challenges for the models (i) The twin paradox There are several general problems concerning the validity of these genetic models. The first emerged from twin studies. To disentangle genetic from

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Review. Epigenesis of lateralization environmental factors, many investigators compared monozygotic (MZ) with dizygotic (DZ) twins. MZ twins are more likely to be concordant concerning handedness than DZ twins (see Sicotte et al. (1999) for a meta-analysis), suggesting genetic inheritance. However, between 10 and 25 per cent of MZ twins are still discordant for handedness (Rife 1940; Bryden 1982; Sicotte et al. 1999). Several suggestions were made to fit this MZ twin discordance phenomenon into genetic models. Based on calculations concerning gene frequencies, Klar (1996) expected 18 per cent of the individuals in the population to be lacking the right gene and thus developing direction of lateralization by chance and this could explain the 18.3 per cent discordance in MZ twins found by Rife (1940). This is because lack of the fully penetrant right alleles in Klar’s model would induce the individual members of MZ twins to develop handedness at chance independently of each other. However, just as many concordant as discordant twins with this genotype are expected on the basis of change, so that 18 per cent of the genotype would lead to 9 per cent discordant and 9 per cent concordant twins. The theory can thus only account for half of the discordant MZ twins observed in the population. Furthermore, it cannot explain the higher incidence of left-handedness in twins compared with singletons (Sicotte et al. 1999). Similarly, both McManus (1985a, 1999) and Annett (1972, 1975) proposed that discordant MZ twins could be homozygotic for the chance allele. In addition, due to the additive nature of their models, discordant MZ twins can also be heterozygotic and in Annett’s model even homozygotic for the right allele. An addition to Annett’s (1978a) model assumes that the right shift caused by the right allele expresses weaker in those who are less mature at birth, and it was proposed that this is the case for twins relative to singletons. This decreased gene expression is assumed to be caused by disturbances of development during a sensitive prenatal period and would explain the high frequency of discordances and the increased incidence of left-handedness in twins compared with singletons (Sicotte et al. 1999, but see Medland et al. 2003). However, Orlebeke et al. (1996) argued that decreased maturation and the supposedly associated reduced expression of the right shift cannot account for increased left-handedness in twins because the firstborn twin is heavier and still more often left-handed than the second-born twin. The model of Levy & Nagylaki (1972) states that individuals with identical genotypes exhibit the same dominant hemisphere for language and the same hand preference, and attributes the prevalence of discordant MZ twins to environmental factors such as pathogenic and mirror-imaging effects (see below). (ii) Explanations of the twin paradox by environmental factors Clearly, solely genetic inheritance is unlikely to explain the twin paradox. Proposed environmental explanations for the high proportion of discordant MZ twins include the suggestion that the MZ twinning process itself is pathological (James 1983; Boklage 1987; Levin 1999; Sommer et al. 1999), and the Phil. Trans. R. Soc. B (2009)

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mirror-imaging theory that states that owing to relatively late splitting of the already slightly lateralized embryo, the members of MZ twins represent the ‘right’ and ‘left’ halves of the egg (Newman 1928; Stocks 1933). However, the finding that the incidence of left-handedness is not different between MZ and DZ twins is in contrast with these two hypotheses (Sicotte et al. 1999). A more viable explanation is that discordant MZ twins are affected by differential environmental factors such as differential perinatal stress that is associated with higher incidences of left-handedness (Soper & Satz 1984; see references in Sicotte et al. (1999) and Hopkins et al. (2000) for chimpanzees). For example, primiparae might be more exposed to birth stress (Orlebeke et al. 1996); twins might influence each other and twin members lay in differential position in the womb (Geschwind & Galaburda 1985), which could affect lateralization in twins. (iii) Sex differences The second challenge concerning the genetic models of handedness is that males show higher incidences of lefthandedness (11.6%) than females (8.6%) (McManus 2002). A simple autosomal genetic theory may thus not explain this sex difference. Annett addressed the sex differences in handedness similarly to the way she addressed the twin paradox: the right allele would express weaker in those who are less mature at birth (Annett 1978a; Davis & Annett 1994), which in this case means less in males than females. The parameters of the model thus changes depending on the sex and singleton/twin state of the offspring. A revision of the McManus’ model (1985a) incorporated a novel rare recessive allele located on the X chromosome, which suppresses the autosomal right allele (McManus & Bryden 1992). Higher incidences of left-handedness are then expected in males because males, having only one X chromosome, need only one of this rare recessive allele, whereas females need two. Several other sex-chromosomal linked models have been proposed (Crow 1993, 1995; Jones & Martin 2000). Laval et al. (1998) found evidence for a quantitative trait locus (QTL) on the X chromosome for linkage to relative hand skill. Although this was partly supported by a genome-wide scan, more important linkages to relative hand skill were found on other chromosomes ( Francks et al. 2002). Another genome-wide analysis found no evidence for the presence of QTL linked to handedness on the X chromosome (Van Agtmael et al. 2003). These studies suggest that handedness has a genetic component, but that a single-gene model is unlikely and that the genetic factor influencing handedness is most probably multifactorial. However, it is conceivable that these multiple genes may inherit as a singlelocus trait. This is for example the case of co-adapted gene complexes that are linked due to their position on the same arm of an inversed part of a chromosome ( Kamping & Van Delden 1999). In the case of genes being distributed over several chromosomes, inheritance as a single locus is, however, not conceivable. However, in that case it may account

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for the random factor postulated to determine lateralization, but not for the dominant allele that would induce right-handedness. Neurodevelopmental disorders are, just as lefthandedness, more common in males. Yeo & Gangestad (1993) proposed that males show higher degrees of polygenetic homozygosity, inducing developmental instability leading to increased left-handedness. They however do not explain the cause of the supposedly increased homozygosity in males. The incidence of left-handedness is higher when the mother is left-handed and the father is not, than when the father is left-handed and the mother is not (Falek 1959; Porac & Coren 1981; McManus 1991; Annett 1994; Mckeever 2000). This either suggests a form of genomic imprinting or parental effects. Annett addressed this problem based on a Carter (1961) effect. However, the Carter effect can occur when an inherited characteristic is genetically multifactorial, whereas Annett’s model is not. As mentioned earlier, McManus & Bryden (1992) suggested an X-linked recessive gene that can suppress the autosomal right gene. This can explain not only the differences in incidences of left-handedness between males and females, but also this maternal effect. A female carrying two copies of this allele should then produce 100 per cent left-handed sons. Unfortunately, this prediction cannot be tested because the locus of this proposed gene is unknown, if it exists at all. Klar (1996) did not explain sex differences by genetic factors but attributes them and the maternal effects to environmental factors, such as differential sensitivity to social pressures (see below). (iv) Explanations of the sex difference and maternal effects by environmental factors Several environmental factors may explain the higher incidence of left-handedness in males. First, men and women may differ in their sensitivity to social pressures. Females more often report to successfully change hand preference owing to social pressures. Furthermore, both males and females may be more under maternal than paternal social pressures, for example owing to more mother–offspring than father–offspring interactions (Morgan & Corballis 1978; Porac et al. 1986). In addition, as suggested by Falek (1959), lefthanded fathers could also be more aware of the disadvantages concerning employment of left-handers than left-handed mothers. This could lead to higher social pressures when the father is left-handed than when the mother is. The offspring of left-handed fathers could thus more often conform to righthandedness. Additionally, it has frequently been suggested that sex differences in lateralization may be due to differential exposure to gonadal steroid hormones (reviewed in Pfannkuche et al. 2009). (v) Inconsistencies with data McManus (1985b) showed that a symmetrical bimodal model can describe the handedness skill distribution data at least for some tasks better than the right-shift model of Annett. The model of Klar also faces a problem. One of the predictions of Klar’s (1996) model Phil. Trans. R. Soc. B (2009)

is that right-cerebral dominance for speech is expected in 50 per cent of left-handed individuals (those lacking right alleles). However, several functional magnetic resonance imaging (fMRI ) studies in non-pathological left-handers are in conflict with this (Jansen et al. 2007). Furthermore, the prediction that left-handed parents produce 50 per cent left-handed children does not hold (Annett 2008). The two-loci model of Levy & Nagylaki (1972) is inconsistent with the observation that left-handers tend towards ambilaterality, whereas right-handers show almost complete specialization of the hemispheres (Goodglass & Quadfasel 1954; Subirana 1964). If full expression of the alleles occurs only when a dominant allele is present at both loci, this problem is solved. This is however a post hoc addition to the model and should be tested in a new dataset. (c) Evidence from animal models To validate the models and to disentangle between genetic and environmental factors influencing handedness, experimental studies should be performed. Owing to obvious ethical reasons, such studies can only be carried out in non-human animals. (i) Descriptive evidence In chimpanzees, handedness was measured by means of a tube task in which peanut butter must be obtained from a tube using one hand. Of the offspring of righthanded mothers 86 per cent were right-handed, but only in second to fifth offspring within a litter in which pregnancies have relatively low developmental instability. In the other offspring, only 46 per cent born to right-handed mothers were right-handed indicating both a heritable and environmental effect (Hopkins et al. 2001). In another study in wild chimpanzees, both maternal-offspring and maternal half-siblings hand preferences were significantly associated and concordance rates in mother–offspring and between maternal half-sibling were higher than chance (Lonsdorf & Hopkins 2005). Annett (2006) suggested that chimpanzees show a genetically determined right shift, although the magnitude of expression was significantly less than that in humans. Although her model may perhaps fit the data, this suggestion is in contrast with her idea that lateralization in handedness has evolved in consort with that for language, since chimpanzees lack the capacity for the latter. Alternatively, the heritable component can be explained by a non-genetical maternal effect (see §3c). (ii) Experimental evidence An attempt to selectively breed mice for the direction of pawedness failed, although selective breeding attempts for the degree of pawedness were successful (see Collins (1985) for a review). Variation within the latter strains was still present, suggesting environmental influences. Collins et al. (1993) showed that differences in total heterozygosity did not explain the difference in degree between the strains as was originally proposed by McManus (1992). We would like to point out that conclusions about the genetic background of a trait based on selective breeding experiments without cross-fostering the

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Review. Epigenesis of lateralization offspring should be made with caution. These experiments are not capable of distinguishing between genetic and environmental effects (such as learning). Moreover, in order to rule out any prenatal effects (such as hormones) on lateralization, zygote translocation is necessary. An artificial selection study in the poeciliid fish Girardinus falcatus on the preference to investigate certain stimuli with either the left or right eye estimated the heritability of degree and direction greater than 0.5 (Bisazza et al. 2000). However, after the first generation, the response to selection ceased. Some potential explanations for the latter finding were suggested in which fish showing the lateralization opposite to the one selected for have an advantage. For example, fish of such opposite lateralization may surprise conspecifics in their approach from the other side, leading to more successful forced copulations or more successful predation (Bisazza et al. 2007). Hori (1993) investigated the inheritance pattern of lateralization in the fish Perissodus microlepis. These fish eat scales from the flanks of prey fish by attacking them from either the left or right side and have therefore a slightly asymmetrical mouth opening, directed to, respectively, the right or left. He suggested that this ‘mouthedness’ is inherited in a Mendelian fashion with right mouthedness being dominant. This is, however, not consistent with the finding that two left-mouthed parents can produce up to 25 per cent right-mouthed offspring. Later, Hori et al. (2007) adjusted the explanation by suggesting that the right-mouthed allele is lethal when homozygous. However, the data of Hori (1993) suggested that homozygous right-mouthed fish are present in the population. The inheritance pattern of this trait thus remains unclear. (d) In conclusion Although several elegant genetic models for lateralization of handedness and language fit well the majority of the distribution and inheritance data by assuming certain rules for genetic inheritance, they require several ad hoc additions for explaining deviations from the main pattern. These additions are not always fully supported by independent data. This may either suggest that the specific deviations, such as the twin, sex and maternal effects, may be best explained by environmental factors, for which indeed some suggestions have been made in the literature; or it may even suggest that the basic assumptions of the models are not correct, as has been discussed earlier. The latter is supported by the fact that the few genome scans performed concerning handedness could not find evidence for a simple genetic model, but suggest a more complex interplay between different genes involved. In any case, the models do not rule out an important role for environmental influences on the development of lateralization. Interestingly, models such as those from Annett (1972, 1985) and Klar (1996) explicitly need environmental factors to fit the observed incidences of left-handedness. Few attempts to identify the potential genetic background of handedness in non-human animals have been performed. So far, the results are inconsistent with each other and with the human models Phil. Trans. R. Soc. B (2009)

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proposed, although Annett (2006) suggested some resemblance between humans and chimpanzees in the genetic inheritance of hand-use lateralization. No genetic models for lateralization in animals have been built and human models have hardly been tested in animals. More animal studies are crucially needed to investigate the inheritance of laterality in animals. This could shed light on its evolution and generate hypotheses for its inheritance in humans. 3. POTENTIAL ENVIRONMENTAL FACTORS Section 2 indicates that there is ample opportunity for environmental factors to affect the development of behavioural lateralization. In this section, we will discuss these factors in more detail, focusing on the potential effects of social modulation such as social pressures and parental effects (including cradling), as well as asymmetric input of stimuli. Additionally, the organizational and activational effects of steroid hormones have been suggested to be relevant for lateralization. This topic will be discussed, together with sex differences in lateralization, in a separate paper where we present the results of several meta-analyses (Pfannkuche et al. 2009). We start with a short description of development of behavioural lateralization in order to establish when, and to what extent, it gradually develops. This may indicate to what degree and in which stage in development there is scope for environmental effects to act. We will not focus on pathological development. It is well known that the incidence of left-handedness is positively related to behavioural disorders, birth stress and low birth weight (Bakan et al. 1973; Coren 1993 for a review), and this is reviewed in another contribution to this issue (Llaurens et al. 2009). (a) Early development of handedness Human foetuses prefer to use the right hand for thumb sucking already in the third trimester independent of lying position in the womb (Hepper et al. 1991). Thumb-sucking behaviour, but no other prenatal hand–mouth contacts (de Vries et al. 2001), is a good predictor for handedness later in life (Hepper et al. 2005). Similarly, prenatal head position shortly before birth correlates with the preferred head position of neonates in a supine position, which again correlates with handedness in reaching tasks 12–74 weeks postpartum (see §3b(ii)). Although these data suggest that predispositions for handedness are already present early in ontogeny, they do not exclude a role for environmental factors affecting lateralization later in life. In fact, prenatal influences may be very important (see below and, e.g. Pfannkuche et al. 2009). In addition, during early childhood, handedness still shows considerable fluctuations (Gesell & Ames 1947; Goldfield & Michel 1986; Corbetta et al. 2006; Michel et al. 2006). Not until the age of 4 years righthanded behaviour predominates and unilateral hand preference is well established at the age of 9 (Gesell & Ames 1947). Therefore, the data suggest that although predispositions for lateralization are present already early in ontogeny, handedness is still open to environmental influences later in life, much as early

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predispositions for motor patterns (courtship postures and calls) and cognition (imprinting on the mother) in birds can still be modified in later life ( Johnson et al. 1985; Groothuis 1993). (b) Environmental factors: asymmetric input of stimuli (i) Head position in humans A few weeks before birth, the foetus’ head position becomes fixed in utero. Of the 97 per cent of foetuses that lie in a cephalic position, two-thirds lie with their right ear and one-third with the left ear facing out (Michel & Goodwin 1979; Previc 1991 and references therein). This position correlates strongly with the head position of the neonates that lie in a supine position (Michel & Goodwin 1979). The supine head orientation affects the experience with the right and left hand. Previc (1991) has argued that this 2 : 1 ratio is more characteristic for many behavioural asymmetries in human and non-human populations than the 9 : 1 ratio typical for human handedness. He proposes that these asymmetries originate from an asymmetrical prenatal development of the ear and labyrinth. Speech is then lateralized through a slight right ear advantage in the mid-frequency sound range. This advantage is derived from an asymmetrical craniofacial development. Vestibular lateralization, which is linked to motor behaviour, can be traced back to the asymmetrical head position of the foetus during the final trimester. This asymmetry would come about through the differential experience of the left and right vestibules in the final trimester caused by motoric movements of the mother, perhaps creating a pathway for maternal effects discussed earlier in §2. Most (70–80%) neonates prefer to turn their head to the right side when they are in a supine position (Michel & Goodwin 1979; Michel 1981; Konishi et al. 1986; Previc 1991; Ronnqvist et al. 1998; Ronnqvist & Hopkins 2000; Damerose & Vauclair 2002). This preference appears at the second day of life, at which time they are also more reactive to sounds on the righthand side ( Turkewitz et al. 1966). This tendency diminishes in the course of development. The supposed effects on functional motor lateralities have therefore been argued to be only transient (Konishi et al. 1986). However, the amount of spontaneous visual experience with each hand, which is dominated by head position, predicts which hand predominated in visually elicited reaching at 12 weeks (Coryell & Michel 1978). Moreover, as already mentioned, head orientation in a supine position correlates with handedness during reaching in the period 12–74 weeks postpartum (Kuo & Shen 1937). Inducing differential experience with hands during early development has been a worldwide natural experiment. Across the globe, there have been large-scale changes in placing babies in a supine or prone position in their cribs, due to change in medical advice. As mentioned, in the supine position, there is a natural bias towards right-hand use, whereas in the prone position there is no expression of preference. This is because of the parental strategy of alternating the baby’s head to the left and right in order to avoid asymmetrical skull development, and because of the baby’s inability to Phil. Trans. R. Soc. B (2009)

change the head position in the first months by itself. Interestingly, there was an increase in non-right-handed toddlers (at 18 months of age) that were reared in the prone position (Konishi et al. 1987). This suggests that head position is causative to handedness. We are currently conducting a study in The Netherlands to see whether we can replicate this finding. (ii) Head position in other animal species Except for birds, it is unknown whether head position is related to lateralization of brain and behaviour in nonhuman species. Owing to the asymmetrical position of the avian head in the egg, one eye is positioned against the body, whereas the other lies against the eggshell. Light can penetrate the shell and induce brain lateralization (see below). However, one should realize that the indirect effect of head position on lateralization via its effect on light input has not been disentangled from a direct effect of head position, irrespective of light exposure. Although avian models are often used to study the development of lateralization, quantitative data support the general idea that bird embryos are folded in the egg in such a way that almost all of them receive light with the right eye due to their head position (Oppenheim 1973) are surprisingly scarce, and some data suggest much more variation (Riedstra 2003). If the variation of head position is substantial, this may severely influence the outcome of experiments manipulating embryonic light exposure. We found that fMRI techniques can be successfully used to identify the turning position in eggs without exposing them to light (B. Riedstra 2007, personal observation). (iii) Asymmetric light input in birds Many bird species (galliformes, pigeons, parrots, raptors and songbirds) show behavioural lateralization in visually guided behaviours (e.g. Andrew & Brennan 1983; ten Cate et al. 1990; ten Cate 1991; Rogers 1996; Alonso 1998; Manns & Gunturkun 1999; Bobbo et al. 2002; Templeton & Gonzalez 2004), motor patterns (Rogers & Workman 1993; Goller & Suthers 1995; Csermely 2004) and cognitive functions (Nottebohm 1970, 1971; Clayton & Krebs 1994, 1995; Floody & Arnold 1997; Gagliardo et al. 2001; Nottelmann et al. 2002). Lateralization of visually guided behaviours is influenced by asymmetrical light exposure in the period shortly before hatching. Light reaching the eye through the eggshell induces growth of the visual projections from the exposed eye to the contralateral hemisphere and induces functional lateralization (Rogers 1996). Hemispheric control of attack and copulation becomes dominant in the hemisphere contralateral of the lightexposed eye, both when exposing the naturally exposed eye or by experimentally exposing the normally occluded eye to light (Rogers 1990). Chicks receiving no light also become lateralized but the direction of lateralization is unpredictable ( Rogers 1982). In addition, dark-incubated chicks become less strongly lateralized and have poorer performances in dual tasks (Dharmaretnam & Rogers 2005). Unfortunately, further studies addressing the extent and nature of lateralization in dark-incubated chicks are lacking, although these could reveal to what extent other factors than light guide the development of lateralization.

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Review. Epigenesis of lateralization It is not our intention here to review the literature on light-induced lateralization in birds since excellent reviews on this topic are available (e.g. Rogers 1996). However, we stress that there is no evidence showing that asymmetrical light exposure during the last phase of incubation is really the default situation in nature. Only one study detailed the amount of light exposure to eggs during the incubation period and concluded that this was sufficient to induce lateralization (Buschmann et al. 2006). As there is large variation in eggshell properties, nest sites determining light availability and incubation patterns among avian species, the generality is questionable. Moreover, the adaptive advantage of lateralization has recently been questioned too (Hirnstein et al. 2008). In addition, only one study has addressed the question of whether manipulation of light exposure during incubation has consequences in adulthood (Manns & Gunturkun 1999). This is very relevant as the effect of early light exposure on asymmetrical visual pathways seem to diminish with age in the chicken (Rogers 1995). Since we are here concerned with the mechanisms of development of lateralization, and not its functional relevance, this will not be a topic of this paper. Finally, light has pleiotropic effects that may confound experiments that manipulate embryonic light exposure. Prenatal light exposure also increases growth rate and hatching time but reduces hatchling weight (Adam & Dimond 1971; Evans & Evans 1999; Shafey & Al-Mohsen 2002; Shafey 2004). If these factors affect behavioural and brain lateralization, as birth weight and perinatal stress in humans, then light may affect lateralization via other pathways than asymmetrical light input only. (iv) Cradling in humans Right-handed and dextro-cordius mothers prefer to hold infants on the left arm (left-handed females have not been reported for right-side-holding biases, but no sufficient data exist; Donnot 2007), whereas males have no preference (Damerose & Vauclair 2002). Cradling by mothers thus induces asymmetrical auditive and visual input, head and arm position, potentially influencing development of lateralization. However, left-handed cradling may actually restrict right-arm movements of the baby and thereby perhaps development of right-handedness. Furthermore, although there is some evidence that the emotional hemispheric specialization of the holder predicts holding bias in left-handed students, but not in left-handed mothers (Donnot 2007), the effect on the baby’s lateralization is not yet known. There is also some evidence that the baby’s head-turning preference modulates the side preference of adult handling, but not the other way around (Bundy 1979). In conclusion, evidence for an influence on lateralization of the baby is lacking. Longitudinal studies on children until their hand preference are stable in relation to cradling experience, for example in societies that differ in cradling behaviour, may be of help. This may perhaps also explain part of the difference in the frequency of left-handedness observed among societies (see also §3e). Phil. Trans. R. Soc. B (2009)

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(c) Environmental factors: adoption in humans and animals In an attempt to disentangle between genetic and environmental factors determining handedness, investigators have focused on adoption studies. Surprisingly, parent–offspring correlations concerning strength and direction of hand preference were absent in both adopted and non-adopted children (Rice et al. 1984), perhaps due to the very young age of the children investigated (12–24 months). Two other studies showed different results. Hicks & Kinsbourne (1976) found that hand preferences of students significantly correlated with the writing hand of their biological parent, but not with that of their step-parent. Although the authors statistically controlled for the time spent living with the step-parent, it is most likely that the hand preference was already established in the students long before the step-parent could influence this preference, since the mean age of the students when the step-parent moved in was approximately 13 years of age (s.d.Z3.12). However, a similar outcome was found in a study in which all adopted children were taken into the participating families before the age of 1 (CarterSaltzman 1980). However, the possibility that lateralization and handedness are determined before that age, although not yet fully expressed, is still conceivable (see §§ 2a and 3b(i)(iv) and Pfannkuche et al. 2009). To our knowledge, only one cross-fostering study on handedness, measured by means of a tube task with peanut butter (see above), has been conducted in non-human animals. In cross-fostered chimpanzee siblings, the concordance rate in hand preference was not greater than chance, whereas this was the case for siblings that were reared together, strongly suggesting that the underlying mechanisms controlling handedness are heritable, but not genetic (Hopkins 1999). In conclusion, early cross-fostering studies suggest a strong heritable component, and the chimpanzee studies indicate that this may be a non-genetic effect. (d) Changes with age In humans, cross-sectional studies reveal that righthandedness increases with age ( Fleminger et al. 1977; Smart et al. 1980; Brackenridge 1981; Brito et al. 1985; Beukelaar & Kroonenberg 1986; Lansky et al. 1988; Dellatolas et al. 1991; Gilbert & Wysocki 1992; Iwasaki et al. 1995; De Agostini et al. 1997; Ellis et al. 1998; McManus 2002). Several hypotheses have been postulated to explain this phenomenon. (i) Since lefthandedness has been correlated to lower survival, this might result in the decrease in the incidence of lefthandedness among elderly people (Halpern & Coren 1988; Coren 1989; Coren & Halpern 1991). (ii) Social pressures against left-handedness over the years declined, so that younger people are less restricted and therefore show higher incidences of left-handedness (Hildreth 1949; Levy 1974; Brackenridge 1981; Leiber & Axelrod 1981 and references in Harris 1990). Furthermore, with increasing age, the number of social contacts increase, which may enhance the probability to switch towards right-handedness. (iii) Humans live in a right-biased world. Tools are made for right-handed individuals and this will in time cause a shift towards dextrality in left-handed individuals and strengthens

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right-handedness in right-handers (Porac & Coren 1981). (iv) Cerebral dominance development is a continuous process that evolves throughout life and causes the increase in right-handedness with age (Brown & Jaffe 1975; Fleminger et al. 1977). (v) An information bias in handedness questionnaires has been proposed, resulting in a change in the categorization of handedness (Fleminger et al. 1977). This does not seem likely as most studies investigating the effect of age on handedness are cohort studies. To distinguish between these hypotheses, longitudinal studies that investigate the development of lateralization within the individuals are clearly needed. (e) Environmental factors: social pressures (i) Evidence in humans Although right-handers outnumber left-handers in all societies studied, differences in the percentages of right-handedness have been observed among different societies: sinistrality being, in general, higher in Western societies than in other societies (Iwasaki (2000) and references therein). These differences could be caused either by environmental factors such as increased social pressures in some societies, or by a decreased number of the proposed right allele in the gene pool of certain populations. McManus (2002) hypothesized that it was possible to disentangle between these genetic and environmental factors by investigating how strongly handedness runs in families. He assumed that if social pressures to be right-handed are strong, left-handedness will run less strongly in families. This assumption is not necessarily right as differences in social pressures may not be equal for all individuals and vary between families. Porac et al. (1986) found some evidence for this. He investigated social pressures within families by assessing the amount of attempts to switch handedness: males from righthanded parents were more likely to switch from left- to right-hand use than males from one or two left-handed parents. McManus’ conclusion that the decreased incidence of left-handedness in non-Western populations is due to a decreased incidence of the right allele might be false as it can also be explained by differential social pressures between families. The hypothesis that social pressures can decrease the incidence of left-handedness is further strengthened by the finding of Dawson (1977) who found that more conforming agriculturalists measured by means of the Asch Conformity Test show low incidences of left-handedness (0.6–3.4%), whereas permissive, nonconforming populations show extensively higher incidences of left-handedness (11.3–10.5%). (ii) Evidence for other animal species To our knowledge, there are no studies that have tested the possibility of social modulation affecting behavioural lateralization in non-human animals. However, we recently found some evidence for this possibility. Eggs of laying hens (Gallus gallus domesticus) were incubated under standard conditions. The chicks were housed in 10 groups of 6 (G1) individuals in the same room. At day 4–6, post-hatching behavioural lateralization was assessed by detour tests. Chicks had to detour a see-through barrier to reach either a group of Phil. Trans. R. Soc. B (2009)

1.0 mealworm detour score

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0.8 0.6 0.4 0.2 0 groups

Figure 2. Detour scores: each circle represents the group mean (Cs.e.) of six chicks, which round a barrier to reach a mealworm. Variation in lateralization was smaller within than between groups (FZ12.66, p!0.001) indicating that lateralization was modulated by post-hatching social interactions.

unknown conspecifics or a mealworm. The side used to detour the barrier was scored in two bouts of five consecutive trials on two consecutive days for both stimuli. Preferred eye use for each stimulus, determined by hemispheric organization, is thought to determine the side of rounding the barrier (Vallortigara et al. 1999). Individuals showed consistent choices between tests (r 2Z0.69, p!0.0001, nZ58), with most individuals preferring to turn right in both tests. This suggests that approaching food and unknown conspecifics are functionally located in the same, predominantly right hemisphere. Interestingly, the variation in lateralization was smaller within groups than among groups (figure 2; FZ12.66, p!0.001). This is the first evidence suggesting that lateralization of visually guided behaviours can be modulated by post-hatching social interactions. This could ensure the hypothesized benefits of a group bias in lateralization, as suggested by Vallortigara & Rogers (2005). However, since the experiment was not designed for testing this hypothesis, this post hoc finding is currently being replicated. Furthermore, Collins (1968) conducted an experiment in which the effects of social pressures were altered. He found that in a non-biased environment (no pressure) in which food could be obtained with either paw equally well, mice had a side preference, but no population bias was observed. When the feeding tube was placed against the right wall in such a way that obtaining food was easier using the right than the left paw (mimicking the right-biased world of humans), 90 per cent of the mice showed a right paw preference (Collins 1975). This result was attributed to a change in paw use in weakly left-lateralized individuals. If this is the case, the direction and degree of handedness are not independent factors. Collins suggested that righthandedness might work similarly in humans. Collins et al. (1993) concluded that the observed differences found in the heritability between degree and direction in humans and mice should not necessarily lead to different underlying mechanisms. In conclusion, evidence exists for social modulation of handedness in both humans and other animal species.

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Review. Epigenesis of lateralization 4. DISCUSSION The long-standing debate about the question of whether lateralization of brain and behaviour is caused by genes or environment actually focuses on a wrong question. Modern developmental biology has recognized for decades that the phenotype develops under the continuous interaction between genetic and environmental influences and that both are indispensable for development. Moreover, in the end product of this interactive developmental process, both factors are impossible to disentangle. Therefore, by demonstrating the influence of either genetic or environmental components, we cannot conclude anything conclusive about the contribution of the other component on the developmental process. However, correlative and experimental studies can demonstrate which factors are important, and how they interact. Unfortunately, gene–environment interactions have not been explicitly studied, but for instance the difference in lateralization between light- and dark-reared birds in which the latter still show some degree of it (Rogers 1995) does suggest such an interaction. Moreover, owing to the historical focus on humans, descriptive studies outnumber experimental studies by far. We hope that this review will stimulate researchers to bring the field more into balance. It has been questioned to what extent lateralization in humans and other vertebrates may be comparable. We agree that it is likely that humans may have speciesspecific adaptations in their lateralized behaviour. This may explain the strong human lateralization in handedness due to selection on efficient tool use or language (Corballis 2003). Nevertheless, we strongly believe that lateralization of brain and behaviour, being such a fundamental aspect of the organization in vertebrates, must share common principles for humans and other vertebrates, similarly to the blueprint for vertebrate skeleton, physiology, brain and behaviour. Evidence for a genetic basis of lateralization in humans is mainly based on demographic and heritability studies of handedness, and the explanatory power of genetic models. As argued earlier, the evidence from demographic and heritability studies does not disentangle genetic from environmental factors such as parental effects, and even early adoption studies cannot circumvent prenatal maternal effects. Evidence from the modelling approach is not yet fully convincing either. Despite their elegance and clever design, the models have limited explanatory power and are not backed up by the data from human genome scans, which suggest a multi-genetic control of human lateralization. Unfortunately, data from animal experiments concerning the genetics of lateralization are also inconclusive. Although the few selection experiments in animals give some support for genomic heritability, the results are ambiguous and the studies not always properly conducted. Although some data suggest exciting possibilities, evidence for environmental influences on lateralization is ambiguous too. Descriptive data that show changes with age are not conclusive for environmental effects since they may be genetically encoded. Moreover, in order to assess developmental principles of lateralization, longitudinal studies are needed. In humans, Phil. Trans. R. Soc. B (2009)

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the available data suggest that although predispositions for handedness may be present already prenatally and predictive for later lateralization, handedness can to some extend still change in later life. The correlation between early developmental disorders and left-handedness suggests a role for early environmental modulation, but does not tell us necessarily much about the environmental effects on undisturbed development. The possibility that in humans, left-handers are in fact a heterogeneous group of pathological and ‘normal’ left-handers complicates research to a large extent. Actually, the genetic models suggest that also the right-handers are a heterogeneous group consisting of both genetically right- and left-handers. Interpretation is further complicated by the use of different criteria to categorize handedness. Finally, more attention should be paid to other forms of behavioural lateralization, which may not always correlate with handedness, and may be more similar to lateralization indices in animals. Unfortunately, in animals even less is known about typical development and to what extent early manipulations still exert their effect in adulthood. Such long-term studies take time, but are very relevant for further progress in the field. Five lines of evidence suggest a role for environmental modulation of lateralized behaviour. First, the finding that rearing position of the neonate seems to affect handedness, based on a natural experiment whereby mothers were instructed differently to keep their babies in a supine or prone position (Konishi et al. 1987). It opens an exciting perspective, although we cannot rule out a confounding effect of time here and the study needs replication. Second, the study of crossfostered chimpanzees (Hopkins 1999) indicated strong rearing effects, although this is in contrast with a study of early cross-fostering in humans (Carter-Saltzman 1980). Third, there is evidence that prenatal exposure to steroid hormones affects lateralization in humans (Pfannkuche et al. 2009). Fourth, our data on social modulation in the domestic chick warrant further research in this direction. Fifth, the effect of asymmetrical light input caused by the asymmetrical position of the head in bird embryos has now become a classical example of how early environmental factors can influence lateralization. This is consistent with the suggestion that pre- and post-natal head position may affect lateralization by asymmetrical perception in humans. Nevertheless, further studies documenting head position and light input in bird eggs and their long-term effects are necessary for interpreting the findings from a functional perspective. Furthermore, by manipulating head position together with light input, the influence of both factors can be disentangled. In conclusion, there is evidence for both genes and environment to affect the development of behavioural lateralization, but evidence for both and especially their interaction is surprisingly incomplete. With the identification of the human genome, and the use of animal models, we believe that substantial progress can be made in the near future. For example, by setting up selection lines for differences in strength or direction in lateralization and exposing them to different environmental influences such as prenatal

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hormone exposure, asymmetrical stimulus input, or exposure to conspecifics that are lateralized in only one direction, gene–environment interactions can be studied experimentally. All experiments were carried out under license of the animal experiments committee of the University of Groningen (DECnr 4519). We thank Reint Geuze and two anonymous referees for their helpful suggestions that improved the manuscript, and Mirre Simons and Gert Stulp for their help with the chick experiment on social modulation. The paper was written with the help of an EU grant (EDCBNL network) to T.G.G.G.

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Ronnqvist, L., Hopkins, B., Van Emmerik, R. & de Groot, L. 1998 Lateral biases in head turning and Moro response in the human newborn: are they both vestibular in origin? Dev. Psychobiol., 339–349. (doi:10.1002/(SICI )10982302(199812)33:4!339::AID-DEV5O3.0.CO;2-R) Shafey, T. M. 2004 Effect of lighted incubation on embryonic growth and hatchability performance of two strains of layer breeder eggs. Br. Poult. Sci. 45, 223–229. (doi:10. 1080/00071660410001715821) Shafey, T. M. & Al-Mohsen, T. H. 2002 Embryonic growth, hatching time and hatchability performance of meat breeder eggs incubated under continuous green light. Asian–Austr. J. Anim. Sci. 15, 1702–1707. Sicotte, N. L., Woods, R. P. & Mazziotta, J. C. 1999 Handedness in twins: a meta-analysis. Laterality 4, 265–286. (doi:10.1080/135765099396980) Smart, J. L., Jeffery, C. & Richards, B. 1980 A retrospective study of the relationship between birth history and handedness at 6 years. Early Hum. Dev. 4, 79–88. (doi:10.1016/0378-3782(80)90011-0) Sommer, I. E. C., Ramsey, N. F., Bouma, A. & Kahn, R. S. 1999 Cerebral mirror-imaging in a monozygotic twin. Lancet 354, 1445–1446. (doi:10.1016/S0140-6736(99)04130-6) Soper, H. V. & Satz, P. 1984 Pathological left-handedness and ambiguous handedness: a new explanatory model. Neuropsychologia 22, 511–515. (doi:10.1016/0028-3932(84) 90046-0) Stocks, P. 1933 A biometric investigation of twins and their brothers and sisters. Ann. Eugen. 5, 1–55. Subirana, A. 1964 The relationship between handedness and cerebral dominance. J. Neurol. 4, 215–234. Templeton, J. J. & Gonzalez, D. P. 2004 Reverse lateralization of visual discriminative abilities in the European starling. Anim. Behav. 76, 783–788. (doi:10.1016/j.anbehav.2003 .04.011) ten Cate, C. 1991 Population lateralization in zebra finch courtship: a re-assessment. Anim. Behav. 41, 900–901. (doi:10.1016/S0003-3472(05)80358-6) ten Cate, C., Baauw, A., Ballintijn, M. R., Majoor, B. & Van der Horst, I. 1990 Lateralization of orientation in sexually active zebra finches: eye use asymmetry or locomotor bias? Anim. Behav. 39, 992–995. (doi:10. 1016/S0003-3472(05)80968-6) Turkewitz, G., Moreau, T. & Birch, H. G. 1966 Head position and receptor organization in the human neonate. J. Exp. Child Psychol. 4, 169–177. (doi:10.1016/00220965(66)90017-8) Vallortigara, G. & Rogers, L. J. 2005 Survival with an asymmetrical brain: advantages and disadvantages of cerebral lateralization. Behav. Brain Sci. 28, 575–633. Vallortigara, G., Regolin, L. & Pagni, P. 1999 Detour behaviour, imprinting and visual lateralization in the domestic chick. Cogn. Brain Res. 7, 307–320. (doi:10. 1016/S0926-6410(98)00033-0) Van Agtmael, T., Forrest, S. M., Del-Favero, J., Van Broeckhoven, C. & Williamson, R. 2003 Parametric and nonparametric genome scan analyses for human handedness. Eur. J. Hum. Genet. 11, 779–783. (doi:10.1038/ sj.ejhg.5201048) Yeo, R. A. & Gangestad, S. W. 1993 Developmental origins of variation in human hand preference. Genetica 89, 281–296. (doi:10.1007/BF02424521)

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Phil. Trans. R. Soc. B (2009) 364, 929–942 doi:10.1098/rstb.2008.0282 Published online 4 December 2008

Review

Does testosterone affect lateralization of brain and behaviour? A meta-analysis in humans and other animal species Kristina A. Pfannkuche1, Anke Bouma2 and Ton G. G. Groothuis1,* 1

Behavioural Biology, University of Groningen, Kerklaan 30, 9750 AA Haren, The Netherlands 2 Clinical and Developmental Psychology, University of Groningen, Grote Kruisstraat 2/1, 9712 TS Groningen, The Netherlands

Lateralization of brain and behaviour has been the topic of research for many years in neuropsychology, but the factors guiding its development remain elusive. Based on sex differences in human lateralization, four hypotheses have been postulated that suggest a role for androgens, specifically testosterone. With the discovery that lateralization is a fundamental principle in the organization of brain and behaviour among vertebrates, it has now become possible to experimentally test such hypotheses in animal models. The use of different taxa, humans, other mammalian species and birds (with oestradiol and not testosterone involved in sexual differentiation in birds) facilitates to differentiate between the hypotheses. We used meta-analyses for analysing papers that provided sufficient information, and a semi-quantitative approach based on all relevant studies that we extracted from the literature. We tested the predictions of these hypotheses regarding strength and direction of lateralization for motor output, language and visuospatial cognition in these three taxa. We tested for sex differences and early organizational effects of testosterone (both correlative and experimental studies). We found sex differences in the direction of lateralization for non-human mammals (motor biases similar to humans) and in direction and strength in birds (visual cognitive tasks). However, the prediction that prenatal testosterone exposure affects the direction of lateralization was not supported for humans. In birds and non-human mammals, opposite trends were found, with the effect in non-human mammals being opposite to the expectation based on sex differences. None of the four hypotheses was sufficiently supported and more studies, testing a wider array of functions in different taxa while reporting the data more completely are needed. Keywords: lateralization; testosterone; meta-analysis; hemispheric dominance; brain asymmetry; development

1. INTRODUCTION Lateralization of brain and behaviour refers to the fact that the two hemispheres of the brain differ in their control of a wide array of functions, while they each predominantly affect the contralateral side of the body. This lateralization has long been thought to exist in humans only, and therefore been the domain of (neuro)psychologists. Although this human-oriented research has yielded many interesting hypotheses and elegant approaches, and revealed much interesting data, it has hampered the experimental testing of hypotheses about the nature, ontogeny and function of lateralization, due to the obvious limitation of especially physiological experimentation with humans and the lack of a comparative approach. One particular area of interest is the epigenesis of lateralization, concerning questions similar to its developmental

plasticity, the extent of sensitivity to, and buffering against environmental influences, the interactions of the latter with the genetic make-up of the individual, and the relationship with health and disease. Now that it has become clear that lateralization is not restricted only to humans, but is a fundamental aspect of the organization of brain and behaviour in at least vertebrates (reviewed in Vallortigara 2000; Rogers 2002; Vallortigara & Rogers 2005), testing hypotheses in animal models has also fallen into the realm of biology. This paper aims at exploring the possibilities for such an approach by reviewing the literature on humans and other vertebrate species on one important aspect of the development of lateralization: the influence of steroid hormones. Hypotheses about the influence of testosterone on lateralization were inspired by sex differences in lateralization of brain and behaviour. In humans, lateralized functions such as spatial orientation, language and hand preferences are thought to display sex differences, not only in performance but also in the direction and strength of lateralized control. The latter

* Author for correspondence ([email protected]). One contribution of 14 to a Theme Issue ‘Mechanisms and functions of brain and behavioural asymmetries’.

