Origin and evolution of the vertebrate telencephalon, with special reference to the mammalian neocortex

193 Advances in Anatomy Embryology and Cell Biology

Editors F. F. Beck, Melbourne · F. Clascá, Madrid M. Frotscher, Freiburg · D. E. Haines, Jackson H.-W. Korf, Frankfurt · E. Marani, Enschede R. Putz, München · Y. Sano, Kyoto T. H. Schiebler, Würzburg

Reviews and critical articles covering the entire field of normal anatomy (cytology, histology, cyto- and histochemistry, electron microscopy, macroscopy, experimental morphology and embryology and comparative anatomy) are published in Advances in Anatomy, Embryology and Cell Biology. Papers dealing with anthropology and clinical morphology that aim to encourage cooperation between anatomy and related disciplines will also be accepted. Papers are normally commissioned. Original papers and communications may be submitted and will be considered for publication provided they meet the requirements of a review article and thus fit into the scope of “Advances”. English language is preferred. It is a fundamental condition that submitted manuscripts have not been and will not simultaneously be submitted or published elsewhere. With the acceptance of a manuscript for publication, the publisher acquires full and exclusive copyright for all languages and countries. Twenty-five copies of each paper are supplied free of charge.

Manuscripts should be addressed to Prof. Dr. F. BECK, Howard Florey Institute, University of Melbourne, Parkville, 3000 Melbourne, Victoria, Australia e-mail: [email protected] Prof. Dr. F. CLASCÁ, Department of Anatomy, Histology and Neurobiology, Universidad Autónoma de Madrid, Ave. Arzobispo Morcillo s/n, 28029 Madrid, Spain e-mail: [email protected] Prof. Dr. M. FROTSCHER, Institut für Anatomie und Zellbiologie, Abteilung für Neuroanatomie, Albert-Ludwigs-Universität Freiburg, Albertstr. 17, 79001 Freiburg, Germany e-mail: [email protected] Prof. Dr. D. E. HAINES, Ph.D., Department of Anatomy, The University of Mississippi Med. Ctr., 2500 North State Street, Jackson, MS 39216-4505, USA e-mail: [email protected] Prof. Dr. H.-W. KORF, Zentrum der Morphologie, Universität Frankfurt, Theodor-Stern Kai 7, 60595 Frankfurt/Main, Germany e-mail: [email protected] Prof. Dr. E. MARANI, Department Biomedical Signal and Systems, University Twente, P.O. Box 217, 7500 AE Enschede, The Netherlands e-mail: [email protected] Prof. Dr. R. PUTZ, Anatomische Anstalt der Universität München, Lehrstuhl Anatomie I, Pettenkoferstr. 11, 80336 München, Germany e-mail: [email protected] Prof. Dr. Dr. h.c. Y. SANO, Department of Anatomy, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, 602 Kyoto, Japan Prof. Dr. Dr. h.c. T.H. SCHIEBLER, Anatomisches Institut der Universität, Koellikerstraße 6, 97070 Würzburg, Germany

F. Aboitiz · J. Montiel

Origin and Evolution of the Vertebrate Telencephalon, with Special Reference to the Mammalian Neocortex

With 15 Figures

123

Francisco Aboitiz, Dr. Departamento de Psiquiatría Escuela de Medicina Pontificia Universidad Católica de Chile Santiago Chile e-mail: [email protected] Juan Montiel, Dr. Facultad de Ciencias de la Salud Universidad Diego Portales Santiago Chile

ISSN 0301-5556 ISBN 978-3-540-49760-8 Springer Berlin Heidelberg New York

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List of Contents

1

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2 2.1 2.1.1 2.1.2 2.1.3 2.2 2.2.1 2.2.2 2.2.3 2.2.4 2.2.5 2.3 2.3.1 2.3.2 2.3.3

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2.3.4 2.3.5

Evolution of the Vertebrate Nervous System and Telencephalon . . . . . . . . Animal Phylogenetic Relationships . . . . . . . . . . . . . . . . . . . . . . . . . . . . Origin and Diversification of Metazoans . . . . . . . . . . . . . . . . . . . . . . . . Phylogenetic Origins of the Nervous System . . . . . . . . . . . . . . . . . . . . . . Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Origin of Vertebrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Early Theories and Fossil Evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Neural Crest and Placodes in Vertebrate Origins . . . . . . . . . . . . . . . Olfactory Placode and Epithelium: Association with Adenohypophysis . . . Origin of the Telencephalon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Evolution of the Telencephalon in Vertebrates . . . . . . . . . . . . . . . . . . . . Taxonomical Relationships Among Vertebrates and Their Early Evolution . Evolution of the Cerebral Hemispheres: Ventral Telencephalon . . . . . . . . The Brain of Jawless Fishes and the Organization of the Ancestral Dorsal Telencephalon . . . . . . . . . . . . . . . . . . . . . . . . . . The Pallium in Jawed Vertebrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3 3.1 3.1.1 3.1.2 3.2 3.2.1 3.2.2 3.2.3 3.2.4 3.2.5 3.2.6 3.3 3.3.1 3.3.2 3.3.3 3.4

Origin of the Mammalian Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The First Mammals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Fossil Mammals and Their Brains . . . . . . . . . . . . . . . . . . . . . . . . . . . . Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Origin of the Mammalian Neocortex: Hypotheses on Homology . . . . . . Mammalian Brain Expansion and the Origin of the Neocortex . . . . . . . . Hypotheses for Neocortical Origins . . . . . . . . . . . . . . . . . . . . . . . . . . . The Recapitulation Hypothesis: Connectional Evidence . . . . . . . . . . . . The Dorsal Cortex of Reptiles: Subicular and Neocortical Characteristics Differences in Connectivity Between the DVR and the Neocortex . . . . . . Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Embryological Evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Developmental Criteria for Homology . . . . . . . . . . . . . . . . . . . . . . . . . Dorsoventral Gradients and Expansion of the Dorsal Pallium . . . . . . . . . Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Olfactory–Hippocampal Hypothesis . . . . . . . . . . . . . . . . . . . . . . .

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34 35 35 38 38 38 39 40 41 43 46 47 47 52 53 54

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VI 3.4.1

List of Contents

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54 58 59 59

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3.5.6 3.6 3.6.1 3.6.2

A Functional Interpretation of Dorsal Pallial Expansion in Mammalian Origins . . . . . . . . . . . . . . . . . . . . . . . . . . . . Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Origin of Neocortical Lamination . . . . . . . . . . . . . . . . . . . . Laminar Organization of the Neocortex . . . . . . . . . . . . . . . . Comparison of Mammalian Neocortex and Reptilian Cortex: Layer Homologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Is There a Preplate in Reptiles? . . . . . . . . . . . . . . . . . . . . . . Origin of the Inside-out Developmental Gradient . . . . . . . . . Pioneer Neurons and the Transition from a Tangential to a Radial Synaptic Organization in the Neocortex . . . . . . . . Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Expansion of the Neocortex . . . . . . . . . . . . . . . . . . . . . . . . Multiplication of Cortical Areas . . . . . . . . . . . . . . . . . . . . . Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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66 67 68 68 71

4 4.1 4.1.1 4.1.2 4.1.3 4.1.4 4.1.5 4.1.6 4.2 4.2.1 4.2.2 4.2.3 4.2.4 4.3

Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . An Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Early Neuronal Differentiation . . . . . . . . . . . . . . . . . . . . . Patterning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diversification of the Hemispheres and Neocortical Origins . Olfaction, the Hippocampus and the Amygdala . . . . . . . . . Cortical Lamination . . . . . . . . . . . . . . . . . . . . . . . . . . . . Tangential Expansion and the Origin of New Areas . . . . . . . Issues with Evolutionary Theory . . . . . . . . . . . . . . . . . . . . Genetic Conservatism Versus Morphological Diversity . . . . Development as a Clue to Evolution . . . . . . . . . . . . . . . . . . Developmental Processes and Homology Criteria . . . . . . . . Development, Adaptation, and Behavior . . . . . . . . . . . . . . Final Comments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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71 71 71 72 74 75 75 77 77 77 78 79 81 83

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

85

3.4.2 3.5 3.5.1 3.5.2 3.5.3 3.5.4 3.5.5

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Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113

Acknowledgements

Some of the results presented in this work have been financed by the Millenium Nucleus for Integrative Neuroscience.

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Introduction

1

1 Introduction There is little doubt that the vertebrate brain is the most complex structure we know. As with any complex structure, there is the immediate question about its origins. How could such a complex design develop from the simplest multicellular animals? This problem has pervaded the study of evolutionary biology since its beginnings. Although Darwin (1859, 1871) proposed an impeccable mechanism (natural selection) for the gradual transformation of species including human origins, even he sometimes expressed certain doubts about the origin of highly complex structures. This issue has been highly debated both within science and outside it. For instance, a rebirth of the old religious argument of intelligent design has gained unexpected strength in the last few years. In essence, this argument follows Paley’s (1802) claim that if we find a clock that has been thrown away we cannot consider that it was created on its own, but rather has to be the consequence of conscious design. Today, creationists have developed a modern version of this argument, that of “intelligent information” (Denton 2002). For example, after sequencing the human genome in 2001, one of Celera Genomics top computer scientists claimed that this complexity suggested design. Although he clarified not to be thinking of God, he asserted that “there’s a huge intelligence there” (quoted in Witham 2002, p 9). As Witham (2002) says, modern computer-literate believers may soon ask the question of whether the universe is self-running or functioning on DOS, a Divine Operating System. In this volume, we have decided to tackle the problem of the origin and evolution of the vertebrate brain, from the simplest nervous system-like elements that we can observe in nature. In doing so, we expect to establish a continuity between the simplest stages and the elaboration of the highly intricate neuronal network that is the mammalian cerebral cortex. For lack of space, we will have to leave aside several other brain structures such as the basal ganglia or the cerebellum, as well as components perhaps comparable to the mammalian cerebral cortex in other vertebrates; as will be seen, the cerebral cortex alone is sufficient to fill up quite an extensive review. Our main point will be to present a case for continuous evolutionary transformation of the central nervous system, from its very origins to the elaboration of the most complex structure that exists on earth. In order to pursue our goal, we will have to discuss some basic concepts of neuroanatomy, embryology, and developmental genetics. This knowledge was unavailable in Darwin’s time, which further emphasizes his genius. We will follow an approach that has been termed developmental evolutionary genetics, which seeks to establish a correspondence between embryological processes and the phylogenetic history of an organism. In other words, if we observe continuity in development between a fertilized egg and an adult brain, we should also expect continuity in its evolutionary history. This approach is not new; its roots can be found in Von Baer’s biogenetic law (Von Baer 1828; see also Gould 1977), stating that embryos start from a general condition (the unicellular egg), shared by all

2

Introduction

animals, and during development they progressively acquire characters that include them in successively restricted taxonomical groups. That is, if at early stages all embryos are similar among them, they subsequently develop characters that define them as say, vertebrates, then mammals, then primates and then as humans. This view was further expressed in a more extreme version by Haeckel (1892), who considered both evolution and development as a linear chain, embryology recapitulating the phylogenetic history of the animal. Thus, the human embryo passed through stages in which it was first a unicellular organism, then an undifferentiated metazoan (morula), then a jellyfish (gastrula), then a fish, then a tailed reptile and so on until he or she became a human. Modern understanding of these hypotheses acknowledges that in fact, early embryos are readily distinguishable among them, and that human embryos are human embryos during all development; they do not pass from a jellyfish stage to a fish stage and so on (Garstang 1922; Gould 1977; Richardson et al. 1997). However, it is also recognized that embryos pass through successive stages in which they acquire the characteristics proper to each of the nested phylogenetic categories to which they belong. Thus, there is a general concordance between embryonic stages and the phylogenetic history. Recent expressions of this approach have taken the name of “evo-devo” (from evolution and development) and have been particularly fruitful after the rise of molecular embryology. This discipline has revealed an exquisite correspondence in the molecular mechanisms underlying similar embryonic processes in a wide group of animals, which nevertheless appear quite diverse in their superficial morphology (McGinnis and Krumlauf 1992; Gerhart and Kirschner 1997; Martindale 2005; Pearson et al. 2005). Furthermore, the bulk of comparative molecular and embryological evidence strongly points toward a relatively conserved embryonic stage (the zootype) that corresponds to the establishment of the taxonomic group’s body plan (Slack et al. 1993). In the case of vertebrates, this corresponds to the point in which the embryo develops the pharyngeal pouches: the pharyngula stage. Thus, there is high diversity in early developmental processes (mainly due to species differences in yolk content and early embryonic adaptations), followed by a convergence in structure at mid-developmental stages, in order to diverge again as development proceeds toward the adult state. Interestingly, the expression of specific and highly conserved regulatory genes (homeobox and related genes) takes place in this converging embryonic stage and participates in patterning the embryo’s body plan. Homeobox (Hox) and related genes have been found to be fundamental in anteroposterior patterning in vertebrates, in the fruit fly Drosophila and in other animal groups, indicating that they represent quite an ancient developmental regulatory system (McGinnis and Krumlauf 1992; Krumlauf 1992; García-Fernández and Holland 1994; Martindale 2005; Pearson et al. 2005; García-Fernández 2005). In a way, this evidence has produced a turn back to the times of the preevolutionary concepts of Transcendental Anatomy, in which the architectural body plans were considered to be established by divine intervention; diversity in design was only the result of variations within a theme, due to adaptations to contingent

Introduction

3

circumstances. This perspective considered adaptation as a constant, universal feature of living beings. The advent of evolutionary theory, putting its focus on diversity rather than on common organization and emphasizing that adaptation was variable, related to successful reproduction, relegated this perspective to a second plane for quite a long time (Desmond 1982). As said, the discovery of a common genetic organization in the body of most animals has produced a strong shift of emphasis into the commonality of type again, this time observed under the light of evolutionary theory. We will pursue an evo-devo view to the phylogenetic history of the brain, showing which genetic processes are shared with other, nonvertebrate animals to underline the genetic conservatism of morphological evolution; but will also put emphasis on the dramatic morphological diversification that has taken place during evolution. It appears that, even given a relatively fixed genetic battery, developmental morphology has taken quite different courses in the different lineages, possibly related to the specific circumstances in which characters have been acquired. Thus, we also intend to emphasize the behavior and way of living of the ancestral organisms, in order to provide an integrated view of the specific conditions that led to the divergence of the distinct lineages. An important theme to be discussed in this section relates to the concept of homology. We will need to compare structures in different species and will have to determine whether they are or not comparable structures. There are many (perhaps too many) criteria to determine the homology between two organs, and as expected they do not always agree. In one particular instance, the origin of the neocortex from a reptilian-like brain, this issue has been highly controversial in the last few years. As the evidence to date indicates strong genetic conservatism with morphological diversification, we have relied on genetic criteria to determine the structure that most likely gave rise to the mammalian neocortex. In general, we will address this issue in the context of a conserved structural organization of the vertebrate brain. As in the concept of the zootype expressed above, in vertebrate brains there is a stage of convergence at about the same developmental stage. For example, a proposal for a neuronal zootype has been recently outlined, considering the basic embryonic elements that determine the organization of the vertebrate brain (Deutsch and le Guyader 1998). However, long before these authors, Bergquist and Källén (1953a,b; 1954) established in the mid1900s that all vertebrate brains at the pharyngula stage have a similarly organized brain, divisible into a series of transverse domains visible as periodic thickenings of the anterior neural tube, which they termed neuromeres. These thickenings were proposed to be centers of proliferative activity, separated by regions where cell division occurs more slowly. Although this view was neglected for a long time, recent studies have confirmed the presence of seven neuromeres in the hindbrain or rhombencephalon (rhombomeres), one in the midbrain (mesomere) and six in the forebrain (prosomeres) (Shimamura et al. 1997; Wilkinson et al. 1989; Fraser et al. 1990; Lumsden 1990; Rubenstein et al. 1994; Puelles and Rubenstein 1993, 2003; Puelles 1995). Furthermore, it was found that the expression boundaries of different Hox genes were largely coincident with the rhombomeric segmentation pattern

4

Introduction

and were highly conserved across vertebrate species (Wilkinson and Krumlauf 1990; Nieto et al. 1991; Kimmel 1993). In the more anterior prosencephalon, which is of more immediate interest to us, evidence for segmentation was for some time difficult to obtain. However, analyzing the expression domains of several transcription factors that were activated in the developing forebrain, Puelles and Rubenstein (1993, 2003) determined that there was a nice fit with Bergquist and Källén’s description of prosomeric segments, which is again largely conserved across vertebrates. While in the prosomeres there is no expression of Hox genes, several homeodomain proteins are expressed, which perform a similar role to that of Hox gene clusters in more caudal segments. For example, genes of the Dlx and the Emx (Emx1 and Emx2) families are respectively expressed in the ventral telencephalon (subpallium) and the dorsal telencephalon (pallium). Dlx genes are closely related to Hox genes (they appear to belong to the same cluster) and are homologs to the Drosophila gene distal-less (Dll), expressed in the embryonic imaginal disks (Panganiban 2000). The linkage between Dlx and Hox genes also exists in invertebrates such as the nematode, suggesting that the primordial Dlx and Hox genes were similarly linked. Importantly, in vertebrate origins there were two duplications of the Dlx-Hox cluster (Digregorio et al. 1995; Stock et al. 1996). On the other hand, Emx genes are orthologs of the Drosophila gene empty spiracles (ems), responsible for the formation of head segments (Dalton et al. 1989; Walldorf and Gehring 1992; Hirth et al. 1995). Puelles and Rubenstein’s (1993, 2003) prosomeric model has faced some criticisms such as the evidence of cell migration across prosomere borders (but not across rhombomere borders), the fact that early patterns of gene expression may be quite dynamic and a static picture like the one presented does not capture this dimension, or the possibility that the authors have disregarded evidence that does not support the model (for review see Striedter 2005). However, comparative evidence has determined that this pattern is highly conserved across vertebrates (it is observed not only in mammals and birds, where it was first reported, but also in teleosts and agnathans; Wulllimann and Puelles 1999; Pombal and Puelles 1999), which strongly suggests that it reflects a phylogenetically stable framework that can be of great utility in species comparisons. Before starting with our analysis, it will be useful to recall some basic concepts of neuroanatomy and embryology. In the early embryo, the central nervous system (CNS) originates from a flat neural plate in the dorsal aspect of the animal, after the action of inductive signals from the mesoderm. In a process called neurulation, this plate develops into a hollow neural tube. Eventually, this tube widens in the cephalic region, forming three main vesicles, from caudal to rostral, the rhombencephalon or hindbrain, the mesencephalon or midbrain, and the prosencephalon or forebrain (Fig. 1). The latter subdivides into a diencephalon and two telencephalic vesicles (the cerebral hemispheres) that contain the future olfactory bulbs, the cerebral cortex and the basal ganglia, among other structures. The cerebral hemispheres have been classically subdivided into a pallium located dorsally and a ventral subpallium (basal ganglia), both separated by the corticostriatal sulcus

Introduction

5

Fig. 1 Early development of the mammalian forebrain. Initially, the forebrain is subdivided into three main components, the segmented rhombencephalon (R); the mesencephalon (M) that contains the main sensory structures in nonmammals; and the prosencephalon, which is later partitioned into a diencephalon (D) and a telencephalon (Tel). E, eye; ON, optic nerve

or pallial-subpallial boundary in the ventricle at the equatorial level of the vesicle (Fig. 2). In the subpallium, the basal ganglia (involved in motor functions) develop in the lateral side from two structures that protrude into the ventricle: the medial and the lateral ganglionic eminences. On the other hand, the pallium has been subdivided into a medial part (giving rise to the hippocampal formation), a dorsal part (giving rise to the neocortex or isocortex), and a lateral part (giving rise to the olfactory cortex), which is connected anteriorly to the olfactory bulb. Although in the adult stage all these are cortical layered structures, the neocortex is different from the olfactory or lateral cortex and from the hippocampus or medial cortex in having six cellular laminae composing it, while the other two structures bear only three laminae. In the border between pallium and subpallium, several structures

6

Introduction

Fig. 2 Main components of the developing mammalian telencephalon. The telencephalic hemispheres consist of a ventral part or subpallium, separated from the pallium by a pallial– subpallial boundary (PSPB). The medial ganglionic eminence (MGE) and the lateral ganglionic eminence (LGE) differentiate in the subpallium and give rise to the globus pallidus (GP) and corpus striatum (CS), respectively. These structures produce inhibitory interneurons for most pallial regions. The pallium consists of a medial pallium (MP) that gives rise to the hippocampal formation (HP), a dorsal pallium (DP) giving rise to the neocortex (NC), a lateral pallium (LP) giving rise to the olfactory cortex (OC), and finally a ventral pallial (VP) territory producing part of the claustroamygdalar complex (AM). In its medialmost aspect, the pallium is bordered by an embryonic structure termed the cortical hem (CH), which separates the medial pallium from the choroid plexus (ChP) that differentiates from the roof plate

develop that collectively make up the so-called cerebral amygdala and other structures, containing both pallial and subpallial elements. Recent analyses have shown that in this region an additional embryonic pallial element is distinguishable (the ventral pallium). In the developing brain vesicle, as in the rest of the neural tube, cell proliferation takes place in the inner walls, lining the ventricular cavity (the ventricular and subventricular zones). Then, immature neurons migrate radially out to make up distinct brain nuclei. In the cerebral cortex, this migration process makes a long journey to establish a mantle of gray matter in the periphery of the pallium. However, there is also migration of some cells in the tangential direction,

Evolution of the Vertebrate Nervous System and Telencephalon

7

i.e., in a direction parallel to the surface of the neural tube, in which neurons originating in the subpallium move dorsally to populate the cerebral cortex. We will start the second section with a review of the phylogenetic history of the nervous system from the earliest multicellular animals until the appearance and diversification of the vertebrate telencephalon. In this section, we will demonstrate a parallelism between some early embryological processes and the phylogenetic events that took place during the evolution of the nervous system. In the third section, we will discuss the origin of the mammalian brain and the mammalian neocortex. In this part, we will address two main aspects, one concerning the structure in the reptilian brain that gave rise to the neocortex (i.e., its reptilian homolog) and the other concerning the origin of neocortical lamination. Finally, we will discuss all this evidence in the light of current concepts in evolutionary theory. The different sections will discuss a wealth of material, much of which may not be retained in the reader’s mind while he or she goes on to the following sections. In order to make this easier for the reader, each subsection is followed by a brief summary of the main points discussed previously. Likewise, along the article, we will be coming back to points made earlier in order to refresh the reader’s memory.

2 Evolution of the Vertebrate Nervous System and Telencephalon This section discusses the vertebrate brain in a phylogenetic framework. We will first analyze the origin of nervous systems from the simplest metazoans, to continue with the origin of a centralized nervous system with an anterior brain in more advanced multicellular animals. We will discuss the origin of vertebrates, as it is largely marked by the appearance of new tissues related to the neural plate (neural crest and placodes) and by the origin of the telencephalic vesicles, possibly in close relation to the development of the olfactory sense. Then we will provide an overview of vertebrate evolution with special emphasis on the diversification of the telencephalon. 2.1 Animal Phylogenetic Relationships 2.1.1 Origin and Diversification of Metazoans Metazoans (multicellular animals) are subdivided into poriferans (sponges), radiates (ctenophores – comb jellies – and cnidarians – jellyfish), and bilaterian animals, i.e., those with bilateral symmetry. Radiates are the first animals to show true germ layers (and hence gastrulation), and nerve cells. They are sometimes described as adult gastrulas, with an endodermal cavity bearing a single terminal opening, which may be considered as the mouth or anus (Nielsen 2001). However, in some species (especially in ctenophores) there are anal pores through which some

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Evolution of the Vertebrate Nervous System and Telencephalon

waste is expelled (Martindale 2005). Thus, the endodermal opening (comparable to the blastopore during gastrulation) would be more akin to a mouth than to an anus. Bilaterians can be subdivided into protostomes (animals in which, after gastrulation, the blastopore is related to the mouth) and deuterostomes (animals in which the blastopore relates to the anus, and a new mouth is formed). Deuterostomes have been traditionally divided in two clades, the first giving rise to echinoderms (sea urchins and starfish), to the enigmatic worm Xenoturbella (Bourlat et al. 2003), and to a group of marine burrowing worms termed hemichordates (Fig. 3). The latter have several characteristics in common with vertebrates, including a postanal tail, a branchial system with gill slits, an endostyle, a stomochord that has been compared to the chordate notochord, and a hollow neural tube in the collar region of the body (Nielsen 2001). Recently, only the gill slits have been considered to be homologous in hemichordates and vertebrates, and specifically at the level of simple ciliated pores without a branchial skeleton. The other characteristics are claimed to have independently arisen in the two groups (Ruppert 2005). The second clade of deuterostomes has been classically considered to include urochordates, or tunicates, and chordates. The former are a group of sessile animals whose larvae have several characteristics that make them akin to vertebrates such as a dorsal, hollow nerve chord, a notochord, and gill pores. Chordates have all these characteristics in the adult state. They have been subdivided into cephalochordates (exemplified by amphioxus or Branchiostoma, a small, filter-feeding fishlike animal that lives buried in the sand and occasionally swims) and vertebrates or craniates. The main differences between these two groups are that Branchiostoma is devoid of paired appendages, lacks specialized sensory organs, and importantly also lacks any signs of telencephalic cerebral hemispheres, all of which are characteristic of vertebrates. Against this traditional conception, a recent report based on molecular evidence proposes that the group closest to vertebrates are the urochordates (both groups making a new clade, appealingly termed olfactores). On the other hand, cephalochordates appear to be more related to echinoderms and hemichordates, but this is still inconclusive (Delsuc et al. 2006; see Fig. 3). More recently, Bourlat et al. (2006) confirmed the monophyletic clade olfactores, with cephalochordates as a sister group. This proposal is supported by anatomical evidence showing that urochordates have a centralized heart, covered by a pericardium, which resembles the vertebrate heart more closely than the cephalochordate heart, consisting of four peristaltic vessels powered by smooth musculature (Schubert et al. 2006). Below we will see that some neural characteristics also point to a close relationship between urochordates and vertebrates. 2.1.2 Phylogenetic Origins of the Nervous System Phylogenetic evidence suggests that the earliest nervous systems originated in metazoans from diffuse subepidermal plexuses that coordinated contractile mechanisms associated to feeding and locomotion (Willmer 1990). In jellyfish (cnidarians), feeding and locomotion are produced by essentially similar mechanisms.

