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NRVS 00022 a0005 4.21 The Evolution of Neuron Types and Cortical Histology in Apes and Humans F C C Sherwood, Kent State University, Kent, OH, USA P R Hof, Mount Sinai School of Medicine, New York, NY, USA OO ª 2007 Elsevier Inc. All rights reserved. FI RS T PR 4.21.1 Introduction 4.21.1.1 Evolutionary History of the Hominoids 4.21.1.2 History of Studies Concerning Hominoid Cortical Histology 4.21.2 Comparative Anatomy of the Cerebral Cortex 4.21.2.1 Topology of Cortical Maps 4.21.2.2 Architecture of the Cortex 4.21.2.3 Primary Visual Cortex 4.21.2.4 Auditory Cortex 4.21.2.5 Primary Motor Cortex 4.21.2.6 Inferior Frontal Cortex 4.21.2.7 Prefrontal Cortex 4.21.2.8 Anterior Cingulate Cortex 4.21.3 Patterns of Cortical Organization in Hominoids 4.21.3.1 The Emergence of Cell Types and their Distribution 4.21.3.2 The Evolution of Cortical Asymmetries 4.21.3.3 How much Variation in Cortical Architecture can be Attributed to Scaling versus Specialization? 4.21.3.4 Genomic Data Provide Insights into Cortical Specializations 4.21.3.5 On the Horizon Many biological traits scale with overall size in a nonlinear fashion. Such allometric scaling relationships can be expressed by the power function: Y¼bXa. The logarithmic transformation of the allometric scaling equation yields: log Y¼log bþa log X. The exponent of the power function becomes the slope of the log-transformed function. The slope of this line can then be interpreted in terms of a biological scaling relationship between the independent and dependent variable. Positive allometry refers to a scaling relationship with an exponent that is greater than 1, which means that the structure in question grows disproportionately larger or more numerous with increases in the size of the reference variable. Negative allometry refers to a scaling relationship with an exponent that is less than 1, which means that Chemoarchitecture EL SE VI g0005 Allometry ER Glossary Dysgranular Cortex Encephalization Granular Cortex Grey Level Index (GLI) 2 2 3 4 4 4 5 8 10 12 13 14 15 15 15 17 18 19 the structure in question becomes proportionally smaller or less numerous with increases in the size of the reference variable. The microanatomical organization of the cerebral cortex revealed by staining for biochemical substances using techniques such as immunohistochemistry and enzyme or lectin histochemistry. A type of cortex that has a weakly defined layer IV because it is variable in thickness. At points, layer IV seems to disappear because neurons from layers IIIc and Va intermingle. A relative measure of a species’s brain size that represents the degree to which it is larger or smaller than expected for a typical animal of its body size. A type of cortex that has a clearly identifiable layer IV. The proportion of an area of reference that is occupied by the projected profiles of all Nisslstained elements. This value g0010 g0015 g0020 g0025 g0030 NRVS 00022 2 The Evolution of Neuron Types and Cortical Histology in Apes and Humans Layers s0010 Apes and humans are members of the primate super- p0005 family Hominoidea (Figure 1). Molecular evidence indicates that the hominoid lineage split from the Old World monkeys about 25Ma (Wildman et al., 2003). The extant representatives of this phylogenetic group include two families. The Hylobatidae comprises gibbons and siamangs, and the Hominidae includes great apes (i.e., orang-utans, gorillas, chimpanzees, and bonobos) and humans (Groves, 2001). Living hominoids are distinguished by a suite of shared derived traits that point to the key adaptations of this clade. These characters include lack of an external tail, modifications of the shoulder girdle and wrist for greater mobility, and stabilization of the lower back (Begun, 2003). These adaptations allow hominoids to exploit resources in small branches of trees by developing suspensory postures to distribute their body weight. This form of locomotion may have been particularly important in allowing certain species to increase body size. In addition, compared to other primates, hominoids have extended periods of growth and development (Schultz, 1969), an increased complexity of social interactions (Potts, 2004), and larger brains than would be expected for a monkey of the same body size (Rilling and Insel, 1999). The increased encephalization and associated life history elongation of these species suggest that cognitive flexibility and learning were important aspects of the hominoid adaptive complex, which allowed them to deal with locating ephemeral resources from fruiting trees and to negotiate more complicated relationships in fission–fusion societies (Potts, 2004). F b0860 FI ER g0050 Neuropil g0055 Supragranular EL SE VI Layers b0675 b0570 b0630 b0570 Humans 6 Ma 7 Ma 14 Ma 18 Ma b0300 b0075 RS g0045 Minicolumn 4.21.1.1 Evolutionary History of the Hominoids OO g0040 Infragranular s0005 PR g0035 Hominoid 4.21.1 Introduction T provides an estimate of the fraction of tissue that contains neuronal somata, glial cell nuclei, and endothelial nuclei versus neuropil. GLI values are highly correlated with the volume density occupied by neurons since glial and endothelial cell nuclei contribute only a very small proportion of the total volume. A phylogenetic clade that includes lesser apes (gibbons and siamangs), great apes (orang-utans, gorillas, chimpanzees, and bonobos), and humans. Cortical layers that are deep to granular layer IV, i.e., layers V and VI. Morphologically, minicolumns appear as a single vertical row of neurons with strong vertical interconnections among layers, forming a fundamental structural and functional unit. The core region of the column contains the majority of the neurons, their apical dendrites, and both myelinated and unmyelinated fibers. A cell-poor region, containing dendritic arbors, unmyelinated axons, and synapses, surrounds each column. The unstained portion of Nissl-stained tissue, which is comprised of dendrites, axons, and synapses. Cortical layers that are superficial to granular layer IV, i.e., layers I, II, and III. 3 Ma Bonobos Chimpanzees Gorillas Orang-utans 25 Ma Gibbons and simiangs 40 Ma Old World monkeys 58 Ma New World monkeys 63 Ma Tarsiers Lemurs and lorises showing the phylogenetic relationships of living hominoids and other primates. Estimated divergence dates f0005 Figure 1 Cladogram b0295 are taken from Goodman et al. (2005). NRVS 00022 The Evolution of Neuron Types and Cortical Histology in Apes and Humans ER FI b0830 SE VI b0420 EL s0015 4.21.1.2 History of Studies Concerning Hominoid Cortical Histology p0020 At the beginning of the twentieth century, neuroanatomists applied new histological staining techniques to reveal the architecture of the cerebral cortex in numerous species, including apes and humans (Campbell, 1905; Mauss, 1908; Brodmann, 1909; Mauss, 1911; Beck, 1929; Filimonoff, 1933; Strasburger, 1937a, 1937b). In addition, with the advent of various techniques for tracing neuronal connectivity based on intracellular b0135 b0100 b0230 b0500 b0505 b0745 b0070 b0750 b0470 OO F b0425 b0650 b0445 b0870 RS b0610 b0835 b0460 PR b0075 pathological changes subsequent to ablation, some studies also examined cortical projection systems in apes (Walker, 1938; Lassek and Wheatley, 1945; Kuypers, 1958; Jackson et al., 1969). After the 1950s, however, the amount of research directed toward understanding variation in the hominoid brain declined. There are three main reasons for this. First, the development of molecular biological techniques caused neuroscientists to focus on a small number of model species under the implicit assumption that many aspects of cortical structure are evolutionarily conserved. These ideas were further bolstered by claims of uniformity in the basic columnar architecture of the cerebral cortex (Rockel et al., 1980). Second, findings from the first systematic studies of great ape behavior from the field and laboratory were beginning to be appreciated (e.g., Kortlandt, 1962; Schaller, 1963; e.g., Yerkes and Learned, 1925; Yerkes and Yerkes, 1929). These studies contributed to a more sophisticated understanding of cognitive and emotional complexity in great apes and suggested that they deserve special protected status with respect to the ethics of invasive neurobiological experimentation. Third, the book Evolution of the Brain and Intelligence (Jerison, 1973) had an enormous influence on the direction of later research in comparative neuroanatomy. This book argued for the predictability of neuroanatomical structure from brain size and encephalization, suggesting that these metrics form the most significant contribution to species diversity in brain organization. Combined with the ready availability of comparative brain region volumetric data in primates and other mammals from the publications of Heinz Stephan, Heiko Frahm, George Baron, and colleagues (e.g., Stephan et al., 1981), a great deal of research effort has been expended in studies of allometric scaling and covariance of large regions of the brain (Finlay and Darlington, 1995; Barton and Harvey, 2000; de Winter and Oxnard, 2001). In contrast, much less attention has been paid to the possibility of phylogenetic variation in cortical histology (Preuss, 2000). Fortunately, advances in quantitative neuroanatomy and immunohistochemical staining techniques have opened new avenues of research to reveal interspecific diversity in the microstructure of hominoid cerebral cortex. The history of studies of hominoid cortical histol- p0025 ogy, therefore, has resulted in two eras of research. The early era comprises several qualitative comparative mapping studies of the cerebral cortex based on cyto- and myeloarchitecture, with the occasional comment regarding species