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Table 1. Expected shifts in strength and hemispheric dominance in laterality when exposed to increasing testosterone levels, according to four different hypotheses. RH, right hemisphere; LH, left hemisphere.

handedness language visuospatial

corpus callosum hypothesis

Geschwind and Galaburda hypothesis

sexual differentiation hypothesis

nonlinearity hypothesis

direction

strength

direction

strength

direction

strength

direction

0 0 0

O O O

/ RH / RH 0

! ! O

RH 0 0

! O O

RH, LH, RH O, Z, O 0 0

is of direct concern here. Males would show more lefthandedness, and, in addition, a stronger dominance of the left hemisphere for language while females, although displaying lateralization in the same direction, are less strongly lateralized for language owing to a stronger involvement of the right hemisphere. Finally, although the right hemisphere is in both sexes dominant for visuospatial cognition, males would be stronger lateralized for this function. Although there is large overlap between the sexes in these laterality indices and the sex differences are minor and not always found, they have been confirmed in several studies, including large meta-analyses for language and cognitive functions ( Voyer 1996) and a smaller meta-analysis for handedness (Sommer et al. 2008). However, two smaller scale meta-analyses did not confirm a sex difference in language function (Sommer et al. 2004, 2008) and the debate about sex differences in lateralization of brain and behaviour is still ongoing. Since prenatal exposure to testosterone is well known to organize brain and behaviour, and in mammals, including humans, males are exposed to higher levels of prenatal androgens than females, several hypotheses for the potential influence on lateralization have been postulated. The first hypothesis stated that testosterone in males would decrease the information exchange between the two hemispheres by stimulating axonal pruning in the corpus callosum, leading to less information exchange between the hemispheres and therefore a stronger lateralization of functions (Witelson & Nowakowski 1991). This hypothesis is based on their finding that in males, but not in females, right-handed persons have a smaller corpus callosum than non-right-handers, the latter assumed to be less strongly lateralized for handedness and language. Since this relationship seems to be present only in males, and the formation of the corpus callosum, including cell death and axonal pruning would occur before birth, a role for prenatal exposure to testosterone is suggested. This hypothesis predicts that prenatal exposure to elevated levels of testosterone induces an increase in the strength of lateralization, but would not affect its direction (table 1). This mechanism may be specific for the male sex, but perhaps only so because males show higher levels and more variation of the hormone levels than females, so that elevated levels in females would induce similar effects as in males. This hypothesis is supported by two animal studies. Denenberg et al. (1991) reported in rats, that males have a smaller corpus callosum than females and that its size can be affected by prenatal hormones. Additionally, Rosen Phil. Trans. R. Soc. B (2009)

strength

(1996) reported that rats with asymmetric brains have a smaller corpus callosum than rats with more symmetric brains. The second hypothesis and most frequently cited one was proposed by Geschwind & Galaburda (1985). It hypothesizes among others that elevated prenatal exposure to testosterone inhibits the growth of the left hemisphere, inducing compensatory growth in corresponding regions of the right hemisphere. As a consequence, those functions that are dominated by the left hemisphere, such as handedness in righthanders (the majority of people, see Schaafsma et al. 2009) and language, would become either less strongly lateralized, or even dominated by the right hemisphere. This would explain the higher incidence of lefthandedness and decreased language lateralization in males relative to females. Visuospatial functions that are dominated by the right hemisphere, would not change in direction, but become even more strongly lateralized by enhanced dominance of that hemisphere (see table 1 for a summary of these predictions). The theory also aims to explain by means of early exposure to androgens, the correlations between left-handedness, developmental disorders and immune diseases, which have received a lot of attention but is not our main concern in this paper. The third hypothesis postulates that the sex differences in lateralization are due to being part of the process of sexual differentiation, which is in mammals under the influence of testosterone and would masculinize the direction and degree of lateralization (for a review see Grimshaw et al. (1993, 1995), see also Smith & Hines 2000). This hypothesis would yield the same predictions as above, except for the strength and direction of language lateralization. Since males would be more strongly lateralized than females for this function, early exposure to elevated testosterone levels would increase instead of decreasing the strength of language lateralization, and induce no change in its direction (see table 1). Finally, more recently a fourth hypothesis has been put forward (Lauter 2007). Aiming to explain individual variation in behavioural and brain lateralization, it postulates an important role for individual variation in prenatal exposure to testosterone. It proposes, in contrast to the corpus callosum hypothesis (CCH), that variation in prenatal exposure to testosterone would induce individual variation in pruning of connectivity throughout the brain and in both sexes. This would have a differential effect on both hemispheres, as the left hemisphere develops relatively late and would be more vulnerable to the pruning effects of

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Review. Testosterone and lateralization testosterone. Although laterality is mainly characterized in terms of skills, and not explicitly in terms of strength or direction, the author makes explicit predictions for handedness and fine motor control. Exposure to low levels of testosterone would allow full development and connectivity in both hemispheres, resulting in the full capacity of the left hemisphere, leading to strong right-handedness. Moderate exposure to prenatal testosterone would primarily affect the left hemisphere (note the similarity with the Geschwind and Galaburda hypothesis (GGH)), inducing more ambidexterity and left-handedness. A higher level of exposure to testosterone would also affect the right hemisphere, and in cases of severe overall pruning it would inhibit the supposed coordinating and ‘nurturing of the left brain’ function of the right hemisphere, releasing (over)growth of the left side. This would lead to strong right-handedness again and so the effect of prenatal testosterone exposure is not linear (see table 1). As summarized in table 1, the four hypotheses make somewhat different predictions for the effect of testosterone on the direction and strength of lateralization of different functions. This can be tested in humans by measuring both direction and strength of lateralization of different functions in relation to testosterone levels, both in normals and in persons exposed to pathologically high or low levels of the hormone. Moreover, the effect of experimental manipulation of hormone levels, not possible in human early development, can be studied in animal models such as primates and other mammals. In addition, using birds as an animal model we have another strategy to compare the hypotheses. First, birds lack a corpus callosum (Cuenod 1974), so that any effect of testosterone on the strength of lateralization in birds cannot be attributed to its effect on a corpus callosum. Second, while sexual differentiation in mammals is primarily under the influence of testosterone, causing masculinization in males, in birds sexual differentiation is under the influence of oestradiol, inducing feminization of females (Schlinger 1998). Although testosterone can be converted to oestradiol by the enzyme aromatase, the enzyme is not very active in male birds, preventing feminization. Therefore, any effect of androgens on lateralization in birds cannot be explained by the sexual differentiation hypothesis (SDH) either. The four hypotheses deal with the so-called organizational effects of testosterone. Such organizational effects are long-term effects inducing structural and irreversible changes in brain and behaviour during an early phase in development. However, scientists have, sometimes referring to one of the four hypotheses, also looked at the effect of hormones in adulthood. Such effects are not considered to be organizational, but activational, inducing highly reversible changes in brain and behaviour, with waning effects when hormone levels decrease. Although the distinction between organizational and activational effects is not absolute (Arnold & Breedlove 1985), the hypotheses mentioned here explicitly deal with prenatal exposure to testosterone, and therefore we only analysed studies dealing with organizational effects. Phil. Trans. R. Soc. B (2009)

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Although not always possible, due to limited numbers of studies, we used meta-analyses for reviewing the literature. To explore the scope for the influence of gonadal hormones, we start by presenting a meta-analysis of potential sex differences in lateralization of brain or behaviour. Since excellent reviews on this topic for humans have recently been published (Voyer 1996; Sommer et al. 2004, 2008), we only present the results for non-human mammals and bird species. Next, we present separate analyses for organizational effects of testosterone in humans, other mammalian species and bird species. A surprisingly large amount of published studies could not be used for proper meta-analyses, owing to incomplete statistical information. Therefore, we additionally calculated the number of studies that investigated the effects of sex or testosterone on either strength or direction of lateralization for motor, language and other cognitive functions. With a binomial test, we checked whether the number of studies showing positive or negative effects deviated from random expectation. 2. MATERIAL AND METHODS (a) Literature search: keywords and selection criteria Literature for the different meta-analyses was searched via Web of Knowledge, with the keyword ‘lateralization’ OR ‘lateralization’, OR ‘asymmetry’ and additional different keywords for every topic. For sex differences: ‘sex difference’ OR ‘gender difference’; for hormone effects: ‘testosterone’ OR ‘hormone’, adding in a separate search ‘CAH’. In addition, we searched the reference lists in the literature found for relevant papers. For testing sex differences, only those studies were included that tested lateralization of males and females against each other. For the effects of androgens only those studies were included in which the hormone levels were actually measured or manipulated early in ontogeny, plus two categories in the human literature. First, we included one study looking at same and opposite sex twins, assuming, based on extensive animal literature, that a female from opposite sex twins would be exposed to relatively high levels of testosterone, produced by her brother in utero. Second, we included studies on patients with congenital adrenal hyperplasia (CAH), which are exposed to abnormal high androgen levels due to enhanced prenatal production (see Mathews et al. 2004). We did not include patients prenatally exposed to elevated levels of oestrogens (offspring of mothers treated with diethylstilbestrol). Although such female offspring might show masculinization, we were specifically interested in the effects of testosterone and, furthermore, the involvement of oestrogens in human sexual differentiation is not clear. We did include studies on dihydrotestosterone, since this hormone has an even higher affinity to the androgen receptor than testosterone. Owing to the low number of animal studies that looked at lateralized behaviour in the adult stage, we were forced to include data collected in younger stages. For the human studies we included only those studies that tested lateralization in older children or adults, when lateralization is expected to have become fixed. Furthermore, we only included studies that reported direct measurements of lateralization, such as hand preference, results from visual half-field or dichotic listening tasks, and indices for brain asymmetry. Especially in humans, indirect measurements of lateralization such as a better performance of spatial

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orientation or language function is often used as an indication of stronger lateralization, but the assumption that performance is directly related to lateralization is not valid ( Friederici et al. 2008). For the direction of lateralization we used, where possible, the standard laterality index (RKL)/(RCL), in which R and L stand for the frequency of right and left performance, respectively. In other cases we were forced to use a slightly different calculation, such as RKL, and this is specified in text, tables and figures. Some authors interpreted these formulae as an indication for strength. However, this is under the assumption that all subjects have the same direction of lateralization, so that a difference in the index is a difference in strength of lateralization. However, evidence for this assumption is not always given, and sometimes obviously not correctly based on the reported data. Therefore, we defined strength as the absolute value of the laterality index. (b) Meta-analysis procedure Meta-analyses were carried out using the program COMPREHENSIVE META ANALYSIS v. 2. Effect sizes, expressed as the correlation coefficient r, were calculated from sample sizes, exact p-values and statistics (F- or t-values and d.f.) which were extracted from the papers or calculated by ourselves when possible. The c2 values (e.g. used for testing the proportion of left- against right-handedness) were transformed into phi-correlations ( Fern & Monroe 1996; Nakagawa & Cuthill 2007). The sign of the correlation coefficient was assigned as follows: for sex differences in strength and direction, a positive value indicated that males show a higher degree in laterality than females and an increased right-hemispheric bias, respectively. In the analyses of organizational effects of testosterone, a positive value means that high testosterone levels are correlated with or induced increased right-hemispheric dominance. Results from the three classes of domains presented in table 1 (handedness in humans or motor behaviour in other mammals; language lateralization in humans (e.g. measured by dichotic listening tasks) and on other (visuospatial) cognitive tasks in humans and other animals), were analysed separately because different hypotheses make different predictions for these functions. We analysed the results separately for taxonomic groups: humans, other mammals, and birds (other taxonomic groups did not yield more than one or two studies, but see below). Owing to the small number of studies in the analyses of organizational effects on strength of lateralization, only studies on direction were analysed in the meta-analyses. In several studies more than one dependent variable was measured. In case these concerned the same function (motor biases, language or visuospatial domains), we used the weighted averages per study for the calculations of overall effect sizes. This is because these are not independent statistical units as they are derived from the same subjects and the same study. We do present them all, however, separately in the tables and graphs. We considered results within one study on males and females (when presented separately) as separate studies since they concern different subjects. The program also analysed the homogeneity of the dataset to test whether the results can be considered replications of each other. Significant deviations from homogeneity can be due to the inclusion of different tests, or differences in study groups or animals and suggests that further partitioning might be necessary. Phil. Trans. R. Soc. B (2009)

In order to control for the stability of overall effects, a failsafe n-test was carried out for each meta-analysis. This test calculates the amount of studies needed to find overall no significant effect and indicates therefore how stable the overall effect size is. (c) Additional analyses A substantial number of studies reported the results in such a way that we could not extract the proper variables for the meta-analyses. This might lead to a bias in the meta-analyses, especially since non-significant results are relatively often incompletely reported. Therefore, we calculated over all studies, including those excluded from the meta-analyses, the number of studies that reported a significant positive or negative effect, or a non-significant effect of sex or hormone exposure, respectively. Similar to the meta-analyses this was calculated for each taxa and functional domain separately. The results of this semi-quantitative approach were tested with a binomial test, testing the number of studies that yielded a sex effect or hormonal effect in either a positive or negative (in the case of strength) or the left or right direction (direction). This was performed under the assumption that with a random distribution the chance of being in one of the two categories (strength: smaller or larger; direction: left or right bias) is 0.50. All studies that we used are listed in tables 2–5, results of the binomial tests are shown in table 6.

3. RESULTS (a) Sex differences (i) Strength of lateralization The meta-analysis for sex differences in non-human mammals could only include three studies and concerned motor biases. It showed no significant effects for strength (rZ0.251, nZ3, pZ0.378; figure 1) whereas heterogeneity was significant ( p!0.001). Numbers were insufficient for testing the results of the semi-quantitative approach (table 2). For birds, no studies could be used for the meta-analysis. However, 11 studies could be used for the semi-quantitative approach (table 3). These concerned the involvement of either eye (in most studies by occlusion of one eye) in the performance of a variety of tasks, often discrimination learning, and were therefore classified under the cognition domain. The results indicate that males show greater strength than females (table 6; pZ0.035). (ii) Direction of lateralization For non-human mammals, the overall sex effect in direction of motor biases is significantly different between males and females (rZ0.160, nZ7, pZ0.038, seven studies, figure 2; table 2). The fail-safe n-test indicated that eight studies with non-significant results must be added to result in an overall pO0.05. Homogeneity of data was however not achieved ( p!0.001). The finding that the right hemisphere is more dominant in males than females was not confirmed in the semi-quantitative approach (table 6). However, both approaches used the same studies and the meta-analyses, being more powerful, is more accurate. For birds, the meta-analysis of sex differences in direction for more cognitive related tasks (see above) also revealed a significant difference (rZ0.097, nZ4, pZ0.044; figure 2; table 3). The data show no

Phil. Trans. R. Soc. B (2009)

Table 2. Summarizing table of literature search on sex differences of lateralization parameters for motor behaviour in non-human mammals. (Non-bold signs not used in the meta-analyses owing to lack of information; cells lacking a sign, data not statistically tested. L, left-side bias; R, right-side bias; 0, no side bias; if direction of lateralization was similar for both sexes: O, stronger side bias; !, less strong bias; Z, equal bias.) direction of lateralization

__

__

\\

summary

0

0

__ show higher strength in motor bias for Alonso et al. left or right in T-maze without incentive

\\

species

test

rats

T-maze

rats (Purdue Wistar)

neonatal tail posture

L

!

L

males and females show a left side bias in neonatal tail posturing with females showing a stronger bias

Denenberg et al.

(1981)

horse

preferred foreleg obstacle avoidance (o.a.) o.a. while ridden rolling

0 L 0 L

! O !

R 0 R R

__ show overall left motor bias (although not always significant), \\ show overall right motor bias (although not always significant); no sex differences in strength (averaged over the four tests)

Murphy et al.

(2005)

O

year (1991)

tape removal

L

O

0

__ preferably use the left paw, \\ show a Quaranta et al. trend to use the right paw, data analysed for first paw used and overall paw use

rats (Purdue Wistar)

neonatal tail posture

L

!

L

males and females show a left side bias in neonatal tail posturing with females showing a stronger bias

rats (Sprague–Dawley) neonatal tail posture

0

!

R

Ross et al. females show a significant right side bias (neonatal tail posturing), whereas males show no significant difference between right and left tail posturing

(1981)

R

\\ preferably use the right paw, __ the left Wells et al. paw, independent of the test; no sex difference in strength; effect size calculated for all experiments

(2003)

dog

paw lifting blanket removal food retrieval

L Z

Rosen et al.

(2004)

(1983)

K. A. Pfannkuche et al.

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Review. Testosterone and lateralization

Z

authors

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strength of lateralization

933

934

direction of strength of lateralization lateralization

chicken

visual projections

zebra finch

food discrimination

__

\\

__

\\

summary

authors

year

O

R

0

in __, projections from RES show higher C/I ratio than from LES, no difference in \\

Adret & Rogers

(1989)

O

R

R

__ make less mistakes; both sexes perform better in binocular Alonso or RE condition

(1998)

chicken

fear response

O

L

0

__ show higher response with LES, no difference in \\

Andrew & Brennan

(1984)

pigeon

visual projections

Z

R

R

tectal asymmetry show larger cells projecting from RES, no sex differences

Gu¨ntu¨rku¨n

(1997)

chicken

food discrimination

!

0

L

\\ tested with LES made the fewest mistakes, no binocular condition

Mench & Andrew

(1986)

chicken

visual projections

O

R

R

in __, projections from RES show higher C/I ratio than from LES; same in \\, but lesser degree

Rajendra & Rogers

(1993)

chicken

novel object

%

L

L

\\ tend to show stronger asymmetry than __

Regolin & Vallortigara

(1996)

chicken

food discrimination (light incubation) food discrimination (dark incubation)

O

R

0

Rogers

(1997)

Z

0

0

__ improve learning under binocular and RES condition, no difference between RES and LES in \\ no differences between RES and LES in __ and \\

O

R

O

R

__ show significantly stronger asymmetry in visual projections than \\

Schwarz & Rogers

(1992)

O

chicken

visual projections

chicken

visual discrimination/ position learning

R

Z

R

__ and \\ learned faster when good box was on their right side; no sex differences

Vallortigara et al.

(1996)

chicken

position learning

L

O

0

Vallortigara et al.

(1988)

turning behaviour

0

0

__ make less mistakes when box is placed on their left side; no difference in \\ without stimulus, naive males turn 50% left, 50% right, naive females 60% right, 40% left

0

__ improve learning under binocular and RES condition, no difference between RES and LES in \\

Zappia & Rogers

(1987)

0 0

__ show left side bias, \\ show tendency towards left side no side preference in __ and \\, higher strength in \\

Brown et al.

(2007)

chicken

food discrimination

O

R

fishes

social detour control detour

!

L 0

O

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test

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species

K. A. Pfannkuche et al.

Phil. Trans. R. Soc. B (2009)

Table 3. Summarizing table of literature search on sex differences of lateralization parameters in birds and fishes (for explanation see legend table 1). (C/IZproportion contralateral to ipsilateral projections from eye to brain. RES, right eye system, LES, left eye system.)

Phil. Trans. R. Soc. B (2009)

Table 4. Summarizing table of literature search on organizational effects of androgens on lateralization parameters in humans and other mammals. (CAHZsubject with congenital adrenal hyperplasia; SDApc, sexually dimorphic area pars compacta; T, testosterone; DHTP, dihydrotestosterone propionate; TP, testosterone propionate; for further details see tables 1 and 2.) strength of lateralization

direction of lateralization

high T

high T

low T

low T

human (__ IHH patients)

handedness dichotic listening split visual field dichotic listening

R R R R

Z Z Z !

R R R 0

human (10 year old girls) human (10 year old boys) \\ (CAH patients) __ and \\ (CAH patients) __ and \\ (CAH patients) __ and \\ (CAH patients) __ (CAH patients)

handedness dichotic listening (FDWT) handedness dichotic listening (FDWT) handedness dichotic listening task handedness

R R R R R R R

O O Z Z Z Z !

R R R R R R R

human (twins)

Z

R

Z

R

handedness

Z

R

Z

R

handedness

R

Z

R

\\ (CAH patients) human (male neonates) human (female neonates) __ and \\ (CAH patients) gerbils (\\) gerbils (__)

handedness grasp reflex

R R

! O

R 0

grasp reflex

R

O

0

dichotic listening task

R

!

0

eye opening eye opening

Z O

R L

Z O

0 0

rhesus monkey

handedness

O

L

Z

L

authors

year

control group and IHH patients (congenital androgen deficiency) show no significant differences in handedness, dichotic listening or split visual field tasks females from opposite sex twin pairs show right ear bias, females from same sex twin pairs show no side bias testosterone levels in girls are associated with right-handedness and right ear advantage (REA) in a fused dichotic word task (FDWT). in boys, testosterone levels are not correlated with handedness or ear advantage in a dichotic listening task (FDWT) no significant differences between CAH patient and matched controls

Cappa et al.

(1988)

Cohen-Behan (2004) et al. Grimshaw et al. (1995)

Helleday

(1994)

CAH patients show a stronger left-handedness bias, when compared with controls, independent of sex CAH and control subjects show a right ear bias, no differences in strength of lateralization no differences in handedness between CAH patients and controls

Kelso et al. Mathews et al.

(1999, 2000) (2004)

significantly more left-handed females in CAH group, no significant differences between control males and CAH patients

Nass et al.

(1987)

right-handedness was positively correlated with testosterone levels in male and female neonates

Tan & Tan

(2001)

(1993) (1993)

(1995)

(Continued.)

935

significantly decreased left ear recall resulting in a right side bias in Tirosh et al. CAH patients Clark et al. intrauterine position influences testosterone levels: offspring are exposed to high T levels between 2 brothers (2M), low T levels between 2 sisters (2F)); 2M males open significantly more often first their left eye than 2F males; 2M females exhibit more frequently primacy right eye opening, but difference is not significant left-handedness bias in rhesus monkeys in both sexes; no differences Drea et al. between experimental group (elevated hormone levels), control group or group with suppressed hormone levels

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dichotic listening task

summary

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test

Review. Testosterone and lateralization

species

936

strength of lateralization

direction of lateralization

high T

high T

low T 0

low T

gerbils (\\)

SDApc size

L

rats (\\, DHTP treatment) rats (\\, TP treatment) rats (__, DHTP treatment) rats (__, TP treatment)

neonatal tail posture

L

Z

L

neonatal tail posture

R

!

L

neonatal tail posture

L

Z

L

neonatal tail posture

L

Z

L

summary

authors

year

\\ emitted after treatment as many ultrasonic sounds as males; left Holman & SDApc size increased (same pattern as found in sexually mature __) Hutchinson Purdue Wistar rats show a left side bias in neonatal tail posturing with Rosen et al. females showing a stronger bias; DHTP treatment during gestation did not change direction of laterality, but TP in females caused a reversal in asymmetry; no effect of treatment in males

(1991) (1983)

Table 5. Summarizing table of literature search on organizational effects of gonadal hormones on lateralization parameters in birds. (For details see legend in tables 1 and 2.) strength of lateralization

species

hormone

test

chicks (__)

DHT

copulatory behaviour (biand monocular)

chicks (__)

oestradiol

chicks (__)

no treatment

treatment

chicks (\\)

no treatment

treatment L

O

0

visual projections

0

!

R

testosterone visual projections

0

O

R

0

Z

R

0

!

R

0

!

R

O

chicks (\\) chicks (__)

direction of lateralization

testosterone food discrimination (bi- and monocular)

!

summary

authors

year

dihydrotestosterone (DHT) treated males show stronger asymmetry; than controls; more copulatory attempts with LES than RES, no difference in controls treated males showed no asymmetries in comparison to control males treated males showed marginal and reversed asymmetries in comparison to control males treated females showed no asymmetries in comparison to control females treated __ show weaker and reversed asymmetry, when compared to control males control and treated \\ did not show superior learning with one eye in monocular test condition; however, treatment negatively effected binocular performance

Bullock & (1992) Rogers

Rogers & (1993) Rajedra Schwarz & (1992) Rogers

Zappia & Rogers

(1987)

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test

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species

K. A. Pfannkuche et al.

Phil. Trans. R. Soc. B (2009)

Table 4. (Continued.)

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937

ns ns ns ()

ns ns

Murphy 2005, 2 ns 

binomial test

K. A. Pfannkuche et al.

Murphy 2005, 1

Murphy 2005, 3 Murphy 2005, 4

0 0 2 4

4 2

Wells 2003 [abs. LI] 1 7

C

semi-quantitative effect in all studies

Murphy 2005, average [abs. LI]

Alonso 1991 [abs. LI] overall effect mammals

Phil. Trans. R. Soc. B (2009)

–0.5

0

0.5

1.0

4 5 4 1 3 3 2 0 8.106 18.610 10.19 0 0 17 K0.940 1.155 K2.549 K0.070 0.098 K0.102

1 7 2 5 49.29 5.61 2.078 2.012 0.160 0.097

8 6

2 3 0 1 18.494 2 0.882

sex differences strength mammals motor domain birds cognitive domain sex differences direction mammals motor domain birds cognitive domain org. effects of androgens humans, language direction humans, handedness direction other mammals, motor domain birds, cognitive domain

0.252

3 3 0 11 7 4 22 6 9 5 2

meta-analyses

test of effect size (r) significance (Z )

fail safe n-test heterogeneity (fixed factor) (Q )

K

0

–1.0

number of studies (n)

Table 6. Overview of the results of the meta-analyses and the semi-quantitative approach concerning sex differences in strength and direction of lateralization, and the organizational (org.) effects of androgens, separated for functional domain and species. (Positive r-values for strength: males stronger lateralized than females. Positive r-values for direction: stronger righthemispheric control in males versus females, or with higher prenatal exposure to testosterone. Semi-quantitative analysis (binomial test) sex differences strength: minus, males less lateralized than females; zero, no difference; plus, males stronger lateralized than females. Sex difference in direction: minus, males show stronger left hemisphere bias than females; zero, no difference; plus, males show stronger right hemisphere bias than females. Organizational effects of hormones: minus, high androgen levels correlated with left hemisphere dominance; zero, no correlation; plus, high androgen levels correlated with right hemisphere dominance. p!0.10, p!0.05, p!0.01, p!0.001; ns, not significant.)

Review. Testosterone and lateralization

Figure 1. Sex differences in the strength of lateralization in mammals. Plotted are effect sizes rG95% CI. Filled circles show results for separate dependent values within one experiment; open circles show averaged weighted effect sizes (r) for each study. Square, overall effect size (r). Positive values indicate higher strength in males than in females. Dependent variables are given in brackets; abs. LIZabsolute value of laterality index (RKL)/(RCL).

significant heterogeneity ( pZ0.132). However, using all, and therefore many more studies in the semiquantitative approach, binomial testing showed no significant effects (table 6). (b) Organizational effects of testosterone (i) Humans The meta-analysis for the effects of androgens on language lateralization in humans showed no significance (rZK0.070, pZ0.347, nZ6; figure 3; table 4). Although the two studies on normal subjects showed a tendency towards a stronger involvement of the left hemisphere and studies on CAH patients showed a right-hemispheric bias, the data did not show significant heterogeneity ( pZ0.150). Using 10 studies, the semi-quantitative approach did not yield a significant effect either, and if at all a trend towards a stronger involvement of the left hemisphere (table 6). The meta-analysis for the effects of androgens on handedness in humans also showed no significant effect (rZ0.098, nZ9, pZ0.248; figure 3; table 4). There was a significant indication for heterogeneity ( pZ0.017), with most CAH studies showing a trend towards right hemispheric bias, and only one CAH study and both studies on normal subjects towards a left-hemispheric bias. In support of the meta-analysis the semi-quantitative approach did not yield a significant result either. For the analysis on organizational effects of androgens in non-human mammals, five studies on motor lateralization could be used. The data indicate that in non-human mammals, in contrast to humans, high prenatal androgen exposure is associated with stronger left-hemispheric dominance (figure 3; table 4; rZK0.102, nZ5, pZ0.011). However, heterogeneity was significant ( pZ0.037) and the semi-quantitative approach including three more studies did not support the meta-analysis. For birds, only two values from one study (males and females) could be used (figure 3). Owing to the small sample size, no meta-analysis was conducted. For the

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Rosen 1983 [nr. left vers. nr. right] Denemberg 1981 [nr. left vers. nr. right] Alonso 1991 [nr. left vers. nr. right] Ross 1981 [nr. left vers. nr. right] Quaranta 2004, 1 Quaranta 2004, 2 Quaranta 2004, average [LI] Murphy 2005, 1 Murphy 2005, 2 Murphy 2005, 3 Murphy 2005, 4 Murphy 2005, average [LI] Wells 2003 [LI] overall effect mammals Vallortigara 1996, 1 Vallortigara 1996, 2 Vallortigara 1996, average [nr. of trials] Regolin 1996 [LI] Andrew 1984 [fear response] Alonso 1998 [nr. of trials] overall effect birds –1.0

–0.5

0.5

0

1.0

Figure 2. Sex differences in direction of lateralization for mammals (upper part) and birds (lower part). Birds were tested for right or left eye involvement in certain tasks, mostly by occlusion of either eye. Positive values indicate a stronger righthemispheric bias in males, negative values indicate a stronger left-hemispheric bias in males. Circles indicate motor behaviour and triangles indicate cognitive tasks. For further details see legend to figure 1. [LI]Zlaterality index: (RKL)/(RCL); [nr. left vers. nr. right]Znumber of animals with left-side bias were tested against number of animals with right-side bias; [nr. of trials]Z number of trials males and females needed to learn a task; [fear response]Znumber of fear responses.

Grimshaw 1995, female DL, FDWT Cohen 2004, twin study, DL [LI] Helleday 1994, female CAH, DL [LI] Mathews 2004, female CAH, DL [LI] Mathews 2004, male CAH, DL [LI] Grimshaw 1995, male DL, FDWT overall effect human language lat. Grimshaw 1995, female handedness [HI] Nass 1987, male CAH handedness [LI] Grimshaw 1995, male handedness [HI] Mathews 2004, male CAH, handedness [HI] Mathews 2004, female CAH, handedness [HI] Helleday 1994, female CAH, handedness [LI] Nass 1987, female CAH handedness [LI] Kelso 1999, male + female CAH, handedness [HI] Kelso 2000, male + female CAH, handedness [HI] overall effect humans handedness Rosen 1983, DHTP in female [nr. left vers. nr right] Rosen 1983, TP in female [nr. left vers. nr. right] Rosen 1983, DHTP in female [nr. left vers. nr. right] Rosen 1983, TP in males [nr. left vers. nr. right] Drea 1995, handedness [nr. left vers. nr. right] overall effect mammals Zappia 1987, female [errors monocular] Zappia 1987, males [errors monocular] –1.0

–0.5

0

0.5

1.0

Figure 3. Organizational effects of gonadal hormones on language lateralization in humans (CAH patients and healthy individuals) (first part); on handedness in humans (CAH patients and healthy individuals) (second part); motor behaviour in other mammals (rhesus monkeys and rats) (third part); and birds (fourth part). Positive values indicate a right-hemispheric dominance (for handedness, motor behaviour and language) with higher levels of testosterone. Circles indicate motor behaviour and/or handedness, diamonds indicate language lateralization (DL, dichotic listening; FDWT, fused dichotic words test). HI, handedness index measured by questionnaires or activity tasks. For further details see legend to figure 1. Phil. Trans. R. Soc. B (2009)

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Review. Testosterone and lateralization semi-quantitative approach we could use six studies, yielding a significant effect of prenatal testosterone on right-hemispheric dominance (table 6).

4. DISCUSSION The epigenesis of lateralization of brain and behaviour is still far from clear. Several genetic models for the explanation of patterns of inheritance of lateralization of language and hand preference or hand skill in humans have been put forward. However, their explanatory power is limited and scope for an important role for especially perinatal environmental factors exists (reviewed by Schaafsma et al. 2009). For at least two decades, there has been much speculation in the literature about the potential effects of androgens on the development of lateralization of brain and behaviour. Based on meta-analyses of a selection of papers and a semi-quantitative approach based on all relevant studies we extracted from the literature, we tested four specific hypotheses that have been put forward concerning the potential role of androgens on lateralization. We summarized the predictions of each of these hypotheses concerning the influence of prenatal exposure to testosterone on strength and direction of lateralization for motor behaviour, language and (other) cognitive functions (see §1 and table 1). The results are summarized in table 6. Based on this, we will discuss the evidence supporting or undermining the four hypotheses. The CCH predicts no effect of sex or androgen exposure on direction, but an increase in strength of lateralization for all three domains investigated. Our data, and data from earlier meta-analyses do not support this. We could not find evidence for an effect of sex on strength of lateralization in non-human mammals. However, sample size was very small and only concerns motor biases. There was a significant effect of sex on the strength of cognitive functions in birds in a total of 11 studies. However, this finding does not differentiate between the four hypotheses since three of them have a similar prediction for the degree of lateralization in visuospatial functions. Furthermore, birds lack a corpus callosum, and this result therefore cannot be in support of the CCH. Moreover, our findings that sex and testosterone affect the direction of lateralization were not predicted by the CCH (see below). Several studies claim to demonstrate an effect on strength whereas they actually do not report direct evidence for this. For example, higher scores for righthandedness might be an indication to a stronger degree but only under the assumption that no left-handers were present in the population. Since such data on direction is not always reported, we could not reliably use such claims, reducing our sample size. The GGH predicts, in contrast to the CCH, a decrease in strength of lateralization for handedness and language and an increase in strength for visuospatial functions with increasing prenatal testosterone exposure (table 1). Only the latter is partly supported by the sex differences in birds, but, as mentioned before, sample sizes do not allow reliable conclusions. Phil. Trans. R. Soc. B (2009)

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The number of studies analysing direction of lateralization allow a more reliable test. Both in humans ( Voyer 1996; Sommer et al. 2008) and mammals (this study, but only in the meta-analysis and not in the semi-quantitative approach), males display a stronger shift to right-hemispheric dominance than females for handedness. This is consistent with the predictions of the GGH. However, in contrast to this, our meta-analyses do not show that prenatal testosterone enhances this direction of lateralization in humans, neither for handedness nor for language. Moreover, and surprisingly, the metaanalysis for motor lateralization in non-human mammals even showed a significant effect of prenatal testosterone in the other direction than that found for humans. Although this finding is not supported by the semi-quantitative approach, it is intriguing and not consistent with the GGH. However, all these studies concern only one specific rat strain and one primate species, in which control animals already show a right-hemispheric dominance (a left bias for motor behaviour) in contrast to left-hemispheric dominance in motor biases than in other species including humans. A second finding also undermines the GGH. In the semi-quantitative approach birds show a consistent and almost significant effect of perinatal testosterone exposure on the direction of lateralization opposite to what the hypothesis predicted. But again this result should be interpreted with caution. The tests on laterality concern the preferred use of the left or right eye in a variety of tests and their homology with visuospatial tasks in humans is not always clear. Moreover, the experimental treatment with androgens concern dosages above the normal physiological range of the species (see endogenous embryonic production as reported in Woods et al. 1975; Tanabe et al. 1979; Woods & Brazzil 1981). The SDH predicts effects of sex and androgens on strength of lateralization (table 1) for which we have, as mentioned above, no sufficient data. It also predicts a stronger right-hemispheric dominance for handedness in males relative to females, and a stronger righthemispheric dominance for handedness due to prenatal exposure to testosterone (table 1). As described above, we did not find this. Moreover, we found an effect of prenatal exposure to testosterone on motor biases in mammals in the direction opposite expectation (see above, table 6). Furthermore, we found a significant effect of sex and an almost significant effect of testosterone on cognitive functions in birds. Since in birds the sexual differentiation is under the influence of oestrogens and not testosterone itself (Schlinger 1998), this undermines the hypothesis. The hypothesis by Lauter (2007) that we termed the nonlinearity hypothesis is more difficult to test. First, many hemispheric functions are labelled differently in other literature and explicit predictions about the influence of prenatal testosterone are made for handedness only. Second, the hypothesis postulates a dose-dependent effect of the hormone, which is not analysed in the studies that we used. Assuming that CAH females are exposed to supraphysiological levels of prenatal testosterone, we would expect a differential

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effect of testosterone in this group versus CAH males or normals. However, there is no indication for this in our dataset (figure 3). In conclusion, we found some evidence for effects of sex and prenatal testosterone exposure on lateralization in humans, other mammals, and bird species. However, none of the hypotheses were convincingly supported. It can be questioned to what extent motor biases in animals such as paw preference are similar to fine motor control in humans. It is obviously even more debatable whether the tests concerning eye use or visual projections in birds should be classified in the same domain as visuospatial functions in humans. Our study clearly reveals a lack of coordination between the different fields of research working on different taxa. For example, birds are excellent models for studying effects of prenatal exposure to hormones on lateralization since the embryos develop outside the mother’s body, facilitating measurement and manipulation of this exposure. However, the effect of this in the adult stage, on motor behaviour, on complex vocalizations and vocal imitation (song birds and parrots), facilitating comparison with humans, has not yet been studied. Comparison between humans and other animals may also be facilitated by measuring lateralization of emotions in relation to sex or hormones, since emotion is a trait that is in evolutionary terms very old, but so far we have only come across one such animal study (on sex differences in lateralization of fear in the domestic chick, Andrew & Brennan 1984). In addition, in all experimental studies care must be taken to manipulate hormone levels within the physiological range. Moreover, a surprising amount of studies did not contain proper data for separating strength and direction of lateralization, nor presented the proper statistical values for using these studies in meta-analyses; severely hampering an adequate overview over the field. We hope that this study will therefore stimulate new studies in this field of research, facilitating a better understanding of the effects of early exposure to androgens on the development of lateralization in humans and other vertebrates. We thank Bernd Riedstra and Sara Schaafsma for valuable discussions, Reint Geuze and two anonymous reviewers for comments on the manuscript, and Jelle Boonekamp for help with the meta-analyses.

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Arnold, A. P. & Breedlove, S. M. 1985 Organizational and activational effects of sex steroids on brain and behavior: a reanalysis. Horm. Behav. 19, 469–498. (doi:10.1016/ 0018-506X(85)90042-X) Brown, C., Western, J. & Braithwaite, V. A. 2007 The influence of early experience on, and inheritance of, cerebral lateralization. Anim. Behav. 74, 231–238. (doi:10. 1016/j.anbehav.2006.08.014) Bullock, S. P. & Rogers, L. J. 1992 Hemispheric-specialization for the control of copulation in the young chick and effects of 5-alpha-dihydrotestosterone and 17-beta-estradiol. Behav. Brain Res. 48, 9–14. (doi:10.1016/S01664328(05)80133-0) Cappa, S. F., Guariglia, C., Papagno, C., Pizzamiglio, L., Vallar, G., Zoccolotti, P., Ambrosi, B. & Santiemma, V. 1988 Patterns of lateralization and performance levels for verbal and spatial tasks in congenital androgen deficiency. Behav. Brain Res. 31, 177–183. (doi:10.1016/01664328(88)90021-6) Clark, M. M., Robertson, R. K. & Galef, B. G. 1993 Intrauterine position effects on sexually dimorphic asymmetries of mongolian gerbils: testosterone, eye opening, and paw preference. Dev. Psychobiol. 26, 185–194. (doi:10.1002/dev.420260402) Cohen-Bendahan, C. C. C., Buitelaar, J. K., Van Goozen, S. M. H. & Cohen-Kettenis, P. T. 2004 Prenatal exposure to testosterone and functional cerebral lateralization: a study in same-sex and opposite-sex twin girls. Psychoneuroendocrinology 29, 911–916. (doi:10.1016/j.psyneuen. 2003.07.001) Cuenod, M. 1974 Commissural pathways in interhemispheric transfer of visual information in the pigeon. In The neurosciences: third study program (eds F. O. Schmitt & F. G. Worden), pp. 21–29. Cambridge, MA: The MIT Press. Denenberg, V. H., Rosen, G. D., Hofmann, M., Gall, J., Stockler, J. & Yutzey, D. A. 1981 Neonatal postural asymmetry and sex-differences in the rat. Dev. Brain Res. 2, 417–419. (doi:10.1016/0165-3806 (81)90048-1) Denenberg, V. H., Fitch, R. H., Schrott, L. M., Cowell, P. E. & Waters, N. S. 1991 Corpus-callosum: interactive effects of infantile handling and testosterone in the rat. Behav. Neurosci. 105, 562–566. (doi:10.1037/0735-7044.105.4. 562) Drea, C. M., Wallen, K., Akinbami, M. A. & Mann, D. R. 1995 Neonatal testosterone and handedness in yearling rhesus monkeys (Macaca mulatta). Physiol. Behav. 58, 1257–1262. (doi:10.1016/0031-9384(95) 02026-8) Fern, E. F. & Monroe, K. B. 1996 Effect size estimates: issues and problems in interpretation. J. Consum. Res. 23, 89–105. (doi:10.1086/209469) Friederici, A. D., Pannekamp, A., Partsch, C. J., Ulmen, U., Oehler, K., Schmutzler, R. & Hesse, V. 2008 Sex hormone testosterone affects language organization in the infant brain. Neuroreport 19, 283–286. Geschwind, N. & Galaburda, A. M. 1985 Cerebral lateralization: biological mechanisms, associations, and pathology .3. A hypothesis and a program for research. Arch. Neuro-Chicago 42, 634–654. Grimshaw, G. M., Bryden, M. P. & Finegan, J. K. 1993 Relations between prenatal testosterone and cerebral lateralization at age 10. J. Clin. Exp. Neuropsychol. 15, 39–40. Grimshaw, G. M., Bryden, M. P. & Finegan, J. A. K. 1995 Relations between prenatal testosterone and cerebral lateralization in children. Neuropsychology 9, 68–79. (doi:10.1037/0894-4105.9.1.68)

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Rosen, G. D. 1996 Cellular, morphometric, ontogenetic and connectional substrates of anatomical asymmetry. Neurosci. Biobehav. R 20, 607–615. (doi:10.1016/01497634(95)00073-9) Rosen, G. D., Berrebi, A. S., Yutzey, A. & Denenberg, V. H. 1983 Prenatal testosterone causes shift of asymmetry in neonatal tail posture of the rat. Dev. Brain Res. 9, 99–101. (doi:10.1016/0165-3806(83)90114-1) Ross, D. A., Glick, S. D. & Meibach, R. C. 1981 Sexually dimorphic brain and behavioural asymmetries in the neonatal rat. Proc. Natl Acad. Sci. USA 78, 1958–1961. (doi:10.1073/pnas.78.3.1958) Schaafsma, S. M., Riedstra, B. J., Pfannkuche, K. A., Bouma, A. & Groothuis, T. G. G. 2009 Epigenesis of behavioural lateralization in humans and other animals. Phil. Trans. R. Soc. B 364, 915–927. (doi:10.1098/rstb. 2008.0244) Schlinger, B. A. 1998 Sexual differentiation of avian brain and behavior: current views on gonadal hormonedependent and independent mechanisms. Annu. Rev. Physiol. 60, 407–429. (doi:10.1146/annurev.physiol.60. 1.407) Schwarz, I. M. & Rogers, L. J. 1992 Testosterone: a role in the development of brain asymmetry in the chick. Neurosci. Lett. 146, 167–170. (doi:10.1016/0304-3940 (92)90069-J) Smith, L. L. & Hines, M. 2000 Language lateralization and handedness in women prenatally exposed to diethylstilbestrol (DES). Psychoneuroendocrinology 25, 497–512. (doi:10.1016/S0306-4530(00)00005-6) Sommer, I. E. C., Aleman, A., Bouma, A. & Kahn, R. S. 2004 Do women really have more bilateral language representation than men? A meta-analysis of functional imaging studies. Brain 127, 1845–1852. (doi:10.1093/ brain/awh207) Sommer, I. E., Aleman, A., Somers, M., Boks, M. P. & Kahn, R. S. 2008 Sex differences in handedness, asymmetry of the planum temporale and functional language lateralization. Brain Res. 1206, 76–88. (doi:10.1016/j.brainres. 2008.01.003) Tan, U. & Tan, M. 2001 Testosterone and grasp-reflex differences in human neonates. Laterality 6, 181–192. (doi:10.1080/13576500042000151) Tanabe, Y., Nakamura, T., Fujioka, K. & Doi, O. 1979 Production and secretion of sex steroid-hormones by the testes, the ovary, and the adrenal-glands of embryonic and young chickens (Gallus domesticus). Gen. Comp. Endocr. 39, 26–33. (doi:10.1016/00166480(79)90189-8) Tirosh, E., Rod, R., Cohen, A. & Hochberg, Z. 1993 Congenital adrenal-hyperplasia and cerebral lateralizations. Pediatr. Neurol. 9, 198–201. (doi:10.1016/08878994(93)90084-P) Vallortigara, G. 2000 Comparative neuropsychology of the dual brain: a stroll through animals’ left and right perceptual worlds. Brain Lang. 73, 189–219. (doi:10. 1006/brln.2000.2303) Vallortigara, G. & Rogers, L. J. 2005 Survival with an asymmetrical brain: advantages and disadvantages of cerebral lateralization. Behav. Brain Sci. 28, 575–589. (doi:10.1017/S0140525x05000105) Vallortigara, G., Zanforlin, M. & Cailotto, M. 1988 Right left asymmetry in position learning of male chicks. Behav. Brain Res. 27, 189–191. (doi:10.1016/0166-4328(88) 90044-7) Vallortigara, G., Regolin, L., Bortolomiol, G. & Tommasi, L. 1996 Lateral asymmetries due to preferences in eye use during visual discrimination learning in chicks. Behav. Brain Res. 74, 135–143. (doi:10.1016/01664328(95)00037-2)

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Voyer, D. 1996 On the magnitude of laterality effects and sex differences in functional lateralities. Laterality 1, 51–83. (doi:10.1080/135765096397874) Wells, D. L. 2003 Lateralised behaviour in the domestic dog, Canis familiaris. Behav. Process. 61, 27–35. (doi:10.1016/ S0376-6357(02)00161-4) Witelson, S. F. & Nowakowski, R. S. 1991 Left out axons make men right: a hypothesis for the origin of handedness and functional asymmetry. Neuropsychologia 29, 327–333. (doi:10.1016/0028-3932(91) 90046-B)

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Woods, J. E. & Brazzill, D. M. 1981 Plasma 17-beta-estradiol levels in the chick-embryo. Gen. Comp. Endocr. 44, 37–43. (doi:10.1016/0016-6480(81)90353-1) Woods, J. E., Simpson, R. M. & Moore, P. L. 1975 Plasma testosterone levels in chick-embryo. Gen. Comp. Endocr. 27, 543–547. (doi:10.1016/0016-6480(75) 90076-3) Zappia, J. V. & Rogers, L. J. 1987 Sex-differences and reversal of brain asymmetry by testosterone in chickens. Behav. Brain Res. 23, 261–267. (doi:10.1016/01664328(87)90026-X)

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Phil. Trans. R. Soc. B (2009) 364, 943–954 doi:10.1098/rstb.2008.0225 Published online 4 December 2008

Hand and paw preferences in relation to the lateralized brain Lesley J. Rogers* Centre for Neuroscience and Animal Behaviour, University of New England, Armidale, New South Wales 2351, Australia Hand preferences of primates are discussed as part of the broad perspective of brain lateralization in animals, and compared with paw preferences in non-primates. Previously, it has been suggested that primates are more likely to express a species-typical hand preference on complex tasks, especially in the case of coordinated hand use in using tools. I suggest that population-level hand preferences are manifested when the task demands the obligate use of the processing specialization of one hemisphere, and that this depends on the nature of the task rather than its complexity per se. Depending on the species, simple reaching tasks may not demand the obligate use of a specialized hemisphere and so do not constrain limb/hand use. In such cases, individuals may show hand preferences that are associated with consistent differences in behaviour. The individual’s hand preference is associated with the expression of behaviour controlled by the hemisphere contralateral to the preferred hand (fear and reactivity in left-handed individuals versus proactivity in right-handed individuals). Recent findings of differences in brain structure between left- and right-handed primates (e.g. somatosensory cortex in marmosets) have been discussed and related to potential evolutionary advances. Keywords: hand preference; hemispheric specialization; coping style; cortisol; cortical structure; common marmoset

1. INTRODUCTION A few years ago, I engaged in a somewhat acerbic debate with Crow on the existence of lateralization in non-human animals (Crow 2004; Rogers 2004; see comments by Corballis 2007). Crow firmly adhered to the earlier, widely held notion that directional asymmetry is unique to modern Homo sapiens and saw it, in association with right-handedness, as the pivotal event in hominid evolution that determined the emergence of language. I, on the other hand, pointed out the now extensive literature on lateralization in a wide range of vertebrate species and argued that there was no such discontinuity in the evolution of lateralization that coincided with the appearance of human language and so placed humans apart from other species on this particular characteristic. As far as I know, we still hold these differences of opinion, although others, such as Corballis (2005, 2007, 2008), who once also defined humans as the lopsided ape (Corballis 1991) and unique in terms of their asymmetrical brains, have now embraced the evidence for lateralization in other vertebrate species and reached the conclusion that it is very unlikely that Crow is correct. Handedness has been important in this continuity/ discontinuity debate, largely because right-handedness in humans is associated with the left hemisphere’s specialization for language and speech production. Not surprisingly, the first attempts to see whether animals other than humans might be lateralized focused on

measuring hand preferences in primates. The first conclusion drawn from these investigations was that non-human primates lacked any species-typical, directional bias for using a preferred hand, although individuals of some species often had hand preferences, left and right in approximately equal numbers, which were seen to be the result of learning through practice (see Warren 1977, 1980). Furthermore, it was concluded that non-human primates preferred to use different hands for different tasks. Later, MacNeilage et al. (1987) re-examined the research on hand preferences in primates and concluded that there was evidence of preferences at the species level and, moreover, that this bias was for use of the right hand and arm to support the body while employing the left hand for snatching at and grasping insects, as seen in the early primates, prosimians (Ward et al. 1993). This specialization of the left hand to grab moving targets has been retained in higher primates, including humans (MacNeilage et al. 1987). As adoption of an upright body posture freed the right hand from its role of supporting the body, the right hand was used to perform fine manipulation of objects and, as evolution proceeded, this hand was adopted for tool using. Recent studies of hand preferences in chimpanzees have supported this hypothesis; chimpanzees show consistent and significant right-hand preferences in tool using (captive chimpanzees: Hopkins et al. 2004; wild chimpanzees: Lonsdorf & Hopkins 2005) and in throwing (Hopkins et al. 2005). The theory of MacNeilage and colleagues has become known as the Postural Origins Theory, meaning that postural changes were instrumental in the origin

*[email protected] One contribution of 14 to a Theme Issue ‘Mechanisms and functions of brain and behavioural asymmetries’.

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of the hemispheric asymmetries present in humans (MacNeilage 1998, 2007). Hence, the emphasis is on motor functions, rather than sensory functions. Meanwhile, during the 1970s and 1980s, evidence of lateralization in non-primate species was coming to light, and in these cases, it had nothing to do with manifested hand or limb preferences but rather with hemispheric differences in sensory processing and/or motor control. Nottebohm (1971) showed that, in the male chaffinch, the motor control of song production is lateralized to the left syringeal nerve and, as he showed later, in the canary, it is lateralized to the vocal centre in the left hemisphere ( Nottebohm et al. 1976). By injecting cycloheximide into the left or right hemisphere of the domestic chick, I showed that the left and right hemispheres control different patterns of behaviour (Rogers & Anson 1979). Using ablation of one or other hemisphere, Denenberg (1981) demonstrated differential functioning of the left and right hemispheres of the rat. Since the time of these initial discoveries of lateralization in non-human species, a growing number of examples have accumulated (summarized by Rogers 2002a; Rogers & Andrew 2002; Vallortigara & Rogers 2005). The finding of hemispheric specialization in the rat was important for the main point that I am discussing here, because it was not associated with the paw preferences of the rats. Although the rats that Deneberg tested exhibited individual paw preferences to use either the left or right paw to reach into a tube to obtain food, there was no population bias for a preferred paw, whereas the lateralization of hemispheric function was present at a population level, as confirmed many times subsequently (Cowell et al. 1997; summarized by Bradshaw & Rogers (1993)). In other words, a brain can be lateralized without that lateralization being manifested as a paw or hand preference. This lack of concordance between hand preference and hemispheric lateralization might have alerted those seeking to find evidence of lateralization in primates by measuring hand preferences, but it did not, probably because the hands of primates are considered to be special and of no comparison with hand/paw use by non-primates. Although I recognize the complexity of some primate hands and their ability to perform fine manipulations, I am not sure whether an absolute distinction between primate hands and non-primate paws is correct. The complexity of hand use, and hand structure, along with the presence or absence of claws, varies enormously across primate species and the whole-hand snatch-grab use of the hands by prosimians may not be qualitatively very different from the rat’s use of its paws to grasp small objects ( Whishaw & Gorny 1994; Whishaw et al. 1998a,b) or the cockatoo’s use of its foot to hold food objects and manipulate them by coordinated use of the foot and beak (Rogers 2007). Internal control of the hand, which enables processing of food, evolved only in some primates. Hence, I am suggesting that hand/paw preferences in nonprimate species might be compared with those of primate species to gain a broader picture of the relationship, or lack thereof, of hand preference with hemispheric specialization. Phil. Trans. R. Soc. B (2009)

Directional bias to use a preferred paw has now been found in some species: toads use the right paw preferentially to wipe objects from their head and to push against a substrate in order to right their body posture (Bisazza et al. 1996), and parrots show preferred use of a foot, the left foot in most species, to hold food (Rogers 1980; Harris 1989). In fact, it has now been found that some strains of laboratory rats express directional biases to use a preferred paw (Tang & Verstynen 2002; Gu¨ven et al. 2003). These examples demonstrate that species-typical hand/paw preferences are present in some primates and non-primates. Even right-hand preference is not exclusive to humans and did not evolve solely in the hominid line in association with language, as postulated by McManus (1999), Annett (2002) and Crow (2002). This does not mean that the right-handedness of humans is unrelated to specialization of the left hemisphere for language, but rather that we cannot consider language as the sole reason for adopting preferred use of a particular hand or limb, or vice versa. In other words, there was no single genetic mutation, no ‘speciation event’ as Crow (2002) hypothesized, that caused hemispheric asymmetry and handedness, and in so doing, brought about the evolution of H. sapiens. The question to be addressed now is what does determine the preferred use of a hand/paw in different species and to what extent is it related to other aspects of brain lateralization?