Animal Phylogenetic Relationships

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Fig. 3 Phylogenetic relations of deuterostomes. According to the most recent phylogenetic analyses, the urochordates (represented by the mobile larval/sessile adult tunicates) are the closest relatives of vertebrates. The position of cephalochordates (represented by amphioxus) has been recently confirmed to be closer to vertebrates and tunicates than to echinoderms. Hemichordates are also related to echinoderms. This evidence supports the concept of a free-living vermiform ancestor for deuterostomes. (Modified from Lacalli 2005, with permission)

At least in three occasions, this plexus has become condensed into a chord at the midline to form a central nervous system (Lowe et al. 2003; Holland 2003). This is consistent with the embryological findings indicating that the default fate of

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Evolution of the Vertebrate Nervous System and Telencephalon

epidermal cells is to become neuronal, and this is blocked by the expression of bone morphogenetic proteins (BMPs, especially BMP-4) from the epidermal cells themselves. The action of inducing factors such as Noggin, Chordin and Follistatin blocks the BMP pathway and permits the differentiation into neuronal phenotypes (Sanes et al. 2006). Genes homologous to the vertebrate neural-inducing factors BMP and chordin have been found in Drosophila as well (decapentaplegic, dpp; and short gastrulation, sog, respectively), which also participate in inductive processes (De Robertis and Sasai 1996; Holley et al. 1995). However, more than participating in neurulation or CNS condensation, the ancestral function of these factors seems to be related to early germ layer specification (Lowe et al. 2006; see below). Nevertheless, the mechanisms of neural specification may be comparable in a wide range of animal groups. In most animals, neurons separate from epithelial cells by delamination and subsequent subepidermal positioning (for review see Sanes et al. 2005). In vertebrates, apart from the internalization that takes place during the formation of the neural tube, there is also a delamination (with subsequent radial migration) of precursor cells that originally line the neurocoele into the walls of the neural tube. Thus, the delamination process may be homologous in invertebrates and vertebrates. Furthermore, the mechanisms for specifying neural phenotypes from a proliferating epithelium seem to be comparable across widely different animal types. In Drosophila, they depend on genetic systems related to the achaete scute proneural family of basic-helix-loop-helix transcription factors (Alonso and Cabrera 1988; Skeath and Carroll 1992). These proneural genes of Drosophila have homologs in vertebrates (Mash1 and other bHLH genes such as those coding for the proteins Neurogenin and NeuroD1), which serve a similar proneural role (Ross et al. 2003). Therefore, germ layer and neural specification processes may be generated by ancestral mechanisms, while neurulation (the formation of a dorsal neural plate and a neural tube) may be conceived as a particular mechanism by which the originally diffuse subepidermal nervous system became condensed in chordate ancestors. In this context, the origin of chordate neurulation has been recently proposed to result from the redistribution of germ layers (especially the presumptive mesoderm) in the blastulae of deuterostomes with respect to protostomes, which resulted in a complete topographic rearrangement of the inductive interactions (Northcutt 2005). An extremely curious observation, originally made by Geoffroy Saint-Hilarie in 1822 (Lowe et al. 2003) is that protostomes not only seem to have a different anteroposterior direction of differentiation (determined by blastopore fate) but also bear their centralized nervous system in a ventral position, while chordates show a dorsal neural tube. More recent analyses have shown that genetic markers of the different embryonic tissues are expressed in inverted dorsoventral positions in vertebrates and protostomes (De Robertis and Sasai 1996), indicating that the whole body plan seems to be dorsoventrally inverted in the two main animal groups (Fig. 4). One hypothesis to explain this finding is that at some point, the vertebrate ancestor started swimming upside-down. Although difficult to demon-

Animal Phylogenetic Relationships

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Fig. 4 Dorsoventral organization in arthropods and vertebrates. These animals are inverted relative to each other not only in the topographical position of their organs but also in the patterns of gene expression. ac-sc, achaete-scute; CNS, central nervous system; EN, endoderm; MES, mesoderm; N, neurogenin. (With permission from Gerhart and Kirchner 1997)

strate, this proposal is supported by the fact that in some burrowing invertebrates it is not easy to determine the dorsal or the ventral surfaces, thus making inversion a relatively likely event (Gerhart 2000). Furthermore, the deuterostome hemichordates have been claimed to be inverted, upside-down versions of chordates, showing a dorsoventral organization similar to that of protostomes (Nübler-Jung and Arendt 1996). Unambiguous specification of dorsal and ventral structures is not easy in hemichordates, and by convention the mouth side had been traditionally considered to be ventral. However, Nübler-Jung and Arendt (1996) noted that the position of the heart, kidney, and gill slits were located in the so-called dorsal aspect of the animal (opposite to the mouth), while in chordates these organs are positioned ventrally, close to the mouth. Moreover, in hemichordates a sensory nerve chord runs ventrally while a motor chord runs dorsally, in an anatomic organization that is inverted with respect to chordates, in which sensory neurons are dorsal to motor neurons. An intriguing detail is that the so-called dorsal tract—at the other side of the animal’s mouth—is internalized in the collar region of the body by a neurulation-like process (Willmer 1990). Recent evidence suggests that the process of nervous system condensation occurred independently in protostomes and deuterostomes and is posterior to the acquisition of dorsoventral organization in bilaterians. In other words, the common bilaterian ancestor of protostomes and deuterostomes may not have had

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Evolution of the Vertebrate Nervous System and Telencephalon

a centralized nervous system. Despite their general protostome-like dorsoventral organization, hemichordates lack a truly centralized nervous system and have a diffuse subepidermal neuronal net whose anteroposterior patterns of homeotic and Hox-related gene expression closely corresponds with the patterns observed in the developing CNS of vertebrates and in Drosophila (Lowe et al. 2003; Holland 2003). Furthermore, more recent analyses have revealed that a dorsal-ventral axis based on a BMP-chordin gradient is present in all bilaterian animals (specifying the ventral-dorsal axis in chordates and the dorsal-ventral axis in protostomes), but as said its ancestral function seems to be more related to germ-layer patterning rather than specifically with neural-epidermal segregation and nervous system condensation (Lowe et al. 2006). Thus, in the case of hemichordates, the BMPchordin gradient is present, but the nervous system fails to condense at either side. Furthermore, the mouth appears on the chordin side, in a position opposite to the gill slits and equivalent to that of the mouth of protostomes (Lowe et al. 2006). In chordates, the mouth would have been relocated in close position to the gill slits (the BMP side, ventral), while in addition, there would have been a process of CNS condensation on the chordin side, leading to neurulation. Overall, this evidence is consistent with the hypothesis that the original body organization was essentially concentrical, with endoderm at the center, surrounded by mesodermal tissue, and then a neuroectoderm consisting of a diffuse nerve net covered by the epidermis contacting the outside; in some bilaterians, this concentric pattern became transformed into a dorsoventral pattern with the acquisition of bilaterality (Willmer 1990). Supporting this idea, other findings suggest that in radiates the molecular machinery for dorsal-ventral patterning is already present, in cryptic form (Finnerty et al. 2004). There is the possibility that the diffuse subepidermal nervous system of hemichordates results from a secondary reduction of the nervous system (Tautz 2003; Lacalli 2003), but this seems unlikely considering the basal position of this group among deuterostomes (Halanych and Passamaneck 2001; see also Vargas and Aboitiz 2005). Another proposal for the origin of the vertebrate CNS suggests that it derives from a set of ciliated bands, including the ciliated apical pole, of some invertebrate larvae (like the auricularia of echinoderms or the tornaria of hemichordates), which became internalized during neurulation (Garstang 1928; Fig. 5). Garstang proposed that these ciliary cells originally served both a locomotory and a sensory role. This hypothesis has in its favor that after neurulation, cells that line the neural tube become ciliated. Furthermore, many special sensory receptors (except taste receptors, which apparently have a different origin; Barlow and Northcutt 1997; Northcutt 2004) indeed consist of ciliated cells that have become internalized in neurulation (photoreceptors) or after placodal invagination (olfactory receptors, inner ear, and lateral line). Some authors have questioned the homologies between vertebrate sensory receptors and sensory cells of adult urochordates. In amphioxus and tunicates, the ectodermal sensory cells are mostly primary neurons sending axons to the CNS. In contrast, vertebrate, placodal-derived mechanosensory cells

Animal Phylogenetic Relationships

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Fig. 5 Garstang’s proposal of transformation of a hemichordate larva into a primitive chordate. The longitudinal band of ciliated cells that acts as a sensory-motor system is displaced dorsally to make up the neural plate. The apical organ containing ciliated cells contributes to the formation of the forebrain. (From Young 1962, with permission)

of vertebrates are all secondary neurons that lack axons (Holland 2005). Nevertheless, myomeric cells of cephalochordates, which are undoubtedly homologous to the segmented musculature of vertebrates, send a projection to the neural tube, which synapses on motor neurons (instead of motor neurons projecting an axon to the muscle cell, as occurs in vertebrates; Wicht and Lacalli 2005). Therefore, the presence or absence of a projection to the CNS may not be a determining factor for establishing homology between these structures. One possibility is that the ancestral subepidermal nerve net is really the precursor of true, delaminated neurons, while the ciliated cells of the deuterostome larvae correspond more closely to different types of localized receptors and to the ciliated cells at the interior of the neural tube. An interpretation related to Garstang’s is that the vertebrate brain derives from a ciliated apical organ found in some invertebrates like cnidarians or ctenophorans, which would be comparable to the apical organ of deuterostome larvae (Martindale 2005). In this context, developmental evidence suggests the possibility that the most anterior parts of the CNS rely on different inducing signals than the more caudal regions, which depend on the notochord for induction. The notochord, secreting Noggin, Chordin, and Follistatin, has its anterior end at the level of the future thalamus, and the most anterior aspect of the neural

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Evolution of the Vertebrate Nervous System and Telencephalon

plate (mostly consisting of the prospective hypothalamus and telencephalon) is supported by the anterior visceral endoderm. The latter expresses the genes Cerberus, Frizzled, and Dickkopf, which are necessary for the differentiation of the forebrain and the anterior part of the head (Hashimoto et al. 2000; Glinka et al. 1998; Kazanskaya et al. 2000; Mukhopadhyay et al. 2001; MacDonald et al. 2004; Leyns et al. 1997). The products of these genes block BMP and WNT signaling, thus suppressing both epidermal and posterior neural plate phenotypes. Thus, a primitive condition might have consisted of a localized anterior (perhaps perioral) network loosely connected to a diffuse subepidermal plexus; this system condensed in posterior regions, generating a midline nerve cord closely connected with the anterior or apical region, which eventually became the anterior CNS (see Lacalli et al. 1994). This view is partly supported by the proposal that at least the echinoderm larva dipleurula (ancestral to both the tornaria and the auricularia of hemichordates and echinoderms, respectively) and the tornaria larva are essentially heads without trunks (according to molecular evidence, they have head but not trunk markers, as occurs in the adult tunicates; Lacalli 2005). The caudal nervous system and the rest of the body develop after metamorphosis from this head region. Furthermore, in the hemichordate larva tornaria, the T-box gene (homologous to Tbr1 in vertebrates, which is expressed in the olfactory/hypophyseal placode and in the dorsal telencephalon) is expressed in the apical sensory organ, close to the eye spot (Willmer 1990; Satoh et al. 2002; see Sect. 2.2.3). 2.1.3 Summary Vertebrates derive from a basal group of deuterostome animals, whose adult stage was possibly free-living. A condensation of the diffuse subepidermal neural plexus, perhaps produced by a reorganization of the blastula, yielded a dorsal central nervous system, which became internalized to form a neural tube. Nevertheless, the process of delamination of neuronal cells from a proliferating epithelium seems to be conserved in invertebrates and vertebrates, as within the vertebrate neural tube prospective neurons delaminate in a similar manner as they do in Drosophila epidermis. Furthermore, the proneural genetic machinery, marking the beginning of neural differentiation, is similar in both groups. Ciliated cells, either lining the neural tube or specialized as localized sensory receptors, may be related to ciliated cells observed in deuterostome larvae, which serve as sensory receptors and also have motile functions. Given that the cephalic end of the vertebrate CNS is induced by different factors than the caudal end, it is possible that the forebrain and neighboring regions have a slightly different origin from the more caudal CNS, originating from an anterior or apical plexus that condensed dorsally. In this context, the cephalic nervous system seems to be the only one present in deuterostome larvae and in sessile deuterostomes, indicating that the two components of the CNS are separable.

The Origin of Vertebrates

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2.2 The Origin of Vertebrates 2.2.1 Early Theories and Fossil Evidence Early ideas about the origin of vertebrates were largely based on Garstang’s hypothesis that considered vertebrates and protochordates to result from a paedomorphic transformation of the larval tunicates (i.e., the swimming larva was transformed into a mobile, reproducing adult; Garstang 1928). However, more recent molecular and morphological phylogenetic analyses suggest that a free-living, swimming, or burrowing condition is ancestral to both deuterostomes and chordates, sessile forms being derived states (see Lacalli 2005; Vargas and Aboitiz 2005). Furthermore, the recent proposal that urochordates are closer to vertebrates than cephalochordates (Delsuc et al. 2006) is consistent with the possibility that both deuterostomes and olfactores (urochordates and vertebrates) were primitively free-living animals (the most basal form of ascidians, Oikopleura, also has an adult mobile condition, implying that ancestral urochordates were also free-living; Gee 2006). Beside embryological evidence, there is some fossil evidence for the origin of vertebrates. The fossil record provides evidence of the very early appearance of chordates during the Cambrian period, a time at which most extinct and living animal phyla also originated (Gould 1989; Conway Morris 1993; Valentine 2004). In the sediments of the Burguess Shale, a highly rich Cambrian fossil deposit, one highly publicized fossil, Pikaia, allegedly bearing a segmented musculature and possibly a notochord, was first claimed to be the earliest chordate (see Gould 1989; Shimeld and Holland 2005). However, additional studies revealed that the affinities of Pikaia with either cephalochordates or vertebrates were unclear (Schubert et al. 2006). Subsequently, an additional early fossil, Yunnanozoon, was first described as a cephalochordate (Chen et al. 1995), then as a vertebrate (Dzik 1995) and later on as the earliest hemichordate (Shu et al. 1996). Further interesting fossils are Haikouichthys and the closely related Myllokunmingia, which have been claimed to be already vertebrates with segmented, chevron-shaped myomeres, paired eyes, otic capsules, and paired olfactory organs (Shu et al. 1999, 2003a). A problematic fossil is Haikouella (Mallatt and Chen 2003b; Shu 2003), as some have interpreted it either as an early deuterostome (Shu et al. 2003b; Shu and Conway Morris 2003) or as a vertebrate-like chordate (Mallatt and Chen 2003a,b). According to the latter interpretation, Haikouella had a large brain, lateral eyes, a pharynx with gill slits, and a ventral heart. Finally, there are Cambrian records of calcified denticles – conodonts – that were initially attributed to early vertebrates, but conclusive evidence for this link came from a nearly complete description of a specimen with a small eel-like body, a caudal fin and fin rays (Briggs et al. 1983). Further analysis of these animals revealed that they had well-formed eyes with extrinsic musculature, comparable to those of agnathans (Briggs 1992; Sansom et al. 1992; Mallatt and Chen 2003a,b). All this evidence indicates that the origin of vertebrates was an

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Evolution of the Vertebrate Nervous System and Telencephalon

early event in animal evolution. Importantly, even if urochordates may be phylogenetically closer to vertebrates than to cephalochordates, in overall morphology the fossils described here resemble more closely amphioxus than urochordates, suggesting that they had a mode of life more similar to it than to modern tunicates. 2.2.2 The Neural Crest and Placodes in Vertebrate Origins The neural crest (NC) and placodes (PL) are embryonic regions located in the region bordering the neural plate, separating it from the rest of the ectoderm. The NC differentiates at levels behind the future prosencephalon (cerebral hemispheres and diencephalon), while the placodal region borders the anterior neural plate, contributing the prospective prosencephalic territory. Cells from the NC migrate laterally above and below the mesodermic somites to invade several regions of the embryo’s body. In the trunk and body, these cells give rise to a large part of the peripheral nervous system and other structures such as pigment cells and neuroendocrine cells in the adrenal glands. In the cephalic region, NC cells contribute to the branchial skeleton and part of the cranial skeletal tissue. Placodes differentiate in several types, such as the olfactory placode (giving rise to olfactory epithelium, whose receptors project directly into the olfactory bulb) and the closely related adenohypophyseal placode (contributing to the anterior pituitary gland). These structures develop in close contiguity with the olfactory bulb and the hypothalamus, respectively (Couly and Le Douarin 1985), and in the adult become closely associated with the anterior end of the neural tube, located in the roof of the mouth. Other placodal structures are the optic (producing the eye’s lens), trigeminal (contributing to cranial sensory ganglia), otic (future internal ear), and epibranchial (contributing to other cranial sensory ganglia). In fish and amphibians, there is also a lateral line placode, which generates the mechanoreceptive and, in many cases, electroreceptive lateral line system. In a now classical piece of work, Northcutt and Gans (1983) and Gans and Northcutt (1983) showed that the majority of shared-derived characters of vertebrates arise from the differentiation of the NC and PL. For example, the vertebrate branchial skeleton is a NC-derived character, while the branchial organs of cephalocordates have only a collagenous skeleton. Furthermore, vertebrate paired sense organs such as eyes, ears, and the olfactory epithelium relate embryologically to the epidermal placodes. The development of a muscularized branchial skeleton permitting a more efficient oxygenation and new feeding possibilities, together with the development of sense organs such as vision, olfaction, and the vestibular system was possibly related to a more active, predatory mode of life as opposed to the ancestral filter-feeding condition. Interestingly, Lacalli (2004) has proposed that these innovations took place at similar times in both early vertebrates and arthropods, leading to an “arms race” between both groups in their competition for prey and possibly also in the establishment of predator–prey relations between them, which speeded morphological evolution.

The Origin of Vertebrates

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Since Northcutt and Gans’s (1983) proposal, several subsequent studies determined that in protochordates there are tissues comparable to the NC and PL (Holland et al. 1996, 2000; Baker and Bronner-Fraser 1997b; Graham, 2000; Shimeld and Holland 2000, 2005; Jeffery et al. 2004) and a peripheral, visceral nervous system, which however, differentiates in situ and does not derive from migratory NC-like cells as in vertebrates (Lacalli 2004). This evidence is not inconsistent with Northcutt and Gans’s (1983) original proposal; after all, morphological structures and their ontogenies do not arise from nothing (Braun and Northcutt 1997). It is now widely considered that the protochordate ancestor of vertebrates included cell populations that modified their developmental pathways to yield definitive neural crest and placodes in vertebrate origins (Shimeld and Holland 2005). Nevertheless, in cephalochordates or urochordates these tissues never acquire the degree of complexity observed in vertebrates, and their migratory capacities, although present in some instances, are much more limited than in vertebrates. Interestingly, in the tunicate Eitenascidia a cell population emerging from near the neural tube migrates through the body and differentiates into pigment cells (Jeffery et al. 2004), which again supports a close phylogenetic relation between urochordates and chordates. During amphioxus neurulation, cells of the non-neural ectoderm bordering the NP, and expressing NC markers such as AmphiDll (ADll, homologous to vertebrate Dlxs, which mark NC and PL), develop lobopodia and crawl over the neural plate to meet and fuse in the dorsal midline, but they never migrate to other sites (Holland et al. 1996, 2000; Holland and Holland 2001). In amphioxus, ADll acts as an ectodermal marker and its epidermal expression pattern is comparable to the amphibian XDll2 (Dirksen et al. 1994) and to the zebrafish homolog gene Dlx3 (Akimenko et al. 1994). In higher craniates, Dlx3 is an epidermal marker (Porteus et al. 1991, 1994; Bulfone et al. 1993b). Nevertheless, in amphioxus, ADll is also expressed in the alar region of the presumptive forebrain, including the alar region of the ventral forebrain (Bulfone et al. 1993a,b). In the mid-neurula, cells near the anterior end of the neural plate become ADll-positive and are incorporated into the dorsal neural tube. These cells and others that express the gene somewhat later demarcate a region comprising the anterior three-fourths of the amphioxus cerebral vesicle, which has been claimed to be homologous to the craniate forebrain (Holland et al. 1996). This evidence underlines the close relation between Dll/Dlx genes and both the developing forebrain and vertebrate neural crest and placodes. While amphioxus has only one ADll gene, this gene duplicated several times in vertebrate origins, each new gene becoming restricted to specific tissues in which the ancestral Dll gene was expressed (for example, Dlx3 in the epidermis, Dlx5 in the placodal region, and Dlx1/2 in the ventral telencephalon; Holland et al. 1996). In this context, it is of interest to recall that Dlx genes are closely related to Hox genes and that vertebrate origins are marked by two duplications of the Dlx–Hox cluster (Digregorio et al. 1995; Stock et al. 1996). Developmentally, Dlx genes are expressed more anteriorly than Hox genes, which in the CNS are active at the level of the hindbrain and spinal cord (Kraus and Lufkin 1999). While the Hox cluster may have been involved in patterning the trunk region and the posterior CNS, Dlx

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Evolution of the Vertebrate Nervous System and Telencephalon

genes were more related to the development of the PL-derived sensory organs and the telencephalon and related cephalic structures. In a recent review, Meulemans and Bronner-Fraser (2005) proposed that in vertebrate origins, recruitment to the neural plate border of some mesendodermal genes activated primitive programs in NC precursors, expanding their developmental potential. According to these authors, the ancestral chordate possessed a neural plate border including lateral neural plate (expressing the neural plate border specifiers Zic, Pax3/7 and Msx, and the NC specifier Snail) and adjacent epidermal ectoderm (expressing the neural plate border genes Pax3/7, Msx, and Dlx3/5). In ascidian urochordates, Snail, Msx, and Zic homologs are expressed within the neural plate. In cephalochordates, Pax3/7 and Msx are not expressed in neural plate borders. In vertebrates, neural plate border cells expressing Zic, Snail, Pax3/7, and Msx also express neural crest specifiers, consistent with co-option of these genes in the vertebrate lineage. In our view, this evidence points to a closer similarity of inducing mechanisms between urochordates and vertebrates than between cephalochordates and vertebrates, thus supporting a close phylogenetic relation between urochordates and vertebrates (Delsuc et al. 2006). Furthermore, in both larval tunicates and cephalochordates, there are primitive sensory organs that serve as navigational aids and may be related to vertebrate sensory organs (despite some homologic uncertainties). Although there is species variability, in all larval ascidians there is a balance organ (an otolith) and an ocellus with a pigment cup, both located in the brain vesicle. In some species, there are additional sensory structures (Lacalli 2001). Amphioxus has a frontal, medial eye, consisting of an accumulation of photoreceptive cells in the ventral anterior part of the forebrain, and a so-called lamellar body more posteriorly and located dorsally (homologous to the vertebrate pineal organ), plus dispersed photoreceptive cells along the spinal cord (the Joseph cells and the organs of Hesse; Wicht and Lacalli 2005); and a putative balance sensory organ consisting of the preinfundibular ciliary bulb cells (Lacalli and Kelly 2003). Most of these structures are found inside the cephalic tube, and if the homology with vertebrate sensory organs is correct, it would imply that the differentiation of head placodes permitted the exteriorization of some sensory organs (such as the inner ear and the olfactory epithelium), and the generation of paired eyes, directed to the periphery. In his more recent update of the theory, Northcutt (2005) rejected his original proposal regarding the origin of the neural crest from a subepidermal plexus comparable to that of hemichordates. As mentioned above, he instead suggested that the NC and PL arose as a consequence of a redistribution of the presumptive territories in the early blastula. This view is partly consistent with the evidence indicating quite an early embryonic origin of the NC territory, at or even before gastrulation (Basch et al. 2006). In our view, although the modification of the gastrula fate maps of deuterostomes could indeed be related to the origin of neurulation and to the presumptive territory of the NC, much embryological evidence also points to an important interaction between the ectoderm and the neural plate during NC and PL differentiation (Baker and Bronner-Fraser 1997a;

The Origin of Vertebrates

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Deardorff et al. 2001; García-Castro et al. 2002; Gammill and Bronner-Fraser 2003; Woda et al. 2003). Thus, while NC and PL precursor tissues possibly appeared in evolution at quite an early stage, concomitant with the process of neurulation, the expansion and differentiation of these tissues in vertebrate origins may have largely depended on neural–epithelial (and mesodermal) interactions, not being a direct consequence of the derived organization of the early blastula. 2.2.3 Olfactory Placode and Epithelium: Association with Adenohypophysis There is developmental evidence suggesting a close relation between the vertebrate olfactory and adenohypophyseal placodes. Early and recent authors have proposed that these two organs derive from a common structure in vertebrate ancestors (De Beer 1924; Olsson 1990; Gorbman 1995; Schlosser 2005), which is confirmed in basal vertebrates such as agnathans, both during development (Leach 1951; Gorbman 1983) and in the adult (Døving 1998). Schlosser (2005) further claims that primitively, there was a panplacodal primordium giving rise to all different placodes, defined by Six1/2 and Eya. According to this author, all cranial placodes arose by stepwise establishment of new gene regulatory interactions from a rostral protoplacode that evolved from the anlage of an ancestral rostral neurosecretory organ. This embryonic anlage may correspond to the vertebrate preoral ectoderm, immediately rostral to the neural plate, that is, between the future mouth and the anterior neuropore. This position makes it closely related to the anterior neural ridge of embryonic vertebrates, which acts as a signaling source to induce both ventral forebrain development and the anterior telencephalon by the secretion of factors such as FGF (Couly and le Douarin 1985). The origin of the olfactory organ from a urochordate- or cephalochordate-like ancestor is, however, somewhat obscure. As mentioned, adult ascidians (urochordates) are sessile animals in which the trunk region is apparently regressed and develop as pure head animals (Lacalli 2003, 2005). Their nervous system consists of a small perioral ganglion comprising the neural gland and the neurohypophyseal duct, which derive from the larval anterior neural tube (Mackie 1995; Di Fiore et al. 2000). Based on gene expression patterns and on anatomical considerations, Manni et al. (1999, 2001, 2005) and Mazet and Shimeld (2005) have proposed homology of these structures with vertebrate olfactory and adenohypophyseal/hypothalamic placodes. Interestingly, both in the vertebrate adenohypophyseal/hypothalamic placode and around the neurohypophyseal duct of ascidians, there are migratory GnRH+ neurons that in vertebrates migrate into the hypothalamus (Manni et al. 2001). Initially, it was thought that in vertebrates, some GnRH+ neurons derived also from the olfactory placode, but subsequent studies determined that these actually derive from the cranial neural crest (Whitlock et al. 2003; Whitlock 2004). In amphioxus there are some receptors dispersed in the front of the head, but it is not clear if they are comparable to vertebrate olfactory receptors (Lacalli 1999). The rostral most epithelium (the nose) is innervated by two pairs of anterior

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Evolution of the Vertebrate Nervous System and Telencephalon

nerves, but apparently they collect mostly mechanosensitive information (Wicht and Lacalli 2005). Some evidence suggests a common origin of the vertebrate adenohypophysis (and the olfactory placode) and the cephalochordate preoral or Hatscheck’s pit, a small opening communicating the anterior end of the neural tube with the exterior (Nieuwenhuys 1997, 1998a; Sherwood et al. 2005; Schlosser 2005; see Fig. 6). This claim is supported by the location of Hatscheck’s pit in front of the larval mouth, by the presence of nerve terminals on it and by its being positive for pituitary-related hormones. Furthermore, the amphioxus AmphiPax6 gene is expressed in the preoral pit of amphioxus, and in the preplacodal region including the olfactory/hypophyseal placode of vertebrates (Glardon et al. 1997, 1998). Likewise, some cutaneous sensory cells with cilia and microvilli of amphioxus (the type 1 receptors) have been claimed to be comparable to olfactory receptors in vertebrates, as they express placodal markers such as Pax6, Msx, and Neurogenin (Shimeld and Holland 2005). However, later in vertebrate development, Pax6 expression is restricted to the lens placode and not to the olfactory placode (Bhattacharyya et al. 2004). Furthermore, others have contended the hypothesis of homology between adenohypophyseal placodes and Hatscheck’s pit, claiming that it is not clear that the latter secretes adenohypophyseal hormones (but admit its positivity for pituitary-specific transcription factors; Wicht and Lacalli 2005). Another presumptive homolog to the olfactory epithelium is Kölliker’s pit (Kölliker 1843; Franz 1923), but this is rather a remnant of the neuropore that lacks obvious chemoreceptors and no nerve terminals have been described on it (Edinger 1906; Tjoa and Welsch 1974). However, this evidence is rather old and it might be appropriate to revisit it.