differences in the microstructure of homologous cortical areas b0660 b0875 T Although only a small number of hominoid species persist today, the fossil record reveals a diverse array of successive adaptive radiations of hominoids in the past. During the Miocene epoch, global climates were warm and humid, supporting dense forests and lush woodlands extending throughout the tropics and into northern latitudes. These environmental conditions were favorable for the diversification of arboreal specialists, such as the hominoids. In fact, hominoids were the most abundant type of anthropoid primate throughout the Miocene in Africa and Eurasia, occupying a range of different ecological niches (Begun, 2003). The earliest apes in the fossil record are characterized by hominoidlike dental morphology, but monkeylike postcranial anatomy. The best known of these early dental apes is the genus Proconsul from the Early Miocene (20–18Ma) of East Africa. Proconsul africanus endocasts show a frontal lobe morphology that is similar to modern hominoids in being gyrified and lacking the simple V-shaped arcuate sulcus that is characteristic of most Old World monkeys (Radinsky, 1974). Furthermore, Proconsul africanus had a relatively larger brain than extant monkeys of comparable body size (Walker et al., 1983). Thus, increased encephalization and perhaps a greater degree of frontal lobe gyrification were present early in the evolution of the hominoids. p0015 With the emergence of arid climates in the transition to the Pliocene and the replacement of forests by mosaic habitats, the arboreal specializations of hominoids were less successful. The relatively slow reproductive rates of these taxa, moreover, made it difficult for many to endure habitat loss resulting from climate change and human encroachment in recent times (Jablonski et al., 2000). In the context of these dramatic environmental changes, one lineage adopted a new form of locomotion, upright bipedal walking, which would give rise to modern humans. Other hominoids, however, fared less well and today apes are restricted to a small number of endangered tropical forest species. p0010 3 b0430 b0740 b0235 b0065 b0195 b0575 NRVS 00022 4 The Evolution of Neuron Types and Cortical Histology in Apes and Humans b0510 b0765 b0810 b0470 b0705 b0080 4.21.2 Comparative Anatomy of the Cerebral Cortex s0020 4.21.2.1 Topology of Cortical Maps s0025 Total brain weight in hominoids ranges from p0040 approximately 90g in Kloss’s gibbons (Hylobates klossii) to 1,400g in humans (Homo sapiens) (Table 1). While there is a large range of variation among hominoids in total brain size, mapping studies of the cortex (Figure 2) generally agree that the location of the primary sensory and motor areas are similar across species (Grünbaum and Sherrington, 1903; Campbell, 1905; Mauss, 1908; Brodmann, 1909; Mauss, 1911; Leyton and Sherrington, 1917; Beck, 1929; Bailey et al., 1950; Preuss et al., 1999; Hackett et al., 2001; Bush and Allman, 2004a, 2004b; Sherwood et al., 2004b). In particular, the primary visual cortex lies within the banks of the calcarine sulcus. Primary auditory cortex is located on the posterior superior plane of the superior temporal gyrus, usually comprising the transverse gyrus of Heschl in great apes and humans. Primary somatosensory cortex is found within the posterior bank of the central sulcus and extends on to the postcentral gyrus. Primary motor cortex is located mostly on the anterior bank of the central sulcus. One notable difference is the fact that primary visual cortex extends to only a very small portion of the lateral convexity of the occipital lobe in humans, whereas a much larger part of the lateral occipital lobe is comprised of striate cortex in apes (Zilles and Rehkämper, 1988; Holloway et al., 2003). This is because the primary visual cortex in humans is 121% smaller than expected for a primate of the same brain size (Holloway, 1996). Other higher-order areas, particularly within the frontal cortex, have also been shown to occupy similar locations across these species (Strasburger, 1937a, 1937b; Semendeferi et al., 1998; Semendeferi et al., 2001; Sherwood et al., 2003a). EL b0365 SE VI ER FI RS b0290 b0325 cerebral cortex, highlighting evidence concerning shared derived traits of hominoids in comparison to other primates, as well as indicating possible species-specific specializations. Hence, the studies reviewed in this chapter provide the most direct evidence currently available to delimit which aspects of cortical histology are uniquely human, which are derived for all hominoids, and which reflect the specializations of each species. F b0100 b0055 OO b0500 b0070 PR b0505 T b0135 (Campbell, 1905; Mauss, 1908; Brodmann, 1909; Mauss, 1911; Beck, 1929; Bailey et al., 1950). Later studies from this era also contributed quantitative data concerning the surface area of particular cortical areas, as well as cellular sizes and densities in a few non-human hominoid species (Mayer, 1912; Tilney and Riley, 1928; von Bonin, 1939; Lassek and Wheatley, 1945; Shariff, 1953; Haug, 1956; Glezer, 1958; Blinkov and Glezer, 1968). These quantitative data, however, were rarely presented in the context of a focused examination of variation among hominoids. p0030 The modern era is characterized by studies that use techniques such as design-based stereology, computerized image analysis, and immunohistochemical and histochemical staining to identify subpopulations of cortical cells. These new approaches are especially appealing for investigations of phylogenetic variation in cortical histology in species that are not common to the laboratory because several enzymatic, cytoskeletal, and other macromolecular constituents that are well preserved in postmortem tissue can be used as reliable markers for subpopulations of distinct neuron types, thereby extending comparative studies of species for which anatomical tracing, electrophysiological mapping, or other experimental procedures would be either unethical or impractical (see 00055). Subsets of pyramidal neurons, for example, can be distinguished immunohistochemically by staining with an antibody (e.g., SMI-32) to nonphosphorylated epitopes on the medium- and high-molecular-weight subunits of the neurofilament triplet protein. These epitopes are particularly enriched in subpopulations of large neurons of the neocortex that have a specific laminar and regional distribution. Because nonphosphorylated neurofilament protein (NPNFP) is involved in the maintenance and stabilization of the axonal cytoskeleton, its expression is associated with neurons that have thick myelinated axons (Hoffman et al., 1987; Kirkcaldie et al., 2002). In addition, the calcium-binding proteins–calbindin D28k (CB), calretinin (CR), and parvalbumin (PV)– are useful markers for understanding the cortical interneuron system because each of these molecules is typically colocalized with GABA in morphologically and physiologically distinct nonoverlapping populations (DeFelipe, 1997; Markram et al., 2004). p0035 While the neuroanatomical structure of one hominoid species in particular has been studied most extensively, it is well beyond the scope of this article to provide a comprehensive review of human cortical architecture. Here we focus explicitly on comparative studies of the histology of hominoid b0200 b0440 b0495 b0305 b0135 b0500 b0505 b0100 b0480 b0070 b0055 b0595 b0310 b0110 b0115 b0730 b0880 b0385 b0375 b0745 b0750 b0690 b0680 b0710 4.21.2.2 Architecture of the Cortex s0030 The general histological architecture of the neocor- p0045 tex in hominoids shares many features in common NRVS 00022 The Evolution of Neuron Types and Cortical Histology in Apes and Humans 5 t0005 Table 1 Endocranial volumes of hominoids (in cc) Species Sex Sample size Mean SD Range White-handed gibbon Hylobates lar Siamang Symphalangus syndactylus Orang-utan Pongo pygmaeus Gorilla Gorilla gorilla Chimpanzee Pan troglodytes Bonobo Pan paniscus Human Homo sapiens M F M F M F M F M F M F M F 44 37 8 12 66 63 283 199 159 204 28 30 502 165 106.3 104.2 127.7 125.9 415.6 343.1 535.5 452.2 397.2 365.7 351.8 349.0 1457.2 1317.9 7.2 7.0 8.2 12.7 33.6 33.6 55.3 41.6 39.4 31.9 30.6 37.7 119.8 109.8 92–125 90–116 99–140 102–143 334–502 276–431 410–715 345–553 322–503 270–450 295–440 265–420 1160–1850 1040–1615 PR OO F Common name Data from Holloway (1996). Endocranial volumes are shown, rather than brain volumes, because larger sample sizes are available for these species. FI b0330 RS b0525 ER b0180 b0165 b0170 SE VI b0175 EL b0010 b0615 b0620 b0370 on the basis of cytoarchitecture and topology, several studies have compared the microstructure of these areas among different hominoid species (reviewed below). On the whole, the cytoarchitecture of homologous cortical areas shows only subtle differences across hominoid species. Indeed, an early quantitative comparative analysis of the cytoarchitecture of primary cortical areas (areas 3, 4, 17, and 41/42), found marked similarities among species (orang-utans, gorillas, chimpanzees, and humans) in terms of the relative thickness of different layers and the proportion of neuropil in each layer (Zilles and Rehkämper, 1988). Only minor differences were noted, such as greater relative thickness of layer III in primary somatosensory cortex (area 3) in humans and gorillas, an increase in the proportion of neuropil in layers V and VI of area 3 in orang-utans, and a relatively thicker layer IV of primary auditory cortex (area 41/42) in orangutans. These results were interpreted to corroborate the qualitative observations of Campbell (1905) and Brodmann (1909), indicating that there are not any substantial differences between humans and apes in the cytoarchitecture of these primary cortical areas. The study