3.08 The Evolution of Classes in the Neocortex of Mammals

P R Hof, Mount Sinai School of Medicine, New York, NY, USA C C Sherwood, The George Washington University, Washington, DC, USA ª 2007 Elsevier Inc. All rights reserved.

3.08.1 Introduction 114 3.08.2 Neuronal Typology and Chemical Specialization 114 3.08.2.1 Pyramidal 114 3.08.2.2 Spiny Stellate Cells 116 3.08.2.3 Inhibitory : Basket, Chandelier, and Double Bouquet Cells 116 3.08.3 Relationships of Neurochemical Phenotype and Phylogenetic Affinities 117 3.08.3.1 General Phylogenetic Patterns 117 3.08.3.2 The Distribution of Some Neuron Classes Closely Matches Phylogenetic Affinities 118 3.08.3.3 Other Phylogenetic Distributions of Cortical Neuron Classes Indicate Convergent Evolution 120 3.08.4 Functional Considerations 121

Glossary Hominidae A primate clade that includes great apes (orangutans, gorillas, chimpan- Afrotheria A clade of placental mammals that is zees, and bonobos) and humans. The thought to have originated in Africa at hylobatids (gibbons and siamangs) a time when it was isolated from other are the sister taxon to the Hominidae. continents. This clade contains homoplasy A structure that is the result of con- Paenungulata (elephants, hyraxes, and vergent evolution, where organisms sirenians), Afrosoricida (tenrecs and that are not closely related indepen- golden moles), Tubulidentata (aard- dently acquire similar characteristics. varks), and Macroscelidea (elephant Homoplasy is contrasted with shrews). Molecular data indicate that homology, which means that struc- the Afrotheria diverged from other pla- tures have a common origin derived cental mammals 110–100 Mya. from a shared ancestor. Anthropoidea A primate clade that includes New Laurasiatheria A supraordinal clade of boreo- World monkeys, Old World mon- eutherian placental mammals that keys, apes, and humans. Tarsiers are includes Cetartiodactyla, Perisso- the sister group to the Anthropoidea. dactyla, Carnivora, Pholidota, and Boreoeutheria A clade of placental mammals that Eulipotyphla. encompasses Euarchontoglires and marsupials A clade of mammals in which the Laurasiatheria. This taxonomic divi- female has a pouch where the young is sion within the Boreoeutheria nurtured through early infancy. There occurred 95–85 Mya in the Cretaceous. are approximately 280 species of living Cetartiodactyla A clade of placental mammals that marsupials, with the majority being includes cetaceans (whales, dolphins, native to Australia and the remainder and porpoises) and artiodactyls living in South America (however, there (even-toed ungulates). This phyloge- is a single North American native mar- netic grouping is based on molecular supial species, the Virginia opossum). evidence indicating that cetaceans monotremes A clade of mammals that lay eggs, evolved from within the artiodactyls rather than giving birth to live young and have their closest relationship like marsupials and placental mam- with the hippopotamus and then mals. The extant representatives of ruminants (cattle and deer). this group, the platypus and the echid- Euarchontoglires A supraordinal clade of boreoeuther- nas, are indigenous to Australia, New ian placental mammals that includes Guinea, and Tasmania. Fossil evidence, Rodentia, Lagomorpha, Dermoptera, however, suggests that monotremes Scandentia, and Primates. were once more widespread. 114 The Evolution of Neuron Classes in the Neocortex of Mammals placental A clade of mammals in which the these cellular phenotypes could be used to assess mammals fetus is nourished during gestation taxonomic affinities and functional differences by a placenta. This group encom- among species. passes the majority of living mammals. Xenarthra A clade of placental mammals pre- 3.08.2 Neuronal Typology and Chemical sent today only in the Americas. This group includes sloths, anteaters, Specialization and armadillos. Molecular data indi- 3.08.2.1 Pyramidal Neurons cate that the Xenarthra diverged from boreoeutherian mammals Pyramidal neurons are the principal excitatory 100–95 Mya. neuronal class in the . They are highly polarized neurons, with a major orientation axis orthogonal to the pial surface of the cerebral 3.08.1 Introduction cortex. Their cell body is roughly triangular on cross section, although a large variety of morpho- A diverse array of neuron types populates the logic types exist with elongate, horizontal or mammalian neocortex. Physiological activity vertical fusiform, or inverted perikaryal shapes. within a cortical area, in turn, is largely deter- They typically have a large number of mined by interactions among these different cell that emanate from the apex and from the base of types and incoming afferents. Neurons in the cer- the cell body. The span of their dendrites may ebral cortex of mammals can be divided into two cover several millimeters and their somata are major classes on the basis of morphology and found in all cortical layers except layer I, with function, pyramidal excitatory cells, and inhibi- predominance in layers II, III, and V. Small pyr- tory interneurons. Each class includes many amidal neurons in layers II and III of the subtypes that can be identified by their size, neocortex have a restricted dendritic tree and shape, dendritic and axonal morphology, and con- form vast arrays of axonal collaterals with neigh- nectivity. These neuronal subtypes exhibit a boring cortical domains, whereas medium to large variable distribution among cortical layers and pyramidal cells in deep layer III and layer V have regions, and some are differentially represented a much more extensive dendritic tree and furnish among species (see Hof et al., 1999, 2000; Hof long corticocortical connections. Layer V also and Sherwood, 2005). Neurons can be further contains very large pyramidal neurons disposed classified based on their expression of various in clusters or as isolated, somewhat regularly proteins, such as proteins (NFPs), spaced elements. These neurons are known to calcium-binding proteins, and neuropeptides. project to subcortical centers such as the basal The morphology of a given neuron, particularly ganglia, brainstem, and . Finally, layer of its dendritic arborizations, reflects the size of its VI pyramidal cells exhibit a greater morphologic receptive field and the specificity of its synaptic variability than those in other layers, and are contacts. Thus, the structure of the dendritic involved in certain corticocortical as well as corti- arbor as well as the distribution of axonal terminal cothalamic projections. The dendrites of ramifications confer a high level of subcellular spe- pyramidal cells show large numbers of dendritic cificity in the localization of particular synaptic spines that receive most of the excitatory synaptic contacts on a given neuron. The three-dimensional inputs. As many as 40 000 spines can be encoun- distribution of the dendritic tree is also a key factor tered on a large pyramidal neuron. with respect to the type of information transferred The major excitatory output of the neocortex is to the neuron. A neuron with a dendritic tree furnished by pyramidal cells. Their extends in restricted to a particular cortical layer may be most cases from the base of the perikaryon and receptive to a very limited pool of afferents, courses toward the subcortical and whereas widely expanding dendritic branches typi- gives off several collateral branches that are direc- cal of large pyramidal neurons will receive highly ted to cortical domains generally located within the diversified inputs in the cortical layers through vicinity of the cell of origin. While many of these which the dendrites course. Considering the varia- branches ascend in a radial, vertical pattern of bility in cortical morphology, size, and cellular arborization, a separate set of projections also tra- organization in mammals, it is important to inves- vels horizontally over long distances. One function tigate how specific characteristics of cortical of the vertically oriented component of the recur- microcircuitry differ among species, and how rent collaterals may be to interconnect layers III The Evolution of Neuron Classes in the Neocortex of Mammals 115 and V, the two major output layers of the neocor- highly specific long corticocortical projections, and tex. Horizontal intrinsic connections are positioned show regional specificity in their distribution pat- to recruit and coordinate the activity of modules of terns (Campbell and Morrison, 1989; Campbell similar functional properties while inhibiting other et al., 1991; Hof and Nimchinsky, 1992; domains. Together these recurrent projections Carmichael and Price, 1994; Hof and Morrison, function to set up local excitatory patterns and 1995; Hof et al., 1995b; Nimchinsky et al., 1995, coordinate the output of neuronal ensembles. 1996, 1997; Preuss et al., 1997, 1999; Sherwood NFP immunoreactivity, chiefly recognized by the et al., 2003a; Vogt et al., 2001, 2005). Although expression of dephosphorylated epitopes of NFP the precise function of NFP is not completely medium and heavy molecular weight subunits, understood, its restricted distribution among cer- characterizes a subpopulation of pyramidal neu- tain subsets of corticocortical circuits in primates rons in the neocortex of mammals that exhibits suggests that it confers unique neurochemical and clear regional and species differences in their dis- morphologic properties subserving a range of tribution and densities (Hof et al., 1992, 1996; van highly specialized functions in neocortical connec- der Gucht et al., 2001, 2005; Kirkcaldie et al., tivity, as well as selective vulnerability to 2002; Boire et al., 2005; Figure 1). The expression neurodegenerative diseases unique to humans of NFP has been studied most comprehensively in (Hof et al., 1995a, 1995b; Nimchinsky et al., primates, where it has been shown that this protein 1996; Bussiee`re et al., 2003; Hof and Morrison, is enriched in a subset of large pyramidal neurons 2004). NFP may be present, to some degree, in that have an extensive dendritic arborization, are functionally homologous subsets of cortical output distributed in well-defined laminar positions, form neurons in many species.