2. SENSORY AND MOTOR LATERALIZATION (a) Sensory lateralization before hand/paw preferences To address the above question, I will consider that specialization of the left and right sides of the brain to perform different functions and process sensory information differently evolved before preferred use of limbs. There is evidence to support this. First, animals without limbs are lateralized (e.g. teleost fishes: Bisazza et al. 2000): fishes show eye preferences to view certain scenes (Bisazza et al. 1997) and conspecifics (Bisazza et al. 1998; Sovrano et al. 1999; Sovrano & Andrew 2006) and they have a preference to capture prey to their right side (Miklosi & Andrew 1999; Takeuchi & Hori 2008). Tadpoles also prefer to view conspecifics with a preferred (left) eye (Bisazza et al. 2002) and show lateralized escape responses (Rogers 2002b) that could depend on both perceptual and motor side biases. Andrew (2002) has developed a plausible hypothesis that lateralization had its origins in the earliest vertebrates, now represented by the Amphioxus larva, which had the mouth positioned on the side of the head and, as a consequence, feeding was under the control of the left side of the anterior central nervous system. This, Andrew argues, may have led to lateralized sensory processing first associated with feeding and then extending to other sensory processing and, presumably, motor control. Recently, however, evidence of lateralization in invertebrates has become apparent. Spiders display lateralized attack behaviour (Ades & Ramires 2002); fruitflies with an asymmetrical structure in the central

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Hand and paw preferences in animals nervous system have superior ability to form long-term memory compared with fruitflies lacking this structure (Pascual et al. 2004) and bees use the right antenna to learn associations between an odour and a food reward (Letzkus et al. 2006), and the left antenna to recall the long-term memory of this association (Rogers & Vallortigara 2008). All of these are examples of directional bias at the species or population level and all involve sensory processing. Considered against the earlier belief, discussed above, that lateralization was a unique feature of the human brain, these examples of lateralization in the invertebrate brain are quite revolutionary: even relatively simple nervous systems are functionally differentiated on the left and right sides. However, this does not mean that lateralization of the invertebrate nervous system is homologous to lateralization of the vertebrate brain. Returning to the question of limb and hand preferences, it seems definite that these motor biases did not evolve prior to brain lateralization for sensory processing, as MacNeilage et al. (1987) implied, although did not discuss in detail. Instead, I suggest, limb/hand preference is determined by which hemisphere’s sensory processing specializations are being used to perform a particular task. Both primates and non-primates might display population biases to use a preferred limb or paw/hand if a task demands the obligate use of a particular hemisphere. For example, since the right hemisphere is used to process geometrical and global spatial cues, known to be the case in a wide range of species (e.g. humans: Wendt & Risberg 1994; rats: Cowell et al. 1997; chicks: Tommasi & Vallortigara 2004), use of the left hand to snatch and grab a moving object might be expected. This might well explain the species-typical left-hand preferences displayed by primates that feed on insects using snatch and grab (i.e. ballistic) tactics, as in the case of prosimians (Forsythe & Ward 1988; Ward et al. 1990), as well as the superior ability of the left hand for ballistic aimed movement in humans (Guiard et al. 1983). The latter is also in keeping with the superior ability of the human right hemisphere for trajectory perception (Boulinguez et al. 2003). Use of the right hemisphere for spatial processing might also explain the use of the left paw by cats to reach for and attempt to grasp small moving targets ( Fabre-Thorpe et al. 1993) and the directional bias of the left-hand preference found in squirrel monkeys when they capture live fish, also using a ballistic movement (King & Landau 1993). Fagot & Vauclair (1991) proposed that population biases to use a preferred hand are more common when the task is complex in terms of postural, perceptual and cognitive demands, and some evidence supports this (e.g. Blois-Heulin et al. 2007). However, we must keep in mind the kind of tasks any particular species may find difficult rather than the assumed difficulty of the task itself, as perceived by the human experimenter. This might explain why some non-mammalian species show limb preferences at a population/species level to perform apparently simple tasks, such as the right-paw preference of toads and the left-footedness of many species of parrots. Postural constraints when performing apparently simple tasks could well be important in Phil. Trans. R. Soc. B (2009)

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lower vertebrates. Malashichev (2006) has argued that amphibians may show species-typical limb preferences depending on whether they move by jumping or crawling. These differences in locomotion are matched by differences in body structure that make it more or less difficult to balance on three or four limbs (Rogers 2007). A toad with its rigid body structure might, therefore, find the task of raising one limb to wipe an object from its head quite a balancing feat. This, I suggest, may demand the use of the right hemisphere to stabilize the body using coordinated visual, possibly spatial, and motor processing, and so lead to preferred use of the left limb and paw to support the body while the right paw is used to remove the offending object from the head or snout. For this species, even this task, apparently simple, requires the obligate use of a limb/paw. It is difficult to give a possible reason for the opposite limb preference in the case of parrots (i.e. left-foot preference to hold food), but since balancing is a very different problem in a bird, other lateralized processes unrelated to postural constraints may be paramount (e.g. visual stabilization of the retinal image while balancing). Now we should consider tasks that are less demanding. These may not demand the obligate use of a particular hemisphere and so leave the limb/hand use unconstrained. One such task, often used to test primates, is the use of the hand to pick up static pieces of food from the floor or a bowl and to hold the piece of food while eating it. In fact, the same squirrel monkeys that display a left-hand preference for capturing fish show no population bias for a preferred hand to pick up static pieces of food (King & Landau 1993). Nonprimate species may also show non-obligate limb use depending on task difficulty: for example, paw use by dogs to steady a bone or a Kong, (a rubber cone-shaped container with food inside) against the ground is present for individuals but not as a population bias (Branson & Rogers 2006). (b) Stability of hand preferences for simple reaching across the lifespan Although non-obligate limb use might, in theory, vary from one time to another in the same individual, even within the performance of one task, evidence suggests that it does not. Individuals often exhibit a consistent hand preference. Measured on the simple reaching task to pick up pieces of food, common marmosets, Callithrix jacchus, establish a preferred hand by the time they are 8–12 months old and each individual uses the same preferred hand across its lifetime (Hook & Rogers 2000). Data for simple reaching by marmosets in our colony at the University of New England are presented in figure 1. This is the most extensive longitudinal study of hand preferences in a primate species: we have measured the hand preference of the same individuals (based on 100 scores per measure) at different times throughout their entire lifespan, some animals reaching the age of 13 years. The results show that the individual’s hand preference remains constant throughout its life. Minor injury can cause a temporary weakening or a reversal of the hand preference, as we have seen in a few cases, but

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per cent left-hand use

90 80 70 60 50 40 30 20 10 0

1

2

3

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Figure 1. Mean per cent preferences for the preferred hand with standard errors are plotted against age in years for leftand right-handed common marmosets separately. These marmosets comprise my colony at the University of New England. A total of 21 left-handed and 17 right-handed were scored for hand preference to pick up pieces of food and take it to the mouth. For each point on the graph, a total of 100 scores were obtained per individual. As no more than 10 scores per marmoset were collected per day, the data for each point was collected over at least 10 days for each individual. A score for each of the 39 marmosets was obtained once per year for the first 4 years of life. From 4 years of age onwards, standard errors are larger because fewer individuals were tested in each year (scores were obtained for 7–12 individuals in any given year) since some members of the colony are currently not older than 4 years, others had missing scores for some years and some had died before the others (two had died before reaching 7 years and eight by 11 years of age). Note that above 7 years is considered to be old for common marmosets (Geula et al. 2002) and the reported lifespan is 10–15 years (Clarke 1994). Most of the marmosets in our colony have survived past this age. A number of different experimenters collected these results and each was blind to the previously scored hand preferences of the marmosets. The variation in years 6 and 7 was not significant, but there is no obvious explanation for these slight discrepancies, apart from possible scorer reliability or temporary injury of a hand in one or more subjects. The testing situation was always the same: the scores were always collected between 12.00 and 13.00 hours during the daily feeding time.

the original preference returns after recovery. No directional bias is present in the group (in our colony 21 prefer the left hand, 17 the right hand and only 2 have shown no consistent hand preference). The studies of colonies of common marmosets by Matoba et al. (1991) and de Sousa et al. (2001) show a similar absence of group bias in the marmosets when reaching for food, although slightly more marmosets appear to prefer the left than the number preferring the right hand, as seen in our colony and noted first by Box (1977). Some of the marmosets (nZ21) in our colony were tested on a range of tasks requiring them to reach for food, including reaching into a bowl through a small hole, taking food from a rotating disc, reaching while suspended on the cage wire to take the food presented on a plate held outside the cage and reaching for a piece of food suspended on a string (Hook & Rogers 2008). On all of the tasks, apart from reaching into the bowl through a hole in the lid (‘bowl test’), individual Phil. Trans. R. Soc. B (2009)

marmosets exhibited the same hand preference across tasks. Although the strength of hand preference varied somewhat according to the task (close to 100% when reaching for the food suspended on the string), the direction of an individual’s hand preference remained constant. The bowl test was an exception: half of the marmosets (9 out of 17) changed over to use the opposite hand on the bowl task, and some of the subjects shifted from the left to right and others from the right to left. No obvious explanation for this shift is apparent since this was not the only task requiring visuospatial reaching, but it could depend on the body posture adopted during this task, one hand being placed on the edge of the bowl to support the body while the other was used to reach for the food (see fig. 1 of Hook & Rogers 2008). For the majority of tasks, however, each marmoset expressed the same hand preference. Hence, each individual has a consistent hand preference across age and a number of tasks, contrary to the original claims that Warren (1977, 1980) made about hand preferences in primates. If we had used any one of these reaching tasks as a measure to determine whether the common marmoset has a lateralization of the brain, we would have concluded that this species has a non-lateralized brain. This would be incorrect, however, since the same group of common marmosets has been shown to display a strong group bias to use the left eye to view pieces of food through a peephole: all but one of the 21 marmosets tested had a significant left-eye preference (Hook-Costigan & Rogers 1998). It seems, therefore, that the common marmoset is no exception to the pattern of hemispheric specialization shown in other vertebrate species and that the hand used for simple reaching is non-obligate, not determined by the functional differences between the hemispheres. We may now ask what determines an individual’s preference to use the same hand consistently throughout its adult life. It could be argued that a random choice is made initially and that the individual retains this preference through practice. However, as elaborated below, left- and right-handed individuals differ in a number of more general characteristics outside hand use per se and it might be differential activation of the hemispheres associated with these aspects of behaviour that leads to the preferred use of one hand. Of course, one cannot exclude causal connection in the opposite direction (from hand preference to the expression of general differences in behaviour) but, in my opinion, this is unlikely, given that sensory lateralization preceded the evolution of limb preferences, and I am considering non-obligate hand use here. Nevertheless, at present, we are merely engaged in documenting the differences in behaviour and physiology between left- and right-handed individuals.

3. HAND PREFERENCE ASSOCIATED WITH GENERAL BEHAVIOUR (a) Response to novelty related to hand preference The first assessment of differences in general patterns of behaviour between left- and right-handed individuals was conducted on chimpanzees by Hopkins & Bennett (1994). This study found greater interaction

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Hand and paw preferences in animals with toy objects by right- than left-handed chimpanzees. Following on from this, Cameron & Rogers (1999) tested the responses of left- and right-handed common marmosets when they were placed into a novel room containing a number of novel climbing structures and objects. They found that the righthanded marmosets came out of the carrying cage in which they had been transported to the room and began to explore the new environment sooner than did the left-handed marmosets. The right-handed marmosets also performed more parallax movements, which are used for depth perception, performed more leaps and touched more of the novel objects. All of these scores show that the right-handed marmosets explored the new environment by interacting with it directly. The left- and right-handed marmosets performed the same amount of head-cocking movements, which are used in visual exploration (Rogers et al. 1993; Kaplan & Rogers 2006), which suggests that the lefthanded marmosets were as interested in exploring the new environment as were the right-handed marmosets, but they preferred to do so visually at some distance rather than actively engage with the novel objects and structures. Their response can be described as reactive, compared with the proactive response of the righthanded marmosets. The difference in behaviour between these two groups may depend on emotional state, viz. the level of fear. Braccini & Caine (2006, in press) have found similar differences in reactivity and proactivity between leftand right-handed Geoffroy’s marmosets (Callithrix geoffroyi ). They found that left-handed marmosets were slower than right-handed marmosets to approach and sniff novel foods and that they froze for longer after hearing the vocalizations of hawks, the latter being predators of marmosets in their natural habitat. Again, the left-handed animals were more fearful. Recently, we (Gordon & Rogers in preparation) have extended the comparison of left- and right-handed common marmosets (10 left compared with 10 right and matched for sex and age) by testing them with stimuli that elicited mobbing behaviour. We found that the right-handed marmosets approached the novel stimuli twice as often as did left-handed marmosets. When they were presented with the stimulus that elicited the most powerful mobbing response, the righthanded marmosets emitted more ‘tsik’ (mobbing) calls than the left-handed marmosets. In another task, the marmosets, tested with their social companions, were presented with crickets, a relatively unfamiliar food to the marmosets of our colony. The right-handed marmosets captured their first cricket after a shorter latency than the left-handed marmosets. They also made more tsik calls when they were observing and capturing the crickets. All of these results indicate less fear and more proactive interaction in the right-handed marmosets compared with the left-handed marmosets, and this matches the known differences between the hemispheres. A large number of studies show that the activity of the right hemisphere is associated with the expression of intense emotions, especially negative emotions, including fear, and with withdrawal (summarized by Rogers & Andrew 2002). Hence, the Phil. Trans. R. Soc. B (2009)

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left-handed marmosets, with the activation of right hemispheric functions, perform as expected. The converse association between preferred use of the right hand and approach to novel stimuli is also expected since the activation of the left hemisphere suppresses fear and, as proposed by Davidson (1995), enhances approach behaviour. (b) Hand preference and temperament or ‘personality’ Although it is a topic under debate, there is a notable amount of evidence that populations comprise individual animals with consistent differences in temperament or coping style (Dall et al. 2004; Bell 2007; Wolf et al. 2007), and that these differences fit with the general categorization as proactive versus reactive (Koolhaas et al. 1997, 1999). The individual may retain its coping style throughout its life, although, of course, the expression of the particular behavioural characteristic varies according to the context. In addition to reactivity, such consistencies in individuals have been reported for aggression (Reichert & Hedrick 1993), activity (Sih et al. 2004), exploration behaviour (Dingemanse et al. 2002), fearfulness (Boissy 1995) and risk taking (Fraser et al. 2001). In fact, there is some evidence that some or many of these types of behaviour are associated or clustered so that individuals have consistent personality types or coping styles (e.g. Øverli et al. 2004). Such differences may have implications for adaptation to change and, in fact, some researchers have argued that maintaining both types within the population may facilitate adaptive change and speciation (Wilson 1998). Consistent differences in behavioural style or type, it seems, may depend on the predominance of the left or right hemisphere in control of processing and behaviour. Hand preference for simple reaching may therefore be a reflection of consistent behavioural types, as we have seen in marmosets. More research comparing the left- and right-handed animals is required to test whether suites of behaviour are consistently associated with one or the other hand preference for simple reaching. Furthermore, it is now possible to make testable predictions about associations between hand preference and social behaviour, including aggressive behaviour, which has been shown to be primarily a function of the regions of the right hemisphere in humans and other species (summarized by Rogers 2002a). Here, it is interesting to note the research showing, in human populations, that the proportion of left-handed individuals correlates positively with homicide rate (Faurie & Raymond 2005), although there are many possible explanations for this association. In fact, Westergaard et al. (2003) have reported that left-handed, male rhesus macaques receive more aggressive interactions and lower levels of grooming from conspecifics and they are more likely to be submissive than right-handed males (summarized in Howell et al. 2007). However, the opposite is the case for females (Westergaard et al. 2004). Research on more species and in more contexts is needed in order to clarify the reasons for these interesting associations between hand preference and social aggression.

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cortisol concentration (nmol l–1)

3000

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a

2000 c 1500

b d

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0 day 2 day 1 unfamiliar home cage home cage cage left-handed

day 1 day 2 unfamiliar home cage home cage cage right-handed

Figure 2. Cortisol concentrations in samples of saliva collected at 09.30 hours (white bars) and 16.30 hours (grey bars) from nine left-handed and eight right-handed common marmosets for the third day after being housed in an unfamiliar cage and for the first 2 days following return to the home cage. Note the diurnal cycle on all days, especially on the days in the home cage: cortisol levels are typically higher in the morning than in the afternoon (Cross & Rogers 2004). Also, note the decline in cortisol levels once the marmosets had been returned to their home cage, but morning cortisol levels of the left-handed compared with the right-handed marmosets are higher on both days in the home cage (the bars marked with a and b differ significantly, twotailed t-test, tZ2.76, pZ0.015, and so do the bars marked c and d, pZ0.04). Values are presented as means and standard errors.

Populations or species comprising roughly equal numbers of left- and right-handed individuals can be considered to be poised for adaptation in response to environmental change (favouring one or the other type through individual selection and depending on which type has the advantage). Does this mean that populations with a directional bias for the use of a preferred hand also have a directional bias for a particular coping style and that those with a left-hand bias are less likely to exploit new resources than those with a right-hand bias? This should be possible to test in natural populations.

4. HAND PREFERENCE ASSOCIATED WITH PHYSIOLOGY AND NEUROANATOMY (a) Stress hormone levels associated with hand preference If left-hand preference is associated with greater fear than is right-hand preference, stress hormone (glucocorticoid) levels should be higher in left-handed animals either chronically or at least in some situations. In fact, as shown in humans, activity of the right hemisphere is associated with higher levels of cortisol secretion ( Wittling & Pflu¨ger 1990; see also Sullivan & Gratton 2002) and greater sympathetic nervous system activity (Wittling 1995, 1997). Also, activity of the right hemisphere is related to both cortisol and fear levels in rhesus macaques (Kalin et al. 1998). Two studies show that this right hemispheric control of the stress response may well be associated with hand preference: Westergaard et al. (2001, 2003) reported an association between hand preference and plasma cortisol levels in rhesus macaques, and Nevue & Moya (1997) found that left-pawed mice have higher corticosterone levels than right-pawed mice. Phil. Trans. R. Soc. B (2009)

Here, I report that salivary cortisol levels tend to be higher in left-handed common marmosets compared with right-handed marmosets in certain circumstances. As part of a study concerned with welfare and housing of primates (Pines et al. 2007), salivary samples were collected from the marmosets in the University of New England colony and assayed for cortisol using a technique that we have developed (Cross et al. 2004). Twice a day, at 09.30 hours and 16.30 hours, saliva samples were collected by an experimenter blind to the hand preferences of the marmosets. These two times were selected because marmosets show the typical cycle of cortisol secretion seen in diurnal animals, cortisol levels being the highest in the morning and decreasing throughout the day (Cross & Rogers 2004). Each marmoset was moved with its cage mate from its home cage to temporary housing into an unfamiliar cage of approximately the same size as the home cage, but with different climbing structures and unfamiliar odours (Pines 2005), where it remained for 3 days before being returned to its home cage after 17.00 hours on that third day. The results of the saliva samples collected on the third day in the novel cage and for the next 2 days back in the home cage are reported here, since they showed significant differences between left- and right-handed marmosets (figure 2). The typical diurnal pattern of cortisol levels was present on all days sampled. Cortisol levels at both times of the day sampled were higher when the marmosets were in the unfamiliar cages than when they were in the home cage. The levels of left-handed marmosets did not differ from those of right-handed marmosets when the marmosets were in the unfamiliar cage but a difference between the left- and righthanded groups occurred after the marmosets were returned to their home cages. On day 1 in the home

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Hand and paw preferences in animals cage, the morning cortisol levels of the left-handed marmosets were significantly higher than those of the right-handed marmosets (U-test, 0.01!p!0.025, one-tailed since the direction of the difference had been predicted). On this day, the morning cortisol levels of the left-handed group had remained elevated, whereas they had declined in the right-handed group. The decline in cortisol levels in the left-handed group was delayed until day 2 in the home cage, but on this day too the levels were significantly higher than those of the right-handed marmosets ( pZ0.04). Therefore, the stressful effects of being in the unfamiliar cage lasted for longer in the left- compared with the right-handed marmosets. Therefore, there is some evidence that hand preference is associated with differing cortisol levels in a manner consistent with the behavioural differences between left- and right-handed individuals. Lefthanded, reactive animals have higher cortisol secretions in certain contexts than do right-handed, proactive animals. In common marmosets, we have other evidence that proactive behaviour lowers cortisol levels: the act of mobbing lowers cortisol levels (Cross & Rogers 2006), and marmosets that consistently perform mobbing more than others have lower cortisol levels (Clara et al. 2007). Hence, it would seem to be a fruitful line of investigation to explore these associations between stress physiology, behaviour and hand preference more fully. Furthermore, it would be interesting to investigate the effects of experience in early life on the stress response, proactive/reactive behaviour and hand preference, since early separation from littermates (mostly studied in rats) is known to have a long-lasting influence on the stress hormone response (e.g. Rees et al. 2006, 2008) and on other behaviour (e.g. Lovic et al. 2001). (b) Brain structure and hand preference Movement of a limb and hand is largely controlled by the motor cortex of the contralateral hemisphere. Entirely consistent with this, predominant use of one hand is matched by enlargement of the cortical representation of that hand in the contralateral motor cortex (Nudo et al. 1992). Also concerning the motor cortex, Hopkins & Cantalupo (2004) found, in chimpanzees, a correlation between structural asymmetry of the precentral gyrus and hand preference on a task requiring coordination of both hands, and Dadda et al. (2006) showed that this asymmetry is restricted to the area of the motor cortex controlling the hands. A similar relationship between asymmetry of the precentral gyrus and hand preference in capuchins has also been reported (Phillips & Sherwood 2005). The question of interest now is whether the use of a preferred hand is associated with structural enlargements or increased connectivity in other cortical regions of the contralateral hemisphere, such as the sensorimotor cortex, the regions used for integrating somatosensory and visual information relating to eye– hand coordination and even the prefrontal cortex. Some evidence indicates that hand preference is associated with asymmetries in the regions of the cortex outside the motor cortex. For example, Hopkins et al. (2007) found that asymmetry of the fronto-orbital Phil. Trans. R. Soc. B (2009)

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sulcus and planum temporale region of the cortex of the chimpanzee correlates with hand preference for tool using. Moreover, the cerebral torque, characterized by broader right frontal and left occipital lobes, is present in the great apes (Pilcher et al. 2001). Recent collaborative research with my colleagues, P. Waite and C. Gorrie, at the University of New South Wales, has revealed, in the common marmoset, that length of the right lateral sulcus, adjusted for brain weight, correlates positively and strongly with per cent right-hand preference (nZ11, rZ0.86, pZ0.001; Gorrie et al. 2008). Thickness of a region of the cortex next to the lateral sulcus, most likely the SII cortex, as far as can be determined from the current brain maps, also correlates positively and strongly with per cent right-hand preference. The latter relationship was found to be significant for the right cortex and there was a close to significant ( pZ0.052) trend for the left cortex. In other words, marmosets with right-hand preferences have thicker SII cortices than left-handed marmosets. Since this region of the cortex is involved in integrating light-touch, somatosensory responses from several digits and the palm of the hand (Krubitzer & Kaas 1990; Kaas 2004) and it is known to have a role in discriminating textures (Murray & Mishkin 1984; Pruett et al. 2000), we have hypothesized that righthanded marmosets might be better than left-handed marmosets in discriminating textures using tactile cues. The SII region of the cortex also has neurons that receive inputs from the frontal visual fields (Krubitzer & Kaas 1990; Kaas 2004), which means SII has a role in visually guided reaching behaviour. The latter might also be superior in right-handed marmosets. These predictions based on the neuroanatomical findings can now be tested empirically. It is plausible that the earlier finding (Cameron & Rogers 1999), that right-handed marmosets touch more novel objects than left-handed marmosets, might depend on superior tactile discrimination ability by right-handed marmosets. In the same study (Gorrie et al. 2008), we found no association between hand preference and the thickness of the ventral somatosensory area, the auditory cortex, the cortical region that may be Brodmann’s area 1 or, surprisingly, the region of the motor cortex that is likely to be concerned with the hands. The association between per cent right-hand preference and thickness of the somatosensory cortex is, therefore, quite specific, although one cannot rule out the possibility that other regions of the cortex not yet measured have size differences associated with hand preference. For certain, anatomical asymmetries outside the motor cortex are associated with hand preference in species other than humans. It is tempting to suggest that the enlarged somatosensory cortex associated with right-hand preference might have been an evolutionary precursor to tool using. Common marmosets have not been reported to use tools but they should be able to learn to do so in a laboratory setting, as shown possible for a rodent in a recent study (Okanoya et al. 2008). Based on right-handed marmosets having a larger SII somatosensory cortex than left-handed marmosets (Gorrie et al. 2008), one can predict that right-handed marmosets might acquire tool using behaviour more readily than left-handed marmosets.

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Hand and paw preferences in animals

5. IMPLICATIONS FOR BEHAVIOUR IN THE NATURAL ENVIRONMENT The association between hand preference for simple reaching and temperament or coping style has been discussed, and the explanation for this association seems to be the predominant use of the left or right hemisphere by individuals. In other words, specialization of the left and right hemispheres (or sides of the brain) to process information in different ways and to control different patterns of behaviour may be the underlying mechanism of expressed behavioural type and hand preference. It seems that each individual has a tendency to use either its left or right hemisphere predominantly and so expresses a consistent coping style or temperament and consistent preference to use the same hand in simple reaching. In some populations, or some species, there may be approximately equal numbers of left-handed, reactive individuals and right-handed, proactive individuals: that is, there is no population asymmetry, although each individual is asymmetrical. At another level, one or the other of these types may be in a majority and hence the population would be asymmetrical. Presumably, as in the case of the common marmoset, having roughly equal numbers of each behavioural type, and its associated hand preference, would allow adaptive changes, both genetic and epigenetic, should the environment change, as others have argued (Dall et al. 2004), but what would it mean if a species shows a strong population bias to use a preferred hand? First, we would need to check that the directional bias has not been imposed by the task used to measure it: as argued above, certain tasks will necessarily demand the use of a particular hemisphere specialized for the processing required. Second, postural constraints may be important. Only simple reaching free from constraints to use the specializations of a hemisphere for processing, in primates at least, reflects behavioural type or coping style. If a strong directional bias to use a preferred hand still exists in the population once task constraints have been eliminated, we would have to conclude that most individuals in the population, or species, express a particular coping style or temperament. There is no reason why the individuals that comprise a species could not adapt to environments in this way. Populations and species may differ in relative dependence on the functions of the left or right hemisphere (as suggested by Vallortigara et al. 2008) and, in some species, this will be reflected in the relative numbers of left- and right-hand preferring individuals. I recognize the difficulties in making such behavioural comparisons across species, but it may not be impossible to assess and compare species along these lines and reliable comparisons of cortisol response could be made. It has been recognized previously that populations and species may vary in behavioural type (e.g. referred to as behavioural syndromes by Sih et al. (2004)), and that this may affect the distribution of species and adaptability to environmental change. I am suggesting that hand preference for simple reaching could be added as a measure of the behavioural ‘syndrome’. Of course, the hand preferences would need to be measured in wild populations. The adaptive flexibility potentially reflected in populations with equal numbers Phil. Trans. R. Soc. B (2009)

of left- and right-handed individuals, as found in our marmoset colony, is not always advantageous and, in the case of captive animals, may result from the absence of natural selection or habitat demands. Directional biases for hand and hemisphere preferences might also depend on social demands. Vallortigara & Rogers (2005) have drawn attention to the possibility that directional biases may be beneficial in terms of predictability of social interactions and a number of studies have shown that animals react differently to conspecifics on their left or right side (baboons: Casperd & Dunbar 1996; anurans: Robins et al. 1998; fishes: Sovrano et al. 1999; birds: Vallortigara et al. 2001; Zucca & Sovrano 2008). Such biases, however, can be expressed quite independently of limb preferences, but any consistent demand for a particular social behaviour, and hence hemisphere, to be expressed may be reflected in a directional bias of preferred limb use. Consistent and frequent agonistic interactions may, for example, mean that the right hemisphere assumes control of behaviour and, along with it, left-hand preference and a reactive coping style may also be expressed. In summary, hand/limb preferences at the individual level are associated with general aspects of behaviour, particularly coping style and its associated approach and withdrawal behaviour. Recognition that hand preference may be a reflection of the dominant hemisphere (the hemisphere contralateral to the preferred hand) has led to the hypothesis that populations or species in which there is a majority of either left- or right-handed individuals have adapted in favour of one or other of the coping styles, or some other aspect of behaviour expressed by one of the hemispheres. The experimental procedures were approved by the Animal Ethics Committee of the University of New England in adherence with the Australian Code of Practice for the Care and use of Animals for Scientific Purposes (Australian Government, 7th edn, 2004). I am grateful to Dr M. K. Pines for collection of the saliva samples and for assaying the cortisol levels, and to Dr M. A. Hook, L. E. Stewart and D. Gordon for collecting some of the hand preference scores presented in figure 1. The research on the common marmosets was funded by an ARC grant to L.J.R.

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marmoset (Callithrix jacchus): incidence and chemical composition. Acta Neuropathol. 103, 48 –58. (doi:10.1007/ s004010100429) Gordon, D. & Rogers, L. J. In preparation. Behavioural differences between left- and right-handed common marmosets. Gorrie, C. A., Waite, P. M. E. & Rogers, L. J. 2008 Correlations between hand preference and cortical thickness in the secondary somatosensory (SII ) cortex of the common marmoset, Callithrix jacchus. Behav. Neurosci. 122, 1343–1351. (doi:10.1037/a0013279) Guiard, Y., Diaz, G. & Beaubaton, D. 1983 Left-hand advantage in right handers for spatial constant error: preliminary evidence in a unimanual ballistic aimed movement. Neuropsychologia 21, 111–115. (doi:10.1016/ 0028-3932(83)90106-9) Gu¨ven, M., Elalmis, D. D., Binokay, S. & Tan, U. 2003 Population right-paw preference in rats assessed by a new computerized food-reaching test. Int. J. Neurosci. 113, 1675 –1689. (doi:10.1080/00207450390249258) Harris, L. 1989 Footedness in parrots: three centuries of research, theory, and mere surmise. Can. J. Physiol. 43, 369 – 396. (doi:10.1037/h0084228) Hook, M. A. & Rogers, L. J. 2000 Development of hand preferences in marmosets (Callithrix jacchus) and effects of ageing. J. Comp. Psychol. 114, 263 –271. (doi:10.1037/ 0735-7036.114.3.263) Hook, M. A. & Rogers, L. J. 2008 Visuospatial reaching preferences of common marmosets (Callithrix jacchus): an assessment of individual biases across a variety of tasks. J. Comp. Psychol. 122, 41–51. (doi:10.1037/0735-7036. 122.1.41) Hook-Costigan, M. A. & Rogers, L. J. 1998 Eye preferences in common marmosets (Callithrix jacchus): influence of age, stimulus, and hand preference. Laterality 3, 109 –130. (doi:10.1080/135765098397322) Hopkins, W. D. & Bennett, A. 1994 Handedness and approach-avoidance behaviour in chimpanzees. J. Exp. Psychol. 20, 413 – 418. (doi:10.1037/0097-7403.20.4.413) Hopkins, W. D. & Cantalupo, C. 2004 Handedness in chimpanzees (Pan troglodytes) is associated with asymmetries of the primary motor cortex but not with homologous language areas. Behav. Neurosci. 118, 1176 –1183. (doi:10. 1037/0735-7044.118.6.1176) Hopkins, W. D., Wesley, M. J., Izard, M. K., Hook, M. & Schapiro, S. J. 2004 Chimpanzees (Pan troglodytes) are predominantly right-handed: replication in three populations of apes. Behav. Neurosci. 118, 659 –663. (doi:10. 1037/0735-7044.118.3.659) Hopkins, W. D., Russell, C., Cantalupo, C., Freeman, H. & Schapiro, S. J. 2005 Factors influencing the prevalence and handedness of throwing in captive chimpanzees (Pan troglodytes). J. Comp. Psychol. 119, 363 – 370. (doi:10.1037/ 0735-7036.119.4.363) Hopkins, W. D., Russell, C. & Cantalupo, C. 2007 Neuroanatomical correlates of handedness for tool use in chimpanzees (Pan troglodytes): implication for theories on the evolution of language. Psychol. Sci. 18, 971– 977. (doi:10.1111/j.1467-9280.2007.02011.x) Howell, S., Higley, J. D. & Westergaard, G. C. 2007 The biological correlates of hand preference in rhesus macaques. In The evolution of hemispheric specialization in primates (ed. W. D. Hopkins), pp. 253–276. Oxford, UK: Elsevier. Kaas, J. H. 2004 Somatosensory system. In The human nervous system (eds G. Paxinos & J. Mai), pp. 1084–1085. 2nd edn. San Diego, CA: Elsevier Academic Press. Kalin, N. H., Larson, C., Shelton, S. E. & Davidson, R. J. 1998 Asymmetric frontal brain activity, cortisol, and Phil. Trans. R. Soc. B (2009)

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Phil. Trans. R. Soc. B (2009) 364, 955–963 doi:10.1098/rstb.2008.0240 Published online 4 December 2008

Ascending and descending mechanisms of visual lateralization in pigeons Carlos-Eduardo Valencia-Alfonso1,†, Josine Verhaal1,2,† and Onur Gu¨ntu¨rku¨n1,2,* 1

Biopsychology, Faculty of Psychology, Institute for Cognitive Neuroscience, and 2International Graduate School of Neuroscience, Ruhr-University Bochum, Universita¨tsstraße 150, 44780 Bochum, Germany

Brain asymmetries are a widespread phenomenon among vertebrates and show a common behavioural pattern. The right hemisphere mediates more emotional and instinctive reactions, while the left hemisphere deals with elaborated experience-based behaviours. In order to achieve a lateralized behaviour, each hemisphere needs different information and therefore different representations of the world. However, how these representations are accomplished within the brain is still unknown. Based on the pigeon’s visual system, we present experimental evidence that lateralized behaviour is the result of the interaction between the subtelencephalic ascending input directing more bilateral visual information towards the left hemisphere and the asymmetrically organized descending telencephalic influence on the tecto-tectal balance. Both the bilateral representation and the forebrain-modulated information processing might explain the left hemispheric dominance for complex learning and discrimination tasks. Keywords: asymmetry; top–down influence; interhemispheric transfer; tectofugal pathway; thalamofugal pathway; Wulst

1. INTRODUCTION For more than a century, the scientific community has known about brain asymmetries. Studies with splitbrain patients and research on language and further lateralized processes uncovered diverse functional hemispheric specializations and thus differences in the way each hemisphere represents and processes information. However, it took until the late twentieth century to realize that lateralization of brain functions is not exclusively human, but also occurs in other species ( Nottebohm 1970). Since then, extensive research has demonstrated that asymmetries are widespread within the animal kingdom, and that lateralized functions across vertebrates follow a common pattern. The right hemisphere is generally related to spatial and instinctive reactions, while the left hemisphere has been linked to experience-based behaviours (Andrew & Rogers 2002). Currently, a significant part of asymmetry research focuses on the common and ancestral characteristics of this phenomenon, and intends to reveal the neurobiological mechanisms underlying this pattern through the use of animal models. In order to produce these lateralized behaviours, each hemisphere must receive or process information about the outside world differently, and, consequently,

might have an asymmetric representation of it. Therefore, one important issue is how exactly these lateralized representations are achieved in each hemisphere. One possibility is that ascending input is guided in a way that each side of the brain receives a different type or a different amount of information. However, it is also conceivable that higher stations in each hemisphere obtain the same information but process it in a different way or influence the way it is gathered. Therefore, it is possible that functional asymmetries are generated in a bottom–up or in a top–down fashion. Using the birds’ visual system as a research model, we extend previous evidences and add new ones, suggesting that lateralized visual functions are related to both ascending and descending pathways. We argue that these two streams shape hemispheric representation of visual information in pigeons. Additionally, we posit that this kind of integration is likely to be the case in many species, including humans.

2. BIRDS AS AN ASYMMETRY MODEL The visual system of birds constitutes an excellent animal model to investigate brain asymmetries. Their optic nerves decussate nearly completely (Weidner et al. 1985), and only limited recrossing commissures at the tectal and diencephalic level allow the necessary interhemispheric communication. As a result of the limited commissural fibres between the two hemispheres, each hemisphere processes mainly visual information from the contralateral eye, but also, to a minor extent, information coming from the ipsilateral eye.

* Author and address for correspondence: Biopsychology, Faculty of Psychology, Institute for Cognitive Neuroscience, RuhrUniversity Bochum, Universita¨tsstraße 150, 44780 Bochum, Germany ( [email protected]). † These authors contributed equally to this work. Electronic supplementary material is available at http://dx.doi.org/10. 1098/rstb.2008.0240 or via http://journals.royalsociety.org. One contribution of 14 to a Theme Issue ‘Mechanisms and functions of brain and behavioural asymmetries’.

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Figure 1. Schematic of the main ascending and descending pathways in the pigeon’s visual system as seen when looking from an anterior position onto the brain; dorsal is at the top. (a) In the tectofugal pathway ( blue arrows), optic nerve fibres project to the contralateral optic tectum (TeO), from where fibres lead bilaterally to the thalamic nucleus rotundus (Rt), which then projects to the ipsilateral entopallium (E) of the forebrain. (b) The thalamofugal pathway (orange arrows) projects from the retina via the contralateral nucleus geniculatus lateralis, par dorsalis (Gld) bilaterally to the visual Wulst in the telencephalon (Gu¨ntu¨rku¨n 2000). From the Wulst, a massive forebrain projection, the tractus septomesencephalicus ( TSM, green arrows) projects to the tectum. The structures are not all normally visible within a single plain because of their different positions in the anterior– posterior axis, but, for explanatory purposes, they are showed here as seeing through a glass brain.

Besides, chicks and pigeons, two of the most popular bird models, show the same basic behavioural dichotomy described above for vertebrates. In these birds, there is a left hemisphere dominance for experience-based object manipulation (Andrew et al. 2000) and visual discrimination (Gu¨ntu¨rku¨n 1985; Zappia & Rogers 1987). In addition, the left side of the brain is related to complex cognitive abilities such as discrimination of two-dimensional artificial patterns (Gu¨ntu¨rku¨n 1985), three-dimensional natural objects (Gu¨ntu¨rku¨n & Kesch 1987), geometrical optic illusions (Gu¨ntu¨rku¨n 1997b), reversal learning (Diekamp et al. 1999) and concept learning ( Yamazaki et al. 2007). By contrast, their right hemisphere is associated with spatial orientation tasks ( Tommasi & Vallortigara 2001) and species-typical or instinct-based reactions such as social discrimination and attack (Vallortigara & Andrew 1991, 1994), fear responses (Phillips & Youngren 1986; Rogers et al. 1998) and sexual behaviour (Rogers et al. 1985). These studies clearly show why the visual system of birds constitutes a very useful tool for investigating the neuronal mechanisms of brain lateralization. In birds, visual representation is processed by two parallel pathways within the brain: the tectofugal and the thalamofugal systems (figure 1). These are suggested to be equivalent to the extrageniculocortical and the geniculocortical visual pathways of mammals, respectively (Shimizu & Karten 1993; Hellmann & Gu¨ntu¨rku¨n 1999). The avian tectofugal pathway is composed of optic nerve fibres projecting to the contralateral optic tectum. From the optic tectum, fibres lead bilaterally to the thalamic nucleus rotundus (Gu¨ntu¨rku¨n et al. 1993), which then project to the ipsilateral entopallium of the forebrain (figure 1a). The thalamofugal pathway projects from the retina to the contralateral nucleus geniculatus lateralis, pars dorsalis. From here, fibres project bilaterally to the visual Wulst in the telencephalon (figure 1b). In spite of the anatomical and functional Phil. Trans. R. Soc. B (2009)

separation between the thalamofugal and tectofugal systems, they have been shown to interact extensively at many levels. An important interaction takes place between the visual telencephalic areas and the subtelencephalic regions. Of particular note is the relationship between the telencephalic Wulst and the optic tectum (Bagnoli et al. 1982). Each Wulst has a direct ipsilateral connection to the optic tectum (Manns et al. 2007) through the tractus septomesencephalicus (TSM, figure 1b). Interhemispheric differences in the tectofugal and thalamofugal pathways and the way they interact with each other might be related to the common asymmetrical pattern observed in vertebrates’ behaviour. 3. ASYMMETRIES OF ASCENDING, DESCENDING AND COMMISSURAL SYSTEMS Several studies in pigeons evince anatomical and physiological asymmetries in tectofugal subtelencephalic ascending pathways that could shape information heading for each hemisphere. Neurons in the optic tectum (Gu¨ntu¨rku¨n 1997a), the rotundus (Manns & Gu¨ntu¨rku¨n 1999) and the associated nucleus subpretectalis (Freund et al. 2008) are larger in the left hemisphere, suggesting lateralized processing of information. Moreover, the number of contralateral tectorotundal projections is asymmetrical, having about twice the number of projections from the right optic tectum to the left rotundus as in the opposite direction (Gu¨ntu¨rku¨n et al. 1998; figure 2a). Thus, the left hemisphere receives more information (at least by the tectal route) about the right visual field than the right hemisphere receives about the left visual field. Electrophysiological studies provide some support for these findings by showing that rotundal single units with responses to ipsilateral eye stimulation occur exclusively in the left thalamus ( Folta et al. 2004). Valencia-Alfonso et al. (in preparation) confirmed in a much larger sample of recorded neurons that twice as many neurons in the left rotundus had bilateral visual

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Figure 2. Asymmetry of the bilateral representation in the left rotundus. (a) Anatomically, cells in the left rotundus show more bilateral afferents from the tectum compared with the right rotundus (Gu¨ntu¨rku¨n et al. 1998). A bilaterality index of 1 describes equal amount of ipsilateral and contralateral afferents, while 0 means only contralateral afferents. (b) Accordingly, electrophysiological evidence ( Valencia-Alfonso et al. in preparation) shows that more neurons respond to both ipsi- and contralateral eye stimulation in the left rotundus. Bars show s.e.; pZ0.01.

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Figure 3. Forced choice task. Before each session, one of the eyes was covered with a patch and the pigeon was subjected to a monocular training in which always the same two isoluminant colours were simultaneously presented, each on one pecking key, over 60 trials. One of them was rewarded (SC) with access to food for 3 s. Pecking of non-rewarded colour (SK) would lead to 20 s of darkness. On the next day, the other eye performed the same task with two different colours. The presentation of SC and SK was balanced in the right and left key to avoid a side bias. As a result, each eye/hemisphere ((a) right eye/left hemisphere training and (b) left eye/right hemisphere training) was exposed to only two colours (known colours), and never to the pair used with the other eye (unknown colours). Discrimination performance was tested for known and unknown stimuli under normal conditions and under reversible tetrodotoxin anaesthesia in the left Wulst (LW), right Wulst (RW), or both Wulsts (BW). For details see the electronic supplementary material.

input, compared with the right rotundus (figure 2b). Additionally, although rotundal cells responding only to contralateral stimulation were strongly modulated by the left Wulst (LW), the aforementioned cells with a bilateral representation were not modulated by descending forebrain projections. Thus, the rotundal neurons that might constitute the asymmetrical representation at the thalamic side were not under top– down control and were only operating in a bottom–up mode. Gu¨ntu¨rku¨n & Hahmann (1999) obtained lesion data that are also in accordance with these anatomical and physiological evidences for an asymmetry of representation. The ascending tectofugal pathway then possibly creates a more bilateral representation at the forebrain level. The first aim of the present study is to test the functional consequences of this ascending asymmetry. Phil. Trans. R. Soc. B (2009)

In addition, commissural pathways are possibly lateralized. Keysers et al. (2000) discovered that the left tectum is able to inhibit activity in the right tectum to a larger extent than vice versa. This would suggest that when the left hemisphere is active, a strong inhibition towards the right hemisphere is exerted, but not the other way around. Transecting this inhibitory intertectal commissure results in a reversal of behavioural asymmetries, probably because the right hemisphere is no longer inhibited (Gu¨ntu¨rku¨n & Bo¨hringer 1987). These studies imply an imbalance of inhibition between the two tecta. Probably, the left tectum has a higher probability to gain control over tectofugal processing by inhibiting the contralateral right side. This lateralized tecto-tectal inhibition is modulated by the forebrain. Two forebrain pathways, the tractus occipitomesencephalicus (TOM) and the TSM,

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descend towards the ipsilateral tectum and are known to modulate tectal response properties (Leresche et al. 1983). Gu¨ntu¨rku¨n & Hoferichter (1985) were able to show that a transection of the left but not the right TOM affected visual discrimination performance. Thus, it is possible that the forebrain interacts not with the neurons within the tectum itself, but with inhibitory tecto-tectal pathways, with the left descending system having a much stronger impact than the right. Up to now, this descending asymmetry was tested for the TOM only. The TSM descends from the Wulst towards the tectum. The second aim of the present study is to analyse the functional consequences of the descending asymmetry via the TSM. This was accomplished by temporarily inactivating the Wulst on either side.