by Zilles and Rehkämper (1988), however, was based on small samples, which did not permit statistical evaluation of species differences. More recent studies using larger samples, different staining techniques, and more refined quantitative methods have revealed interesting phylogenetic differences among hominoids in cortical histological structure. T with other primates and mammals in general, such as a fundamental six-layered and columnar organization (Mountcastle, 1998). Compared to other mammals of similar brain size, however, the cerebral cortex of hominoids is reported to have a relatively low density of glial cells and a greater variety of neuron soma sizes (Haug, 1987). Astroglia of the cerebral cortex in great apes, as revealed by immunohistochemistry for glial fibrillary acidic protein (GFAP), resemble other primates in forming long, radially oriented interlaminar processes spanning supragranular cortical layers (Colombo et al., 2004). This configuration may be unique to primates, as GFAP staining in the cortex of other mammals appears distinctly different, comprising a network of stellate astroglial somata with short, branching processes (Colombo, 1996; Colombo et al., 2000; Colombo and Reisin, 2004). p0050 Comparison of mammalian brains indicates that the surface area of the cortical sheet can vary by more than five orders of magnitude, while the thickness of the cortex varies by less than one order of magnitude (Allman, 1990). Accordingly, evolutionary changes in the size of the cerebral cortex have occurred primarily in the tangential dimension, while the vertical dimension of the cortex may be more constrained by the development of columnar units (Rakic, 1988, 1995). Nonetheless, the cortical sheet does tend to display increased thickness in mammals with larger brains (Hofman, 1988). Due to these scaling trends, hominoids have thicker cortices than other smaller-brained primates and homologous cortical areas in humans tend to be thicker than in apes (Figure 3). p0055 With the relative ease of establishing homology among the primary sensory and motor cortical areas b0880 b0135 b0880 4.21.2.3 Primary Visual Cortex s0035 Important modifications of primary visual cortex p0060 (Brodmann’s area 17) histology, particularly of the NRVS 00022 T PR OO F 6 The Evolution of Neuron Types and Cortical Histology in Apes and Humans (b) SE VI ER FI RS (a) EL (c) (d) 2 Parcellation maps of the cerebral cortex of apes. Chimpanzee (Pan troglodytes) cortical maps reproduced from f0010 Figure b0135 b0055 b0135 (1905) and (b) Bailey et al.b0880 (1950). Orang-utan (Pongo pygmaeus) cortical maps reproduced from (c) Campbell (1905) (a) Campbell b0500 b0505 and (d) Mauss (1908, 1911) compiled in Zilles and Rekämper (1988). thalamic recipient layer IV, have taken place at several points in the evolution of hominoids. Distinct parallel ascending fiber systems arising from retinal ganglion cells project to the lateral geniculate nucleus (LGN) of the thalamus. The M-type retinal ganglion cells give rise to the magnocellular channel, which is involved in the analysis of motion and gross spatial properties of stimuli. The P-type ganglion cells process visual information with high acuity and color sensitivity, and project to parvocellular layers of the LGN. In the geniculostriate component of these parallel pathways, different systems derive from distinct portions of the NRVS 00022 The Evolution of Neuron Types and Cortical Histology in Apes and Humans 7 I II I II I II III F III IV OO III IV V V VI VI wm wm Long-tailed macaque Chimpanzee VI wm PR IV V Human VI ER FI b0100 EL SE b0595 metabolic activity within this sublayer. However, in the hominoid species examined to date (orangutans, chimpanzees, and humans), intense CO staining in layer IVA is absent, suggesting that the direct parvocellular-geniculate projection to layer IVA was either reduced or more dispersed to include both layers IVA and IVB in the last common ancestor of this phylogenetic group (Preuss et al., 1999; Preuss and Coleman, 2002). Primary visual cortex of great apes and humans is further distinguished from monkeys in having increased staining of CBimmunoreactive (-ir) interneurons and neuropil in layer IVA (Preuss and Coleman, 2002). Layer IVA of primary visual cortex in humans p0070 exhibits additional modifications to the basic hominoid plan described above. In humans, a meshwork pattern is observed in which compartments of neuropil that stain intensively for Cat-301 and nonpyramidal NPNFP-ir cells, and neurites alternate with bands of high densities of CB-ir interneurons (Preuss and Coleman, 2002). These changes in human primary visual cortex have been interpreted to reflect a closer association of this layer to M-pathway inputs than observed in any other primates. The functional implications of these histological changes are unclear; however, it has been suggested that these alterations are related to specializations in humans for the visual perception of rapid orofacial gestures in speech (Preuss and Coleman, 2002). Another distinctive feature of primary visual cor- p0075 tex organization in many primates is ocular dominance columns, which correspond to the horizontal segregation of inputs from the two retinae to RS LGN and synapse within separate sublayers of layer IV in primary visual cortex. The complexity of segregated geniculostriate projects is reflected in the development of at least three subdivisions of layer IV in primates as demarcated by Brodmann (1909). Two cell-rich layers, IVA and IVC, are separated by a cellpoor layer IVB, which contains a dense plexus of myelinated axons known as the stria of Gennari. Neurons in the magnocellular layers of the LGN project to the upper half of layer IVC. Neurons in the parvocellular layers of the LGN project to layer IVA. p0065 The chemoarchitecture of layer IVA is markedly different in hominoids compared to other primates (Figure 4). In most monkeys, except the nocturnal owl monkey, there is a dense band of cytochrome oxidase (CO)-rich staining in layer IVA (reviewed in Preuss et al., 1999), reflecting high levels of T f0015 Figure 3 Cytoarchitecture of primary somatosensory cortex (area 3b) in long-tailed macaque (Macaca fascicularis), chimpanzee (Pan troglodytes), and human (Homo sapiens), showing interspecific variation in the thickness of the cortex. Scale bar¼250mm. b0595 b0580 b0580 b0580 b0580 f0020 Figure 4 Comparative chemoarchitecture of layer IV in primary visual cortex of squirrel monkeys (Saimiri ), macaques (Macaca), chimpanzees (Pan), and humans (Homo). b0580 Reproduced from Preuss and Coleman (2002). NRVS 00022 8 The Evolution of Neuron Types and Cortical Histology in Apes and Humans b0240 b0530 FI b0490 SE VI ER b0720 I II III EL IVA (a) F b0845 b0850 RS b0720 IVB IVC V VI wm (b) f0025 Figure 5 The location and morphology of Meynert cells in an orang-utan (Pongo pygmaeus). Meynert cells are located at the boundary between layers V and VI, as indicated by the arrow in the Nissl-stained section (a). The morphology of Meynert cells as revealed by immunostaining for NPNFP with Nissl counterstain is shown (b). Scale bar (a)¼250mm. Scale bar (b)¼50mm. OO b0760 PR b0015 context of the general scaling patterns of Meynert cells, it is interesting that soma volumes of these neurons fit closely with predictions among humans (2.84 times larger than neighboring pyramidal cells) and gorillas (2.98 times), whereas they are relatively large in chimpanzees (3.78 times) and relatively small in orang-utans (1.94 times). These differences in neural organization for the processing of visual motion may relate to socioecological differences among these apes. Because wild chimpanzees engage in aggressive incursions into the territory of neighboring groups (Watts and Mitani, 2001) and hunt highly mobile prey such as red colobus monkeys (Watts and Mitani, 2002), we speculate that relatively large Meynert cells evolved in this species to enhance detection of visual motion during boundary patrolling and hunting. In contrast, relatively small Meynert cells in orang-utans may relate to the fact that these apes are solitary, large-bodied, committed frugivores (van Schaik and van Hooff, 1996), which allows them to maintain low levels of vigilance for motions of predators, competitors, and food items. b0805 T different compartments in layer IV of primary visual cortex. Ocular dominance columns have been anatomically demonstrated in Old World monkeys, humans, and some other primates, such as the New World spider monkey and the strepsirrhine galago (reviewed in Allman and McGuinness, 1988). A similar pattern of alternating patches of ocular representation within primary visual cortex has been described in a chimpanzee after monocular injection of a transneuronal tritiated tracer substance (Tigges and Tigges, 1979). It is worth noting, however, that this study revealed geniculate projections to layer IVC, but not to layer IVA, as is observed in monkeys. p0080 Large pyramidal neurons, which are found at the boundary between layers V and VI, called Meynert cells, are prominent in the primary visual cortex of primates, and their soma size displays interspecific variation (Figure 5) (Sherwood et al., 2003c). These cells can be distinguished as a unique subtype on the basis of their morphology and connectivity. Their thick axon collaterals project to both area MT/V5 and the superior colliculus, suggesting that these cells are involved in processing visual motion (Fries et al., 1985; Movshon and Newsome, 1996; Livingstone, 1998). In a comparative study, Meynert cell somata were found to be on average 2.8 times lager than other layer V pyramidal neurons across a range of primates (Sherwood et al., 2003c). Because the basal dendrites and axon collaterals of Meynert cells