NRVS 00022

a0005 4.21 The Evolution of Neuron Types and Cortical Histology in Apes and Humans

C C Sherwood, Kent State University, Kent, OH, USA P R Hof, Mount Sinai School of Medicine, New York, NY, USA ª 2007 Elsevier Inc. All rights reserved.

4.21.1 Introduction 2 4.21.1.1 Evolutionary History of the Hominoids 2 4.21.1.2 History of Studies Concerning Hominoid Cortical Histology 3 4.21.2 Comparative Anatomy of the 4 4.21.2.1 Topology of Cortical Maps 4 4.21.2.2 Architecture of the Cortex 4 4.21.2.3 Primary 5 4.21.2.4 8 4.21.2.5 Primary 10 4.21.2.6 Inferior Frontal Cortex PROOF 12 4.21.2.7 13 4.21.2.8 Anterior 14 4.21.3 Patterns of Cortical Organization in Hominoids 15 4.21.3.1 The Emergence of Cell Types and their Distribution 15 4.21.3.2 The Evolution of Cortical Asymmetries 15 4.21.3.3 How much Variation in Cortical Architecture can be Attributed to Scaling versus Specialization? 17 4.21.3.4 Genomic Data Provide Insights into Cortical Specializations 18 4.21.3.5 On the Horizon 19 FIRST Glossary the structure in question becomes proportionally smaller or less g0005 Allometry Many biological traits scale with numerous with increases in the overall size in a nonlinear fashion. size of the reference variable. Such allometric scaling relation- Chemoarchitecture The microanatomical organization g0010 ships can be expressed by the of the cerebral cortex revealed by power function:ERY¼bXa. The loga- staining for biochemical substances rithmic transformation of the using techniques such as immuno- allometric scaling equation yields: histochemistry and enzyme or log Y¼log bþa log X. The expo- lectin histochemistry. nent of the power function becomes Dysgranular A type of cortex that has a weakly g0015 the slope of the log-transformed Cortex defined layer IV because it is vari- function. The slope of this line can able in thickness. At points, layer then be interpreted in terms of a IV seems to disappear because neu- biological scaling relationship rons from layers IIIc and Va between the independent and intermingle. dependent variable. Positive allo- Encephalization A relative measure of a species’s g0020 metry refers to a scaling brain size that represents the degree relationship with an exponent that to which it is larger or smaller than ELSEVIis greater than 1, which means that expected for a typical animal of its the structure in question grows dis- body size. proportionately larger or more Granular Cortex A type of cortex that has a clearly g0025 numerous with increases in the identifiable layer IV. size of the reference variable. Grey Level Index The proportion of an area of refer- g0030 Negative allometry refers to a scal- (GLI) ence that is occupied by the ing relationship with an exponent projected profiles of all Nissl- that is less than 1, which means that stained elements. This value NRVS 00022

2 The Evolution of Neuron Types and Cortical Histology in Apes and Humans

provides an estimate of the fraction 4.21.1 Introduction s0005 of tissue that contains neuronal 4.21.1.1 Evolutionary History of the Hominoids s0010 somata, glial cell nuclei, and endothelial nuclei versus neuropil. Apes and humans are members of the primate super- p0005 GLI values are highly correlated family Hominoidea (Figure 1). Molecular evidence with the volume density occupied indicates that the hominoid lineage split from the b0860 by neurons since glial and endothe- Old World monkeys about 25Ma (Wildman et al., lial cell nuclei contribute only a 2003). The extant representatives of this phylogenetic very small proportion of the total group include two families. The Hylobatidae com- volume. prises gibbons and siamangs, and the Hominidae g0035 Hominoid A phylogenetic clade that includes includes great apes (i.e., orang-utans, gorillas, chim- lesser apes (gibbons and siamangs), b0300 great apes (orang-utans, gorillas, panzees, and bonobos) and humans (Groves, 2001). chimpanzees, and bonobos), and Living hominoids are distinguished by a suite of humans. shared derived traits that point to the key adaptations g0040 Infragranular Cortical layers that are deep to of this clade. These characters include lack of an Layers granular layer IV, i.e., layers V external tail, modifications of the shoulder girdle and and VI. wrist for greater mobility, and stabilization of the b0075 g0045 Minicolumn Morphologically, minicolumns lower back (Begun, 2003). These adaptations allow appear as a single vertical row of hominoids to exploit resources in small branches of neurons with strong vertical inter- trees by developingPROOF suspensory postures to distribute connections among layers, forming their body weight. This form of locomotion may have a fundamental structural and func- tional unit. The core region of the been particularly important in allowing certain species column contains the majority of the to increase body size. In addition, compared to other primates, hominoids have extended periods of growth neurons, their apical dendrites, and b0675 and development (Schultz, 1969), an increased com- both myelinated and unmyelinated b0570 fibers. A cell-poor region, contain- plexity of social interactions (Potts, 2004), and larger ing dendritic arbors, unmyelinated brains than would be expected for a monkey of the b0630 axons, and synapses, surrounds same body size (Rilling and Insel, 1999). The each column. increased encephalization and associated life history g0050 Neuropil The unstained portionFIRST of elongation of these species suggest that cognitive flex- Nissl-stained tissue, which is com- ibility and learning were important aspects of the prised of dendrites, axons, and hominoid adaptive complex, which allowed them to synapses. g0055 Supragranular Cortical layers that are superficial deal with locating ephemeral resources from fruiting trees and to negotiate more complicated relationships Layers to granular layer IV, i.e., layers I, II, b0570 and III. ER in fission–fusion societies (Potts, 2004).

Humans 6 Ma

3 Ma Bonobos 7 Ma Chimpanzees 14 Ma Gorillas 18 Ma Orang-utans 25 Ma Gibbons and simiangs

40 Ma ELSEVI Old World monkeys

58 Ma New World monkeys

63 Ma Tarsiers

Lemurs and lorises Figure 1 Cladogram showing the phylogenetic relationships of living hominoids and other primates. Estimated divergence dates f0005 b0295 are taken from Goodman et al. (2005). NRVS 00022 The Evolution of Neuron Types and Cortical Histology in Apes and Humans 3 p0010 Although only a small number of hominoid spe- pathological changes subsequent to ablation, some cies persist today, the fossil record reveals a diverse studies also examined cortical projection systems in b0835 b0470 array of successive adaptive radiations of hominoids apes (Walker, 1938; Lassek and Wheatley, 1945; b0460 b0425 in the past. During the Miocene epoch, global cli- Kuypers, 1958; Jackson et al., 1969). After the mates were warm and humid, supporting dense 1950s, however, the amount of research directed forests and lush woodlands extending throughout toward understanding variation in the hominoid the tropics and into northern latitudes. These envir- brain declined. There are three main reasons for onmental conditions were favorable for the this. First, the development of molecular biological diversification of arboreal specialists, such as the techniques caused neuroscientists to focus on a hominoids. In fact, hominoids were the most abun- small number of model species under the implicit dant type of anthropoid primate throughout the assumption that many aspects of cortical structure Miocene in Africa and Eurasia, occupying a range are evolutionarily conserved. These ideas were b0075 of different ecological niches (Begun, 2003). The further bolstered by claims of uniformity in the earliest apes in the fossil record are characterized basic columnar architecture of the cerebral cortex b0650 by hominoidlike dental morphology, but monkey- (Rockel et al., 1980). Second, findings from the first like postcranial anatomy. The best known of these systematic studies of great ape behavior from the early dental apes is the genus Proconsul from field and laboratory were beginning to be appre- b0445 b0660 the Early Miocene (20–18Ma) of East Africa. ciated (e.g., Kortlandt, 1962; Schaller, 1963; e.g., b0870 b0875 Proconsul africanus endocasts show a Yerkes and Learned, 1925; Yerkes and Yerkes, morphology that is similar to modern hominoids in 1929). ThesePROOF studies contributed to a more sophis- being gyrified and lacking the simple V-shaped arc- ticated understanding of cognitive and emotional uate that is characteristic of most Old World complexity in great apes and suggested that they b0610 monkeys (Radinsky, 1974). Furthermore, Proconsul deserve special protected status with respect to the africanus had a relatively larger brain than extant ethics of invasive neurobiological experimentation. b0830 monkeys of comparable body size (Walker et al., Third, the book Evolution of the Brain and b0430 1983). Thus, increased encephalization and perhaps Intelligence (Jerison, 1973) had an enormous influ- a greater degree of frontal lobe gyrification were ence on the direction of later research in present early in the evolution of the hominoids. comparative neuroanatomy. This book argued for p0015 With the emergence of arid climates in the transi- the predictability of neuroanatomical structure from tion to the Pliocene and the replacement of forestsFIRSTbrain size and encephalization, suggesting that these by mosaic habitats, the arboreal specializations of metrics form the most significant contribution to hominoids were less successful. The relatively slow species diversity in brain organization. Combined reproductive rates of these taxa, moreover, made it with the ready availability of comparative brain difficult for many to endure habitat loss resulting region volumetric data in primates and other mam- from climate change and human encroachment in mals from the publications of Heinz Stephan, Heiko b0420 b0740 recent times (Jablonski et al., 2000). In the context Frahm, George Baron, and colleagues (e.g., Stephan of these dramatic environmentalER changes, one line- et al., 1981), a great deal of research effort has been age adopted a new form of locomotion, upright expended in studies of allometric scaling and covar- b0235 bipedal walking, which would give rise to modern iance of large regions of the brain (Finlay and b0065 b0195 humans. Other hominoids, however, fared less well Darlington, 1995; Barton and Harvey, 2000; de and today apes are restricted to a small number of Winter and Oxnard, 2001). In contrast, much less endangered tropical forest species. attention has been paid to the possibility of phylo- b0575 genetic variation in cortical histology (Preuss, 2000). Fortunately, advances in quantitative neu- s0015 4.21.1.2 History of Studies Concerning roanatomy and immunohistochemical staining Hominoid Cortical Histology techniques have opened new avenues of research to p0020 At the beginning of the twentieth century, neuroa- reveal interspecific diversity in the microstructure of natomistsELSEVI applied new histological staining hominoid cerebral cortex. techniques to reveal the architecture of the cerebral The history of studies of hominoid cortical histol- p0025 cortex in numerous species, including apes and ogy, therefore, has resulted in two eras of research. b0135 b0500 humans (Campbell, 1905; Mauss, 1908; The early era comprises several qualitative com- b0100 b0505 b0070 Brodmann, 1909; Mauss, 1911; Beck, 1929; parative mapping studies of the cerebral cortex b0230 b0745 b0750 Filimonoff, 1933; Strasburger, 1937a, 1937b). In based on cyto- and myeloarchitecture, with the addition, with the advent of various techniques for occasional comment regarding species differences tracing neuronal connectivity based on intracellular in the microstructure of homologous cortical areas NRVS 00022