(a) (b) (c)

(d) (e) (f) Figure 1 Examples of cytoarchitecture and cellular typology using an antibody against NFP. a, Organization of the primary visual cortex in a long-tailed macaque monkey (Macaca fascicularis). NFP-immunoreactive neurons are predominant in layers III, IVB, and V. b and c, Distribution of NFP-immunoreactive neurons in the primary visual cortex of two carnivores, the dog (b, Canis familiaris), and the California sea lion (c, Zalophus californianus). Note the prominent labeling of very large cells in layer V and smaller cells in layer III, whereas layer IV in the middle is devoid of labeled neurons. The large size and extensive dendrites of NFP-immunoreactive neurons is obvious. d, NFP-immunoreactive cells in the visual area of the camel (Camelus dromedarius). The labeled neurons are relatively small and predominate in the deep layers. e and f, NFP immunolabeling in the visual cortex of the pigmy sperm whale (e, Kogia breviceps), and of the beluga whale (f, Delphinapterus leucas). Note the prominent clusters of large immunoreactive neurons in layer IIIc/V only. Scale bar (on f): 300 mm. Reproduced from Hof, P. R. and Sherwood, C. C. 2005. Morphomolecular neuronal phenotypes in the neocortex reflect phylogenetic relationships among certain mammalian orders. Anat. Rec. A 287, 1153–1163, with permission from John Wiley & Sons, Inc. 116 The Evolution of Neuron Classes in the Neocortex of Mammals