extend horizontally in layers V and VI to integrate information and facilitate responses across widespread areas of visual space, interspecific variation in Meynert cell size appears to be largely constrained by their function in the repetitive stereotyped local circuits that represent the retinal sheet in primary visual cortex. In the 4.21.2.4 Auditory Cortex s0040 There are two parallel thalamocortical projections p0085 from the medial geniculate nucleus (MGN) to the superior temporal cortex of primates. Neurons in the ventral division of the MGN supply a tonotopic projection to the core region of auditory cortex (Brodmann’s areas 41 and 42). Neurons in the dorsal and medial divisions of the MGN project to areas surrounding the core. The core region of auditory cortex has been identified in macaques, chimpanzees, and humans as a discrete architectural zone as compared to the surrounding belt cortex (Hackett et al., 2001). The core can be recognized by a broad layer IV that receives a dense thalamic projection, heavy myelination, and intense expression of acetylcholinesterase (AChE), CO, and PV in the neuropil of layer IV. In macaques, the relatively high density of cells and fibers makes the auditory cortex core appear structurally homogeneous as compared to the hominoids. In contrast, the medial and lateral domains of the core region of auditory cortex are more clearly differentiated in humans and chimpanzees because of the lower packing density of structural elements. Additionally, the network of small horizontal and tangential myelinated fibers in layer III appears most complex in humans, intermediate in chimpanzees, and least elaborate in macaques. The auditory core region is enveloped by several p0090 higher-order belt and parabelt fields (Figure 6). The b0310 NRVS 00022 The Evolution of Neuron Types and Cortical Histology in Apes and Humans 41 Tpt HG auditory cortex are not well understood, but they are likely to be important for higher-order processing of natural sounds, including those used in communication. Neurons in the lateral belt cortex areas of rhesus macaques, for example, respond better to species-specific vocalizations than to energymatched pure tone stimuli (Rauschecker et al., 1995). The comparative anatomy of one particular p0095 region of auditory association cortex has been studied most extensively. In humans, Wernicke’s area, a region important for the comprehension of language and speech, is located in the posterior superior temporal cortex. Gross anatomic observations indicate that asymmetries similar to humans are present in the superior temporal lobe of nonhuman primates, such as leftward dominance of the planum temporale in great apes (Gannon et al., 1998; Hopkins et al., 1998) and a longer left sylvian fissure in many anthropoid species (LeMay and Geschwind, 1975; Yeni-Komshian and Benson, 1976; Heilbroner and Holloway, 1988; Hopkins et al., 2000). Several investigations have examined the micro- p0100 structure of the cortical area most closely associated with Wernicke’s area. Area Tpt (Galaburda et al., 1978) or area TA1 (von Economo and Koskinas, 1925) comprises a portion of posterior Brodmann’s area 22 located on the upper bank of the superior temporal gyrus and sometimes extending to part of the parietal operculum and the convexities of the temporal and parietal lobes (Galaburda et al., 1978). This area represents a transition between auditory association cortex and cortex of the inferior parietal lobule (Shapleske et al., 1999). Cortex with the cytoarchitectural characteristics of area Tpt has been described in galagos, macaques, chimpanzees, and humans (Galaburda and Pandya, 1982; Preuss and Goldman-Rakic, 1991; Buxhoeveden et al., 2001a, 2001b). The microstructure of area Tpt in these primates is distinguished by a eulaminate appearance, with a poorly defined border of layer IV due to the encroachment of pyramidal cells in adjacent layers IIIc and Va, and an indistinct border between layers IV and V due to curvilinear columns of neurons that bridge the two layers (Galaburda and Sanides, 1980). There are differences among rhesus monkeys, p0105 chimpanzees, and humans in the details of minicolumn structure in area Tpt. In the left hemisphere, area Tpt of humans has wider minicolumns as compared to macaques or chimpanzees, whereas the width of minicolumns is similar in the non-human species (Buxhoeveden et al., 2001b). These findings suggest that wider minicolumns in human area Tpt S P PR (a) OO F b0625 PT I II b0275 b0400 III I b0475 b0865 b0350 IV VI 41 (TC) wm Tpt (TA1) (b) FI V RS III V b0405 T II IV VI wm (c) b0260 b0825 b0260 SE VI ER f0030 Figure 6 Cytoarchitecture of auditory cortex of an orang-utan (Pongo pygmaeus). A parasagittal section of the superior temporal gyrus shows the location of regions detailed below (a). Higher-power micrographs show cytoarchitecture in (b) the core of primary auditory cortex (Brodmann’s area 41 or von Economo and Koskinas’ area TC) and (c) area Tpt (posterior Brodmann’s area 22 or von Economo and Koskinas’ area TA1). HG¼Heschl’s gyrus; PT¼planum temporale; S¼superior; P¼posterior. Scale bar¼500mm. EL belt areas of auditory cortex, which are less precise in their tonotopic organization, receive major inputs from the core and diffuse input from the dorsal division of the MGN. The belt region is bordered laterally on the superior temporal gyrus by a parabelt region of two or more divisions that are activated by afferents from the belt areas and the dorsal MGN, but not the ventral MGN or the core. Interestingly, AChE-stained pyramidal cells in layer III and V of the belt region are more numerous in chimpanzees and humans compared to macaques (Hackett et al., 2001). Neurons in the belt and parabelt project to auditory-related fields in the temporal, parietal, and frontal cortex. Other types of processing that occur in the other divisions of b0310 9 b0700 b0255 b0585 b0120 b0125 b0250 b0125 NRVS 00022 The Evolution of Neuron Types and Cortical Histology in Apes and Humans I II III F may be a species-specific specialization that allows for more extensive neuropil space containing interconnections among neurons. p0110 The microstructure of area Tpt has also been shown to be asymmetric in humans, possibly as a neural substrate of hemispheric dominance in the cerebral representation of language. Long-range intrinsic connections within area Tpt labeled in postmortem brains with lipophilic dyes have revealed greater spacing between interconnected patches in the left hemisphere compared to the right (Galuske et al., 2000). Furthermore, left area Tpt has a greater number of the largest pyramidal cells in layer III, known as magnopyramidal cells, that give rise to long corticocortical association projections (Hutsler, 2003). In addition, AChE-rich pyramidal cells display greater cell soma volumes in the left hemisphere despite lacking asymmetry in number (Hutsler and Gazzaniga, 1996). In humans, left area Tpt has also been shown to contain a greater amount of neuropil and axons with thicker myelin sheaths (Anderson et al., 1999). Of particular significance, a comparative analysis of area Tpt found that only humans, but not rhesus macaques or chimpanzees, exhibit left dominant asymmetry in area Tpt, with wider minicolumns and a greater proportion of neuropil (Buxhoeveden et al., 2001a). OO 10 V b0410 b0415 s0045 4.21.2.5 Primary Motor Cortex FI b0120 ER The primary motor cortex (Brodmann’s area 4) has a distinctive cytoarchitectural appearance in primates (Geyer et al., 2000; Sherwood et al., 2004b), containing giant Betz cells in the lower portion of layer V, low cell density, large cellular sizes, an indistinct layer IV, and a diffuse border between layer VI and the subjacent white matter (Figure 7a). In humans, the region of primary motor cortex that corresponds to the representation of the hand exhibits interhemispheric asymmetry in its cytoarchitectural organization. Concomitant with strong population-wide right handedness in humans, most postmortem brains display a greater proportion of neuropil volume in the left hemisphere of this part of primary motor cortex (Amunts et al., 1996). Interestingly, brains of captive chimpanzees (Hopkins and Cantalupo, 2004) and capuchin monkeys (Phillips and Sherwood, 2005) show humanlike asymmetries of the hand region of the central sulcus that are correlated with the direction of individual hand preference. However, the histology of primary motor cortex in non-human primates has not yet been examined for asymmetry (see 00021). b0730 SE VI b0285 EL p0115 VI wm (b) T Figure 7 Cytoarchitecture of primary motor cortex and mor- f0035 phology of Betz cells in an orang-utan (Pongo pygmaeus). Betz cells can be seen in the bottom of layer V, as indicated by the arrow in the Nissl-stained section (a). The morphology of Betz cells as revealed by immunostaining for NPNFP with Nissl counterstain is shown (b). Scale bar (a)¼250mm. Scale bar (b)¼50mm. RS b0035 (a) PR b0270 b0025 b0390 b0565 While the cytoarchitectural organization of pri- p0120 mary motor cortex is generally similar across species, interspecific differences have been described. The cytoarchitecture of the region corresponding to orofacial representation of primary motor cortex in several catarrhine species (longtailed macaques, anubis baboon, orang-utans, gorillas, chimpanzees, and humans) was analyzed using the Grey Level Index (GLI) method (Sherwood et al., 2004b). Compared to Old World monkeys, great apes and humans displayed an increased relative thickness of layer III and a greater proportion of neuropil space. A stereologic investigation of NPNFP and calcium-binding protein-ir neurons was also conducted in this same comparative sample (Sherwood et al., 2004a). Primary motor cortex in great