4 The Evolution of Neuron Types and Cortical Histology in Apes and Humans

b0135 b0500 b0100 (Campbell, 1905; Mauss, 1908; Brodmann, 1909; cerebral cortex, highlighting evidence concerning b0505 b0070 b0055 Mauss, 1911; Beck, 1929; Bailey et al., 1950). Later shared derived traits of hominoids in comparison studies from this era also contributed quantitative to other primates, as well as indicating possible data concerning the surface area of particular corti- species-specific specializations. Hence, the studies cal areas, as well as cellular sizes and densities in a reviewed in this chapter provide the most direct b0510 few non-human hominoid species (Mayer, 1912; evidence currently available to delimit which b0765 b0810 b0470 Tilney and Riley, 1928; von Bonin, 1939; Lassek aspects of cortical histology are uniquely human, b0705 b0325 and Wheatley, 1945; Shariff, 1953; Haug, 1956; which are derived for all hominoids, and which b0290 b0080 Glezer, 1958; Blinkov and Glezer, 1968). These reflect the specializations of each species. quantitative data, however, were rarely presented in the context of a focused examination of variation among hominoids. 4.21.2 Comparative Anatomy s0020 p0030 The modern era is characterized by studies that of the Cerebral Cortex use techniques such as design-based stereology, 4.21.2.1 Topology of Cortical Maps s0025 computerized image analysis, and immunohisto- chemical and histochemical staining to identify Total brain weight in hominoids ranges from p0040 subpopulations of cortical cells. These new approximately 90g in Kloss’s gibbons (Hylobates approaches are especially appealing for investiga- klossii) to 1,400g in humans (Homo sapiens) tions of phylogenetic variation in cortical histology (Table 1). While there is a large range of variation in species that are not common to the laboratory among hominoidsPROOF in total brain size, mapping stu- because several enzymatic, cytoskeletal, and other dies of the cortex (Figure 2) generally agree that the location of the primary sensory and motor areas are macromolecular constituents that are well preserved b0305 similar across species (Gru¨nbaum and Sherrington, in postmortem tissue can be used as reliable markers b0135 b0500 b0100 1903; Campbell, 1905; Mauss, 1908; Brodmann, for subpopulations of distinct neuron types, thereby b0505 b0480 1909; Mauss, 1911; Leyton and Sherrington, extending comparative studies of species for which b0070 b0055 b0595 1917; Beck, 1929; Bailey et al., 1950; Preuss et al., anatomical tracing, electrophysiological mapping, b0310 b0110 1999; Hackett et al., 2001; Bush and Allman, or other experimental procedures would be either b0115 b0730 unethical or impractical (see 00055). Subsets of pyr- 2004a, 2004b; Sherwood et al., 2004b). In particu- amidal neurons, for example, can be distinguished lar, the primary visual cortex lies within the banks immunohistochemically by staining with anFIRST anti- of the . Primary auditory cortex is body (e.g., SMI-32) to nonphosphorylated epitopes located on the posterior superior plane of the super- on the medium- and high-molecular-weight subu- ior temporal , usually comprising the nits of the neurofilament triplet protein. These transverse gyrus of Heschl in great apes and epitopes are particularly enriched in subpopulations humans. Primary somatosensory cortex is found of large neurons of the neocortex that have a specific within the posterior bank of the and laminar and regional distribution. Because nonpho- extends on to the . Primary motor sphorylated neurofilament proteinER (NPNFP) is cortex is located mostly on the anterior bank of the involved in the maintenance and stabilization of central sulcus. One notable difference is the fact that the axonal cytoskeleton, its expression is associated primary visual cortex extends to only a very small with neurons that have thick myelinated axons portion of the lateral convexity of the b0365 b0440 (Hoffman et al., 1987; Kirkcaldie et al., 2002). In in humans, whereas a much larger part of the lateral occipital lobe is comprised of striate cortex in apes addition, the calcium-binding proteins–calbindin D- b0880 b0385 28k (CB), calretinin (CR), and parvalbumin (PV)– (Zilles and Rehka¨mper, 1988; Holloway et al., are useful markers for understanding the cortical 2003). This is because the primary visual cortex in humans is 121% smaller than expected for a pri- interneuron system because each of these molecules b0375 is typically colocalized with GABA in morphologi- mate of the same brain size (Holloway, 1996). cally and physiologically distinct nonoverlapping Other higher-order areas, particularly within the b0200 b0495 frontal cortex, have also been shown to occupy populations (DeFelipe, 1997; Markram et al., b0745 ELSEVI similar locations across these species (Strasburger, 2004). b0750 b0680 1937a, 1937b; Semendeferi et al., 1998; p0035 While the neuroanatomical structure of one b0690 b0710 hominoid species in particular has been studied Semendeferi et al., 2001; Sherwood et al., 2003a). most extensively, it is well beyond the scope of this 4.21.2.2 Architecture of the Cortex s0030 article to provide a comprehensive review of human cortical architecture. Here we focus explicitly on The general histological architecture of the neocor- p0045 comparative studies of the histology of hominoid 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)

Common name Species Sex Sample size Mean SD Range

White-handed gibbon Hylobates lar M 44 106.3 7.2 92–125 F 37 104.2 7.0 90–116 Siamang Symphalangus syndactylus M 8 127.7 8.2 99–140 F 12 125.9 12.7 102–143 Orang-utan Pongo pygmaeus M 66 415.6 33.6 334–502 F 63 343.1 33.6 276–431 Gorilla Gorilla gorilla M 283 535.5 55.3 410–715 F 199 452.2 41.6 345–553 Chimpanzee Pan troglodytes M 159 397.2 39.4 322–503 F 204 365.7 31.9 270–450 Bonobo Pan paniscus M 28 351.8 30.6 295–440 F 30 349.0 37.7 265–420 Human Homo sapiens M 502 1457.2 119.8 1160–1850 F 165 1317.9 109.8 1040–1615

Data from Holloway (1996). Endocranial volumes are shown, rather than brain volumes, because larger sample sizes are available for these species.