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4. TESTING THE PROCESSING OF UNIHEMISPHERIC INFORMATION The aim of the present study was twofold. First, we intended to test the functional consequences of an asymmetrical representation during the acquisition of a colour discrimination task. Second, we wanted to analyse the functional architecture of the asymmetrical top–down forebrain regulation at a behavioural level. To this end, we trained pigeons on a monocular forced choice task in which the animals had to discriminate between rewarded (SC) and nonrewarded (SK) colours on two pecking keys. These were presented simultaneously to one eye, while the other one was temporarily covered with an eye cap. Each eye learned to discriminate a different pair of colours with display isoluminance. The colours used were balanced across subjects and presentation side in the Skinner box (figure 3). Daily training sessions (60 trials) were performed with alternating eyes until each eye reached 90 per cent of correct responses in three successive sessions. Owing to the almost total crossing in the visual pathway of the pigeon, occlusion of an eye restricts visual input mostly to the hemisphere contralateral to the seeing eye. Thus, at the end of the training sessions, each hemisphere had only experience with one pair of colours, but was never directly exposed to the other pair. As a consequence, there was a pair of ‘known’ and ‘unknown’ colours for each eye/ hemisphere (figure 3). After discriminations were monocularly learned, the pigeons were chronically implanted with steel canules in the hyperpallium accessorium of the left and right Wulst (RW; anterior 12.0, lateral G1.5 and depth 2.0, according to Karten & Hodos pigeons’ brain atlas, 1967; for details see methods in the electronic supplementary material). After one week of recovery, the animals were tested with normal training sessions to evaluate any post-surgery effects on performance. All pigeons showed discrimination performance above 90 per cent with each eye, evincing no impairments owing to the surgery. Then, each eye was separately tested with a mixture of trained (known) and untrained (unknown) colours. Trials presenting unknown colours constituting 10 per cent of the session, were presented randomly and were not rewarded (catch trials) in order to prevent any direct learning. These test sessions were performed under normal conditions (None), and Phil. Trans. R. Soc. B (2009)

right eye

Figure 4. Superior performance of the right eye/left hemisphere for the discrimination of the unknown colour pair, which was learned with the other eye. In order to evaluate the interhemispheric transfer of information after the training phase, we tested each eye with the colours learned by the other eye. Both hemispheres performed above chance but correct responses with the right eye were significantly higher (tZ2.13; pZ0.001) compared with the left. Bars show s.e.; pZ0.001.

under temporarily inactivation of the LW, RW or both Wulsts (BW). Transitory inactivation of the Wulst was accomplished with injections of tetrodotoxin, which temporarily blocks neuronal sodium channels, through the implanted canules. The sessions were performed on different days to allow recovery from the injections. The order of Wulst inactivation conditions as well as the eye tested were balanced across the subjects. In order to test our first hypothesis concerning the functional consequences of an asymmetric bilateral representation in ascending pathways, the difference in performance between the left and right eye under normal conditions (None) was tested using a Student’s t-test. Because ascending systems promote a more bilateral representation within the left hemisphere, we expected that under normal conditions, the right eye (left hemisphere) would have better performance discriminating unknown colours that were learned with the left eye (right hemisphere). Our results corroborate this hypothesis confirming an asymmetrical subtelencephalic basis for a more bilateral representation within the left side of the brain. Since pigeons learned the task equally fast with both hemispheres during the training phase (t-test, pO0.05), both hemispheres were performing equally well on the visual discrimination task. Coherently, no asymmetry in discrimination performance for the known stimuli was found. When tested for their performance on the unknown stimuli, the pigeons performed above chance level with both the left and the right hemispheres. However, there was a higher interhemispheric transfer of information towards the left side of the brain. The right eye/left hemisphere system showed a significantly higher performance (tZ2.31; pZ0.001) for the stimuli learned with the ipsilateral eye (figure 4). Since discrimination performance was equal for the known colour for the left and the right eye, the asymmetry

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0.9 0.8 0.7 0.6 0.5 0.4 0.3

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Figure 5. Asymmetric modulation of the left Wulst (LW) on the colour discrimination task. LW inactivation impaired performance of the left eye (black diamonds, LE) and the right eye (grey circles, RE) for (a) known and (b) unknown stimuli compared with the None condition, while right Wulst (RW) or both Wulst (BW) inactivation showed no significant changes compared with None. (a) During Wulst inactivation, the discrimination performance of known stimuli was significantly affected (F3,36Z3.94; pZ0.016). The main influence was determined by anaesthesia in the LW ( pZ0.012), while there was no such significant difference after the anaesthesia of RW ( pZ0.408) or BW ( pZ0.085). (b) In a similar way, analysis of performance to unknown stimuli showed that there was a significant impact of Wulst anaesthesia (F3,36Z4.22; pZ0.012). Post hoc analyses showed that the main influence in this effect was the decrease in performance under the LW condition ( pZ0.002), while performance was not significantly affected after RW ( pZ0.095) or BW anaesthesia ( pZ0.131). Bars show s.e.; pZ0.05.

found when discriminating the unknown colours is likely to occur due to a higher amount of transfer towards the left hemisphere and not due to a generally higher discrimination performance using this hemisphere. Thus, these results confirm the superior capacity of the left hemisphere to handle a more bilateral representation of the visual stimulus in the brain compared with the right hemisphere. Our second goal was to analyse the functional implications of a possible asymmetric top–down modulation through the TSM. We therefore compared each eye performance in the discrimination task under different conditions of Wulst inactivation. The analysis was conducted with a repeated-measure ANOVA using the trained eye (left–right) and Wulst inactivation (None, LW, RW and BW) as within factors for both known and unknown stimuli. Bonferroni post hoc tests were used to test for specific differences. This gave us the opportunity to test whether this descending system has an asymmetrical effect similar to what was obtained by Gu¨ntu¨rku¨n & Hoferichter (1985) for the TOM. We expected that inactivation of the Wulst would reduce activity within the descending telencephalotectal pathway via the TSM. The multivariate analysis with Wulst inactivation and eye as within factors showed no significant differences for the trained eye factor in the discrimination performance. Using the right or the left eye, the pigeons showed similar discrimination levels in all experimental conditions, suggesting that both hemispheres were equally capable of performing the task, and were similarly affected by the different forebrain inactivation. Therefore, they were analysed as a single population of data. However, inactivation of the Wulst had an important impact (F3,36Z3.95; pZ0.016). Inactivation of the LW accounts for most of the variance, because, during inactivation of this Wulst, the discrimination performance of both eyes for the trained colours (known colours) was significantly lower compared with the None condition ( pZ0.012), while inactivation of the RW or even BW was not significantly Phil. Trans. R. Soc. B (2009)

different from the None condition (figure 5a). The same situation occurred for ‘unknown colours’. There was a significant impact of the forebrain inactivation on the pigeon’s performance for both eyes while discriminating colours to which they were previously never exposed (F3,36Z4.22; pZ0.012). The post hoc analysis showed again that this was mainly caused by an impaired discrimination performance after the LW was inactivated compared with the None condition ( pZ0.002), while there was no significant decrement when the RW or even BW were inactivated (figure 5b). In summary, we observed that inactivation of the LW led to significant impairments in discrimination not only in the right eye/left hemisphere, but also in the left eye/right hemisphere, for both known and unknown stimuli (figure 5). Inactivation of the RW, and more remarkably, of BW, produced no significant changes. This suggests that there is an asymmetric left forebrain influence on tectofugal ascending activity, supporting the idea of a top–down modulation that contributes to the generation of lateralized representation. Taken together, our main results support, at the behavioural level, both the more bilateral representation and the asymmetric forebrain influence associated with the left hemisphere. In the following sections, these two main issues are discussed in the context of ascending and descending mechanisms for brain asymmetries. (a) Asymmetric transfer of interhemispheric information and ascending systems Given the almost total crossing of the visual system in birds, behavioural experiments involving monocular training allow us to investigate the ‘knowledge’ that one hemisphere possesses. The better performance of the left hemisphere in discriminating colours learned exclusively with the right hemisphere is in accordance with the evidence reviewed above that the left-sided rotundal projections transmit a high proportion of bilateral visual information. Thus, already at the level of ascending systems, the left hemisphere knows more

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about the input to the right than vice versa. This finding could also explain the results of Diekamp et al. (1999), who found a more efficient transfer from left-eye knowledge towards the right than vice versa. This means that the left rotundus receives more information about the colours learned by the right hemisphere. It is therefore able to integrate information from both eyes to a higher extent than the right rotundus. As a consequence of these anatomical and functional properties of the interhemispheric commissures, the more bilateral information might then be transposed to the forebrain, giving the left hemisphere a more bilateral representation of the monocular discrimination task. As demonstrated in several bird species (Catania 1965; Ogawa 1966; Mello 1968; Meier 1971; Green 1978; Francesconi et al. 1982; Remy & Watanabe 1993), interhemispheric transfer of information can only be accomplished through one of the subtelencephalic commissures, and it seems to be sensitive to lesions in the tecto- but not in the thalamofugal system (Watanabe et al. 1986). More specifically, interocular transfer of pattern, brightness and colour discrimination was impaired by section of supra-optic decussation (Francesconi et al. 1982) but not by the tectal commissure (Catania 1965; Cue´nod & Zeier 1967; Meier 1971; Cue´nod 1974; Burkhalter & Cuenod 1978). In addition, only birds with lesions of the ventral supra-optic decussation (where tectorotundal information passes) showed impaired transfer ( Watanabe 1985). Taken together, these experiments show that interhemispheric transfer of information is likely to occur through the tecto-rotundal commissure. Since these fibres are asymmetrically organized (Gu¨ntu¨rku¨n et al. 1998), this can explain the bias of bilateral information towards the left hemisphere. Although bottom–up ascending systems explain asymmetric bilateral representations and lateralized interhemispheric transfer, they are not sufficient to elucidate why inactivation of the left but not of both forebrains reduces task performance. Therefore, the possibility of an asymmetric descending forebrain modulation of inhibitory commissural interactions is discussed in §4b. (b) Descending asymmetric modulation Following inactivation of the LW, monocular discrimination performance was impaired for both eyes for known and unknown stimuli. Neither inactivation of the RW nor, astonishingly, simultaneous inactivation of both forebrain structures resulted in significant deficits (figure 5). Consequently, there is an asymmetric telencephalic modulation, but this effect cannot be attributed to a unihemispheric left forebrain influence, but to a descending impact on the balance of subtelencephalic interactions that is more affected by the left hemisphere. Such a deficit pattern cannot be explained by only referring to asymmetries of ascending visual pathways. A possible explanatory mechanism was already proposed in the 1960s. Sprague (1966) investigated the influence of telencephalic and mesencephalic lesions on visually guided behaviour in cats. Their results showed that unilateral posterior cortical lesions resulted in contralateral hemianopia, which was Phil. Trans. R. Soc. B (2009)

abolished by damaging the contralateral superior colliculus. This suggests that the two superior colliculi constitute an inhibitory balance across the midbrain commissures. Descending projections from the cortex excite the ipsilateral colliculus. Shifts of visual attention from one visual hemifield to the other are then funnelled as descending activations towards one colliculus, leading to an inhibition of the other side. Lesions of one cortex result in an imbalance of the colliculo-collicular inhibition and therefore produce a complete inhibition of the lesioned side. Given that the interhemispheric commissure between the colliculi has inhibitory properties, this balance could be restored when the contralateral colliculus is lesioned. This hypothesis was confirmed by transecting the commissure, resulting in a restoration of the behavioural effects of the cortical lesion. Additional research in mammals supports this hypothesis at the behavioural (Wood 1973; Sherman 1974) and electrophysiological (Goodale 1973; Saraiva et al. 1976; Silakov 1977) level. Studies in birds corroborate the asymmetric nature of forebrain modulation on the subtelencephalic balance. Unilateral lesions of the left TOM, connecting the telencephalic arcopallium with the optic tectum in pigeons, lead to severe deficits in the total number of pecking responses emitted under both monocular and binocular conditions, while lesions of the right and of the bilateral TOM lead to no deficits at all (Gu¨ ntu¨ rku¨ n & Hoferichter 1985). Furthermore, Nau & Delius (1981) found deficits after unilateral, but not after bilateral lesions of the Wulst in pigeons. In our study, only unilateral inactivation of the LW impaired discrimination performance, while inactivation of BW had a less pronounced effect. This behavioural evidence is supported by electrophysiological findings showing that the Wulst is capable of influencing the neural responses within the optic tectum (Bagnoli et al. 1979). Since functional lateralization depends strongly on a dynamic asymmetrical balance between left and right subtelencephalic processes, descending projections acting on one or the other side could differently affect the equilibrium. Anatomically, the descending pathways from the Wulst onto the tectum have the same amount of ipsilateral fibres within each hemisphere (Manns et al. 2007). Thus, it is likely that not the descending system is lateralized, but the telencephalothalamic transmission at the tectal level. Indeed, inhibitory intertectal regulation is stronger from the left to the right optic tectum (Keysers et al. 2000). Inactivation of the LW could therefore alter the dynamics of the intertectal inhibition more profoundly than RW anaesthesia. This telencephalic participation might provide the left hemisphere with a dominant executive control as outlined below. Taken together, these experiments lead to the general concept that lateralization at the midbrain level is modulated in a top–down manner by the forebrain. Since the intertectal connection is asymmetrically organized, inactivation of the left can cause a greater imbalance in the intertectal interaction, resulting in the observed asymmetric performance in a discrimination task. Therefore, asymmetric ascending pathways and descending modulatory inputs cooperate

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5. COMPARATIVE PERSPECTIVES IN AN ASYMMETRIC REPRESENTATION The experimental evidence reviewed and presented in this paper leads to the general idea that asymmetries of visual function in pigeons result at least in part from a dynamic interaction between ascending and descending systems. On the one hand, there is a bottom–up asymmetric subtelencephalic system, which sends more bilateral information via the thalamic rotundus to the left telencephalon. This explains the higher capacity of this hemisphere to process bilateral information and its access to information that is processed by the other hemisphere. On the other hand, the forebrain exerts a modulation on the asymmetric intertectal balance, adding telencephalic influence to an asymmetrically organized brainstem system that results in left hemisphere dominance for executive control. Asymmetrical representations are common among many species, including humans. For both hand movements and visual attention tasks, there is evidence that one hemisphere has a better bilateral representation than the other one. For hand motor control, the left hemisphere seems to have a more bilateral representation. Movements of both the right and left fingers activate responses within the left hemisphere. By contrast, the right hemisphere was only activated by movements of the left fingers (Kim et al. 1993; Durwen & Herzog 2008; Herzog & Durwen 2008). For visuospatial attention, by contrast, it is the right hemisphere that has a more bilateral representation. This is visible in visuospatial attention tasks in which the right parietal lobe is active during attentional shifts towards both visual fields, while the left parietal lobe is only active after shifts towards the contralateral hemisphere (Corbetta et al. 1993; Vandenberghe et al. 1997). As a result of this bilateral representation on the right side, patients with right parietal lesions neglect the left visual hemifield, while left lesions usually produce no neglect (Weintraub & Mesulam 1988). There is also evidence that in humans such bilateral representations could be linked to an asymmetric velocity of transfer towards the specialized hemisphere ( Nowicka et al. 1996). Marzi et al. (1991) found that visuomotor information was transferred faster from the right to left hemisphere and then vice versa (Nalcaci et al. 1999). Asymmetries for a certain brain function could therefore go along with asymmetries of the respective representation. This arrangement might result from the need of the dominant system to integrate all information across hemifields to properly guide behaviour. Since an integration of sensory information via forebrain commissures goes along with long delays owing to the commissural conduction time (Ringo et al. 1994), a bilaterality of ascending projections towards the functionally dominant representation could be the evolutionary solution. Our second major result is that the left hemisphere has a higher impact on the inhibitory tecto-tectal system. By this mechanism, the left forebrain is Phil. Trans. R. Soc. B (2009)

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essentially able to temporarily gain control over the behavioural output of the animal. Theories on the evolutionary advantage of cerebral asymmetries have always revolved around the concept of a singular executive control to decide between two behavioural alternatives that result from processes within the two hemispheres (Vallortigara & Bisazza 2002). These theories usually assume partly overlapping and thus hemisphere-specific modes of information processing. Information is subsequently transferred for executive control to the functionally dominant side (Aboitiz 1992; Ringo et al. 1994). Most probably, the virtually complete unilateral control of language or other processes in split-brain patients results from such a process (Heilmann 1995; Gazzaniga 2000). In birds, this exclusive single-hemisphere control could be enabled via descending forebrain pathways onto an asymmetrically organized inhibitory tecto-tectal system. All subjects were kept and treated according to the German guidelines for the care and use of animals in neuroscience, and the research was approved by the national committee of the State of Nordrhein Westfalen, Germany. This research was financed by the German Service of Academic Exchange ( DAAD) under Contract No. A0421646 (C.E.V. ) and a Marie Curie Early Stage Research Training Fellowship of the European Community’s Sixth Framework Programme under contract number MESTCT-2005-020385 ( J.V. ). We would like to thank Katharina Banscherus for her collaboration in the experiments.

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Phil. Trans. R. Soc. B (2009) 364, 965–981 doi:10.1098/rstb.2008.0229 Published online 4 December 2008

Review

Lateralization of social cognition in the domestic chicken (Gallus gallus) Jonathan Niall Daisley, Elena Mascalzoni, Orsola Rosa-Salva, Rosa Rugani and Lucia Regolin* Department of General Psychology, University of Padova, Via Venezia 8, Padova 35131, Italy In this paper, we report on the ongoing work in our laboratories on the effect of lateralization produced by light exposure in the egg on social cognition in the domestic chick (Gallus gallus). The domestic chick possesses a lateralized visual system. This has effects on the chick’s perception towards and interaction with its environment. This includes its ability to live successfully within a social group. We show that there is a tendency for right brain hemisphere dominance when performing social cognitive actions. As such, chicks show a left hemispatial bias for approaching a signalled target object, tend to perceive gaze and faces of human-like masks more effectively when using their left eye, are able to inhibit a pecking response more effectively when viewing a neighbour tasting a bitter substance with their left eye, and are better able to perform a transitive inference task when exposed to light in the egg and when forced to use their left eye only compared to dark-hatched or right eye chicks. Some of these effects were sex specific, with male chicks tending to show an increased effect of lateralization on their behaviours. These data are discussed in terms of overall social cognition in group living. Keywords: chick; Gallus gallus; lateralization; social cognition; brain hemisphere

1. INTRODUCTION It is now well known that brain asymmetries occur throughout the animal kingdom (Rogers & Andrew 2002; Vallortigara & Rogers 2005). What was once considered a uniquely human characteristic since being described by Broca (1865), brain lateralization and its behavioural effects has been found and studied in a wide range of species, including non-human primates (e.g. Fernandez-Carriba et al. 2002), birds (e.g. Rogers 1997), amphibians ( Vallortigara et al. 1998), fishes (e.g. Sovrano et al. 1999) and invertebrates (Ades & Ramires 2002; Letzkus et al. 2007; Rogers & Vallortigara 2008). This paper concerns itself with the research carried out in our laboratories on the domestic chick (Gallus gallus domesticus), specifically in relation to the effect of brain lateralization on its social cognition. By social cognition, we would suggest this to mean the way the chick interacts and perceives others, including non-conspecifics such as predators, in such a manner as to perform biologically relevant responses important for its survival within a group context. The development and behavioural effects of brain lateralization have been extensively studied using the chick as a model (see Rogers 1995). As such, the domestic chick, as with other avian species studied, provides a highly malleable experimental model to

study lateralization owing to the fact that the embryo develops outside the female’s body, independently in an egg. Lateralization of the chick’s brain is triggered by the exposure of the embryo in the egg to light (Rogers & Sink 1988). During development, the embryo turns so that the right eye faces outward, towards the translucent egg shell and to any available light. At the same time, the left eye is turned towards the body mass and receives little or no light. While still in the egg, a visual pathway in the chick, known as the thalamofugal pathway, undergoes differentiation. During a critical period (from embryonic day 17 to 21; see Rogers 2008), exposure to light produces an asymmetrical stimulation of the two eyes such that there is an increase in forebrain projections from the left side of the thalamus (fed by the light-stimulated right eye) compared with the right side (Rogers & Deng 1999; Koshiba et al. 2003). It is thought that as little as 2 hours exposure to light prior to hatching is sufficient to induce these brain asymmetries (Rogers 1997). However, if the chick does not receive light during incubation, this lateralization is largely prevented (see Rogers & Bolden 1991). Nevertheless, there are some forms of lateralization in chicks that do not depend on light exposure of the embryo, including social recognition (Deng & Rogers 2002b), response to olfactory versus visual cues (Rogers et al. 1998) and components of object or spatial-specific cues (Chiandetti et al. 2005: also see Vallortigara & Rogers 2005). Factors such as the position of the nest, the threat of predation and the

* Author for correspondence ( [email protected]). One contribution of 14 to a Theme Issue ‘Mechanisms and functions of brain and behavioural asymmetries’.

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social status of the female may all help to determine the amount of light the chick embryo is exposed to. Also, the chick itself appears to regulate its light exposure from within the egg by manipulating the hen’s behaviour: chicks call to the hen during the critical period before hatching to stimulate the hen to turn the egg and expose the embryo to light ( Tuculescu & Griswold 1983). The physical asymmetries of the thalamofugal pathway inevitably turn out to have behavioural consequences: experimentally induced changes in anatomical asymmetry are accompanied by changes in behavioural asymmetry. For example, research has shown that the left eye system (i.e. the left eye and its contralateral connections to the right hemisphere) plays a preferential role in spatial representations, specifically in the learning and memory for global, distally located spatial information (Rashid & Andrew 1989; Vallortigara 2000; Prior et al. 2002; Regolin et al. 2004). In addition, the right hemisphere tends to focus on broad attentional cues and also controls fear and escape responses and response to novelty (see Andrew 1991; Vallortigara & Andrew 1994). The right eye system (left hemisphere), on the other hand, is important for learning about the features of the goal but also for the representation of local, landmark cues to locate goals in space ( Tommasi & Vallortigara 2001). In this way, the left hemisphere is able to discern cues that separate relevant stimuli from distracting stimuli (e.g. food from pebbles). Thus, it has been suggested that the left hemisphere works on the level of defining an item at a categorical level while the right hemisphere determines the more specific values of an object (see Rogers & Andrew 2002; Vauclair et al. 2006). Anatomical lateralization and its behavioural correlates remain largely confined to each hemisphere in chicks because the avian brain does not have a corpus callosum and displays a virtual complete decussation of optic fibres at the optic chiasm (Csillag & Montagnese 2005). Methodologically speaking, this means that the visual input to the chick’s brain can be restricted to one hemisphere without the need for invasive surgical procedures. Specifically, a simple patch over the eye can be used to discern hemisphere specializations (Rogers 1997; Gu¨lbetekin et al. 2007). In addition, birds can use their eyes independently allowing, for example, the scanning for predators with one eye while categorizing food and non-food items with the other (Rogers 2000). This spontaneous eye use can also allow us to discern hemispheric specializations. Indeed, it appears that behavioural and analytical processes are generally carried out by the eye connected to the hemisphere most adapted for carrying out these different activities. These processes also include those required for social interactions. The domestic fowl derives from the red jungle fowl (Gallus gallus spadiceus), which is a highly social species living in flocks of between 4 and 30 adults in addition to the young birds (Mench & Keeling 2001). The chick, on hatching, will spend its lifetime interacting, initially, with its siblings and mother, then later on with other conspecifics within the group. The ability to interact successfully with its fellows requires an individual to possess skills in social cognition (Zuberbuhler & Byrne 2006). Social Phil. Trans. R. Soc. B (2009)

cognition implies that an individual not only understands other individuals within a group but also controls its own actions and controls processes that involve the interaction between itself and other members of the social group. In this way, the chick will be able to find food and shelter and avoid predators not only by itself but also by watching and learning from others. The ability to learn from the actions of others allows the individual to subsequently interact with its environment with greatly reduced fitness costs. Living in groups is also a predisposition for social facilitation and social learning behaviours. Indeed, fowl engage in social learning during foraging, dust bathing and preening (Lundberg 2002; Nicol 2004). When young, social learning is of an increased importance because chicks are apparently unable to recognize food types and have to learn to avoid items that are not worthwhile eating, to the extent that Hogan (1984) reported chicks will die owing to their preference for ingesting gravel to food if they are not shown otherwise. There are a variety of mechanisms that an individual can employ in order to learn from the behaviour of others (see Nicol 1995): these include enhancement (local or social), in which another animal (known as the demonstrator) may increase a motivational component to enhance the individual’s attention to an action or place coupled with a reward. Also, copying and emulating the demonstrator’s actions in order to produce similar results (in terms of access to food; see Zentall 2003), known as imitation, may be employed. In these ways, an animal can learn to exploit new food types, determine food quality, the dominance status of others in its group, etc (see Heyes & Galef 1996). All these are important for the chick because it is a precocial animal which, upon hatching from its egg, must quickly imprint on its mother and conspecifics, while initiating feeding. Being a social species, it is important for the chicks to recognize their conspecifics and to be able to interpret the social interactions between them (from Queiroz & Cromberg 2006; also, Regolin et al. 1994). This becomes more apparent when agonistic activity begins and social hierarchies are formed. All these types of social behaviour may be impinged upon by the anatomical, and subsequent behavioural, asymmetries in brain development, most notably of the visual system, caused by the light exposure in the egg. These asymmetries appear to be conserved throughout avian species. For example, the ability to recognize familiar from unfamiliar conspecifcs appears to be a right hemisphere process in the precocial domestic chick (Gallus gallus; Vallortigara 1992a; Andrew et al. 2004), as does predator detection and avoidance in the altricial Australian magpie (Gymnorhina tibicen; Koboroff et al. 2008) and later in life, courtship and copulatory behaviours (in this case in a precocial wader, the black-winged stilt Himantopus himantopus; Ventolini et al. 2005). The left hemisphere appears to be more involved in approach towards predators (Koboroff et al. 2008) and in prey detection (Ventolini et al. 2005). In the following, we will examine work from our laboratories showing that the two hemispheres are differentially involved in social cognition tasks in the

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domestic chick G. gallus. This is apparent in initial pecking responses, both with regard to a model hen demonstrating what to peck and with regard to learning what not to peck by observing another conspecific, in the perception of human gaze and in face recognition and, when older, using a pecking response to demonstrate that a dominance hierarchy has been learnt.

2. LATERALIZATION OF RESPONSE TO ‘TIDBITTING’ In humans, it is well documented that there is an asymmetry of spatial attention (e.g. Bottini & Torraldo 2003). In the human brain, a form of pseudoneglect exists, with a left-hemispace bias in perception of length, size and numerosity being present (Orr & Nicholls 2005). A leftward attentional bias has also been reported in birds (Diekamp et al. 2005): a left-sided visuospatial bias was seen when birds were given a free choice to orient towards and peck at grains spread evenly over an area in front of them. In addition, Rugani et al. (2007) found that chicks, when identifying the position of a hole in a series, would start from the left end of the series, and not the right, in order to refer to the correct hole. This confirms Regolin’s (2006) work describing a left bias in a line-bisection task. This propensity for a leftward bias of asymmetry is thought to be associated with the right brain hemisphere’s superior ability to perform in spatial tasks compared to the left. We investigated this visuospatial bias further based on the chick’s response to an auditory and visual tidbitting signal, which the hen performs on encountering a suitable food item. This consists of the female hen emitting pulsatile food calls and at the same time performing a visual display, involving a repeated, rhythmic motion of the head and neck often picking up and dropping the food item chosen (Stokes & Williams 1972; Smith & Evans 2008). This behaviour allows a form of social learning in which the chick learns which foods are good to eat as signalled by its mother (Allen & Clarke 2005), since it attracts chicks to the area where the hen is (Moffatt & Hogan 1992). Chicks subsequently learn to emulate the hen’s preferences in food choice; in this way, a form of social transmission of food choice may evolve (Gajdon 2001). Previously, Suboski & Bartashunas (1984) successfully investigated the social transmission of pecking preferences in chicks using a specially designed model arm. An arrow operated to produce vertical ‘pecking’ movements was found to both elicit and to direct pecking in naı¨ ve newly hatched chicks. We decided to carry out a similar experiment to see whether there would be an attentional bias, presumably to the left hemispace. In order to investigate this phenomenon we used day-old chicks of both sexes, which had no previous experience of, or exposure to, any food items. Chicks were placed in an arena consisting of a wooden box with one side made of a see-through glass ‘window’ through which a mechanical arm and bead set-up could be seen (similar to Suboski & Bartashunas 1984): two translucent glass pots containing coloured plastic beads (3 mm in diameter; one with blue beads and one with yellow beads), one on the left and one on the right side of the apparatus (figure 1). The arrow was made to oscillate Phil. Trans. R. Soc. B (2009)

Figure 1. A diagrammatic representation of the chick in the tidbitting apparatus. The motor arm was made to oscillate above one of two pots of coloured beads; in this case, the pot containing the blue (darker) beads, to signal it as the target.

vertically (visual signal) and produced a tapping sound on the downstroke when encountering the stimulus (auditory signal): one of two pots. The arrow therefore emulated the female hen’s tidbitting display, providing both visual and auditory components. A procedure involving an initial attraction of the chick to an object followed by a habituation was invoked. For this, chicks were attracted to one or the other of the two sets of beads (defined as the target) by the motion of the tidbitting arm pecking at the pot of beads in bursts of 10 s on and 10 s off. When the chick had approached the area near to the motor arm, the action became a continuous motion (enhancing subsequent habituation). Inevitably, the chick would lose interest in this motion action, because it was unable to interact directly with either the motor arm or the object of the arm’s intent. According to the criterion employed, habituation was considered to have occurred when the chick looked away from the moving motor arm for at least 10 s. Dependent measures considered during the test were: time required to attract chicks’ attention to the target object and time that elapsed before losing chicks’ attention (habituation time), signifying the end of the experiment. A significant interaction of the sex of the chicks and the colour of the beads in the pot was found, which suggested that the two sexes were reacting differently according to the colour of target. Male chicks were found to have their attention drawn to the target differently according to an interaction between the target colour and the target’s position: they were significantly faster to attend to the stimulus when the blue target was presented on the left side compared with the right. This was specific to the blue target because no such positional effect was present when the target was yellow for attention. Females showed no differences in either habituation or attention responses. It appears that the chicks prefer (are quicker, at least) to go to their left when the target is blue, than to their right. This is a colour- (blue only) and sex-specific (male only) effect.

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A leftward attentional bias has been reported in birds (Diekamp et al. 2005). Both pigeons (Columba livia) and chicks display a left-sided visuospatial bias. It is argued that neural circuits in the right hemisphere can attend to and represent both left and right sides, while the left hemisphere attends to the contralateral side only. Our results again demonstrate a left-sided bias. However, most interestingly, this bias was both object and sex specific. Only when the stimulus signalled was blue did the male chicks (but not females) show any differentiation in terms of directional bias in approaching the stimuli. Colour preference has been observed in chicks (Mastrota & Mench 1995; Taylor et al. 1969 from Ham & Osorio 2007). Thus, predispositions are present in these young birds. Whether sex differences were present in previous colour choice experiments was not noted, however. Sex differences do exist, though, in food detection in a pebble-floor task (Rogers 1997). Females also appear to be more attentive to a primary target ( Tommasi & Vallortigara 2004), although this appears not to be the case in our work. The sex differences found in this and other experiments will be discussed further in §7. A strong selective feeding is shown when (female) chicks use both eyes, but there is less selectivity when they are in the monocular mode (Prior & Wilzeck 2008). There is some lateralization though, with the left hemisphere (right eye) chicks being more selective than the left eye chicks. However, irrespective of which hemisphere is being used, the brain of female chicks appears to require the coordinated activity of both left and right to fully discriminate. It is likely that male chicks would show less selectivity since this would be associated with the increased hemispatial bias we have demonstrated in the present work. It appears that there is a left-sided bias in male chicks at least, though why this should be limited to one object type only (the blue bead jar) remains unknown.

3. PASSIVE AVOIDANCE LEARNING As we have seen above, the chick is predisposed to peck at objects shortly after hatching. However, equally important may be the inhibition of this response: if the item was either a non-food item or, more saliently, an aversive or potentially poisonous item, it would be advantageous for the chick to refrain from pecking at such an item. Being able to learn from others about how edible a food type is would be of the utmost importance. Nevertheless, this ability does not always seem to be present in animal species (e.g. rats; Galef 1996). Sherwin et al. (2002) demonstrated that nineweek-old (adult) observer hens were not able to learn to avoid pecking at a coloured food that elicited a ‘disgust’ reaction from another hen, but they will avoid pecking at one kind of food if they see another hen standing near the food without pecking it. Young chicks learning for the first time to classify particles as edible or inedible may be more sensitive to the consequences of the feeding behaviour of others owing to the importance of learning about palatable Phil. Trans. R. Soc. B (2009)

items as quickly as possible. This sensitivity, however, reduces as the chicks mature and consequences of ingestion become an important source of information about food palatability via individual associative learning ( Nicol 2004). Pecking avoidance can be investigated experimentally in a procedure (passive avoidance learning, PAL) in which a chick is presented with a bead covered in a bitter-tasting substance (usually methyl anthranilate, MeA). On pecking the bead, the chick exhibits a disgust response (shaking its head, wiping its bill on the ground and emitting distress calls) associated with the ingestion/taste of the MeA. The chick will subsequently not peck again when presented with a similar bead at a time point (minutes to hours) later. It has been shown that memory formation for the inhibition of the pecking response occurs over a time course of several hours. During this period, there is a range of biochemical, physiological and morphological changes that will lead to a permanent memory associated with different memory phases (e.g. short-term, intermediate-term and long-term memory; see Gibbs et al. 2003; Chiandetti et al. 2007). It appears that specific brain areas are involved during these memory phases (including the mesopallium and medial striatum) and that there is a lateralization in activity of these areas, which is also time dependent (Rose 2000). Thus, a ‘flow’ of memory has been described in which there is a transfer of memory from the left mesopallium to the right mesopallium and then later to the left and right medial striata (e.g. Patterson et al. 1990). Lesion studies indicate that the bilateral or left, but not right, pre-training mesopallium lesions interfere with the acquisition of this task (Patterson et al. 1990), and this is backed up by biochemical evidence showing that the memory appears to consolidate first in the left mesopallium and then in the right (Sandi et al. 1993; also see Rose 2000). The right mesopallium may also be necessary for transfer of information to the basal ganglia (Patterson et al. 1990). In PAL, chicks are trained and tested in pairs ( Ng et al. 1991). This allows the possibility of investigating the presence of social information transmission between the cage mates. It is likely that the first chick that pecks at the bitter-tasting bead attracts the attention of the other chick towards the bead and conveys some information about the aversive nature of the bead (Galef 1988). However, some of the first experiments conducted seemed to indicate that the behaviour of one chick does not influence the behaviour of its cage mate (Gibbs & Ng 1977; De Vaus et al. 1980). This contrasts with the evidence indicating the presence of social learning for pecking avoidance in day-old chicks (Johnston et al. 1998). Johnston et al. (1998) used pairs of chicks in which one of the pair (the ‘demonstrator’) was presented with a chrome bead dipped in either MeA or water. The second chick in each pair was termed the ‘observer’, and was prevented from pecking at the training bead by the presence of wire mesh dividing the cage into two parts. During the test phase, the demonstrator and observer chicks were presented, one at a time, with a dry chrome bead for 10 s at specific time points after training (0.5, 3 or 24 hours), followed, after a further

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demonstrator Figure 2. PAL. (a) The pre-training phase in which both birds are presented with a white bead three times, (b) the training phase in which one bird (the demonstrator) is presented with a red (darker) bead (either dry or covered with the bittertasting substance MeA) and (c) the testing phase in which both chicks are presented with (i) a dry red (darker) bead followed by (ii) a dry white bead.

5 min delay, by a 10 s presentation of a dry white bead to determine whether the chicks’ response was general or specific to the bead, i.e. whether the chick was able to inhibit pecking on a specific (discriminatory) basis or merely inhibit all responses. They found that both demonstrator and observer chicks avoided pecking at the chrome bead at test up to 24 hours after the observer chick had seen its demonstrator pecking a similar, but bitter-tasting, bead and displaying a disgust response. Chicks continued to peck at the dry chrome bead if, during the training phase, the demonstrator had pecked a similar bead that was coated in water, and which did not elicit any disgust reaction. They also demonstrated that this social learning occurred during training, but not at testing. We have recently repeated this experimental procedure in order to investigate differential hemisphere use in the social learning version of this task (Daisley et al. 2007; Rosa Salva et al. in preparation). Chicks were maintained in pairs for 24 hours after hatching. Using the procedure described above, we were able to confirm the results of Johnston et al. (1998), in that observer chicks were able to successfully discriminate between two differently coloured beads. Specifically, following a pre-training in which chicks were presented with a dry white bead three times (figure 2a), half of the chicks (one from each pair; the demonstrator) were presented with an identical, but red, bead (figure 2b). The red bead was either dipped in 100 per cent solution of MeA (MeAchicks) or was dry (dry-chicks). Thirty minutes after the end of training, the demonstrator (dem-chick) of each Phil. Trans. R. Soc. B (2009)

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couple was presented with a dry red bead (figure 2c(i): lower chick). The observer (obs-chick) was then presented with a dry red bead (figure 2c(i): upper chick). Then, following a 5 min delay, dem- and obschicks were individually presented (in random order) with a dry white bead (figure 2c(ii)). The number of pecks during the test phase, to both red and white beads, was analysed. Both observers and demonstrators learnt to avoid the bitter-tasting red bead and/or preferred to peck the white bead with respect to the red one. Observers appeared to master this task by direct observation of the demonstrators’ behaviour, since there was a correlation between what the observer was doing in relation to its demonstrator for these MeA pairs. Following this, we investigated whether there was a lateralization in the recall of this task in the observer chicks. We trained pairs of chicks in the same way as above: the observer chick was allowed to watch, using both eyes, the interaction of its demonstrator with the bead (coated in MeA or dry) at training. Directly afterwards, however, the observer was eye-patched such that either the right or the left eye was covered with a patch in order to obscure vision. After 30 min both chicks were tested, again as previously described. This meant that the observer chick was able to retrieve the memory for the bead from its contralateral hemisphere only. Thus, if chicks were largely using their left hemisphere to learn the task it may be that by patching the right eye they would no longer be able to successfully retrieve components of the memory necessary to produce the appropriate response. Analysing the sexes and the eye used separately we found a significant difference between the left-eye system ( LES) male MeA-obs-chicks and their controls (male LES-dry-obs-chicks) but not the right-eye system (RES) male chicks and their controls. Indeed, the LES observer males were significantly better at recalling the task than the RES males. Thus, there is again evidence for the differential involvement of the two cerebral hemispheres, this time in a social learning task. Males that used their left eye (right hemisphere) at test and both groups of monocular females were able to recall what they had learnt by observing their demonstrator during training, whereas males using their right eye (left hemisphere) were not, and consequently they did not prefer to peck the white bead with respect to the red one. With regard to hemispheric lateralization associated with the task, there is a consensus that the memory for the interactive component of this task in its standard non-social version forms in the left hemisphere (Gibbs et al. 2003). This is suggested to be due to the left hemisphere involvement in the control of inhibition of the pecking response (Mench & Andrew 1986). As mentioned previously, the left hemisphere is also known to be necessary for distinguishing local specific cues associated with the target, in this case the bead, while the right hemisphere is generally concerned with spatial, topographical cues that are unlikely to be relevant for a successful discrimination as seen for the LES male chicks here. However, the results we have found suggest a successful discrimination based on

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the right hemisphere use, which would potentially point to a function of the right hemisphere in assessing the behavioural components of the demonstrator’s interaction with the bead. It should be noted that the task observers had to perform was somewhat different with respect to the standard PAL task, in that the observers did not have any direct contact with the stimulus whose properties chicks had to learn (the red bead). Indeed, learning could be achieved only by observing a familiar conspecific that interacted with the relevant stimulus. Thus, one argument could be that this social learning version of the task may involve a mixture of components consisting of behavioural cues (from the demonstrator) associated with the bead’s visual cues. In males, the fact that only the LES individuals were able to integrate these two components in order to produce the appropriate discriminatory response may suggest that for males, either the information necessary is held exclusively in the right hemisphere and/or that the left hemisphere requires information from the right (which, in the monocular RES context it is unable to do). For females, no such lateralization is seen, with chicks learning in either monocular condition, suggesting that females can access both hemispheres either directly or indirectly in order to produce the appropriate response. It has been postulated that the memory for this task (and in general) may be distributed in ‘fragments’, involving both left and right brain structures, of differing informational content following initial exposure to the learning stimulus (see Gibbs et al. 2003). In addition, the two hemispheres undergo different patterns of cyclicity: the left has so-called ‘retrieval events’ in periods of 16 min (i.e. at 16, 32, 48 min, etc.) and the right at 25 min (i.e. 25, 50, 75 min, etc.; Andrew 1999). Testing 30 min after seeing the demonstrator’s response may, therefore, still be a ‘right hemisphere event’, at least in males. The timing (30 min) also appears to coincide with the intermediate-term memory formation. According to Gibbs et al. (2003), information in the right hemisphere may be necessary to the left hemisphere during this phase. Our data would be in agreement with this and, in addition, it may also suggest that the timing for this memory formation or transfer between hemispheres is different in male and female birds, at least in relation to information retrieval for this social learning task.

4. LATERALIZATION OF FEAR RESPONSES (GAZE CUES) Following the first few days after hatching, chicks start to show fear to novel stimuli. This is thought to be due to either the imprinting process per se (Bateson 1964) or the chick’s running tendency (Hess 1959). In this way, the chick keeps in close contact with the hen and its siblings, thus receiving protection from predators (Rogers 1995). An animal’s ability to experience fear and to react to fearful events appropriately is essential for its survival. The perception of fear elicits a ‘fight or flight’ response in which the individual’s heart rate and breathing are increased. In many animals, including gallinaceous Phil. Trans. R. Soc. B (2009)

birds, the fear response may manifest itself as ‘freezing’ in which the animal remains immobilized. This is thought to be adaptive by removing motion cues used by predators (Jones 1992). Previously, it has been shown that human gaze directed at a chicken will increase the period of tonic freezing the bird experiences in comparison with an averted gaze (Gallup et al. 1971). Also, younger birds (3-day-old chicks) have been shown to have an increased latency to move in a novel environment when they are directly under the gaze of a dummy face (Vallortigara & Zanforlin 1988). In chicks, functional asymmetries between the two hemispheres are also involved in the control of a fearrelated response, suggesting the presence of a lateralized brain results adaptive also for a fear response. Dimond (1968) observed that chicks hatching from eggs incubated in the dark (‘non-lateralized’) showed a reduced fear response in comparison with lighthatched (‘lateralized’) chicks. This reduction in fear may be a critical factor in allowing the dark-hatched chicks of lower dominance rank to be able to compete more successfully for food with their more dominant siblings and conspecifics but may also ensure that they are at increased risk of predation (Rogers & Workman 1989; Queiroz & Cromberg 2006). This suggests to there being a lateralization of the fear response. Indeed, Phillips & Youngren (1986) demonstrated, using biochemical interventions, that the right hemisphere (specifically, the right archistriatum—now called the arcopallium following Reiner et al. (2004)) is involved in the control of avian fear behaviour. For example, it has been shown that the fear responses to predators are much quicker or more pronounced when the predator is detected by the left eye than by the right eye of domestic chicks (Andrew et al. 1982; Rogers 1997 for a review; Rogers 2000; Rogers et al. 2004). Indeed, the left eye is preferentially used to scan for a predator after advertisement of its presence (Evans et al. 1993) and, using the left eye system, chicks are quicker to detect the predator when engaged in a dual-task paradigm (selective feeding together with predator detection; Rogers et al. 2004). We decided to investigate the effect of gaze perception in chicks using a human face-like mask and to determine whether fear responses associated with the predator’s gaze were being differentially perceived/modulated by the two hemispheres (see Rosa Salva et al. 2007). Chicks (8 days old) were given the choice of moving towards a pebble floor (a small area covered in small stone chips of similar size, shape and colour to the chicks’ usual food together with food grains) or a clear floor in a novel testing arena. A mask with movable eyes was placed overlooking the arena. The eyes were placed so that they were either gazing towards the, more interesting, pebble floor or away from it (and at the clear floor; figure 3). The eye used by the chick to look at the mask was noted at all times together with the latency to approach the experimental surface. These chicks were quicker to approach the pebble floor when the mask’s eyes were directed towards this surface. They also predominantly used their left eye (right

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However, when naı¨ ve to the gaze’s intent, chicks are still able to determine that the mask and its eyes are a relevant cue to which a fear response is required. What components of the face or mask constitute a biologically relevant stimulus? Obviously, the gaze of the eyes is followed, but is it the face as a whole that is recognized and what constitutes a ‘face’ that can produce a response?

Figure 3. Gaze perception in the chick. A schematic representation of the chick in the starting position inside the arena showing gaze of the mask’s eyes towards either the pebble floor (black arrows) or the clear surface (grey arrows).

hemisphere) to monitor the mask when it was gazing away from the pebble floor. Therefore, it would seem that these chicks were used to having gaze directed towards them in a benign context by the experimenter, e.g. when the experimenter would provide food and water to the birds. Thus, no perception of fear was associated with gaze when the gaze was towards a biologically salient cue (the more interesting pebble floor). However, when the gaze was directed away from the pebble floor this produced an increased latency to approach. This result is unclear, but suggests either an increase in the chick’s fear perception associated with the novel experience of a gaze looking away from the subject or an increased propensity to wish to follow the gaze (to the clear surface). In order to investigate these responses more specifically, chicks completely naı¨ ve to human gaze were used. For this, great care was taken to ensure that the chicks were never exposed to human gaze throughout their raising period. This time the chicks took longer to approach the pebble floor when the mask’s eyes were directed towards it and had a tendency to use their left eye (right hemisphere) to look at the mask. In this case, the mask’s gaze appeared to be perceived as a fearful stimulus. These two results demonstrate that chicks have a predisposition to attend to potentially threatening stimuli with their left eye–right hemisphere system. These results also show that chicks have an innate ability to recognize eye shapes (i.e. gaze direction) and perceive them as being biologically active and relevant with regard to themselves. These results also support the view that the perception of fear is a right hemisphere event. Overall, when a face representation is familiar (and has been learnt), chicks are no longer fearful of the presence of the gaze, but react to it, following what may be a biologically relevant cue (when the gaze is directed towards an area/stimulus of apparent interest). Phil. Trans. R. Soc. B (2009)

5. LATERALIZATION OF PREFERENCE FOR FACE-LIKE CONFIGURATIONS In addition to gaze perception, the right hemisphere is also thought to be involved in face perception. Data from human studies, including the data from neuroimaging and from brain disorder patients, show face perception (and emotional perception) as being a right hemisphere process, centred on the fusiform gyrus (De Renzi et al. 1994; Kanwisher et al. 1997; De Haan 2001). Also, the recognition of individual conspecifics is mainly processed using the right hemisphere, e.g. in humans (Sergent & Signoret 1992), sheep (Peirce et al. 2000) and chicks (Vallortigara & Andrew 1991, 1994). We decided to investigate brain lateralization with regard to preference for faces and other top-heavy non-face-like stimuli (i.e. stimuli having more highcontrast elements in their upper part, as opposed to bottom-heavy configurations having more elements in their lower part) in chicks. Chicks have been shown to display a preference for face-like configurations with respect to other top-heavy stimuli (Rosa Salva et al. submitted). This makes ecological sense, since the hen bird and indeed the other nest mates will be characterized by a triangular face-like arrangement of features that will be biologically salient to the newly hatched chick (these cues should be followed and attended to in order to obtain food and other necessary resources). In a first experiment conducted, chicks were exposed to an imprinting stimulus directly following hatching. The imprinting stimulus consisted of a masklike cut-out that was superimposed on one of the walls in each cage (figure 4a). The mask was empty (representing a ‘featureless face’), thus providing the chicks with no information regarding the internal features of a face. On test, each chick was allowed a free choice between two stimuli placed at the opposite ends of a runway. The two stimuli consisted of a facelike stimulus (figure 4b) and a non-face-like one (figure 4c; the face-like stimulus was defined as the ‘target stimulus’, for which a preference was expected). Test stimuli were identical to the imprinting object with the only difference being the presence of three square black blobs representing the stimuli’s internal features. In the face-like stimulus, the blobs were arranged in a way that they represented the three main internal features of a face (the two eyes and the mouth/bill), whereas in the non-face-like one they were all aligned along the central vertical axis of the figure in a way that did not represent a face. Test stimuli were created by manipulating configurations that had been already employed in developmental studies on spontaneous preference for face-like displays in human newborns (see Morton & Johnson (1991) for a review). Chicks’

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(a)

(b)

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Figure 4. Face preference. (a) The imprinting object (representing a featureless face) employed in all the experiments. Test stimuli employed in the first (b,c) and second (d,e) experiments conducted, representing a topheavy face-like stimulus (b), a bottom-heavy face-like stimulus (d ) and top-heavy non-face-like stimuli (c,e).

behaviour was observed for a total of six consecutive minutes. The presence of lateralization effects was investigated by studying the effects of the eye used to view the face-like configuration at the beginning of the test on the time spent near the first stimulus approached. The expected effect of this manipulation was to increase or decrease (depending on the hemisphere processing the target stimulus) a general social facilitation effect (a facilitation to approach and stay near either test stimuli, which can be considered social objects also owing to their resemblance with the chicks’ imprinting object). In this context, the social facilitation effect was defined as the longer time spent in the proximity of one stimulus when approaching it for the first time. Results of this first experiment showed that chicks having the face-like stimulus (i.e. the preferred stimulus) in their left monocular visual field (right hemisphere) at the beginning of the test, spent more time near the first stimulus approached (regardless of whether it was the face or non-face one). Therefore, there seemed to be a general facilitation effect on social behaviour determined by the presence of a face-like configuration in the visual field that is mainly Phil. Trans. R. Soc. B (2009)

processed by the right hemisphere, i.e. when a face-like configuration was presented to the right hemisphere, chicks made a more decided choice when approaching one of two stimuli that were both equally similar to their imprinting object. In a second experiment, stimuli structure was manipulated so that in the face-like stimulus the blobs were arranged in a triangular bottom-heavy face-like configuration (figure 4d ), whereas in the non-face-like one they were arranged according to the same configuration but with upside-down orientation (figure 4e). Test stimuli were created by manipulating configurations that had been already employed with newborns by Turati et al. (2002). The same lateralization effect, already demonstrated in the previous experiment, was also obtained in the present one: chicks having the face-like stimulus in their left monocular visual field (right hemisphere) at the beginning of the test spent more time near the first stimulus approached. Thus, here we confirmed the presence of a dominant role of the right hemisphere in face perception, regardless of whether stimuli employed were top-heavy or bottom-heavy configurations. Overall, our results suggest that the mechanisms lateralized in favour of the right hemisphere could underlie chicks’ preference for faces, independent from any—possible—preference for top-heavy configurations. In fact, a general social facilitation effect is determined by the presentation of a face-like stimulus to the right hemisphere, and this is true regardless of whether the face-like stimulus is a top-heavy (first experiment) or a bottom-heavy configuration (second experiment). Moreover, it seems that in the presence of a face-like stimulus, the right hemisphere could play a predominant role in controlling chicks’ social behaviour (first and second experiments). We have seen in the previous session a tendency for chicks to use their left eye–right hemisphere to discern gaze initially, at least, in relation to a fear response. Once having determined that the gaze is benign, the chick will still preferentially use its left eye system to analyse the face as found by the stronger social facilitation when the face was placed to the left of the animal. Thus, chicks react to gaze and are able to recognize the structural configuration of a face. These findings are reiterated by the fact that shortly after hatching, domestic chicks become capable of discriminating between individual conspecifics, at least to the level of the distinction between familiar and non-familiar individuals. Following approximately 12 hours of direct contact (Porter et al. 2005), chicks will prefer to remain near their cage mates (Riedstra & Groothuis 2002) and will have a tendency to peck more often at an unfamiliar partner (Rajecki et al. 1976). Indeed, the frequency of pecks directed at familiar and unfamiliar conspecifics appears to be the most sensitive measure of social discrimination in young birds (cf. Porter et al. 2006). It is proposed that pecking intensity may be a form of social exploration (Riedstra & Groothuis 2002) or aggression ( Vallortigara 1992b). Either way, this interaction may subserve a mechanism that is involved in social hierarchy formation: testing the chick’s relative level of dominance within a group.