3.08.2.2 Spiny Stellate Cells with dendrites extending in all directions for several hundred micrometers such that the vertically Spiny stellate cells are the other class of cortical oriented dendrites cross several layers. Their axon excitatory neurons and are found in highest numbers arises vertically, quickly bifurcates and travels long in neocortical layer IV. The spiny stellate cell is a distances, forming multiple pericellular arrays as it small multipolar neuron with local dendritic and spreads horizontally. The basket cells predominate axonal arborizations. These neurons resemble pyra- in layers III and V in the neocortex and are numer- midal cells in that they are the only other cortical ous amid hippocampal pyramidal neurons. neurons with large numbers of dendritic spines, but Chandelier cells generally have a variably bitufted differ from them in lacking most of an apical or multipolar dendritic tree. The defining character- and having a restricted dendritic arbor that generally istic of this cell class is the very striking appearance does not extend beyond the layer in which the cell of its axonal endings. In Golgi or immunohistoche- body resides. The of spiny stellate neurons are mical preparations, the axon terminals appear as primarily intrinsic and form links between layer IV, vertically oriented cartridges, each consisting of a that receives a major input from the thalamus, and series of axonal swellings linked together by thin layers III, V, and VI. In some respects, the axonal connecting pieces making them look like old- arbor of spiny stellate cells mirrors the vertical style chandeliers. These neurons exclu- plexuses of recurrent collaterals, albeit in a more sively on the axon initial segment of pyramidal restricted manner. Given its axonal distribution, cells. Most of the chandelier cells are located in spiny stellate neurons appear to function as a layer III and their primary target appears to be high-fidelity translator of thalamic inputs, maintaining pyramidal cells in layer III, and to a lesser extent strict topographic organization and setting up initial layer V. One may receive inputs links of information transfer within a cortical area. from multiple chandelier cells, and one chandelier cell may innervate more than one pyramidal cell. 3.08.2.3 Inhibitory Interneurons: Basket, This cell exerts powerful inhibition on postsynap- Chandelier, and Double Bouquet Cells tic pyramidal cell firing. There is a large variety of types in the Double bouquet cells are mostly prevalent in cerebral cortex. These neurons contain the neuro- layers II and III, and are also present in layer V of transmitter -aminobutyric acid (GABA), and exert the neocortex. These interneurons are characterized strong local inhibitory influences on postsynaptic by a vertical bitufted dendritic tree and a tight bun- neurons. The dendritic and axonal arborizations of dle of vertically oriented varicose axon collaterals interneurons offer important clues as to their role in that traverse layers II through V. Many double bou- the regulation of pyramidal cell function. In addition, quet cells synapse on spines of pyramidal cells and many morphologic classes of GABAergic interneur- most of their remaining are on fine dendri- ons can be further defined by a particular set of tic shafts, in striking contrast to the basket and neurochemical characteristics. Three major subtypes chandelier cells. Another subclass of double bou- of cortical interneurons are classically described, quet cell has similar synaptic targets but primarily principally based on rodent and primate studies, in layer V, thus influencing the activity of different namely basket, chandelier, and double bouquet populations of pyramidal cells. cells. It must be noted, however, that interneurons GABAergic interneurons can also be classified in exhibit a rich variety of size and morphologies, such nonoverlapping subtypes based on their content in as clutch cells, neurogliaform cells, Martinotti-type the calcium-binding proteins parvalbumin (PV), cal- and Cajal–Retzius cells, bipolar cells and other stel- bindin (CB), and calretinin (CR), as well as several late cells, and multipolar neurons, which all have neuropeptides (Hendry et al., 1989; Andressen diverse representations depending on the region et al., 1993; Conde´ et al., 1994; DeFelipe, 1997; as well as on the species studied. Gonchar and Burkhalter, 1997; Glezer et al., 1998; Basket cells are characterized by axonal endings Morrison et al., 1998; Hof et al., 1999; Markram that form a basket of terminals surrounding a pyr- et al., 2004). CB- and CR-expressing interneurons amidal cell and provide most of the inhibitory share many morphologic similarities, and are GABAergic synapses to the soma and proximal den- mainly bitufted, bipolar, and double bouquet neu- drites of pyramidal cells. One basket cell may rons, as well as a few pyramidal neurons, with contact numerous pyramidal cells, and in turn sev- minimal overlap among these subpopulations in eral basket cells can contribute to the pericellular the rodent and primate neocortex (Rogers, 1992; basket of one pyramidal cell. The basket cells have a DeFelipe, 1997; Morrison et al., 1998). PV-immu- relatively large soma and multipolar morphology noreactive neurons are mainly observed in layers II The Evolution of Neuron Classes in the Neocortex of Mammals 117 to V, and are principally basket and chandelier cells as well as small pyramidal-like neurons in layers V (Blu¨ mcke et al., 1990; Van Brederode et al., 1990; and VI in the lateral cortex. Compared to CR- Hof and Nimchinsky, 1992; Conde´ et al., 1994; immunoreactive neurons, CB is more sparsely pre- Nimchinsky et al., 1997). PV has also been reported sent in bipolar and bitufted neurons in the to occur in certain pyramidal neurons in primate supragranular layers throughout the cortex, and in somatosensory and motor cortex (Preuss and Kaas, some larger multipolar neurons in the deep layers. 