with other primates and mammals in general, such on the basisPROOF of cytoarchitecture and topology, sev- as a fundamental six-layered and columnar organi- eral studies have compared the microstructure of b0525 zation (Mountcastle, 1998). Compared to other these areas among different hominoid species mammals of similar brain size, however, the cere- (reviewed below). On the whole, the cytoarchitec- bral cortex of hominoids is reported to have a ture of homologous cortical areas shows only subtle relatively low density of glial cells and a greater differences across hominoid species. Indeed, an b0330 variety of neuron soma sizes (Haug, 1987). early quantitative comparative analysis of the Astroglia of the cerebral cortex in great apes, as cytoarchitecture of primary cortical areas (areas 3, revealed by immunohistochemistry for glial fibril- 4, 17, and 41/42), found marked similarities among lary acidic protein (GFAP), resemble other primates species (orang-utans, gorillas, chimpanzees, and in forming long, radially oriented interlaminar pro- humans) in terms of the relative thickness of differ- cesses spanning supragranular corticalFIRST layers ent layers and the proportion of neuropil in each b0180 b0880 (Colombo et al., 2004). This configuration may be layer (Zilles and Rehka¨mper, 1988). Only minor unique to primates, as GFAP staining in the cortex differences were noted, such as greater relative of other mammals appears distinctly different, com- thickness of layer III in primary somatosensory cor- prising a network of stellate astroglial somata with tex (area 3) in humans and gorillas, an increase in b0165 short, branching processes (Colombo, 1996; the proportion of neuropil in layers V and VI of area b0175 b0170 Colombo et al., 2000; ColomboER and Reisin, 2004). 3 in orang-utans, and a relatively thicker layer IV of p0050 Comparison of mammalian brains indicates that primary auditory cortex (area 41/42) in orang- the surface area of the cortical sheet can vary by utans. These results were interpreted to corroborate b0135 more than five orders of magnitude, while the thick- the qualitative observations of Campbell (1905) and ness of the cortex varies by less than one order of Brodmann (1909), indicating that there are not any b0010 magnitude (Allman, 1990). Accordingly, evolution- substantial differences between humans and apes in ary changes in the size of the cerebral cortex have the cytoarchitecture of these primary cortical areas. b0880 occurred primarily in the tangential dimension, The study by Zilles and Rehka¨mper (1988), how- while the vertical dimension of the cortex may be ever, was based on small samples, which did not more constrained by the development of columnar permit statistical evaluation of species differences. b0615 b0620 units (Rakic, 1988, 1995). Nonetheless, the cortical More recent studies using larger samples, different sheet does tend to display increased thickness in staining techniques, and more refined quantitative b0370 mammalsELSEVI with larger brains (Hofman, 1988). Due methods have revealed interesting phylogenetic dif- to these scaling trends, hominoids have thicker cor- ferences among hominoids in cortical histological tices than other smaller-brained primates and structure. homologous cortical areas in humans tend to be thicker than in apes (Figure 3). 4.21.2.3 Primary Visual Cortex s0035 p0055 With the relative ease of establishing homology Important modifications of primary visual cortex p0060 among the primary sensory and motor cortical areas (Brodmann’s area 17) histology, particularly of the NRVS 00022

6 The Evolution of Neuron Types and Cortical Histology in Apes and Humans

PROOF (a) (b)

FIRST

ER

(c) (d) Figure 2 Parcellation maps of the cerebral cortex of apes. Chimpanzee (Pan troglodytes) cortical maps reproduced from f0010 b0135 b0055 b0135 (a) Campbell (1905) and (b) Bailey et al. (1950). Orang-utan (Pongo pygmaeus) cortical maps reproduced from (c) Campbell (1905) b0500 b0505 b0880 and (d) MaussELSEVI (1908, 1911) compiled in Zilles and Reka¨mper (1988). thalamic recipient layer IV, have taken place at several the analysis of motion and gross spatial properties of points in the evolution of hominoids. Distinct parallel stimuli. The P-type ganglion cells process visual infor- ascending fiber systems arising from retinal ganglion mation with high acuity and color sensitivity, and cells project to the lateral geniculate nucleus (LGN) of project to parvocellular layers of the LGN. In the the thalamus. The M-type retinal ganglion cells give geniculostriate component of these parallel pathways, rise to the magnocellular channel, which is involved in 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 III I II III

III IV IV V IV V VI V VI VI wm wm wm

Long-tailed macaque Chimpanzee Human

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 thePROOF thickness of the cortex. Scale bar¼250mm.

LGN and synapse within separate sublayers of layer metabolic activity within this sublayer. However, IV in primary visual cortex. The complexity of segre- in the hominoid species examined to date (orang- gated geniculostriate projects is reflected in the utans, chimpanzees, and humans), intense CO stain- development of at least three subdivisions of layer IV ing in layer IVA is absent, suggesting that the direct b0100 in primates as demarcated by Brodmann (1909). Two parvocellular-geniculate projection to layer IVA cell-rich layers, IVA and IVC, are separated by a cell- was either reduced or more dispersed to include poor layer IVB, which contains a dense plexus of both layers IVA and IVB in the last common ances- b0595 myelinated axons known as the stria of Gennari. tor of this phylogenetic group (Preuss et al., 1999; b0580 NeuronsinthemagnocellularlayersoftheLGNpro- Preuss and Coleman, 2002). Primary visual cortex ject to the upper half of layer IVC. NeuronsFIRST in the of great apes and humans is further distinguished parvocellular layers of the LGN project to layer IVA. from monkeys in having increased staining of CB- p0065 The chemoarchitecture of layer IVA is markedly immunoreactive (-ir) interneurons and neuropil in b0580 different in hominoids compared to other primates layer IVA (Preuss and Coleman, 2002). (Figure 4). In most monkeys, except the nocturnal Layer IVA of primary visual cortex in humans p0070 owl monkey, there is a dense band of cytochrome exhibits additional modifications to the basic homi- oxidase (CO)-rich staining in layerER IVA (reviewed in noid plan described above. In humans, a meshwork b0595 Preuss et al., 1999), reflecting high levels of pattern is observed in which compartments of neu- ropil that stain intensively for Cat-301 and nonpyramidal NPNFP-ir cells, and neurites alter- nate with bands of high densities of CB-ir b0580 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 ELSEVI has been suggested that these alterations are related to specializations in humans for the visual percep- b0580 tion of rapid orofacial gestures in speech (Preuss and Coleman, 2002). Another distinctive feature of primary visual cor- p0075 f0020 Figure 4 Comparative chemoarchitecture of layer IV in pri- tex organization in many primates is ocular mary visual cortex of squirrel monkeys (Saimiri ), macaques (Macaca), chimpanzees (Pan), and humans (Homo). dominance columns, which correspond to the hor- b0580 Reproduced from Preuss and Coleman (2002). izontal segregation of inputs from the two retinae to NRVS 00022

8 The Evolution of Neuron Types and Cortical Histology in Apes and Humans

different compartments in layer IV of primary visual context of the general scaling patterns of Meynert cortex. Ocular dominance columns have been ana- cells, it is interesting that soma volumes of these tomically demonstrated in Old World monkeys, neurons fit closely with predictions among humans humans, and some other primates, such as the (2.84 times larger than neighboring pyramidal cells) New World spider monkey and the strepsirrhine and gorillas (2.98 times), whereas they are relatively b0015 galago (reviewed in Allman and McGuinness, large in chimpanzees (3.78 times) and relatively 1988). A similar pattern of alternating patches of small in orang-utans (1.94 times). These differences ocular representation within primary visual cortex in neural organization for the processing of visual has been described in a chimpanzee after monocular motion may relate to socioecological differences injection of a transneuronal tritiated tracer sub- among these apes. Because wild chimpanzees b0760 stance (Tigges and Tigges, 1979). It is worth engage in aggressive incursions into the territory of b0845 noting, however, that this study revealed geniculate neighboring groups (Watts and Mitani, 2001) and projections to layer IVC, but not to layer IVA, as is hunt highly mobile prey such as red colobus mon- b0850 observed in monkeys. keys (Watts and Mitani, 2002), we speculate that p0080 Large pyramidal neurons, which are found at the relatively large Meynert cells evolved in this species boundary between layers V and VI, called Meynert to enhance detection of visual motion during bound- cells, are prominent in the primary visual cortex of ary patrolling and hunting. In contrast, relatively primates, and their soma size displays interspecific small Meynert cells in orang-utans may relate to b0720 variation (Figure 5) (Sherwood et al., 2003c). These the fact that these apes are solitary, large-bodied, b0805 cells can be distinguished as a unique subtype on the committed frugivoresPROOF (van Schaik and van Hooff, basis of their morphology and connectivity. Their 1996), which allows them to maintain low levels of thick axon collaterals project to both area MT/V5 vigilance for motions of predators, competitors, and and the superior colliculus, suggesting that these food items. b0240 cells are involved in processing visual motion (Fries b0530 et al., 1985; Movshon and Newsome, 1996; b0490 4.21.2.4 Auditory Cortex s0040 Livingstone, 1998). In a comparative study, Meynert cell somata were found to be on average There are two parallel thalamocortical projections p0085 2.8 times lager than other layer V pyramidal neu- from the medial geniculate nucleus (MGN) to the b0720 rons across a range of primates (Sherwood et al., superior temporal cortex of primates. Neurons in 2003c). Because the basal dendrites and axonFIRST col- the ventral division of the MGN supply a tonotopic laterals of Meynert cells extend horizontally in projection to the core region of auditory cortex layers V and VI to integrate information and facil- (Brodmann’s areas 41 and 42). Neurons in the dor- itate responses across widespread areas of visual sal and medial divisions of the MGN project to space, interspecific variation in Meynert cell size areas surrounding the core. The core region of audi- appears to be largely constrained by their function tory cortex has been identified in macaques, in the repetitive stereotyped local circuits that repre- chimpanzees, and humans as a discrete architectural sent the retinal sheet in primary visualER cortex. In the zone as compared to the surrounding belt cortex b0310 (Hackett et al., 2001). The core can be recognized by a broad layer IV that receives a dense thalamic projection, heavy myelination, and intense expres- I sion of acetylcholinesterase (AChE), CO, and PV in II the neuropil of layer IV. In macaques, the relatively III high density of cells and fibers makes the auditory IVA cortex core appear structurally homogeneous as IVB compared to the hominoids. In contrast, the medial IVC and lateral domains of the core region of auditory V cortex are more clearly differentiated in humans and ELSEVIVI chimpanzees because of the lower packing density wm of structural elements. Additionally, the network of (a) (b) small horizontal and tangential myelinated fibers in f0025 Figure 5 The location and morphology of Meynert cells in an layer III appears most complex in humans, inter- orang-utan (Pongo pygmaeus). Meynert cells are located at the mediate in chimpanzees, and least elaborate in boundary between layers V and VI, as indicated by the arrow in the Nissl-stained section (a). The morphology of Meynert cells as macaques. revealed by immunostaining for NPNFP with Nissl counterstain is The auditory core region is enveloped by several p0090 shown (b). Scale bar (a)¼250mm. Scale bar (b)¼50mm. higher-order belt and parabelt fields (Figure 6). The NRVS 00022 The Evolution of Neuron Types and Cortical Histology in Apes and Humans 9