Fig. 6 Scheme of a sagittal secion through the cerebral vesicle of the cephalochordate amphioxus. Ventrally there is a cluster of photoreceptors and more dorsally there is a small opening, Hatscheck’s pit, which has been considered by some authors a precursor of the nasohypophyseal duct of early vertebrates. (Modified from Wicht and Lacalli 2005, with permission)

The Origin of Vertebrates

21

2.2.4 Origin of the Telencephalon Another claim made by Nortchcutt and Gans (1983) and by Northcutt (1996a, 2005) regarding vertebrate origins is that the rostral head of vertebrates is a neomorphic unit. This statement implies that, together with the NC and PL derivatives, most anterior brain structures including pretectum, epithalamus adenohypophysis, preoptic area, telencephalic hemispheres and olfactory sensory organs arose at relatively the same time. Intermediate forms bearing only some of these characters are considered unlikely to have existed. Alternatively, Butler (2000a,b; 2006) proposed a sequential acquisition of the different neural characters in vertebrate origins, with an initial condition similar to that found in the extant amphioxus, where a frontal eye projects to the tectal region. In an intermediate stage, paired eyes developed, inducing the origin of a diencephalon. According to Butler (2006), this stage is perhaps comparable to that of the fossil Haikouella (and maybe to conodonts, who also had paired eyes). The final stage is marked by the origin of paired telencephalic vesicles in the dorsal forebrain. We somewhat agree with Butler in that this alternative is more likely to occur than a sudden transformation yielding all characters. However, a macrotransformation is not an impossible event, and more evidence is needed to determine which hypothesis is correct. Further analyses of fossil material such as Haikouella or conodonts may help resolve this issue. Developmental evidence indicates a close relationship between telencephalic and placodal territories, especially with the olfactory placode. The differentiation of the forebrain and olfactory bulb depend on inductive interactions with the olfactory placode (Gong and Shipley 1995; De Carlos et al. 1995; Reiss and Burd 1997). Moreover, at least in zebrafish the presumptive telencephalic territory limits rostrally with that of the preplacodal region, especially with the olfactory placode, and there is initially an important overlap between them (Whitlock 2004). Both NC/PL and the telencephalon are partly determined by regulatory genes of the Dlx family, such that NC and PL are specified by Dlx genes (particularly Dlx5 in the placodal region), while at later stages, the ventral telencephalon expresses the genes Dlx1 and Dlx2 (Holland et al. 1996; Whitlock 2004; see Sect. 2.2.2). Therefore, it is conceivable that the differentiation of the placodal region yielding sensory systems, and of the telencephalon, were sequential but closely related acquisitions, in which one innovation facilitated the development of a second innovative feature. A related issue concerns the existence of precursors for the telencephalon in nonvertebrates. In this sense, both Northcutt (1996a,b; 2005) and Butler (2000a,b; 2006) agree that there are no signs of a telencephalic structure in living nonvertebrate deuterostomes (Northcutt 2005, claims that even the presence of a mesencephalon is questionable in amphioxus). Nevertheless, recent comparative developmental evidence has revealed that embryonic territories comparable to the forebrain can be found in urochordates and in cephalochordates. Molecular genetic analyses of the brains of larval urochordates, cephalochordates, and developing vertebrates indicate a strong conservatism of the gene expression patterns in the rostrocaudal di-

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Evolution of the Vertebrate Nervous System and Telencephalon

mension of the neural tube (Fig. 7). As in vertebrates, Hox genes pattern the caudalmost aspects of the cephalochordate and tunicate neural tube, while the anterior neural tube (the brain vesicle) is marked by the expression of the forebrain marker Otx2 (Williams and Holland 1996). Furthermore, in amphioxus there is a region in the anteriormost neural tube expressing the gene Brain factor 1 (BF1), which is also expressed in the vertebrate ventral telencephalon (Toresson et al. 1998), and we have mentioned the expression of the Dlx-like gene ADll in the presumptive alar forebrain (Sect. 2.2.2). Amphioxus also expresses markers of the dorsal telencephalon of vertebrates. This animal has one T-box gene (see Sect. 2.1.2), which is initially expressed in the archenteron and is downregulated in the neurula, but later appears in the preoral pit (Hatscheck’s pit in the adult), which, as we have seen, is claimed to be comparable to the olfactory/adenohypothyseal placode of vertebrates (Satoh et al. 2002). In other deuterostomes (echinoderms and hemichordates), the T-box gene is also expressed in the archenteron (Satoh et al. 2002). In vertebrates, there was a duplication of the T-box gene (Tbr1 and Tbr2), where Tbr2 is confined to the endoderm and Tbr1 expression is restricted to the olfactory/hypophyseal placode, but later both genes appear in the dorsal telencephalon, since they are required for the development of projection neurons, reelin expression, and proper laminar development of the cerebral cortex. Thus, the duplication of Tbr genes in vertebrate origins may have permitted the co-option of Tbr1 for brain and especially for telencephalic development. Moreover, this evidence further suggests a close relation between the olfactory placode, the adenohypophyseal placode, and early telencephalic markers. Finally, in amphioxus, the notochord reaches levels in front of the neural tube, supporting it in its entire length. This condition has led some to conclude that the neural tube of amphioxus may not include CNS structures that in vertebrates are positioned anterior to the notochord, like the forebrain. However, in larval urochordates (which again may be closer to vertebrates than amphioxus; Delsuc et al. 2006), the notochord ends behind the visceral ganglion, which is located posterior to the cerebral vesicle, a condition reminiscent of that in embryonic vertebrates, in which the notochord ends at the level of the thalamus (Sect. 2.1.2). It is thus possible that the position of the notochord in amphioxus represents a derived condition. 2.2.5 Summary The origin of vertebrates is marked by the appearance of differentiated tissues derived from the neural crest, of paired sensory organs derived from the epidermal placodes, and of paired telencephalic hemispheres (Fig. 8). Concomitantly, at least two duplications of the Hox-Dlx cluster were involved in vertebrate origins. While Hox genes have been mostly involved in patterning the brain stem and spinal cord, Dlx genes mark neural crest, placodes, and ventral telencephalic structures. Although in larval urochordates and in cephalochordates, sensory organs are located within the brain vesicle, in vertebrates, some of these organs differentiate in the

The Origin of Vertebrates

23

Fig. 7 Gene expression patterns in the anterior brain of hemichordates, urochordates, cephalochordates and vertebrates, indicating homology of the anterior vesicle with the vertebrate forebrain

placodal domain and localize outside the CNS. The origin of the olfactory epithelium is not yet clear, but is apparently related to the adenohypophysis, which has been associated with the preoral or Hatscheck’s pit of amphioxus (although there are dissenting opinions). In the amphioxus forebrain, there are some telencephalic

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Evolution of the Vertebrate Nervous System and Telencephalon

Fig. 8 Diagram depicting the main characters of the ancestral vertebrate brain, bearing paired sense organs, an olfactory system, and paired cerebral hemispheres. The animal also had a notochord, segmented musculature, and a branchial skeleton. Note that contrary to amphioxus, in which the notochord reaches the anterior tip of the animal, the notochord does not reach the forebrain, which is supported by a prechordal platform. (Modified with permission from Lacalli 2005)

markers that suggest a close relation between the olfactory/hypophyseal placode and the ventral telencephalon. In cephalochordates there is also expression of a vertebrate dorsal telencephalic marker (T-box/Tbr1), but this is located in the preoral pit, possibly related to olfactory structures. Thus, it is possible that this gene was subsequently co-opted for dorsal telencephalic differentiation. In this context, it is of interest to recall that in vertebrate development, early telencephalic fates are initially of ventral character (mainly in response to FGF8 emanating from the anterior neural ridge). Subsequently, exposure to Wnts and BMPs form the overlying ectoderm prompts some cells to acquire a dorsal phenotype (Gunhaga et al. 2003). This sequence is broadly consistent with a phylogenetic sequence in which there is an initial differentiation of a ventral forebrain, related to the olfactory epithelium and adenohypophysis (perhaps related to Hatscheck’s pit in amphioxus); later, there is differentiation of olfactory structures and an originally ventral telencephalon that eventually acquires a dorsal component. 2.3 Evolution of the Telencephalon in Vertebrates 2.3.1 Taxonomical Relationships Among Vertebrates and Their Early Evolution Vertebrates – or craniates – are divided into agnathans (jawless vertebrates) and gnathostomes (jawed vertebrates like most fishes and all terrestrial vertebrates).

Evolution of the Telencephalon in Vertebrates

25

Agnathans are subdivided into the more primitive myxinoids such as the hagfish, and cyclostomes such as the lamprey. Among gnathostomes, chondrychthian fishes are represented by sharks, rays, and related cartilaginous fishes, while the osteichthies are the bony fish like trouts and most fish we know. Sarcopterygians are a group of bony fish that are considered related to the ancestors of terrestrial vertebrates, as they bear lobed fins that resemble primordial limbs, and some have developed lungs to breathe air. Terrestrial vertebrates are divided into anamniotes (amphibians), who put their eggs in water and have a larval aquatic stage; and amniotes (reptiles, birds, and mammals), whose eggs are covered by an amniotic fluid and can be placed outside water. The amniotic cavity locates either within the egg shell such as in reptiles, birds, and monotreme mammals, or develops inside the maternal uterus such as in marsupials and placental mammals (see Fig. 9). As mentioned, some of the earliest vertebrate fossils appear to be represented by the conodonts, soft-bodied vertebrates that had not yet developed an ossified skeleton. Skeletal agnathan fossils date from the early Silurian, and are commonly termed ostracoderms (shell-skinned), as they developed an extensive exoskeleton that could have the form of a solid carapace, large bony plates, or scales (Carroll 1988). These animals were probably not excellent swimmers, but those with light, flexible armors and a fusiform body may have lived in the open water. Those with heavier armors and a dorsoventrally flattened body were probably benthonic. Ostracoderms clearly show paired eyes, large semicircular canals, and nasal openings, indicating a well-developed olfactory system. Two major groups of ostracoderms have been recognized according to the structure of their nasal openings: the pteraspids or diplorhins were considered to represent the more primitive condition in which there are paired nasal sacs and external narial openings. On the other hand, the presumably more advanced cephalaspids or monorhins had

Fig. 9 Phylogenetic relations among vertebrates. Turtles (Chelonia) are now considered to be more related to lepidosaurians than to stem reptiles

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Evolution of the Vertebrate Nervous System and Telencephalon

a single, medial nasal sac and narial opening that is confluent with the hypophyseal duct. Some of these animals may have developed electric organs. Hagfishes, considered to represent the most basal group of living agnathans, were initially proposed to evolve from the more primitive diplorhins (Stensio 1964). In fact, myxinoids were considered to represent a primitive clade, the outgroup of the clade formed by lampreys and jawed vertebrates. On the other hand, the configuration of the endocranial cavities of monorhins suggested a brain structure similar to that of the lamprey Petromyzon. In this animal, the anterior portion of the brain stem is expanded laterally to locate the telencephalon just below the nasal cavity that leads to the nasohypophyseal opening, which continues ventrally into the area of the hypophysis (Moy-Thomas and Miles 1971). More recent reports suggest that modern agnathans have no direct relations with fossil ostracoderms, being more basal than these and related the fossils like Haikouichthys. The rest of the vertebrates are an outgroup of cyclostomes, and subdivide into conodonts and ostracoderms. Jawed vertebrates originat as a sister group of osteostracans. a clade of monorhin ostracoderms (Gess et al. 2006). One of the most important advances among primitive vertebrates was the origin of jaws, allowing a truly predatory way of life. The earliest jawed fishes appear in the lower Silurian period. These are called placoderms, but are not closely related to modern cartilaginous or bony fish. Most were benthonic and probably poor swimmers, despite the clear presence of pectoral fins. They had no teeth but rather bony plates in the margin of their jaws. Beside the fossil placoderms, two major radiations took place: cartilaginous fishes and bony fishes. Although these two groups differ in many respects, the structure of their jaw and the pattern of tooth replacement indicate that they have a common ancestry that is separate from that of the placoderms (Carroll 1988). These two taxa also share the absence of an exoskeleton and the presence of well-developed paired fins. Both groups developed as good swimmers, but bony fish developed a swimbladder, while cartilaginous fishes attempted to solve the problem by developing cartilage instead of bone, and a large, oil-filled liver that greatly reduces their specific gravity. Early cartilaginous fish radiated in the Devonian period, producing a series of different families with unclear relationships among them. As mentioned, the extant members of this class include sharks, rays, and the deep-sea holocephalians. On the other hand, osteichthyes or bony fish became an extremely diverse group that has dominated marine and freshwater environments since the paleozoic. This class is divided into two major subclasses, the highly diversified ray-finned or actinopterygian fishes such as the trout and the much less common lobe-finned or sarcopterygian fishes, including the coelacanth and the lungfish. The lobe fins of the latter represent the ancestry of the limbs of terrestrial vertebrates. Furthermore, considering that the teleostean swimbladder is a derivative of the lung sacs of lobe-finned fishes, it is possible that the common ancestor of ray-finned and lobe-finned fishes was phenotypically close to the early members of the sarcopterygia. In fact, the more basal extant members of the actinopterygia (polypter-

Evolution of the Telencephalon in Vertebrates

27

iforms or brachiopterygians) bear lobed fins and vascularized lungs (Nieuwenhuys 1998b, c). Tetrapods originated from a group of primitive sarcopterygians, possibly living in quiet freshwater ponds. The earliest tetrapods were large-bodied fossil amphibians living in the Devonian period that vaguely resembled modern crocodiles, and bearing fishlike characteristics such as lateral line canals, a tail fin, opercular bones, as well as fully tetrapod features such as a massive ribcage and robust feet with digits. Representatives of this group are Acanthostega, Ichthyostega and the possible basal amniote Tulerpeton (Jarvik 1980, 1996; Coates and Clack 1990, 1991). Recent interpretations, supported by the discovery of gill bars in Ichthyostega, consider that these animals had a fully or largely aquatic lifestyle, using their limbs to swim rather than to walk (Clack et al. 2003). In the Carboniferous period, a large radiation of these early amphibians took place, in which animals were progressively adapting to live on ground. Among these were the herbivorous diadectids and the crocodile-like limnoscelids, which are possibly the closest relatives to the amniotes. One of these lineages eventually became fully terrestrial, developing internal fertilization, an amniotic egg, reduced skin permeability partly provided by scales, a water-reabsorbing cloaca that excreted solid uric acid to retain water. These were the first reptiles, whose earliest known member is possibly Casineria, but its affinities are dubious because of poor conservation of the skeleton. More definite amniote features are present in the small-bodied Hylonomus, Paleothyris, and Westlothiana, members of the Prothorothyrididae family (Clack 2002). These animals represent the stem reptiles, usually considered to be the earliest amniotes in the planet. Reptiles have been classified on the basis of the pattern of openings in the dermal skull behind the orbits. In primitive reptiles such as the prothorothyridids (subclass anapsida), there are no openings and the roof of the skull is completely covered by bone. Members of this class include fossil reptiles, and some authors have placed turtles among them, based on the absence of cranial openings in this group (see Carroll 1988). For this reason, turtles have been considered in many instances to be the reptiles closest to the point of reptilian– mammalian divergence, and their brains have been considered as models of the ancestral amniote brain. However, some paleontologists have considered the inclusion of turtles into the subclass anapsida somewhat arbitrary, as it disregards many other aspects that strongly suggest that this group is rather a highly derived one (see Carroll 1988). Moreover, recent phylogenetic analyses based on morphology and on molecular evidence place turtles as a rather modified group of reptiles, with no direct relation to the ancestral anapsids (Mannen and Li 1999; Rieppel and Reisz 1999; Zardoya and Meyer 2001). Therefore, the absence of temporal openings in the skull of turtles may be secondary and not reflect an ancestral condition. The diapsid reptilian condition, in which there are two postorbital skull openings, possibly originated from a group of anapsid reptiles. This subclass represents most living reptiles and includes two main groups: lepidosaura, with lizards, snakes, and a primitive New Zealand reptile called the tuatara; and archosaura, which includes crocodiles, dinosaurs, and birds. According to some phyloge-

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Evolution of the Vertebrate Nervous System and Telencephalon

netic analyses mentioned above, turtles may also belong to the diapsids. There is also the subclass parapsida, represented by fossil marine reptiles (Clack, 2002; Carroll 1988). The last reptilian subclass is represented by the synapsid condition (with a cranial opening in the cheek region of the skull), exemplified by the mammal-like reptiles from which the first mammals emerged. Synapsids appear at about the same time as the stem anapsids: Protoclepsydrops is considered to be a synapsid as old as the early anapsid Hylonomus (Carroll 1988), but the classification of the former has not been confirmed (Reisz 1986). In any case, there are indisputable synapsids of the pelicosaur group only slightly younger than Hylonomus, namely Archaeothyris (Reisz 1972). The general consensus is that amniotes are a monophyletic group that nevertheless diverged into the stem reptiles (protorothyridids) and the mammal-like synapsids (pelicosaurs) at quite an early stage. 2.3.2 Evolution of the Cerebral Hemispheres: Ventral Telencephalon Agnathans already possess a differentiated telencephalon, although its organization is somewhat different than that of gnathostomes. The ventral telencephalon of agnathans is quite a simple structure, containing a medial septum and a lateral striatum. In myxinoids (hagfishes), the septum is unpaired and is wedged between the olfactory bulbs on the ventral side of the brain, receiving olfactory projections via the medial olfactory tract (Wicht and Northcutt 1993). However, the numerous neurochemical dissimilarities between this structure and the gnathostome septum have made some authors question their homology (Wicht and Northcutt 1994). In cyclostomes (lampreys), a septal nucleus receives secondary afferents from the olfactory bulb (Polenova and Vesselkin 1993). The striatum of lampreys is better known (Nieuwenhuys and Nicholson 1998), receiving numerous terminal arborizations with several neurotransmitters including dopamine, which in gnathostomes has proved to be a reliable marker for this structure. Furthermore, the lamprey subpallium contains a large number of neurosecretory cells, which project to the infundibular region and contribute to the preopticohypophysial neurosecretory system (Pombal et al. 1997a,b; Nieuwenhuys and Nicholson 1998). This underlines the relation between the subpallium and the basal forebrain in this group. As far as is known, the evolution of the basal ganglia has been rather conservative in the history of jawed vertebrates (Parent 1986; Medina and Reiner 1995; Marín et al. 1998; Smeets et al. 2000). However, a few changes in striatal input have taken place in mammals. For example, in amphibians the major striatal input comes from the dorsal thalamus, but in reptiles and birds it comes from a structure termed the dorsal ventricular ridge (DVR). In mammals, this input comes mainly from the neocortex (Guirado et al. 2000; Parent and Hazrati 1995a,b). In addition, some authors have described in mammals an emphasis of projections from the basal ganglia to the dorsal thalamus, which in turn projects to the neocortex (Brauth 1990; Medina and Reiner 1995). Perhaps this has some relation to the loss

Evolution of the Telencephalon in Vertebrates

29

of the pretectal pathway from the basal ganglia to the optic tectum (in mammals, the optic tectum is significantly reduced in relative size) and may be concomitant with the development of the mammalian corticospinal tract. In reptiles, projections from the basal ganglia to the dorsal thalamus appear to be less developed, although there has been an independent development of pallidothalamic connections in birds (Brauth 1990). Another difference in output relates to the pathways connecting the basal ganglia with the mesencephalic optic tectum. There are multiple pathways for this connection, of which the most important are a ventral route via the substantia nigra, which is present in all tetrapods, and a dorsal route via the pretectal nuclei. The pretectal pathway is most developed in anurans, some lizards, turtles, crocodiles, and birds, although it is weak or absent in urodeles, some lizards, snakes, and mammals, suggesting that it is a highly variable trait (Marín et al. 1998). The ventral telencephalon of jawed vertebrates also contains structures like the olfactory tubercle in the ventral striatum, which receives olfactory information and has relations with the olfactory cortex and the olfactory nucleus, corresponding to lateral and medial pallial components, respectively (Butler and Hodos 1996). 2.3.3 The Brain of Jawless Fishes and the Organization of the Ancestral Dorsal Telencephalon Myxinoids have a highly distorted brain in which there are four paired ventricles in the embryo (two telencephalic and two diencephalic); these ventricles become obliterated in the adult, and there is a fusion of the anterior walls of the diencephalic vesicle with the posterior walls of the telencephalic vesicle. This region gives rise to an evaginated component termed the central prosencephalic complex, which includes paired cerebral ventricles containing both telencephalic and diencephalic components, but its functions and connectivity remain obscure. This component has been compared to the medial pallium of other vertebrates (Jansen 1930), but this proposal has been challenged (Wicht and Northcutt 1998). Nevertheless, recent embryological evidence indicates that the medial pallium corresponds to the caudal forebrain, and it is separated from the more posterior thalamus by the zona limitans intrathalamica (Kimura et al. 2005). Therefore, the topographic position of the hagfish medial prosencephalic complex might be consistent with the embryonic position of the medial pallium. Furthermore, the zona limitans intrathalamica of mammals might perhaps be comparable to the region in which the telencephalic and diencephalic walls fuse in myxinoids, as this region is a focus of extensive neuronal proliferation and migration. The pallium of agnathans receives an extensive olfactory projection, covering it almost completely (Northcutt 1996a; Northcutt and Puzdrowski 1988; Wicht and Northcutt 1992, 1993, 1998; Wicht 1996; Northcutt and Wicht 1997). The olfactory bulbs are particularly well developed in both myxinoids and cyclostomes, but in the latter olfactory structures resemble much more closely those of jawed vertebrates. In hagfishes, the olfactory bulbs receive numerous olfactory nerve bundles (about ten per side) and project to the telencephalon in three main bundles: the medial,

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Evolution of the Vertebrate Nervous System and Telencephalon

the lateral, and the ventral olfactory tracts, respectively innervating the septum, the pallium, and the basal forebrain. The pallium of hagfishes is unique in that it has a superficial cortical mantle of gray matter that is subdivided into several layers or fields. It also has reciprocal connections with diencephalic regions including the dorsal thalamus, with a strong tectothalamic-telencephalic component, and has interhemispheric connections (Wicht and Northcutt 1993, 1998). Despite this complexity, in myxinoids it is not possible yet to recognize ventral, lateral, dorsal, and medial components with certainty (Myojin et al. 2001), which has led some authors to propose that the entire pallium is homologous to the lateral pallium of higher vertebrates (see Butler and Hodos 1996). (As mentioned, these animals also have the above-mentioned central prosencephalic complex, which might be comparable to the medial pallium.) Although in the lamprey the olfactory bulbs are clearly evaginated, evagination is not complete in the caudal telencephalon, forming the telencephalon impar in which the two hemispheres are fused in the midline (Nieuwenhuys and Nicholson 1998). In the lamprey, this structure contains the septum (ventral pallium), the primordium hippocampi (dorsal pallium), and parts of the corpus striatum (subpallium). In elasmobranchs, dipnoans, the coelacanth Latimeria and amphibians, a telencephalon impar can still be observed, but is much less extensive and most telencephalic structures are evaginated. Lampreys already show a subdivision into at least medial, dorsal, and lateral pallium. A ventral pallial field has not been yet reported in agnathans, but if fate-mapping evidence is correct in positioning the olfactory bulb in this subdivision (Cobos et al. 2001), this should also be a primitive vertebrate characteristic. As in most jawed fishes, in the lamprey, dorsal thalamic projections, particularly from the tectothalamic route, end in the small medial pallium, which nonetheless also receives olfactory projections (Northcutt and Wicht 1997). Most olfactory projections end in the expanded lateral pallium, and there is a subhippocampal lobe that has been homologized to the gnathostome dorsal pallium, also receiving olfactory input. Therefore, while the agnathan pallium is entirely olfactory, there is also a substantial diencephalic projection, which in hagfishes is spread over the pallium, overlapping with secondary olfactory afferents, but in lampreys is confined to the medial pallium (where it also overlaps with less dense secondary olfactory projections; Northcutt and Wicht 1997; Wicht and Northcutt 1998). The projection from dorsal thalamus to the medial pallium is shared with several gnathostomes, excluding amniotes (Northcutt 1995). This evidence led Wicht and Northcutt (1998) to propose a tentative morphotype of the ancestral gnathostome brain, in which extensive olfactory projections to the pallium and also thalamopallial projections are a primitive character for agnathans. Nevertheless, ascending spinal or bulbar lemniscal systems do not reach the dorsal thalamus, which is innervated mainly by tectothalamic or collothalamic projections (lemniscal systems end in the mesencephalic tegmentum, which in turn projects to the thalamus; Ronan and Northcutt 1990; Butler and Hodos 1996). This condition is also observed in most fish (with some exceptions), with tetrapods the first group in which the development of a strong ascending lemnotha-

Evolution of the Telencephalon in Vertebrates

31

lamic system is consistently evident (Ronan and Northcutt 1990; Muñoz et al. 1994, 1997). Nevertheless, there are direct retinothalamic visual projections that reach the telencephalon at least in all jawed vertebrates (cartilaginous fish: Ebbesson and Schroeder 1971; Schroeder and Ebbesson 1974; Smeets 1990; Northcutt 1990b; bony fish: Nieuwenhuys and Meek 1990; tetrapods Butler, 1994a,b). Finally, in all vertebrates, the pallium also receives projections from the preoptic region, and there is a projection from the posterior tuberculum to the subpallium and sometimes to the pallium (in agnathans, Polenova and Vesselkin 1993; Wicht and Northcutt 1998). Furthermore, the pallium projects to the thalamus and tectum in hagfish and lamprey, indicating that these connections are primitive. 2.3.4 The Pallium in Jawed Vertebrates An early scenario of gnathostome brain evolution implied that the pallium was dominated by olfactory afferents in most fishes, while in terrestrial vertebrates, thalamic projections restricted the extension of olfactory afferents, confining them to the lateral pallium and related structures (Ebbesson and Heimer 1970; Smeets 1983). However, it was later found that all jawed fishes display several pallial fields (medial, dorsal, lateral and more recently, ventral), and an olfactory projection restricted to lateral regions (for review see Northcutt 1995; Northcutt and Kaas 1995), which dramatically changed the concept of early brain evolution. The acquisition of predatory lifestyles by the early gnathostome vertebrates, involving the further development of other sensory modalities, implied the progressive development of ascending visual, somatosensory, and lateral line afferents to the pallium via the dorsal thalamus. The expansion of these sensory projections was concomitant with the enlargement of the telencephalic components receiving the respective inputs (Northcutt 1981; Northcutt and Puzdrowski 1988; Wicht and Northcutt 1992, 1993; Striedter 1997; Wicht 1996). With the exception of amphibians, which are considered to have a secondarily simplified brain (Northcutt 1981; Neary 1990), this phenomenon is also evident among terrestrial vertebrates. Nevertheless, this expansion process appears to have been a relatively late event in the evolution of each vertebrate class (the basal exponents usually bear quite simple brains), and pallial morphology evolves via clearly divergent lines in each group. In cartilaginous fishes, a division between a pallium and a ventral subpallium is generally acknowledged, but there is no agreement on their precise boundaries. The pallium is subdivided into medial (hippocampal), lateral (piriform), and the dorsal or general pallium between them. The latter component occupies most of the telencephalic roof and is further divided into an internal or central component (which is the largest and located in the midline; recall the telencephalon impar of cyclostomes), and a superficial or cortical region. Little is known about the afferents to this region, but its output is directed to the hypothalamus. As mentioned, the medial pallium receives most collothalamic sensory projections from the dorsal thalamus, and the lateral pallium receives most olfactory projections, together with