1996; Sherwood et al., 2004). A major difference between marsupials and other mammalian taxa is the remarkable paucity of PV- immunoreactive neurons and fibers. PV is 3.08.3 Relationships of Neurochemical observed only in a few small interneurons, Phenotype and Phylogenetic Affinities whereas it is much more prevalent in other small-bodied mammals as well as in primates 3.08.3.1 General Phylogenetic Patterns and carnivores. Surprisingly, PV-containing neu- Phylogenetic patterns in the distribution of NFP and rons in layer II have a morphology resembling the three calcium-binding proteins appear to be asso- double bouquet cells that are usually labeled by ciated with interspecific variation in other aspects of CB in rodents and primates. This may represent a the cytoarchitecture of mammalian neocortex. neuronal specialization in certain marsupials that Monotremes (i.e., echidnas and the platypus) are is not found in placental mammals. the sister taxon to all therian mammals. In these A current limitation to interpreting regional pat- species, neurons containing CB, CR, and PV are terns of distributions of neuron classes is the found throughout the cortex, although CR-immu- paucity of data from the phylogenetic groups noreactive neurons are most dense in the piriform that diverged close to the base of the adaptive cortex where they predominate as a polymorphic radiation of placental mammals, the Xenarthra phenotype. In monotremes (Hof et al.,1999), CB (i.e., sloths, anteaters, and armadillos) and and PV comprise morphologic types that resemble Afrotheria (i.e., tenrecs, golden moles, elephant those found in placental mammals, including large shrews, aardvarks, manatees, hyraxes, and ele- PV-immunoreactive multipolar neurons that are phants). Substantially more is known regarding similar to basket cells. In echidnas, however, PV variation in cortical architecture of the other pla- is present in a unique cell type characterized by a cental mammals, the Boreoeutheria. Among large pyramidal-like or multipolar morphology that boreoeutherian mammals, species showing a high is common in layers V and VI. Such PV-labeled degree of morphologic differentiation of neocorti- neurons have not been observed in any other mam- cal areas, a variable development of layer IV, and malian species. It is also worth noting that the substantial variation in neuronal size and packing Australian echidna (Tachyglossus aculeatus)pre- densities across the cortical plate are also generally sents NFP-expressing cells in layer V of its characterized by a balanced representation of the neocortex (Hassiotis et al.,2004). Although there three calcium-binding proteins and morphological are no studies of NFP staining in the most closely diversity of NFP-immunoreactive pyramidal neu- related taxon, the platypus, NFP is enriched in rons across cortical regions (Hof et al., 2000). In layer V neurons in the marsupial tammar wallaby contrast, species characterized by greater cytoarch- (Macropus eugenii) throughout its cortex, as well itectural monotony throughout the cortical mantle, as occasionally in layer III neurons of select sensory a poorly defined or lack of layer IV in most regions, and association regions (Ashwell et al., 2005). In and the presence of very large pyramidal cells in all placental mammals, NFP-containing pyramidal neocortical areas, display a predominance of CB- neurons are found frequently in layers III, V, and and CR-containing populations in comparison to VI. Thus, NFP-rich cells in layer V may be inter- PV-immunoreactive neurons, and rather uniform preted as a conservative trait among mammals, NFP-containing pyramidal cell morphology. The with variable patterns of NFP expression in other first type occurs in primates, rodents, carnivores, layers having arisen in different lineages in subse- and to some extent megachiropterans, as well as in quent evolution (Figure 1). tree shrews and lagomorphs. Most of the taxa that All species of marsupials examined to date display are characterized by this cortical organization are comparable staining patterns in the neocortex for members of the supraordinal group PV, CB, and CR (Hof et al., 1999). The most pre- Euarchontoglires, with the exception of carnivores valent calcium-binding protein in marsupials and bats. In contrast, the second type of cortical appears to be CR, which is present in numerous organizational pattern is present in cetaceans, small bipolar neurons located in layers II and III, artiodactyls, and perissodactyls, which are all 118 The Evolution of Neuron Classes in the Neocortex of Mammals members of the Laurasiatheria. Thus, the distribu- encountered in layers V and VI, especially in the