41 auditory cortex are not well understood, but they are likely to be important for higher-order proces- sing of natural sounds, including those used in communication. Neurons in the lateral belt cortex Tpt HG areas of rhesus macaques, for example, respond better to species-specific vocalizations than to energy- b0625 matched pure tone stimuli (Rauschecker et al., 1995). The comparative anatomy of one particular p0095 PT region of auditory association cortex has been stu- died most extensively. In humans, Wernicke’s area, S a region important for the comprehension of lan- guage and speech, is located in the posterior P (a) superior temporal cortex. Gross anatomic observa- tions indicate that asymmetries similar to humans are present in the superior of non- I human primates, such as leftward dominance of the b0275 II in great apes (Gannon et al., b0400 1998; Hopkins et al., 1998) and a longer left sylvian III b0475 fissure in many anthropoid species (LeMay and b0865 I Geschwind,PROOF 1975; Yeni-Komshian and Benson, b0350 b0405 II IV 1976; Heilbroner and Holloway, 1988; Hopkins et al., 2000). Several investigations have examined the micro- p0100 III V structure of the cortical area most closely associated b0260 with Wernicke’s area. Area Tpt (Galaburda et al., b0825 VI IV 1978) or area TA1 (von Economo and Koskinas, V 1925) comprises a portion of posterior Brodmann’s area 22 located on the upper bank of VI the and sometimes extend- 41 (TC) wm Tpt (TA1) wm FIRSTing to part of the parietal and the (b) (c) convexities of the temporal and parietal lobes b0260 f0030 Figure 6 Cytoarchitecture of auditory cortex of an orang-utan (Galaburda et al., 1978). This area represents a (Pongo pygmaeus). A parasagittal section of the superior tem- transition between auditory association cortex and b0700 poral gyrus shows the location of regions detailed below cortex of the (Shapleske (a). Higher-power micrographs show cytoarchitecture in (b) the et al., 1999). Cortex with the cytoarchitectural char- core of primary auditory cortex (Brodmann’s area 41 or von Economo and Koskinas’ area TC) and (c) area Tpt (posterior acteristics of area Tpt has been described in galagos, ER b0255 Brodmann’s area 22 or von Economo and Koskinas’ area TA ). macaques, chimpanzees, and humans (Galaburda 1 b0585 HG¼Heschl’s gyrus; PT¼planum temporale; S¼superior; and Pandya, 1982; Preuss and Goldman-Rakic, b0120 b0125 P¼posterior. Scale bar¼500mm. 1991; Buxhoeveden et al., 2001a, 2001b). The microstructure of area Tpt in these primates is dis- belt areas of auditory cortex, which are less precise tinguished by a eulaminate appearance, with a in their tonotopic organization, receive major inputs poorly defined border of layer IV due to the from the core and diffuse input from the dorsal encroachment of pyramidal cells in adjacent layers division of the MGN. The belt region is bordered IIIc and Va, and an indistinct border between layers laterally on the superior temporal gyrus by a para- IV and V due to curvilinear columns of neurons that b0250 belt region of two or more divisions that are bridge the two layers (Galaburda and Sanides, activated by afferents from the belt areas and the 1980). dorsal MGN,ELSEVI but not the ventral MGN or the core. There are differences among rhesus monkeys, p0105 Interestingly, AChE-stained pyramidal cells in layer chimpanzees, and humans in the details of minicol- III and V of the belt region are more numerous in umn structure in area Tpt. In the left hemisphere, chimpanzees and humans compared to macaques b0310 area Tpt of humans has wider minicolumns as com- (Hackett et al., 2001). Neurons in the belt and para- pared to macaques or chimpanzees, whereas the belt project to auditory-related fields in the width of minicolumns is similar in the non-human b0125 temporal, parietal, and frontal cortex. Other types species (Buxhoeveden et al., 2001b). These findings of processing that occur in the other divisions of suggest that wider minicolumns in human area Tpt NRVS 00022

10 The Evolution of Neuron Types and Cortical Histology in Apes and Humans

may be a species-specific specialization that allows for more extensive neuropil space containing inter- I connections among neurons. II 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 III 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 b0270 V right (Galuske et al., 2000). Furthermore, left area Tpt has a greater number of the largest pyr- amidal cells in layer III, known as magnopyramidal cells, that give rise to long corti- b0410 VI cocortical association projections (Hutsler, 2003). In addition, AChE-rich pyramidal cells display greater cell soma volumes in the left hemisphere b0415 despite lacking asymmetry in number (Hutsler and (a) wm (b) Gazzaniga, 1996). In humans, left area Tpt has PROOF also been shown to contain a greater amount of Figure 7 Cytoarchitecture of and mor- f0035 phology of Betz cells in an orang-utan (Pongo pygmaeus). Betz neuropil and axons with thicker myelin sheaths b0035 cells can be seen in the bottom of layer V, as indicated by the (Anderson et al., 1999). Of particular significance, arrow in the Nissl-stained section (a). The morphology of Betz a comparative analysis of area Tpt found that cells as revealed by immunostaining for NPNFP with Nissl coun- only humans, but not rhesus macaques or chim- terstain is shown (b). Scale bar (a)¼250mm. Scale bar panzees, exhibit left dominant asymmetry in area (b)¼50mm. Tpt, with wider minicolumns and a greater pro- b0120 portion of neuropil (Buxhoeveden et al., 2001a). While the cytoarchitectural organization of pri- p0120 mary motor cortex is generally similar across species, interspecific differences have been s0045 4.21.2.5 Primary Motor Cortex FIRST described. The cytoarchitecture of the region corre- p0115 The primary motor cortex (Brodmann’s area 4) has sponding to orofacial representation of primary a distinctive cytoarchitectural appearance in pri- motor cortex in several catarrhine species (long- b0285 b0730 mates (Geyer et al., 2000; Sherwood et al., 2004b), tailed macaques, anubis baboon, orang-utans, gor- containing giant Betz cells in the lower portion of illas, chimpanzees, and humans) was analyzed using b0730 layer V, low cell density, large cellular sizes, an the Grey Level Index (GLI) method (Sherwood indistinct layer IV, and a diffuseER border between et al., 2004b). Compared to Old World monkeys, layer VI and the subjacent white matter great apes and humans displayed an increased rela- (Figure 7a). In humans, the region of primary tive thickness of layer III and a greater proportion of motor cortex that corresponds to the representation neuropil space. A stereologic investigation of of the hand exhibits interhemispheric asymmetry in NPNFP and calcium-binding protein-ir neurons its cytoarchitectural organization. Concomitant was also conducted in this same comparative sample b0725 with strong population-wide right handedness in (Sherwood et al., 2004a). Primary motor cortex in humans, most postmortem brains display a greater great apes and humans was characterized by a proportion of neuropil volume in the left hemi- greater percentage of neurons enriched in NPNFP sphere of this part of primary motor cortex and PV compared to the Old World monkeys b0025 (Amunts et al., 1996). Interestingly, brains of cap- (Figure 8). Conversely, the percentage of CB- and b0390 tive chimpanzees (Hopkins and Cantalupo, 2004) CR-ir neuron subtypes did not significantly differ ELSEVIb0565 and capuchin monkeys (Phillips and Sherwood, among these species. These modifications of parti- 2005) show humanlike asymmetries of the hand cular subsets of neuron types might contribute to the region of the central sulcus that are correlated with voluntary dexterous control of orofacial muscles the direction of individual hand preference. exhibited in the vocal and gestural communication However, the histology of primary motor cortex in of great apes and humans. Enhancement of PV-ir non-human primates has not yet been examined for interneuron-mediated lateral inhibition of cell col- asymmetry (see 00021). umns may enhance specificity in the recruitment of NRVS 00022 The Evolution of Neuron Types and Cortical Histology in Apes and Humans 11