apes and humans was characterized by a greater percentage of neurons enriched in NPNFP and PV compared to the Old World monkeys (Figure 8). Conversely, the percentage of CB- and CR-ir neuron subtypes did not significantly differ among these species. These modifications of particular subsets of neuron types might contribute to the voluntary dexterous control of orofacial muscles exhibited in the vocal and gestural communication of great apes and humans. Enhancement of PV-ir interneuron-mediated lateral inhibition of cell columns may enhance specificity in the recruitment of b0730 b0725 NRVS 00022 The Evolution of Neuron Types and Cortical Histology in Apes and Humans 11 CR (a) (b) PV F CB (c) FI b0460 b0095 b0670 ER b0515 b0640 b0465 EL SE VI b0725 b0720 T Specializations of biochemical phenotypes are p0130 known for certain regionally restricted subsets of pyramidal neurons. Although calcium-binding proteins are expressed transiently during prenatal and early postnatal development (Moon et al., 2002; Ulfig, 2002), their expression in pyramidal neurons of adult mammals is more limited. Neurons expressing the calcium-binding proteins – CB, CR, and PV – are thought to have relatively high metabolic rates associated with fast repolarization for multiple action potentials (Baimbridge et al., 1992). While such calcium buffering mechanisms are most commonly associated with GABAergic interneurons, the presence of calcium-binding proteins in pyramidal cells might reflect a neurochemical specialization for higher rates of activity. In this context, it is interesting that faint CR immunoreactivity is observed in isolated medium- and large-size layer V pyramidal neurons in primary motor cortex of great apes and humans, but not in macaques or baboons (Hof et al., 1999; Sherwood et al., 2004a). PV-ir pyramidal neurons are also very rarely observed in the neocortex of mammals (see 00055). However, large layer V pyramidal neurons, including Betz cells, have been reported to express PV immunoreactivity in primary motor cortex of humans (Nimchinsky et al., 1997; Sherwood et al., 2004a). Evidence concerning the existence of PV-ir pyramidal neurons in other nonhuman primates is somewhat contradictory. In one study, PV-ir pyramidal neurons were observed in primary motor and somatosensory cortices of galagos and macaques (Preuss and Kaas, 1996). Another study, however, failed to label PV-ir pyramidal cells in macaques (DeFelipe et al., 1989), probably due to methodological discrepancies among experiments. A comparative study of primary motor cortex using the same b0520 b0800 RS different muscle groups for dynamic modulation of fine orofacial movements (Scheiber, 2001). Increased proportions of NPNFP-ir pyramidal cells, on the other hand, may be a correlate of greater descending cortical innervation of brainstem cranial motor nuclei by heavily myelinated axons to allow for more voluntary control (Kuypers, 1958). p0125 The giant Betz cells are found in the lower half of layer V of primary motor cortex and possess a large number of primary dendritic shafts that leave the soma at several locations around its surface (Figure 7b) (Braak and Braak, 1976; Scheibel and Scheibel, 1978; Meyer, 1987). They are largest and most numerous in the cortical representation of the leg, where axons project farther along the corticospinal tract to reach large masses of muscles (Lassek, 1948; Rivara et al., 2003). Betz cells are strongly immunoreactive for NPNFP among humans, great apes, and Old World monkeys (Sherwood et al., 2004a). An analysis of scaling of Betz cell somata volumes in the region of hand representation of primates revealed that these cell subtypes become relatively enlarged with increases in brain and body size (Sherwood et al., 2003c). At larger sizes, there is an increase in the distance to the spinal representation of target muscles and a greater number of less densely distributed corticospinal neurons (Nudo et al., 1995). In larger brains and bodies, Betz cell axons need to become thicker to maintain conduction speed to reach more distant targets in the spinal cord. Accordingly, Betz cells are scaled to global connectivity constraints and therefore increase in somatic volume in a manner that is correlated with brain size. Due to these scaling trends, among hominoids Betz cells are relatively largest in humans (10.96 times larger than neighboring pyramidal cell), then gorillas (8.37 times), chimpanzees (7.02 times), and orang-utans (6.51 times). PR OO f0040 Figure 8 Calcium-binding protein-immunoreactive neurons in layer III of primary motor cortex of a chimpanzee (Pan troglodytes). Neurons stained for calbindin (CB) (a), calretinin (CR) (b), and parvalbumin (PV) (c) are shown. Morphologically, CR-ir interneurons correspond mostly to double-bouquet cells. They are predominantly found in layers II and III, and have narrow vertically oriented axonal arbors that span several layers. CB-ir neurons are morphologically more varied, including double-bouquet and bipolar types, with many showing a predominantly vertical orientation of axons. In contrast, the morphology of PV-ir interneurons includes large multipolar types, such as large basket cells and chandelier cells, which have horizontally spread axonal arbors spanning across cortical columns within the same layer as the parent soma. Scale bar¼50mm. b0545 b0060 b0355 b0725 b0535 b0725 b0590 b0205 NRVS 00022 12 The Evolution of Neuron Types and Cortical Histology in Apes and Humans immunohistochemical procedures across species found that PV-ir pyramidal neurons were either not present or sparse in Old World monkeys, whereas they were considerably more numerous in great apes and humans (Sherwood et al., 2004a). I II I II III III b0725 IV IV 44-Nissl (a) b0340 PR b0710 b0815 b0710 b0835 b0560 EL SE VI ER FI b0255 b0340 45-Nissl T b0455 b0710 VI wm (c) I II III III IV IV V V VI wm VI 45-NPNFP wm (d) Figure 9 The architecture of areas 44 and 45 in a chimpanzee f0045 (Pan troglodytes). Area 44 is shown stained for Nissl substance (a) and NPNFP (b). Area 45 is shown stained for Nissl substance (c) and NPNFP (d). Scale bar¼500mm. RS b0055 44-NPNFP I II b0090 b0030 wm (b) b0820 b0050 V OO The microstructure of the inferior frontal cortex, the region that contains Broca’s area in humans, has been described in hominoids on the basis on cyto-, myelo-, and NPNFP-architecture (von Economo, 1929; Bailey and von Bonin, 1951; Braak, 1980; Amunts et al., 1999; Hayes and Lewis, 1995; Sherwood et al., 2003a). Cytoarchitectural studies of chimpanzee and orang-utan frontal cortex describe a dysgranular region anterior to the inferior precentral sulcus comprising a part of pars opercularis and designated Brodmann’s area 44 (von Bonin, 1949; Sherwood et al., 2003a), FCBm (Bailey et al., 1950), or areas 56 and 57 (Kreht, 1936). In chimpanzees, this region has been shown to receive projections from the mediodorsal nucleus of the thalamus (Walker, 1938). In macaques, a field with similar cytoarchitectural characteristics in the caudal bank of the inferior limb of the arcuate sulcus has been denoted area 44, with area 45 located rostrally (Galaburda and Pandya, 1982; Petrides and Pandya, 1994). The cytoarchitecture of area 44 is characterized by a columnar organization similar to ventral premotor area 6, but it is distinguished by the development of a thin layer IV and clustered magnopyramidal neurons in the deep part of layer III. Layer IV in area 44 has an undulating appearance due to the invasion of pyramidal cells from layer III and layer V. Nonphosphorylated neurofilament protein staining in area 44 of chimpanzees and humans displays clusters of large pyramidal neurons at the bottom of layer III and a lower band of immunoreactive layer V cells and neuropil (Figure 9) (Hayes and Lewis, 1995; Sherwood et al., 2003a). p0140 The cytoarchitecture of area 45 is distinguished from area 44 by the presence of a more prominent layer IV, a more homogeneous distribution of pyramidal cells in the deep portion of layer III, and the absence of conspicuous cell columns. Nonphosphorylated neurofilament protein staining in area 45 is characterized by a clearer separation of immunoreactive neurons into upper (layer III) and lower (layer V) populations and by the absence of the intensely stained magnopyramidal clusters, as seen in area 44. p0145 Considering the preponderance of left hemisphere dominant control of language in humans, several studies have examined the cortex of the inferior p0135 V VI F s0050 4.21.2.6 Inferior Frontal Cortex frontal gyrus in humans for microstructural asymmetries. Using GLI profile analysis methods to quantify regional variation in cytoarchitecture, area 44 has been shown to display left dominance in terms of volume and an increased proportion of neuropil space, whereas area 45 does not show a consistent direction of asymmetry (Amunts et al., 1999). In addition, the total length of pyramidal cell dendrites is longer in the left opercular region of the inferior frontal gyrus due to a selective increase in the length of higher-order segments (Scheibel et al., 1985). Using different methods, another study examined asymmetries in only magnopyramidal cells in layer III of area 45 and found total dendritic length, dendritic complexity (numbers of branches and maximal branch order), and spine densities to be greater in the right (Hayes and Lewis, 1996). In area 45, AChEpositive layer III magnopyramidal cells have larger somata in the left hemisphere, despite lacking asymmetry in their density (Hayes and Lewis, 1995; Garcia et al., 2004). While asymmetries of the inferior frontal cortex p0150 are well established in humans, the condition of non-human primates is less clear. Although population-level leftward asymmetry of the fronto-orbital sulcus, a