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Review. Lateralization of social cognition J. N. Daisley et al. 6. TRANSITIVE INFERENCE LEARNING Dominance relationships are formed within the social groups. They can be followed by observations of overt aggressive and submissive behaviours when individuals confront one another (Craig 1986). In chickens, such dominance relationships may begin to form within the first week following hatching (Rogers & Astiningsih 1991), and are usually well developed by five or six weeks of age (McBride et al. 1969). Animals have the ability to infer judgements on other individuals’ ranks by observation only, and perhaps, therefore, to infer their own rank status: Paz-y-Min˜o et al. (2004) determined that Pinyon jays (Gymnorhinus cyanocephalus) can infer a judgement about their own dominance by observing strangers interacting with different known birds. This ability to make inferences means that the animal is able to predict the outcome of competition for resources (food, mating opportunities, etc.) and thus avoid unnecessary and potentially injurious fights with other conspecifics. Keeping track of the social position of others within the group requires a significant cognitive ability. Indeed, this process of inference, termed transitive inference (TI ), has been described as a measure of logical reasoning ability (Piaget 1928). Chickens have been shown to have the ability to emit a suitable social response on the judgement of interactions between dyads (Beaugrand et al. 1997). By watching another individual that was known to be dominant to them winning against an unknown bird, the bystander would behave as if it was of roughly equal status as the defeated newcomer. If the new bird defeated the bystanders’ dominant bird, however, the bystander would be submissive to the new bird when in its presence. That a lateralization in hemisphere use may be present in learning this task is implied by the data from Rogers & Workman (1989), in which they found that chicks which had been exposed to light in the egg formed more stable hierarchies when placed in a group together than did groups of dark-hatched (and therefore ‘less lateralized’) chicks. The lowest ranked lighthatched chicks tended to consistently receive less time at a feeding situation than did dark-hatched chicks. Thus, the social structure of dark-hatched chicks was more changeable and less rigid than in groups of chicks that had been exposed to light, and since the ability to perform TI may be linked to social complexity in animals, we considered it a likely possibility that there may be an improved ability of light-hatched (lateralized) chicks to perform TI successfully. Thus, we tested two groups of birds, one of which had received light for the last days of incubation, and would be assumed to have lateralized brains, the other darkhatched and therefore non-lateralized (Daisley et al. in preparation). Following shaping, in which they learnt to peck at a stimulus (a small dot, 4 mm in diameter) to receive a food reward, chicks (12 days old) were confronted with paired presentations of stimuli in such a way as to learn a hierarchical order of the training stimuli: AOBOCO DOE. Each stimulus was of a different shape (star, circle, square, triangle and diamond) and colour (yellow, red, brown, blue and green) to aid discrimination Phil. Trans. R. Soc. B (2009)

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(figure 5). The training stimuli were presented pairwise: one when pecked gave a food reward (C; i.e. the experimenter opened the box that held food) and the other did not (K; the box not containing food was opened). The stimulus pairs were presented in the order: ACBK, BCCK, CCDK and DCEK, ‘C’ indicating reinforcement, with each pair being presented until the chick had reached a criterion level. Twenty-four hours after the end of the training session, chicks were again presented with the training pairs (AB, BC, etc.) but, in addition and interspersed within them, were presented the previously unseen pairs AE and BD (unrewarded) a total of 20 times across four testing sessions. The pair AE involved the ability to discriminate between a stimulus that had always been reinforced (A) and one that had never been reinforced (E) during the training; AE represented a non-transitive novel pairing. The pair BD represented the test of transitivity, because in order to discriminate successfully the pair BD (i.e. pecking B) chicks needed to remember the hierarchical arrangement of the stimuli (i.e. demonstrate TI learning), because stimuli B and D, in the training phase, were reinforced and not reinforced for the same number of trials. Both groups were able to demonstrate the associative discrimination (AE). Also, both groups of chicks performed significantly above chance at test with the choice of B versus D as well. On comparing lightversus dark-hatched chicks, however, a difference emerged. As was predicted, those chicks hatched from eggs exposed to light during the sensitive period of incubation (days 19–21), and thus likely to have increased hemispheric lateralization, were performing better than those hatched in the dark. This makes sense in the light of the data from Rogers & Workman (1989). If light-hatched chicks are forming more stable hierarchies than dark-hatched ones, this may be owing to these chicks being more able to determine individual differences and/or discern social interactions. Thus, it appears that TI performance may indeed be intertwined with social group formation and dominance hierarchies and is associated with brain lateralization. Is there a particular hemisphere necessary for TI performance? We investigated this further by using another group of chicks, all light-hatched (lateralized). Chicks underwent the same training procedure as before. This time, however, a single box was used: the stimuli ACBK, etc. were now placed in the vertical plane as opposed to having two boxes with stimuli aligned horizontally. This was because at the test the chicks were in the monocular condition. One group of chicks performed the test with the right eye only (the left eye being covered by a patch of black cloth); the other group were tested using only the left eye, with the right eye being patched. Thus, after a suitable time in which the chicks were allowed to adapt to being eye-patched, they were tested in the same way as before: a total of 20 trials of being shown the pairs A and E, and B and D. The eyepatch itself did not hinder the performance of the task: both groups performed AE. However, only the chicks that were using their left eye (and hence, were accessing their right hemisphere) were successful in carrying out the TI discrimination (B versus D). The difference in

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Figure 5. Diagram of the apparatus used to train and test chicks on a TI task. The four stimulus pairs, which the chick had to learn, are shown at the bottom of the figure together with the box from which the chick would receive a food reward when it pecked the correct stimulus (i.e. the stimulus that had been chosen as being the higher of the two in a hierarchical sequence).

performance between the two groups over the 20 trials was not significant, however. Does this mean that the difference is not real, though? Investigating further, we found that there was a significant difference between the two groups on the very first test, i.e. in the number of times B was chosen in the first set of five choices performed by the chicks. This may be owing to the fact that at test, whether choosing correctly (B) or incorrectly (D), the chicks received no feedback because the drawer was not opened to reveal whether the choice made was correct. Thus, the beginning of the test may be more pertinent to the testing of true TI learning since it is likely that the lack of feedback in further test trials may produce an additional learning. Indeed, when comparing the very first response peck made by the chicks at the very first presentation of BD, left-eye chicks were found to have chosen B more often than right-eye chicks. It is thus clear that access to the right hemisphere is necessary for TI performance in these chicks. This also appears to be the case in humans where the right anterior hippocampus appears to be the area used in order to perform a TI task (Heckers et al. 2004). This is in general agreement with data showing that the hippocampus of mammals is involved in the organization of the representation of stimulus relationships (e.g. Dusek & Eichenbaum 1997). The initial learning and recognition of the sequences per se is carried out by other areas, though, most notably the parahippocampal gyrus. We cannot determine from our results which areas are involved either in learning the pairs or remembering the sequence. Previously, however, Strasser et al. (2004) found that even hippocampal-lesioned pigeons were able to perform a TI task. They suggested that a form of value transfer may have been used by the participants in other experiments and this may itself be hippocampal dependent. Furthermore, Frank et al. (2003) produced a model that would see the hippocampus being Phil. Trans. R. Soc. B (2009)

used during training, but not necessarily responding to the TI task. Whatever the brain area involved, our chicks required the right hemisphere to retrieve the necessary information and/or to produce the appropriate response. Distinguishing between the different stimuli is likely to be a right hemisphere-specific process because the left eye system is known to respond to specific properties of the stimulus. It appears that distinguishing the different shapes associated with the stimuli may be more important than the colours intrinsic to those shapes (colour differentiation being more likely a left hemisphere specialization). Linking TI performance to left eye–right hemisphere use is the fact that chicks using their left eye will perform better at distinguishing between familiar and unfamiliar conspecifics (Vallortigara 1992a; Deng & Rogers 2002a,b): the formation of social hierarchies is almost certainly dependent on the recognition of individual conspecifics. The left hemisphere may still be involved, since Deng & Rogers (2002a,b) showed that after being exposed for a time to a group of chicks, right-eye tested birds could now distinguish familiar individuals. Our results, assuming the TI test we perform is related to social hierarchy evaluation, would agree with their conclusion in that the right hemisphere may still be preferred when chicks are tested binocularly and may also be more efficient at carrying out this differentiation. The ability to perform TI may be linked to the social complexity of the species studied: Bond et al. (2003) found that the less social scrub jay (Aphelocoma californica) although able to perform a TI task in which they had to learn a series of coloured keys, pecking at the higher ‘ranked’ key in order to receive a food reward, it was less capable than the Pinyon jay in performing a discriminative version of the task. Is this also related to individual experience? Can the left hemisphere be trained to perform TI? We are presently undertaking

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Review. Lateralization of social cognition J. N. Daisley et al. work to determine whether individuals kept in social groups during raising are more competent at a TI task, i.e. if the act of being exposed socially to other conspecifics allows the transfer of skills to stimulus premise pair recognition and subsequent unseen pair comparisons. Also, since prior experience of conspecifics means chicks could discriminate the familiarity of others with the left hemisphere, does this mean that the group-raised birds also show this property?

7. DISCUSSION (a) Right hemisphere advantage in social cognition The right hemisphere seems to play an important role in many of the processes that we have examined. In fear responses to different directions of the gaze of masks, the right hemisphere is largely used. Further to this, having assessed the qualities associated with gaze direction and the face, chicks are able to recognize faces from other objects and to discern different individuals (Andrew et al. 2004). This appears also to be a right hemisphere process. Chicks also appear to use right hemisphere processes in order to evaluate other individuals in a group as discerned by the TI data. Recognizing not only other individuals, but also the exact qualities associated with stimuli presented (probably shape, but possibly also colour) seems to rely on right hemisphere processes too. Finally, the ability to learn to identify the right kind of food and assume the same from the experience of others is again a right hemisphere process. Right hemisphere use in social cognition appears to be a phylogenetically conserved process. In humans (De Renzi et al. 1994), sheep (Kendrick 2006) and monkeys (Hauser 1993), the right hemisphere has been demonstrated to be involved in the perception of facial expression and in face recognition. In addition, fishes also use their left eye to examine a mirror reflection of themselves (Sovrano & Andrew 2006, also in Sovrano et al. 2001), again suggesting right hemisphere involvement in viewing conspecifics. We would suggest that this ability to recognize other individuals is a key factor in social cognition from which other abilities, such as social learning, learning inferences about others, etc., stem. Indeed, recent work in the realm of ‘self-related cognition’ (see Uddin et al. 2007) has identified the right hemisphere as playing a vital role in aspects of human and primate social cognition. Specifically, the right frontoparietal area of the human brain contains mirror neurons that are linked to imitative behaviour (Iacoboni 2005) and to social cognition (Iacoboni et al. 2005). These neurons are activated not only when performing certain goaloriented actions but also when viewing them being performed by others. In the domestic chick, it has been shown previously that there is a right hemisphere advantage for social recognition (see Vallortigara 1992a). This also holds true for another gallinaceous species, the quail (Coturnix sp.), which shows detour behaviour that differs in laterality according to whether the social target is a familiar (left eye used) or unfamiliar (right eye) bird (Zucca & Sovrano 2008). Vallortigara (1992a) suggested that the neural structures fed by the left eye Phil. Trans. R. Soc. B (2009)

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(mainly located at the right hemisphere) are better at processing and/or storing of visual information that allows recognition of individual conspecifics. This may be part of a wider tendency to respond to small changes in any of a variety of intrinsic stimulus properties. What does this leave for the left hemisphere in terms of social cognition? It seems that the left hemisphere may be more involved in the production of intentional social signals. In the human brain, the left hemisphere is dominant in the production of speech and signed language (Corballis 2002). In addition, Reynolds Losin et al. (2008) have shown that the motor control of facial movements associated with the production of learned sounds is lateralized to the left hemisphere. This coincides with work from Nottebohm (1999) who showed that the lesions to the left but not the right hypoglossal nerve resulted in significant deficits in song production in a song bird. Together, these suggest that the expression of a intentionally produced communicative action is a left hemisphere event (excluding the spontaneous expression of emotion; Stone et al. 1996), while the right hemisphere is required either for the emission of a simple event or social action (e.g. the pecking response in the left hemifield) or for the interpretation of a perceived event (e.g. from our data; the gaze of another, the interaction of a conspecific with a bitter-tasting bead or the dominance status of another). (b) Lateralization of social behaviours It has been argued that an advantage of having a lateralized brain is that it allows simultaneous processing of different information in the two hemispheres, with each hemisphere performing a function for which it is specialized (see Vallortigara & Rogers 2005). This is apparent in a dual task in which chicks have to simultaneously detect a predator (right hemisphere process) while controlling their pecking response (left hemisphere process; Rogers 2000). Those chicks exposed to light in the egg were able to detect the predator sooner than the dark-hatched chicks and also to learn to peck at grain and disregard the pebbles. It is thought that this ‘optimal’ lateralization of response may also have a consistent direction at the population level, specifically when individuals are required to interact with each other in social groups. Lateralization at a population level may form an evolutionarily stable strategy if there are frequencydependent costs and benefits associated with being lateralized in one or the other direction (Ghirlanda & Vallortigara 2004). It seems that there may be social constraints imposed on the asymmetrical individual when in a social group such that what is better for an (asymmetrical) individual to do may depend on what other (asymmetrical) individuals in the group are doing in order for a fitness advantage to accrue (from Vallortigara & Rogers 2005). It may favour an individual to be predictable in certain social situations (cooperative and coordinative interactions with other individuals) while in others (agonistic interactions, escape from predators) it may pay to be unpredictable (see also in this issue, Ghirlanda et al. (2009)). That hemispheric lateralization can be explained in terms of population-level interactions also points to

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lateralization as being important for social cognition throughout the chick’s life, but undoubtedly, most relevant during its early life. The experiments we have described previously have outlined some different investigations of these general, population-level lateralizations. However, a next step might be to open up the discussion with regard to individual lateralization(s) and its effect at the population level. Specifically, to determine the level and direction of the lateralization within the population. This would lead us to perform tests at the level of the individual. Once, having established the propensity of individual biases in laterality, we could ascertain its performance within the group context. Does it pay to be a less lateralized individual or an individual with the reverse lateralization compared to the group? Or, do the fitness consequences of producing differently lateralized young within a clutch (and that are raised together) outweigh the disadvantages possibly associated with having some chicks that are less socially viable? Either or both of these cases should be in the affirmative, according to Ghirlanda & Vallortigara (2004). (c) Sex differences In our work, we have found instances of there being sex differences in the expression of behavioural asymmetries. A prominent left visuospatial bias found in the tidbitting experiments is seen only with the male chicks (and, also, only when they are interacting with a specific target, a blue-coloured pot of beads). Also, where observation of another, same-sex, individual is involved in the PAL task, male chicks show a hemisphere bias but not females. It is argued that females seem to be able to use one hemisphere at a time to take overall control of attentional strategies; in other words, the hemisphere that is in control can impose its own attentional strategies to the partner, thus reducing the behavioural lateralization. On the contrary, this effect seems not to be present in males and therefore they show more pronounced asymmetries in the visual control of behaviour. Why should this be the case? It points towards differences in the development of male and female brains in terms of the level of lateralization seen between the two hemispheres. Indeed, it has previously been shown that sex differences in brain lateralization exist in chicks and that this has an anatomical basis: the asymmetry of the thalamofugal pathway has been shown to be greater in males than in females (see Deng & Rogers (2002a) in Rogers & Andrew (2002)). The right hemisphere of males, therefore, receives a larger amount of binocular input than does the equivalent hemisphere of females. The sex difference in lateralization also has implications for social behaviours and social cognition of the two sexes. Vallortigara & Andrew (1994) determined a difference in social attachment between the males and the females. In males, choice between a familiar and an unfamiliar chick was completed only when using the right hemisphere. Females also tended to use their right hemisphere; however, they were more adept at choosing their familiar partner. Females show a reduced latency to approach familiar birds rather than unfamiliar ones in approach response tests (Vallortigara 1992b). They also tend to choose to remain closer to their cage mates. Male Phil. Trans. R. Soc. B (2009)

chicks, on the other hand, tend to interact more aggressively with other conspecifics, e.g. by eliciting more pecks at social partners, than do females (Vallortigara 1992b) and they have a tendency to approach and stay with unfamiliar chicks more than females. Females run faster towards their cage mates whereas males run faster towards a food goal (Vallortigara et al. 1990). (d) The effect of light and hormones on lateralization of social interactions The sex differences in the expression of brain lateralization, potentially related to the greater level of asymmetry in male chick brains, leads to differences in sociality between the two sexes. According to the literature, females show greater social bonding and attachment while males show increased aggression (e.g. Vallortigara 1992b). This may lead, for example, to female adult birds being more competent (owing to increased opportunities) at social learning tasks. When required to perform the social tasks, we employed it is the male chicks that show more evidence of laterality than the females. This, we suppose, may be related to the increased bias in laterality shown in male chicks previously reported in the literature (see above) and also to the nature of the tasks used. Only in the PAL is there observation of another; all the other tasks, although suggested to require a social competence, do not involve the presence of another chick. Even in PAL there is only ever observation of a conspecific, not a direct interaction. It is worth noting that Nicol & Pope (1999) have investigated social learning effects in hens but not in cockerels. These sex differences may be due to interactions between hormone levels and light exposure (Rogers & Rajendra 1993). Halpern et al. (2005) go on to suggest that the interaction between the hormones and laterality may allow a role for the stress response of the hen to impinge upon and modulate the strength of asymmetry in her chicks. In addition, it has been reported that chicks are able to influence maternal effects to light exposure by inducing egg turning (Tuculescu & Griswold 1983). However, the maternal influence on the developing embryo is likely to be greater. Considering the female chicken, it is quite possible that her choice of nesting site may be influenced by her rank status; this itself may influence not only the amount of light to which her eggs are exposed but also the amount of hormones they receive. Individual differences in phenotype that are produced by this differential hormone exposure are related to learning possibilities in geese (according to dominance: Pfeffer et al. 2002) and to fear responses in quail (Daisley et al. 2004). The addition of exogenous testosterone influences brain lateralization (Schwarz & Rogers 1992). Daisley et al. (2004) have shown that differences in sociality exist in quail following the application of exogenous testosterone to eggs: with treated birds, presumably those with increased lateralization, subject to increased stress response in the presence of others. The effect of social interactions early in life may also impinge upon the level of lateralization. In the rhesus monkey (Macaca mulatta), it has been shown that early rearing conditions play an important role in the development of lateralization: those

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Review. Lateralization of social cognition J. N. Daisley et al. monkeys raised not by their mother, but in a nursery with only same age individuals for companionship, showed a greater left-hand bias when reaching for a reward in a tube (Bennett et al. 2008). Also, rats, having been exposed to novel (potentially, more stressful) environments as pups, became less right-pawed as adults (Tang & Verstynen 2002). This shift appears to have an anatomical basis, with there being a commensurate increase in right hippocampal volume (Verstynen et al. 2001). Although the domestic chick is a precocial animal, it is still likely that some forms of lateralization may be shaped during early experiences out of the egg. Therefore, it is likely that a hen experiencing social stress might end up nesting in thicker cover, leave the nest less often and deposit higher stress hormones in her eggs (according to Rogers 2008). This in turn could lead to reduced lateralization within her brood, which, although potentially increasing their survival in terms of food intake owing to a reduction in dominance hierarchy stability, may impinge upon her offspring’s success within the context of the social group: according to our research, such individuals may not be able to successfully judge other’s dominance in relation to them and may be at a disadvantage in learning.

8. CONCLUSIONS It is likely that not all individuals are as lateralized as each other, whether through the different amounts of light received in the egg, the hormones deposited there by the female or even owing to the different levels of social interaction they received when shortly out of the egg. For example, it could be that differently ranked chicks in a group may have differences in social awareness (as judged by their performance in a TI task) and this could, in turn, be due to an increased lateralization found prior to hatching, or because of early experiences when out of the egg. In addition, the work we have reported has relied upon implied social cognition, with the exception of the passive avoidance task where observation learning was used by the chicks. This has demonstrated a bias in lateralization for males. We would like to continue our investigations, but also to include more exacting social tests and tasks in which the naturally expressed lateralized behaviours can be related to direct social interactions. Finally, it should be noted that many of the lateralization processes seen when the bird is young disappear when the bird reaches maturity (Rogers & Andrew 2002). This would suggest that the underlying anatomical asymmetries in the thalamofugal pathway are largely lost during later ontogeny (Rogers & Deng 1999). However, sexual behaviour, or at least the visual component of it, may still be guided by right/left differences: both for courtship and consummatory behaviour there is preferential right hemisphere use (Ventolini et al. 2005). Thus, there may be long-lasting effects of the initial asymmetries. The experiments comply with the current Italian and European Community laws for the ethical treatment of animals. This research is a part of the project Evolution and Development of Cognitive, Behavioural and Neural Lateralisation, (EDCBNL Phil. Trans. R. Soc. B (2009)

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2006–2009), supported by the Commission of the European Communities within the framework of the specific research and technological development programme ‘Integrating and strengthening the European Research Area’ (initiative ‘What it means to be human’), through a financial grant to L.R. The authors would like to thank the following for their help with gathering the data and caring for the chicks: Adriana Berti, Consuelo Besazza, Diana Castelli, Federico Del Gallo, Alessio Fracasso, Tania Mattarello, Camilla Romor and Fabrizio Spinedi.

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Phil. Trans. R. Soc. B (2009) 364, 983–989 doi:10.1098/rstb.2008.0241 Published online 4 December 2008

Light during embryonic development modulates patterns of lateralization strongly and similarly in both zebrafish and chick R. J. Andrew*, D. Osorio and S. Budaev School of Life sciences, Centre for Biology and Environmental Sciences, University of Sussex, Brighton BN1 9QG, UK Some aspects of lateralization are widespread. This is clear for the association between left-eye (LE) use and readiness to respond intensely to releasing stimuli presented by others, which has been found in representatives of all major groups of tetrapods and in fishes. In the chick, this behavioural asymmetry is linked developmentally to greater ability to sustain response against distracting stimuli with right-eye (RE) use, in that both reverse with the reversal of the normal RE exposure to light. In the zebrafish, the same two asymmetries (normally) have similar associations with the LE and the RE, and both also reverse together (owing to epithalamic reversal). Here, we show that light exposure early in development is needed in zebrafish to generate both asymmetries. Dark development largely abolishes both the enhanced abilities, confirming their linkage. Resemblance to the chick is increased by the survival in the chick, after dark development, of higher ability to assess familiarity of complex stimuli when using the LE. A somewhat similar ability survives in dark-developed zebrafish. Here, LE use causes lesser reliance on a single recent experience than on longer term past experience in the assessment of novelty. Such resemblances between a fish and a bird suggest that we should look not only for resemblances between different groups of vertebrates in the most common overall pattern of lateralization, but also for possible resemblances in the nature of inter-individual variation and in the way in which it is generated during development. Keywords: lateralization; light; zebrafish

1. INTRODUCTION Some features of lateralization are widespread among vertebrates (Andrew & Rogers 2002). The left-eye system (LES) has an advantage in the analysis of topography and position (chick: Rashid & Andrew 1989; Tommasi et al. 1997; marsh tit: Clayton & Krebs 1994; rat: Bianki 1988; human: Kosslyn et al. 1992). Furthermore, the LES is more likely to respond to various releasers. This is true of attack and sexual behaviour, when it is the left eye (LE) that sees the stimulus rather than the right (e.g. toad: Robins et al. 1998; lizard: Deckel 1998; chick: Rogers et al. 1985; baboon: Casperd & Dunbar 1996). By contrast, the right-eye system (RES, left hemisphere) use is associated with a response to an identified target such as a prey item (zebrafish: Miklo´si & Andrew 1999; toad: Vallortigara et al. 1998; chick: Andrew et al. 2000). In the rat, the left hemisphere is especially involved in a rapid choice of the correct response (Bianki 1988). Now that it is clear that cerebral lateralization is very widespread among vertebrates, the next objective must be to understand the extent to which it varies between individuals and between species. A major obstacle is that the observed behavioural asymmetries may be

affected by factors that are not themselves integral to lateralized brain mechanisms. Moreover, such factors may affect different behavioural asymmetries differently. It is very clear in fishes, for example, that motivational differences, which change the significance of test stimuli, can also change the observed behavioural asymmetries; thus, the evocation of sexual motivation can bring different brain mechanisms to bear, generating behavioural asymmetries of a different kind (Bisazza et al. 1998). A promising simplification is to study the effects on well-established behavioural asymmetries of known changes in brain lateralization. Here, we present evidence for unexpected resemblances between the domestic chick and zebrafish in behavioural lateralization. In both, the same two asymmetries are tightly linked in development, in that both reverse their allocation together: when one shifts from association with right-eye (RE) use to association with the LE, the other shifts in the opposite direction. In the chick, the first asymmetry (visual control of response, VCR) is the use of the RE to select and sustain an approach to a target (Andrew et al. 2000), and to sustain selection of targets rather than distractors (Rogers & Anson 1979); this bias is present also in the zebrafish (Miklo´si & Andrew 1999). The second is the readier evocation of responses when appropriate and highly effective stimuli are perceived with the LE rather than with the RE. The examples so far described chiefly relate to the releasers of

* Author for correspondence ([email protected]). One contribution of 14 to a Theme Issue ‘Mechanisms and functions of brain and behavioural asymmetries’.

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responses such as attack and sexual behaviour (chick: Rogers et al. 1985; many groups of vertebrates: reviewed in Vallortigara & Bisazza 2002). The widespread use of the LE when a fish views its own reflection (Sovrano et al. 2000) suggests that the releasers of social responses are also more effective when seen with the LE. This use of the LE is also present in the zebrafish (Andrew et al. in press). Here, we add an additional class of releasers for the zebrafish: we used a simple pattern providing visual heterogeneity, such as might serve to identify a potential refuge, and showed that there was an asymmetry of response according to which eye saw it. A convenient overall term for such a feature of behaviour is a ready response to releasers (RRR). In both species, VCR and RRR are linked in development. In the chick, they both reverse their allocation as a result of experimental reversal of the normal asymmetric exposure of the eyes late in development (Deng & Rogers 1997). The RE normally faces outwards, and so receives light entering through the shell. If the LE is exposed to light instead, then VCR and RRR shift in the opposite directions (Rogers 1990). In the zebrafish, the reversal of the habenular asymmetry results in exactly the same shifts as in VCR and RRR (Barth et al. 2005). Eye use in mirror tests reverses, and the LE is used instead of the RE in an approach to a target. Developmental effects of light in the zebrafish during development have already been demonstrated. These include the loss of bias to LE use in the mirror test when light is absent during development (Andrew et al. in press), and elevation of boldness in fry exposed to light (Budaev & Andrew in press). A major component of the boldness syndrome was elevated locomotion in a strange environment, which correlated with the degree of approach to a predator model. Both these features of behaviour would be well explained by an enhanced ability to sustain a response (i.e. elevated VCR), once initiated, which is present in light- but not darkdeveloped zebrafish. In the chick, the absence of light late in development minimizes (or perhaps abolishes) both behavioural asymmetries (Rogers 1982; Zappia & Rogers 1983). Here, we provide similar evidence for zebrafish. This is important because it suggests that light is involved in the generation of the specific brain asymmetry (or asymmetries) that generates VCR and RRR, rather than in some way reversing the direction of brain lateralization as a whole. This conclusion is reinforced in dark-developed chicks by the presence of some clear differences between behaviour shown with the LE or the RE in use (Mascetti & Vallortigara 2001; Deng & Rogers 2002; Chiandetti et al. 2005). It is particularly important that higher interest in novelty when the LE is in use is present in dark chicks (Rogers et al. 2007).

2. MATERIAL AND METHODS Breeding zebrafish came from a pet shop (Brighton, UK). They were maintained in aquaria (300!155!155 mm) at 288C on a 14 L : 10 D cycle, and fed daily with dry zebrafish pellets (ZM-400; ZM Ltd, Winchester, England, UK). We Phil. Trans. R. Soc. B (2009)

used fry from four different batches coming from the spawning of one female with two males. We did not note pronounced differences in behaviour or other characteristics between these batches. Approximately 3 hours after fertilization, the eggs were removed from the parental aquarium and transferred to white plastic boxes (140!80!50 mm). The eggs and the larvae (‘fry’) were maintained in these boxes in groups of approximately 15–20. For protection against fungi, a few drops of methylene blue solution were added to each box. Approximately 6 hours after fertilization, the eggs were divided into two experimental groups, held in boxes in separate aquaria at 288C. The first group was maintained under the normal 14 L : 10 D cycle. The second group developed in darkness (!0.01 lux measured with Extech EasyView EA30 digital light meter). The eggs and fry of the dark group were taken to light only for a short time (!2 min each time) every second day for maintenance, inspection and cleaning. The dark group was returned to the normal 14 L : 10 D cycle in the evening of the day 6 post fertilization. On the 8th day post-fertilization (DPF), both the light and dark groups were further divided into two treatments. The first treatment (EXPER) had home-box experience of the vertical black stripe stimulus used in subsequent behavioural experiments, whereas the second (NO EXPER) had no such experience. The black stripe was inserted in the middle of the longer walls of the white maintenance boxes of the EXPER group, whereas NO EXPER fry were maintained in empty boxes. The behavioural experiments were conducted on 11 DPF, so that the EXPER group had 3 days experience of the black stripes in their home boxes. The fry were not fed prior to the tests. All tests used a white plastic swim-way (320!125 mm) with seven compartments (50!40 mm, from which we used only four) filled with water to a depth of 25 mm (figure 1a). All adjacent compartments were connected by vertical 5 mm slits in the middle of the connecting walls. Two plastic bars were attached at each side of the slit to create a 9 mm long corridor (figure 1b). Each compartment contained two lamps mounted above the left and right sides, which could not be directly seen by the fry. The lighting of each compartment was controlled by switches and a rheostat. A small video camera could be slid along a glass sheet covering all the compartments and monitoring each in turn. The whole apparatus was covered by black cloth to exclude light from other sources. The individuals were tested only once and water in the experimental swim-way was changed after each fry. Full details are given by Watkins et al. (2004) and Budaev & Andrew (in press). The testing procedure is schematized in figure 1a. At test each fry was sucked into a large pipette (entrance diameter 6 mm), together with an adequate amount of water, and released gently into the first compartment of the swim-way, which was lit by the lamps. All other compartments were darkened. The fry was left undisturbed for 4 min. Subsequently, the light in the test compartment was slowly dimmed to darkness over 20 s. The video camera was immediately shifted to monitor the second compartment. Illumination was then similarly raised in this second compartment. The fry entered this novel compartment under positive phototaxis. After entering the second compartment, the fry was left to explore it for a further 1 min. Thereafter, the same sequence of changes in lighting was used to attract the fry into subsequent compartments (figure 1b). The third and fourth

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Figure 1. Scheme of the experiments. (a) An outline of the swim-way used in the experiments with the sequence of tests (indicated by an arrow, from top down); (b) the stimuli used in the STR1 and STR2 tests: (i) hatched and (ii) black stripes; and (c) an outline of the groups used in the study. Ha, hatched stripe; Bl, black stripe. compartments had a large vertical stripe at the closest end of the entry wall, which was on the left or the right, keeping the same position for the first and second stripe tests (STR1 and STR2). The stripe was placed so that it could be seen monocularly before entry, but only when the fry had arrived at the end of the short between-compartment corridor. Two stripes were used: a hatched stripe made up of alternating black and white lines, 5 mm wide and angled at 458, and a uniformly black stripe of the same size (figure 1b). After entry, the fry was left to explore the compartment and stripe for 1 min. Three designs were used (figure 1c). The EXPER fry saw a hatched stripe in STR1 and a black stripe in STR2, while NO EXPER saw either a hatched stripe, followed by a black, or a black in both the tests. One reason for this design was that it was already known (Andrew et al. in press) that RE use tended to be dominated by immediately prior experience, whereas LE use was more affected by long-term experience. The behaviour of the fry in both the stripe tests was video recorded and analysed using an on-screen measurement software. We recorded distances between the fry and the stripe every 10 s. In the following analysis, we use the minimum distance achieved during the test between the fry and the stripe. This allowed us to measure whether the fry responded differently to the stimuli presented to the LE or the RE. The sample sizes within each experimental combination were slightly different (nZ4–7) because of fry availability. The total number of fry was 42. We used ANOVAs and randomization tests for statistical comparisons (R software package; p-values are two-tailed).

3. RESULTS AND DISCUSSION (a) Overall analyses Light and dark fry showed different left/right patterns (figure 2). Overall, the experimental groups exhibited significant differences in their responses in the STR1 test (experience, EXPER or NO EXPER; side, stripe on the left or the right; development, light or dark: experience!side!development F1,22Z5.194, pZ0.033). This was partly due to the different responses of the NO EXPER fry (stimulus, hatched or black; stimulus! side: F1,34Z7.037, pZ0.012; side!development: F1,34Z4.941, pZ0.033). There was no overall significant differences between the groups in the second Phil. Trans. R. Soc. B (2009)

stripe (STR2) test, but the two NO EXPER STR2 groups still showed significant differences (side! development: F1,35Z6.676, pZ0.014). (b) Light fry Within the NO EXPER groups, the left/light fry showed a close approach to the hatched but not to the black stripe, while the right/light fry showed if anything the reverse (figure 2). In the STR1 test for the light fry, there was, as a result, a significant interaction in the NO EXPER condition for stimulus!side (F1,17Z10.459, pZ0.005). The close approach by the left/light fry to hatched in the STR1 test was unaffected by EXPER, when STR1 hatched tests were compared between EXPER and NO EXPER (figure 2). The right/light fry, by contrast, showed a striking close approach in the EXPER condition, when compared with NO EXPER. As a result, the interaction for side! experience, in the hatched tests, was suggestive (F1,12Z4.64, pZ0.052), entirely due to the change in the right/light groups. The absence of a close approach in the NO EXPER condition was accompanied by pronounced interindividual differences in the pattern of the latency distribution: some individuals showed very long latencies, although most came out quickly as usual. This wide spread was completely absent in the EXPER condition (and in left/light in both conditions), suggesting that some right/light individuals had difficulty in assessing the hatched stripe when seen in the absence of any comparable experience. The difference in variances between the EXPER and NO EXPER conditions in right/light was significant (Ansari–Bradley (AB) test, nZ28, ABZ132, pZ0.0129). The very different behaviour in the EXPER condition is perhaps due to a combination of readiness to accept before the emergence a crude match with the record from hometank experience, coupled with a high ability to sustain an approach to examine further (see §4). The special response of the left/light fry to hatched stripes was absent in left/dark (figure 2). A comparison of the response to the black or hatched stripes in STR1 NO

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Figure 2. The minimum distance to the stimulus in the different experimental groups. (a–c) The first stripe test (STR1) and (d– f ) the second stripe test (STR2). The plots include experience, condition and the type of the stimulus (e.g. EXPER, hatched for experienced fry in test with the hatched stripe): (a) EXPER, hatched; (b) NO EXPER, hatched; (c) NO EXPER, black; (d ) EXPER, black; (e) NO EXPER, black; ( f ) NO EXPER, black. Dark fry, grey boxes; light fry, white boxes. Median, quartiles (25–75%) and extremes are shown.

EXPER in the left tests produced a significant interaction (stimulus!development: F1,19Z5.145, pZ0.035), owing to the anomalous approach by left/light. The special response of light fry to the properties of hatched when seen by the LE is probably one aspect of greater responsiveness of the LES to valent stimuli: in this case, visual heterogeneity of the environment, such as might be presented by potential refuges or landmarks (see §4). (c) Dark fry An important issue here is whether there are any left/right differences in the dark fry. The left/dark and right/dark fry were affected differently by home-tank experience (figure 2). A comparison of the EXPER group with both NO EXPER groups in the STR2 test showed a significant interaction (experience!side: F1,24Z5.739, pZ0.025). The experience of black in the home tank caused left/dark to approach, presumably because the stripe was assessed to be a familiar refuge or landmark. In the absence of home-tank experience, black was not approached. The right/dark fry showed a quite different pattern: they approached closest when they had had one previous experience of the same stripe (i.e. in the NO EXPER group with black in the first and second emergence) and least when they had home-tank experience of black. These results are best explained by supposing that, in the dark fry, the LES relies to a marked degree on the use of established traces in assessing the stripes. The left/dark fry were unaffected by a single experience of either a black or hatched pattern in a second encounter with a stripe: whether there had been home-tank experience or not, the STR1 and STR2 responses were almost identical. If the black stripes had been present in the home tank, then the stripes (whether Phil. Trans. R. Soc. B (2009)

black or hatched) were approached, presumably because they were judged (relatively) familiar and interesting. Even in the case of the black stripes, the stimulus was a familiar object in a strange place. If no stripe had been seen in the home tank, then avoidance was persistent. The right/dark groups clearly differ. In the NO EXPER condition, a prior brief exposure to black caused approach to appear in STR2, quite unlike the absence of change in left/dark. By contrast, after home-tank experience of black, black is not approached in STR2, (unlike both NO EXPER groups). This may represent the assessment as a familiar landmark or obstacle, which should be ignored; in any event, EXPER affects the right/dark fry, but quite differently from the left/dark fry. It is impossible to tell whether a comparable left/right difference is present in the light groups, because of the special response of left/light to hatched. This does not apply to the NO EXPER condition, with black in both STR1 and STR2. Here, there was a change in the pattern of response owing to the first exposure (figure 2), with left/light increasing approach in STR2 and right/light avoiding more (side!test: F3,47Z3.417, pZ0.025, repeated-measures ANOVA). This was chiefly due to the change in left/light (twosample permutation test: left/light nZ14, TZ1827, pZ0.002; right/light nZ13, TZ1081, pZ0.677). Here, the STR1 exposure changes behaviour in STR2 in both left/light and right/light, but not in the corresponding dark groups. Only a tentative interpretation is possible and the effects require replication. The marked shift to approach shown in STR2 (black) by left/light may represent treating black as a refuge, once it is familiar. This would probably be advantageous: taking up a position against a large dark fixed

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Lateralization in zebrafish and chick R. J. Andrew et al. object would make the fry less conspicuous. The avoidance shown by right/light in STR2 may reflect a decision taken in the first emergence that the black stripe is an obstacle, which is strongly sustained in the second emergence. Another odd result, which also requires further work, is the fact that the right/light groups differ suggestively between EXPER and NO EXPER for STR1 hatched. Hatched is avoided in the NO EXPER condition, but approached very close in the EXPER condition (side!experience: F1,12Z4.641, pZ0.052). Here, home-tank experience may allow a judgement of sufficient novelty as to cause a close approach in investigation, which is then sustained by high VCR.

4. GENERAL DISCUSSION The abilities that in both a fish and a bird depend on the effects of light during development (VCR and RRR) are linked in the zebrafish to the habenular asymmetry, in that both reverse in association with the reversal of the habenular asymmetry (Barth et al. 2005). The normal asymmetry of the zebrafish habenula is for lateral habenula enlargement on the left and medial enlargement on the right (Aizawa et al. 2005). Outflow is strikingly separate, with the left lateral habenula predominantly supplying the dorsal division of the main relay nucleus (the interpeduncular nucleus, IPN), and the right medial habenula the ventral IPN. There is a striking resemblance between the functions of the lateral habenulae in zebrafish and mammals: in rats during a targeting and pursuit task, firing in the lateral habenular units correlates with targeting head movements (Sharp et al. 2006). The use of the RE in the selection and pursuit of targets by zebrafish (Barth et al. 2005) is clearly comparable, as is the ability to sustain choice by inhibiting pecks at irrelevant stimuli shown by chicks when using the RE (Deng & Rogers 1997, 2000). The lateral habenulae are also concerned in mammals, with the inhibition of response to the stimuli that predict the absence of reward in a task where reward is expected (Matsumoto & Hikosaka 2007), and with the inhibition of premature responses (Lecourtier & Kelly 2005). These two functions can be reconciled if it is supposed that one of the ways in which the lateral habenulae sustain an ongoing response is to inhibit a response to other stimuli, which are potentially powerful in evoking a response. The medial habenulae are involved in reward in mammals (as shown by the effects on self-stimulation for morphine; Taraschenko et al. 2007). The zebrafish findings suggest an extension of this function to the promotion of response to any stimulus that is intrinsically powerful in evoking a response. The LE viewing of a mirror reflection is shown only by the lightdeveloped fry (Andrew et al. in press). Such persistent bias strongly suggests that a response is here being driven by especial interest of the LES in the motivating properties of social fellows. The dark fry do not lack interest in their reflection. They show persistent viewing, but with alternating long periods of LE or RE use, allowing both eye systems an opportunity to assess. It is thus chiefly the asymmetry that is lacking. Phil. Trans. R. Soc. B (2009)

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Here, we have shown that the left/light, but not the left/dark, fry respond strongly (and innately) to properties, which are likely to be associated with potential refuges. The dissected character of the stimulus matches the properties of vegetation or debris. Small fishes are often attracted to visually heterogeneous patterns such as alternating stripes in a novel environment and begin to feed earlier in their proximity (Mikheev et al. 1997). Also, the presence of visual heterogeneity may reduce the fear response of fishes to the predator’s odour (Afonina et al. 2005). Approaching such potentially camouflaging heterogeneous patterns should therefore be adaptive for small fry. On the other hand, fry should avoid visually homogeneous areas where they would be more conspicuous to predators. Taken together, the evidence suggests that after light, but not dark, development, the LES has heightened interest in, and response to, motivating stimuli. It will be interesting to see whether this extends to conditioned stimuli that were originally neutral, but have become very valent. (a) Asymmetry present in the dark fry Zebrafish fry show some behavioural asymmetry after dark development. Here, we have shown that the left/dark fry are strongly affected by long-term experience of stripes in the home tank, but (unlike right/dark) hardly at all by the nature of the stripe seen in the first emergence. Such an asymmetry is likely to interact with the assessment of novelty and complexity. The preferential and sustained use of established long-term records would promote such assessment. Greater use of recently elaborated records (such as is present in the right/dark, and perhaps in the right/light fry) would oppose accurate evaluation of identity, both in the long run by making difficult use of records that allows many experiences to be taken into account, and in the short term by making records based on current experience, the main determinants of judgements of familiarity. However, it would, at the same time, promote continuing choice of a particular stimulus or type of stimulus. Dark-developed chicks show a greater interest in and ability in assessing novelty when using the LES (Deng & Rogers 2002; Andrew et al. 2004; Rogers et al. 2007). This is thus another probable resemblance between a fish and a bird. (b) Functions of lateralization A number of functions have been suggested, which may all be to some extent true. The existence of (basically) similar suites of structures on the right and the left probably does ‘increase capacity’ when the two are independently searching different areas of space. It is also likely that some functions require neural organizations incompatible with other functions, if they are to be well performed. Establishing the identity of a complex stimulus with past experience requires extensive use of a detailed record, in which the properties of the record determine the analysis. The behaviour of the left/dark fry, which is reported here, may provide an example of a high degree of such use. This is quite different, for example, from the use of

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a particular cue to select possible targets efficiently and quickly. Here, the choice of eye with which to view allows appropriate abilities to be brought to bear. However, it is likely that the determination of the sort of behaviour that is likely to be evoked is an additional important function. The sort of variation that is important here is whether initiated responses are sustained against distraction and danger, or whether much time is spent investigating slight change. The effects on such suites of behaviour might act over relatively short intervals: motivational factors such as being frightened are an obvious example. Alternatively, the effects might act over longer periods or a complete lifetime. Here, long-acting physiological conditions such as levels of sex hormones, or genetic and environmental effects during development (such as are considered here) are likely causes. Variations in boldness are a revealing example since their consequences under natural conditions have been extensively studied in great tits. Drent et al. (2003) summarized the properties of the two extreme personality types. Active (bold) individuals take rapid decisions, establish routines based on past success and are aggressive to fellows. Passive (shy) individuals are cautious, responsive to external stimuli rather than sustaining routines (so that exploration is thorough) and less aggressive. The light fry are bold and the dark fry are shy, as measured by a ‘shyness’ construct, derived from the tests in the same apparatus as that used in the present study (Budaev & Andrew in press). The construct was derived from levels of locomotion after entry to compartments, and the degree of approach to a crude model of the front view of a larger fish, measures which showed a positive correlation. Boldness in the light fry is likely to be due to the developmental effects of light on VCR, making it easier for locomotion to be initiated and sustained in a novel environment, including approach to a potentially dangerous stimulus. The effects on the development of an environmental factor, which could act in the field, offers a source of interindividual variation, which may be more resistant than genetic control to fixation of one or other extreme pattern of behaviour, to fixation within a population by strong selective pressures.

5. CONCLUSION Past speculation (e.g. Andrew 2002) has raised the possibility that a single pattern of lateralization is at least widely characteristic of vertebrates. It is now necessary to change this hypothesis by adding that there is commonly inter-individual variation in some aspects of this pattern, which, however, may itself be relatively standard. The resemblances set out here between a fish and a bird suggest a specific hypothesis. When there is a marked behavioural asymmetry in VCR and RRR in an individual, LE use (right brain control) will go with elevated RRR, and RE use (left brain control) with high ability to sustain an initiated response. Inter-individual variation will involve shifts between behavioural asymmetry and near symmetry in these behavioural patterns. At the same time, other aspects of lateralization, in particular the Phil. Trans. R. Soc. B (2009)

LES assessment of novelty or identity, will not vary (except as an indirect consequence of change in VCR and RRR). All experimental work was carried out under Home Office licence. We gratefully acknowledge support from the EU Sixth Framework Programme.