CB CR PV

(a) (b) (c)

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.

different muscle groups for dynamic modulation of Specializations of biochemical phenotypes are p0130 fine orofacial movements (Scheiber, 2001). known for certain regionally restricted subsets of Increased proportions of NPNFP-ir pyramidal pyramidal neurons.PROOF Although calcium-binding pro- cells, on the other hand, may be a correlate of teins are expressed transiently during prenatal and b0520 greater descending cortical innervation of brainstem early postnatal development (Moon et al., 2002; b0800 cranial motor nuclei by heavily myelinated axons to Ulfig, 2002), their expression in pyramidal neurons b0460 allow for more voluntary control (Kuypers, 1958). of adult mammals is more limited. Neurons expres- p0125 The giant Betz cells are found in the lower half of sing the calcium-binding proteins – CB, CR, and PV – layer V of primary motor cortex and possess a large are thought to have relatively high metabolic rates number of primary dendritic shafts that leave the associated with fast repolarization for multiple b0060 soma at several locations around its surface action potentials (Baimbridge et al., 1992). While b0095 b0670 (Figure 7b) (Braak and Braak, 1976; Scheibel and such calcium buffering mechanisms are most com- b0515 Scheibel, 1978; Meyer, 1987). They are largest and monly associated with GABAergic interneurons, most numerous in the cortical representationFIRST of the the presence of calcium-binding proteins in pyra- leg, where axons project farther along the corticosp- midal cells might reflect a neurochemical b0465 inal tract to reach large masses of muscles (Lassek, specialization for higher rates of activity. In this b0640 1948; Rivara et al., 2003). Betz cells are strongly context, it is interesting that faint CR immunoreac- immunoreactive for NPNFP among humans, great tivity is observed in isolated medium- and large-size b0725 apes, and Old World monkeys (Sherwood et al., layer V pyramidal neurons in primary motor cortex 2004a). An analysis of scaling ofER Betz cell somata of great apes and humans, but not in macaques or b0355 b0725 volumes in the region of hand representation of baboons (Hof et al., 1999; Sherwood et al., primates revealed that these cell subtypes become 2004a). PV-ir pyramidal neurons are also very relatively enlarged with increases in brain and body rarely observed in the neocortex of mammals (see b0720 size (Sherwood et al., 2003c). At larger sizes, there is 00055). However, large layer V pyramidal neu- an increase in the distance to the spinal representa- rons, including Betz cells, have been reported to tion of target muscles and a greater number of less express PV immunoreactivity in primary motor b0545 b0535 densely distributed corticospinal neurons (Nudo cortex of humans (Nimchinsky et al., 1997; b0725 et al., 1995). In larger brains and bodies, Betz cell Sherwood et al., 2004a). Evidence concerning the axons need to become thicker to maintain conduc- existence of PV-ir pyramidal neurons in other non- tion speed to reach more distant targets in the spinal human primates is somewhat contradictory. In one cord. Accordingly, Betz cells are scaled to global study, PV-ir pyramidal neurons were observed in connectivityELSEVI constraints and therefore increase in primary motor and somatosensory cortices of gala- b0590 somatic volume in a manner that is correlated with gos and macaques (Preuss and Kaas, 1996). brain size. Due to these scaling trends, among homi- Another study, however, failed to label PV-ir pyr- b0205 noids Betz cells are relatively largest in humans amidal cells in macaques (DeFelipe et al., 1989), (10.96 times larger than neighboring pyramidal probably due to methodological discrepancies cell), then gorillas (8.37 times), chimpanzees (7.02 among experiments. A comparative study of pri- times), and orang-utans (6.51 times). mary motor cortex using the same NRVS 00022

12 The Evolution of Neuron Types and Cortical Histology in Apes and Humans

immunohistochemical procedures across species I found that PV-ir pyramidal neurons were either I II II not present or sparse in Old World monkeys, III whereas they were considerably more numerous III b0725 in great apes and humans (Sherwood et al., 2004a). IV

IV V s0050 4.21.2.6 Inferior Frontal Cortex V VI VI p0135 The microstructure of the inferior frontal cortex, the 44-Nissl wm 44-NPNFP wm region that contains Broca’s area in humans, has (a) (b) been described in hominoids on the basis on cyto-, b0820 myelo-, and NPNFP-architecture (von Economo, I I b0050 b0090 1929; Bailey and von Bonin, 1951; Braak, 1980; II II b0030 b0340 Amunts et al., 1999; Hayes and Lewis, 1995; b0710 III Sherwood et al., 2003a). Cytoarchitectural studies III of chimpanzee and orang-utan frontal cortex describe a dysgranular region anterior to the inferior IV IV precentral sulcus comprising a part of pars opercu- V b0815 V laris and designated Brodmann’s area 44 (von b0710 VI VI Bonin, 1949; Sherwood et al., 2003a), FCBm PROOF b0055 b0455 45-Nissl wm 45-NPNFP wm (Bailey et al., 1950), or areas 56 and 57 (Kreht, (c) (d) 1936). In chimpanzees, this region has been shown Figure 9 The architecture of areas 44 and 45 in a chimpanzee to receive projections from the mediodorsal nucleus f0045 b0835 (Pan troglodytes). Area 44 is shown stained for Nissl substance of the thalamus (Walker, 1938). In macaques, a field (a) and NPNFP (b). Area 45 is shown stained for Nissl sub- with similar cytoarchitectural characteristics in the stance (c) and NPNFP (d). Scale bar¼500mm. caudal bank of the inferior limb of the arcuate sul- cus has been denoted area 44, with area 45 located frontal gyrus in humans for microstructural asymme- b0255 b0560 rostrally (Galaburda and Pandya, 1982; Petrides tries. Using GLI profile analysis methods to quantify and Pandya, 1994). The cytoarchitecture of area regional variation in cytoarchitecture, area 44 has 44 is characterized by a columnar organizationFIRST simi- been shown to display left dominance in terms of lar to ventral premotor area 6, but it is distinguished volume and an increased proportion of neuropil by the development of a thin layer IV and clustered space, whereas area 45 does not show a consistent b0030 magnopyramidal neurons in the deep part of layer direction of asymmetry (Amunts et al., 1999). In III. Layer IV in area 44 has an undulating appear- addition, the total length of pyramidal cell dendrites ance due to the invasion of pyramidal cells from is longer in the left opercular region of the inferior layer III and layer V. Nonphosphorylated neurofila- frontal gyrus due to a selective increase in the length b0665 ment protein staining in area 44 ofER chimpanzees and of higher-order segments (Scheibel et al., 1985). humans displays clusters of large pyramidal neurons Using different methods, another study examined at the bottom of layer III and a lower band of immu- asymmetries in only magnopyramidal cells in layer noreactive layer V cells and neuropil (Figure 9) III of area 45 and found total dendritic length, den- b0340 b0710 (Hayes and Lewis, 1995; Sherwood et al., 2003a). dritic complexity (numbers of branches and maximal p0140 The cytoarchitecture of area 45 is distinguished branch order), and spine densities to be greater in the b0345 from area 44 by the presence of a more prominent right (Hayes and Lewis, 1996). In area 45, AChE- layer IV, a more homogeneous distribution of positive layer III magnopyramidal cells have larger pyramidal cells in the deep portion of layer III, somata in the left hemisphere, despite lacking asym- b0340 and the absence of conspicuous cell columns. metry in their density (Hayes and Lewis, 1995; b0280 Nonphosphorylated neurofilament protein staining Garcia et al., 2004). in area 45ELSEVI is characterized by a clearer separation of While asymmetries of the inferior frontal cortex p0150 immunoreactive neurons into upper (layer III) and are well established in humans, the condition of lower (layer V) populations and by the absence of non-human primates is less clear. Although popula- the intensely stained magnopyramidal clusters, as tion-level leftward asymmetry of the fronto-orbital seen in area 44. sulcus, a portion of the , has b0145 p0145 Considering the preponderance of left hemisphere been reported in great apes (Cantalupo and dominant control of language in humans, several Hopkins, 2001), it remains to be known whether studies have examined the cortex of the inferior humanlike microstructural asymmetries are present NRVS 00022 The Evolution of Neuron Types and Cortical Histology in Apes and Humans 13