portion of the inferior frontal gyrus, has been reported in great apes (Cantalupo and Hopkins, 2001), it remains to be known whether humanlike microstructural asymmetries are present b0030 b0665 b0345 b0340 b0280 b0145 NRVS 00022 The Evolution of Neuron Types and Cortical Histology in Apes and Humans 13 b0030 b0710 Area 13 is a dysgranular field located in the pos- p0160 terior orbitofrontal cortex (Figure 10). This cortical area is remarkably integrative, receiving inputs from olfactory, gustatory, and visceral centers, as well as premotor, somatosensory, auditory, visual, and parahippocampal cortices (Carmichael and Price, 1995; Cavada et al., 2000). Damage to this region disrupts performance on tasks that require behavioral inhibition and causes impairments in emotional control (Fuster, 1998; Roberts and Wallis, 2000). In a study of the cytoarchitecture of area 13 across macaques and hominoids, several similarities were observed that suggest homology among these species (Semendeferi et al., 1998). This cortical area is distinguished by a poorly defined layer IV, horizontal striations of cells in layers V and VI, large pyramidal cells in layer V, relatively thick infragranular layers as compared with supragranular layers, and greater neuropil space in supragranular layers as compared with deeper layers. Among hominoids, area 13 is located in the posterior portion of the medial orbital and posterior orbital gyri. This concords with the earlier description of an area labeled FF in the posterior orbitofrontal cortex of chimpanzees that seems to correspond to these cytoarchitectural features (Bailey et al., 1950). While general similarities are found in the p0165 cytoarchitecture of area 13 of hominoids, quantitative analyses have identified some interspecific differences. For example, layer IV in orang-utans is relatively wide, making this cortex appear more similar to granular prefrontal cortex. Compared to other hominoids, area 13 in humans and bonobos occupies a small proportion of total brain b0150 b0155 While it has been a popular notion that human cognitive abilities are associated with disproportionate enlargement of the frontal or prefrontal cortex, recent data show that the human frontal cortex is no larger than expected for a hominoid of the same brain size (Semendeferi et al., 1997; 2002). Furthermore, progressive increase in the relative size of the frontal cortex accompanies enlarging brain size for primates in general, with hominoids simply continuing this scaling trend (Bush and Allman, 2004a) (see 00061, 00066, 00081). At present, the comparative quantitative data available concerning the volume of specific prefrontal cortical areas in hominoids are scanty, representing only areas 10 and 13 in one individual per species (Semendeferi et al., 1998, 2001). Taken together, however, it does not seem that these prefrontal areas are disproportionately enlarged in human beyond what is expected for a hominoid of the same brain size (Holloway, 2002). Nonetheless, quantitative cytoarchitectural analyses have shown that some prefrontal cortical areas differ in their histological organization among hominoid species. b0685 b0695 AU1 RS b0110 b0690 FI b0680 VI ER b0380 I I II SE II III III EL b0680 PR p0155 T s0055 4.21.2.7 Prefrontal Cortex b0645 OO b0245 F in the inferior frontal cortex of these species. In humans and chimpanzees, the borders of areas 44 and 45 have been shown to correspond poorly with external sulcal landmarks (Amunts et al., 1999; Sherwood et al., 2003a). Thus, determination of whether asymmetries are evident in regional volumes and intrinsic circuitry of areas 44 and 45 of great apes will require histological studies. IV V IV b0055 I II I II III III I II III VI IV V V VI V V VI V III IV IV IV I II VI VI VI wm Human wm Bonobo wm Chimpanzee wm Gorilla wm Orang-utan b0680 wm Gibbon f0050 Figure 10 The cytoarchitecture of area 13 in hominoids. Scale bar¼500mm. Modified from Semendeferi et al. (1998). NRVS 00022 The Evolution of Neuron Types and Cortical Histology in Apes and Humans b0245 ER FI b0690 F In layer Vb of anterior cingulate cortex (subareas p0175 24a, 24b, and 24c), large spindle-shaped cells are found only in great apes and humans, to the exclusion of hylobatids and other primates (Nimchinsky et al., 1999). These neurons have a very elongate, gradually tapering, large soma that is symmetrical about its vertical and horizontal axes (Figure 12). This distinctive somatic morphology arises from the presence of a large apical dendrite that extends toward the pial surface, as well as a single large basal dendrite that extends toward the underlying white matter, without any other dendrites branching from the basal aspect of the cell. These unique neurons are also substantially larger in size than other neighboring pyramidal cells. Interestingly, spindle neurons increase in soma size, density, and clustering from orang-utans to gorillas, chimpanzees, bonobos, and humans. Furthermore, spindleshaped neurons have been observed in layer Vb of area 24b in a fetal chimpanzee (E 224), indicating that this specialized projection cell type differentiates early in development (Hayashi et al., 2001). Notably, neurons with a spindle phenotype also have a phylogenetically restricted distribution within another region, the frontoinsular cortex. Spindle cells are found in layer V in the frontoinsular cortex only in humans and African great apes (i.e., gorillas, chimpanzees, and bonobos), being far b0540 b0335 VI b0690 I II SE I II III EL s0060 RS b0555 4.21.2.8 Anterior Cingulate Cortex OO b0690 raise uncertainty regarding whether a homolog of area 10 is present in gorillas. In particular, the cortex of the frontal pole in gorillas has a prominent layer II and Va, features that are not found in macaques or other hominoids. PR volume and more cytoarchitectonic subdivisions occupy the orbitofrontal cortex adjacent to area 13. In contrast, area 13 of orang-utans is relatively large and thus occupies the majority of the orbitofrontal region. p0170 Area 10 is a granular cortex that forms a part of the frontal pole in most hominoid species, including humans, chimpanzees, bonobos, orangutans, and gibbons (Figure 11) (Semendeferi et al., 2001). This cortical area is involved in planning and decision-making (Fuster, 1998). Area 10 receives highly processed sensory afferents from corticocortical connections in addition to inputs from the mediodorsal nucleus of the thalamus, striatum, and many limbic structures (Öngür and Price, 2000). In hominoids, the cytoarchitecture of area 10 is characterized by a distinct layer II, a wide layer III with large pyramidal cells in its deep portion, a clearly differentiated granular layer IV, large pyramidal cells in layer Va, and a sharp boundary between layer VI and the white matter. Quantitative analyses reveal a similar pattern of relative laminar widths among humans, chimpanzees, and bonobos, such that the supragranular layers are relatively thick compared to the infragranular layers (Semendeferi et al., 2001). In contrast, the infragranular layers comprise a greater proportion of cortical thickness in the other hominoids. When GLI profile curves describing laminar variation in neuron volume densities are compared among taxa, apes and macaques follow a similar pattern with roughly equal GLI throughout the cortical depth. The proportion of neuropil space in layers II and III relative to infragranular layers, however, is greater in humans. Notably, Semendeferi et al. (2001) T 14 I II I II III III III I II IV III IV V V VI VI I II IV V IV IV III V V IV VI VI VI V VI wm Human wm Bonobo wm Chimpanzee wm Gorilla wm Orang-utan b0690 wm Gibbon f0055 Figure 11 The cytoarchitecture of area 10 in hominoids. Scale bar¼500mm. Modified from Semendeferi et al. (2001). NRVS 00022 The Evolution of Neuron Types and Cortical Histology in Apes and Humans 15 4.21.3 Patterns of Cortical Organization in Hominoids s0065 4.21.3.1 The Emergence of Cell Types and their Distribution s0070 f0060 Figure 12 Morphology of spindle-shaped neurons in layer Vb of anterior cingulate cortex in a bonobo (Pan paniscus) (a) and gorilla (Gorilla gorilla) (b). Scale bar¼80mm. Modified from b0540 Nimchinsky et al. (1999). more numerous in humans compared to the apes (see 00165; Hakeem et al., 2004). p0180 In addition to spindle-shaped neurons, the anterior cingulate cortex of great apes and humans contains another unique pyramidal cell phenotype. A survey of the anterior cingulate cortex of several primate species revealed a small subpopulation of CR-containing layer V pyramidal neurons that are only found in great apes and humans (Hof et al., 2001). These neurons are located in the superficial part of layer V in areas 24 and 25. In orang-utans, they comprise 0.5% of all layer V pyramidal cells in the anterior cingulate, 2% in gorillas, 4.1% in chimpanzees, and 5.3% in humans. The occurrence of these cells decreases sharply at the boundary between anterior and posterior cingulate cortex, suggesting that they are not directly involved in the somatic motor functions associated with the posterior cingulate motor areas. p0185 The restricted phylogenetic distribution of spindle-shaped cells and CR-ir pyramidal neurons in layer V of anterior cingulate cortex may reflect specializations of projection neurons in this region for a role in the control of vocalization, facial expression, attention, the expression and interpretation of emotions, and autonomic functions (Nimchinsky et al., 1999; Allman et al., 2001; Hof et al., 2001). Of particular interest, in humans, CR-immunoreactive layer V pyramidal neurons are also present in the anterior paracingulate cortex (area 32) (Hof et al., 2001). The presence of this distinctive projection cell type in area 32 of