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Rogers, L. J. 1982 Light experience and asymmetry of brain function in chickens. Nature 297, 223 –225. (doi:10.1038/ 297223a0) Rogers, L. J. 1990 Light input and the reversal of functional lateralisation in the chicken brain. Behav. Brain Res. 38, 211–221. (doi:10.1016/0166-4328(90)90176-F) Rogers, L. J. & Anson, J. M. 1979 Lateralisation of function in the chicken forebrain. Pharmacol. Biochem. Behav. 10, 679 –686. (doi:10.1016/0091-3057(79)90320-4) Rogers, L. J., Zappia, J. V. & Bullock, S. P. 1985 Testosterone and eye–brain asymmetry for copulation in chickens. Experientia 41, 1447–1449. (doi:10.1007/BF01950028) Rogers, L. J., Andrew, R. J. & Johnston, A. N. B. 2007 Light experience and the development of behavioural lateralisation in chicks. III. Learning to distinguish pebbles from grains. Behav. Brain Res. 177, 61–69. (doi:10.1016/ j.bbr.2006.11.002) Sharp, P. E., Turner-Williams, S. & Tuttle, S. 2006 Movement-related correlates of single cell activity in the interpeduncular nucleus and habenula of the rat during a pellet-chasing task. Behav. Brain Res. 166, 55 –70. (doi:10.1016/j.bbr.2005.07.004) Sovrano, V., Rainoldi, C., Bisazza, A. & Vallortigara, G. 2000 Roots of brain specialisations: preferential left-eye use during mirror-image inspection in six species of teleost fish. Behav. Brain Res. 106, 175 –180. (doi:10.1016/ S0166-4328(99)00105-9) Taraschenko, O. D., Shulan, J. M., Maisonneuve, I. M. & Glick, S. D. 2007 18-MC acts in the medial habenula and interpeduncular nucleus to attenuate dopamine sensitization to morphine in the nucleus accumbens. Synapse 61, 547–560. (doi:10.1002/syn.20396) Tommasi, L., Vallortigara, G. & Zanforlin, M. 1997 Young chicks learn to localise the centre of a spatial environment. J. Comp. Physiol. A 180, 567–572. (doi:10.1007/s0035 90050073) Vallortigara, G. & Bisazza, A. 2002 How ancient is brain lateralisation? In Comparative brain lateralisation (eds L. J. Rogers & R. J. Andrew), pp. 9–69. Cambridge, UK: Cambridge University Press. Vallortigara, G., Rogers, L. J., Bisazza, A., Lippolis, G. & Robins, A. 1998 Complementary right and left hemifield use for predatory and agonistic behaviour in toads. NeuroReport 9, 3341– 3344. (doi:10.1097/00001756199810050-00035) Watkins, J., Miklo´si, A. & Andrew, R. J. 2004 Early asymmetries in the behaviour of zebrafish larvae. Behav. Brain Res. 151, 177–183. (doi:10.1016/j.bbr.2003.08.012) Zappia, J. V. & Rogers, L. J. 1983 Light experience during development affects asymmetry of forebrain function in chickens. Dev. Brain Res. 11, 93 –106. (doi:10.1016/01653806(83)90204-3)

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Phil. Trans. R. Soc. B (2009) 364, 991–1003 doi:10.1098/rstb.2008.0260 Published online 4 December 2008

Zebrafish and medaka: model organisms for a comparative developmental approach of brain asymmetry Iskra A. Signore1, Ne´stor Guerrero1, Felix Loosli2, Alicia Colombo1, Aldo Villalo´n1, Joachim Wittbrodt3 and Miguel L. Concha1,* 1

Laboratory of Experimental Ontogeny, Nucleus of Neural Morphogenesis, Anatomy and Developmental Biology Program, ICBM, Faculty of Medicine, University of Chile, Independencia 1027, 8380453 Santiago, Chile 2 Institut fu¨r Toxikologie und Genetik, Forschungszentrum Karlsruhe, Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany 3 Developmental Biology Programme, EMBL-Heidelberg, Meyerhofstrasse 1, 69012 Heidelberg, Germany Comparison between related species is a successful approach to uncover conserved and divergent principles of development. Here, we studied the pattern of epithalamic asymmetry in zebrafish (Danio rerio) and medaka (Oryzias latipes), two related teleost species with 115–200 Myr of independent evolution. We found that these species share a strikingly conserved overall pattern of asymmetry in the parapineal–habenular–interpeduncular system. Nodal signalling exhibits comparable spatial and temporal asymmetric expressions in the presumptive epithalamus preceding the development of morphological asymmetries. Neuroanatomical asymmetries consist of left-sided asymmetric positioning and connectivity of the parapineal organ, enlargement of neuropil in the left habenula compared with the right habenula and segregation of left–right habenular efferents along the dorsoventral axis of the interpeduncular nucleus. Despite the overall conservation of asymmetry, we observed heterotopic changes in the topology of parapineal efferent connectivity, heterochronic shifts in the timing of developmental events underlying the establishment of asymmetry and divergent degrees of canalization of embryo laterality. We offer new tools for developmental time comparison among species and propose, for each of these transformations, novel hypotheses of ontogenic mechanisms that explain interspecies variations that can be tested experimentally. Together, these findings highlight the usefulness of zebrafish and medaka as comparative models to study the developmental mechanisms of epithalamic asymmetry in vertebrates. Keywords: brain asymmetry; development; teleosts; laterality; epithalamus; heterochrony

1. INTRODUCTION Asymmetry is a fundamental and conserved feature of the brain, which is thought to enhance information processing and task performance in behaviours central for species survival, such as feeding, predator detection and memory (Gu¨ntu¨rku¨n et al. 2000; Rogers 2000; Pascual et al. 2004; Vallortigara & Rogers 2005; Rogers & Vallortigara 2008). In addition, asymmetry has been proposed as the basis of speech and other behavioural traits (Sherman et al. 1982; Rogers & Andrew 2002; Hutsler & Galuske 2003; Toga & Thompson 2003) and abnormal asymmetry appears to associate with several neuropathologies including schizophrenia (Li et al. 2007), autism (Escalante-Mead et al. 2003) and neuronal degenerative diseases (Toth et al. 2004). In the last decade, experimental studies have provided valuable insights into the developmental basis of brain asymmetry. Particularly helpful have been genetic model organisms that allow a comprehensive

bottom-up (gene to behaviour) study of this phenomenon (Concha 2004). For example, recent work in the teleost zebrafish has unveiled genetic mechanisms that control the development of neuroanatomical asymmetries (reviewed in Halpern et al. 2003; Concha 2004) and established the first operational links between genetics, asymmetric morphology and lateralized behaviours (Barth et al. 2005). One of the best-studied cases of brain asymmetry is observed in the epithalamus of vertebrates (Concha & Wilson 2001; Bianco & Wilson 2009). In zebrafish, epithalamic asymmetry is established through a sequence of developmental modules. Initially, asymmetry (structural differences between left and right sides at the individual level) and laterality (directionality of asymmetry at a population level) are determined by the coordinated activity of members of the fibroblast growth factor ( J. Regan, M. Concha, M. Roussigne, C. Russell and S. Wilson 2007, unpublished data) and nodal (Concha et al. 2000) signalling pathways, respectively. Then, a sequential programme of asymmetric morphogenesis generates neuroanatomical asymmetries in the epithalamic pineal complex and

* Author for correspondence ([email protected]). One contribution of 14 to a Theme Issue ‘Mechanisms and functions of brain and behavioural asymmetries’.

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Figure 1. (a) Zebrafish and (b) medaka share an overall pattern of molecular and morphological epithalamic asymmetry. ((i),(ii)) Asymmetric expression of components of the nodal signalling pathway in the presumptive epithalamus. mRNA expression of orthologue genes was detected by whole-mount in situ hybridization (arrows) at (i) normalized STU 35 (Dr-lefty1, Ol-lefty) and (ii) 43 (Dr-pitx2c, Ol-pitx2c) (table 2). The lateral flexure of the third ventricle is indicated by arrowheads. (iii) Left-sided positioning and efferent projection of the parapineal organ. Expression of GFP was detected in medaka Tg( fRx2::GFP ) and zebrafish Tg(FoxD3::GFP ) and pseudo-coloured in blue and green to label pineal and parapineal organs, respectively. The red arrowhead points to the terminal dandelion seed-head-shaped domain of parapineal efferent connectivity. (iv) Asymmetric organization of neuropil in the habenulae. Arrows indicate the regions of neuropil, which exhibit dissimilar growth between the left and right habenulae, as detected by immunostaining against acetylated a-tubulin. The red arrowhead points to a neuropil domain that is detected exclusively in the left habenula of medaka. (v) Asymmetric organization of neuronal cell bodies in the habenulae. Asterisks indicate equivalent regions of the left and right habenulae. The red arrowhead points to a domain devoid of fluorescent Nissl staining that is detected exclusively in the left habenula of medaka. ((vi),(vii)) Dorsoventral segregation of left–right habenular efferents in the IPN. Left and right habenular projections were labelled with DiD (red) and DiO (green), respectively. Images correspond to ((i)–(vi)) dorsal and (vii) lateral views with anterior and dorsal to the top, respectively. Stages of development correspond to 120 HPF (zebrafish, at 268C) and Iwamatsu’s stage 39 (medaka), unless otherwise stated. ((iii)–(vii)) Three-dimensional projections from confocal z-stacks. L, left; R, right; Lh, left habenula; Rh, right habenula; hc, habenular commissure; Lfr, left fasciculus retroflexus; Rfr, right fasciculus retroflexus; dIPN, dorsal domain of the IPN; vIPN, ventral domain of the IPN. Scale bars, ((i)–(v)) 20 mm, ((vi),(vii)) 30 mm.

habenulae. Early asymmetries of the pineal complex involve the asymmetric migration of the photoreceptive parapineal organ to the left side (Concha et al. 2003). Subsequent habenular asymmetries are characterized by differential growth of sub-nuclei (Aizawa et al. 2005, Phil. Trans. R. Soc. B (2009)

2007; Gamse et al. 2005) and neuropil domains (Concha et al. 2000) between the left and right sides. Finally, asymmetries in the ratios of different subtypes of habenular projection neurons result in asymmetric target connectivity wherein left and right habenular

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Figure 2. Heterotopic parapineal efferent connectivity in the left habenula of (a) zebrafish and (b) medaka. (a(i)–(vi)) Parapineal efferents blend into a dorsomedial neuropil domain of the left habenula in zebrafish whereas in (b(i)–(vi)) they segregate from other sources of habenular neuropil to form a distinct dorso-anteromedial domain in the left habenula of medaka. Images correspond to dorsal views of the left habenula with anterior to the top. Images were obtained after three-dimensional maximum projections from confocal z -stacks. The parapineal organ was pseudo-coloured in blue (parapineal body) and green (parapineal efferents) after immunostaining against GFP in (a(i),(iv)) 120 HPF zebrafish Tg(FoxD3::GFP ) and (b(i),(iv)) St.39 medaka Tg( fRx2::GFP ). Distribution of neuropil and nuclei in the left habenula were detected by (ii) immunostaining against acetylated a-tubulin and (v) fluorescent To-pro staining, respectively. Merged images of double labelling are shown in the bottom panels ((iii),(vi)). Asterisks indicate nuclei-free domains of the left habenula where parapineal connectivity is distributed in zebrafish. Arrowheads point to the terminal dandelion seed-head-shaped domain of parapineal efferent connectivity in medaka. (vii) Summary model of parapineal efferent connectivity in zebrafish and medaka. (a(vii)) In zebrafish, parapineal efferents distribute broadly within a large dorsomedial neuropil domain of the left habenula situated immediately anterior to the habenular commissure. (b(vii)) In medaka, parapineal efferents form a thick bundle of axons, which after entering the left habenula, make a turn towards the midline to end in a well-defined dandelion seed-head-shaped neuropil domain situated in the most dorso-anteromedial aspect of the left habenula. All images correspond to dorsal views, with anterior to the top. The body of the parapineal organ and its efferent connectivity are shown in black, the habenular commissure in grey and neuropil domains in yellow. L, left; R, right; Lh, left habenula; Rh, right habenula; hc, habenular commissure. Scale bars, 20 mm.

efferents are segregated along the dorsoventral axis of the interpeduncular nucleus (IPN) in the ventral midbrain (Aizawa et al. 2005; Gamse et al. 2005; Bianco et al. 2008). Three main aspects are important to highlight about the development of epithalamic asymmetries. First, genetic pathways that establish asymmetry are autonomous from those that control laterality (Concha et al. 2000). Such independence in the developmental control of asymmetry and laterality makes the epithalamus of zebrafish an attractive vertebrate model to study the ontogenic (genetic and epigenetic) mechanisms that underlie directional asymmetries, in which most individuals are asymmetrical in the same Phil. Trans. R. Soc. B (2009)

direction within the population (Van Valen 1962). Second, laterality of epithalamic asymmetry is coupled to laterality of visceral asymmetry (Concha et al. 2000; Long et al. 2003; Carl et al. 2007) in contrast to other structural and functional asymmetries of the vertebrate brain, e.g. asymmetries associated to speech and handedness (Torgersen 1950; Kennedy et al. 1999; Tanaka et al. 1999). This indicates that asymmetries controlled by independent mechanisms coexist in the vertebrate brain. Finally, epithalamic asymmetries are immersed in an evolutionarily conserved circuit involved in limbic-system-related responses (Sutherland 1982; Klemm 2004; Bianco & Wilson 2009), which has been implicated in the origin of neuropsychiatric disorders

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(Sandyk 1991; Ellison 1994). Altogether, these observations underscore the relevance of understanding the evolutionary origin, genetic control, circuit configuration and behavioural correlates of epithalamic asymmetry to begin dissecting general principles of directional asymmetries and the specific role of the epithalamus, and its associated asymmetric circuit in normality and pathology. Recent comparative surveys have revealed a striking conservation of epithalamic asymmetry among a wide range of vertebrate species (Concha & Wilson 2001; Guglielmotti & Cristino 2006). However, the lack of systematic comparative analyses addressing the genetic and developmental bases hampers the examination of general principles of epithalamic asymmetry development. In this context, the emergence of zebrafish and medaka as complementary model organisms suitable for comparative developmental approaches (FurutaniSeiki & Wittbrodt 2004) offers a unique opportunity. As lineages of zebrafish (Danio rerio, Order Cypriniformes) and medaka (Oryzias latipes, Order Beloniformes) diverged 115–200 Myr ago, comparison has the potential to unveil those aspects that represent the backbone of epithalamic asymmetry and those that are subjected to evolutionary variation. In this study, we carried out a first systematic interspecies comparison of brain asymmetry development in teleosts. We analysed the morpho-topological organization of epithalamic asymmetry and studied the temporal organization of developmental modules using a novel method for time normalization based on the rate of somitogenesis. We found a strikingly conserved overall pattern of asymmetry in the parapineal–habenular–interpeduncular system. In spite of this, we observed heterotopic changes in the organization of parapineal efferent connectivity, heterochronic shifts in the timing of developmental events underlying the establishment of asymmetry and divergent degrees of population-level laterality. Altogether, these findings highlight the usefulness of zebrafish and medaka as comparative tools to study the developmental mechanisms of epithalamic asymmetry in vertebrates. 2. MATERIAL AND METHODS (a) Fish lines Zebrafish (D. rerio) lines used in this work were wild-type Tu¨bingen and Tg( foxD3::GFP ) (Gilmour et al. 2002). Medaka (O. latipes) lines were wild-type Cab, Tg( fRx2::GFP ) and Tg( fRx2/DE::GFP ) ( Wittbrodt et al. 2002). Embryos and fry were obtained by natural spawning, raised at 26–288C in standard embryo medium, and staged according to morphology (Kimmel et al. 1995; Iwamatsu 2004) and age (hours post fertilization, HPF ). (b) Whole-mount in situ hybridization, immunohistochemistry, fluorescent Nissl and To-Pro staining In situ hybridization was performed according to standard protocols for medaka (Loosli et al. 1998) and zebrafish ( Westerfield 1996). RNA antisense probes targeted Dr-lefty1 (Bisgrove et al. 1999; Thisse & Thisse 1999), Dr-pitx2c (Essner et al. 2000), Ol-lefty (Soroldoni et al. 2007) and Ol-pitx2 ( Jaszczyszyn et al. 2007). Tubulin immunostaining was performed in larvae fixed in 2 per cent TCA/PBS at room temperature for 1.5 (medaka) and 3 (zebrafish) hours, as Phil. Trans. R. Soc. B (2009)

described earlier (Concha et al. 2003). Mouse anti-acetylated a-tubulin (Sigma, 1 : 1000), rabbit-anti-green fluorescent protein (GFP) (Abcam, 1 : 1000) and Alexa-488/647 conjugated secondary (Molecular Probes, 1 : 200) antibodies were used. Fluorescent Nissl staining comprised an overnight incubation with NeuroTrace 530/615 red Nissl (Molecular Probes, 1 : 200) at 48C. Incubation with To-Pro-3 iodide stain (642/661) (Molecular Probes, 1 : 1000) for 1 hour was used for nuclear counterstaining. Embryos were mounted in glycerol for microscopic observation and photography. (c) Labelling of habenular efferent projections For the labelling of habenular projections, larvae and embryos were immersed in fixative (4% PFA/PBS) and the skin covering the dorsal diencephalon and eyes removed. Crystals of lipophilic dyes DiD and DiO (Molecular Probes) were applied in left and right habenulae using tungsten needles connected to a micromanipulator (Aizawa et al. 2005). Labelled larvae were incubated in 0.5 per cent PFA/PBS at 48C for 2 days in darkness, to allow lipophilic dyes reach the IPN. (d) Image acquisition, processing and three-dimensional reconstruction Fluorescent samples were imaged on either Zeiss LSM 5 Pascal confocal or UltraView RS spinning disc (Perkin Elmer) microscopes using an Achroplan 40!/0.8 W dipping objective or a Plan-Apochromat 40!/1.2 W objective. Images were deconvolved to reduce blurring and noise using Huygens Professional and Scripting DECONVOLUTION softwares. Threedimensional image projections were obtained using the opacity reconstruction model in VOLOCITY software (Improvision). (e) Rationale and methodology for normalization of developmental time According to a hypothetical model of developmental time control, the overall rate of embryo development depends on both intrinsic clock and temperature-sensitive mass-specific metabolic rate signals (Reiss 2003). Zebrafish and medaka exhibit similar size of embryos, larvae and adults and probably share comparable mass-specific metabolic rates. To avoid the influence of temperature upon this variable, we considered the timing of onset and offset of developmental events at a single constant temperature (268C). In zebrafish, developmental events were determined as HPF at 288C and then scaled to HPF at 268C according to Kimmel et al. (1995). In medaka, timings of developmental events were expressed as HPF at 268C using the Iwamatsu developmental stage table (Iwamatsu 2004). To scale the influence of the internal clock, we normalized absolute times based on the rate of somitogenesis. This periodic segmentation process is known to be controlled by a molecular clock linked to oscillatory gene expression (Saga & Takeda 2001; Freitas et al. 2005) that depends on the rates of transcription and translation (Giudicelli & Lewis 2004). We considered the time needed for making a single somite during the linear phase of somitogenesis as a time-normalizing factor, and expressed the newly calculated normalized times in somite time units (STU). The calculation method used available data on the rate of somitogenesis at 268C in zebrafish (Kimmel et al. 1995) and medaka (Iwamatsu 2004). Somite number versus time was plotted using ORIGINPRO v. 7.0220. The linear phase of somitogenesis extended between 4 and 30 somites for both species, and the total number of somites formed was 34 and 35 for zebrafish and medaka, respectively. Linear regression of the data revealed that zebrafish and medaka form 1.7 and 0.797 somites per hour, respectively. The reciprocal of the slope

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Comparative development of asymmetry values indicated the time needed for making a single somite (t-1som) in both species. Normalized times of development were obtained by dividing absolute time by t-1som.

3. RESULTS (a) Morphological and topological organization of epithalamic asymmetries (i) Asymmetric expression of nodal signalling genes in the embryonic epithalamus In zebrafish, several components of the nodal signalling pathway are asymmetrically expressed in the epithalamus preceding the onset of asymmetric morphogenesis (Concha et al. 2000; Liang et al. 2000). For example, the nodal inhibitor lefty1 (Dr-lefty1) and the downstream transcriptional effector pitx2c (Dr-pitx2c) define restricted dorsal domains of expression in the left side of the neural tube, posterior to the lateral flexure of the diencephalic ventricle (figure 1a(i),(ii)). Recent reports in medaka have shown that Ol-lefty (Carl et al. 2007; Soroldoni et al. 2007) and Ol-pitx2 (Jaszczyszyn et al. 2007) also display asymmetric expression in the dorsal diencephalon, and a close examination indicates that the extent and topology of expression of these genes are similar to zebrafish (compare figure 1a(i),b(i) and a(ii),b(ii)). (ii) Left-sided asymmetric positioning and connectivity of the embryonic parapineal organ In zebrafish, asymmetric morphogenesis of the parapineal organ involves an initial phase of migration from the dorsal midline to the left side of the brain followed by the development of efferent connectivity directed to the left habenula (Concha et al. 2003). Confocal imaging of transgenic Tg( foxD3::GFP ) zebrafish embryos reveals that the parapineal organ is located on the left and ventral sides of the pineal organ, and sends axonal projections that distribute broadly in the left habenula (figure 1a(iii)). In medaka, the parapineal organ of Tg( fRx2::GFP) embryos is also observed on the left side and develops efferent connectivity directed to the left habenula (figure 1b(iii)). However, the volume of the parapineal organ compared with the pineal organ is considerably larger in medaka (ratio of 0.6/1G0.13, nZ3 embryos, meanGs.d.) than zebrafish (ratio of 0.1/1G0.02, nZ3) (compare figure 1a(iii),b(iii)). In addition, parapineal efferents form a thick and long bundle of axons that make an orthogonal turn towards the anterior, dorsal and the midline to end in a well-defined neuropil domain with the shape of a dandelion seed head (figure 1b(iii)). (iii) Asymmetric cytoarchitectonic organization of the larval habenulae In zebrafish, left and right habenular nuclei undergo distinct patterns of neurogenesis (Aizawa et al. 2007) and display asymmetric growth of neuropil domains (Concha et al. 2003; Gamse et al. 2003). We performed immunostaining against acetylated a-tubulin to reveal the distribution of neuropil (figure 1a(iv)) and fluorescent-Nissl staining to expose the spatial organization of neuronal cell bodies (figure 1a(v)). We confirmed that neuropil asymmetries in zebrafish are limited to a dorsomedial region of the left habenula Phil. Trans. R. Soc. B (2009)

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located in the vicinity of the habenular commissure (arrows in figure 1a(iv)). In medaka, neuropil asymmetries define a compact and Nissl well-delimited neuropil domain situated in the most dorso-anteromedial aspect of the left habenula (arrowheads in figure 1b(iv),(v)). Such a singular domain is not observed in the right habenula of medaka and is absent from both left and right habenulae of zebrafish (figure 1a(iv),(v),b(iv),(v)). (iv) Contribution of parapineal connectivity to habenular asymmetry Double immunostaining against acetylated a-tubulin (neuropil) and GFP (parapineal organ) in transgenic embryos reveals that parapineal efferents make a hidden morphological contribution to habenular asymmetry in zebrafish. Parapineal efferent connectivity blends into a neuropil domain situated immediately anterior to the habenular commissure, which becomes asymmetrically enlarged in the left habenula compared with the right counterpart (asterisks in figure 2a(i)–(vii); Concha et al. 2003). By contrast, parapineal efferents make a more explicit contribution to morphological asymmetry in medaka. Most parapineal axonal terminals segregate from other sources of habenular neuropil to form a distinct dorso-anteromedial domain situated distant from the habenular commissure, which corresponds to the singular left-sided habenular neuropil domain defined by acetylated a-tubulin and Nissl staining (arrowheads in figure 2b(i)–(vii); see also arrowheads in figure 1b(iv),(v)). (v) Dorsoventral segregation of left–right habenular efferents in the larval midbrain The target regions of habenular neurons can be determined by labelling left and right habenular nuclei with the lipophilic dyes DiD and DiO, respectively (Aizawa et al. 2005). In zebrafish larvae, efferent connectivity from left and right habenular nuclei forms distinct and segregated ring-shaped domains within dorsal and ventral regions of the IPN, respectively (figure 1a(vi),(vii); Aizawa et al. 2005; Gamse et al. 2005; Bianco et al. 2008). A similar pattern of habenular efferent connectivity is observed in the larval IPN of medaka (see figure 1b (vi),(vii); Carl et al. 2007). However, the cross-sectional area of the central fibre-free region of IPN rings, compared with the crosssectional area of the entire IPN appears relatively larger in medaka (26.7G3% of total IPN, nZ3 embryos, meanGs.d.) than in zebrafish (8.8G4.6% of total IPN, nZ3). (vi) Laterality of epithalamic asymmetries and its correspondence to organ laterality In zebrafish, the development of parapineal and habenular asymmetries is interdependent and result in larvae showing concordant laterality of epithalamic asymmetries (Concha et al. 2003; Gamse et al. 2003). In addition, laterality of epithalamic and visceral asymmetries are coupled as both depend on left-sided nodal signalling emerging from a common symmetrybreaking event (Concha 2004; Levin 2005). In medaka, we scored the laterality of parapineal (GFP),

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Table 1. Concordant laterality of epithalamic and heart asymmetries in zebrafish and medaka. habenular lateralitya parapineal laterality

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a

Concordant laterality of parapineal and habenular asymmetries was analysed by immunostaining against acetylated a-tubulin (habenulae) and GFP (parapineal) in Tg(Foxd3::GFP ) (zebrafish, 140 HPF at 268C) and Tg( fRx2::GFP ) (medaka Iwamatsu St.39, 216 HPF at 268C). b Concordant laterality of epithalamic and heart asymmetries was analysed in living embryos by scoring the orientation of heart jog/looping, and the position of the parapineal organ in Tg(Foxd3::GFP ) (zebrafish, 56 HPF at 268C), Tg( fRx2::GFP ) and Tg( fRx2/DE::GFP ) (medaka, Iwamatsu St.27, 58 HPF at 268C).

habenular (acetylated a-tubulin) and organ (heart looping) asymmetries and found a similar concordant laterality pattern (table 1). Surprisingly, we were unable to find a single case of reversal from normal heart laterality in three different strains of medaka (Tg( fRx2:: GFP), nZ317 embryos; Tg( fRx2/DE::GFP), nZ153; and cab, nZ148), a situation that is common (5% of individuals on average) in other teleost species (Palmer 2004). (b) Temporal analysis of epithalamic asymmetry development To analyse how developmental time of epithalamic asymmetry has changed during the evolution of zebrafish and medaka lineages, we compared three main aspects: sequence (temporal arrangement of developmental modules); relative timing (onset/offset of developmental events with respect to some intrinsic time scale); and duration (overall rate of development). We found that all main developmental modules of epithalamic asymmetry were present in both species and temporally arranged in a similar sequential manner. For example, asymmetric nodal expression preceded left-sided positioning of the parapineal organ, which in turn was followed by the establishment of habenular asymmetry and segregation of habenular efferents in the IPN (figure 3a). To perform a meaningful comparison of relative timing and duration, we scaled the absolute time of onset/offset of homologous developmental events to the duration of a conserved periodic process that depends on intrinsic embryo dynamics (e.g. somitogenesis), and produced a normalized time scale that could be compared among taxa (figure 3b and table 2; see rationale and description of methodology in §2). Comparison of normalized developmental times between zebrafish and medaka uncovered three main groups of events that reveal unexpected similarities/ differences in the relative timing. A first group comprised early embryonic processes whose timing of onset became highly coordinated in both species after time normalization. Within this group, we found epiboly, gastrulation (shield formation), onset of expression of hatching enzymes genes (Inohaya et al. 1995, 1997) and somitogenesis (figure 3b). A second Phil. Trans. R. Soc. B (2009)

group included developmental events whose absolute differences in timing become inverted after time normalization. Important examples within this group were the onset of asymmetric epithalamic nodal signalling, onset of parapineal axonal projection and the initiation of habenula–IPN connectivity (figure 3b). The onset of asymmetric epithalamic nodal expression exhibited a delay of approximately 6 STU towards later developmental times after normalization, when compared with medaka (table 2; figure 3b). Interestingly, the magnitude of this delay was comparable with the delay in the onset of heart beating (13 STU) but was considerably smaller than the temporal shift in the initiation of both parapineal axonal projection (50 STU) and habenula–IPN connectivity (40 STU; figure 3b). Finally, a third group included developmental events whose differences in timing were conserved after time normalization. The single example of this group corresponded to hatching, which occurred at an earlier developmental time in zebrafish than medaka (figure 3b). A last step of comparison concerned the duration of developmental events. We focused our analysis on the expression of nodal signalling genes, as they were transient and could be determined with accuracy. Absolute duration of expression of Ol-lefty and Ol-pitx2 doubled that of Dr-lefty1 and Dr-pitx2c, respectively (table 2; figure 3a). However, the ratio between the lengths of lefty and pitx2 expressions was equivalent in both species (zebrafishZ0.25; medakaZ0.24) suggesting that the differences in the absolute length of gene expression could result from variations in the intrinsic speed of embryo development. To test this hypothesis, we compared normalized lengths of gene expression and found them strikingly similar for each pair of orthologue genes: differences represented less than 15 per cent for lefty and 10 per cent for pitx2 when calculating the ratio zebrafish/medaka (figure 3b). 4. DISCUSSION (a) Overall conservation of asymmetry in the parapineal–habenular-IPN system of teleosts In this study, we compared the main developmental modules of epithalamic asymmetry in two related teleost species with 115–200 Myr of independent

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onset of hatching enzyme genes hatching onset of nodal-related 2 (L-LPM) lefty expression (epithalamus) pitx2 expression (epithalamus)

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asymmetric epithalamic morphogenesis asymmetric epithalamic nodal signalling onset of parapineal axonal projection initiation of habenula–IPN connectivity

Figure 3. Comparison of sequence, relative timing and duration of developmental events during the establishment of epithalamic asymmetry in zebrafish and medaka. The diagrams show the temporal occurrence of key steps of asymmetric brain morphogenesis in zebrafish and medaka, expressed in (a) absolute and (b) normalized times. To provide a contextual view, the timing of main embryonic events is also included. The colour codes shown at the bottom of the figure indicate different developmental events (lines) and periods ( boxes or bars) analysed in the temporal plots of (a,b). For clarity, equivalent events in medaka and zebrafish are joined. Diagrams of developmental stages were obtained from the literature (Kimmel et al. 1995; Iwamatsu 2004). Schematic of epithalamic asymmetry events (bottom right) correspond, from top to bottom, to: a frontal view of the epithalamus depicting left-sided asymmetric nodal expression, a dorsal view of the pineal complex showing the initiation of left-sided parapineal axonal projection and a dorsal view of the IPN (white circle) revealing habenular efferent connectivity reaching dorsal and ventral regions of the IPN. The scale was maintained in (a,b) to emphasize the effect of time normalization. Zebrafish and medaka show a conserved sequence of developmental events of epithalamic asymmetry although they exhibit distinct relative timing ( heterochrony).

evolution. Our findings reveal a striking conservation of both the overall spatial organization of brain asymmetry and the temporal sequential arrangement of developmental modules underlying the formation of the parapineal–habenular–IPN system. Such conservative ontogenetic trajectory suggests a causal dependency between the different asymmetry modules. This idea is supported by recent experimental evidence showing that habenular asymmetry is affected by physical removal of the parapineal organ (Concha et al. 2003; Gamse et al. 2003; Bianco et al. 2008). In addition, segregation of habenular efferents in the IPN Phil. Trans. R. Soc. B (2009)

depends on the proper development of asymmetry in the habenulae (Aizawa et al. 2005; Gamse et al. 2005; Carl et al. 2007; Kuan et al. 2007; Bianco et al. 2008). Evolutionary conservation also suggests that the overall pattern of asymmetry in the parapineal–habenular–IPN axis is plesiomorphic to teleosts. Indeed, habenular and parapineal asymmetries are described in a number of teleost species (Concha & Wilson 2001) and recent observations extend these findings to the IPN of the southern flounder (Paralichthys lethostigma; Kuan et al. 2007) and guppy (Poecilia reticulata; A. Villalo´n & M. L. Concha 2007, unpublished data). Interestingly, despite

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Table 2. Comparison of developmental events of brain asymmetry between zebrafish and medaka. zebrafish (Danio rerio) developmental event

time (HPF)a

epithalamic nodal expression lefty onset 19.8G1 offset 28.5G1 duration 8.7G1 pitx2 onset 19.8G1 offset 54.7G1 duration 34.9G1 parapineal asymmetry onset of axonal 57G1 projection habenular efferents in IPN initiation of 64G6 connectivityd

medaka (Oryzias latipes) STUb

time (HPF)b

STUb

(17G1) (24.5G1) (6.5G1)

34.4G2 49.4G2 13.4G2

36G2 52G2 16G2

(St.21–22) (St.25–26)

28.7G2 41.4G2 12.7G2

(17G1) (47G1) (21.5G1)

34.4G2 94.4G2 58.4G2

36G2 103.5G3 67.5G3

(St.21–22) (St.32–33)

28.7G2 82.5G3 53.8G3

(49G1)c

98.2G2

66G8

(St.27–29)

52.6G7

(74G7)

128G12

111G10

(St.32–33)

88.5G8

a

Staging is expressed in hours post-fertilization (HPF) at 268C ( Kimmel et al. 1995; Iwamatsu 2004). Corresponding times at 288C (zebrafish) and Iwamatsu stages (St) (medaka) are indicated in brackets. Timing of onset/offset was calculated as the midpoint between the stage when the developmental event is first observed and the preceding/following stage, respectively. Variability corresponds to half the duration of the interval between these stages. b Normalized times are expressed in STU (see §2). c Taken from Concha et al. (2000, 2003). d Initiation of connectivity between the habenula and IPN is defined by the initial axonal branching of left and right fasciculi retroflexus within the IPN, prior to the establishment of dorsal and ventral ring-shaped domains.

the overall conservation of habenular asymmetry among a wide range of vertebrate groups (Concha & Wilson 2001) the segregation of left–right habenular efferents along the dorsoventral axis of the IPN appears unique to teleosts as it is absent in frogs (Rana clamitans), salamanders (Ambystoma maculatum) and mice (Kuan et al. 2007). Whether or not this peculiar asymmetry trait represents a variation of form evolved exclusively by the teleost lineage will need further experimental testing. (b) Heterotopic parapineal efferent connectivity suggests divergent principles of development between zebrafish and medaka Our results support the notion that left-sided positioning of the parapineal organ is a shared feature of asymmetric brain morphogenesis within the teleost group (Borg et al. 1983; Concha & Wilson 2001). However, the relative size of the parapineal organ (compared with the pineal organ) and its pattern of efferent connectivity greatly differ between zebrafish and medaka. In zebrafish, the body of the parapineal organ is relatively small in size (G10% of the pineal) and its efferent connectivity distribute broadly in the left habenula. By contrast, the parapineal organ of medaka is larger (G60% of the pineal) and its efferent connectivity forms a large and well-defined anterodorsomedial neuropil domain within the left habenula (figure 2). Although the number and nature of parapineal–habenular synapses remains unknown, our results suggest that divergent principles of development and circuit configuration emerged during the independent evolution of zebrafish and medaka lineages. Such a variation in the relative size of pineal and parapineal organs is not exclusive to teleosts as it is also observed among species of reptiles developing a parietal eye Phil. Trans. R. Soc. B (2009)

(the homologous structure to the parapineal organ; Concha & Wilson 2001). Previous results suggest that the spatial organization of parapineal efferents depends on a bidirectional interaction established between the parapineal organ and habenulae during development (figure 4). Initially, early asymmetry in the presumptive habenular region is thought to guide asymmetric parapineal migration (Concha et al. 2003). Subsequent left-sided positioning of the parapineal organ is required for the amplification (and perhaps the topological setting) of distinct differentiation programmes in the left and right habenulae (Gamse et al. 2003; Bianco et al. 2008). Finally, parapineal axons distribute in regions of the left habenula, which exhibit enlarged neuropil (Concha et al. 2003) and asymmetric leftover expression (Gamse et al. 2003), therefore linking the topology of parapineal efferent connectivity to the underlying organization of differentiation domains within the left habenula. Based on these observations, we propose two developmental models to explain the different topologies of parapineal efferent connectivity observed in zebrafish and medaka (figure 4). In the first model, the molecular/connectional identity of parapineal target cells is conserved in the two species, but the topological organization has diverged owing to changes in the spatial and/or temporal organization of a shared set of signals that pattern the habenulae (model 1; figure 4b). In the second model, the molecular/connectional identity of parapineal target cells has diverged as a result of divergent signalling mechanisms involved in either guiding parapineal connectivity or patterning the habenulae (model 2; figure 4c). The proposed models have potential dissimilar implications in the function of the parapineal– habenular–IPN system. Whereas solitary changes in

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Comparative development of asymmetry the topology of parapineal target cells probably represent no major functional modification of the system (model 1; figure 4b), transformations in the identity of parapineal target cells might result in distinct neurotransmitter and/or connectional influences of the habenulae upon the IPN (model 2; figure 4c). Given the overall morphological and connectional conservation of the parapineal–habenular–IPN circuit, it seems reasonable to expect a conservation of parapineal functionality in the circuit (model 1). Nevertheless, it is possible that the parapineal organ plays no major role in this asymmetric circuit and that the observed phenotypic variation in the topology of parapineal efferent connectivity is a direct consequence of this feature (Hallgrı´msson 2003). To date, we have no sufficient data to either sustain or discard this possibility. As the parapineal organ contains both photoneuroendocrine cells and projection neurons, it is possible that circadian variations of light influence the neuroendocrine activity of the parapineal organ and consequently the function of the habenular–IPN system (Concha & Wilson 2001). However, it has also been reported that parapineal photoreceptors are rather rudimentary (Rudeberg 1969; Van Veen 1982; Ekstrom et al. 1983) and that in many species the parapineal organ appears to have regressed in adulthood (Borg et al. 1983). (c) Heterochronic shifts and the ontogeny of epithalamic asymmetry The dimension of time is critical for development and a key factor in the generation of evolutionary diversity (Gould 1977). The examination of the temporal dimension of development among species allows the study of developmental trajectories, the detection of heterochronies (shifts in timing), the making of inferences about the coupling/uncoupling of developmental modules and the reconstruction of the ancestral sequence of developmental events ( Reiss 2003; Zelditch 2003). In the present study, we searched for events of conservation and variation in each of the three main aspects of time underlying the development of epithalamic asymmetries. We found a major conservation in the sequence of developmental modules of brain asymmetry (see above). For a proper examination of relative timing and duration, we developed a method to normalize the intrinsic time scale of zebrafish and medaka development based on the clock properties of somitogenesis. Using this normalization method, we could synchronize the relative timing of early embryonic events. In addition, we found that duration of the expression of genes involved in the control of brain laterality matched after time normalization. This finding provides support to the usefulness of this normalization method for the comparison of developmental time among related species, compared with that of alternative methods (Dettlaff & Dettlaff 1961; Reiss 1989; Chipman et al. 2000; Clancy et al. 2001). Moreover, this observation suggests that both species share a similar tempo of nodal-dependent laterality determination, and that absolute differences in the duration of nodal signalling depend primarily on the intrinsic rate of embryo development of each species. The normalization method also allowed the distinction of interspecies changes in the relative timing of Phil. Trans. R. Soc. B (2009)

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epithalamic asymmetry events. Three main heterochronic shifts involved the onset of epithalamic nodal signalling, the onset of parapineal axonal efferent projection and the initiation of habenula–IPN connectivity expressed as the initial branching of left and right axons emerging from the fasciculus retroflexus within the IPN (figure 3). The direction of these shifts is consistent with previous reports suggesting that brain development is delayed relative to somitogenesis in zebrafish compared with medaka ( Wittbrodt et al. 2002). More recent data add extra support to this general concept as it reveals a reversal in the relative timing of expression of specific components of the nodal signalling pathway in the brain with respect to the lateral plate mesoderm (LPM) in the two species, e.g. in medaka mRNA of nodal-related 2, lefty and pitx2 are detected earlier in the brain than that in the LPM while the opposite is observed in zebrafish (figure 3b; Rebagliati et al. 1998; Bisgrove et al. 2000; Soroldoni et al. 2007). Unexpectedly, the onset of parapineal axonal projection and the initiation of habenula–IPN connectivity exhibited a pronounced heterochronic shift with respect to the onset of nodal signalling, being largely delayed in zebrafish with respect to medaka (figure 3b). As parapineal connectivity appears to be linked to the programme of habenular differentiation, it is possible that the latter is delayed in zebrafish, and that the more dispersed distribution of parapineal target cells of the zebrafish larvae represents a transitional state towards a more segregated distribution reached in the habenulae at post-larval stages. Consistent with the idea of a shift in the timing of habenular differentiation, we observed that the onset of axonal branching of habenular efferents within the IPN is also delayed in zebrafish compared with medaka (figure 3b). Further experimental testing of this hypothesis might provide a causal link between the heterotopic and heterochronic changes described in this study. It is important to note that aspects of organogenesis such as the onset of heart beating are shifted in the same temporal direction as shifts in brain development. This observation opens the possibility that organogenesis as a whole has undergone a heterochronic shift during the evolution of medaka and zebrafish lineages. In this respect, it is intriguing that hatching shows a reversed heterochronic shift to that observed for organogenesis, e.g. it is delayed in medaka compared with zebrafish. As the onset of expression of hatching enzyme genes is comparable in zebrafish and medaka (figure 3b; Inohaya et al. 1995, 1997), it is likely that the differences in hatching time are a result of dissimilar chorion composition and thickness between the two species (Hart et al. 1984; Hart & Donovan 2005). Regardless of the underlying developmental mechanism, a main consequence of the heterochronic shift in hatching is the definition of zebrafish as altricial (immature) and medaka as precocial (more developed) species (MacArthur & Wilson 1967). (d) Is the laterality of asymmetry canalized in medaka? Although left-sided laterality of heart asymmetry is a well-conserved trait of vertebrates, a small percentage of individuals in the population show spontaneous

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hc Lh Rh projection to region of distinct identity and topology

Figure 4. Developmental models of heterotopic parapineal efferent connectivity. (a) Zebrafish: asymmetries of the parapineal organ and habenulae interact in three consecutive steps during development. (i) Initial left–right biases in the presumptive habenular region guide parapineal migration to the left side. (ii) Subsequent left-sided positioning of the parapineal organ is involved in the induction/propagation of a distinct spatial pattern of habenular differentiation. (iii) Finally, the topology of subdomains arising after habenular differentiation determines the position of habenular neurons receiving parapineal efferent connectivity. (b) Medaka (model 1): heterotopic parapineal efferent connectivity arises from a different topological organization of habenular subdomains. In this model, spatial differences in the location of the parapineal organ at the time of habenular differentiation and/or underlying differences in habenular (i) pre-patterning lead to (ii) distinct topological programmes of habenular subdomain differentiation and (iii) subsequent positioning of parapineal target cells. (c) Medaka (model 2): heterotopic parapineal efferent connectivity arises from different selection of parapineal target cells within the habenulae. In this model, parapineal migration and habenular differentiation are equivalent in both species. However, parapineal projections reach different target neurons in the habenula of both species owing to the differences in axon guidance cues. (i) Shaded green regions depict molecular left–right biases within the presumptive habenulae. The movement of the parapineal organ from the midline to the left side (arrows) is represented as partially overlapping drawings of parapineal outlines. (ii) White and red regions illustrate putative subdomains of the habenulae. Arrows illustrate the direction of the inductive properties of the parapineal organ. (iii) The topological pattern of parapineal efferent connectivity (black) and the location of parapineal target cells within the habenula (colours) are shown (see also figure 2). Colours represent equivalent cellular identities. All diagrams correspond to dorsal views, with anterior to the top. For clarity, only the left habenula is illustrated, and the right habenula is depicted with dotted lines. L, left; R, right; Lh, left habenula; Rh, right habenula; hc, habenular commissure.

reversal of this asymmetry. Incidence of heart reversals have declined during vertebrate evolution from fishes (approx. 5%) through amphibians and birds (1–2%) to mammals (less than 0.1%), indicating a canalization of heart laterality during vertebrate evolution (Palmer 2004). Our finding that medaka showed 0 per cent of heart reversals indicates that this species deviates from the expected teleost pattern (e.g. zebrafish, trout and salmon). Although we cannot discard the notion that the inbreeding nature of the medaka strains (Wittbrodt et al. 2002) reduces the normal fluctuation of individual laterality, it is possible that symmetrybreaking mechanisms are more robust and resistant to genetic and environmental perturbations in medaka than in the other teleosts that have been analysed. A major mechanism of vertebrate laterality determination involves the generation of extracellular leftward fluid flow (the so-called nodal flow) within the ventral node of mice (Hirokawa et al. 2006) and the Kupffer’s vesicle (KV ) of teleosts (Essner et al. 2005; Kramer-Zucker et al. 2005; Okada et al. 2005). Recent reports have revealed that the KV of medaka shares more similarities to the mammalian node than to the zebrafish KV, when Phil. Trans. R. Soc. B (2009)

considering the cytoarchitectonic organization of ciliated cells and the robustness of the nodal flow (Essner et al. 2005; Kramer-Zucker et al. 2005; Okada et al. 2005; Hirokawa et al. 2006; Oteiza et al. 2008). Hence, we propose that the canalization of embryo laterality may be linked to the morphology of laterality organs and consequently the nature of the nodal flow they produce. In this context, other developmental conditions that have been proposed to make laterality decisions more predictable (e.g. placental environments; Palmer 2004) would play only additive roles.

5. CONCLUSIONS: ZEBRAFISH AND MEDAKA AS MODELS FOR COMPARATIVE DEVELOPMENTAL BIOLOGY OF VERTEBRATE BRAIN ASYMMETRY Since the initial proposal of medaka and zebrafish as complementary model organisms suitable for comparative developmental biology ( Furutani-Seiki & Wittbrodt 2004), several reports have made use of the experimental and evolutionary advantages of these genetic organisms to start revealing conserved and species-specific principles of vertebrate development

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Comparative development of asymmetry (e.g. Lynn Lamoreux et al. 2005; Gajewski et al. 2006; Carl et al. 2007). The present study brings additional support to this notion, offers new tools for time comparison between these species and provides novel comparative data and hypotheses to start addressing the ontogenic mechanisms that explain interspecies variations of epithalamic asymmetry. Together, these findings highlight the usefulness of zebrafish and medaka as comparative models of brain asymmetry development and function. All procedures of animal care and management conformed to high standards in agreement with the revised Council of Europe guidelines (ETS123) on housing, and were approved by a local Committee of Bioethics on Animal Experimentation at the Faculty of Medicine, University of Chile. We are particularly grateful to Jorge Mpodozis, Gonzalo Marı´n, Francisco Aboitiz, Stephen Wilson, Isaac Bianco and Mathias Carl for their valuable comments on the versions of the manuscript, and to Dina Silva, Micaela Ricca and Alejandro Chamorro for fish care. Work on the epithalamus and asymmetry in our group is supported by the Howard Hughes Medical Institute (HHMI INTNL 55005940), the Chilean Commission of Science and Technology (PBCT ACT47, BMBF/CONICYT 2003-4-124), the Millennium Scienice Initiative (ICM) and a grant from the European Communities entitled ‘Evolution and Development of Cognitive, Behavioural and Neural Lateralisation’ (FP62004-NEST-PATH EDCBNL).