in the inferior frontal cortex of these species. In Area 13 is a dysgranular field located in the pos- p0160 humans and chimpanzees, the borders of areas 44 terior (Figure 10). This cortical and 45 have been shown to correspond poorly with area is remarkably integrative, receiving inputs from b0030 external sulcal landmarks (Amunts et al., 1999; olfactory, gustatory, and visceral centers, as well as b0710 Sherwood et al., 2003a). Thus, determination of premotor, somatosensory, auditory, visual, and b0150 whether asymmetries are evident in regional parahippocampal cortices (Carmichael and Price, b0155 volumes and intrinsic circuitry of areas 44 and 45 1995; Cavada et al., 2000). Damage to this region of great apes will require histological studies. disrupts performance on tasks that require beha- vioral inhibition and causes impairments in b0245 b0645 emotional control (Fuster, 1998; Roberts and s0055 4.21.2.7 Prefrontal Cortex Wallis, 2000). In a study of the cytoarchitecture of p0155 While it has been a popular notion that human area 13 across macaques and hominoids, several cognitive abilities are associated with dispropor- similarities were observed that suggest homology b0680 tionate enlargement of the frontal or prefrontal among these species (Semendeferi et al., 1998). cortex, recent data show that the human frontal This cortical area is distinguished by a poorly cortex is no larger than expected for a hominoid defined layer IV, horizontal striations of cells in b0685 of the same brain size (Semendeferi et al., 1997; layers V and VI, large pyramidal cells in layer V, b0695 2002). Furthermore, progressive increase in the relatively thick infragranular layers as compared relative size of the frontal cortex accompanies with supragranular layers, and greater neuropil enlarging brain size for primates in general, with space in supragranularPROOF layers as compared with dee- hominoids simply continuing this scaling trend per layers. Among hominoids, area 13 is located in b0110 (Bush and Allman, 2004a) (see 00061, 00066, the posterior portion of the medial orbital and pos- AU1 00081). At present, the comparative quantitative terior . This concords with the earlier data available concerning the volume of specific description of an area labeled FF in the posterior prefrontal cortical areas in hominoids are scanty, orbitofrontal cortex of chimpanzees that seems to representing only areas 10 and 13 in one indivi- correspond to these cytoarchitectural features b0680 b0690 b0055 dual per species (Semendeferi et al., 1998, 2001). (Bailey et al., 1950). Taken together, however, it does not seem that While general similarities are found in the p0165 these prefrontal areas are disproportionately cytoarchitecture of area 13 of hominoids, quanti- enlarged in human beyond what is expected for tative analyses have identified some interspecific b0380 FIRST a hominoid of the same brain size (Holloway, differences. For example, layer IV in orang-utans 2002). Nonetheless, quantitative cytoarchitectural is relatively wide, making this cortex appear more analyses have shown that some prefrontal cortical similar to granular prefrontal cortex. Compared areas differ in their histological organization to other hominoids, area 13 in humans and bono- among hominoid species. ER bos occupies a small proportion of total brain

I I I I I II II II II II I II III III III III III

III IV IV IV IV IV V V V IV V VI V VI V VI VI ELSEVI VI VI

wm wm wm wm wm wm

Human Bonobo Chimpanzee Gorilla Orang-utan Gibbon b0680 f0050 Figure 10 The cytoarchitecture of area 13 in hominoids. Scale bar¼500mm. Modified from Semendeferi et al. (1998). NRVS 00022

14 The Evolution of Neuron Types and Cortical Histology in Apes and Humans

volume and more cytoarchitectonic subdivisions raise uncertainty regarding whether a homolog of occupy the orbitofrontal cortex adjacent to area area 10 is present in gorillas. In particular, the 13. In contrast, area 13 of orang-utans is rela- cortex of the frontal pole in gorillas has a promi- tively large and thus occupies the majority of the nent layer II and Va, features that are not found orbitofrontal region. in macaques or other hominoids. p0170 Area 10 is a granular cortex that forms a part of the frontal pole in most hominoid species, 4.21.2.8 Anterior Cingulate Cortex s0060 including humans, chimpanzees, bonobos, orang- b0690 utans, and gibbons (Figure 11) (Semendeferi et al., In layer Vb of anterior cingulate cortex (subareas p0175 2001). This cortical area is involved in planning 24a, 24b, and 24c), large spindle-shaped cells are b0245 and decision-making (Fuster, 1998). Area 10 found only in great apes and humans, to the exclu- b0540 receives highly processed sensory afferents from sion of hylobatids and other primates (Nimchinsky corticocortical connections in addition to inputs et al., 1999). These neurons have a very elongate, from the mediodorsal nucleus of the thalamus, gradually tapering, large soma that is symmetrical b0555 striatum, and many limbic structures (O¨ ngu¨r and about its vertical and horizontal axes (Figure 12). Price, 2000). In hominoids, the cytoarchitecture of This distinctive somatic morphology arises from the area 10 is characterized by a distinct layer II, a presence of a large apical dendrite that extends wide layer III with large pyramidal cells in its toward the pial surface, as well as a single large deep portion, a clearly differentiated granular basal dendrite that extends toward the underlying layer IV, large pyramidal cells in layer Va, and a white matter,PROOF without any other dendrites branch- sharp boundary between layer VI and the white ing from the basal aspect of the cell. These unique matter. Quantitative analyses reveal a similar pat- neurons are also substantially larger in size than tern of relative laminar widths among humans, other neighboring pyramidal cells. Interestingly, chimpanzees, and bonobos, such that the supra- spindle neurons increase in soma size, density, and granular layers are relatively thick compared to clustering from orang-utans to gorillas, chimpan- b0690 the infragranular layers (Semendeferi et al., zees, bonobos, and humans. Furthermore, spindle- 2001). In contrast, the infragranular layers com- shaped neurons have been observed in layer Vb of prise a greater proportion of cortical thickness in area 24b in a fetal chimpanzee (E 224), indicating the other hominoids. When GLI profile curves that this specialized projection cell type differenti- b0335 describing laminar variation in neuron volumeFIRSTates early in development (Hayashi et al., 2001). densities are compared among taxa, apes and Notably, neurons with a spindle phenotype also macaques follow a similar pattern with roughly have a phylogenetically restricted distribution equal GLI throughout the cortical depth. The pro- within another region, the frontoinsular cortex. portion of neuropil space in layers II and III Spindle cells are found in layer V in the frontoinsu- relative to infragranular layers, however, is greater lar cortex only in humans and African great apes b0690 in humans. Notably, SemendeferiERet al. (2001) (i.e., gorillas, chimpanzees, and bonobos), being far

I I II II I III II I I III II II IV III III III I IV IV V II IV III V IV V ELSEVI V IV V VI VI VI VI VI V VI

wm wm wm wm wm wm

Human Bonobo Chimpanzee Gorilla Orang-utan Gibbon b0690 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 s0065 Organization in Hominoids

4.21.3.1 The Emergence of Cell Types s0070 and their Distribution

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 (a) (b) that they are indicators of phylogenetic relation- ships (Table 2). For example, in all great apes and f0060 Figure 12 Morphology of spindle-shaped neurons in layer Vb of anterior cingulate cortex in a bonobo (Pan paniscus) (a) and humans, spindle-shaped neurons are found in layer gorilla (Gorilla gorilla) (b). Scale bar¼80mm. Modified from V of anterior cingulate cortex. Also in these taxa, b0540 Nimchinsky et al. (1999). CR-ir pyramidal cells are found in layer V of ante- rior cingulate cortex and primary motor cortex. In just African great apes and humans, layer V spindle- more numerous in humans compared to the apes b0315 shaped neurons are found in frontoinsular cortex. (see 00165; Hakeem et al., 2004). And only in humans, CR-ir pyramidal neurons in p0180 In addition to spindle-shaped neurons, the ante- layer V are foundPROOF in anterior paracingulate cortex. rior cingulate cortex of great apes and humans Thus, novel neuron phenotypes have appeared at contains another unique pyramidal cell phenotype. several different times in hominoid evolution. A survey of the anterior cingulate cortex of several It is tempting to speculate that the evolution of p0195 primate species revealed a small subpopulation of each unique neuron type marks specializations of CR-containing layer V pyramidal neurons that are b0360 the cortical areas involved. In particular, the mor- only found in great apes and humans (Hof et al., phomolecular characteristics of these novel neuron 2001). These neurons are located in the superficial types suggest that there have been modifications of part of layer V in areas 24 and 25. In orang-utans, specific efferent projections to facilitate high levels they comprise 0.5% of all layer V pyramidal cells in of activity or higher conduction velocity for outputs. the anterior cingulate, 2% in gorillas, 4.1% inFIRST chim- The possibility that the great ape and human clade is panzees, and 5.3% in humans. The occurrence of distinguished by such specializations of projection these cells decreases sharply at the boundary cells is especially intriguing in light of recent hypoth- between anterior and posterior cingulate cortex, eses that intelligence among mammals is correlated suggesting that they are not directly involved in the with the rate of information processing capacity as b0655 somatic motor functions associated with the poster- represented by axonal conduction speed (Roth and ior cingulate motor areas. Dicke, 2005). The presence of unique neuron classes p0185 The restricted phylogenetic distributionER of spin- in great apes and humans extends this hypothesis to dle-shaped cells and CR-ir pyramidal neurons in suggest that specific cortical efferents located within layer V of anterior cingulate cortex may reflect spe- behaviorally relevant circuits may be selectively cializations of projection neurons in this region for a modified. It is also significant that a common fea- role in the control of vocalization, facial expression, ture of these novel projection cells is their attention, the expression and interpretation of emo- b0540 localization in layer V. This laminar distribution tions, and autonomic functions (Nimchinsky et al., b0020 b0360 indicates that evolutionary modifications have 1999; Allman et al., 2001; Hof et al., 2001). Of been focused upon descending cortical control over particular interest, in humans, CR-immunoreactive targets in the brainstem and spinal cord. layer V pyramidal neurons are also present in the b0360 anterior paracingulate cortex (area 32) (Hof et al., 4.21.3.2 The Evolution of Cortical Asymmetries 2001). TheELSEVI presence of this distinctive projection s0075 cell type in area 32 of humans is intriguing, consid- A substantial body of evidence shows that the p0200 ering that this cortical area has been found to be human cerebral cortex expresses lateralization in recruited in tasks that require theory of mind the control of language and fine motor actions of b0265 b0770 (Gallagher et al., 2000), which is the capacity to the hand (Toga and Thompson, 2003). Asymmetries attribute mental states such as attention, intention, in histological structure have been demonstrated and beliefs to others and may be a cognitive capacity across cortical areas implicated in these processes b0775 that is exclusive to humans (Tomasello et al., 2003). in humans, including Broca’s area (areas 44 and 45), 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