tion of these particular aspects of the cortical neocortex of large artiodactyls, such as the giraffe phenotype follows a major taxonomic division that (Giraffa camelopardalis), llama (Lama glama), and occurred about 80–90 Mya at the base of the radia- camel (Camelus dromedarius), whereas they are less tion of boreoeutherian mammals (Murphy et al., numerous in the pig (Sus scrofa), and in smaller 2001a, 2001b). While these general patterns appear ruminants. A few pyramidal-like neurons in layer III to differentiate cortical organization in major bor- are also faintly CR-containing in dolphins, and the eoeutherian clades, the lack of data from large pyramidal neurons in layer IIIc/V contain low xenarthrans and afrotherians makes it difficult to levels of CB. The distribution and morphology of clearly establish which character states are conserva- NFP-immunoreactive neurons are also comparable tive and which are derived for placental mammals. in cetaceans and artiodactyls, but differ considerably This is a particular challenge because cortical cell from those in primates, carnivores, and rodents. In types in monotremes and marsupials often differ sig- cetartiodactyls, NFP is expressed in very large pyra- nificantly from placental mammals and from each midal neurons located in the deep portion of layer III other. Our examination of calcium-binding protein and in upper layer V (Hof et al., 1992). These neu- immunoreactivity in the xenarthran giant anteater rons are present as clusters of three to six neurons, (Myrmecophaga tridactyla), however, shows simila- regularly spaced throughout the cortical mantle and rities with marsupials and cetartiodactyls in that intensely labeled with prominent apical dendrites PV-immunoreactive neurons are very sparse, whereas extending well into layer I, with no major regional CB- and CR-immunoreactive neurons are expressed variability in their densities. in a morphologically diverse population of cells that Another cell class that shows a restricted phylo- includes a high frequency of pyramidal neurons (Hof genetic distribution is the spindle-shaped neuron, and Sherwood, 2005; Figures 2 and 3). which is found exclusively in the cerebral cortex of hominids (i.e., great apes and humans). Spindle- shaped cells are characterized by a vertical, fusiform 3.08.3.2 The Distribution of Some Neuron morphology, very large size, and high levels of NFP Classes Closely Matches Phylogenetic Affinities immunoreactivity (Nimchinsky et al., 1995, 1999). Reports of the cyto- and chemoarchitecture of odon- They are prevalent in a restricted sector of the ante- tocete cetaceans, particularly of visual and auditory rior cingulate cortex (areas 25, 24a, and 24b; Vogt regions, and analysis of neocortical neurons in a few et al., 1995) and are also numerous in the antero- large artiodactyls have revealed commonalities in ventral agranular insular cortex (see The Evolution cortical organization between these sister taxa of Neuron Types and Cortical in Apes (Morgane et al., 1988, 1990; Glezer et al., 1992, and Humans, Role of Spindle Cells in the Social 1993, 1998; Hof et al., 1992; 1999). In both groups, Cognition of Apes and Humans). These neurons PV is present only in sparsely distributed large stellate are found exclusively in hominids and have not neurons located in layer IIIc/V. A few small pyrami- been reported in any other mammalian species dal neurons in layer III also exhibit PV investigated thus far (including other primate spe- immunoreactivity in dolphins. In cetaceans and artio- cies; Nimchinsky et al., 1999; Hof et al., 2000). The dactyls, CB- and CR-immunoreactive cells are far volume of spindle-shaped cells is strongly correlated more numerous than PV-immunoreactive cells, with encephalization, which is not the case for the occurring in large fusiform, bipolar, or multipolar other neuron types (Nimchinsky et al., 1999). neurons in layers I, II, and superficial layer III. CB- These spindle-shaped cells are a particular type containing neurons are much less numerous and less of projection neuron, as they send an axon in intensely stained than CR-immunoreactive neurons. the subcortical white matter, although their exact The CR-containing neurons located in layer I have a domain(s) of projection cannot be ascertained in morphology quite comparable to that of the bipolar/ the species in which they are present. They may, bitufted CB- or CR-expressing neurons typically seen however, provide well-defined projections, similar in layer II of other mammals such as rats, carnivores, to Meynert cells or Betz cells (Sherwood et al., and primates (Ballesteros Ya´n˜ez et al., 2005), 2003b). Furthermore, although CR-immuno- whereas the CR-containing neurons in layers II reactive pyramidal neurons have been reported in and III are much larger and more variable in the entorhinal cortex of several mammalian spe- shape than in other species, with a predominance cies, CR-containing small pyramidal neurons in of multipolar and fusiform types. These neurons layer Va of anterior cingulate cortex (area 24) have long dendrites that extend into layers I and appear to be present exclusively in hominids, pos- III. Very large CR-immunoreactive neurons are also sibly indicating a recent evolutionary character in The Evolution of Neuron Classes in the Neocortex of Mammals 119