humans is intriguing, considering that this cortical area has been found to be recruited in tasks that require theory of mind (Gallagher et al., 2000), which is the capacity to attribute mental states such as attention, intention, and beliefs to others and may be a cognitive capacity that is exclusive to humans (Tomasello et al., 2003). SE VI ER FI b0360 RS b0315 b0540 b0360 EL b0020 PR (b) T (a) OO F Particular cellular subtypes appear to have phylo- p0190 genetically restricted distributions. It is interesting that among hominoids, the presence of these unique neuron phenotypes accords with the hierarchical nested structure of monophyletic taxa, suggesting that they are indicators of phylogenetic relationships (Table 2). For example, in all great apes and humans, spindle-shaped neurons are found in layer V of anterior cingulate cortex. Also in these taxa, CR-ir pyramidal cells are found in layer V of anterior cingulate cortex and primary motor cortex. In just African great apes and humans, layer V spindleshaped neurons are found in frontoinsular cortex. And only in humans, CR-ir pyramidal neurons in layer V are found in anterior paracingulate cortex. Thus, novel neuron phenotypes have appeared at several different times in hominoid evolution. It is tempting to speculate that the evolution of p0195 each unique neuron type marks specializations of the cortical areas involved. In particular, the morphomolecular characteristics of these novel neuron types suggest that there have been modifications of specific efferent projections to facilitate high levels of activity or higher conduction velocity for outputs. The possibility that the great ape and human clade is distinguished by such specializations of projection cells is especially intriguing in light of recent hypotheses that intelligence among mammals is correlated with the rate of information processing capacity as represented by axonal conduction speed (Roth and Dicke, 2005). The presence of unique neuron classes in great apes and humans extends this hypothesis to suggest that specific cortical efferents located within behaviorally relevant circuits may be selectively modified. It is also significant that a common feature of these novel projection cells is their localization in layer V. This laminar distribution indicates that evolutionary modifications have been focused upon descending cortical control over targets in the brainstem and spinal cord. b0655 b0360 b0265 b0775 4.21.3.2 The Evolution of Cortical Asymmetries s0075 A substantial body of evidence shows that the p0200 human cerebral cortex expresses lateralization in the control of language and fine motor actions of the hand (Toga and Thompson, 2003). Asymmetries in histological structure have been demonstrated across cortical areas implicated in these processes in humans, including Broca’s area (areas 44 and 45), b0770 NRVS 00022 16 The Evolution of Neuron Types and Cortical Histology in Apes and Humans t0010 Table 2 Phylogenetic distribution of some cortical histological traits Primary visual cortexb Primary visual cortexb Primary visual cortexb Auditory belt cortexc a þ þ þ ? þþ ? þþ ? þþ ? þ þþ ? þþ þþ þþ ? þ þ ? þ þ ? þ þ ? ? þ ? ? þ ? ? ? þþ ? þþ ? ? ? þ þþ þþ þþ þ þ þþ ? þþ þ þ ? þ ? ? þþ þ þ þ ER Anterior cingulate cortexd Anterior cingulate cortexe Anterior paracingulate cortexe Frontoinsular cortexf ? F Primary motor cortexa þ FI Primary motor cortexa CR-ir pyramidal neurons Layer V PV-ir pyramidal neurons Layers NPNFP-ir III and neurons V Layer Loss of COIVA dense band Layer Dense CB-ir IVA neurons and neuropil Layer Meshwork with IVA dense NPNFP and Cat-301 staining in mesh bands alternating with dense CB in interstitial zones Layers AchE-stained III and pyramidal V cells Layer Spindle-shaped Vb neurons Layer CR-ir pyramidal Vb neurons Layer CR-ir pyramidal Vb neurons Layer Spindle-shaped Vb neurons Gorilla Pongo Hylobates Macaca gorilla pygmaeus sp. sp. OO Layer V Homo Pan Pan sapiens paniscus troglodytes PR Primary motor cortexa Trait T Layer RS Cortical area b0725 (Sherwood et al., 2004a) b0580 (b0310 Preuss and Coleman, 2002) c (Hackett et al., 2001) b0540 d (Nimchinsky et al., 1999) b0360 e (b0315 Hof et al., 2001) f (Hakeem et al., 2004) þ¼present; þþ¼present and abundant in comparison to other species; ¼absent SE VI b EL Wernicke’s area (area Tpt), and the hand representation of primary motor cortex (area 4). Some authors have hypothesized that these anatomical asymmetries are exclusive adaptations of the human brain that are encoded genetically and comprise the chief evolutionary novelty in the speciation of modern humans (Crow, 2000; Annett, 2002). p0205 An alternative view is that functional and anatomical lateralization may be a byproduct of increases in overall brain size (Ringo et al., 1994; Hopkins and Rilling, 2000). One cost of increasing brain size is that axons must propagate action potentials over a greater distance to communicate between the hemispheres (Harrison et al., 2002). While these b0190 b0635 b0320 b0040 b0395 delays in conduction can be overcome to some extent by increasing axon cross-sectional area and myelination (Changizi, 2001), the design problems associated with large brains ultimately may necessitate increased modularity of processing and more of an emphasis on local network connectivity (Kaas, 2000). In particular, as brains grow in size, the efficiency of interhemispheric transfer of information by long connections diminishes because costs, in terms of wiring space, dictate that axons cannot increase cross-sectional area sufficiently to keep pace with demands for processing speed (Aboitiz and Montiel, 2003). Hence, it is expected that cortical processes in large brains, especially those that b0160 b0435 b0005 NRVS 00022 The Evolution of Neuron Types and Cortical Histology in Apes and Humans 17 F b0185 ER FI RS b0120 OO b0395 PR b0635 b0550 b0310 hominoids (Hackett et al., 2001) is of functional importance until we have developed a clearer understanding of the scaling principles that govern the distribution of AChE-enriched neurons in general? Hence, whenever possible it is best to evaluate phylogenetic variation in cortical histology from the perspective of allometric scaling. Accordingly, the case for declaring that a trait is a phylogenetic specialization is strengthened when it can be demonstrated that individual species depart from allometric expectations or that an entire clade scales along a different trajectory (i.e., grade shift). It is well established that cortical neuron density p0220 varies among mammalian species. Across a large sample of mammals ranging from mouse to elephant, there is a negative correlation between cortical neuron density and brain size (Tower, 1954; Cragg, 1967; Haug, 1987; Prothero, 1997). Despite this broad trend, however, some evidence suggests that neuron densities may be higher in hominoids (gorilla, chimpanzee, and human) than expected for their brain size (Haug, 1987). It has also been shown that the fraction of the cortex that is comprised by neuropil space versus cell somata increases in a negative allometric fashion with greater brain size (Shariff, 1953; Tower, 1954; Bok, 1959; Tower and Young, 1973; Zilles et al., 1982; Armstrong et al., 1986; Haug, 1987). These empirical findings fit with a model predicting that a constant average percent interconnectedness among neurons cannot feasibly be maintained in the face of increasing gray matter volume, so the reach of processing networks cannot keep pace with brain size variation (Changizi, 2001). Many of these theories concerning the scaling of p0225 network connectedness across brain size, however, were developed to explain variation in mouse to elephant comparisons. Are these predicted allometric relationships between neuron density, neuropil space, and brain size maintained when comparisons are restricted to the hominoids? AU2 Table 3 shows the results of stereologic estimates of neuron density and GLI from recent comparative studies of areas 4, 10, and 13 in hominoids. In each of these cortical areas, there is not a correlation between neuron densities or GLI and brain size. Therefore, the mammal-wide relationship between these parameters and brain size may not explain interspecific variance in interconnectedness within cortical areas of hominoids. This raises the interesting possibility that differences among hominoid species in these variables might instead correspond to functionally significant modifications in the organization of cortical interconnections. s0080 4.21.3.3 How much Variation in Cortical SE Interpretation of interspecific differences in the histological structure of the cortex in hominoids requires parsing the source of this variation. Certainly a portion of it can be attributed to specific alterations of circuitry that generate behavioral differences among species. Another cause, however, may be the effects of allometric scaling. That is, as overall brain size changes, predictable changes occur in cell sizes, cell packing density, dendritic geometries, and other aspects of microstructure (Jerison, 1973; Striedter, 2005). Thus, with variation in brain size among hominoids, some of the observed interspecific differences may simply be the result of scaling to maintain functional equivalence and may not indicate any significant differences in computational capacities. For example, how can we know whether greater densities of AChE-stained neurons in the auditory belt of EL p0215 VI Architecture can be Attributed to Scaling versus Specialization? b0430 b0755 b0780 b0330 T depend on rapid computations, will come to rely on specialized processing that is dominant in one hemisphere. Indeed, it has been shown that increasing brain size is accompanied by reduced hemispheric interconnectivity