Homo Pan Pan Gorilla Pongo Hylobates Macaca Cortical area Layer Trait sapiens paniscus troglodytes gorilla pygmaeus sp. sp.

Primary motor cortexa Layer V CR-ir pyramidal þ ? þþþ? neurons Primary motor cortexa Layer V PV-ir pyramidal þþ ? þþ ? þþ ? þ neurons Primary motor cortexa Layers NPNFP-ir þþ ? þþ þþ þþ ? þ III and neurons V Primary visual cortexb Layer Loss of CO- þ ? þ ? þ ? IVA dense band Primary visual cortexb Layer Dense CB-ir þ ? þ ? þ ? IVA neurons and neuropil Primary visual cortexb Layer Meshwork with þ ? ? ? IVA dense NPNFP and Cat-301 staining in mesh bands alternating PROOF with dense CB in interstitial zones Auditory belt cortexc Layers AchE-stained þþ ? þþ ?? ? þ III and pyramidal V cells Anterior cingulate Layer Spindle-shaped þþ þþ þþ þ þ cortexd Vb neurons Anterior cingulate Layer CR-ir pyramidal þþ ? þþ þ þ ? cortexe Vb neurons Anterior paracingulate Layer CR-ir pyramidal þ ? ? cortexe Vb neurons FIRST Frontoinsular cortexf Layer Spindle-shaped þþ þ þ þ Vb neurons

b0725 a(Sherwood et al., 2004a) b0580 b(Preuss and Coleman, 2002) b0310 c(Hackett et al., 2001) b0540 d(Nimchinsky et al., 1999) b0360 e ER (Hof et al., 2001) b0315 f(Hakeem et al., 2004) þ¼present; þþ¼present and abundant in comparison to other species; ¼absent

Wernicke’s area (area Tpt), and the hand represen- delays in conduction can be overcome to some tation of primary motor cortex (area 4). Some extent by increasing axon cross-sectional area and b0160 authors have hypothesized that these anatomical myelination (Changizi, 2001), the design problems asymmetries are exclusive adaptations of the associated with large brains ultimately may necessi- that are encoded genetically and com- tate increased modularity of processing and more of b0435 prise the chief evolutionary novelty in the speciation an emphasis on local network connectivity (Kaas, b0190 b0040 of modernELSEVI humans (Crow, 2000; Annett, 2002). 2000). In particular, as brains grow in size, the p0205 An alternative view is that functional and anato- efficiency of interhemispheric transfer of informa- mical lateralization may be a byproduct of increases tion by long connections diminishes because costs, b0635 b0395 in overall brain size (Ringo et al., 1994; Hopkins in terms of wiring space, dictate that axons cannot and Rilling, 2000). One cost of increasing brain size increase cross-sectional area sufficiently to keep b0005 is that axons must propagate action potentials over pace with demands for processing speed (Aboitiz a greater distance to communicate between the and Montiel, 2003). Hence, it is expected that cor- b0320 hemispheres (Harrison et al., 2002). While these tical processes in large brains, especially those that NRVS 00022 The Evolution of Neuron Types and Cortical Histology in Apes and Humans 17

b0310 depend on rapid computations, will come to rely on hominoids (Hackett et al., 2001) is of functional specialized processing that is dominant in one hemi- importance until we have developed a clearer under- sphere. Indeed, it has been shown that increasing standing of the scaling principles that govern the brain size is accompanied by reduced hemispheric distribution of AChE-enriched neurons in general? b0635 interconnectivity via the corpus callosum (Ringo Hence, whenever possible it is best to evaluate phy- b0550 et al., 1994; Olivares et al., 2001) and the develop- logenetic variation in cortical histology from the ment of more pronounced gross cerebral perspective of allometric scaling. Accordingly, the b0395 asymmetries among anthropoid primates (Hopkins case for declaring that a trait is a phylogenetic spe- and Rilling, 2000). cialization is strengthened when it can be p0210 One consequence of lateralized hemispheric spe- demonstrated that individual species depart from cialization of function may be divergence in the allometric expectations or that an entire clade scales histological organization of homotopic cortical along a different trajectory (i.e., grade shift). areas. Unfortunately, there is a surprising absence It is well established that cortical neuron density p0220 of data from non-humans concerning microstruc- varies among mammalian species. Across a large tural asymmetries in the homologues of Broca’s sample of mammals ranging from mouse to ele- area, Wernicke’s area, and primary motor cortex. phant, there is a negative correlation between b0780 At present, the sole study of such histological asym- cortical neuron density and brain size (Tower, b0185 b0330 b0605 metry indicates that lateralization is not present in 1954; Cragg, 1967; Haug, 1987; Prothero, 1997). area Tpt of chimpanzees or macaques, while asym- Despite this broad trend, however, some evidence metry of neuropil space and minicolumn widths are suggests thatPROOF neuron densities may be higher in b0120 observed in humans (Buxhoeveden et al., 2001a). hominoids (gorilla, chimpanzee, and human) than b0330 Although this is an important finding, it should be expected for their brain size (Haug, 1987). It has kept in mind that there are many other aspects of also been shown that the fraction of the cortex that microstructural organization that have been demon- is comprised by neuropil space versus cell somata strated to be asymmetric in the human cortex, such increases in a negative allometric fashion with b0705 b0780 as distributions of cell volumes and dendritic geo- greater brain size (Shariff, 1953; Tower, 1954; b0085 b0785 b0885 metry, which have yet to be investigated in other Bok, 1959; Tower and Young, 1973; Zilles et al., b0045 b0330 species. Thus, at the present time, there are still 1982; Armstrong et al., 1986; Haug, 1987). These insufficient data to adequately resolve whether empirical findings fit with a model predicting that a many of the observed microstructural asymmetriesFIRSTconstant average percent interconnectedness among of the human cerebral cortex are unique species- neurons cannot feasibly be maintained in the face of specific adaptations that are related to language increasing gray matter volume, so the reach of pro- and handedness. cessing networks cannot keep pace with brain size b0160 variation (Changizi, 2001). 4.21.3.3 How much Variation in Cortical s0080 Many of these theories concerning the scaling of p0225 Architecture can be Attributed to Scaling network connectedness across brain size, however, versus Specialization? ER were developed to explain variation in mouse to p0215 Interpretation of interspecific differences in the his- elephant comparisons. Are these predicted allo- tological structure of the cortex in hominoids metric relationships between neuron density, requires parsing the source of this variation. neuropil space, and brain size maintained when Certainly a portion of it can be attributed to specific comparisons are restricted to the hominoids? AU2 alterations of circuitry that generate behavioral dif- Table 3 shows the results of stereologic estimates ferences among species. Another cause, however, of neuron density and GLI from recent compara- may be the effects of allometric scaling. That is, as tive studies of areas 4, 10, and 13 in hominoids. overall brain size changes, predictable changes In each of these cortical areas, there is not a occur in cell sizes, cell packing density, dendritic correlation between neuron densities or GLI and geometries, and other aspects of microstructure brain size. Therefore, the mammal-wide relation- b0430 b0755 (Jerison,ELSEVI 1973; Striedter, 2005). Thus, with varia- ship between these parameters and brain size may tion in brain size among hominoids, some of the not explain interspecific variance in interconnect- observed interspecific differences may simply be edness within cortical areas of hominoids. This the result of scaling to maintain functional equiva- raises the interesting possibility that differences lence and may not indicate any significant among hominoid species in these variables might differences in computational capacities. For exam- instead correspond to functionally significant ple, how can we know whether greater densities of modifications in the organization of cortical AChE-stained neurons in the auditory belt of interconnections. 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 10b Area 13c