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Evolution of the Vertebrate Nervous System and Telencephalon

connections from some ventral telencephalic structures including the septum and the superficial striatum (Smeets 1990). The brains of bony fish are noticeable because their hemispheres do not show the typical evaginated appearance, but their medial pallia separate from the midline, opening the ventricular cavity, which remains covered by a thin layer of choroid plexus (Butler 2000c). This process, termed eversion, results in the inversion of the topography of cell masses, where the ventricular zone becomes the most superficial aspect and the pial surface becomes internal to it. This is reminiscent of a condition in which the neural tube has failed to close in its anterior region (Nieuwenhuys and Meek 1990). Interestingly, a relatively similar condition is observed in the holocephalans (basal cartilaginous fishes), in the lobe-finned coelacanth and in the lungfish Neoceratodus; in these species, the hemisphere walls are separated and are connected by an extensive ependymal membrane (Smeets 1998; Nieuwenhuys 1998d,e). This perhaps suggests that the brain of ancestral gnathostomes had its medial pallia largely separated at the midline by an extensive mantle of choroid plexus. This condition may have facilitated the eversion process in bony fish, which according to Striedter and Northcutt (2006) occurs as a consequence of the very small size of ray-finned fish embryos, which does not permit evagination of the hemispheres, forcing these cell masses to squeeze into the space rostral to the eyes. The pallium of lungfishes and amphibians is generally evaginated and consists in large part of periventricular cells that show a limited degree of radial migration; these cells do not make up a true cortical architecture. This has been interpreted to be a manifestation of neoteny or paedomorphosis (i.e., retention of a juvenile stage; Ten Donkelaar 1998c). The amphibian pallium has been subdivided into lateral, dorsal, medial, and ventral components (Holmgren 1922; Neary 1990; Bruce and Neary 1995; Puelles 1995; Brox et al. 2004; Moreno and González 2006). Based in large part on the relative absence of direct olfactory input and on the presence of at least thalamic visual and somatosensory projections, the medial pallium has been considered to be comparable to both the medial/dorsomedial cortex and the dorsal cortex of reptiles (Bruce and Neary 1995; see also Ten Donkelaar 1998b,c). On the other hand, the dorsal pallium receives substantial input from the main olfactory bulb and has been compared to parts of the lateral and olfactory cortices of reptiles and mammals. The lateral pallium of amphibians is subdivided into a dorsal component, also comparable to parts of the lateral cortex of amniotes, and a basal part which has been compared to the basolateral amygdalar complex of mammals and to the DVR of birds and reptiles. In amphibians, there is also a caudal striatum (subpallial) considered to be homologous to the striatal amygdala of reptiles and to the central amygdalar complex of mammals (Bruce and Neary 1995; Moreno and González 2003, 2004, 2005; Moreno et al. 2004; Laberge et al. 2006). The reptilian pallium has a three-layered cortex, consisting of a medial and a dorsomedial moiety (both comparable to the mammalian hippocampal formation), plus a lateral (olfactory) cortex (Ulinski 1990), and finally a dorsal cortex (equivalent to the archistriatum accessorium, or Wulst, of birds) located between these two, part of which receives visual projections from the dorsal lateral genic-

Evolution of the Telencephalon in Vertebrates

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ulate nucleus, as well as some somatosensory input (Medina and Reiner 2000). In reptiles and birds, many nonolfactory sensory projections (visual, auditory, and somatosensory) terminate in the DVR (Ten Donkelaar 1998b; Ulinski 1983), which in birds consists of three components, originally termed the archistriatum, neostriatum, and hyperstriatum. The DVR was originally considered to be part of the basal ganglia (Elliot Smith 1919; Johnston 1923), but subsequent studies (Karten 1968, 1969; Karten and Hodos 1970; Nauta and Karten 1970) established that this structure receives a strong sensory input, which was claimed to support a pallial origin. Furthermore, histochemical analyses probing acetylcholinesterase activity determined that the limits of the corpus striatum were located immediately ventral to those of the DVR (Parent and Olivier 1970; Parent 1986; Ulinski 1983). Considering these findings, a more recent nomenclature has changed these names into arcopallium (for archistriatum), nidopallium (for neostriatum), mesopallium (for the hyperstriatum ventrale), and hyperpallium (for the hyperstriatum accesorium, or Wulst; Reiner et al. 2004; Jarvis et al. 2005). The DVR is the most expansive telencephalic component of reptiles and birds and is a main integratory center in their brains. In reptiles, it consists of an anterior part (ADVR) and a posterior or basal part (PDVR). The output of the ADVR is directed mainly to the subpallial corpus striatum and to the PDVR. The latter (corresponding to the archistriatum/arcopallium in birds) has been compared to parts of the mammalian amygdala and projects mainly to the hypothalamus (Lanuza et al. 1998, 1999; Ten Donkelaar 1998b; Novejarque et al. 2004). Finally, mammals are characterized by the possession of the neocortex or isocortex, which originates during development at least in large part from the dorsal pallium (Rakic 1988; 1995; Northcutt and Kaas 1995; Voogd et al. 1998). The isocortex receives ascending sensory input from the thalamus and projects to the hippocampus and to the amygdala, as well as sending output to many lower brain centers including the thalamus, corpus striatum, various brainstem nuclei, and the spinal cord. In the adult brain, medial to the isocortex is the hippocampal formation (medial pallium), and lateral to it is the olfactory cortex (lateral pallium). Finally, there is a highly complex claustroamygdaloid complex in the ventral pallium. 2.3.5 Summary The first vertebrates (agnathans) were free-living animals with well-developed senses and already had a conspicuous telencephalon receiving a strong and widespread olfactory projection covering large extensions of the pallium, as well as some ventral pallial components such as the septal area and olfactory bulbs. While more basal aspects of the telencephalon may have been associated with the ventral forebrain and were possibly related to motor functions, the more dorsal regions were mainly olfactory but also received dorsal thalamic input from the collothalamic system. Although in hagfishes it is difficult to separate different pallial components (perhaps the central prosencephalic complex relates to the

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Origin of the Mammalian Brain

medial pallium, while the rest of the pallium consists of a laterodorsal pallium), in the lamprey it is already possible to separate medial, dorsal, and lateral components of the pallium, as in gnathostomes. In the latter, olfactory projections became largely restricted to the lateral pallium. Interestingly, the medial pallium receives a strong input from the dorsal thalamus, largely conveying sensory information that is relayed in the mesencephalon. This condition persists in most fish, but changes in tetrapods, in which information from lemniscal systems also reach the thalamus and project to the telencephalon. In early gnathostomes, the hemispheres increased in size and may have originally tended to an everted condition in which the medial hemispheres are separated by an extended sheet of choroid plexus. This trend is readily apparent in bony fishes, in which hemispheres become everted. However, cartilaginous fishes developed a prominent dorsal pallium with an internal nucleus centered at the midline (the central nucleus), thus closing the two hemispheres and generating an evaginated brain. Lungfishes and amphibians are characterized by a juvenilized brain with evaginated hemispheres as well. Amniotes are the first true land vertebrates, as they are able to reproduce on land. Amniotes split very early in two main lineages: stem reptiles, or anapsids, and mammal-like reptiles, or pelycosaurs. These early animals had very simple brains, which were possibly similar to those of present-day amphibians, where olfactory input reaches the lateral and the dorsal pallium, while dorsal thalamic projections reach the medial pallium. Reptiles develop a small cortex, consisting of medial, dorsomedial, dorsal, and lateral fields, plus a large periventricular structure termed the dorsal ventricular ridge, receiving most collothalamic input. Lemnothalamic inputs are sent mostly to the dorsal cortex. Mammals develop a large, six-layered neocortex that is topographically equivalent to the reptilian dorsal cortex and receives both lemnothalamic and collothalamic inputs.

3 Origin of the Mammalian Brain This section reviews the origin of the mammalian brain, especially the neocortex, which is the most salient and expanding neural component in this group. We will first discuss the fossil evidence on early mammals and their brains, and will follow with a comparison between reptilian and mammalian brains. In the reptilian brain, the lack of any structure obviously corresponding to the mammalian neocortex is quite evident. For this reason, there have been intense controversies in relation to the possible reptilian homologs to the neocortex. One such approach is based on connectional evidence indicating a similar sensory input between parts of the neocortex and the reptilian dorsal ventricular ridge; while other evidence, based on connectional and developmental criteria, suggests homology between the whole mammalian neocortex and the reptilian dorsal pallium. We will discuss these different approaches, and will propose a hypothesis for neocortical origins based on a dorsalization mechanism by which the dorsal pallium expanded in

The First Mammals

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response to signals emanating from the medial hemisphere (cortical hem), the lateral hemisphere (cortical antihem), and the frontal hemisphere. Then we will address the origin of cortical lamination, as the mammalian neocortex consists of six laminae, instead of the three laminae found in the reptilian brain; and the origin of the inside-out developmental gradient that is observed in the mammalian neocortex. In this process, the subventricular zone, a late embryonic proliferating compartment, probably played a special role. We will also offer a scenario in which olfaction was an especially important sense in early mammals and contributed to early neocortical expansion. Finally, we will briefly discuss the growth and diversification of the cerebral cortex in the mammalian radiations. 3.1 The First Mammals 3.1.1 Fossil Mammals and Their Brains The first radiation of mammal-like reptiles (synapsids) gave rise to the pelycosaurs, which were relatively large, lizard-like animals. In the upper permian, pelycosaurs were gradually replaced by their descendants, the therapsids. The hands and feet of the latter faced more directly forward instead of being oriented sideways as in other reptiles, which gave those animals a more mammalian-like gait. Some therapsids grew to achieve large sizes, and they are classified into carnivorous and herbivorous therapsids. Most therapsids became extinct by the end of the Triassic, but one group of carnivorous therapsids, the cynodonts, survived well into the Jurassic (Kemp 2005; Carroll 1988). Cynodonts were relatively small-bodied and had a more mammal-like jaw musculature, but the ear ossicles were still attached to the lower jaw, as they are in reptiles. From cynodonts arose the eucynodonts or mammaliaforms, which include Jurassic fossils such as Sinoconodon and Morganucodon, whose gross morphology resembled that of some present-day insectivores (Rowe 1996a,b). True mammals descend from eucynodonts, and are defined by the presence of a single dentary bone making up the inferior mandible and the complete detachment of the middle ear ossicles, as in the fossils Hadrocodium (Z.X. Luo et al. 2001, 2002), Gobiconodon, and Repenonamus (Wang et al. 2001; however, according to these authors, Hadrocodium is a juvenile form and it is not clear whether it had a fully mammalian middle ear). Further evolution of mammals includes the origin of monotremes, marsupials, and placental mammals. Triconodon is another interesting fossil, originally considered to be close to Morganucodon (Carroll 1988), but according to newer analyses it has been classified as a true mammal, perhaps belonging to the therians (marsupials and placental mammals; Rowe 1996a,b). Endocasts are molds of the cranial cavity of fossil animals. Analysis of these casts indicates that early mammal-like reptiles (therapsids) had quite narrow, tubular hemispheres with no signs of telencephalic expansion (Hopson 1979; Quiroga

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1980; Kielan-Jaworowska et al. 2004; Kemp 2005; see Fig. 10). Furthermore, in cynodonts the volume of the endocast was much larger than the volume of the brain, because ossification of the braincase was not as complete as in mammals and it is not possible to observe anatomical details of the brain. In true mammals, anatomical fissures and folds are much more clearly shown in the endocast, indicating a narrow fit between the braincase and the volume of the brain. Increase in brain size from cynodonts to early mammals is clearly shown in a comparison of their respective encephalization quotients (EQ, i.e., brain size given a specific body size). EQs of mesozoic mammals are twofold higher than those of advanced cynodonts (see Kielan-Jaworowska et al. 2004). This is closely correlated with an increase in the width of the braincase relative to skull width (Z.X. Luo et al. 2001). (Interestingly, modern primates also have a brain that is about twice the size of the brain of an average mammal of the same size; see Aboitiz 1996.) The braincase in stem mammals is narrower than in modern mammals, but is significantly wider than in nonmammalian cynodonts despite having a much smaller body size. For example Morganucodon, a primitive mammaliaform taxonomically intermediate between Triconodon and smaller-brained, more primitive therapsids, shows only partial expansion of the brain. In this species, widening of the pari-

Fig.10 Brain endocasts from fossil mammaliaforms and Didelphys (living marsupial). Brain expansion took place as a late event, closely associated with the origin of true mammals. (Modified from Aboitiz et al. 2003, with permission)

The First Mammals

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etal parts of the hemispheres can be observed (Kielan-Jaworowska et al. 2004; Rowe 1996a,b). Admittedly, endocast information can be difficult to interpret, since there are few anatomical details to identify as landmarks. Nevertheless, this feature may be partly attributed to the early development of the dorsal cortex – a possible precursor of the neocortex – in Morganucodon. Concomitant with the increase in size of the neocortex, the cerebellum also underwent a dramatic expansion in early mammalian evolution, with a clear differentiation of the vermis and an enlargement of the cerebellar hemispheres (reviewed in Kielan-Jaworowska et al. 2004). A dramatic increase in brain size, resulting from a generalized growth of the isocortex, occurs in the recent fossil mammals Triconodon and Hadrocodium. In these fossils, the detachment of the auditory bones from the mandible to form the mammalian middle ear coincides with enlargement of the brain (Rowe 1996a,b; Z.X. Luo et al. 2001). However, in other fossil mammals such as Repenomanus and Gobiconodon, braincases are narrow despite detachment of the ear ossicles (Wang et al. 2001). Therefore, brain expansion may have occurred after the origin of the middle ear, more than the reverse, i.e., brain enlargement triggering ossicle detachment for mechanical reasons (Wang et al. 2001; Gilissen and Smith 2003). The development of auditory projections into the neocortex was likely an important factor in the expansion of the latter and may have contributed to enhanced hearing (Aboitiz et al. 2003c). In this context, the mammalian auditory cortex contains binaural cells, many of which are interconnected interhemispherically by fibers of the corpus callosum (Pallas 2001) and may participate in spatial localization of sounds. On the other hand, the DVR of birds and reptiles has few or no interhemispheric connections, which may limit telencephalic auditory spatial processing in these animals. Early mammals also developed a keen sense of smell but apparently lost in part their visual ability to distinguish colors, which is consistent with their presumed nocturnal habits (Jerison 1973; Kemp 2005). In many protomammals, the intranasal bones formed a complex system for retaining water and heat (Hillenius 1994). Furthermore, mammals developed a diaphragm that made respiration more efficient. These conditions were probably of benefit for the expansion of olfactory capacities, as protomammals had large olfactory bulbs relative to their brains (Stephan 1983; Kemp 2005). In this context, it is of interest to note that the two largest-brained vertebrate taxa are birds and mammals, both of which also developed homeothermy. It is not unlikely that the increase in basal metabolism permitted the expansion of an energetically costly brain (Hopson 1979). Nevertheless, at least among mammals the relation between metabolic rate and brain size is a highly debated topic (for reviews, see Aboitiz 1996 and Striedter 2005). An additional possibility, not exclusive with the latter, is that the increased activity associated with an elevated metabolism co-evolved with the acquisition of a progressively more complex, goal-oriented organization of behavior.

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3.1.2 Summary Although early mammal-like reptiles diversified into several branches, their brains as seen in endocasts are surprisingly simple, perhaps more similar to present-day amphibian brains than to the differentiated brains of extant reptiles. The origin of true mammals is a late evolutionary event in the lineage of mammal-like reptiles, and is marked by the detachment of the middle-ear ossicles from the lower jaw, which served to increase auditory acuity. Early mammals also had large olfactory bulbs, indicating a well-developed sense of smell, but apparently their visual system was reduced as a consequence of their nocturnal habits. These events (especially the detachment of the middle-ear bones) are related to a subsequent increase in brain size, mainly due to expansion of the neocortex and cerebellum. As in birds, brain expansion may have been related to the acquisition of endothermy, which permitted a more active behavior and provided energy requirements for the development of a costly large brain. 3.2 Origin of the Mammalian Neocortex: Hypotheses on Homology 3.2.1 Mammalian Brain Expansion and the Origin of the Neocortex The neocortex or isocortex is a six-layered organ that is located between the threelayered lateral or olfactory cortex (lateral pallium) and the medial or hippocampal cortex (medial pallium, also bearing three main layers), in a topographic position corresponding to that of the dorsal pallium (Rakic 1988; Voogd et al. 1998; see Fig. 11). This structure is unique to mammals, is a conserved feature of all mammalian brains and is responsible for most of the increase in forebrain size in early and late mammalian evolution. Although in reptiles there are some laminated cortical structures (dorsal, medial, and lateral cortices), these never acquire the degree of tangential expansion and laminar differentiation that is observed in the mammalian neocortex. Furthermore, in reptiles, most sensory projections are delivered to the noncortical DVR instead of to the neocortex, as is observed in mammals (Fig. 11). In view of these differences, it has not been easy to determine the structure homologous to the neocortex in reptiles. In other words, the question of the ancestry of the mammalian neocortex, i.e., of which structure in the ancestral amniote brain gave rise to it, has not been solved despite about two centuries of studies in comparative neuroanatomy and neuroembryology. This problem is further complicated by the absence of a single criterion to establish homology of neural structures. Commonly used criteria for similarity are connectivity (Bruce and Neary 1995; Butler 1994a,b; Karten 1969, 1997; Medina and Reiner 2000; Reiner 2000), neurochemistry (Reiner 1991, 1993), and embryonic origins (Aboitiz 1992, 1995; Källén 1951; Puelles et al. 1999, 2000; Smith Fernández et al. 1998; Striedter 1997).

Origin of the Mammalian Neocortex: Hypotheses on Homology

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Fig. 11 The cerebral hemispheres of reptiles and mammals. The pallium of reptiles has a cortex, subdivided into medial/dorsomedial (MC), dorsal (DC) and lateral (LC) components; and a dorsal ventricular ridge (DVR). The medial and dorsomedial cortices of reptiles have been compared to the hippocampal formation (HP) of mammals; and the lateral cortex is considered homologous to the mammalian olfactory cortex (OC). The dorsal cortex of reptiles resembles both the mammalian entorhinal cortex (adjacent to the hippocampal formation; not shown) and the neocortex (NC). There is no agreement with respect to the homology of the dorsal ventricular ridge. Some authors claim that this structure corresponds to the lateral neocortex, and other authors argue that it relates to the mammalian claustroamygdaloid complex (AM). PT, pallial thickening. (Modified from Northcutt and Kaas 1995, with permission)

Unfortunately, when intending to identify structures homologous to the isocortex, there have been discrepant conceptions derived from these different approaches. 3.2.2 Hypotheses for Neocortical Origins Two alternative hypotheses have been raised regarding the origins of the mammalian isocortex, which have been elegantly summarized by Northcutt and Kaas (1995) as the recapitulation hypothesis and the out-group hypothesis. Proponents of the recapitulation hypothesis suggest that a DVR-like structure existed in the common ancestor of mammals and reptiles, which somehow became transformed into parts of the isocortex in the origin of mammals. This perspective is mostly based on studies on adult neuronal connectivity, and more specifically on the patterns of termination of thalamic afferents to the telencephalon (Karten 1968, 1997; Nauta and Karten 1970; Shimizu and Karten 1993). Karten’s approach was originally challenged on topographical and developmental grounds by Aboitiz (1992a,b; 1993, 1995), who proposed that the mammalian neocortex as a whole derived from the reptilian dorsal pallium, while the reptilian DVR originated deep to the lateral

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Origin of the Mammalian Brain

pallium. Later, Bruce and Neary (1995), Striedter (1997), Smith-Fernández et al. (1998), and Puelles et al. (1999, 2000), based on connectional and developmental evidence, proposed homology between the DVR and parts of the mammalian ventral pallium, including the lateral amygdala and the dorsal claustrum. This claustroamygdalar proposal was first stated by Holmgren (1922) but remained unacknowledged for a long time. These considerations were summarized in the out-group hypothesis (Northcutt and Kaas 1995), according to which the common ancestor of reptiles and mammals would have had a cerebral hemisphere similar in its topographic organization to that of present-day amphibians. In this case, the most likely candidate for homology with the isocortex is the reptilian dorsal pallium. Below, we will consider some of the evidence argued in favor of each of these hypotheses. 3.2.3 The Recapitulation Hypothesis: Connectional Evidence Butler (1994a,b) classified dorsal thalamic nuclei as either lemnothalamic or collothalamic. Lemnothalamic nuclei receive their main sensory projections from lemniscal ascending systems, which do not synapse in the mesencephalic colliculi, like the visual thalamofugal pathway (which relays on the lateral geniculate nucleus), and the spinothalamic and dorsal column somatosensory pathways (relaying in the ventral posterior thalamic nucleus). On the other hand, collothalamic nuclei receive sensory projections from the mesencephalic colliculi (like the visual tectofugal and the auditory pathways). Visual projections from the superior colliculus (or optic tectum) end in the posterior thalamic nuclei (mainly the pulvinar nucleus in mammals, and the nucleus rotundus in birds and reptiles), while auditory projections from the inferior colliculus end in the medial geniculate body of all amniotes. Lemnothalamic nuclei project to the dorsal cortex of reptiles and birds, and to the more medial/dorsal aspects of the neocortex of mammals (such as the striate or primary visual cortex and the somatosensory cortex), whereas collothalamic nuclei project to the anterior DVR (ADVR) of reptiles and birds, and to more lateral/ventral regions of the mammalian neocortex (the extrastriate visual cortex and the auditory cortex). The recapitulation hypothesis of homology between the ADVR and parts of the mammalian neocortex has been largely based on the comparative analysis of the collothalamic and lemnothalamic projections in birds and mammals. Shortly, the hypothesis specifies homology between the reptilian/avian dorsal cortex and the dorsal neocortex of mammals, and between the reptilian/avian ADVR and the lateral neocortex of mammals. Furthermore, relying on similarities in intrinsic connectivity, it has been proposed that different components of the avian DVR correspond to specific neocortical layers in mammals. In this perspective, the avian ectostriatum or entopallial nucleus, the general nidopallium (Reiner et al. 2004) and the archistriatum/arcopallium correspond to the mammalian visual extrastriate cortical layers IV, II–III, and V–VI, respectively

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Fig. 12 Karten’s hypothesis (1969, 1997) of the equivalent circuit in the mammalian neocortex and the avian dorsal ventricular ridge (DVR). I, II, III, IV, V, VI represent distinct neocortical layers; Arc, arcopallium; En, entopallium (a component of the nidopallium); H, hyperpallium; N, nidopallium; P, pulvinar; R, nucleus rotundus

(Karten 1997; Nauta and Karten 1970; Shimizu and Karten 1993; Veenman et al. 1995; Wild 1997; see Fig. 12). Recent studies indicate that avian areas of the DVR receiving sensory projections display markers such as RORB/Nr/1/2 and the voltagedependent potassium channel EAG2/KCNH5, which are also found in layer IV of primary sensory areas of the mammalian neocortex (Schaeren-Wiemers et al. 1997; Dugas-Ford and Ragsdale 2003). (Nevertheless, these markers are also detected in thalamorecipient areas of the avian Wulst, belonging to the dorsal pallium.) Related hypotheses have proposed equivalence between the postero-dorsolateral nidopallium (neostriatum) and the mammalian prefrontal cortex (Gagliardo and Divac 1993; Divac et al. 1994; Güntürkün 2005) and between the arcopallium (archistriatum) and the cortical frontal eye fields of mammals (Knudsen et al. 1995). 3.2.4 The Dorsal Cortex of Reptiles: Subicular and Neocortical Characteristics The recapitulationist hypothesis has been largely based on the comparison between avian and mammalian brains. However, in reptiles the situation is slightly more complicated, as it has been argued that lemnothalamic systems reaching the dorsal cortex are not strictly comparable to those in mammals (see MartínezGarcía 2003; Guirado 2003). For example, somatosensory projections to the dorsal cortex have not been observed either in lizards (Bruce and Butler 1984a,b; Lohman and Van Woerden-Verkley 1978; Neary and Wilczynski 1977) or turtles (Hall and Ebner 1970). In the case of visual projections, the thalamic lateral geniculate nucleus projects to a region that in turtles includes the dorsal cortex and the pallial thickening (a thickening in the lateral aspect of the pallium that is observed in

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some reptiles; see Fig. 11), and in lizards is restricted to the pallial thickening (Hall and Ebner 1970; Kenigfest et al. 1997; Lohman and Van Woerden-Verkley 1978). In addition, multimodal projections from the dorsal thalamus reach the basal ganglia and the dorsal pallium in both amphibians and reptiles (Wilczynski and Northcutt 1983; González et al. 1990; Marín et al. 1997; Ten Donkelaar 1998a,b,c; Guirado et al. 2000; Martínez-García 2003; Guirado 2003). In amphibians, there are multimodal projections, carrying both lemnothalamic and collothalamic information to the mediodorsal (and lateral) pallium from the anterior thalamic nucleus (Vesselkin et al. 1971), and in reptiles a similar projection reaches the medial and dorsal cortices from the dorsolateral anterior thalamic nucleus (Bruce and Butler 1984a; Desan 1988; Lohman and Van Woerden-Verkley 1978; Belekhova and Ivazov 1983; Ivazov and Belekhova 1982). A more recent hodological study in the turtle determined that the dorsomedial anterior nucleus of the thalamus projected mostly to the ipsilateral medial cortex, while the dorsolateral anterior nucleus projected to the dorsomedial cortex, and the dorsal lateral geniculate nucleus projected to the dorsal cortex, thus making a mediolateral topographic map between the distinct thalamic nuclei and the cortical regions (Zhu et al. 2005). (This work also described a descending pathway linking cortical regions [especially medial cortex] with the brainstem red nucleus via the suprapeduncular nucleus of the hypothalamus, thus providing an indirect cortical control of the red nucleus that in mammals becomes direct.) Considering this evidence, it has been proposed that the visual projection from the lateral geniculate is a derived rather than an ancestral feature of reptiles (Martínez-García 2003; Guirado 2003). According to these and other authors (Powers 2003), the multimodal dorsomedial pallium of amphibians and reptiles resembles more the mammalian hippocamposubicular cortex. This proposal is supported by anatomical evidence indicating that, like the entorhinal cortex, the reptilian dorsal cortex has important connections with the medial/dorsomedial or hippocampal cortices (Hoogland and Vermeulen-Vanderzee 1989; Northcutt and Ronan 1992; Guirado and Dávila 2002; Martínez-Marcos et al. 1999). Furthermore, behavioral evidence in lesioned animals indicates that the reptilian dorsal cortex does not participate in vision but rather in learning and memory (Powers 1990). Lesions in the dorsal cortex produce deficits in acquisition and reversal of pattern discriminations (Blau and Powers 1989; Cranney and Powers 1983), spatial discriminations (Grishman and Powers 1990), and in a variety of other learning tasks (Grisham and Powers 1989; Avigan and Powers 1995; Day et al. 2001; Peterson 1980; Petrillo et al. 1994; Moran et al. 1998), which strongly relate this structure with the medial (hippocampal) cortex, which participates in spatial and other forms of learning in a variety of vertebrates (Grisham and Powers 1989; O’Keefe and Nadel 1978; Rodríguez et al. 2002a,b). Thus, the dorsal cortex of reptiles may be compared to the entorhinal cortex of mammals, but also containing a direct visual sensory input that, if perhaps not being the true homolog of the mammalian visual cortex, serves to feed visual information to the hippocampus for establishing sensory associations during learning. Furthermore,

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the dorsal cortex of reptiles differs from the amphibian dorsal pallium in that it receives much stronger dorsal thalamic inputs, lacks direct projections from the olfactory bulb, and projects to several extratelencephalic targets (Bruce and Butler 1984a,b), characters that are reminiscent of the mammalian neocortex. 3.2.5 Differences in Connectivity Between the DVR and the Neocortex There is also some connectional evidence that points to differences between the reptilian DVR and the mammalian isocortex. Firstly, the mammalian extrastriate visual cortex receives an important input from the primary or striate visual cortex (Montero 1993; Rosa and Krubitzer 1999). Although in reptiles, projections from the dorsal cortex to the DVR have been described (Ten Donkelaar 1998b; Ulinski 1990), these are much less prominent than the striate-extrastriate connections of mammals. Secondly, the mammalian isocortex projects reciprocally to the entorhinal cortex and from there to the hippocampus (Haberly 1990; Rosene and Van Hoesen 1987; Van Hoesen 1982), while in reptiles few connections if any have been reported from the DVR to the medial/dorsomedial cortex or hippocampus (Ten Donkelaar 1998b; Ulinski 1983, 1990). Moreover, based on comparisons of connectivity, Bruce and Neary (1995) have argued that the reptilian DVR is most similar to the mammalian lateral amygdala, since both structures receive projections from collothalamic nuclei and both project to the corpus striatum, the striatal amygdala, and the ventromedial hypothalamus. (More precisely, the reptilian ADVR would correspond to the mammalian basolateral amygdala, while the whole DVR might correspond to the whole lateral amygdalar nucleus.) On the other hand, the isocortex projects to many other brain regions in the brainstem and spinal cord, and does not project to the hypothalamus. These authors claim that fewer changes in connectivity are required by assuming homology between the lateral amygdala of mammals and the DVR of reptiles than by considering homology between the isocortex and the DVR. An additional difference between sauropsids and mammals is that the corpus striatum receives its major projection from the ADVR and from the isocortex, respectively. Nevertheless, the basolateral amygdala of mammals and the dorsal cortex of reptiles also project to the corpus striatum (Bruce and Neary 1995; Ten Donkelaar 1998b), which is consistent with the similarity of connections between the ADVR and the mammalian basolateral amygdala, and between the dorsal cortex of reptiles and the mammalian isocortex. Note that other hodological studies have concluded that the mammalian basolateral amygdala corresponds to the reptilian posterior DVR (PDVR) and lateral amygdala, instead of the ADVR (Martínez-García et al. 2002; Moreno and González, 2004, 2006; Moreno et al. 2004; Novejarque et al. 2004; Laberge et al. 2006). In this context, one particularly controversial issue concerns the thalamic lateral posterior/pulvinar (LP/P) nucleus of mammals and its presumed homology with the reptilian and avian rotundus nucleus. The mammalian LP/P, receiving projections from the superior colliculus and projecting to the extrastriate visual