(c)

(a) (b)

(d) (e) (f)

(g) (h) (i)

(j) (k) (l)

(m) (n) (o) Figure 2 Immunoreactivity patterns of calcium-binding proteins in the neocortex of various mammals. a and b, CB (a) and PV (b) immunoreactivity in the primary somatosensory cortex of the echidna (Tachyglossus aculeatus). There is a large population of small neurons that express CB, whereas PV is contained in a heterogeneous collection of neurons, some very large and multipolar. This differs radically from other members of the Australian fauna (Hof et al.,1999), such as the koala (Phascolarctos cinereus, c), which displays a rather sparse population of CB-containing cells. d and e, The giant anteater (Myrmecophaga tridactyla) is also characterized by a sparse population of relatively large CB-immunoreactive multipolar neurons (d) and PV-expressing neurons (e). These patterns are fully distinct from that in rodents (f, CR immunoreactivity in the somatosensory cortex of the chinchilla, Chinchilla laniger), carnivores (g, CR immunoreactivity in a dog motor cortex displaying bipolar neurons as well as pyramidal-like neurons), and a cetacean visual cortex (h, the bottlenose dolphin, Tursiops truncatus). Layers I and II are particularly enriched in the cetacean (layer II is located about one-third down from the top of the photomicrograph). Panels (i–l) show details of the chemoarchitecture of the frontal cortex of a Siberian tiger (Panthera tigris). CR-immunoreactive neurons exhibit a typical distribution predominating in the superficial layers (i, k), and large multipolar CB-immunoreactive (j) and PV-immunoreactive (l) neurons are encountered in deep layer III. Large multipolar CR-containing neurons are found in layer III of a dog (Canis familiaris) primary motor area (m). Note the large size of this neuron and compare it to the CR-immunoreactive giant neuron located in layer VI of a giraffe (n, Giraffa camelopardalis), and to a typical in layer III of the mouse visual cortex (o, Mus musculus). Scale bar (on n): 300 mm(a,b);400mm(f–i);50mm (c–e, j–o). Reproduced from Hof, P. R. and Sherwood, C. C. 2005. Morphomolecular neuronal phenotypes in the neocortex reflect phylogenetic relationships among certain mammalian orders. Anat. Rec. A 287, 1153–1163, with permission from John Wiley & Sons, Inc. this primate clade (Hof et al., 2001). These obser- My in cortical regions that play major roles in vations of multiple novel cellular specializations the regulation of autonomic function, cognition, suggest the occurrence of functional modifications self-awareness, emotionality, and vocalization along the hominid lineage during the last 15–20 (Figures 2 and 3). 120 The Evolution of Neuron Classes in the Neocortex of Mammals

PV

CB

CR

Echidna QuollHedgehog Flying fox Macaque RatDog Dolphin Giraffe monkey Figure 3 Schematic representation of the major calcium-binding protein-immunoreactive neuronal types in the mammalian neocortex. A few representative species of monotremes, marsupials, and placentals are shown. Many species have comparable neuronal types, especially with respect to small CR-immunoreactive bipolar neurons and CB-containing bitufted and double-bouquet cells. Primates, rodents, and carnivores, with the exception of CR, tend to show comparable patterns. The shading of the neurons indicates the relative intensity of the staining. Faintly labeled neurons are shown as empty symbols, moderately labeled neurons as gray symbols, and intensely labeled neurons as black symbols. Dotted triangles indicate the presence of PV-immunoreactive basket terminals on pyramidal neurons. Triangles represent pyramidal and pyramid-like neurons; black dots represent small multipolar or round neurons; diamonds represent large multipolar neurons and basket cells. Other symbols identify CB- and CR-immunoreactive bipolar, bitufted, and double bouquet cells, as well as neurons with atypical morphology. Note the presence in the monkey and the rat of CB-immunoreactive neurogliaform (represented as small star-shaped elements), and Martinotti cells (shown as large, ovoid horizontally oriented elements), in layers V and VI, that have not been reported in other species. On each panel, the dashed lines identify layers I and IV. Note the thick layer I and the absence of layer IV in cetaceans and ungulates. Layer IV is also not clearly defined in the hedgehog. Adapted from Hof, P. R., Glezer, I. I., Conde´, F., et al. 1999. Cellular distribution of the calcium-binding proteins parvalbumin, calbindin, and calretinin in the neocortex of mammals: Phylogenetic and developmental patterns. J. Chem. Neuroanat. 16, 77–116, Elsevier.