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Phil. Trans. R. Soc. B (2009) 364, 1005–1020 doi:10.1098/rstb.2008.0213 Published online 4 December 2008

Review

The habenular nuclei: a conserved asymmetric relay station in the vertebrate brain Isaac H. Bianco1,2,* and Stephen W. Wilson1,* 1

Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK 2 Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA

The dorsal diencephalon, or epithalamus, contains the bilaterally paired habenular nuclei and the pineal complex. The habenulae form part of the dorsal diencephalic conduction (DDC) system, a highly conserved pathway found in all vertebrates. In this review, we shall describe the neuroanatomy of the DDC, consider its physiology and behavioural involvement, and discuss examples of neural asymmetries within both habenular circuitry and the pineal complex. We will discuss studies in zebrafish, which have examined the organization and development of this circuit, uncovered how asymmetry is represented at the level of individual neurons and determined how such left–right differences arise during development. Keywords: habenula; asymmetry; interpeduncular nucleus; zebrafish; dorsal diencephalic conduction system

1. ANATOMY AND CONNECTIVITY The dorsal diencephalic conduction (DDC) system is one of two major pathways that interconnect the limbic forebrain and sites in the mid- and hindbrain, the other pathway being the medial forebrain bundle (MFB; Sutherland 1982). These two pathways appear to represent parallel neural circuits—they share sources of afferent inputs as well as efferent targets and there is an overlap in their physiology and function. The DDC comprises three core components: the habenular nuclei; the stria medullaris (SM), which is the main fibre tract through which inputs from the forebrain arrive at the habenulae; and the fasciculus retroflexus (FR), a prominent fibre tract that predominantly carries efferent axons from the habenula towards the targets in the midbrain/hindbrain. In this review, we will focus on the anatomy and connectivity of the habenulae and the interpeduncular nucleus (IPN). The latter is a major target of habenular efferent connectivity in all vertebrates and consequently plays a pivotal role in the modulation of nuclei downstream of the DDC. In §3, we will review the various classes of neural asymmetry that have been described in the DDC, especially of anamniotes, and in §4, we will discuss work in zebrafish that has addressed the developmental mechanisms by which DDC circuit asymmetries emerge. (a) Habenula The bilaterally paired habenular nuclei (Hb) are positioned adjacent to the third ventricle, rostral to * Authors and addresses for correspondence: Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA ([email protected]); Department of Cell and Developmental Biology, University College London WC1E 6BT, UK ([email protected]). One contribution of 14 to a Theme Issue ‘Mechanisms and functions of brain and behavioural asymmetries’.

the posterior commissure and the habenular commissure runs between them ( Nieuwenhuys et al. 1998; Butler & Hodos 2005). In mammals, the habenular complex comprises two separate nuclei on each side: the ‘medial’ (MHb) and ‘lateral’ (LHb) habenulae. The LHb is further subdivided into principal medial and lateral subdivisions. Despite sharing some sources of afferent inputs and efferent targets, the medial and lateral habenulae appear to represent largely distinct subcircuits within the DDC (Herkenham & Nauta 1977, 1979; Kim & Chang 2005). In outlining the anatomy of this circuit, we shall focus primarily on the patterns of connectivity in the rat, which have been well studied (figure 1). Some species differences will also be mentioned, where relevant, but we will not attempt a description of the comparative neuroanatomy of the DDC in any detail. (i) Medial habenula MHb circuitry is highly conserved (Sutherland 1982). The MHb primarily receives inputs from the septum and projects to the IPN of the ventral midbrain. This efferent connection comprises the ‘core’ of the FR and appears to be conserved in all vertebrate species that have been examined. Afferent connectivity The major source of afferent innervation of the MHb derives from the supracommissural septum, with axons coursing in the SM (Herkenham & Nauta 1977). Septal sites themselves receive inputs from the hippocampus and subiculum. Axons from the two most significant septal nuclei also terminate in different subdomains of the MHb—the septofimbrial nucleus innervates the rostral MHb while the nucleus triangularis innervates the caudal MHb. In the rat, almost

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HippoF

P septum sf tr

MHb

IPN

DBB

Dors. Teg. region DTN, VTN, NI

Acb Thal FrCx SC Circad. SCN retina LH LPO

raphe nuclei LC LHb

EP

VTA

SNc CPu

Figure 1. Connectivity of the DDC. This schematic shows the principal connections of the medial and lateral habenulae and interpeduncular nucleus as described in mammals, in particular the rat. Thick arrows highlight the septum–MHb–IPN axis and the convergence of limbic and striatal inputs into the lateral habenula. Notably, there are very limited data regarding the relative functional importance of the various connections shown here. Acb, nucleus accumbens; Circad., potential sources of circadian information; CPu, caudate/putamen; Dors. Teg. region, dorsal tegmental region; DBB, nucleus of diagonal band; DTN, ventral tegmental nucleus of Gu¨dden; EP, entopeduncular nucleus; FrCx, frontal cortex; HippoF, hippocampal formation; IPN, interpeduncular nucleus; LC, locus coeruleus; LH, lateral hypothalamic area; LHb, lateral habenula; LPO, lateral preoptic area; MHb, medial habenula; NI, nucleus incerta; P, pineal; SC, superior colliculus; SCN, suprachiasmatic nucleus; SNc, substantia nigra pars compacta; sf, septofimbrial nucleus; Thal, thalamic nuclei; tr, nucleus triangularis; VTA, ventral tegmental area; VTN, ventral tegmental nucleus of Gu¨dden.

every neuron in these two septal nuclei is likely to project to the MHb. More minor inputs derive from the nucleus of the diagonal band (DBB). The MHb also receives ascending inputs, principally derived from monoaminergic nuclei, which are also the targets of both medial and lateral habenular efferent axons. Dopaminergic inputs derive from the interfascicular nucleus of the ventral tegmental area (VTA; Phillipson & Pycock 1982) and noradrenergic inputs from the locus coeruleus (Gottesfeld 1983). These latter axons reach the MHb by coursing anteriorly in the MFB and then joining the SM. Efferent connectivity The main target of MHb axons is the IPN (Herkenham & Nauta 1979). The MHb contains both cholinergic neurons (in its ventral two-thirds) and dorsally located substance P-containing neurons (Contestabile et al. 1987). Both types are contacted by the major afferent axons from the septofimbrial nucleus and nucleus triangularis, and both project down the core of the FR to innervate the IPN. MHb axons terminate in a topographic manner, wherein the neurons of the dorsal MHb innervate the lateral IPN, those of the medial Phil. Trans. R. Soc. B (2009)

MHb innervate the ventral IPN and lateral MHb neurons project to the dorsal IPN (Herkenham & Nauta 1979; Contestabile & Flumerfelt 1981). After making lesions in the MHb, Ronnekleiv & Moller (1979) observed degenerating terminals in the pineal organ, suggesting that it may also be an MHb efferent target. Although little is known about the intrinsic habenular circuitry and the extent to which communication exists between the MHb and LHb, two observations provide evidence for a medial-to-lateral connection. A subset of MHb axons project through the LHb and in so doing display en passant boutons that might represent presynaptic terminals ( Kim & Chang 2005), and sectioning of the MHb efferent axons has been reported to reduce substance P levels in the LHb (see Sutherland 1982). (ii) Lateral habenula When compared with the MHb, the LHb shows broader and less evolutionarily conserved connectivity. It is thought to be involved in the motor–limbic interface because it receives significant pallidal inputs as well as afferent connections from numerous

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Review. The habenular nuclei components of the limbic system. The LHb projects to a wide range of targets, especially in the ventral midbrain tegmentum (Sutherland 1982). Afferent connectivity The LHb is a point of convergence for neural information from the basal ganglia and limbic forebrain. A major source of innervation of the LHb in the rat derives from the entopeduncular nucleus (EP, which is the non-primate equivalent of the internal segment of the globus pallidus). In the rat, virtually every entopeduncular neuron appears to project to the LHb, suggesting that the axons are collaterals of the pallido-thalamic pathway (Herkenham & Nauta 1977). This pallido-habenular pathway also exists in cats and monkeys. However, in monkeys, it appears that while the LHb receives substantial innervation from the internal segment of the globus pallidus, this innervation derives from a different group of pallidal neurons to those that innervate premotor neurons in the thalamus and brainstem (Parent et al. 2001). Limbic regions of the forebrain constitute the second major source of afferent innervation of the LHb. A continuous band of cells, stretching from the anterior lateral preoptic area, through the lateral hypothalamus, to the mid-hypothalamus, project to the LHb (Herkenham & Nauta 1977). A small descending input derives from septal regions, including the DBB and lateral septal nucleus. Additionally, the LHb receives inputs from the nucleus accumbens and medial frontal cortex (Greatrex & Phillipson 1982). The suprachiasmatic nucleus, which is concerned with the generation of circadian rhythms in mammals, projects vasopressin-containing axons to the LHb (Buijs 1978; Sofroniew & Weindl 1978). A second source of circadian information is suggested by the finding that in mice, melanopsin-expressing retinal ganglion cells project to the LHb (Hattar et al. 2006). The LHb receives ascending innervation from monoaminergic nuclei, at least some of which overlap with the sources innervating the MHb. Thus, axons from the median raphe and locus coeruleus provide serotonergic and noradrenergic inputs (Herkenham & Nauta 1977; Gottesfeld 1983; Vertes et al. 1999). Midline neurons of the VTA (interfascicular and paranigral nuclei) provide dopaminergic inputs to the medial part of the LHb, probably via the FR (Phillipson & Pycock 1982; Gruber et al. 2007). Notably, this region of the VTA contains many neurons belonging to the A10 region, which gives rise to the mesolimbic ‘reward’ pathway. In summary, the afferent connectivity of the LHb may enable motivational/emotional states (encoded by limbic inputs) to modulate motor behaviours (represented by pallidal efferents). Efferent connectivity The LHb contains predominantly glutamatergic neurons as well as some GABAergic and cholinergic cells and establishes efferent connectivity with a wide range of targets. Many of these targets are themselves sources of afferent inputs to the LHb (Herkenham & Nauta 1979; Lecourtier & Kelly Phil. Trans. R. Soc. B (2009)

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2007). For example, the LHb projects to the limbic forebrain, including the lateral hypothalamic area, lateral preoptic area, substantia innominata and ventrolateral septum. The LHb establishes descending connectivity with numerous monoaminergic nuclei in the mid- and hindbrain. A major projection, especially from the medial LHb, innervates the median and dorsal raphe; LHb activity inhibits the raphe (Wang & Aghajanian 1977), probably as a result of activation of GABAergic interneurons in the nucleus (e.g. Varga et al. 2003). The LHb innervates and inhibits the dopaminergic VTA (Araki et al. 1988) and the substantia nigra pars compacta (SNc; see below, §2). There are several routes for feedback in this circuit: the VTA projects directly to the LHb and also to the nucleus accumbens, which is a source of LHb afferent innervation. Dopaminergic neurons of the SNc project, via the nigrostriatal tract, to the dorsal striatum (caudate/putamen), which in turn connects to the pallidum, a major source of afferent innervation of the LHb. The connectivity of the DDC therefore enables the striatum to regulate the activity of midbrain dopaminergic (DA) neurons that provide its afferent inputs; Sasaki et al. (1990) have provided functional data supporting a role for the EP, SM and habenula in negative feedback control over the SNc. Other efferent targets of the LHb include several thalamic nuclei (centromedial, mediodorsal, ventromedial, parafascicular nucleus), the superior colliculus, the dorsal tegmental region and locus coeruleus (Herkenham & Nauta 1979). (b) Interpeduncular nucleus The IPN receives most of the efferent axons from the MHb, and therefore is central to MHb control over downstream circuitry. The IPN is a singular, unpaired structure, located at the ventral midline of the posterior midbrain/isthmus. It comprises a number of morphologically defined subnuclei. In the rat, Lenn & Hamill (1984) have identified seven subnuclei, including three that are described as unpaired, being located at the midline and which are flanked laterally by four bilaterally paired subnuclei. In addition to the MHb, the IPN is interconnected with numerous sites in the forebrain and brainstem, and a multitude of neurotransmitters are expressed in a spatially organized manner within its subnuclei. These features suggest that the IPN is an important integrative centre and relay station within the limbic system (see Morley 1986). (i) Afferent connectivity A major source of innervation of the IPN is from the MHb, a connectivity pattern that is conserved throughout the vertebrate lineage (Shibata et al. 1986; Butler & Hodos 2005). Afferent inputs derive from several other sites within the limbic forebrain, which in the rat include the medial frontal cortex, DBB, substantia innominata, preoptic and hypothalamic nuclei and the supramammillary nucleus. In addition, various nuclei within the brainstem project to the IPN including the raphe, locus coeruleus and dorsal tegmental region (including the dorsal tegmental nucleus of Gu¨dden, laterodorsal tegmental nucleus and nucleus incerta;

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Contestabile & Flumerfelt 1981; Hamill & Jacobowitz 1984; Shibata et al. 1986; Vertes & Fass 1988; Takagishi & Chiba 1991). Biochemical studies have identified extremely high levels of acetylcholine, choline acetyltransferase, acetylcholine esterase and high-affinity choline uptake within the IPN, and the habenulo-interpeduncular pathway is considered one of the major cholinergic pathways in the brain (Contestabile & Fonnum 1983). Cholinergic innervation is likely to derive from both the MHb and the dorsal tegmental region and neurons in the basal forebrain (septum and preoptic area); the latter are thought to project the axons that extend, uninterrupted, through the habenula and FR to reach the IPN (Contestabile & Fonnum 1983; Woolf & Butcher 1985). There is evidence that a wide range of additional neurotransmitters are present in the IPN, including g-aminobutyric acid (GABA, probably deriving from the DBB), substance P (from the MHb) and various monoamines (noradrenaline, dopamine and serotonin) and neuropeptides (including cholecystokinin, leucineencephalin, methionine-encephalin, vasointestinal peptide and somatostatin) (see Morley 1986). As mentioned above, MHb axons terminate in a topographic manner within the IPN, and accordingly, Contestabile et al. (1987) and Eckenrode et al. (1987) have shown that cholinergic and substance P-containing inputs are largely segregated within the IPN. Cholinergic fibres are confined in the unpaired midline core of the IPN, whereas substance P signalling shows greater localization to the peripheral subnuclei. (ii) Efferent connectivity The dorsal tegmental region and the raphe are the major targets of IPN efferent connectivity (Shibata & Suzuki 1984). In addition, the IPN makes ascending projections to various neuronal nuclei, several of which are the sources of afferent inputs to the habenulae, thus establishing further feedback circuits. Thus, efferent targets in the forebrain include the DBB and the lateral septal nucleus, preoptic area, dorsolateral hypothalamus, mediodorsal nucleus of the thalamus and the hippocampus and entorhinal cortex (Shibata & Suzuki 1984; Groenewegen et al. 1986; Morley 1986; Vertes & Fass 1988).

2. PHYSIOLOGICAL AND BEHAVIOURAL FUNCTIONS In accordance with the diversity of its afferent inputs and efferent targets, the DDC is involved in a diverse range of cerebral functions (previously reviewed in Sutherland 1982; Klemm 2004; Lecourtier & Kelly 2007). One central theme is the importance of the DDC (especially the habenular nuclei) in regulating the activity of monoaminergic nuclei in the ventral midbrain. (a) Control of dopaminergic circuitry: motor activity and reward prediction Several recent reports provide evidence for strong functional links between the LHb and dopaminergic cells in the ventral midbrain, which are involved in Phil. Trans. R. Soc. B (2009)

modulating motor behaviours and learning new behavioural responses to salient stimuli. Habenular lesions increase exploratory behaviour and locomotor activity in rats, especially in response to novel environmental stimuli (Lee & Huang 1988). This effect is likely to be mediated by midbrain DA neurons that are innervated by the LHb. Electrical stimulation of the LHb inhibits the activity of DA neurons in the VTA and SNc (Christoph et al. 1986), probably as a result of excitatory LHb efferents activating GABAergic interneurons in the ventral midbrain, which in turn inhibit DA cells (Ji & Shepard 2007). Conversely, habenular lesions result in increased dopaminergic transmission (Lisoprawski et al. 1980; Nishikawa et al. 1986), suggesting that habenular efferent circuitry exerts a tonic inhibitory effect upon DA neurons. Lecourtier et al. (2008) have suggested that within the VTA, neurons involved in reward seeking, which project to the nucleus accumbens, are preferentially inhibited. Suppressing LHb activity with a GABA antagonist causes increases in DA release in the Acb and striatum of similar timecourse and magnitude to those observed during reward-seeking behaviour (but causes a significantly smaller increase in the prefrontal cortex). The elevated DA levels in the nucleus accumbens (Acb) and striatum correlated with increases in spontaneous locomotor activity and stereotyped behaviours (grooming, sniffing, digging and rearing), respectively. Short ‘phasic’ responses of midbrain DA neurons are thought to provide teaching signals that modulate the selection of motor programmes in the striatum and are involved in appetitive learning of new behavioural responses to positive reinforcers (‘rewards’; Schultz 1998). The LHb is one of the few regions of the brain to be inhibited by hedonic stimuli (Gallistel et al. 1985), and recently, Matsumoto & Hikosaka (2007) have shown that the LHb instructs midbrain DA neurons as to the absence of a reward. In monkeys performing a visually guided saccade task, LHb neurons are activated by visual targets that signify the absence of a reward and inhibited by targets that predict forthcoming reward (whereas DA neurons of the SNc show the opposite responsiveness). In unrewarded trials, the activation of LHb neurons preceded the inhibition of SNc neurons and mild electrical stimulation of the LHb inhibits the SNc. Therefore, it appears that the LHb provides information regarding the nature of salient environmental stimuli to the midbrain reward circuits in the form of negative reward-related signals. Thus, it is likely to be involved in the adjustment of behavioural strategies. Notably, functional magnetic resonance imaging (fMRI ) has shown that the habenula of human subjects is activated in response to the informative negative feedback that indicates behavioural errors and also when positive feedback following correct responses is omitted (Ullsperger & von Cramon 2003). It is likely, therefore, that DDC circuitry is also involved in reward processing in humans, wherein Hb activation is expected to reduce the probability of phasic DA activation in the VTA and SNc.

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Review. The habenular nuclei (b) Cognition The DDC has been implicated in cognitive processes, in particular relating to spatial learning and attention. An involvement of the habenular complex in spatial learning is suggested by the studies in rats using the classical Morris water maze test. Villarreal et al. (2002) found that after training in the water maze, aged, memory-impaired rats showed reduced cytochrome oxidase activity (a read-out of neuronal activity) in the LHb when compared with young unimpaired rats. The LHb was one of only a few brain regions to show this change and it was not observed after control swimming in the absence of learning, suggesting that LHb metabolic activity is correlated with spatial memory performance. Supporting a functional role for the habenula in spatial reference memory, Lecourtier et al. (2004) showed that (medial and lateral) Hb lesions impaired memory acquisition and retrieval in the Morris water maze. Spatial memory involves the hippocampus, which also contributes the major afferent input to the septofimbrial nucleus and nucleus triangularis. These septal nuclei in turn provide the major input to the MHb (§1a). Therefore, the habenula might be involved in learning via the integration of hippocampal signals, relating to memory formation or retrieval, with the activity of the Acb, relating to whether a behavioural strategy has been rewarded (Lecourtier & Kelly 2007). Moreover, habenular lesions alter synaptic plasticity between the hippocampus and Acb (Lecourtier et al. 2006). Experiments using a specific behavioural assay of attention in rats, the 5-choice serial reaction time test, implicated the habenulae in attentional mechanisms (Lecourtier & Kelly 2005). In this test, habenular lesions result in an increase in premature responding, which might represent the emergence of an impulsive mode of behaviour. The effect is blocked by haloperidol, suggesting that it is caused by increased dopaminergic transmission from the midbrain DA neurons, which are inhibited by the descending habenular efferents (above). A second effect is that rats display a progressive deterioration in choice accuracy, which is probably not due to dysregulation of DA signalling. While the mechanism of this defect is unclear, it might involve changes in noradrenergic or cholinergic transmission, both of which are affected by DDC circuitry (discussed in Lecourtier & Kelly 2007). The observation that choice accuracy is not impaired immediately after surgery, but subsequently shows a progressive decline, is an unusual feature, and Lecourtier & Kelly (2007) draw attention to the progressive alterations in serotonergic and GABAergic function within the IPN that occur after FR lesions (Takishita et al. 1990). (c) Aversive responses The LHb is responsive to various noxious stimuli in the rat (Benabid & Jeaugey 1989) and the activation of LHb neurons by nociceptive inputs may be responsible for the inhibition of DA neurons of the SNc (Gao et al. 1996). In addition, induction of Fos immunoreactivity, which is indicative of neuronal activation, occurs in the LHb in response to stress (Smith et al. 1997) and both electrical stimulation or Phil. Trans. R. Soc. B (2009)

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morphine injections into the habenula produces analgesia in a rat model of tonic pain (Cohen & Melzack 1985, 1986). Several studies indicate that the DDC is involved in learning conditional avoidance responses (behavioural responses to avoid aversive stimuli). Habenular lesions appear to inhibit learning by reducing behavioural flexibility, especially under stressful conditions. For instance, in an operant one-way active avoidance task, Thornton & Bradbury (1989) found that habenularlesioned rats were able to learn an escape response when the aversive stimulus (electroshock) was mild and the interstimulus time was long, but were defective, when compared with control animals, under more stressful conditions (higher stimulus intensities and shorter intervals between shocks). Furthermore, in a pre-pulse inhibition (PPI ) task, designed to assess sensory gating and information filtering, mice with habenular lesions failed to show an increase in PPI after exposure to a fear-conditioning paradigm (Heldt & Ressler 2006). One explanation is that stress associated with fear-conditioning causes an increase in PPI in the wild-type mice, mediated by habenular effects on monoamine systems. Further support for a role of the DDC in adaptation to stress derives from the observation that plasma corticosterone levels are chronically elevated in FR-lesioned rats (Murphy et al. 1996). Recently, Pobbe & Zangrossi (2008) have investigated the involvement of the LHb in defence responses to stressful stimuli and shown opposite regulatory effects on escape behaviour (related to panic) versus inhibitory avoidance behaviour (related to generalized anxiety). (d) Circadian rhythms The nuclei comprising the dorsal diencephalon are involved in regulating circadian rhythms. In addition to the habenulae, the epithalamus contains the pineal complex, and the pineal has a conserved role in the generation and/or regulation of circadian rhythms (for reviews, see Korf 1994; Falcon 1999). In lower vertebrates, the pineal is directly photoreceptive, enabling its circadian activity to be entrained to the 24 hour day–night cycle. In non-mammalian vertebrates, it comprises the clock, or pacemaker, of the circadian system and in all vertebrates is involved in the regulation of rhythmic behaviours and physiological responses through the secretion of melatonin ( Falcon 1999). In mammals, the suprachiasmatic nuclei (SCN) of the hypothalamus act as the major pacemaker and receive light information via the retinohypothalamic pathway. The SCN clock controls the rhythmic activity of the pineal (Klein & Moore 1979) via the sympathetic nervous system and the pineal continues to modulate behaviour through the release of melatonin. In addition to the pineal, the habenular complex appears to be involved in circadian functions. The LHb expresses melatonin receptors (Weaver et al. 1989) and in some species habenular cells synthesize melatonin (Sato et al. 1991). Hannibal (2002) identified numerous cell bodies, in both the MHb and LHb of the rat, which synthesize pituitary adenylate cyclaseactivating peptide, which is also expressed in the retinohypothalamic tract and has been implicated in

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shifting the clock phase of the SCN (Harrington et al. 1999). Additionally, the LHb is innervated by SCN neurons (Buijs 1978) and melanopsin-expressing retinal ganglion cells (Hattar et al. 2006). Zhao & Rusak (2005) have shown that Hb neurons, especially in the LHb, respond to retinal illumination and show higher baseline firing in vivo during the day than the night. Moreover, LHb cells maintain this rhythmicity in vitro for at least 48 hours. While the functions of these oscillations and retinal illumination responses are unclear, accumulating evidence suggests that the habenular complex might form part of the output pathway regulating circadian rhythms that are generated in the SCN (e.g. Tavakoli-Nezhad & Schwartz 2006). Certainly, many of the behaviours influenced by the DDC show circadian variations, including sleep (below). Intriguingly, the LHb response to stress (assessed by c-Fos immunoreactivity) is greater during the night than the day (Chastrette et al. 1991). (e) Sleep Evidence suggests that both the habenula and IPN are involved in regulating aspects of sleep. The habenula shows a significant increase in glucose usage during rapid eye movement (REM) sleep in cats (Lydic et al. 1991) and electrical stimulation of the LHb causes a decrease in REM sleep and an increase in non-REM sleep (Goldstein 1983). Both the FR and IPN appear to be important regulators of normal sleep patterns and duration. Transecting the FR disrupts both the REM and nonREM components of sleep and hippocampal theta rhythms (Haun et al. 1992; Valjakka et al. 1998). Eckenrode et al. (1992) showed that transplants of a suspension of foetal habenular cells near the denervated IPN of FR-lesioned rats can restore normal patterns of substance P and/or choline acetyltransferase innervation. When substance P innervation of the IPN was restored, there was recovery of the integrity of REM sleep, whereas transplants that re-established cholinergic innervation restored the non-REM component (resulting in the recovery of sleep duration; Haun et al. 1992). Moreover, the extent of recovery was correlated with the number of transplanted cells. It was proposed that the function of the IPN in REM sleep might be mediated by its projection to the dorsal tegmentum, which in turn innervates the ‘REM sleep induction zone’ of the dorsomedial pons. (f) Reproductive and maternal behaviour DDC circuitry appears to be involved in female sexual behaviour (Modianos et al. 1974). However, lesion studies have produced inconsistent results, showing either an increase or decrease in the receptivity of female rats after habenular lesions (discussed in Sutherland 1982). In male birds, the IPN displays changes in metabolic activity (as measured by increased deoxyglucose incorporation) during either appetitive or consummatory sexual behaviour (Dermon et al. 1999). Intriguingly, Kemali et al. (1990) observed that in the frog, the habenulae are larger in spring than in winter and this seasonal change in habenular size was most noticeable in females. As frogs are sexually active in spring, they hypothesized that hormonal signals Phil. Trans. R. Soc. B (2009)

initiating reproduction might mediate this effect on the habenula. Maternal behaviour is also influenced by the DDC as evidenced by a reduction in pup retrieval, nursing and nest building following LHb lesions in rats (Matthews-Felton et al. 1995). (g) Involvement in psychosis DDC circuitry is implicated in various psychological conditions including depression, anxiety, schizophrenia and neuropathological responses to addictive drugs. In three animal models of depression, metabolic activity in the LHb is specifically increased (CaldecottHazard et al. 1988) and administration of the antidepressant drug tranylcypromine inhibits the elevation of metabolic rate in the LHb as well as the depressive behaviours. Furthermore, Thornton et al. (1985) found that habenular lesions blocked the effect of an antidepressant drug in reversing depressed behaviours that were induced in rats by forced swimming. The habenular complex provides the main forebrain projection to the raphe and exerts control over the activity of raphe neurons (Wang & Aghajanian 1977). LHb activity appears to inhibit raphe neurons as a result of activation of GABAergic interneurons (above). The midbrain raphe is the major source of cerebral serotonin and clinically effective antidepressants are thought to work by facilitating serotonergic signalling, suggesting that serotonin deficiency may underlie depression. Morris et al. (1999) observed that in human patients where depressive relapses were triggered by rapid depletion of blood tryptophan (the precursor to serotonin), positron emission tomography signals displayed correlated increases in the habenula and dorsal raphe as patients’ rating of their depressed mood worsened. Recently, Yang et al. (2008) have reported that in two rat models of depression (where serotonin levels in the dorsal raphe are depleted), LHb lesions improved the behavioural responses of the rats and this was accompanied by an increase in the dorsal raphe serotonin levels. Overactivity of the LHb may therefore contribute to the pathogenesis of depression by inhibiting the raphe. Pathology of the habenula may also contribute to schizophrenia (e.g. Lecourtier et al. 2004). In a human fMRI study, where subjects had to perform a difficult mental task and therefore made numerous errors, the habenular complex was activated when informative feedback was given about errors. Such activation did not occur in schizophrenic patients, who were also impaired in the task (Shepard et al. 2006). This result indicates that impaired activity of DDC circuitry is correlated with impaired cognitive performance in schizophrenia. Shepard et al. (2006) suggested that LHb dysfunction would limit a person’s ability to learn from errors, which is one of the most characteristic cognitive deficits associated with schizophrenia. Although the cause and effects of the observed habenular dysfunction are unknown, there are some clues regarding potential pathological mechanisms. First, an elevated incidence of habenular and pineal calcification has been observed in schizophrenic patients (Sandyk 1992; Caputo et al. 1998). Second, influenza A virus, which increases the risk of

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Review. The habenular nuclei (a)

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Figure 2. Asymmetric habenular circuitry in zebrafish. (a) Schematic showing connectivity of the habenular complex in larval zebrafish. A significant afferent input derives from migrated neurons of the eminentia thalami, which is thought to form the entopeduncular/peripeduncular complex in adult zebrafish (note that the teleostean entopeduncular complex is not part of the pallidum and does not correspond to the EP of amniotes; Wullimann & Mueller 2004). EmT neurons project bilaterally, innervating both left and right habenulae. A subset of left- and right-sided neurons in the anterior pallium are a source of asymmetric innervation, selectively terminating in a small medial domain of the right habenula (indicated in purple). In addition, a small afferent input may derive from the posterior tuberculum ( Hendricks & Jesuthasan 2007). In the epithalamus, the left-sided parapineal exclusively innervates the left habenula (Concha et al. 2003). Habenular neurons project efferent axons that course in the fasciculus retroflexus. A major target is the interpeduncular nucleus: left- and rightsided axons are segregated along the dorso-ventral (DV) axis of the IPN in a laterotopic manner (Aizawa et al. 2005). A smaller and apparently symmetric contingent of habenular axons terminates caudal to the IPN in the serotonergic raphe. (b) Neuroanatomical asymmetries in the dorsal diencephalon. Anti-acetylated tubulin immunostaining (red) shows that the left habenula contains a greater density of neuropil, especially in the dorsomedial aspect of the nucleus. The pineal (blue) and parapineal (green) are visualized by the expression of green fluorescent protein (GFP) in a Tg( foxD3:GFP) transgenic larva. The parapineal is asymmetric in both its location and connectivity, and its efferent axons preferentially terminate in the asymmetric medial neuropil of the left habenula. Dorsal view, anterior top. (c) Three-dimensional confocal reconstruction showing habenular axon terminals in the ventral midbrain labelled using lipophilic tracer dyes applied to the habenulae. Left-sided axons were labelled with DiD (red) and right-sided axons with DiI (green). The dorsal IPN is almost exclusively innervated by left-sided axons, whereas the ventral target receives a majority of right-sided inputs. Dorsal view, anterior top. Tel, telencephalon; EmT, eminentia thalami; PT, posterior tuberculum; Pa, pallium; sm, stria medullaris; Hb, habenula; hc, habenular commissure; pp, parapineal, P, pineal; pc, posterior commissure; FR, fasciculus retroflexus; TeO, optic tectum; IPN, interpeduncular nucleus; a, anterior; p, posterior; l, left; r, right; d, dorsal; v, ventral. Adapted from Bianco et al. (2008). A number of these asymmetry phenotypes are conserved in the distantly related teleost medaka (Oryzias latipes; Signore et al. 2009).

schizophrenia if experienced prenatally, selectively attacks the habenula, paraventricular thalamic and brain stem monoaminergic areas when introduced into the mouse brain via the olfactory bulb (Mori et al. 1999). DDC circuitry appears to be specifically vulnerable to the neurotoxic effects of addictive drugs (reviewed in Ellison 2002). Continuous administration of drugs that potentiate dopamine signalling, including cocaine, D -amphetamine and methamphetamine causes degeneration of axons in the sheath of the FR deriving from LHb neurons, whereas continuous nicotine causes a remarkably specific degeneration of axons from MHb neurons, which descend in the core of the FR. The FR may represent a ‘weak link’ that mediates the progressive effects of drug taking such as addiction and relapse and FR pathology may be involved in various psychoses (Ellison 2002). De Biasi & Salas (2008) have suggested that the effects of nicotine withdrawal are mediated by b4 nicotinic acetylcholine receptors in the MHb–IPN pathway. Phil. Trans. R. Soc. B (2009)

3. ASYMMETRY WITHIN THE EPITHALAMUS AND DDC A striking feature of the epithalamus is that its constituent nuclei display left–right (LR) asymmetries in many animal species. Indeed, structural asymmetries in this region have been described in virtually all classes of vertebrates (reviewed in detail by Concha & Wilson 2001). Asymmetries are most conspicuous in fishes, amphibians and reptiles, while birds and mammals show more subtle lateralization. (a) Habenular asymmetry The habenulae display LR differences in size, cytoarchitectonic organization, neurochemistry and connectivity. (i) Size In the lamprey, the right habenular nucleus is considerably larger than the left (Yanez & Anadon 1994). This mode of lateralization is common in fishes; most actinopterygii (ray-finned bony fishes),

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with the exception of some teleost species, show rightward asymmetries in habenular size (see Concha & Wilson 2001). In amphibians, the habenulae are divided into major dorsal and ventral nuclei, which are equivalent to the MHb and LHb of mammals, respectively (Harris et al. 1996; Guglielmotti & Fiorino 1999). Asymmetries have been described between the dorsal nuclei; the frog Rana esculenta shows a number of pronounced epithalamic asymmetries, including a larger dorsal nucleus on the left (Braitenberg & Kemali 1970; Kemali et al. 1990). Habenular size asymmetries are considerably more subtle in birds and mammals. However, quantitative volumetric analyses have uncovered LR differences. Thus, in the albino rat, the left MHb is slightly (5%) larger than the right (Wree et al. 1981), whereas in the albino mouse rightward lateralization is apparent in the LHb during development and adulthood (Zilles et al. 1976). (ii) Cytoarchitecture and cell morphology Amphibians and reptiles show asymmetries in the subnuclear organization of the habenulae. Such asymmetries are also apparent in fish species, but are less conspicuous than the LR differences in size (see below; Signore et al. 2009). In the enlarged right habenula of the lamprey, neurons are organized into three major layers, which are arranged dorsoventrally and separated by areas of neuropil, whereas only a single domain of periventricular neurons is seen on the left ( Yanez & Anadon 1994). In R. esculenta, the larger left dorsal habenula is subdivided into quite distinct medial and lateral subnuclei, whereas only a single nucleus comprises the right dorsal habenula (Gugliemotti & Fiorino 1998, 1999). In terms of both cytoarchitecture and cell morphology, the lateral subnucleus on the left is similar to the single right-sided nucleus. The left medial subnucleus possesses distinctive features and can be further subdivided into medial and lateral neuropils. It contains a unique population of large and ramified projection neurons that are absent from both the left lateral subnucleus and the right dorsal habenula. (iii) Neurochemistry Habenular lateralization is also manifest in terms of molecular differences between the left and right sides, including asymmetries in the distribution of neurotransmitters. For example, in the coho salmon, a discrete serotonin-immunoreactive subnucleus is found exclusively within the left habenula (Ekstrom & Ebbesson 1988). The unique character of the medial subnucleus of the left dorsal habenula of the frog is further evidenced by its distinctive neurochemical properties. For instance, this subnucleus alone displays high levels of melatonin binding ( Wiechmann & Wirsig-Wiechmann 1993) and calretinin immunoreactivity (Guglielmotti et al. 2004). Furthermore, NADPH-diaphorase histochemistry (which reports the presence of nitric oxide synthase in neural tissue; Hope et al. 1991) is exclusively localized within the lateral neuropil of the Phil. Trans. R. Soc. B (2009)

left medial subnucleus, but is not detected in the left lateral subnucleus nor the right dorsal habenula (Guglielmotti & Fiorino 1999). (iv) Fibre tracts LR differences between the habenulae are associated with asymmetries in the major efferent pathway from the dorsal diencephalon, the FR. Thus, in both the lamprey and the Siberian sturgeon, the larger right habenula is associated with a thicker right FR, and in the sturgeon, right-sided axons are larger in calibre than those on the left (Adrio et al. 2000). Asymmetries in myelination have also been described. For instance, in the cartilaginous fish Scyllium stellare, only the larger left habenula contains neurons extending myelinated axons (Kemali et al. 1980; Miralto & Kemali 1980). In addition to the asymmetrical subnuclear organization of the dorsal habenula in R. esculenta, the routing of axons towards the IPN is also asymmetric (Gugliemotti & Fiorino 1998). On the left side, the lateral subnucleus of the dorsal habenula gives rise to a tract that follows a peripheral route through the thalamus, whereas neurons of the medial subnucleus project axons along a more medial trajectory, bordering the third ventricle. These two contingents of the FR merge before innervating the IPN. On the right side, medial and lateral tracts are also formed, but they both derive from the single dorsal subnucleus of the right habenula. As we discuss below, projections from the left and right habenulae also target different regions of the IPN in teleosts. (b) Pineal complex asymmetry The pineal complex comprises the pineal, or epiphysis, and in some species a second nucleus, the parapineal. The pineal is likely to be present in all vertebrates and serves a neuroendocrine role, producing the hormone melatonin; in lower vertebrates, it is a photoreceptive structure (Falcon 1999; Concha & Wilson 2001). The pineal does not display overt asymmetry, being located at the dorsal midline of the epithalamus (although subtle asymmetries have been described in the location of the pineal stalk; Liang et al. 2000). A second photoreceptive structure, the parapineal, or parietal eye, may also evaginate from the diencephalic roof plate. A parapineal has been described in lampreys, teleosts and certain species of lizard, but has not been detected in amphibians, birds or mammals. The parapineal consistently displays asymmetric connectivity within the epithalamus, projecting efferent axons that exclusively innervate the left habenula. In the species of lizards possessing a parietal eye,1 efferent axons innervate a restricted region of the left MHb (pars dorsolateralis; Engbretson et al. 1981). In teleosts, parapineal axons terminate in a defined rostrodorsal region of the left habenula (Concha et al. 2003; Signore et al. 2009); in the coho salmon, this terminal field may be coincident with the unilateral serotonergic subnucleus that is exclusively found in the left habenula (Ekstrom & Ebbesson 1988; Concha & Wilson 2001).

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Review. The habenular nuclei In lampreys and lizards, the parapineal/parietal eye is located at the dorsal midline, but in teleosts it is asymmetric both in its connectivity and location, being located entirely on the left side of the midline.

4. DDC ASYMMETRIES IN ZEBRAFISH The dorsal diencephalon and the associated circuitry of zebrafish have emerged as a useful model system for studying the development of neural lateralization (Concha 2004). Asymmetry phenotypes in the epithalamus emerge early in the development of zebrafish embryos—from one day post-fertilization— with very high reliability and consistent population laterality.2 Considerable progress has been made in understanding both the developmental pathways that produce asymmetry and that assign the laterality (direction or orientation) of those asymmetries. Moreover, in vivo analysis at the level of individual neurons has revealed a previously unrecognized mechanism by which neural circuitry on the left and right sides of the brain can be anatomically and functionally differentiated. (a) Lateralization in the zebrafish epithalamus By larval stages, several molecular and neuroanatomical asymmetries distinguish the left and right sides of the dorsal diencephalon (figure 2). As in other teleosts, zebrafish possess a parapineal, which is asymmetrically located on the left side of the midline and exclusively innervates the left Hb (Concha et al. 2000, 2003; Signore et al. 2009). The parapineal has a bilateral origin: from approximately 28 hpf, precursor cells from the left and right sides of the midline in the anterior pineal anlage form a coherent group and begin to migrate towards the left Hb (Concha et al. 2003). This asymmetric migration represents one of the earliest signs of asymmetry in the dorsal diencephalon and is dependent upon fibroblast growth factor signalling. In zebrafish fg f8 mutants, parapineal cells fail to migrate away from the dorsal midline (Regan et al. in press). The larval habenulae also develop several asymmetric features, despite the fact that they display only modest LR differences in overall size (the left Hb is approx. 20% larger than the right; Halpern et al. 2003). The left habenula develops a greater density of neuropil than the right (Concha et al. 2000) and several molecular markers are expressed asymmetrically. Especially notable are the related genes, leftover (lov), right-on (ron) and dexter (dex), which are the members of the potassium channel tetramerization domaincontaining family (Gamse et al. 2003, 2005). While lov is expressed more strongly on the left, ron and dex are expressed more extensively in the right Hb. By adult stages, the dorsal region of the Hb contains discrete medial and lateral subnuclei that display distinct patterns of gene expression and efferent connectivity (Aizawa et al. 2005). The relative sizes of these subnuclei are LR asymmetric: in the left Hb, the lateral subnucleus is enlarged, whereas on the right side, the lateral subnucleus is small and the medial subnucleus contains the majority of neurons. Phil. Trans. R. Soc. B (2009)

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(b) Asymmetric habenular circuitry Recent studies have uncovered asymmetries in both the afferent and efferent connectivities of the larval zebrafish habenulae (figure 2). A subset of pallial neurons, on both sides of the brain, project axons that innervate the habenulae asymmetrically and terminate within a small medial domain of the right habenula (Hendricks & Jesuthasan 2007). Using lipophilic dye tracing to examine Hb efferent connectivity, Aizawa et al. (2005) showed that at larval stages, the Hb establishes strong projections to the IPN and anterior raphe. While the projection to the raphe appears symmetric, the origin of habenular axons innervating the IPN is conspiculously asymmetric. Left Hb axons preferentially terminate in a dorsal subdomain of the IPN (dIPN) and to a lesser degree in the ventral region of the IPN (vIPN), whereas almost all right habenular axons innervate the vIPN. This pattern of asymmetric connectivity is maintained at adult stages, at which time it is associated with a substantial asymmetry in the size ratios of habenular subnuclei: the adult left habenula contains a large lateral subnucleus,3 which innervates the dIPN, whereas in the right habenula, the lateral subnucleus is small and instead the medial subnucleus, which innervates the vIPN, is enlarged (Aizawa et al. 2005). To our knowledge, this represents one of the first examples in the vertebrates of LR differences in target connectivity for bilaterally paired neuronal nuclei. Because left and right axons become segregated along the dorso-ventral (DV) axis of their target, the Hb–IPN connectivity can be described as laterotopic. The translation of LR asymmetry to a dorsoventral asymmetry potentially provides a mechanism to preserve LR coding in downstream circuitry. To address this hypothesis and determine whether distinct ‘left-derived’ and ‘right-derived’ circuits are maintained downstream of the IPN, future research should determine whether the dIPN and vIPN project to distinct efferent targets. Another aspect of the Hb–IPN connectivity pattern is that the convergence of Hb axons onto a unilateral midline target provides a means for lateralized, asymmetric neural processing in the epithalamus to modulate behaviours that require the regulation of bilateral motor circuitry on both sides of the midline. (i) Lateralization in circuit microarchitecture A recent study in our laboratory used focal electroporation to examine the morphology and connectivity of individual habenular projection neurons, which enabled the organization of the asymmetric Hb–IPN circuitry to be analysed at single-cell resolution (Bianco et al. 2008). This approach led to the identification of two projection neuron subtypes that have axon terminal arbours with distinct morphologies and target connectivity (figure 3). Both subtypes are found in both the left and right habenula, but in substantially different ratios. Thus, the vast majority (84%) of left habenular neurons form ‘L-typical’ axon arbours that are tall and highly branched and localized to the dIPN. Only a very small percentage of the right-sided neurons form L-typical arbours. Instead, over 90 per cent of the rightsided cells elaborate ‘R-typical’ arbours that are

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Figure 3. Zebrafish Hb–IPN projection neurons elaborate one of two distinct axon terminal arbour morphologies. (a) Threedimensional reconstruction showing a single right habenular projection neuron that was labelled by focal electroporation with a construct driving the expression of membrane GFP, in an intact larval zebrafish brain (4 days post-fertilization). The cell body, located in the right habenula (rHb) extends an axon down the right FR (indicated by arrow) that terminates in the IPN. Habenular neurons elaborate remarkable axon arbours within the IPN that cross the ventral midline multiple times. Scale bar, 100 mm. (b(i),c(i)) Dorsal and (b(ii),c(ii)) lateral confocal reconstructions of single habenular axon arbours in the IPN. (b(i),(ii)) Example of an L-typical axon arbour, formed by 84% of left habenular neurons. These arbours are located in the dorsal IPN and are shaped similar to a domed crown and arborize over a considerable dorsoventral extent (compare dorsal (b(i)) and lateral (b(ii)) views of an example L-typical arbour). (c(i),(ii)) Example of an R-typical axon arbour, which is considerably flatter, localized to the ventral IPN and formed by 90% of right habenular neurons. Adapted from Bianco et al. (2008).

flattened along the DV axis and localized to the vIPN. This arbour morphology is adopted by only a small number (16%) of left habenular neurons. Because these two arbour subtypes differentially innervate the dorsal and ventral domains of the IPN, the substantial asymmetry in the cell type composition between the left and right habenulae accounts for the laterotopic Hb–IPN connectivity pattern. This study has identified a fundamental strategy by which neural tissue on the left and right sides of the central nervous system (CNS) may become asymmetric. It gives rise to a model where the same or very similar circuitry components are produced on both sides, but in greatly different ratios, resulting in LR asymmetry in circuit microarchitecture that presumably translates into functional asymmetry. Figure 4 contrasts this model with two other models for how neural circuits might be lateralized. In perhaps the simplest model, equivalent regions on the left and right sides would contain the same classes of neuron and patterns of circuitry but differ only in size (figure 4a). As a result of such ‘scaling’, a particular cognitive function might be lateralized simply as a result of more neural substrate existing on one or the other side. In support of this possibility, Rosen (1996) observed that in the rat somatosensory/somatomotor cortex, asymmetry in tissue volume is strongly associated with the LR differences in the numbers of two subtypes of neuron, but there is only a weakly significant difference in cell packing density for one of the neuronal subtypes, suggesting that the left and right sides have similar neural architectures and show a proportional scaling to achieve differences in the quantity of neural tissue. In a third model, certain types of neuron, or patterns of connectivity, might be specific to one side and would Phil. Trans. R. Soc. B (2009)

not be present on the other side of the CNS (figure 4b). Hence, circuits on the left and right might receive different types of afferent inputs, perform different neural computations and/or connect to different downstream targets to mediate distinct types of cognition or behaviour. This mode of lateralization might be especially applicable to the zebrafish DDC: the parapineal projects exclusively to the left habenula and a subset of pallial neurons exclusively innervate a subdomain of the right habenula (above). (c) Development of circuit asymmetry (i) Nodal signalling specifies the laterality of neural asymmetry The discovery that components of the Nodal signalling pathway are expressed asymmetrically in the left dorsal diencephalon prior to the leftward migration of the parapineal and development of other lateralized phenotypes (Sampath et al. 1998; Concha et al. 2000; Liang et al. 2000) provided an entry point for the studies that have uncovered how neural asymmetry develops in the zebrafish DDC. Work by Concha et al. (2000) and Gamse et al. (2003) established that the function of the left-sided Nodal signalling is to specify the direction, or laterality of asymmetry in the dorsal diencephalon. Over 95 per cent of wild-type larvae develop with a left-sided parapineal and left-sided elevation of lov expression; this strong population laterality requires unilateral, leftsided Nodal signalling. In experimental contexts where Nodal signalling is absent, or where it is activated bilaterally and therefore the asymmetry of its expression is lost, normal asymmetry phenotypes develop, but with randomized laterality: in 50 per cent of such embryos, the parapineal migrates to the left and

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The timing of neurogenesis was found to correlate with neuronal fate. Neurons born early tend to enter the LHb subnucleus. At adult stages, this subnucleus establishes connectivity exclusively with the dIPN and so it is very likely that these early-born neurons are L-typical, with basket-shaped, dorsally localized axonal arbours (see above). Later-born neurons tend to enter into the MHb subnucleus. As this connects to vIPN in adults, these later-born neurons are expected to comprise the R-typical subtype. Moreover, the timecourse of neurogenesis was found to be LR asymmetric. On the left side, most neurons are born early, whereas on the right, neurogenesis is delayed and most neurons are born late. This is compatible with the observation that the majority of left-sided neurons acquire L-typical fate and the majority of right-sided neurons become R-typical (Bianco et al. 2008). The basis for this asymmetry in neurogenesis is as yet unknown.