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isocortex, has been long considered to be homologous to the reptilian or avian nucleus rotundus, which receives projections from the optic tectum and sends efferents to the ADVR (Butler 1994b). Furthermore, Major et al. (2000) described marked similarities in the dendritic morphology of motion-sensitive tectopulvinar neurons in mammals and the tectorotundal neurons in birds. In both groups, such neurons have dendritic arborizations that end in monostratified arrays of spiny terminal specializations called bottlebrush endings. The homology between the LP/P and the rotundus nuclei has been a strong element in the theory of homology between the lateral isocortex and the ADVR, since these two nuclei have been considered to form part of the collothalamic, tectofugal visual pathway in mammals and reptiles, respectively. According to Bruce and Neary (1995), because in mammals, the thalamic nuclei projecting to the lateral amygdala belong to the intralaminar complex, these nuclei and not the LP/P nucleus should be considered homologous to the thalamic nucleus rotundus of reptiles and birds. In this line, some reports have claimed that the mammalian LP/P nucleus receives a different type of tectal projections than the reptilian rotundus. In birds and reptiles, the rotundus nucleus receives input from early-born cells in the deep tectal stratum griseum centrale, while in mammals the tectopulvinar cells are presumably lateborn and located in the more superficial stratum opticum (Dávila et al. 2000, 2002; Guirado et al. 2000; Redies et al. 2000; Yoon et al. 2000). These authors subdivide the thalamic nuclei into three tiers: the intermediate and ventral tiers receive projections from the mesencephalic colliculi, and the dorsal tier receives projections from lemniscal systems. According to this view, the reptilian nucleus rotundus and the mammalian intralaminar nuclei might correspond to intermediate tier nuclei, while the mammalian LP/P might be a dorsal tier nucleus that acquired a tectal input in the origin of mammals. This interpretation was recently challenged, among others, by Güntürkün (2003), who claims that in the mammalian superior colliculus, the distinction between superficial and deep layers is determined by the position of the stratum opticum. However, in birds and reptiles the stratum opticum is more superficially located and it is not possible to establish a clear-cut distinction between superficial and deep layers. Furthermore, Güntürkün argues that according to the data reported by Altman and Bayer (1981), in mammals there are no birth time differences between those collicular neurons projecting to the LP/P or to the posterior or intralaminar nuclei (see also Katoh and Benedek 1995), and that the birthdates of the tectorotundal pathway of birds and the colliculo-LP/P pathway in monkeys are quite similar if the differences in developmental times are taken into account (Wu et al. 2000). Güntürkün then dismisses the three-tier concept of thalamic organization by assuming lack of evidence, and argues that quite many differences in connectivity between the intralaminar and the rotundal nucleus would have to be explained if these were considered homologous. Some of these arguments have been recently contested by Guirado et al. (2005), who observed that telencephalic projections of the posterior/intralaminar complex of the mammalian thalamus can be compared with the telencephalic projections

Origin of the Mammalian Neocortex: Hypotheses on Homology

45

of the nucleus rotundus. More specifically, the mouse suprageniculate nucleus (which receives fibers from intermediate and deep collicular strata, thus according to these authors being more comparable to the tectorotundal projection in birds), shares a number of afferents and efferents with the nucleus rotundus, such as the corpus striatum, the lateral amygdala in the ventral pallium, and the dorsal claustrum in the lateral pallium. These authors contend that the mammalian intermediate stratum of the superior colliculus corresponds to the stratum griseum centrale in birds and reptiles. They further argue that the intermediate layers of the optic tectum of birds/reptiles, and of the superior colliculus of mammals, receive somatosensory and auditory inputs in addition to visual ones, and can be used as a reference to compare superficial and deep strata between birds and mammals. Furthermore, they cite evidence that nuclei in the posterior thalamus of the rat (which include the suprageniculate nucleus, the medial division of the geniculate body, the posterior intralaminar nucleus, and the peripeduncular nucleus) project upon the striatum and the claustroamygdaloid complex, in addition to specific cortical areas (Doron and LeDoux 1999, 2000; Linke 1999). As intense as it is, this controversy may not be crucial for the issue of neocortical origins. The outgroup hypothesis was first proposed by assuming homology between the mammalian LP/P and the avian/reptilian rotundus nucleus; the main point is that the pallial projection of these nuclei reaches different, nonhomologous targets in mammals and sauropsids (Aboitiz 1992a,b; 1995). Furthermore, recent evidence indicates that at least the mammalian lateral posterior nucleus (a component of the LP/P complex) projects heavily to the striatum, lateral amygdala, and neocortex (but lacks connections with the dorsal claustrum; Guirado et al. 2005; Doron and LeDoux 1999). In this context, in mammals including humans, there is evidence for a subcortical, subconscious alarm system that bypasses the primary visual cortex and includes activation of the superior colliculus, LP/P nucleus, and the lateral amygdala (Shi and Davis 2001; Liddell et al. 2005). This pathway may represent an evolutionarily ancient response system to threatening stimuli, and be the heir of an ancestral collothalamic-ventral pallial or collothalamic-subpallial pathway in early reptiles or amphibians. Thus, the mammalian projection from LP to the striatum and amygdala may be likened to the rotundal projections to the striatum and DVR in reptiles. In this way, if the LP/P and rotundus are indeed homologues, the outgroup hypothesis would consider that the LP/P retained some projections to the claustroamygdalar complex (equivalent to the ADVR) while projecting additional inputs to the dorsal pallium. One possibility among others would be that in the mammalian lineage, the equivalent to the sauropsidian nucleus rotundus became fragmented and subdivided into several nuclei, including the lateral posterior, the pulvinar and posterior/intralaminar complexes including the suprageniculate nucleus. Thus, in mammals there would have been a separation of two collothalamic pathways, one originating in cells of the deep collicular layers and projecting to the mammalian suprageniculate nucleus, and the other originating from more superficial collicular cells and projecting to the LP/P complex. In this way, the LP/P pathway might have retained many features of the original

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tecto-rotundal-ventral pallial pathway, including the morphology of tectal efferents and the presence of specific synaptic markers (Luksch et al. 1998; Dugas-Ford and Ragsdale 2003), but adding a projection to the lateral neocortex. This process would be entirely consistent with the concepts of neural pathway parcellation and segregation in evolution (Ebbesson 1980, 1984; Krubitzer 1995, 2000), and if correct, it should be reflected in a common embryonic specification of these nuclei. Furthermore, the development of new connections like the collothalamic–lateral cortex projections is not an unusual feature of the mammalian brain, as can be witnessed by the interhemispheric callosal tract and the corticospinal projection (see Sect. 3.6.1). The other main collothalamic pathway conveys auditory information, and is commonly described as being relayed from the thalamic medial geniculate nucleus to the DVR in reptiles and birds, and from the homologous nucleus to the auditory cortex in mammals. However, in mammals thalamic auditory projections from the medial geniculate body pars medialis also reach the lateral amygdala (LeDoux et al. 1990, 1991; Turner and Herkenham 1991; Frost and Masterton 1992, 1994; Doron and LeDoux 1999), and participate in the response to fearful stimuli, making a rapid alarm system similar to that in the visual LP/P–lateral amygdala projection. Furthermore, medial geniculate nucleus plasticity in fear conditioning is strongly dependent on an intact basolateral amygdala (Maren et al. 2001). Therefore, the two collothalamic pathways (visual and auditory) that project to the reptilian and avian DVR, project to both the lateroventral neocortex and the lateral amygdala of mammals, the latter connection subserving escape behaviors. Considering this evidence, the lateral amygdala appears at least as an equally probable candidate for homology with the reptilian DVR as the ventrolateral neocortex. 3.2.6 Summary In nonmammals, there is no structure that clearly corresponds to the mammalian neocortex. In the search for a homolog of this structure, one hypothesis asserts that the avian anterior dorsal ventricular ridge corresponds to the lateroventral aspects of the neocortex, receiving auditory and visual collothalamic projections, while the avian Wulst (dorsal pallium) corresponds to the primary visual and somatosensory cortices. Other evidence, based on work on reptiles, suggests that the reptilian dorsal cortex has features of both the entorhinal cortex and the neocortex, and in mammals there is evidence of collothalamic projections to the ventral pallium (the claustroamygdalar system), which may be likened to the collothalamic projections to the avian/reptilian DVR. Furthermore, the overall connectivity of ventral pallial sectors such as the basolateral amygdala resembles the reptilian DVR more than the neocortex.

Embryological Evidence

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3.3 Embryological Evidence 3.3.1 Developmental Criteria for Homology During embryogenesis, the DVR (especially its anterior part) develops from a position largely ventral and deep to the olfactory cortex. This was determined in early embryological work on snakes (Warner 1946), lizards (von Hetzel 1974), Sphenodon (Hines 1923), crocodiles (Källén 1951), and turtles (Holmgren 1922; Källén 1951; Kirsche 1972), and more recently on birds (Striedter et al. 1998), establishing that the DVR arises as a late proliferation process, after the migration of cells belonging to lateral cortex has been completed. Later in development, the DVR bulges into the ventricle, locating ventral to lateral cortex and immediately dorsal to the corpus striatum (Ulinski 1983). Considering this early evidence, Northcutt (1969) originally proposed that both the lateral cortex and the DVR of reptiles were homologous as a whole with the mammalian lateral cortex and parts of the neocortex (although he changed his view in subsequent writings, being more sympathetic with the outgroup hypothesis; Northcutt and Kaas 1995; Northcutt 2003). Taking a perhaps more radical position, Aboitiz (1992b, 1995) proposed that the DVR, arising in a region that overlaps with the lateral cortex, consisted of late-produced cells (late in relation to lateral cortex development), largely originating from a similar embryonic region as the lateral cortex itself. Furthermore, much of the adult avian and reptilian DVR would consist of late-produced cells that have no strict homolog in the adult mammalian brain. This hypothesis is supported by the fact that the amphibian lateral pallium receives not only olfactory projections but also some inputs from the dorsal thalamus (Kicliter and Northcutt 1975), implying that this structure is comparable to both the lateral and the ventral pallium of reptiles, or that the amphibian lateral pallium also contains a ventral pallial component (see also Moreno and González 2004; Moreno et al. 2004). Considering this evidence, for the ADVR to be ancestral to the neocortex, a massive migration of excitatory cells from the proliferative zone underneath the lateral cortex (the region giving rise to the ADVR) toward the visual extrastriate and auditory cortex would have to be demonstrated. However, to date evidence suggests that in mammals these cortical areas arise from the cortical neuroepithelium (Parnavelas 2000), while the neuroepithelial region corresponding to the embryonic reptilian DVR produces ventral pallial components (Tole et al. 2005). The migration of inhibitory interneurons from subcortical structures appears to be a phylogenetically ancient character and may not be directly related to neocortical origins, being possibly present also in agnathans (Marín and Rubenstein 2001; Meléndez-Ferro et al. 2002; Brox et al. 2003; Molnár et al. 2006). Literally turning this issue around, Reiner (1993) and Butler (1994a) proposed a topographic position of the DVR that is equivalent to that of lateral neocortex, that is, between the dorsal and lateral cortices. Reiner (1993) asserted that the

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dorsal pallial sector of stem amniotes possessed a lateral zone that was the forerunner of both DVR in sauropsids and lateral neocortex in mammals. In primitive reptiles like Sphenodon, the DVR appears continuous with the dorsal cortex in its anterior region, and in turtles this domain of continuity corresponds to the pallial thickening (Ten Donkelaar 1998b; Ulinski 1990; Reiner and Northcutt 2000). Nevertheless, Reiner (1993) did not mention the position of the lateral cortex, which appears interposed between the DVR and the dorsal cortex through most of their extent (Senn 1979; Ulinski 1990). Raising an additional hypothesis, Butler (1994a) suggested homology between the DVR and the neocortex on the basis of the presence of a subventricular zone (SVZ) in the two structures during development, from which both the lateral neocortex of mammals and the DVR of reptiles would emerge (Smart and Smart 1977; Yanes et al. 1987). We will come back to this proposal in Sect. 3.5.1. This problem has been recently clarified by studies of expression patterns of regulatory homeobox-like genes in the embryonic forebrain, which have revealed a conserved mosaic organization where the different compartments develop into specific adult brain components (Gellon and McGinnis 1998; Moens et al. 1998; Puelles and Rubenstein 1993; Seo et al. 1998). The embryonic lateral and medial ganglionic eminences, located in the lateral subpallium and giving rise to the corpus striatum and globus pallidus, express the marker genes Dlx1 and Dlx2 (Anderson et al. 1997b). The cerebral cortex arises mostly from the embryonic pallium and is characterized by the expression of genes of the Emx and the Otx families (Acámpora and Simeone 1999; Mallamaci et al. 1998; Pannese et al. 1998; Puelles and Rubenstein 1993; Simeone et al. 1992). Smith Fernández et al. (1998) identified for the first time what they termed an intermediate territory in the equatorial region of the hemisphere, between the pallium and the subpallium of amphibians, reptiles, birds, and mammals, which does not express either the Emx1 or Dlx1 markers of the pallium and subpallium, respectively, but is largely positive for the gene Pax6 (another pallial marker; Smith-Fernández et al. 1998). More recent reports (Puelles et al. 1999, 2000) confirmed the existence of the intermediate territory (which has been termed ventral pallium by these authors), and extended the previous findings by showing that Pax6 and Tbr1 are expressed in the whole pallium including the ventral pallium, but PAX6 appears mainly near the ventricular zone and TBR1 has a more superficial activity. Thus, the medial, the dorsal, and part of the lateral pallium express Emx1 and Tbr1 superficially and Pax6 more internally, whereas the ventral pallium expresses Tbr1 superficially and Pax6 deeply, but not Emx1. The presence of a ventral pallium has also been confirmed in amphibians (Brox et al. 2002, 2004; Moreno and González 2004, 2006; Moreno et al. 2004), indicating that it is an ancestral character and not a derived feature of amniotes (reptiles, birds, and mammals). In sauropsids, an important part of the DVR (more specifically, its anterior component, including the neostriatum/nidopallium and ectostriatum/entopallial nucleus of birds) and part of the lateral cortex develop from the Emx1-negative ventral pallium, whereas in mammals, the basolateral amygdalar complex, part

Embryological Evidence

49

of the claustral complex, the endopiriform nucleus, and parts of the lateral or olfactory cortex – among other structures – were claimed to derive from this region (Puelles et al. 1999, 2000; Smith-Fernández et al. 1998; see Fig. 13). More recently, Medina et al. (2004) described the anterior and posterior amygdalar areas and the amygdalo-hippocampal area as ventropallial structures. On the other hand, the claustrum proper (formerly the dorsolateral claustrum), the posterior endopiriform nucleus, the dorsal part of the piriform cortex, the basolateral amygdalar nucleus, and the posterolateral cortical amygdalar area appear to belong to the lateral pallium. As mentioned, two mammalian structures have recently been proposed to correspond to the ADVR: the basolateral amygdala (Bruce and Neary 1995; Puelles et al. 1999; Smith Fernández et al. 1998) and the endopiriform nucleus (Striedter 1997). Developmental evidence favors both the basolateral amygdala and the endopiriform nucleus as comparable to the DVR (Smith Fernández et al. 1998; Puelles et al. 1999). On the other hand, while some connectional evidence indicates similarity between the ADVR and the basolateral amygdala (Bruce and Neary 1995), other evidence suggests similarity between the PDVR and the basolateral amygdala (Martínez-García et al. 2002; Moreno and González 2004; Moreno et al. 2004; Novejarque et al. 2004), and the connections of the endopiriform nucleus parallel quite closely those of the olfactory cortex (Behan and Haberly 1999). Homology of the DVR with the mammalian claustrum was originally questioned as a first report communicated the absence of a claustrum in monotremes (Butler et al. 2002), while a more recent report refuted this observation (Ashwell et al. 2004). Thus, although it seems clear that the reptilian ADVR derives from a ventral pallial component, there are disagreements regarding the precise mammalian homolog of this structure. Smith-Fernández et al. (1998) argued that in reptiles and birds the ventral pallium remains as a distinct neuroepithelial zone until late development, the period in which it gives rise to most of the ADVR, which is in agreement with previous embryological studies (Holmgren 1922; Källén 1951; Kirsche 1972). On the contrary, in mammals, this territory was described as producing only early-generated components, becoming obliterated between the Emx1-positive and the Dlx1/2positive zones in later development (Smith-Fernández et al. 1998). In agreement with this interpretation, Swanson (2000) and Künzle and Radtke-Schuller (2001) suggest that the mammalian claustral complex has developmental timing similar to early-produced cortical elements such as the mammalian subplate (an embryonic layer that develops before the definitive cerebral cortex in mammals); both structures make up about the earliest pallial neurons. Although Puelles et al. (1999) seem to disagree with the concept of the ventral pallium disappearing from the neuroepithelial surface in mammals, they admit that this territory is considerably compressed between the lateral pallium and the developing striatum. To us, this evidence suggests that in mammals, some ventral pallial components such as the claustrum consist of early produced components and may not be directly comparable to those late-generated components of the reptilian – and especially avian – highly developed DVR (Källén 1951). This agrees with the concept

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Origin of the Mammalian Brain

Fig. 13 Embryonic telencephalic territories based on regulatory gene expression data. The medial, dorsal and lateral pallia (violet) express the markers Emx1, Tbr1 and Pax6, while the ventral pallium (yellow) expresses Tbr1 and Pax6 but not Emx1. The subpallium (green) expresses Dlx genes. According to this data, the anterior dorsal ventricular ridge (ADVR) and the avian nidopallium (N) derive mainly from the ventral pallium. a, vc, termination of auditory and visual collothalamic pathways, respectively; vl, termination of visual lemniscal pathways. STR, corpus striatum. (Modified from Aboitiz et al. 2003, with permission. Data from Smith Fernández et al. 1998 and Puelles et al. 1999, 2000)

Embryological Evidence

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that in mammals there is no strict homology to the reptilian and avian ADVR, or at least to a large part of it (Aboitiz 1992, 1995). In this way, much of the avian DVR may consist of phylogenetically new cell groups, produced during late development, a situation that is similar to what is observed in the mammalian neocortex, in which superficial layers represent an evolutionary acquisition of the mammalian brain (see Sect. 3.5.1). Nevertheless, connections from the collothalamic dorsal thalamus to the ventral pallium are present in both reptiles and mammals, and therefore may reflect a primitive character even if they do not reach exactly homolog regions in each group. Considering this evidence, Reiner (2000) modified his original proposal suggesting that in the common ancestor to reptiles and mammals there was a structure that diverged into the lateral isocortex of mammals and into the ADVR of reptiles. This structure was either Emx1-negative and acquired Emx1 expression in mammals, or, alternatively, was Emx1-positive and lost Emx1 expression in reptiles and birds. A somewhat similar hypothesis was raised by Butler and Molnár (2002) and Molnár and Butler (2002a,b), who proposed an alternative hypothesis by which the ventrolateral neocortex, together with the mammalian claustrum and the pallial amygdala, are field homologs of the sauropsidian ADVR, the former arising from a duplication event in the ventrolateral pallium yielding a dorsal (cortical) and a ventral (amygdaloclaustral) component. Again, difficulties with these interpretations concern the ventral embryological origin of the DVR and the adult position of the lateral cortex, which separates the DVR and the dorsal cortex through most of their extent. The concept that the mammalian lateral cortex gained Emx1 expression (or that the DVR lost it) would need to be supported by embryological tracing studies, indicating common embryonic origins of both structures. In this context, Butler and Molnár (2002) reported the development of a DVR-like structure in the Pax6–/– mutant, indicating an evolutionarily atavic condition. However, this mutant has been reported to develop a dysgenic ventral pallium (Tole et al. 2005), which is not entirely consistent with the development of a ventral pallial DVR-like structure. In general, although these hypotheses may be consistent with the concept of phylogenetic parcellation (Ebbesson 1980, 1984), they lack positive evidence supporting them, such as a clear sign of ventral pallial origin of the lateral neocortex. Furthermore, they might be impossible to refute, as any dorsal pallial sign in these regions could be interpreted to result from the transformation of this ventral pallial region into a dorsal pallial one. Additional issues requiring further study concern the mammalian homologies of the reptilian posterior DVR or avian archistriatum/arcopallium, and the hyperstriatum ventrale/mesopallium (corresponding to the dorsolateral anterior DVR; Guirado et al. 2000; Puelles et al. 2000) of birds. According to Smith-Fernández et al. (1998), the reptilian posterior DVR and the avian archistriatum/arcopallium, or at least part of these structures, express pallial markers and are comparable to the corticomedial and central amygdala of mammals (Swanson and Petrovich 1998). On the other hand, Puelles and colleagues (Puelles et al. 1999) argue that only the posterior archistriatum/archipallium is pallial. The hyperstriatum ventrale or

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mesopallium of birds expresses Emx1 during development, suggesting that it may derive from the dorsal or lateral pallium and not from the IT/VP. This structure has recently been compared to the Emx1-positive dorsolateral ADVR of reptiles and to the dorsolateral claustrum of mammals (Puelles et al. 2000; Guirado et al. 2000). 3.3.2 Dorsoventral Gradients and Expansion of the Dorsal Pallium Considering the evidence reviewed in the above sections, we have argued that the mammalian neocortex arose through the tangential expansion of the reptilian dorsal pallium (Aboitiz 1992, 1993, 1995, 1999a,b). More recently (Aboitiz et al. 2003c), we proposed that a dorsalization mechanism, producing an increase in proliferation of dorsal pallial sectors, would have generated the required telencephalic expansion leading to the origin of the neocortex. Considering that much evidence implies a strong similarity between the reptilian dorsal cortex and the entorhinal/subicular cortex, one interesting possibility is that the dorsal cortex expanded medially to become the entorhinal/subicular complex and laterally to become the sensory neocortex (Powers 2003). The dorsal hemisphere and the mammalian cerebral cortex are patterned by virtue of several interacting signaling cascades. Genes of the Wnt family are essential for hippocampal development and are also expressed strongly in the caudomedial margin of the cortical pallium (Kim et al. 2001). Wnt receptors of the Frizzled family are most concentrated in the isocortical neuroepithelium, while being sparse or entirely absent in the more medial hippocampal neuroepithelium (Kim et al. 2001). Similarly, two Wnt inhibitors (secreted Frizzled-related proteins 1 and 3) are expressed in opposing anterolateral to caudomedial gradients in the telencephalic ventricular zone. In addition, the Emx2 gene, whose expression domain is similar to that of Emx1 but includes subpallial sectors (Gulisano et al. 1996), has been found to be arranged in a gradient with maximal concentrations in the posteromedial isocortex and minimal concentrations in the anterolateral isocortex (Mallamaci et al. 2000). Furthermore, the Pax6 gene is expressed in a gradient that is complementary to that of Emx2, being maximally expressed in the anterolateral isocortex and minimally expressed in the posteromedial isocortex (Bishop et al. 2000). The modulation of overall dorsoventral, frontocaudal, and/or mediolateral gradients of expression of the above-mentioned regulatory genes may have profound effects in the development of specific telencephalic components (Chapouton et al. 1999; Stoykova et al. 2000; Muzio et al. 2002; Grove et al. 1998; Monuki et al. 2001; Shinozaki et al. 2002; Meyer et al. 2002, 2004; Shimogori et al. 2004; Tole et al. 2005). It is therefore possible that the expansion of the dorsal pallium in primitive mammals occurred partly as a consequence of the enhancement of a dorsalizing signal in telencephalic development. Since the structure that expanded most in mammalian evolution is the dorsal pallium (neocortex) rather than the medial pallium, the lateral pallium, and the ventral pallium, there may be some yet unknown genes exclusively determining the fate of this structure, which increased their do-

Embryological Evidence

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mains of expression and enhanced cell proliferation specifically in this region. In particular, genes involved in the regional specification of the cortical proliferative zone, such as Wnt3a, Neurogenin, and others, may have been fundamental in the expansion of this structure (Monuki and Walsh 2001). In a way, the dorsal pallial territory can be conceived as an interphase between different embryonic fields, one corresponding to the medial pallium and determined by morphogens emanating from the cortical hem (Gli3, Wnts, BMPs, and others; Grove et al. 1998), another corresponding to more anterior regions including the lateral/ventral pallium and olfactory structures from where FGFs are being produced (Shimogori et al. 2004), and perhaps a third source expressing EGF factors and dependent on Pax6, located along the ventrolateral pallium (the cortical antihem; Assimacopoulos et al. 2003). The partly antagonistic interaction between these fields may have yielded an upand down-regulation of genes such as Wnts, Emx1/2, Lhx2, Pax6, Neurogenin, and other genes generating a new territory produced by an increased rate of progenitor cell proliferation in the ventricular zone (see Medina 2003). In this context, a recent report indicates that transgenic mice expressing β-catenin in neural precursors develop an enlarged cortical surface area, while maintaining a normal cortical depth (Chenn and Walsh 2002). Another report indicates that ASPM, a gene essential for mitosis in embryonic neuroblasts, is required for attaining a normal cortical size (Bond et al. 2002). Perhaps these genes are downstream elements in the cascade triggered by the interaction between these morphogenetic fields. The expansion of the presumptive dorsal pallial territory may have produced a ventrolateral displacement of the lateral pallium, which perhaps differentiated in territory originally destined to the ventral pallium. In this way, through shifts in the boundaries of the territories of regulatory gene expression, cells that initially differentiated in one specific compartment may have acquired patterns of differentiation of other telencephalic areas. The obliteration or compression of the ventral pallium that has been described in the mammalian telencephalon (Smith-Fernández et al. 1998) might result from tangential expansion of the expression domain of Emx1 and related markers, from invasion of this territory by tangentially migrating Emx1-positive cells, or simply from its elimination by cell exhaustion or cell death. Of course, this may not be the whole story, because, in addition to the displacement of pallial boundaries, there has also been an overall increase in brain size, which possibly was largely produced by an increase in proliferative activity within the dorsal pallium and other regions. On the other hand, the pallium of reptiles may present an enlarged ventral pallium because of a ventralizing pallial influence that maintains a restricted expression of Emx1 and other dorsal pallial genes. 3.3.3 Summary Early developmental evidence indicated that the reptilian and avian DVR originates from a late-proliferative region located deep to the lateral cortex, in a position topographically equivalent to that of the mammalian claustroamygdalar system.