3.08.3.3 Other Phylogenetic Distributions of comparable to that observed in anthropoid pri- Cortical Neuron Classes Indicate Convergent mates. Some of these large multipolar neurons may Evolution be basket cells, due to the presence of PV-immuno- Although many aspects of cortical architecture reactive basket terminals around unstained reflect phylogenetic affinities, it is likely that many pyramidal perikarya. Furthermore, CR is present cortical phenotypes present examples of homoplasy, in a very dense population of bipolar and double where certain characters have evolved indepen- bouquet cells in layer II and the upper portion of dently in nonrelated groups of mammals. In this layer III, as observed in primates and rodents. These regard, it is noteworthy that there are several traits aspects of chemoarchitecture in carnivores that are shared by Carnivora and Euarchontoglires, such as similar to primates, rodents, and other the distribution and typology of calcium-binding Euarchontoglires are not derived from a common protein-containing neurons (Glezer et al., 1993, ancestral state and hence have arisen due to conver- 1998; Hof et al., 1999; Ballesteros Ya´n˜ ez et al., gent evolution. Other features of carnivore cortical 2005). For example, in the dog neocortex, PV is organization resemble traits observed in their close present in a large population of morphologically relatives in the Laurasiatheria, the perissodactyls diverse interneurons with a typology generally and cetartiodactyls, and so were probably inherited The Evolution of Neuron Classes in the Neocortex of Mammals 121 from the last common ancestor of these taxa. For the role of calcium-binding protein in cortical inte- example, in canids, felids, and pinnipeds, gigantic gration is likely to be similar to a large degree intensely labeled CR-immunoreactive, multipolar among rodents, carnivores, and primates, suggest- neurons occur in layer III of agranular motor cor- ing that similar mechanisms exist across tices. These neurons are morphologically boreoeutherian mammals at least. However, differ- comparable to the very large CR-containing neu- ences are present at the level of particular neuronal rons found in layers III, V, and VI throughout the subclasses, as recently revealed in a study of CB- neocortex of large artiodactyls and cetaceans (Hof expressing interneurons in primates compared to et al., 1996, 1999), which shows a poorly differen- rodents, lagomorphs, carnivores, and artiodactyls tiated layer IV only in certain regions (Morgane (Ballesteros Ya´n˜ ez et al., 2005). These authors et al., 1990; Glezer et al., 1993, 1998; Hof et al., reported that, in the nonprimate species, axon bun- 1999). It is interesting that in spite of many simila- dles of CB-immunoreactive double bouquet cells are rities in cortical organization and connectivity not observed except for some in the visual cortex of between carnivores and primates, the dog neocortex carnivores, indicating that although somata that displays several differences in neurochemical orga- resemble typical CB-expressing cell types from pri- nization compared to anthropoids (Hof et al., 1996, mates can be found in these species, their axonal 1999). Canids have a high degree of cellular specia- projections are likely to differ from primates. lization in primary motor and sensory cortices, Whether such differences in axonal organization contrasting with fairly homogeneous patterns in can be extended to PV- and CR-immunoreactive association cortices. Large PV- and CB-containing neurons remains to be demonstrated. pyramidal cells are present only in primary motor The degree to which functional interpretations of and visual regions, and high numbers of large PV- biochemical neuron types can be applied to all immunoreactive basket cells and multipolar CR- mammalian orders is difficult to determine owing containing interneurons occur only in primary to large differences in morphological phenotypes motor, somatosensory, and visual areas (Hof et al., and distributions for any given cell type across spe- 1996). cies. The relative rarity of PV-immunoreactive Besides these observations in carnivores, other neurons in cetaceans and artiodactyls could be examples show that the distribution of cortical neu- interpreted as an ancestral retention for the ron classes exhibit a mosaic pattern of evolution, Laurasiatheria because it also occurs in other laur- with some unique specializations, in particular asiatherians such as echolocating bats and lineages and other examples of homoplasy (for hedgehogs, which may show many plesiomorphic instance, a paucity of PV expression is observed in features (Glezer et al., 1988). The neocortex of the neocortex of cetartiodactyls and marsupials). cetaceans and large artiodactyls appears to contain The predominance of CB and CR in the neocortex an inordinate number of cortical modules revealed and subcortical systems of cetartiodactyls is similar by clusters of large NFP-containing pyramidal cells to the calcium-binding protein distributions in layer IIIc/V (Glezer et al., 1988; Morgane et al., observed in microchiropterans and hedgehogs but 1988; Hof et al., 