via the corpus callosum (Ringo et al., 1994; Olivares et al., 2001) and the development of more pronounced gross cerebral asymmetries among anthropoid primates (Hopkins and Rilling, 2000). p0210 One consequence of lateralized hemispheric specialization of function may be divergence in the histological organization of homotopic cortical areas. Unfortunately, there is a surprising absence of data from non-humans concerning microstructural asymmetries in the homologues of Broca’s area, Wernicke’s area, and primary motor cortex. At present, the sole study of such histological asymmetry indicates that lateralization is not present in area Tpt of chimpanzees or macaques, while asymmetry of neuropil space and minicolumn widths are observed in humans (Buxhoeveden et al., 2001a). Although this is an important finding, it should be kept in mind that there are many other aspects of microstructural organization that have been demonstrated to be asymmetric in the human cortex, such as distributions of cell volumes and dendritic geometry, which have yet to be investigated in other species. Thus, at the present time, there are still insufficient data to adequately resolve whether many of the observed microstructural asymmetries of the human cerebral cortex are unique speciesspecific adaptations that are related to language and handedness. b0605 b0330 b0705 b0085 b0780 b0785 b0045 b0885 b0330 b0160 NRVS 00022 18 The Evolution of Neuron Types and Cortical Histology in Apes and Humans t0015 Table 3 Neuron densities (in neurons per mm3) and Grey Level Index (GLI) values for different cortical areas in hominoids and Old World monkeys Area 4a Area 10 b Area 13 c GLI Neuron density GLI Neuron density GLI Neuron density Homo sapiens Pan troglodytes Pan paniscus Gorilla gorilla Pongo pygmaeus Hylobates lar Macaca sp. Papio anubis 11.65 13.19 – 8.76 10.61 – 15.58 14.85 18,048 22,177 – 24,733 18,825 – 50,798 33,661 15.17 17.52 18.17 15.87 20.10 19.80 20.34 – 34,014 60,468 55,690 47,300 78,182 86,190 – – 14.18 18.63 16.98 14.62 18.55 13.33 18.36 – 30,351 50,686 44,111 54,783 42,400 53,830 – – OO b0735 RS b0785 ir neurons scale against total neuron density with positive allometry in areas V1 and V2, resulting in a smaller percentage of CB-ir interneurons in apes compared to monkeys in these areas (Sherwood et al., 2005). Further studies using allometric approaches to examine the scaling of different neuron subtypes will be necessary to elucidate phylogenetic specializations of cortical circuitry. T Other aspects of network scaling in the cerebral cortex are less well understood. For example, there does not appear to be a correlation between brain size and the density of glial cells (Tower and Young, 1973; Haug, 1987). However, phylogenetic differences in glial cell densities have not yet been systematically examined using modern immunohistochemical markers to identify astrocytes and oligodendrocytes separately. Furthermore, questions regarding the scaling of subpopulations of interneurons and pyramidal cells have only begun to be addressed. Evidence suggests that the proportion of pyramidal neurons that are enriched in NPNFP may increase with brain size. In the orofacial representation of primary motor cortex, there is a striking increase in the percentage of neurons stained for NPNFP in larger-brained great apes and humans in comparison to smaller-brained Old World monkeys (Sherwood et al., 2004a). Tsang and colleagues (2000) also found increasing NPNFP labeling in primary motor cortex across a sample including rats, marmosets, rhesus macaques, and humans. In addition, Campbell and Morrison (1989) found a larger proportion of NPNFP-ir pyramidal neurons, particularly in supragranular layers, in humans compared to macaque monkeys across several different cortical areas. p0235 Interneuron subtypes, as revealed by labeling for calcium-binding proteins, appear to adhere to different scaling trends in anthropoid primates depending on the cortical area. For example, when regressed on total neuron density, the density of PV-ir neurons scales with negative allometry in the primary motor cortex and thus a greater proportion of PV-ir neurons is observed in hominoids compared to Old World monkeys (Sherwood et al., 2004a). In contrast, CBp0230 PR Inb0715 all studies, neuron densities were estimated by the optical dissector method. b0730 a (Sherwood et al., 2003b; Sherwood et al., 2004b) b0690 b (b0680 Semendeferi et al., 2001) c (Semendeferi et al., 1998) F Species VI ER FI b0330 EL SE b0725 b0725 b0140 b0790 4.21.3.4 Genomic Data Provide Insights into Cortical Specializations s0085 Recent studies of phylogenetic variation in gene p0240 sequences and expression provide additional insights into cortical specializations among hominoids. While most of these studies have been directed at determining the genetic basis for human neural uniqueness (Enard et al., 2002a; 2002b; Caceres et al., 2003; Dorus et al., 2004; Uddin et al., 2004), some molecular data point to changes that occurred at earlier times in the hominoid radiation. For instance, all hominoids have evolved a novel biochemical mechanism to support high levels of glutamate flux in neurotransmission through the retroposition of the gene GLUD1 (Burki and Kaessmann, 2004). This duplicated gene, GLUD2, which is unique to hominoids, encodes an isotype of the enzyme glutamate dehydrogenase that is expressed in astrocytes. All hominoid GLUD2 sequences contain two key amino acid substitutions that allow the GLUD2 enzyme to be activated in astrocytes during conditions of high glutamatergic neurotransmitter flux. Concordant with this evidence for alterations in the molecular machinery necessary for enhanced neuronal activity in apes, it has been shown that the gene encoding the b0215 b0130 b0220 b0210 b0795 b0105 NRVS 00022 The Evolution of Neuron Types and Cortical Histology in Apes and Humans 19 s0090 OO F There remains an extraordinary amount to learn p0260 regarding the microstructure of the cerebral cortex of hominoids. Even the basic cytoarchitecture of many cortical areas, such as the posterior parietal cortex, inferior temporal cortex, posterior cingulate cortex, and premotor cortex, has not yet been explored using the methods of modern quantitative neuroanatomy. Moreover, there is not a single recent study of parcellation for any part of the cerebral cortex using chemoarchitectural staining techniques in apes. It will also be important to examine the scaling patterns that govern the distribution of neurochemically identified subsets of pyramidal neurons, interneurons, and glia across different cortical areas from a broad phylogenetic perspective in order to clearly distinguish network allometric scaling from phylogenetic specialization. Finally, determination of whether humanlike histological asymmetries of cortical areas important in language and control of the hand are present in other apes still requires systematic study. By taking seriously the task of understanding such speciesspecific neural adaptations, we stand to learn an extraordinary amount about the underlying substrates of the cognitive abilities of humans and our closest relatives. FI RS b0485 4.21.3.5 On the Horizon PR b0855 is any hope of understanding how such molecular differences translate into modifications of the computational capacities of cortical circuits. T cytochrome c oxidase subunit 4-1 underwent rapid nonsynonymous evolution in the hominoid stem, followed by purifying selection in descendent lineages (Wildman et al., 2002). Because these nucleotide substitutions have functional consequences for the manner and rate at which electrons are transferred from cytochrome c to oxygen, it is likely that these modifications were selected to serve the needs of cells with high aerobic energy demands, such as neurons. p0245 Also of significance, an alternative splice variant of neuropsin (type II) has originated in recent hominoid evolution (Li et al., 2004). Neuropsin is expressed in hippocampal pyramidal neurons and is involved in neuronal plasticity. The high incidence of polymorphisms in the coding region of this protein in gibbons and orang-utans, however, suggests that it may not be functional in these species. In contrast, the coding region of the type II splice form of neuropsin shows relatively little variation in gorillas, chimpanzees, and humans, signifying that it is maintained by functional constraint and that it might be involved in a molecular pathway important for learning and memory in these hominoids. p0250 With respect to brain size, several genes that are involved in controlling the development of cerebral cortex size have undergone accelerated rates of sequence evolution in the hominoid lineage. The microcephalin gene shows an upsurge of nonsynonymous amino acid substitutions in a protein-coding domain of the last common ancestor of great apes and humans (Wang and Su, 2004). Additionally, the ASPM gene shows evidence of adaptive sequence evolution in all African hominoids (i.e., gorillas, chimpanzees, bonobos, and humans) (Kouprina et al., 2004). p0255 These data put into phylogenetic context evidence that, in the lineage leading to humans, several genes important in the development, physiology, and function of the cerebral cortex show positive selection (Enard et al., 2002b; Dorus et al., 2004; Evans et al., 2004). Furthermore, findings from studies that have compared human and chimpanzee transcriptomes indicate that the human cerebral cortex is distinguished by elevated expression levels of many genes associated with energy metabolism (Caceres et al., 2003; Uddin et al., 2004), suggesting that levels of neuronal activity might be higher in humans compared to chimpanzees (Preuss et al., 2004). 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