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Furthermore, more recent studies of gene expression patterns during development indicate that the avian and reptilian DVR, as well as the mammalian claustrum and amygdala, largely develop from the ventral or lateral pallial territory. During development, the reptilian and avian proliferative zones giving rise to the DVR continue producing neurons until late stages, while in mammals it appears that ventral pallial neuronal production is restricted to earlier stages, producing a relatively much smaller adult structure. Thus, large parts of the avian/reptilian DVR may consist of cells newly acquired in the evolution of the reptilian lineage and may not be strict homologs to any mammalian cells. The mammalian neocortex derives from a Pax6, Tbr1, and Emx1-positive territory in the dorsal hemisphere that greatly expands during development, as compared to the equivalent zone of the reptilian brain. Thus, a dorsalization process is proposed in which the region corresponding to the dorsal pallium increased neuronal production in response to some morphogenetic activity or to a combination of activities, perhaps including Gli3, Wnts, Emxs, Lhx2, Pax6, FGFs, and other factors derived from at least three signaling sources: the anterior forebrain, the medially located cortical hem, and the lateral antihem. A second possibility is that the neocortex expanded by either a massive migration of cells from the ventral pallium into the dorsal cortex, somehow acquiring Emx1 expression during development, or by a transformation of a ventral pallial region into a dorsal pallial structure. Unfortunately, at this point there is no positive evidence indicative of these processes. Therefore, we conclude that at this point, developmental evidence favors homology between the mammalian neocortex and the dorsal pallium of reptiles. 3.4 The Olfactory–Hippocampal Hypothesis 3.4.1 A Functional Interpretation of Dorsal Pallial Expansion in Mammalian Origins If the neocortex arose from an expansion of a small field bordering the medial pallium and the lateral pallium, the question of the adaptive benefit to develop this structure arises. We consider that early neocortical expansion was largely due to a strictly contingent situation that was not observed in early reptiles and relates to the development of the sense of olfaction (see also Sagan 1977). In reptiles, the dorsal cortex is an interface connecting the olfactory and the hippocampal cortices and relaying dorsal thalamic input into the latter for visuospatial learning. In early mammals, olfactory input may have been especially important for several behaviors including learning. This condition produced an unusual development of the olfactory–dorsal cortex–hippocampal networks, which resulted in an initial expansion of the dorsal pallium. Subsequently, increasing lemnothalamic and collothalamic projections were directed toward the dorsal pallium, thus contributing to its further expansion.

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As previously discussed, the reptilian medial and dorsal cortices receive multimodal sensory projections from the lateral anterior thalamic nucleus, and at least visual projections from the lateral geniculate nucleus. However, the most important sensory pathway is the collothalamic projection to the ventral pallial ADVR, carrying visual, auditory and somatosensory input. In turn, the ADVR projects heavily into the PDVR, which sends afferents to hypothalamic regions (Novejarque et al. 2004). Thus, in reptiles the ventral and dorsomedial pallia receive largely different sensory pathways, and there is relatively little cross-talk between them. The situation is different in mammals. The lemnothalamic-receiving primary visual cortex projects massively to the extrastriate cortical areas (which receive the collothalamic visual projection), and these, together with the auditory and somatosensory cortical areas and the olfactory cortex, project (through a series of successive corticocortical projections) to the hippocampus (via the entorhinal cortex) and to the amygdala, in order to process different types of mnemonic information (spatial/episodic and emotional, respectively; Lynch 1986; Maren 1999). This implies that in mammals there is a confluence of the lemnothalamic and collothalamic processing pathways to a degree that is not observed in reptiles (Aboitiz 1992; Aboitiz et al. 2003b,c; Butler 1994b). (Recall that in mammals there is also a remnant of the collothalamic projection to the ventral pallium, which is important in the generation of automatic emotional responses; Sect. 3.2.5.) Furthermore, the direct dorsal thalamic input to the medial pallium in amphibians is weakened in reptiles and disappears in both mammals and birds (Neary 1990; Ulinski 1990). Thus, reptiles and amphibians have two parallel routes of dorsal thalamic input to the medial pallium (via the dorsal pallium and directly from the thalamus), while in mammals (and in birds) the main entrance of thalamic sensory input to the medial pallium is via the dorsal pallium. In addition to the thalamic sensory projections, in terrestrial vertebrates there is an important olfactory input via the lateral pallium into the medial pallium. The projections from both the lateral and dorsal pallium (receiving olfactory input) into the medial pallium in amphibians may have served as precursors for the development of olfactory–hippocampal circuits in amniotes (Ten Donkelaar 1998b,c). In reptiles, there is a well-defined circuit connecting the medial (hippocampal), the dorsal (receiving the lemnothalamic pathways), and the olfactory cortices (Lynch 1986; Ten Donkelaar 1998a). There is evidence that in reptiles and probably in most other vertebrates, the medial and the dorsal pallia participate in spatial learning (Rodríguez et al. 2002a,b; see Sect. 3.2.4). Among reptiles, active foraging lizards tend to have larger medial and dorsal cortices than species that hunt with a sit-and-wait strategy (Day et al. 1999). In addition, lesions in these regions impair spatial learning in these animals (Day et al. 2001; Rodríguez et al. 2002a,b). The authors further argue that these cortical areas may use nonspatial clues for spatial navigation, which is important in relation to new concepts of hippocampal function described below. In mammals, a classical understanding of hippocampal function is that this structure creates a cartesian representation of space, in which the different places

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and coordinates are mapped onto the structure itself (O’Keefe and Nadel 1978). This concept was partly proposed on the basis of the discovery of place-cells in the hippocampus of experimental animals, which are activated by specific positions of the animal in a given space (O’Keefe and Dostrowsky 1971). However, the situation is slightly more complex, as evidence has shown that many hippocampal cells fire in response to nonspatial determinants such as odors, and that the activity of the cells depends on the behavioral state of the animal (see Eichenbaum 1999; Eichenbaum et al. 1999). Hippocampal cells can recognize rewarded and nonrewarded cues, spatial configurations of odors, differences between odors, or fire at specific behavioral instances (Wiener et al. 1989; Wood et al. 1999, 2000). In addition, it has been found that spatial and nonspatial (olfactory) information are segregated in interleaved, oblique stripes along the hippocampus (Hampson et al. 1999). This structure has also been shown to be required for nonspatial olfactory tasks, such as tests of transitive inference, higher-order sequential associations, or the social transmission of food preferences (Galef 1990; Bunsey and Eichenbaum 1996; Dusek and Eichenbaum 1997; Alvarez et al. 2001; Ergorul and Eichenbaum 2006). In summary, there is substantial evidence that the mammalian hippocampus participates in olfactory memory and in other memory processes in addition to spatial mapping (Eichenbaum 1998, 2006). Partly based on this evidence and on the finding that place cells are more consistently controlled by local cues (see Eichenbaum et al. 1999), it has been proposed that the representation of space in the hippocampus consists of the specification of behaviorally relevant spots. These spots are identified by cues such as odors and other (visual) characteristics of the environment, and include a collection of independent representations of places, linked among them by the behavioral context in which the animal explores its environment (Eichenbaum 1999, 2000a,b; Eichenbaum et al. 1999; Ergorul and Eichenbaum 2004). For these authors, a fundamental function of the hippocampus is its participation in episodic memory, that is, memory of the events that take place during a particular behavioral action. Spatial memory emerges as consequence of the integration of successive episodes during an exploration task and involves associations between different sensory modalities, including vision and olfaction. This proposal could reconcile the apparently discrepant findings that, in animals, the hippocampus participates in spatial memory, whereas in humans, it participates in declarative memory. Instead of spatial memory, Eichenbaum prefers to speak of a memory space, which is an organized representation of memory episodes linked by their common features (Eichenbaum 2000b; Eichenbaum et al. 1999; however, see alternative view by O’Keefe 1999). We suggest that in the process of generating this memory space, olfaction (which is an important sense used to investigate the environment by many small mammals such as rodents and insectivores) may participate as a “glue” that helps linking many of these spots, creating a cohesive map of the behaviorally relevant points. In present-day mammals such as the rat, visual input is necessary for the firing of a large number of hippocampal cells, while olfactory information can be used to compensate for the lack of visuospatial information (Save et al.

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2000). Therefore, visual information may have been progressively involved in the associative hippocampal–olfactory networks during the origin of mammals, thus triggering the expansion of the dorsal cortex. This is not to say that visual cues have little importance in spatial or episodic learning in nonmammals, but rather that the visual input to the mammalian hippocampus is more complex, so that more accurate representations of both behavioral situations and their spatial context can be made. The olfactory–hippocampal–dorsal cortex circuit may have been put to use by the first mammals to make relatively elaborate, largely olfactory-based representations of space, in which specific odors labeled particular places and routes (recall that early mammals were presumably nocturnal and may not have been able to rely on visual information as strongly as reptiles or laboratory mammals; Jerison 1973, 1990; Sagan 1977; Kemp 2005). Nevertheless, the contribution of the visual system undoubtedly became necessary in the elaboration of more precise maps of space, especially when mammals invaded diurnal niches after the decline of dinosaurs. The dorsal cortex, receiving visual information from the thalamofugal visual pathway, may have been an important element for associative learning in the early mammalian brain, as it is now in reptiles (Aboitiz 1992a,b). Although there is evidence for a strong conservatism in hippocampal general function and in its participation in spatial learning (Salas et al. 2003; Colombo 2003), there are also important differences in hippocampal connectivity between mammals and reptiles (reviewed in Butler 1994a,b; Striedter 2005), which suggest that there have been some changes in this overall conserved architecture, perhaps facilitating in mammals an expansion of associative functions and the elaboration of more subtle forms of spatial and episodic memory. Electrophysiological evidence indicates that the neuronal dynamics present in primitive olfactory–cortical circuits, including modulations of frequency, phase, and amplitude of oscillations during olfactory processing are also observed in neocortical circuits, suggesting that olfactory associative processing formed the basis for large-scale couplings involving the expanding isocortex (Hermer-Vazquez and Hermer-Vazquez 2003). Furthermore, these olfactory–hippocampal tangential circuits may have facilitated the establishment of strong pallio-pallial connectivity that is related to slow-wave sleep, a characteristic that is absent in reptiles and appears independently in mammals and birds (Rattenborg 2006). Our point is that within a generally conserved framework, early mammals made more use of olfactory–hippocampal associations than other amniotes, and that this situation was related to the expansion of the dorsal pallium, which received increasing dorsal thalamic input. Eventually, the mammalian hippocampus received quite a strong thalamic sensory input via the association areas of the neocortex and the entorhinal cortex, perhaps at the expense of the disappearance of direct thalamohippocampal projections. In a way, in early mammaliaforms there may have been a stronger emphasis on hippocampal function, which in part propelled dorsal pallial expansion. In this context, a dorsalizing effect on dorsal pallial development as we have suggested before, triggering an expansion of the dorsal cortex, may have been of

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great benefit for the development of olfactory–hippocampal–cortical networks. This expansion may have permitted the invasion of collothalamic sensory routes into the dorsal pallium, which were originally projected to the ventral pallium (or to the subpallium, as in present-day amphibians; see also Northcutt 1969; Northcutt and Kaas 1995). In addition, the auditory projection to the cerebral cortex instead of to the ventral pallium may have benefited from the cortical representation of space by developing a more elaborate sound localization system. Thus, we postulate that a major innovation in the origin of the mammalian brain has to do with the increasing confluence of the lemnothalamic and the collothalamic pathways in the dorsal pallium, in order to process information which, among other things, participated in spatial learning and episodic memory. In this process, the hippocampus may have become a fundamental component in which both types of sensory pathways converged. The lateral pallial basolateral amygdala is an additional component in this process, which also received a strong input from the dorsal pallium, in addition to the direct collothalamic projection. In mammals, this structure establishes strong connections with the orbitofrontal cortex and may have served as an additional element in these networks, establishing an olfactory–amygdalar–hippocampal associative axis (McDonald 1991; Bota 2003; see Aboitiz et al. 2003b,c). 3.4.2 Summary In reptiles, the medial pallium or hippocampus receives ascending sensory projections from the thalamus and dorsal cortex, and olfactory projections via the lateral cortex. There are some projections from the dorsal cortex into the ADVR, but these are probably not as robust as the cortical projections to the mammalian amygdala. It is possible that a somewhat similar situation existed in ancestral mammal-like reptiles, in which there was a tangentially oriented, olfactory-related network connecting the lateral, dorsal, and medial pallia, plus a dorsal thalamic sensory projection to the dorsal and medial pallia. Early mammals presumably had a well-developed sense of olfaction and may have used this skill to make behavioral maps of their surroundings. The development of extensive olfactory-hippocampal networks may have facilitated the expansion of the dorsal pallium, which began to receive an extensive input from lemnothalamic projections but also from collothalamic projections that were originally destined to the ventral pallium. This permitted the strong confluence of the lemnothalamic and collothalamic sensory systems, and perhaps contributed to the elaboration of more elaborate forms of memory than simple spatial location in the hippocampus. Other sensory inputs such as the auditory were possibly quite important in neocortical expansion as well. Finally, a remnant of a collothalamic projection to the ventral pallium exists in the dorsal thalamic projection to the mammalian amygdala.

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3.5 Origin of Neocortical Lamination 3.5.1 Laminar Organization of the Neocortex In the adult, the neocortex consists of six layers, the most superficial of them (layer I) characterized for containing very few neuronal elements and many tangentially oriented fibers; layers II and III contain small pyramidal cells and some interneurons and establish associative contacts with neighboring regions. Layer IV contains spiny stellate cells that receive thalamic afferents arriving radially from the underlying white matter and send projections to superficial layers, and layers V and VI contain projection neurons to different subcortical targets (layer VI cells mostly send a reciprocal projection to the thalamus). The development of this structure is a highly ordered process (Fig. 14). During corticogenesis, there are successive waves of neuronal migration from the cortical neuroepithelium and other regions. The first wave constitutes an embryonic preplate (PP) that, with the posterior arrival of cortical plate (CP) neurons, will split into a superficial marginal zone (MZ, future layer I), and a deeper subplate (SP). Eventually, most cells from the MZ and SP die in late development or become highly diluted due to telencephalic expansion. CP neurons arrange between the MZ and the SP and will make the adult layers II–VI of the neocortex. These layers are generated in an inside-out sequence in which early born neurons remain in deeper positions, while neurons born later migrate past the earlier ones and locate more superficially (Angevine and Sidman 1961; Rakic 1974).

Fig. 14 Laminar organization of the neocortex. There are several waves of cell migration making up the distinct layers of the adult neocortex. Initially, a preplate is formed which is later split into a superficial marginal zone (MZ) and a subplate (SP) by the arrival of cells forming the cortical plate (CP). There, cells arrange in an inside-out gradient in which early-produced cells locate in deep layers and late-produced cells locate in superficial layers. Arrow points to progressively later generation times in the cortical plate

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In early development, the MZ contains some pioneer neurons (PNs) and reelinpositive Cajal-Retzius cells (Meyer et al. 1998, 1999), while the SP consists of PNs plus sparsely distributed polymorphic neurons (Kostovic and Rakic 1990). PNs are the first cells to arrive to the cortex and their axon, directed subcortically, serves as a guide for growing thalamocortical axons (McConnell et al. 1989, 1994). Thalamic and corticocortical axons arriving from the underlying white matter usually reach the SP and remain there for some time before entering the developing CP. CajalRetzius cells in the MZ help in radial glia maintenance and provide clues for radialmigrating neurons that will form the CP (Soriano et al. 1997; Supèr et al. 1998a,b, Xie et al. 2002). Thus, the MZ and SP participate in regulating cell proliferation, neuronal migration, axonal growth, and thalamocortical synaptogenesis in the CP (Alcántara et al. 2006; Kanold 2004; Marín-Padilla 1998; Xie et al. 2002; Alcántara et al. 2006). Neurons populate the PP and the developing cortex from several sources: one is the subcortical ganglionic eminence (principally its medial ad caudal components), which contributes PNs and GABAergic interneurons (Anderson et al. 1997a,b; Bystron et al. 2005; Deng and Elberger 2001, 2003; Jiménez et al. 2002a,b; Kriegstein and Noctor 2004; Lavdas et al. 1999; Marín and Rubenstein 2001, 2003; McConnell et al. 1989; Morante-Oria et al. 2003; Nadarajah and Parnavelas 2002). A more important source is the cortical neuroepithelium, providing excitatory, radially migrating cells mostly to the SP and CP (Rakic 1995, 2000; Nadarajah et al. 2003; Kriegstein and Noctor 2004; O’Leary and Borngasser 2006). Nevertheless, other pallial regions contribute tangentially migrating, excitatory neurons to the PP (like the dorsomedial cortical hem, providing Cajal-Retzius cells) and perhaps also to the CP (Del Río et al. 1995; Meyer et al. 1998, 2002, 2004; Yang et al. 2000; Abraham et al. 2004; Bielle et al. 2005). 3.5.2 Comparison of Mammalian Neocortex and Reptilian Cortex: Layer Homologies Compared to the reptilian cortex, which has only a few neurons in its radial depth (Ulinski 1990; Voogd et al. 1988), the mammalian neocortex is characterized by its radial expansion, being organized in radial columns about 100 cells in depth (Rockel et al. 1980; Rakic 1988). In mammals, neurons at different levels of the radial column belong to each of the six tangential laminae that make up this structure, which in reptiles are no more than three. In this context, Marín-Padilla (1971, 1972, 1978, 1992, 1998) and Marín-Padilla and Marín-Padilla (1982) originally proposed that the amphibian pallial cells and the reptilian cortical cells actually corresponded to the mammalian embryonic preplate (especially the SP). His view was that the developmentally earliest cortical cells might be the best candidates for homology with the ancestral reptilian cells. Thus, the entire CP (adult cortical layers II–VI), which develops after the PP, might be considered a newly developed structure in mammalian evolution. Although sometimes viewed as an outdated recapitulationist view, this interpretation is consistent with the heterochronic concept of hypermor-

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phosis, in which additional stages are added at the end of embryonic development (see Gould 1977; McKinney and McNamara 1991). A somewhat similar hypothesis was provided by Ebner (1969) and Reiner (1991, 1993), who proposed that instead of corresponding to the mammalian preplate, the reptilian cortex mostly corresponds to the deep layers VI and V of the mammalian CP. Cells in the superficial layers IV–II are connectionally, morphologically, and neurochemically different from reptilian cells, and can be considered as a derived character of the mammalian neocortex. Moreover, early-produced, deep-layer cortical neurons migrate radially by translocation (a mode of migration independent of radial glia, in which the apical process of the cell contacts the subpial layer, and the cell body is dragged toward the surface while the apical process shortens), while late-produced, more superficial neurons migrate to the cortex by locomoting along a radial glia that serves as a substrate, a process that requires the action of the cyclin-dependent kinase cdk5 and its activator p35 (Nadarajah et al. 2001). These differences in migratory processes may reflect different phylogenetic origins in time (Aboitiz 1999a, 2001a). Furthermore, other authors consider that much of the mammalian SP is not ancestral; instead, this structure can be viewed as an embryonic acquisition of the mammalian brain, since it is most complex in those areas that appear later in mammalian evolution, and in mammals with more complex brains (Kostovic and Rakic 1990). These authors proposed that the SP evolved as an embryonic device to support the development of corticocortical connectivity. Other evidence suggests the existence of a preplate-like structure in embryonic reptiles (Nacher et al. 1996), which would imply that the preplate does not correspond to an adult but to an embryonic ancestral structure. In this context, it is important to note that in mammals, the difference between the embryonic SP and the deepest layers of the adult cortical plate are not absolutely clear-cut, and that these structures may be developmentally related. For example, the gene Tbr1 marks subplate neurons and the earliest CP neurons; and mutations in this gene cause defects in both the preplate and the deepest layer VI of isocortex (Hevner et al. 2001; Kolk et al. 2005), suggesting similarities in genetic organization between these structures. In a similar line, in the rat and other mammals with a limited or moderate degree of isocortical expansion, many subplate cells survive into adulthood, forming layer VII (Reep 2000; Woo et al. 1991; Harman et al. 1995). Furthermore, some authors claim that in marsupials there is no subplate; rather, the equivalent to the subplate consists of the earliest generated layer VI cells that become incorporated into the lower CP (Harman et al. 1995; Reep 2000). This would imply that an embryonic subplate is not ancestral to mammals. Despite these controversies (some of which we will intend to clarify below), it seems generally acknowledged at this point that the superficial cortical layers represent a new acquisition of the mammalian brain. We originally proposed that the Pax6 gene was involved in the evolutionary origin of the isocortical superficial layers (see Aboitiz et al. 2001b, 2003), and that this involvement consisted of the recruitment of the cortical subventricular zone (SVZ) in the neurogenetic process. The SVZ is a proliferating compartment of the cortical neuroepithelium that is located peripheral to the ventricular zone,

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an earlier proliferative layer. Mutants for Pax6 exhibit cortical migration defects, consisting of the inability to migrate and differentiate of superficial, late-generated isocortical neurons belonging to layers IV to II, which are generated in the SVZ (Caric et al. 1997; Fukuda et al. 2000). Furthermore, Pax6 promotes conversion of ventricular zone to SVZ progenitors and stimulates neurogenesis (Heins et al. 2002; Scardigli et al. 2003). The genes Ngn1 and Ngn2 also regulate the transit of cortical progenitors from the ventricular to the subventricular zones (Britz et al. 2006), but possibly in a Pax6-dependent manner (Scardigli et al. 2003). Further evidence indicates that, while activation of the genes Ngn1 and Ngn2 is required to specify the laminar characteristics of early-born cortical neurons, upper layer cortical neurons are specified in an Ngn-independent manner, requiring instead the synergistic activities of Pax6 and Tlx (Schuurmans et al. 2004). Recently, Molnár et al. (2006) and Kriegstein et al. (2006) presented evidence indicating a progressive development of the subventricular zone in large-brained mammals, its near absence in the reptilian embryonic dorsal cortex, and its parallel development in the avian nidopallium, which supports the interpretation above. It will be of interest to determine if there is a contribution of the subventricular zone and of the Pax6 gene and related ones to dorsal cortical development in reptiles. In cortical development, the subventricular zone appears first in the lateral aspect of the hemisphere, near the pallial-subpallial boundary, and in later stages expands into more dorsal regions (Nieto et al. 2004; Zimmer et al. 2004). Perhaps one possibility to reconcile the two hypotheses of lateral neocortical origins (ventral pallial/DVR vs dorsal pallial; see Sects. 3.2 and 3.3) is that the mammalian cortical subventricular zone originated in evolution as a consequence of the propagation of a late-proliferating activity originally restricted to the lateral aspect of the hemisphere. This event might be related to the enhanced morphogenetic activity of the cortical antihem or a related source in the lateral and ventral pallium, and to the consequent diffusion of some morphogenetic signal(s) into more dorsal pallial regions. This wave inducing late proliferative activity recruited neural precursors from the dorsal neuroepithelium and gave rise to the neocortical subventricular zone. In this way, although originating in the dorsal pallial region, cells from the subventricular zone could have arisen as a consequence of the influence of a late-proliferating ventral or lateral pallial proliferative activity. This possibility would be partly consistent with Butler’s (1994a) proposal of the involvement of a subventricular zone in the origin of both the reptilian DVR and the mammalian neocortex and could also help explain the complex relation between cortical layering and the claustrum in the insula of some basal insectivores (Künzle and Raddtke-Schuller 2001). 3.5.3 Is There a Preplate in Reptiles? A conspicuous component of the mammalian PP are the superficially located reelin-positive Cajal-Retzius cells. Reelin-positive neurons have been observed in

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the MZ of the developing cortex of turtles, lizards, and crocodiles; at lower levels, reelin expression has also been detected below the developing cortex of turtles and lizards and in the ventricular zone of crocodiles (Bar et al. 2000; Bernier et al. 2000; Goffinet et al. 1999; Pérez-García et al. 2001; Tissir et al. 2003). In crocodiles, these neurons were found to co-express p73 (Tissir et al. 2003), which is a marker of reelin-positive Cajal-Retzius cells that derive from the cortical hem in the medial hemisphere (Meyer et al. 2002). Considering that in the mammalian dentate gyrus, one of the roles of reelin is to guide growing entorhinal axons (Förster et al. 2006b), it is possible that the ancestral function of this molecule in early amniotes was to attract dorsal cortex axons into the medial cortex. This would explain the origin of most Cajal-Retzius cells from the cortical hem in the dorsomedial aspect of the telencephalon. Interestingly, a recent report showed that HAR1F, an RNA gene co-expressed with reelin in Cajal-Retzius cells, has been the subject of intense selection during human evolution (Pollard et al. 2006). In mammals, both the level of reelin expression per cell and the number of reelin-positive neurons in the marginal zone are much higher than in reptiles, indicating that with the appearance of the neocortex there has been a unique amplification of reelin expression in Cajal-Retzius cells (Bar and Goffinet 2000; Bar et al. 2000). Furthermore, the levels of reelin expression seem to correlate with the degree of cortical columnarity in different reptilian species (Bar and Goffinet 2000; Bar et al. 2000; Meyer et al. 2002). It is possible that in mammals, the increase of reelin expression occurred in the context of controlling the final stages of cortical migration and layer positioning (Aboitiz 1999; Aboitiz et al. 2001, 2003c). Nevertheless, the fact that in reptiles reelin is expressed in the marginal zone and in other regions below the cortex suggests that this protein may have other functions besides controlling the end stages of neuronal migration. In the developing reptilian cortex, some authors argue for the presence of an incipient PP that is split by the arrival of the CP (Bernier et al. 1999; Goffinet et al. 1999; Supèr et al. 1998b; Tissir et al. 2003). In our view, this preplate-like structure might consist in large part of Cajal-Retzius-like cells and subpallial, tangentially migrating cells, but it is not clear that it contains radial-migrating excitatory elements. Early migration of subpallial, inhibitory neurons into the pallium has been suggested in amphibians (Brox et al. 2003), birds (Cobos et al. 2001a), and reptiles. In the developing lizard brain, Nacher et al. (1996) described the presence of somatostatin-positive cells appearing first in the inner plexiform layer and later in the outer plexiform layer of the medial and dorsal cortices. Cordery and Molnár (1999) observed cells positive for neuropeptide Y, scattered in all regions of the ventral pallium of the turtle. Finally, some early tangentially migrating neurons observed in the mammalian intermediate zone may perhaps correspond to tangential neurons traveling in the reptilian intermediate zone (Cordery and Molnár 1999; Bar et al. 2000). Therefore, although in reptiles there may be early tangentially migrating neurons, some of which are perhaps comparable to interneurons of the mammalian preplate and SP, it is possible that the latter are more complex in terms of cell numbers and types.