(c)

Figure 4. Models for lateralization of neural tissue. (a) Equivalent regions on the left and right of the CNS are identical in composition and differ only in overall size. (b) Unique types of neuron, or patterns of connectivity, may be specified on either the left or right or both sides (indicated by unique red neurons on the left in this schematic). (c) Identical circuit components might exist on both sides of the CNS, but in different ratios. Note that these models are in no way mutually exclusive. In fact, it is likely that all three strategies may be involved in the lateralization of DDC circuitry (see the main text).

the left Hb innervates the dIPN, but in the other 50 per cent the parapineal migrates to the right and the LR origin of axons in the dorsal and ventral IPN is perfectly reversed (Concha et al. 2000; Aizawa et al. 2005). Thus, Nodal signalling is not required for the development of neural asymmetry, but rather it appears to bias a stochastic laterality decision, to ensure consistent population laterality. Recently, Carl et al. (2007) and Inbal et al. (2007) have shown that proper regulation of Wnt/Axin/b-catenin signalling and functioning of Six3 proteins is required during gastrulation to repress Nodal signalling; this is an essential prerequisite to allow later unilateral activation of the pathway exclusively on the left side of the brain. In addition to understanding how the laterality of neural asymmetries is specified, progress has been made in elucidating how asymmetry itself emerges in the DDC and resolving the developmental signalling mechanisms that control this process. (ii) Asymmetric neurogenesis Using BrdU birthdating to analyse the dynamics of Hb neurogenesis, Aizawa et al. (2007) provided an explanation for the substantially different ratios of distinct neuronal subtypes in the left and right habenulae. Phil. Trans. R. Soc. B (2009)

(iii) Symmetry breaking and the parapineal It has been suggested that the presence of a parapineal nucleus and the development of habenular lateralization might be causally associated (discussed in Engbretson et al. 1981; Harris et al. 1996; Concha & Wilson 2001; Guglielmotti & Cristino 2006). In species of lizard that possess a parietal eye, more pronounced asymmetries in habenular subnuclear organization are apparent than in species of reptiles lacking a parietal eye. However, in the lamprey, although the parapineal innervates the left habenula, it is the right nucleus that is enlarged. Moreover, striking habenular asymmetries have been described in vertebrates that appear not to possess a parapineal (e.g. amphibians), questioning any link between asymmetry in the habenulae and pineal complex. Laser ablation studies in zebrafish have demonstrated that the parapineal is essential for the normal development of habenular lateralization. In larvae lacking a parapineal, both habenulae display patterns of gene expression and neuropil organization similar to those seen in the wild-type right habenula, and both sides project predominantly to the vIPN (Concha et al. 2003; Gamse et al. 2003, 2005; Bianco et al. 2008). However, subtle LR differences are retained in the molecular and neuroanatomical characteristics of the epithalamus (Concha et al. 2003; Bianco et al. 2008). Furthermore, despite the fact that they both target the vIPN, the axons of left- and right-sided habenular neurons retain distinct terminal morphologies (Bianco et al. 2008). This suggests that the parapineal does not specify LR identity in a binary manner, but rather it acts in concert with other, as yet unidentified, developmental signals to amplify LR asymmetry. These signals would then account for the maintenance of subtle lateralization following parapineal ablation. The mechanism by which the parapineal acts and the molecular players involved in its signalling is as yet unknown. It is possible that the parapineal influences the time-course of Hb neurogenesis, possibly by modulating Notch signalling (the parapineal would be expected to suppress the Notch pathway on the left such that neurons are born early and acquire the L-typical/lateral subnucleus identity). However, the different terminal arbour morphologies of the left- and

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right-sided neurons in ablated larvae might be a result of interactions between axons that innervate the same target region (vIPN) at different times. In this model, the asymmetric time-course of Hb neurogenesis would be retained in parapineal-ablated larvae and the parapineal might contribute to Hb lateralization by promoting the proper differentiation of early-born leftsided neurons (including, for example, upreglation of guidance receptors that result in axon targeting to the dIPN; Kuan et al. 2007). (d) Asymmetric circuitry and asymmetric behaviour What is the physiological and behavioural significance of the widespread asymmetries in the DDC? Although the answer to this question is unclear, behavioural analyses in zebrafish with alterations in DDC architecture and lateralization have the potential to help resolve the functions of this circuit and the importance of neural asymmetry. Zebrafish display behavioural asymmetries in the form of biased turning direction and differential eye use for particular viewing tasks. This visual system lateralization takes a similar form to that in tetrapods where the right eye is used for examining complex or novel scenes and the left eye is used for viewing familiar objects (Miklosi et al. 1997; Miklosi & Andrew 1999). Moreover, a number of behavioural asymmetries are already apparent at larval stages (Watkins et al. 2004; Barth et al. 2005; Andrew et al. 2009). Barth et al. (2005) examined both lateralized and nonlateralized behaviours in larvae and adults of the frequent situs inversus ( fsi ) line, in which a high frequency of fishes show concordant reversals in the laterality of both visceral (heart, pancreas, gut) and DDC asymmetries. While some asymmetric behaviours, including the pattern of left and right eye use in a mirror viewing task, are reversed in fsi fish with anatomical reversals, other lateralized behaviours do not reverse. Moreover, a novel, non-lateralized behaviour was observed in anatomically reversed larvae, which is not apparent in normally lateralized fsi fish or wild-types. These results suggest that there are multiple pathways specifying brain laterality, at least one of which is not concordant with visceral laterality and not affected in fsi. The emergence of novel behaviours might be a consequence of the erroneous superposition (or separation) of neural processing functions, arising from the reversals of a subset of neural asymmetries. While the laterality of certain behaviours correlates with the reversals in the DDC, more work will be required to establish causal links between the activity and lateralization of this pathway and specific behavioural outputs. To this end, a variety of emerging technologies have the potential to be used in zebrafish: in vivo calcium imaging can be used to image activity in populations of neurons during animal behaviour (Niell & Smith 2005; McLean et al. 2007). Moreover, direct modulation of neural activity, for instance, using ectopically expressed proteins to excite or silence selected neurons ( Knopfel 2008), should allow lateralized neurophysiology to be directly linked to specific behaviours. Phil. Trans. R. Soc. B (2009)

5. CONCLUSION In summary, the epithalamus constitutes the epicentre of the DDC. This highly conserved circuit is involved in a diverse range of behaviours, which we are still only beginning to understand. Neural asymmetries are present in this pathway in many species and range from LR differences in neurotransmitter expression to asymmetric patterns of connectivity. Several modes of lateralization can be seen in the DDC, including asymmetries in size and the production of unique circuitry components on one or the other side. Furthermore, large differences in the ratios of projection neuron subtypes generate LR asymmetric circuit microarchitectures. These neuronal subtypes are produced at different times during development, and asymmetries in the time-course of neurogenesis between the two sides of the epithalamus result in lateralized cell type compositions. Nodal signalling determines the laterality, or orientation, of such asymmetries. Signalling from the parapineal makes an important contribution to the development of asymmetry in the DDC of zebrafish, but other developmental signals must also be involved and the search for these continues. We thank the members of our laboratory and reviewers for their useful comments on the manuscript. The work on the epithalamus and asymmetry in our group is supported by the Wellcome Trust, the BBSRC and a European Communities grant entitled “Evolution and Development of Cognitive, Behavioural and Neural Lateralisation”.

ENDNOTES 1

The parietal eye is considered an equivalent of the parapineal but forms a more sophisticated photoreceptive organ than is found in lampreys and teleosts. Its structure resembles the lateral eyes, and electrophysiological studies show it to be a fully functional photoreceptive organ; it emerges from a foramen in the skull. 2 If an asymmetry phenotype shows a consistent directionality in the majority of individuals in a population, it is said to show ‘directional asymmetry’ or ‘population laterality’. By contrast, if an asymmetric structure appears with equal probability on either the left or right side, there will be no consistent laterality within a population of animals, a situation referred to as ‘antisymmetry’. 3 The medial and lateral subnuclei described in the adult zebrafish habenula are not equivalent to the MHb and LHb of reptiles and mammals. Indeed, the entire teleost habenula is suggested to be homologous to only the MHb of reptiles/mammals (e.g. Yanez & Anadon 1996). However, further work is needed to determine homologies between habenular subnuclei among different classes of vertebrates.

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Phil. Trans. R. Soc. B (2009) 364, 1021–1032 doi:10.1098/rstb.2008.0234 Published online 5 December 2008

Determining the function of zebrafish epithalamic asymmetry Lucilla Facchin1, Harold A. Burgess2, Mahmud Siddiqi1, Michael Granato2 and Marnie E. Halpern1,* 1

Department of Embryology, Carnegie Institution for Science, 3520 San Martin Drive, Baltimore, MD 21218, USA 2 Department of Cell and Developmental Biology, University of Pennsylvania, 1210 Biomedical Research Building II/III, 421 Curie Boulevard, Philadelphia, PA 19104, USA As in many fishes, amphibians and reptiles, the epithalamus of the zebrafish, Danio rerio, develops with pronounced left–right (L–R) asymmetry. For example, in more than 95 per cent of zebrafish larvae, the parapineal, an accessory to the pineal organ, forms on the left side of the brain and the adjacent left habenular nucleus is larger than the right. Disruption of Nodal signalling affects this bias, producing equal numbers of larvae with the parapineal on the left or the right side and corresponding habenular reversals. Pre-selection of live larvae using fluorescent transgenic reporters provides a useful substrate for studying the effects of neuroanatomical asymmetry on behaviour. Previous studies had suggested that epithalamic directionality is correlated with lateralized behaviours such as L–R eye preference. We find that the randomization of epithalamic asymmetry, through perturbation of the nodal-related gene southpaw, does not alter a variety of motor behaviours, including responses to lateralized stimuli. However, we discovered significant deficits in swimming initiation and in the total distance navigated by larvae with parapineal reversals. We discuss these findings with respect to previous studies and recent work linking the habenular region with control of the motivation/reward pathway of the vertebrate brain. Keywords: habenula; brain asymmetry; behaviour

1. INTRODUCTION The functional significance of brain laterality has been a long-debated topic in cognitive neuroscience. Theories abound as to the advantages of the left–right (L–R) specialization of the nervous system and as to why directional biases in neuroanatomy and behaviour are found throughout the animal kingdom (Vallortigara & Rogers 2005). For example, light-induced neuroanatomical asymmetry in the visual system of developing birds correlates with some enhanced visual behaviours in adulthood (Gu¨ntu¨rku¨n et al. 2000; Rogers 2008), and preferential eye use has been argued to mediate shoaling behaviour in social fish species (Bisazza et al. 2000). Fishes are a valuable system for examining functional lateralization at the individual and population level (Bisazza et al. 1998). Because the eyes are positioned laterally on the head and each is exposed to a different visual landscape, left or right eye use upon viewing familiar or novel objects, or when self-viewing (‘mirror test’) provides a simple assay to detect biases (Facchin et al. 1999; Sovrano et al. 1999; De Santi et al. 2001; Sovrano et al. 2001). Systematic preferences in eye use are proposed to be a behavioural manifestation of specialization of the two sides of the brain in processing incoming visual information, since each * Author for correspondence ([email protected]). One contribution of 14 to a Theme Issue ‘Mechanisms and functions of brain and behavioural asymmetries’.

eye predominately projects to the contralateral side of the brain (Vallortigara 2000). Turning to avoid barriers or to navigate complex environments, prey capture and aggressive behaviours also have been found to have a preferred directional component in some fish species (e.g. Heuts 1999; Bisazza et al. 2000, 2001; Bisazza & de Santi 2003; Reddon & Hurd 2008 and refer to Vallortigara & Bisazza 2002). The zebrafish, Danio rerio, has obvious benefits in exploring behavioural laterality, as a well-studied developmental model amenable to genetic manipulations. Functional lateralization in this species has been previously documented for a number of behavioural tests both in adults (Miklo´si et al. 1997, 2001; Heuts 1999; Miklo´si & Andrew 1999) and in young fry (Watkins et al. 2004; Barth et al. 2005; Sovrano & Andrew 2006). Adult zebrafish show a right eye preference when first exposed to new objects or complex scenes that require immediate monitoring and response (Miklo´si et al. 2001; Miklo´si & Andrew 2006). However, the left eye is preferentially used on subsequent trials, for visual inspection of familiar stimuli or those with moderate novelty and, presumably, comparisons with the memory of similar stimuli. Thus, left eye viewing appears to be better equipped for comprehensive assessment of familiarity, while the right eye system has been proposed to be more resistant to distraction and to mediate decision-making responses (Miklo´si et al. 1997; Miklo´si & Andrew 2006). Adults also tend

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to use the right eye when approaching an object to bite; however, no bias in eye use is found when a familiar object is investigated and not bitten (Miklo´si & Andrew 1999). When faced with a barrier blocking access to a perceived predator, adult zebrafish show a detour response that is biased for left eye inspection and turning to the right (Bisazza et al. 2000). Larval zebrafish as young as 8 days post-fertilization (dpf ) appear to exhibit behavioural biases. Watkins et al. (2004) described biases in the directionality of turning, which were correlated with changes in light intensity that an 8-day-old larva experienced while navigating through a multicompartment swimway. They also found preferential left eye inspection and less avoidance behaviour in larvae exposed to a dark stripe that had previously been presented in the left visual field. Their findings were consistent with the left eye bias described for adult zebrafish in assessing stimuli with respect to prior experiences (Miklo´si et al. 1997). Sovrano & Andrew (2006) modified the mirror test to study the development of visual lateralization in zebrafish larvae and also found a preference for left eye viewing. However, left eye bias was strain, age and distance dependent and was sustained for varying periods within the testing window. A more recent study (Andrew et al. in press) also suggests that, as in developing chicks (refer to Rogers 2008), early exposure to light may influence bias in L–R eye use.

2. THE ZEBRAFISH AS A MODEL OF EPITHALAMIC L–R ASYMMETRY Recently, it has become possible to tackle the problem of how brain asymmetry arises developmentally using molecular genetic approaches afforded by the zebrafish model. Although there remains some controversy about the nature of the initial symmetry-breaking event in the early embryo, the ciliated Kupffer’s vesicle present in the caudal midline at somitogenesis (Bisgrove et al. 2005; Essner et al. 2005) and Wnt signalling (Carl et al. 2007; Inbal et al. 2007) have been implicated in the determination of L–R differences. Components of the Nodal signalling pathway involved in specifying the L–R axis across vertebrates also show a conserved function in the establishment of zebrafish visceral asymmetry (refer to Liang & Rubinstein 2003; Schier 2003). However, only in fishes have Nodal-related TGF-b family members been shown to influence L–R determination in the brain, specifically in the epithalamic region of the dorsal diencephalon (Concha et al. 2000; Liang et al. 2000). Loss of Nodal-related signals (cyclops/nodalrelated 2 or southpaw/nodal-related 3) does not disrupt L–R asymmetry, but rather results in a randomization in directional asymmetry across the population. For example, more than 95 per cent of all wild-type zebrafish embryos form a parapineal organ on the left side of the brain (Concha et al. 2000; Gamse et al. 2002). The parapineal is closely associated with the pineal organ and arises from cells in a shared pineal complex anlage (Concha et al. 2003; Snelson et al. 2008). In approximately 50 per cent of embryos with Nodal signalling blocked or that lack southpaw (spaw) function, the parapineal develops to the left of the pineal, while the other 50 per cent form the parapineal on the right. Phil. Trans. R. Soc. B (2009)

While this might seem like a minor disruption, the position of the parapineal has striking consequences on the development of the epithalamic region flanking the pineal complex, the bilateral habenular nuclei, and their connectivity with a shared midbrain target. In the vast majority of larvae, the left habenula is in close apposition to the parapineal and is larger, exhibits more dense neuropil and a different gene expression profile than the right habenula (Concha et al. 2003; Gamse et al. 2003, 2005; Kuan et al. 2007a,b). L–R patterns of gene expression appear to correlate with differences in subnuclear organization and proliferation of habenular neurons (Gamse et al. 2003; Aizawa et al. 2007). The right habenula may be a default state because, when the parapineal is destroyed, the left habenular nucleus develops with properties more similar to the right habenula (Concha et al. 2003; Gamse et al. 2003). However, an exception is that distinct left and right neuronal morphologies appear to still be maintained (Bianco et al. 2008). Neurons from the left habenula normally project their axons to dorsal and ventral regions of the interpeduncular nucleus (IPN) in the ventral midbrain, whereas projections from the right habenular neurons are confined ventrally (Gamse et al. 2005). Expression of the gene encoding the axon guidance receptor Neuropilin-1 (Nrp1) is restricted to the left habenula, which most probably accounts for the L–R difference in target connectivity (Kuan et al. 2007a,b). Morpholinomediated disruption of Nrp1 or parapineal ablation leads to a similar outcome, with both left and right habenular efferents primarily innervating the ventral target. Larvae with the parapineal on the right side of the brain not only show a L–R reversal in habenular identity as assessed by differences in size, amount of dense neuropil and gene expression (including right habenular expression of nrp), but they also exhibit a corresponding reversal in the IPN innervation pattern (Gamse et al. 2005; Kuan et al. 2007a,b). Because neither the distinct functions of the dorsal and ventral IPN nor their postsynaptic partners have yet been determined in zebrafish, it is unknown what effect parapineal and, hence, habenular L–R reversal would have on neural pathways influenced by the habenular-IPN connection. Mutations in a variety of developmentally important genes disrupt directional asymmetry in zebrafish embryos, and L–R randomization in mutants can uncouple visceral and brain asymmetries (Sampath et al. 1998; Essner et al. 2000). A zebrafish line, frequent-situs-inversus ( fsi ), that has a tendency to produce a higher than usual frequency of larvae with concordant heart, gut, pancreas and parapineal L–R reversals has also been described (Barth et al. 2005). This trait does not segregate as a simple single-gene mutation, but intercrosses within the fsi line variably increase the rate of situs inversus from 5 to 25 per cent in a single clutch. Analyses of fsi individuals with L–R reversed epithalamic neuroanatomy indicated a corresponding reversal in the directionality of some lateralized behaviours (Barth et al. 2005). The ability to alter the L–R orientation of the brain in a predictable manner by genetic manipulations is a valuable feature of the zebrafish system for studies on the behavioural consequences of an asymmetric nervous system.

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Function of zebrafish epithalamic asymmetry Using an antisense morpholino (MO) against the spaw gene (Long et al. 2003) injected into one-cell stage embryos, we can reliably generate four distinct classes of zebrafish larvae: those with the typical pattern of left parapineal and right pancreas (designated LppR pa) that is found in more than 95 per cent of wild-type populations; those showing situs inversus or reversal of this pattern (designated R ppL pa); and two discordant classes with a right parapineal and right pancreas (R ppR pa) or a left parapineal and left pancreas (L ppL pa) (Gamse et al. 2005). Following this experimental manipulation, the four classes are not found in equal frequencies (figure 1e); however, a significantly greater number of larvae show reversed epithalamic and visceral asymmetry compared with wild-type strains. The MO is introduced into doubly transgenic progeny from matings between Tg( foxd3:GFP ) fkg17 (Gilmour et al. 2002) and Tg(ela3l:GFP )gz2;Tg( fabp 10:dsRed )gz4 (Dong et al. 2007) adults, in which the pineal complex and pancreas, and the liver, are labelled with green fluorescent protein (GFP) and red fluorescent protein (RFP), respectively (figure 1a–d ). The resultant larvae can be unambiguously sorted at 3 dpf on the basis of the position of the GFPC parapineal to the left or right of the pineal organ, and at 5 dpf for the location of the GFPC pancreas on the left or the right side of the body (figure 1e). This approach allows larvae (and adults) to be maintained in four discrete anatomical classes and ensures the availability of large numbers for behavioural analyses. The L ppR pa group, bearing the configuration of the majority of wild-type or transgenic larvae, also serves as an internal control for potential artefacts associated with MO injection.

3. EPITHALAMIC REVERSAL DOES NOT AFFECT MOTOR RESPONSES To test whether sensory and motor responses differ between the four anatomical groups, we took advantage of the Flote automated system for high-speed video recording and analysis. Flote was designed to measure the detailed kinematics of individual motor behaviours simultaneously in groups of larvae, in an observer-independent manner (Burgess & Granato 2007a). We first examined whether pre-sorted parapineal and pancreas reversed (R ppL pa) or discordant (L ppL pa and R ppR pa) larvae showed differences from the L ppR pa group in the directionality of their spontaneous movements. To assess spontaneous movements, groups of 7 dpf larvae (8–10 per group) were pre-adapted to a set level of light (170 mW cmK2) consistent with the intensity of illumination in the testing arena. After dishes were transferred to the testing arena, larvae were given 3 min to stabilize the levels of locomotor activity prior to video recording. Under unperturbed conditions, larvae typically swim in bouts of forward-directed movements termed ‘slow swims’ or ‘scoots’ and also execute reorienting movements referred to as ‘routine turns’ (R-turns; Budick & O’Malley 2000; Burgess & Granato 2007b). For each anatomical group tested, the kinematics of turning were normal (data not shown) and there was no difference between the groups in the percentage of R-turns executed in a Phil. Trans. R. Soc. B (2009)

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rightward direction (no effect of parapineal laterality (F1,4Z0.39, pZ0.56) or visceral laterality (F1,4Z 0.003, pZ0.96) using two-way ANOVA). Combining all groups, 50.3G3.2% of R-turns were initiated in a rightward direction (one-sample t-test for 50%; t7Z0.11, pZ0.93), indicating that there was no intrinsic L–R bias in turning behaviour under baseline conditions. We measured the responsiveness and kinematics of larval startle responses following exposure to an intense acoustic/vibrational stimulus (refer to Burgess & Granato (2007a) for details of the startle paradigm). Zebrafish larvae have two primary stereotyped response modes to an acoustic startle stimulus, an explosive C-bend with a short latency (4–8 ms, short latency C-start or SLC) and a second type of C-bend initiated with slower and prolonged duration and with a much longer latency (20–50 ms, long-latency C-start or LLC) (Kimmel et al. 1974; Burgess & Granato 2007a). Both responses are followed by burst swimming movements, which rapidly propel larvae away from their initial position.

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Figure 2. Equivalent startle responses in L–R reversed larvae. (a) Initiation frequencies for the short latency C-start (SLC) and (b) long latency C-start (LLC) responses. Movement initiation frequencies correspond to the percentage of trials in which SLC and LLC responses were observed. Larvae were tested in a 9-well grid and scored individually (nZ18 per group). (c) Percentage of SLC and (d ) LLC responses initiated in a rightward direction. A few larvae produced either no SLC (nZ7/72) or LLC (nZ 1/72) responses and these were excluded from the analysis of directionality. Startle stimuli were generated and responses were recorded as previously described (Burgess & Granato 2007a) using a 1000 Hz horizontal vibrational stimulus of 3 ms duration and maximum acceleration 150 ms. Each set of larvae was tested with a series of 40 stimuli, presented at 15 s intervals. For these and all other assays, larvae were raised at a standard density of 30 larvae per 6 cm plastic Petri dish in E3 embryo media (5 mM NaCl, 0.17 mM KCl, 0.33 mM CaCl2 and 0.33 mM MgSO4; Nu¨sslein-Volhard & Dahm 2002) and maintained at 27–288C under uniform lighting in a 14 L : 10 D cycle.

In spaw MO-injected larvae, no differences were found in the initiation frequency for either SLC responses (F3,68Z0.80, pZ0.50; figure 2a) or LLC responses (F3,68Z0.52, pZ0.66; figure 2b) between the four anatomical classes. The kinematics of the SLC and LLC responses were also indistinguishable. For example, for the first C-bend of the LLC responses, the latency (F3,67Z0.30, pZ0.83), magnitude (F3,67Z1.13, pZ0.34), duration (F3,67Z1.69, pZ0.18) and angular velocity (F3,67Z0.57, pZ0.63) showed no group effect, nor was any group significantly different by t-test from the L ppR pa group. These results indicate that all larvae, regardless of their anatomical laterality, sense the startle stimulus normally and respond with a stereotypic C-bend and characteristic succession of movements. As a population, wild-type zebrafish larvae do not show an intrinsic directional bias in the acoustic startle assay, with 50 per cent of both SLC and LLC responses being initiated in a rightward direction (Burgess & Granato 2007a). Directional bias was also not observed in spaw MO-injected L ppR pa larvae for either mode of startle response, with 44.9G8.5% of SLC responses initiated in a rightward direction (one-sample t-test against 50%, t14Z0.60, pZ0.56) and 45.3G6.4% of LLC responses initiated rightward (t16Z0.74, pZ 0.47). Moreover, there were no significant differences between the four anatomical groups for directionality of either SLC (F3,61Z0.17, pZ0.91) or LLC (F3,67Z 1.6, pZ0.19) responses. Thus, parapineal or visceral asymmetry was not associated with a L–R bias in C-bends during the startle response. Phil. Trans. R. Soc. B (2009)

4. MOTOR RESPONSES TO DIRECTIONAL STIMULI Next, we employed two tests in which motor responses of zebrafish larvae were directionally modulated by an asymmetrically presented stimulus, in the expectation that epithalamic reversal would disrupt lateralization of behavioural activity. For both assays, statistical analyses confirmed that visceral sidedness had no measurable effect, e.g. directionality of responses were not significantly different in either the dark flash test (independent samples t-test, t15Z0.45, pZ0.66) or the looming escape response (t7Z1.4, pZ0.21), allowing grouping of L ppR pa with L ppL pa and R ppL pa with R ppR pa into two datasets (refer to figure 3). The first test used an abrupt reduction in illumination from an asymmetrically positioned light source (‘dark flash’). Wild-type larvae respond to a dark flash with a stereotyped movement initiated with a large amplitude C-bend (termed ‘O-bend’; Burgess & Granato 2007b). Because they tend to turn towards the extinguished light source (Burgess & Granato 2007b), directionality of an O-bend depends on which side of the larva initially faced the light. Larvae with a left or right parapineal showed a similar level of responsiveness to a dark flash (independent samples t-test, t15Z0.16, pZ0.87; figure 3a) and O-bends were executed with equivalent kinematics in the two groups. For example, latency (L ppZ458G 22 ms and R ppZ458G20 ms, t15Z0.002, pZ0.99) and C-magnitude (LppZ1418G48and R ppZ1468G48, t15 Z0.90, pZ0.38) were almost identical. The tendency of O-bends to be initiated towards the light

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Function of zebrafish epithalamic asymmetry source (‘bias’, figure 3b) was significant (one-sample t-test against 0, for L pp t8Z3.9, pZ0.005 and for R pp t7Z4.3, pZ0.004) and of similar magnitude for the two groups (t15Z0.12, pZ0.91). The second test is based on the observation that many species of fishes, including adult zebrafish, are known to swim away from a looming object by reorienting in the same direction as the moving shadow, and then swimming vigorously forward (Dill 1974; Li & Dowling 1997). To assess the looming escape response, free-swimming larvae in a 6 cm dish were exposed to a moving shadow sweeping across the testing area at a constant rate. For each group of L pp and R pp larvae, eight repetitions of the looming stimulus were presented at 60 s intervals in alternating directions. In this assay, larvae initiate turning manoeuvres to reorient away from the looming shadow, and then perform bouts of forward swimming in the same direction the shadow moves (H. Burgess & M. Granato 2007, unpublished observations). No significant difference in the frequency of turn initiations was detected between L pp and R pp larvae (independent samples t-test with unequal variance, t4.3Z2.3, pZ0.08; figure 3c). Moreover, the two groups showed very similar movement kinematics, including latency to movement (L ppZ412G28 ms and R ppZ395G25 ms, t7Z0.46, pZ0.66) and C-magnitude (L ppZ97G48 and R ppZ 101G48, t7Z0.56, pZ0.59). Thus, larvae with parapineal reversals both detect visual stimuli and have a normal magnitude of response. This assay also tests the directionality of response, as larvae show a strong bias to initiate turns away from the approaching shadow. Thus, larvae facing the shadow with their left side tend to turn rightward, whereas those facing the shadow with their right side primarily turn leftward. The directional bias of turn movements away from the shadow was almost identical in L pp and R pp larvae (t7Z0.14, pZ0.89; figure 3d ). These experiments demonstrate that sensory acuity for acoustic and visual stimuli, movement kinematics and levels of responsiveness are all normal in larvae with parapineal reversals.

5. LARVAL POPULATIONS DO NOT SHOW CONSISTENT EYE PREFERENCE A behavioural test with inherent directionality is the choice of left or right eye used by a larva to view its mirror image. The procedure used to measure eye preference in zebrafish larva was adapted from the mirror test of Sovrano et al. (1999) for adult fish, and was similar to that described by Sovrano & Andrew (2006). At 8 dpf, each larva was tested individually by gently placing it in the middle of a tank lined with mirrors and recording over a 5 min period its self-viewing approaches towards the mirrors using the left or right eye. Mock-injected larvae showed no population bias in eye use (nZ50; one-sample t-test against 50%, t49Z0.277, pZ0.78; figure 4c). Transgenic larvae injected with spaw MO (nZ200, 50 for each anatomical class; figure 4b) also did not exhibit statistically significant differences in eye use upon mirror image viewing (F3,199Z2.03, pZ0.11). To confirm this finding, we also examined uninjected transgenic larvae, screening through several thousands to identify the small number that showed spontaneous parapineal reversals Phil. Trans. R. Soc. B (2009)

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(refer to figure 1e). As a group, neither R ppL pa (nZ28) nor R ppR pa (nZ37) larvae showed an eye preference in the mirror test and their viewing behaviour was indistinguishable from transgenic siblings with normal L ppR pa (nZ53) orientation (F2,117Z1.41, pZ0.25; figure 4c). In every control or experimental larval class, a subset did in fact show a left or right eye preference in mirror approaches (figure 4d,e); however, there was no consistent bias at the population level. While L–R eye use was measured over the entire 5 min period, larval viewing behaviours were also quantified during each 1 min interval, as previous work had suggested that larvae can shift their L–R preference over the course of testing (Barth et al. 2005; Sovrano & Andrew 2006). In a minuteby-minute analysis, L pp and R pp larvae also failed to exhibit a significant difference in L–R eye preference (figure 4f; interaction between time in minutes and laterality, F4,724Z1.23, pZ0.3). 6. PARAPINEAL REVERSED LARVAE EXHIBIT NAVIGATIONAL DELAY AND REDUCED EXPLORATION In the course of executing the mirror test, we observed that larvae with the right parapineal configuration showed a significant lag in the onset of navigation (Kruskal–Wallis test, c23Z64.65, p!0.001; figure 5a). The onset was defined as the time that elapsed between the introduction of a larva into the testing chamber and its swimming a distance comparable to twice its body length. Swimming delay was unrelated to positioning of the viscera, as both R ppL pa and R ppR pa larvae had a pronounced lag of 66.6G9.2 and 54.9G7.68 s, respectively, compared to 13.5G2.5 s for L ppR pa, 14.9G3.7 s for L ppL pa and 4.67G1.05 for the mockinjected L ppR pa group. Analyses of transgenic larvae with spontaneous parapineal reversals provided further support for a correlation with delayed navigational behaviour. Spontaneous R ppL pa and R ppR pa larvae also showed a significant lag in the onset of navigation compared to their L ppR pa siblings (Kruskal–Wallis test, c22Z45.54, p!0.001; figure 5b). By tracking movements over a 5 min period, we also measured the total distance covered by individual 8 dpf larvae (nZ118, 35 L ppR pa, 33 L ppL pa, 30 R ppR pa, 20 R ppL pa) and their average speed for all swimming episodes. Not only do larvae with parapineal reversals exhibit a navigational delay compared to their left parapineal siblings, but they also cover far less territory (F3,117Z8.15, p%0.001; figure 5d ) and show a reduced average swimming speed (F 3,117Z8.18, p!0.001; figure 5e). This finding was independent of visceral orientation (Scheffe post hoc test, p!0.001). A minute-by-minute analysis of the distance traversed (data not shown) indicates that the altered behaviour of R pp larvae persists throughout the testing period (F19,569Z9.89, p!0.001). 7. DISCUSSION The results from a battery of behavioural tests indicate that the motor responses of larval zebrafish with reversed laterality of the epithalamus and viscera are largely indistinguishable from those of their siblings with the predominant L ppR pa anatomical configuration. Neither

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complete nor partial L–R reversals affect a larva’s ability to react appropriately to acoustic and light stimuli; therefore, modified swimming behaviours cannot be accounted for merely by deficits in sensory processing, motor control or muscle activity. Because all four classes of MO-injected individuals are viable and develop into fertile adults (Long et al. 2003; Gamse et al. 2005), it is unlikely that they harbour severe malformations, such as the vascular abnormalities that are frequently associated with situs defects in mammals (Icardo & Colvee 2001; Peeters & Devriendt 2006). We were concerned that altered visceral asymmetry might compromise swimming ability. However, opposite placement of the pancreas and liver (and presumably reversed directional coiling of the heart and intestines) in close to 50 per cent of larvae derived from spaw MO-injected embryos did not appear to modify spontaneous movements, the frequency or properties of C-bends during startle and escape responses, or the directional turning elicited by sudden changes in light. A probable reason for normal behavioural responses is that, even though the location and morphology of the heart and viscera are L–R reversed, the internal organs do not exhibit abnormal positioning with respect to one another (e.g. situs ambiguous or heterotaxia). For example, at 6 dpf, we never observed larvae that had their liver and pancreas positioned in the same orientation or both organs situated in the midline. In their initial description of spaw-depleted embryos, Long et al. (2003) found uncoupled defects in the directionality of the jogging and looping stages of heart tube morphogenesis, but Phil. Trans. R. Soc. B (2009)

they did not report whether these changes were concordant with L–R positioning of the pancreas or other visceral organs. An unaccounted for observation, however, is that the L ppL pa group was always significantly underrepresented following MO injection. L ppL pa larvae have also not been spontaneously recovered from wild-type populations. There may be an early developmental disadvantage for this configuration compared to the other groups, although this has not been directly determined. We and others had previously shown that the position of the parapineal is tightly coupled to the directional asymmetry of the paired habenular nuclei, including differences in their size, amount of dense neuropil, gene expression and innervation of their shared midbrain target, the IPN (Concha et al. 2000, 2003; Gamse et al. 2003, 2005; Aizawa et al. 2005; Kuan et al. 2007a,b). Thus, reversal of parapineal position, which is typically observed in 2–3% of larvae from wild-type strains, is a readily scored indicator of more pronounced changes in the epithalamus and in epithalamic connectivity. However, whether the position of the parapineal represents directional asymmetry throughout the nervous system in either natural or genetically manipulated populations remains to be demonstrated. It may not be the case that a reversal in parapineal position is indicative of reversed asymmetry throughout the brain or predictive of a corresponding shift in lateralized behaviours. Indeed, L–R reversed fsi larvae also exhibited some lateralized behaviours with normal directionality (Barth et al. 2005; Andrew 2006).

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Figure 4. Larval populations do not show consistent eye preference in the mirror test. (a) The mirror test is conducted in a rectangular tank (10!4 cm) with two mirrors as the longer walls and two white screens as the shorter walls. The tank contains 288C water at a depth of 3 cm, is evenly illuminated by overhanging 15 W fluorescent lamps and can be monitored in its entirety by a video camera suspended above the apparatus. Measurements of L–R eye use are confined to the lateral monocular visual field and scored by a larva’s body position with respect to the closest mirror at 1 s intervals. Larvae in the 10 mm wide central area of the testing chamber (shaded in light grey) or at angles of either 08 or more than 908 with respect to the mirror are not scored. The frequency of right-eye use was calculated as (frequency of right-eye use)/(frequency of right-eye useCfrequency of left–eye use)!100. Analysis of variance was carried out using SPSS v. 16.0 (SPSS Inc., Chicago, IL) to detect significant differences between anatomical classes. Mean and standard deviation of right eye use in (b) spaw MO-injected, (c) mock-injected and spontaneous anatomical larval groups. L ppL pa larvae were not found spontaneously from transgenic intercross progeny (refer to figure 1). (d ) Percentage of spaw MO-injected larvae showing a statistically significant bias (left or right) or no bias in eye use for each anatomical group. For every individual, the statistical significance of eye use was determined by a chi-squared test at a level of 5%. (e) Percentage of larvae showing a statistically significant bias (left or right) or no bias in eye use for mock-injected and uninjected spontaneous anatomical larval groups, calculated as in (d ) (white bars, left bias; grey bars, right bias; black bars, no bias). ( f ) Mean and standard error of eye use during each minute of viewing by spaw MO-injected larvae with a left (nZ65) or right (nZ85) positioned parapineal (grey squares, left parapineal; black squares, right parapineal).

Although previous studies have indicated that adult and larval zebrafish as well as many other teleost species exhibit a left eye bias upon self-viewing (Sovrano et al. 1999, 2001; De Santi et al. 2001; Watkins et al. 2004), we recorded no baseline difference in eye preference in the doubly transgenic larvae used in this study. Analyses of L pp and R pp larvae from the fsi strain Phil. Trans. R. Soc. B (2009)

indicated that they exhibited opposite eye preference upon mirror viewing and an inverse shift in eye preference occurred over time in both groups (Barth et al. 2005). We did not find evidence for similar population biases in eye use for any of the spaw MO-injected groups. Moreover, transgenic larvae we collected that showed spontaneous parapineal reversals

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Figure 5. Larvae with reversed epithalamic asymmetry show altered navigational behaviour. (a) Mean and standard error of the elapsed time (in seconds) before a larva moves a distance equivalent to twice its body length in spaw MO-injected larvae. Differences between the four classes were calculated using the Kruskal–Wallis test (p!0.001). (b) Mean and standard error of the onset of navigation behaviour in mock-injected or uninjected L ppR pa and uninjected R ppR pa and R ppL pa larvae. Spontaneous L ppL pa larvae were not recovered. Differences between the three classes were calculated using the Kruskal–Wallis test (p!0.001). (c) Representative swim paths of two spaw MO-injected larvae over 5 min. Swimming behaviour was recorded to videotape (30 frames sK1) and was subsequently digitized. Video processing and analysis were performed using MATLAB (The MathWorks, Natick, MA). Larval position is indicated by an open circle at the start, and a black square at the end of recording ((i) left parapineal and (ii) right parapineal). (d ) Mean and standard deviation of the total distance covered (in mm) over a 5 min period starting from the first movement of individual spaw MO-injected larvae. Differences between the four classes were calculated using the ANOVA test (p!0.001). (e) Mean and standard deviation of the average speed (mm sK1) for the total swimming episodes of spaw MO-injected larvae. Differences between the four classes were calculated using the ANOVA test (p!0.001).

also did not demonstrate a statistically significant bias in L–R eye preference. In addition, we have not observed other behavioural asymmetries during responses to a variety of directional and non-directional stimuli. A simple explanation for these apparently conflicting results is the existence of variability between zebrafish strains. The transgenic lines used in this study have complex genetic backgrounds, as they were initially produced in undefined fish strains (Wan et al. 2006) or in the golden pigment mutant (Gilmour et al. 2002), and maintained in our aquatics facility through outcrosses to the Oregon AB line ( Walker 1999), followed by intercrosses to preserve transgene homozygosity. Behavioural differences between strains of zebrafish have been previously observed in the mirror test (Sovrano & Andrew 2006; Andrew et al. in press), and could explain why we did not obtain evidence for consistent eye preference at the population level. The fact that some individuals in all laterality groups did demonstrate a left or right bias indicates that our testing paradigm for self-image viewing was a robust assay and was unlikely to be the source of the observed discrepancy between our results and prior work. Not only do strain differences exist in L–R eye preference, but it has also been Phil. Trans. R. Soc. B (2009)

suggested that single larvae modify their eye use for self-viewing during the course of a testing session, as their familiarity with the apparatus and visual stimuli increases. However, we did not find evidence for minute-by-minute changes in eye preference for any of the anatomical classes tested. Another possible explanation for the differences observed between studies is that zebrafish larvae identified fortuitously in control populations, from strains with an enhanced predisposition for L–R reversals (Barth et al. 2005), or following genetic manipulations such as spaw MO injection, may not be morphologically identical. While this hypothesis cannot be ruled out, we do not favour it, as R pp larvae showed very similar viewing behaviour irrespective of their derivation from injected or uninjected transgenic embryos. Moreover, spaw expression is restricted to the caudal region and left lateral plate mesoderm of developing embryos and has not been detected in the nervous system (Long et al. 2003). It is therefore unlikely that the spaw antisense MO would directly perturb brain development outside of its effect on L–R determination. Similarly, the fsi strain has only been described as increasing the frequency of concordant

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Function of zebrafish epithalamic asymmetry visceral and epithalamic reversals and has not been associated with other developmental defects (Barth et al. 2005). The ability to generate large numbers of parapineal-reversed larvae using spaw MO should enable strain differences in mirror image viewing to be examined more rigorously and, perhaps, in parallel with tests on individuals from the fsi strain. In our study, all larval groups displayed similar responsiveness and kinematics in tests for motor responses. Thus, it may appear contradictory that R pp larvae showed a delay in the onset of movement and reduced overall swimming in the mirror test. However, there are important operational differences between these behavioural assays. Testing of rapid kinematic responses to acute stimuli is performed simultaneously on small groups of larvae in a preadapted environment. The mirror testing chamber provides an unfamiliar environment, one in which individually assayed larvae repeatedly encounter their reflection and have an increased area to explore. We propose that these differences account for the behavioural response, in that a R pp larva, while possessing normal motor reactivity, appears less motivated or more fearful to initiate exploration in a novel environment. Recent work in mammals has uncovered an interesting link between the habenular region and control of the dopaminergic mesolimbic pathway that mediates fear, motivation and reward (Heldt & Ressler 2006; Morissette & Boye 2008). Specifically, the lateral habenula nucleus was found to provide inhibitory signals to dopaminergic neurons in the ventral midbrain (Matsumoto & Hikosaka 2007). Midbrain dopaminergic neurons in turn send input to the limbic system and, notably, to the amygdala and nucleus accumbens, brain areas implicated in fear and reward (Di Chiara & Bassareo 2007; LeDoux 2007). The lateral habenular nuclei also receive substantial dopaminergic input, suggesting a further level of crossregulation (Gruber et al. 2007). Zebrafish seem to lack structures equivalent to the lateral habenula (Concha & Wilson 2001); however, as in other recent studies, comparative gene expression analyses may identify brain regions that are functionally homologous with mammals ( Wullimann & Rink 2002; Mueller et al. 2008). Moreover, there is recent evidence from rats that the medial habenula and IPN are also involved in modulating the dopaminergic pathway ( Taraschenko et al. 2007a,b). Intriguingly, the firing rates of neurons in the medial and lateral habenulae, as well as the IPN, closely correspond with locomotor activity in rats (Sharp et al. 2006). In zebrafish, a mesolimbic-like circuit is present in larvae and adults, although there are some differences in the location of dopaminergic neurons (Rink & Wullimann 2002). Pharmacological studies have also implicated dopamine in the control of larval locomotor activity (Giacomini et al. 2006; Boehmler et al. 2007; Thirumalai & Cline 2008). It will be of great interest to examine whether the altered exploratory behaviour of parapineal-reversed larvae is caused by changes in the differentiation, connectivity or function of dopaminergic neurons. However, why L–R reversal of habenular identity and efferent projections to the dorsal and Phil. Trans. R. Soc. B (2009)

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ventral IPN would disrupt this proposed modulatory function is unclear. In addition to modulating the dopaminergic pathway, the habenulo-interpeduncular system has been implicated in regulating monoaminergic and cholinergic transmission in the mammalian brain, and in functions as diverse as olfaction, feeding, mating, nociception, attention, sleep/wake cycling, stress, fear and learning (reviewed in Sutherland 1982; Klemm 2004; LeCourtier & Kelly 2007). To assess behavioural impact, lesioning of the habenulae in rats or mice is typically performed, but experimental approaches often do not discriminate between the medial and lateral habenular nuclei or take their complex subnuclear organization into account. Notwithstanding these caveats, impairments in attention, learning and memory have been widely documented. For instance, habenularlesioned animals have difficulty in learning conditioned avoidance to aversive stimuli (Rausch & Long 1974) and show a marked increase in premature responses (Sasaki et al. 1990). Following habenular lesions, rats also respond prematurely in a spatial learning paradigm, suggesting that behaviour becomes more impulsive (LeCourtier & Kelly 2005). In some cognitive assays, the effect of habenular loss is enhanced if stress levels are increased (Thornton & Bradbury 1989; Heldt & Ressler 2006). There is also evidence that habenular neurons respond to retinal illumination and may serve to link circadian and motivational pathways in the brain (Zhao & Rusak 2005). An essential goal for future studies in the zebrafish will be to learn more about the targets of the IPN and how L–R reversal of habenular connections with the IPN might influence neuronal activity elsewhere in the brain. Although the habenulo-IPN projection is highly conserved across vertebrates (Sutherland 1982; Concha & Wilson 2001), knowledge of its integration with other conduction systems is lacking. Without this information, it will remain a challenge to understand why epithalamic laterality evolved and persisted in fishes, amphibians and reptiles. In addition, even though pineal-associated structures and the habenulae are asymmetric in these species (Concha & Wilson 2001), only fishes seem to exhibit differential innervation of the dorsal and ventral IPN by left and right habenular neurons (Kuan et al. 2007a,b). A further mystery is why morphological differences between the left and right habenular nuclei are rarely found in mammals (Sutherland 1982), suggesting that functional specialization of this part of the brain may be more important for aquatic species. While the behaviours associated with epithalamic L–R asymmetry may prove more complicated and variable than previously appreciated, the zebrafish model has emerged as a valuable system for genetic manipulation of asymmetry, analyses of neuroanatomical development and connectivity and the application of diverse functional assays to tackle this exciting problem. Protocols for use of zebrafish were approved by the Institutional Animal Care and Use Committee of the Carnegie Institution Department of Embryology. This work was supported in part by an NRSA postdoctoral fellowship to H.A.B. and grants to M.G. from the National

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Institutes of Health (MH075691 and HD 37975). L.F. and M.E.H. gratefully acknowledge funds from the Eppley Foundation for Research, which partially supported this study. We thank Michelle Macurak and Lea Fortuno for technical assistance, Brian Hollenback and Nicole Gabriel for animal care, Allen Strause for manufacturing testing chambers, Fouad Siddiqi for assistance with MATLAB, and Courtney Akitake and Mary Goll for their help with figure 1. We also thank Steve Leach ( Johns Hopkins Medical Institutions, Baltimore) and Darren Gilmour (European Molecular Biology Laboratory, Heidelberg) for generously providing transgenic zebrafish lines.

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. number 1519 . pages 853–1032

Mechanisms and functions of brain and behavioural asymmetries Papers of a Theme Issue compiled and edited by Luca Tommasi Introduction Mechanisms and functions of brain and behavioural asymmetries L. Tommasi

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Articles Intraspecific competition and coordination in the evolution of lateralization S. Ghirlanda, E. Frasnelli & G. Vallortigara

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The evolution and genetics of cerebral asymmetry M. C. Corballis

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Why are some people left-handed? An evolutionary perspective V. Llaurens, M. Raymond & C. Faurie

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Asymmetries of the human social brain in the visual, auditory and chemical modalities A. Brancucci, G. Lucci, A. Mazzatenta & L. Tommasi

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Epigenesis of behavioural lateralization in humans and other animals S. M. Schaafsma, B. J. Riedstra, K. A. Pfannkuche, A. Bouma & T. G. G. Groothuis

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Hand and paw preferences in relation to the lateralized brain L. J. Rogers

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Ascending and descending mechanisms of visual lateralization in pigeons C.-E. Valencia-Alfonso, J. Verhaal & O. Güntürkün

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Lateralization of social cognition in the domestic chicken (Gallus gallus) J. N. Daisley, E. Mascalzoni, O. Rosa-Salva, R. Rugani & L. Regolin

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Light during embryonic development modulates patterns of lateralization strongly and similarly in both zebrafish and chick R. J. Andrew, D. Osorio & S. Budaev Zebrafish and medaka: model organisms for a comparative developmental approach of brain asymmetry I. A. Signore, N. Guerrero, F. Loosli, A. Colombo, A. Villalón, J. Wittbrodt & M. L. Concha

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The habenular nuclei: a conserved asymmetric relay station in the vertebrate brain I. H. Bianco & S. W. Wilson

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Determining the function of zebrafish epithalamic asymmetry L. Facchin, H. A. Burgess, M. Siddiqi, M. Granato & M. E. Halpern

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Mechanisms and functions of brain and behavioural asymmetries

Does testosterone affect lateralization of brain and behaviour? A meta-analysis in humans and other animal species K. A. Pfannkuche, A. Bouma & T. G. G. Groothuis

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volume 364

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Mechanisms and functions of brain and behavioural asymmetries Papers of a Theme Issue compiled and edited by Luca Tommasi

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12 April 2009