1992). Much cortical integration differs from that in rodents and primates (Glezer in cetaceans may take place in the cellular, thick et al., 1993, 1998; Hof et al., 1999). In addition, layer I that contains 70% of the neocortical large multipolar PV-containing neurons are found synapses in these species (Glezer and Morgane, in the deep layers of the neocortex of hedgehogs and 1990). Consistent with this observation, most CB- dolphins, unlike in rodents, carnivores, and pri- and CR-containing interneurons are located in mates, where PV-expressing cells are more layers I and II in cetaceans, and the few PV-immu- common in layers III and IV. It is also notable that noreactive cells lie in nearby layers IIIc/V and VI megachiropterans are characterized by the absence pyramidal cells. The PV-immunoreactive neurons of neocortical expression of CR, whereas their tha- may represent basket cells, and axons of CB- and lamic neurons do express it. CR-immunoreactive interneurons may be located in a position to interact with inputs to the neocortex 3.08.4 Functional Considerations and connect the apical dendrites of the deep layers of pyramidal neurons (Glezer et al., 1988; Morgane Calcium-binding protein-containing interneurons et al., 1988). It is possible that in cetartiodactyls are known to influence the activity of pyramidal calcium-binding protein-immunoreactive neurons neurons in a manner specific to each cell class play a comparable role in neocortical microcircuits (Conde´ et al., 1994; DeFelipe, 1997; Hof et al., as in primates and rodents. The similarities in neu- 1999; Ballesteros Ya´n˜ ez et al., 2005), and as such rochemical specialization of the cetartiodactyl 122 The Evolution of Neuron Classes in the Neocortex of Mammals neocortex parallel the paleontological and molecu- Carmichael, S. T. and Price, J. L. 1994. Architectonic subdivision lar evidence, indicating that these species share a of the orbital and medial prefrontal cortex in the macaque relatively recent common ancestor, and that much monkey. J. Comp. Neurol. 346, 366–402. Conde´, F., Lund, J. S., Jacobowitz, D. M., Baimbridge, K. G., and like primates, the evolution of the species with the Lewis, D. A. 1994. Local circuit neurons immunoreactive for largest (the delphinids) is a recent event calretinin, calbindin D-28k or parvalbumin in monkey pre- (Marino et al., 2005). frontal cortex: Distribution and morphology. J. Comp. Although there are major gaps in our knowledge of Neurol. 341, 95–116. the evolutionary history of neocortical organization in DeFelipe, J. 1997. Types of neurons, synaptic connections and chemical characteristics of cells immunoreactive for calbin- mammals and of the chemical organization of the din-D28k, parvalbumin and calretinin in the neocortex. cerebral cortex in most species, collectively these J. Chem. Neuroanat. 14, 1–19. observations indicate that brain organization and neu- Glezer, I. I. and Morgane, P. J. 1990. Ultrastructure of synapses rochemical cellular specialization reflect evolutionary and Golgi analysis of neurons in neocortex of the lateral gyrus relationships among many mammalian species. (visual cortex) of the dolphin and pilot whale. Brain Res. Bull. 24, 401–427. Glezer, I. I., Jacobs, M. S., and Morgane, P. J. 1988. The ‘initial’ brain concept and its implications for brain evolution in ceta- Acknowledgments cea. Behav. Brain Sci. 11, 75–116. Glezer, I. I., Hof, P. R., and Morgane, P. J. 1992. Calretinin- This work was supported by the National Science immunoreactive neurons in the primary visual cortex of dol- Foundation (BCS-0515484 and BCS-0549117), the phin and human brains. Brain Res. 595, 181–188. Wenner-Gren Foundation for Anthropological Glezer, I. I., Hof, P. R., Leranth, C., and Morgane, P. J. 1993. Research, and the James S. McDonnell Foundation Calcium-binding protein-containing neuronal populations in (grant 220020078). Brain materials were made mammalian visual cortex: A comparative study in whales, insec- tivores, bats, rodents, and primates. Cereb. Cortex 3, 249–272. available from the Great Ape Aging Project, the Glezer, I. I., Hof, P. R., and Morgane, P. J. 1998. 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Glezer, I. I., Hof, P. R., Leranth, C., and Morgane, P. J. 1993. Hof, P. R. and Sherwood, C. C. 2005. Morphomolecular neuro- Calcium-binding protein-containing neuronal populations in nal phenotypes in the neocortex reflect phylogenetic mammalian visual cortex: A comparative study in whales, insec- relationships among certain mammalian orders. Anat. Rec. tivores, bats, rodents, and primates. Cereb. Cortex 3, 249–272. A 287, 1153–1163. Glezer, I. I., Hof, P. R., and Morgane, P. J. 1998. Comparative Hof, P. R., Glezer, I. I., Conde´, F., et al. 1999. Cellular analysis of calcium-binding protein-immunoreactive neuronal distribution of the calcium-binding proteins parvalbumin, populations in the auditory and visual systems of the bottle- calbindin, and calretinin in the neocortex of mammals: nose dolphin (Tursiops truncatus) and the macaque monkey Phylogenetic and developmental patterns. J. Chem. (Macaca fascicularis). J. Chem. Neuroanat. 15, 203–237. Neuroanat. 16, 77–116.