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Summarizing, many elements forming the reptilian preplate-like structure arise from tangential migration from subpallial regions (and presumably from the cortical hem); these might correspond to some tangentially migrated cells in the mammalian PP. Nevertheless, the mammalian SP also contains an important population of glutamatergic, excitatory cells whose development has been poorly characterized (Finney et al. 1998; Hanganu et al. 2001, 2002). In this context, a recent report has described an important radial contribution to the PP and SP, presumably consisting of excitatory cells (O’Leary and Borngasser 2006). According to Harman et al. (1995), SP neurons (excitatory) derive from the earliest CP neurons. One possibility is that, in placental mammal evolution, SP excitatory neurons may have originated from the CP itself, being generated in progressively earlier developmental stages to support the development and connectivity of the later-appearing true CP cells (Kostovic and Rakic 1990; Harman et al. 1995; Aboitiz et al. 2005). 3.5.4 Origin of the Inside-out Developmental Gradient Another characteristic of the mammalian cortex is the inside-out developmental gradient of lamination, in which late-produced, radial migrating neurons move past the layers of neurons produced earlier. This pattern is common to all mammalian cortical regions, including the hippocampus (Petrone et al. 2003), but is found only in the mammalian cortex. In reptiles, the cortex develops in an outside-in pattern, with younger cells locating below the older ones (Goffinet et al. 1986). Furthermore, the synaptic organization of the mammalian neocortex differs dramatically from other cortical structures such as the olfactory cortex and the hippocampal formation, and from the reptilian cortex. In the neocortex of advanced mammals, thalamocortical and corticocortical axons travel predominantly via the white matter below the cortex and penetrate the cortex upwards, in a radial direction to make synapses in layer IV (Rakic 1988). On the other hand, in the reptilian cortex and in archicortical and paleocortical mammalian structures, afferents (cortical and thalamic) run tangentially in the superficial MZ, synapsing in series a number of apical dendrites from pyramidal cells (Supèr et al. 1998a,b). The mammalian inside-out developmental gradient has been proposed to result from a developmental strategy oriented to gain synaptic contacts between the phylogenetically new late-born neurons during radial cortical expansion, and the cortical afferents (from both the thalamus and other cortical regions) located in the MZ. In order to establish such contacts, late-born neurons had to migrate past the layers of early-born neurons (Aboitiz 1999, 2001; see Fig. 15). This is consistent with the hypothesis that some glutamatergic Cajal-Retzius cells may attract migrating neuroblasts through the CP, thus contributing to generate the inside-out gradient (Del Río et al. 1995; Alcántara et al. 2006). Another interpretation is that the shift of thalamic afferents from the superficial layer I to the subcortical white matter released a barrier that permitted the expansion of the cortex in an inside-out manner (Supèr and Uylings 2001). This hypothesis links the processes of preplate

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Fig.15 This diagram depicts a possible sequence in the acquisition of laminar characteristics of the neocortex. In reptiles, with an outside-in neurogenetic gradient (arrow upwards) afferents follow the pioneer neurons (red diamonds) in the superficial marginal zone, above the cortex (ovals). In the hippocampus, there is already an inside-out gradient (arrow downwards) but afferents and pioneer neurons are still located superficially. In Erinaceus, axons enter the cortical plate from below but may run obliquely and end in the marginal zone. Finally, in the primary sensory cortex of advanced mammals, most pioneer neurons locate in the subplate, and axons enter the cortex radially, synapsing with neurons in layer IV

splitting into a MZ above and a SP (containing PNs that guide thalamic axons) below the developing CP, with the origin of the inside-out neurogenetic gradient (this link is supported by recent developmental evidence; Rakic et al. 2006). However, it leaves wanting an adaptive explanation of these changes (Aboitiz et al. 2003b). In addition, comparative evidence suggests that inside-out lamination and the change from superficial to deep position of afferents are dissociable to some extent. The mammalian hippocampus has an inside-out laminar pattern while its afferents are still organized superficially in layer I, suggesting that the insideout lamination pattern originated before the rerouting of afferents (Aboitiz et al. 2003c). Furthermore, in the neocortex of small-brained insectivores, axons initially enter the cortical plate in a radial direction, but then follow an oblique course, reach the superficial layer I and run tangentially in it for a long distance (Valverde et al. 1986; Supèr et al. 1998a,b), indicating that the superficial, tangential arrangement of thalamic afferents remained an important feature after the origin of inside-out cortical lamination. Considering that early-produced cortical plate cells may represent an ancestral phenotype, while late-produced cells are considered to be an evolutionary acquisition, we have suggested that the cdk5/p35 pathway, which assists late-produced neurons while migrating along the radial glia (Nadarajah et al. 2001; see Sect. 3.5.2), is somehow related to the migration of the phylogenetically new cell types of the mammalian isocortex and to the origin of the inside-out neurogenetic gradient of the isocortex (Aboitiz 1999a, 2001; Aboitiz et al. 2001a,b). More specifically, although cdk5 is required for locomotion along the radial glia, its activator p35 is

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important for migrating neurons to cross the previously produced layers of cells inside the CP. Cells in isocortical layer V might represent an intermediate condition between the ancestral phenotypes and the new ones, as they originate in the deep ventricular zone instead of the subventricular zone, and are morphologically and neurochemically reptilian-like; but like younger cells, they seem to be more dependent on cdk5 than cells of layer VI to cross the subplate and other cortical layers. Again, the study of cdk5/p35 expression in the developing cortex of reptiles may provide substantial information on isocortical evolution. “Additionally, reelin may have contributed to the inverted layering by arresting migration and detaching neurons from the radial glia, thus permitting late-born neurons to use the latter to migrate past early-born neurons. If reelin fails as in the reeler mutant, neurons stack in a roughly outside-in gradient, maintaining abnormal attachments to the radial glia (Caviness 1976; Pinto-Lord et al. 1982).” 3.5.5 Pioneer Neurons and the Transition from a Tangential to a Radial Synaptic Organization in the Neocortex The transition from a tangential to a radial organization of cortical inputs in neocortical origins implies that afferents (thalamocortical and corticocortical) have been gradually displaced from a superficial, tangential position to a deep, white matter position with a radial entrance to the cortex (Fig. 15). It is conceivable that ancestrally, the pioneer neurons that guide thalamocortical and corticocortical axons migrated mostly through the superficial MZ, attracting axons superficially, while in isocortical evolution there has been a gradual shift in the position of pioneer neurons to a subplate position that becomes located underneath the cortical plate. In this way, more and more afferents were progressively dragged below the cortex instead of above it in the MZ. In support of this view, data from our laboratory shows the existence of PN in the MZ of the developing reptilian cortex, which are followed by growing thalamocortical afferents (Montiel et al. 2004; Aboitiz et al. 2005). Additional evidence indicates that in embryonic turtles, there are early migrating cells within the lateral forebrain bundle and striatum, projecting their axons to the thalamus (Cordery and Molnár, 1999). This suggests that a PN-guidance axis also exists in reptilian telencephalic development. Consistent with the concept of a gradual shift in the location of pioneer neurons and the superficial arrangement of some cortical afferents in primitive mammals (Valverde et al. 1986), a higher proportion of PNs is left in the subplate of humans than in the subplate of rodents, where many PNs remain in the MZ (Meyer et al. 1998, 2000). In addition, in some mutant mice such as the reeler and the SRK, the SP is malpositioned above the CP. This might be due to abnormal cell-to-cell attachments among SP cells, which act as a barrier imoending CP cells to migrate past them. In these mutants, axons tend to follow in the anomalously superficial superplate and then descend into the cortical plate to establish synapses with the corresponding cells, suggesting that axons have followed the pioneer neurons that are superfi-

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cially malpositioned (Caviness 1976; Caviness et al. 1988; Molnár 1998; Molnár and Cordery 1999; Higashi et al. 2005). Moreover, like the normal SP, the reeler superplate expresses neurocan, which serves as a guide for thalamocortical axonal growth (Li et al. 2005b). In addition, in prenatally irradiated mice, in which the subplate is partially destroyed, thalamocortical axons traverse the CP obliquely to run up to the marginal zone, somewhat resembling more primitive arrangements (Li et al. 2005a). Likewise, cdk5 and p35 mutants apparently show defects in preplate splitting and an alteration of the trajectory of thalamic axons, which may be a consequence of a misplacement of PNs (Rakic et al. 2006). Overall, this evidence may indicate that the reelin and cdk5/p35 signaling systems were also involved in the repositioning of PNs during neocortical evolution. 3.5.6 Summary The neocortex evolves from a three-layered, tangentially organized ancestral cortex into a six-layered, radially organized structure. First, there was possibly a radial expansion of the primitive mammalian cortex, producing late-born, phylogenetically new neurons, possibly by the contribution of an expanded subventricular proliferative zone and the action of the Pax6 gene. This process may have been triggered by the influence of a spreading morphogenetic activity emanating from the cortical antihem or a related lateral or ventral pallial source. Subsequently, the inside-out neurogenetic gradient was produced in order to maximize synaptic contacts between the new, late-born neurons and the superficially located cortical afferents. In this process, the cdk5 signaling cascade may have been fundamental in the acquisition of new mechanisms of radial migration, and the cdk5 activator p35 was especially important in permitting late-born neurons to cross the barrier formed by previously migrated cells. In addition, an important increase in the expression of reelin by Cajal-Retzius cells permitted the preservation of a neuron-free marginal zone by arresting below it, and contributed to the inverted lamination by detaching neurons from the radial glia. Finally, and partly due to the enormous tangential expansion of the neocortex, a shortcut for thalamocortical axons was found via the subcortical white matter. This was possible by virtue of the change in position of the pioneer neurons that guide thalamocortical axons from a superficial position in the marginal zone to a deeper position in the subplate. Signaling systems involved in neocortical lamination, such as reelin and cdk5/p35, are also related to preplate splitting. This suggests that there is an important evolutionary link between these processes, although they are dissociable to some extent. There are natural conditions in which, despite an inside-out laminar organization, afferents tend to synapse in the superficial marginal zone, indicating that many pioneer neurons remain in a superficial position.

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3.6 Expansion of the Neocortex 3.6.1 Multiplication of Cortical Areas After the neocortex acquired its basic laminar structure and its main visual, auditory, and somatosensory inputs, it began a progressive tangential expansion in several mammalian lineages, leading to the multiplication of sensory and motor areas receiving distinct thalamic inputs. Thus, while some small-brained mammals may have less than 20 distinct cortical areas, in macaques there may be more than 50 (Northcutt and Kaas 1995; Catania et al. 1999; Van Essen et al. 1992). Although Brodmann (1909) counted roughly the same number of areas in the human brain, it is quite likely that this number is an underestimation (Wallace et al. 2002; Striedter 2005). Possibly, the last common ancestor of extant mammals already had a primary and a secondary visual area, an auditory area, a primary and a supplementary somatosensory area, and a motor area that probably overlapped to some extent with the somatosensory area (Northcutt and Kaas 1995). These areas have been found in all mammals studied, and therefore are likely to have been present in their common ancestor. Across species, the increase in the number of so-called higher-order cortical areas that receive input from these primary areas (although corticocortical connections are largely reciprocal) is related to the tangential expansion of the neocortex. Although increase in total cortical surface also produces some increase in the size of each area, this does not account for the full expansion of the cortical mantle (Changizi 2001; Changizi and Shimojo 2005). Tangential cortical expansion has occurred several times in mammals (for example, primates and carnivores, the most well-studied orders), producing a proliferation of distinct cortical areas, many of them being largely unimodal but several being polymodal, integrating different types of inputs. Some similarities have been observed in the organization of these higher-level sensory areas between primates and carnivores (Payne 1993), but it is not clear if these represent true homology or parallelism. The addition of new cortical areas in phylogeny has been proposed to result from the parcellation of initially overlapping inputs into distinct cortical fields (Ebbesson 1980, 1984). Similarly, Krubitzer (1995, 2000) and Krubitzer and Kahn (2003) proposed that new cortical areas emerged from the selective aggregation of modular heterogeneities within phylogenetically more ancient areas. One such example could be the overlap between the somatosensory and motor areas observed in some marsupials, which become segregated in placental mammals (Lende 1963). Another, not alternative possibility is that the addition of new cortical areas results from the expansion of the morphogenetic fields generated by distinct signaling sources during cortical development. Disbalances in FGF, EMX, or PAX6 signaling during corticogenesis may have profound effects in the relative extension of occipital vs frontal areas (Bishop et al. 2000, 2002; Muzio and Mallamaci 2005; Zhou et al. 2001; Mallamaci et al. 2000; Grove and Fukuchi-Shigomori 2003). This situation can be likened to the expansion of distinct cortical fields in different species: for

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example, in rodents there is an enlargement of the vibrissae somatosensory representation; the star-nosed mole has an extremely elaborated nose representation; in echolocating bats the auditory areas occupy a large extension of the neocortex; and in the platypus the somatosensory representation of the electrosensory beak is enormous (Catania 1999; Krubitzer and Kahn 2003; Striedter 2005). Thus, the modulation of distinct morphogenetic signals may produce the expansion or reduction of specific areas, thus providing a plausible target for natural selection to act upon. But how does this process result in the addition of new areas? It is quite likely that cortical expansion has a fundamental role in this process (Changizi 2001; Changizi and Shimojo 2005; Striedter 2005). If there is an expansion of the cortical field, the morphogen sources become increasingly separated, leaving a large territory with very low morphogen activity. One possibility is that additional signaling sources have been selected between these regions, in order to preserve cortical connectivity or as a direct demand for processing capacity (Allman et al. 1971; Allman 1999; Striedter 2005). An interesting point is that neighboring areas sharing a sensory modality usually have mirror-image topographic representations of the periphery, and are thus joined either at the midline representation or at the peripheral representation of the sensory surface. If the anteriorizing signal FGF8 is ectopically placed in the occipital cortex of a normal developing mouse, a second vibrissae representation develops, caudal to the original, which is organized in a mirror-image manner with respect to the normal area (Fukuchi-Shigomori and Grove 2001). Thus, the appearance of new signaling sources might partly produce the mirror-image organization of the different sensory areas of the neocortex. One possible signaling source of this type is area MT of primates, which emerges quite early in cortical development (Rosa 2002; Bourne and Rosa 2006). This area has been proposed to act as a source of morphogens that organize the arrangement of visual cortical areas between it and the primary visual area. It is not clear if there is a homolog of MT in nonprimates; if there was not, this putative signaling center would be an acquisition of the primate brain. Finally, the mammalian neocortex is also unique in terms of its extrinsic connectivity: the neocortex sends a robust projection to the brainstem and also to the spinal cord, largely but not exclusively from the motor cortex; and there are also strong projections from the neocortex to the contralateral hemisphere. The corticospinal tract permits direct cortical control of the spinal motor neuron pool. In a first study, it was found that corticospinal axons penetrate deeper into the spinal laminae (approaching the motoneuron somata more closely), and the length of the corticospinal tract is longer (reaching lower levels of the spinal cord) in animals with higher manual dexterity such as primates (Heffner and Masterton 1975). However, after removing the phylogenetic effects, only tract length was correlated with dexterity, while laminar penetration had no effect in dexterity (Iwaniuk et al. 1999). For example, the armadillo is an interesting case, with a high laminar penetration but a quite short corticospinal tract and little dexterity. There is also a relation between cortical size and the development of the corticospinal tract,

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indicating that dexterity is not the only factor involved in its growth (Nudo and Masterton 1990a,b; Striedter 2005). Nevertheless, considering a fixed brain size, animals with higher dexterity tend to have an increased length of the corticospinal tract. Furthermore, the large-brained ungulates and cetaceans have been omitted from these analyses, which could become important exceptions to the dependency of this tract on brain size. Interhemispheric connections are also a feature of mammalian brains. We (Aboitiz and Montiel 2003; Aboitiz et al. 2003a) have proposed that these fibers originated in early mammals as a consequence of the development of precise topographic maps of the sensory surfaces (visual, somatosensory, and also the tonotopic representations of the auditory cortices). In these conditions, each hemisphere contained a topographic map of the contralateral sensory field, there being no continuity between them at the midline. Thus, interhemispheric fibers may have served as a bridge between the two hemi-representations at the midline, restoring the continuity of the sensory field (Lepore et al. 1985, 1986; Ptito 2003). In the case of audition, the connection between the hemispheres may have contributed to the spatial location of sounds at an additional, cortical level (sound localization mechanisms are already present at brainstem levels). In reptiles, topographic sensory representations are largely localized in the optic tectum, which has a welldeveloped tectal commissure to serve the midline fusion process, but mammals had to develop a similar system when the neocortex acquired topographic maps of the sensory surface. Speed of communication between the hemispheres may have been crucial at these early processing levels, which is consistent with the fact that primary and secondary sensory areas have the largest and faster-conducting callosal fibers (with the largest fibers communicating auditory areas; Aboitiz et al. 1992). In many marsupials, interhemispheric connections make a long turn via the anterior commissure, but in some larger-brained marsupials, interhemispheric axons take a shortcut via the fasciculus aberrans running via the internal capsule to the anterior commissure. In placental mammals, interhemispheric fibers run via the massive corpus callosum, which develops dorsal to the hippocampal commissure, thus minimizing axonal distance and signal transmission time between the hemispheres (Shang et al. 1997). During development, callosal axons cross the midline via the formation of a glial wedge that establishes a sort of bridge between the hemispheres (Shu and Richards 2001). Furthermore, the molecular control of this process is based on an ancient mechanism consisting on the orchestrated action of genes such as Robo and Slit, which are related to midline axonal crossing in both vertebrates and invertebrates (T Shu et al. 2003). Thus, while the development of a glial structure allowing callosal axon passage across the midline may be a novelty of early placental mammals, the molecular mechanisms involved were probably co-opted from pre-existing devices.

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3.6.2 Summary Early mammals presumably had at least two visual, two somatosensory/motor, and one auditory cortical areas. Neocortical expansion has resulted in the increase in area sizes but more importantly in the proliferation of new cortical areas. Hypotheses to explain the addition of new cortical areas relate to the segregation of initially heterogeneous cortical areas in a trend to increase connectional specificity and processing speed, and to the addition of new sources of morphogenetic activity as the brain expands. Other characteristics of the neocortex are the development of corticospinal axons, which permit direct cortical control over the spinal motoneurons and an increase in manual dexterity, as well as interhemispheric connections, which in placental mammals course via the corpus callosum. The latter may have originated as a consequence of the development of topographic sensory representation in the mammalian cerebral cortex, making it possible to establish a continuity between the two hemirepresentations of the sensory surfaces that are located in separate hemispheres.

4 Discussion 4.1 An Overview We have attempted to provide an overview of both vertebrate brain development and evolution in order to illustrate the correspondence between developmental and evolutionary processes, and the notorious conservatism in neuronal developmental programs that can be observed in distinct phylogenetic groups. We could obviously not cover all aspects of the “evo-devo” of brain development, and there are many neural systems that had to be left aside. Nevertheless, we believe we have succeeded in providing a broad scenario for the origin and continuous evolution of the vertebrate brain, emphasizing the dorsal pallium and later the mammalian neocortex, which is the structure of most interest to us, mammals. 4.1.1 Early Neuronal Differentiation Embryonic neural specification, in which epidermal cells are prevented from acquiring neural fates by autosecretion of BMP proteins, is paralleled with the evidence on the earliest nervous systems as basiepidermal neural nets derived from the proliferating ectoderm. Furthermore, the delamination from a proliferating epithelium and the participation of bHLH factors in early neuronal differentiation seem to be common mechanisms in a wide variety of animals (Ross et al. 2003). Likewise, the aggregation of ciliated cells (receptors) may have also been

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a relatively common mechanism in primitive metazoans, which in chordates led to the process of neurulation producing a CNS consisting of a hollow neural tube. Apparently there were two main components making up this early neural tube: a rostral component, related to the hemichordate larval apical organ and other ciliated structures, and a caudal component, corresponding to other ciliated elements. In modern vertebrates, different inducing signals are required for both components, the more caudal depending on the notochord and axial mesoderm (secreting Noggin, Chordin, and Follistatin), and the more anterior parts depending on the visceral anterior endoderm (secreting Cerberus and Dickkopf among other signals; Wilson and Rubenstein 2000; Martindale 2005). In sessile urochordates and some larval hemichordates, only cephalic markers are present, while the rest of the body and nervous system is apparently lacking, indicating a developmental separation between head-related and trunk-related neural tissues. The process of CNS condensation is directed dorsally in vertebrates, but in arthropods and other animals it is directed ventrally (De Robertis and Sasai 1996). The body organization of arthropods and vertebrates is an upside-down version one of the other, in both morphological and genetic terms. One interpretation of this inverted organization is that at some point, deuterostome ancestors began to swim upside-down. However, recent evidence shows a more complicated picture, in which hemichordates have a protostome-like dorsoventral organization but also bear a basiepidermal net with small signs of condensation; therefore CNS condensation appears to be a late evolutionary event in deuterostomes and may have occurred independently of CNS condensation in protostomes (Lowe et al. 2003). 4.1.2 Patterning Anterior–posterior patterning is a highly conserved process in phylogeny, as quite similar genetic mechanisms are involved in animals as different as vertebrates and Drosophila (Pearson et al. 2005). They particularly depend on genes of the homeobox cluster and related genes, which serve to determine an anteroposterior axis despite great morphological divergences. The origin of vertebrates is marked by a double duplication of the Hox cluster, which includes the Dlx genes located anterior to them (García-Fernández 2005). Vertebrates are characterized by the differentiation of tissues surrounding the neural plate (epidermal placodes and the neural crest) and by the neural tissue neighboring the placodal region, that develops as the telencephalic hemispheres. In this process, Dlx genes play a crucial role determining the limits of the placode/neural crest tissue. Noticeably, the molecular networks involved in the specification of the preplacodal region and the individual placodes are quite similar to those observed in Drosophila for the specification of sensory structures from imaginal disks. For example, the lens and nasal placode precursors arise from a common territory; however, in later development, cells tend to segregate and then converge into specific placodes. The Dlx5 and Pax6 genes are initially co-expressed in the future lens and olfactory cells,

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encircling the presumptive forebrain. Nevertheless, in later stages Dlx5 transcripts segregate in the olfactory placode and PAX6 segregates in the lens (Bhattacharyya et al. 2004). These events closely resemble the separation of eye and antennal primordia from a common imaginal disk in Drosophila, where there is antagonistic expression of the Distalless (Dll) and eyeless genes (homologs to Dlxs and Pax6 in vertebrates, respectively). Later in vertebrate development, Dlxs appear expressed in the ventral forebrain and in the presumptive subpallium of the hemispheres (T. Luo et al. 2001a,b). Placodes are essential for the differentiation of paired sensory organs (Whitlock 2004), and it is possible that ancestrally, sensory organs were all located in the anterior brain vesicle as they are in larval urochordates and perhaps in cephalochordates. In this context, cephalic neurulation may have been closely associated with the condensation and invagination of sensory components (in Drosophila a similar process may consist of the formation of imaginal disks, which depends on the gene Dll; Panganiban 2000). Of particular interest to us is the anterior neural ridge (Couly and Le Douarin 1985), which secretes FGFs and in the cephalic region acts as a promoter of ventral and anterior fates (Lupo et al. 2006). The olfactory and the hypothalamic placodes originate in association with this region. The olfactory placode participates in forebrain and telencephalic differentiation by inducing the formation of an olfactory bulb and the telencephalic vesicles (De Carlos et al. 1995). Thus, we suggest that the development of the olfactory sense in early vertebrate ancestors was associated with the origin of a dorsal forebrain structure receiving these inputs, which differentiated as an olfactory bulb and the cerebral hemispheres. Modern agnathans partly retain this ancestral condition in which the cerebral hemisphere is dominated by olfactory input. Nevertheless, they also have ascending dorsal thalamic input, which may have been present in the early dorsal forebrain. In gnathostomes, thalamic sensory inputs tend to displace olfactory inputs from the medial pallium, restricting the latter afferents to the lateral pallium. In amniotes, some thalamic inputs begin to deviate to the dorsal and ventral pallium, and in birds and mammals they become practically absent from the medial pallium (Wicht and Northcutt 1998). The forebrain, midbrain, and hindbrain can be subdivided into a series of transverse segments termed neuromeres (prosomeres in the forebrain), which appear to be highly conserved in different species. An organizational scheme, termed the prosomeric model, has been proposed as a topographic framework for brain organization in different vertebrates (Puelles and Rubenstein 1999, 2003) According to this model, the vertebrate telencephalon (consisting of a medial, a dorsal, a lateral, and a ventral pallium, plus a subpallium) is located dorsal to the presumptive hypothalamic region. Posterior to them are the prethalamus, dorsal thalamus, and other structures. A slightly different interpretation is that the medial pallium really consists of a more posterior component than the rest of the forebrain (Kimura et al. 2005). The patterning of the cerebral hemispheres depends on several signaling sources (Sur and Rubenstein 2005). On one hand, there are the anterior signals derived from

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the anterior neural ridge, secreting FGF8, which is later expressed in the dorsal aspect of the frontal hemisphere; caudally, there is the telencephalic roof plate, secreting several factors (BMPs, Wnts) that induce other factors (Emxs, Pax6), which in some instances cooperate but in others (as in the cerebral cortex) they antagonize each other. These factors trigger development of the medial pallium and the dorsal pallium at the border between the FGF and the BMP/Wnt signaling fields. An additional morphogenetic center is the antihem, located in the lateral pallium. The dorsal pallium is quite a narrow strip of tissue in most nonmammals, but expands significantly with the origin of the mammalian neocortex. 4.1.3 Diversification of the Hemispheres and Neocortical Origins The cerebral hemispheres of vertebrates have diversified enormously, having increased in size and complexity independently in each phylogenetic group. In cartilaginous fish, there is an expansion of the central nucleus, while in teleosts, with an everted brain, the area dorsalis is the largest. Amphibians have quite simple brains, perhaps secondarily reduced; while in reptiles and birds a ventral pallial component termed the dorsal ventricular ridge (DVR) becomes the most prominent telencephalic structure. Mammals are characterized by the expansion of the neocortex. Which brain component is ancestral to the mammalian neocortex? This has been considered to be one of the thorniest problems in comparative neuroanatomy (Northcutt 2003). Early studies of sensory connectivity proposed that parts of the neocortex (the lateral neocortex, receiving visual extrastriate and auditory inputs) was comparable to the avian and reptilian DVR by virtue of receiving similar sensory inputs from sensory pathways that are relayed in the mesencephalon (collothalamic). This was challenged by noting that the topographic position and developmental origins of the DVR did not correspond to the position and origin of the lateral neocortex, which was presumably of dorsal pallial origin (Aboitiz 1992, 1993, 1995). Subsequent authors proposed homology between the DVR and mammalian components like the basolateral amygdala or the dorsal claustrum, but there is no agreement as to which precise component corresponds to the DVR (Bruce and Neary 1995; Striedter 1997). Furthermore, developmental and genetic evidence confirmed the ventral pallial identity of the reptilian DVR (Pax6-positive, Emx1-negative), and the dorsal pallial identity of the mammalian neocortex (Pax6-positive, Emx1-positive; Smith-Fernández et al. 1998; Puelles et al. 1999, 2000). The growth of the dorsal pallium in primitive mammaliaforms may have resulted from the increased activity and interaction of genes related to the developmental expansion of this structure, such as Wnts, Emxs, Lhx2, and Pax6, depending on morphogenetic activity emanating from the medial pallium; from FGF8 and other factors emanating from the anterior forebrain, and from factors derived from the lateral pallial antihem (Monuki et al. 2002; Assimacopoulos et al. 2003; Sur and Rubenstein 2005). Thus, the dorsal pallium, from being a small territory bordering the lateral/ventral pallium and the medial

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pallium in nonmammals, expanded into a prominent cortical sheet by virtue of the interaction between these different morphogenetic sources. 4.1.4 Olfaction, the Hippocampus and the Amygdala The expansion of the dorsal pallium in early mammals may have related to the development of extensive networks connecting the olfactory cortex and hippocampus. These circuits are present in amphibians and reptiles, but in early mammals the sense of olfaction acquired great relevance owing to their presumed nocturnal habits (Jerison, 1973; Sagan, 1977; Lynch, 1986; Kemp 2005). Likewise, there was a noticeable development of the auditory apparatus, making it possible to localize sound sources in the dark. Although primitive cynodonts and mammal-like reptiles had quite a narrow braincase with no signs of telencephalic expansion, the acquisition of the mammalian grade (marked by the detachment of the inner ear ossicles from the inner jaw) roughly coincides with a dramatic increase in brain size (Kielan-Jaworowska et al. 2004). This may have been related to the growth of the dorsal pallium, which began to receive an increasing number of sensory afferents, both lemnothalamic and collothalamic. These inputs were then relayed to both the hippocampus and the amygdala (Aboitiz et al. 2003, 2003c). This situation contrasts with that observed in reptiles, in which the bulk of collothalamic projections is sent directly to the ventral pallial DVR, with little interaction with the medial pallium. Nevertheless, in mammals a direct connection from the collothalamus to the amygdala persists and operates as a fast-response system in situations of alarming stimuli. This system relates to emotional responses to threatening stimuli and to the response to stressful events. 4.1.5 Cortical Lamination A distinct feature of the mammalian neocortex is its lamination. As opposed to the reptilian cortex, consisting of only three thin tangential layers, the mammalian neocortex consists of six layers. Embryologically, the neocortex first develops a transient structure termed the preplate, which is later split into a marginal zone (future layer I) and a subplate by the arrival of the cells making up the true cortical plate (layers II–VI). Neurons in the cortical plate migrate in an inside-out gradient, late-generated cells locating above cells that are produced early, the former having to migrate radially past the layers of older cells. In reptiles, however, lamination occurs according to an outside-in gradient in which late-born neurons locate below early-born neurons. Furthermore, thalamic axons enter the neocortex radially, from the underlying white matter, while in reptiles they arrange tangentially in the superficial marginal zone. Marín-Padilla (1971) originally proposed that the reptilian cortex corresponded to the early-appearing mammalian subplate, but there are some discrepant facts

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such as the apparent absence of a subplate proper in some marsupials (the subplate appears to be included in the deepest cortical plate layers; Harman et al. 1995; Reep 2000). Perhaps more parsimonious, but in the same line, is the interpretation that the deepest cortical plate cells correspond to the cells of the reptilian dorsal cortex. More superficial, later-appearing and phylogenetically newer cortical neurons are produced in the subventricular zone instead of the ventricular zone and depend on Pax6 for their differentiation (Schuurmans et al. 2004). Thus, we proposed that this gene along with others were fundamental in the acquisition of the superficial layers of the neocortex, which derived mostly from the proliferative subventricular zone (Aboitiz et al. 2003c). Thus, a fundamental event in neocortical origins consisted of the differentiation of a subventricular zone in the cortical neuroepithelium, which was probably associated with both the tangential and radial expansion of the dorsal pallium. This proliferating zone originates in the lateral aspect of the hemisphere, and in reptiles and birds it may have been related to the development of the DVR, since it was restricted to ventral pallial sectors. Another curious neocortical feature is its inside-out neurogenetic gradient. We suggested that this was a strategy for these late-produced neurons to establish synaptic contacts with the thalamic and cortical afferents that were located superficially in layer I. The hippocampus resembles this primitive condition, in which the developmental gradient is inside-out, and the afferents are located superficially in layer I. In the development of the inside-out gradient, the signaling pathway of the cyclin-dependent kinase 5 (cdk5) was possibly of special importance; in particular, its activator p35 may have been crucial for neurons to be able to cross the layers of previously migrated cells (Chae et al. 1997). Furthermore, the protein reelin, secreted by Cajal-Retzius cells in the marginal zone, may have contributed to this organization by permitting the generation of a cell-free layer I, which these neurons, with increased migratory capacity, tended to penetrate. In addition, reelin is hypothesized to block neural-glia, and perhaps neuron-to-neuron, attachments, mechanism that may have provided interneuronal space for cortical plate neurons to cross the subplate and layers of older neurons (this does not exclude other developmental functions for reelin). As the neocortex expanded tangentially, some axons begun to enter the cortex via the underlying white matter, instead of running in the superficial marginal zone as they do in the reptilian cortex. This new position served as a shortcut to access the dorsal pallium. Intermediate forms are seen in primitive mammals, where axons penetrate the cortex from the underlying white matter but later cross to the marginal zone to run tangentially along it for some distance. In this process, the position of pioneer neurons, migrating from the subpallium and directing the growth of thalamocortical axons, gradually shifted from an ancestral position in the superficial marginal zone to a deeper position below the cortical plate, in the mammalian subplate. Genes and signaling pathways involved in the generation of the inside-out cortical lamination such as reelin and cdk5/p35 may have been co-opted for the redistribution of pioneer neurons.

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4.1.6 Tangential Expansion and the Origin of New Areas Finally, the cortical sheet expands dramatically in some mammals with the consequent increase in number of cortical areas. Most mammals share at least two visual areas (striate, lemnothalamic-receiving, and extrastriate, collothalamicreceiving), an auditory (collothalamic) area, and a somatosensory/motor (lemnothalamic) area. However, in large-brained mammals the number of areas may exceed 50. The origin of new areas has been explained on the basis of segregation of heterogeneous inputs to one region and the consequent homogeneization of these fields; and on the appearance of new signaling centers that trigger the differentiation of new cortical regions (Krubitzer 1995, 2000; Allman 1999; Krubitzer and Kahn 2003; Striedter 2005). Both mechanisms may be valid; for example in marsupials there is significant overlap between the somatosensory and motor areas, while in placental mammals these regions are well separated; in addition, it has been postulated that the primate visual area MT is a signaling center that patterns the organization of other visual areas (Rosa 2002). The isocortex is also notorious for its connectivity: it develops a long corticospinal tract, related to increasing voluntary control of the spinal cord, and interhemispheric connections, which we proposed to be originally related to the fusion of the two hemirepresentations of the sensory surfaces in each hemisphere at the midline (Aboitiz and Montiel 2003). Auditory interhemispheric connections are among the fastest-conducting of all and may have participated in the localization of sound sources. Provided this synopsis of the subjects dealt with in this article, we will now turn into some more general issues that bear relation with theoretical concepts of evolutionary biology and comparative morphology. 4.2 Issues with Evolutionary Theory 4.2.1 Genetic Conservatism Versus Morphological Diversity One of our goals was to establish a continuity from the origin of the vertebrate central nervous system to the appearance and diversification of the mammalian cerebral cortex. In doing this, it became apparent that there have been key innovations such as the grouping of ciliated sensory receptors in both the imaginal disks of Drosophila and in the neural tube of vertebrates, and the delamination process by which neurons segregate from the proliferating epithelium, which are shared by many metazoans and may reflect common developmental mechanisms. These correspondences may reflect a common origin or a different origin starting from a shared ancestral developmental schedule. Considering the morphological dissimilarities in the different taxa (for example, that neurulation appears to be a late event in the history of protostomes; Lowe et al. 2003, 2006), we tend to prefer

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the hypothesis that there was a common developmental schedule prior to the diversification of protostomes and deuterostomes, which became involved in different morphogenetic processes in the different lineages. One particularly good example of this situation is the role of the Pax6 gene in eye development; mutations in this gene produce defects in eye development in Drosophila, mouse, and humans (Quiring et al. 1994). Furthermore, if the mouse Pax6 gene is expressed ectopically in Drosophila, it triggers the development of eye structures in regions such as wings or legs (Halder et al. 1995). The Pax6 gene has been involved in photoreceptor development in a variety of animals and is likely to have had a role in the original specification of photoreceptors (Gehring 1996; Glardon et al. 1997; Pineda et al. 2000). However, the morphogenetic processes giving rise to the different types of eye were acquired independently in the history of each lineage (for example, arthropods and insects, mollusks and vertebrates), with Pax6 being a crucial element in all of them, perhaps owing to its early participation in photoreceptor specification. This situation is somehow reminiscent of the old discussion about whether all animals could be described according to a common body plan or instead each phylum was characterized by a unique body structure. This controversy dates from at least two centuries ago, clearly exemplified by the Cuvier-Geoffroy debate of pre-Darwinian times, in which Etienne Geoffroy Saint-Hilarie defended the unity of composition doctrine, while Georges Cuvier posited four basic plans of animal organization: vertebrates, articulates, mollusks, and radiates (Appel 1987). Since 1830, it became widely accepted that separate phyla are indeed characterized by their unique body plans, thus supporting Cuvier’s position, which interpreted morphology from a functional viewpoint (although being antievolutionist in the sense that it rejected Lamarck’s transformism). In light of recent evidence, showing the striking conservation of regulatory genes such as the Dlx/Hox cluster and other genes that are essential for the formation of the body plan in most known phyla, these ideas may be reconciled by considering an ancestral genetic patterning device that generated different morphogenetic mechanisms in each lineage (Slack et al. 1993). Thus, although vertebrate brains share molecular patterning mechanisms with Drosophila and other animals, the morphogenetic processes in which they participate have diverged in each phylum, making a specific morphological organization for vertebrates, another for arthropods, another for mollusks and so on. 4.2.2 Development as a Clue to Evolution Another issue is that developmental processes may yield clues about how evolutionary changes occurred. Although Haeckel’s concept that ontogeny recapitulates phylogeny is usually seen as an outdated preformist conception, evidence has shown an important concordance between developmental events and evolutionary transitions. In this sense, we should consider the developmental process not as strictly recapitulating earlier adult phylogenetic stages as considered by Haeckel, but rather

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as the sequential acquisition of embryonic characters that were acquired during the phylogenetic history, as proposed by Von Baer’s biogenetic law (see Gould 1977). Naturally, there are distortions of this process that may generate profound evolutionary changes, most of them occurring through the process of heterochrony in which the developmental timing of specific events is delayed or anticipated. In the case of the lamination of the mammalian cerebral cortex, we have proposed that a main heterochronic process has been the mechanism of hypermorphosis, in which development is lengthened and additional stages are added to the end of it, generating a mosaic of phylogenetically new and phylogenetically old structures (Gould 1977). The expansion of morphogenetic fields such as the dorsal pallium in mammals, giving rise to the neocortical mantle, has been proposed to result from increased cell proliferation owing to the action of several morphogens and their receptors, thus in a way adding new stages to the developmental program. An especially interesting finding in this context is that many brain structures that appear late in development also tend to increase more in size (see Finlay and Darlington 1995; Finlay et al. 2001). In this way, the telencephalic vesicles and the pallium of vertebrates are both among the latest developing and the more expanding and diversified brain structures. In general, telencephalic evolution has been characterized by increasing growth of specific structures (the telencephalic vesicles and then the expansion of different components within them, such as the central pallial nucleus of sharks, the area dorsomedialis in bony fish, the dorsal ventricular ridge in reptiles and the neocortex in mammals; Northcutt 1981). In these cases, in which terminal stages are added in a rough sequence, concomitant with continuous growth, it is possible to track the evolutionary sequence with at least some confidence. Nevertheless, morphology is complicated in its essence. There are always exceptions to these general rules, which have led to profound disagreements in the interpretations of brain evolution. Fortunately, the phylogenetically conserved gene expression patterns during development have appeared as important elements that can disambiguate the origin of several structures and, in our view, have helped to clarify the origin of several structures such as the mammalian neocortex. In this context, even if it may require further elaboration, the prosomeric model proposed by Puelles and collaborators (Puelles and Rubenstein 2003) has come as a fundamental reference for comparative studies. Although many criticisms have been raised concerning this model, it is undoubtedly one of the first serious attempts to make a comprehensive framework for vertebrate brain organization. 4.2.3 Developmental Processes and Homology Criteria Perhaps the most basic issue in comparative biology relates to the concept of homology. In order to determine the ancestry of a given structure, a criterion for homology must be established. The modern concept of homology specifies identity between two structures, each present in one of two different species, which is established in the context of the hypothesis of a common ancestor that

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had the same character. Thus, homology is a hypothesis of evolutionary continuity through a common ancestor (Northcutt 1996b). However, the original definition of homology was pre-evolutionary and made reference to the distinction between real or apparent similitude between organs (Owen 1837; see Aboitiz 1988, 1989, 1995; Panchen 1994). Thus, homologous organs were the same organ under all its variety of forms in different species (i.e., vertebrate arms and wings), while analogous organs were those that looked similar and had comparable functions, but were not the same (i.e., vertebrate and insect wings). Criteria to establish homology were strictly comparative and were based on topographic position in the body (assuming a common overall architectural plan in the anatomy of different species), embryological origins, or general similarity (there is even a concept of serial homology between organs of the same animal, as in the case of paired limbs; Aboitiz 1995). With the advent of evolutionary theory, homology came to imply common ancestry (Aboitiz 1988, 1995). However, the criteria for establishing homology remain strictly comparative, in which homology is no more proved than before Darwinian times (however, more accurate evidence is now available, allowing more educated guesses). Two main approaches have been used to determine phylogenetic homology. One of these is the comparison between adult structures and the other is the comparison of the embryonic primordia that give rise to these structures (Russel 1916; Garstang 1922; Northcutt 1990a, 1996b; Striedter and Northcutt 1991; Striedter 1997; see also Aboitiz 1995; Aboitiz et al. 2003c). None of these is infallible, as there are examples of undoubtedly homologous adult organs deriving from quite different embryonic components and cases of strikingly similar adult structures that have been acquired independently in evolution (De Beer 1971; Striedter and Northcutt 1991). A particularly conflicting case is when two structures derive from the same embryonic field but have undergone different evolutionary histories as adult structures. Some authors use the term “field homology” to describe these events (Butler and Molnár 2002; Puelles and Medina 2002), while others are clearly not in concordance with this concept (Northcutt 1999, 2003). In Norhcutt’s terms (2003), even if two structures arise from the same germinal compartments, they are not necessarily homologous; they must also possess homologous stages in their development, indicating a common history of transformations. For this reason, we prefer to use the concept of embryonic homology to specify homologous embryonic structures that give rise to nonhomologous adult structures in two species, while the term “adult homology” indicates direct homology between the respective adult organs (Aboitiz et al. 2003b,c). In any case, the question remains as to whether embryonic or adult structure are better criteria for determining the phylogenetic continuity of two structures. In our view, there are two extreme possibilities: if phylogenetic evidence points to adult conservation with embryonic diversity, adult comparisons may be a better criterion for homology, while if in phylogeny there is adult diversity and embryonic conservation, embryonic comparisons should be considered a stronger criterion for homology (Aboitiz 1995). In the case of the vertebrate telencephalon, the evidence reviewed points to a noticeable conservatism in early developmental processes and topographic arrangement,

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while there is also good evidence for dramatic divergence in brain structure during late development (Northcutt 1981, 1984, 1990b, 2002; Striedter 2005). One particularly controversial case of homology is the origin of the neocortex. Hypotheses based on adult connectivity have pointed to homology between the lateral neocortex and the reptilian DVR, while other hypotheses (based on topography, developmental patterns and on adult connectivity, Aboitiz 1992, 1995; Bruce and Neary 1995) have proposed homology with the reptilian dorsal pallium. We conclude that the reptilian/avian DVR and the mammalian neocortex have different developmental origins and are not likely to be homologs. Nevertheless, according to Northcutt (2003) even if these structures had a similar developmental origin, a differentiated DVR should prove to be ancestral to the neocortex to be considered its homolog. Fossil evidence indicates that early mammal-like reptiles had quite a simple telencephalon with no signs of expansion, indicating that reptilian and mammalian brains underwent independent histories of brain development. 4.2.4 Development, Adaptation, and Behavior Finally, a purely developmental perspective is left wanting of a functional interpretation of brain organization and evolution. The adaptationist paradigm affirms that most important evolutionary changes have been the result of adaptations to specific circumstances. Other evolutionists do not seem to agree with pan-adaptationist interpretations and propose an active role of developmental processes and their variations in determining the evolutionary trajectories (Arthur 2004). In our view, this disagreement is in principle easy to solve. The proper Darwinian concept of descent with modification (Darwin 1859) implies that natural selection may act only on the available variability; it cannot create anything. Thus, genetic and developmental processes clearly set a frame in which selection is able to work. The point is that, via the accumulation of small changes (cumulative selection; see Dawkins 1997), major evolutionary transformations may take place. Therefore, the problem may be restated in terms of how much genetic and developmental variability is available for a given evolutionary transformation; this is an empirical question and does not invalidate the action of selective processes. Perhaps the point of more controversy relates to the possibility that evolutionary changes may have been abrupt, produced by dramatic reorganizations of the developmental program (Arthur 2004). A common argument against the gradualistic interpretation is that natural selection exists but produces only small changes like the variations in beak length in Darwin’s finches, which vary according to feeding habits (Weiner 1995). Major evolutionary transformations would require other kinds of mechanisms (Gould 1977; Arthur 2004). As mentioned, Darwin did not differentiate between small or large changes; he considered that major transformations could take place through the successive accumulation of small changes. In this context, Dawkins (2003) argues that the argument of micro vs. macro evolution is misleading: it is as if, when looking at a tree we considered that the small buds could

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not give rise to big branches because they look so different. The possibility of major changes occurring through the accumulation of small changes is logically possible, and although for practical reasons has not been demonstrated, there is no evidence against it. This does not mean that in some instances there may be some discontinuous changes, such as polyploidy, as it occurs in several plant species or some homeotic transformations of body parts. For example, most mammals (including the giraffe) have a fixed number of cervical vertebrae (seven). However, in birds the number of cervical vertebrae is highly variable (Carroll 1988), and the addition or deletion of vertebrae must have occurred by discontinuous events (one individual may be born with one extra vertebra but not half of it). Something similar may happen with frameshift events in which the identity of some body parts or segments have been displaced caudally or rostrally (Wagner and Chiu 2001). But these are relatively simple developmental changes, involving the number or relative position of already formed organs. In our opinion, the evolution of biologically complex structures such as the eye, in which the development of different tissues must be tightly coordinated in order to produce an elaborate optic device, is unlikely to have arisen in a single or a few steps. Rather, phylogenetic evidence strongly indicates a series of intermediate steps prior to the acquisition of complex eyes such as those of insects, cephalopods, or vertebrates (Dawkins 1997). For example, in the evolution of the mollusk eye, small improvements in image formation took place (gradual increase in curvature, forming either a concave or a convex light-receiving surface, and eventually, the gradual narrowing of the pupil and the formation of a lens in concave eyes). Likewise, the origin of the mammalian cerebral cortex, although it is a structure at first sight radically different from comparable structures in reptiles, can be explained by a series of changes in region-specifying genes and neuronal migration-controlling genes. Theories invoking macromutations producing the whole diverse array of structural characteristics of the neocortex, i.e., its inverted lamination, radial organization, tangential expansion and proliferation of sensory areas, are still in lack of serious supporting evidence. Another issue refers to the origin of the vertebrate brain. While Northcutt (2005) argues for a practically simultaneous origin of the different vertebrate characters, Butler (2006) claims for a serial transformation in which telencephalic origin was the latest event. In our view, this may have been a continuous but rapidly changing scenario, in which acquisition of one character facilitated the development of new characters and so on (Sect. 3.2.4). In this context, a major discontinuity in the origin of vertebrates is evidenced by the double duplication of the Dlx-Hox cluster (Digregorio et al. 1995; Stock et al. 1996). Although the genetic duplication events were most likely discrete (but possibly appearing in more than one individual), this does not imply that morphological change occurred equally suddenly. Rather, it is quite likely that in a first instance, this mutation had no major phenotypic consequences. In fact, recent evidence indicates that mammalian Hox genes, despite being present in larger numbers than other vertebrates, are in many cases redundant in function and the loss of redundancy does not imply major phenotypic changes (García-Fernández 2005; Tvrdik and Capecchi 2006). After genetic duplication, genes may have started

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to diverge, acquiring complementary functions, which may have facilitated the gradual acquisition of novel morphological characters (Taylor and Raes 2004; Schubert et al. 2006). In morphological adaptation, a fundamental element is function and behavior. Although developmental variability determines the possible morphological variations, function, or behavior, determines which of these variants serves the individual better. In other words, if the ancestors of giraffes had not browsed in the highest branches, no selective trend toward increasing their necks would have ever started. Thus, behavior and functions that are critical for survival determine the direction of natural selection by favoring those structural variations that better serve them (see Aboitiz 1990). This view has been sometimes dismissed for being considered a form of neo-Lamarckism, because it implies that function precedes form. However, it is fully consistent with modern genetic concepts and does not imply the inheritance of acquired characteristics. It only affirms that, among the independently arising developmental variants, those that fit a function that is critical for survival better will become selected. It is in this context that we have intended to provide a behavioral scenario for brain evolution, associating the evolutionary events to behavioral changes. Obviously, there can be no swimming behavior without a swimming apparatus, but swimming may have appeared as a co-option of structures initially serving a different function. Once this new function was acquired and became useful for survival, a selective trend may have been initiated in which more efficient structures were selected, leading to increased swimming behavior and so on, in a mutually reinforcing loop between structure and function. In the cases of the origin of the cerebral hemispheres and of the mammalian neocortex, we have proposed that one particular sensory function (olfaction) was of particular importance. Again, a primitive chemosensory system must have preexisted in the ancestors of both groups, but the relevance of this modality for the behavior of the first vertebrates and the first mammals was probably a triggering event for brain expansion (this is not to exclude other sensory systems such as audition in the case of mammals). This led to an expansion of other sensory capacities and the elaboration of a more diverse behavioral repertoire, from which new evolutionary trends emerged, producing the vertebrate and the mammalian radiations in each case. 4.3 Final Comments There has been a renewed interest in the study of the relation between development and evolution, which promises to yield a wealth of interesting evidence that may dramatically change many of our current conceptions. Although this interest has been focused on many systems, we consider that the case of the central nervous system may be a particularly enlightening example of this relation. This is not only for the selfish reason that in our brains resides the capacity to be thinking beings, but also because this is probably one of the systems in which the relations

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between form and function acquire their most elaborate expression. Thus, interdisciplinary approaches including physiology, development, behavior, and genetics may become especially fruitful to unveil these complex interactions. More than trying to confirm and make known our own views, our intention here has been to provide a series of working hypotheses that may motivate other workers to pursue experimental and theoretical work on these lines.

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Subject Index

Acanthostega 27 adenohypophysis (adenohypohysea) 16 ADll (AmphiDll) 17, 22 agnathans 24, 28, 73 amniotes 27 amphibians 31, 32 amphioxus 8, 9, 12 amygdala 6, 33, 51 – basolateral 43, 48, 49, 58 – lateral 43, 45, 46 – striatal 43 anapsid 27 anterior commissure 70 anterior neural ridge 19, 73 anterior thalamic nucleus 42, 55 anterior visceral endoderm 14 antihem 74 apical organ 13, 72 apical pole 12 Archaeothyris 28 arcopallium 33, 40, 51 area dorsomedialis 79 area MT 69 auditory area 68 bHLH (basic helix-loop-helix) 71 bilaterian 7 biogenetic law 1, 79 blastopore 8 blastula 18 BMP (BMP4) 10, 12, 14, 53, 74 bony fish 25, 26, 32 Brain factor (BF1) 22 branchial skeleton 16, 24 Branchiostoma see amphioxus Burguess Shale 15 Cajal-Retzius cells

60, 63, 64

cartilaginous 26 cartilaginous fishes 25, 31 Casineria 27 catenin 53 cdk5 (cyclin-dependant kinase 5) 61, 65 central prosencephalic complex 29 central prosencephalic nucleus 79 cephalochordates 8, 9, 13, 15, 17, 21 Cerberus 14, 72 cerebellum 37 chordates 8, 11, 15 Chordin 10, 12, 13, 72 cilia (ciliated) 12–14, 20, 71 claustroamygdalar complex 6 claustroamygdaloid complex 33, 39 claustrum 45, 49, 51, 62 cnidarians 7, 13 CNS condensation 9–11 collothalamic 31, 40, 44, 55, 58 conodonts 15, 25 corpus callosum 37, 70 cortex – dorsal 32, 38, 39, 41, 43, 57 – dorsomedial 32, 39, 43 – lateral 32, 38, 39, 47 – medial 32, 38, 42, 43 cortical plate (CP) 59, 61, 63, 64, 76 corticospinal tract 29, 69, 77 corticostriatal sulcus 4 ctenophorans 13 ctenophores 7 cyclostomes 25, 31 cynodonts 35, 36 deuterostome 11 deuterostomes 8, 15 developmental evolutionary genetics see evo-devo

114 diapsid 27 Dickkopf 14, 72 dipleurula 14 Dlx (Dlx1, Dlx2) 4, 17, 21, 48–50, 72 dorsal ventricular ridge see DVR dpp (decapentaplegic) 10 Drosophila 2, 4, 10, 12, 72, 77, 78 DVR 28, 33, 39, 47, 48, 74, 79, 81 – anterior (ADVR) 33, 44, 49–51, 55 – posterior (PDVR) 33 ear ossicles 35 echinoderms 8, 14 Eitenascidia 17 ems (empty spiracles) 4 EMX 68 Emx (Emx1, Emx2) 4, 48–50, 52 encephalization 36 endocasts 35 endopiriform nucleus 49 entopallial nucleus 40 entorhinal cortex 39, 42, 43, 57 episodic memory 56, 58 evo-devo 1–3 eye – evolution 82 – medial 18 – paired 21, 25 eye development 78

Subject Index Haikouichthys 15 HAR1F 63 Hatscheck’s pit 20 hem – cortical 6, 63 hemichordate 14, 72 hemichordates 8, 11, 12, 18 hippocampal 6 hippocampus 33, 39, 43, 55, 64 homeobox see Hox homeothermy 37 homology 3, 38, 44, 51 Hox 2, 4, 22, 48, 72 Hylonomus 27, 28 hypermorphosis 79 hyperpallium 33 hypophyseal duct 26 hypophyseal placode 14 hypothalamus 16, 19, 31 Ichthyostega 27 imaginal disks 72 inside-out 76 insula 62 interhemispheric connections interneurons 6, 59, 60 inversion – dorsoventral 10 Joseph cells

fasciculus aberrans 70 FGF (FGF8) 19, 68, 69, 74 Follistatin 10, 13, 72 Frizzled 14, 52 ganglionic eminences 6, 48, 60 gastrula 2, 7 gastrulation 8 geniculate nucleus – lateral 41, 42, 55 – medial 46 Gli3 53 glial wedge 70 gnathostome 31 gnathostomes 24, 73 Gobiconodon 35, 37 Hadrocodium 35, 37 hagfish 25, 30 Haikouella 15, 21

70, 77

18

lamprey 25 lateral posterior and pulvinar complex 43–45 lemnothalamic 31, 40, 55, 58 locomotion 61 LP/P nucleus 45 lungfishes 32 macro evolution 81 marginal zone (MZ) 59, 63–66 mesencephalon 5 mesomere 3 mesopallium 33, 51 migration – radial 61, 63 – tangential 63 monorhins 25 Morganucodon 35 motor area 68

Subject Index Myllokunmingia 15 myxinoids 25, 29 neocortex 28, 33, 39, 81 neural crest (NC) 21, 72 neural gland 19 neurocan 67 neuroepithelium 47, 62 Neurogenin (Ngn) 10, 20, 53, 62 neurohypophyseal duct 19 neuromeres 3, 73 neuropeptide Y 63 neurulation 4, 10, 12, 77 nidopallium 33, 40, 50 Noggin 10, 13, 72 notochord 8, 24 nucleus rotundus 40, 43, 45 ocellus 18 Oikopleura 15 olfactores 15 olfactory bulb 16, 28, 29, 73 olfactory cortex 6, 39, 47, 49, 55, 64 olfactory placode 14, 21 optic tectum 29, 40, 44, 70 organs of Hesse 18 ostracoderms 25 otolith 18 out-group hypothesis 39, 47 p35 61, 65 p73 63 paedomorphosis 32 Paleothyris 27 pallial – dorsal 57 pallial thickening 39, 41 pallium 31, 48 – dorsal 4, 6, 42, 43, 52, 58 – lateral 6, 30, 33, 54 – medial 6, 30, 32, 54 – ventral 6, 30, 33, 47, 48, 52 parcellation 68 Pax 18 PAX6 68, 73 Pax6 20, 48, 50, 52, 53, 62, 78 pharyngula 2, 3 Pikaia 15 pineal organ 18 pioneer neurons (PN) 60, 65, 67

115 place cells 56 placodes (PL) 21, 72 polyploidy 82 poriferans 7 preplate (PP) 64 prosencephalon (prosencephalic) 5 prosomeres (prosomeric) 3, 4, 73 prosomeric model 4, 73, 79 Protoclepsydrops 28 protostomes 8, 11 pulvinar 40 pyramidal cells 59 radial glia 61 radiates 7 recapitulation hypothesis 39 reeler 66 reelin 60, 63 Repenomanus 37 Repenonamus 35 reptiles 32 rhombencephalon 5 rhombomeres (rhombomeric) Robo (Roundabout) 70

3

sarcopterygian 26 septum 28 Sinoconodon 35 sleep 57 Slit 70 sog (short gastrulation) 10 somatosensory area 68 spatial learning 55, 58 spatial memory 56 Sphenodon 47, 48 striatum 28, 33 subpallium 4, 28 subplate (SP) 61, 65, 67, 75, 76 substantia nigra 29 subventricular zone 6, 48, 61, 62, 76 superior colliculus 40, 44 synapsid 28, 35 Tbr (T-brain) 14, 22, 48, 50, 61 telencephalon impar 30, 31 tetrapods 30 thalamus – dorsal 28, 30, 42, 47 therapsids 35 tornaria 14

116

Subject Index

Transcendental Anatomy 2 translocation 61 Triconodon 35, 37 Tulerpeton 27 tunicates see urochordates

Westlothiana 27 WNT 14 Wnt (Wnt3, Wnt3a) Wulst 32

urochordates

Yunnanozoon

8, 12, 15, 17, 21

ventricular zone 6, 32, 76 vibrissae 69 visual area 42, 68

Xenoturbella

52, 53, 74

8 15

Zic 18 zona limitans intrathalamica zootype 2

29