Species GLI Neuron density GLI Neuron density GLI Neuron density

Homo sapiens 11.65 18,048 15.17 34,014 14.18 30,351 Pan troglodytes 13.19 22,177 17.52 60,468 18.63 50,686 Pan paniscus – – 18.17 55,690 16.98 44,111 Gorilla gorilla 8.76 24,733 15.87 47,300 14.62 54,783 Pongo pygmaeus 10.61 18,825 20.10 78,182 18.55 42,400 Hylobates lar – – 19.80 86,190 13.33 53,830 Macaca sp. 15.58 50,798 20.34 – 18.36 – Papio anubis 14.85 33,661 – – – –

In all studies, neuron densities were estimated by the optical dissector method. b0715 b0730 a(Sherwood et al., 2003b; Sherwood et al., 2004b) b0690 b(Semendeferi et al., 2001) b0680 c(Semendeferi et al., 1998)

p0230 Other aspects of network scaling in the cerebral ir neurons scalePROOF against total neuron density with cortex are less well understood. For example, there positive allometry in areas V1 and V2, resulting in a does not appear to be a correlation between brain smaller percentage of CB-ir interneurons in apes b0785 b0735 size and the density of glial cells (Tower and Young, compared to monkeys in these areas (Sherwood b0330 1973; Haug, 1987). However, phylogenetic differ- et al., 2005). Further studies using allometric ences in glial cell densities have not yet been approaches to examine the scaling of different neu- systematically examined using modern immunohis- ron subtypes will be necessary to elucidate tochemical markers to identify astrocytes and phylogenetic specializations of cortical circuitry. oligodendrocytes separately. Furthermore, ques- tions regarding the scaling of subpopulations of interneurons and pyramidal cells have only begun 4.21.3.4 Genomic Data Provide Insights s0085 FIRSTinto Cortical Specializations to be addressed. Evidence suggests that the propor- tion of pyramidal neurons that are enriched in Recent studies of phylogenetic variation in gene p0240 NPNFP may increase with brain size. In the orofa- sequences and expression provide additional cial representation of primary motor cortex, there is insights into cortical specializations among homi- a striking increase in the percentage of neurons noids. While most of these studies have been stained for NPNFP in larger-brained great apes directed at determining the genetic basis for human b0215 b0220 and humans in comparison to smaller-brainedER Old neural uniqueness (Enard et al., 2002a; 2002b; b0725 b0790 b0130 b0210 b0795 World monkeys (Sherwood et al., 2004a). Tsang Caceres et al., 2003; Dorus et al., 2004; Uddin and colleagues (2000) also found increasing et al., 2004), some molecular data point to changes NPNFP labeling in primary motor cortex across a that occurred at earlier times in the hominoid radia- sample including rats, marmosets, rhesus macaques, tion. For instance, all hominoids have evolved a b0140 and humans. In addition, Campbell and Morrison novel biochemical mechanism to support high levels (1989) found a larger proportion of NPNFP-ir pyr- of glutamate flux in neurotransmission through the b0105 amidal neurons, particularly in supragranular retroposition of the gene GLUD1 (Burki and layers, in humans compared to macaque monkeys Kaessmann, 2004). This duplicated gene, GLUD2, across several different cortical areas. which is unique to hominoids, encodes an isotype of p0235 Interneuron subtypes, as revealed by labeling for the enzyme glutamate dehydrogenase that is calcium-bindingELSEVI proteins, appear to adhere to differ- expressed in astrocytes. All hominoid GLUD2 ent scaling trends in anthropoid primates depending sequences contain two key amino acid substitutions on the cortical area. For example, when regressed on that allow the GLUD2 enzyme to be activated in total neuron density, the density of PV-ir neurons astrocytes during conditions of high glutamatergic scales with negative allometry in the primary motor neurotransmitter flux. Concordant with this evi- cortex and thus a greater proportion of PV-ir neurons dence for alterations in the molecular machinery is observed in hominoids compared to Old World necessary for enhanced neuronal activity in apes, it b0725 monkeys (Sherwood et al., 2004a). In contrast, CB- has been shown that the gene encoding the NRVS 00022 The Evolution of Neuron Types and Cortical Histology in Apes and Humans 19

cytochrome c oxidase subunit 4-1 underwent rapid is any hope of understanding how such molecular nonsynonymous evolution in the hominoid stem, differences translate into modifications of the com- followed by purifying selection in descendent putational capacities of cortical circuits. b0855 lineages (Wildman et al., 2002). Because these nucleotide substitutions have functional conse- 4.21.3.5 On the Horizon s0090 quences for the manner and rate at which electrons There remains an extraordinary amount to learn p0260 are transferred from cytochrome c to oxygen, it is regarding the microstructure of the cerebral cortex likely that these modifications were selected to serve of hominoids. Even the basic cytoarchitecture of the needs of cells with high aerobic energy demands, many cortical areas, such as the posterior parietal such as neurons. cortex, inferior temporal cortex, posterior cingulate p0245 Also of significance, an alternative splice variant of cortex, and , has not yet been neuropsin (type II) has originated in recent hominoid b0485 explored using the methods of modern quantitative evolution (Li et al., 2004). Neuropsin is expressed in neuroanatomy. Moreover, there is not a single hippocampal pyramidal neurons and is involved in recent study of parcellation for any part of the cere- neuronal plasticity. The high incidence of poly- bral cortex using chemoarchitectural staining morphisms in the coding region of this protein in techniques in apes. It will also be important to gibbons and orang-utans, however, suggests that it examine the scaling patterns that govern the distri- may not be functional in these species. In contrast, bution of neurochemically identified subsets of the coding region of the type II splice form of neu- pyramidal neurons, interneurons, and glia across ropsin shows relatively little variation in gorillas, different corticalPROOF areas from a broad phylogenetic chimpanzees, and humans, signifying that it is main- perspective in order to clearly distinguish network tained by functional constraint and that it might be allometric scaling from phylogenetic specialization. involved in a molecular pathway important for learn- Finally, determination of whether humanlike histo- ing and memory in these hominoids. logical asymmetries of cortical areas important in p0250 With respect to brain size, several genes that are language and control of the hand are present in involved in controlling the development of cerebral other apes still requires systematic study. By taking cortex size have undergone accelerated rates of seriously the task of understanding such species- sequence evolution in the hominoid lineage. The specific neural adaptations, we stand to learn an microcephalin gene shows an upsurge of nonsynon- extraordinary amount about the underlying sub- ymous amino acid substitutions in a protein-codingFIRSTstrates of the cognitive abilities of humans and our domain of the last common ancestor of great apes b0840 closest relatives. and humans (Wang and Su, 2004). Additionally, the ASPM gene shows evidence of adaptive sequence evolution in all African hominoids (i.e., gorillas, b0450 Acknowledgements chimpanzees, bonobos, and humans) (Kouprina et al., 2004). This work was supported by the National Science p0265 Foundation (BCS-0515484 and BCS-0549117), the p0255 These data put into phylogeneticER context evidence that, in the lineage leading to humans, several genes Wenner-Gren Foundation for Anthropological important in the development, physiology, and Research, and the James S. McDonnell Foundation function of the cerebral cortex show positive selec- (22002078). The great ape brain materials were b0220 b0210 b0225 tion (Enard et al., 2002b; Dorus et al., 2004; Evans available from the Great Ape Aging Project, et al., 2004). Furthermore, findings from studies Cleveland Metroparks Zoo, and the Foundation that have compared human and chimpanzee tran- for Comparative and Conservation Biology. scriptomes indicate that the human cerebral cortex is distinguished by elevated expression levels of Further Reading many genes associated with energy metabolism b0130 b0795 (Caceres et al., 2003; Uddin et al., 2004), suggesting Bailey, P., von Bonin, G., and McCulloch, W. S. 1950. The b0890 Isocortex of the Chimpanzee. University of Illinois Press. that levels of neuronal activity might be higher in ELSEVI b0600 Holloway, R. L. 1996. Evolution of the human brain. b0895 humans compared to chimpanzees (Preuss et al., In: Handbook of Human Symbolic Evolution (eds. A. Lock 2004). While the phenotypic correlates of many of and C. R. Peters), pp. 74–114. Oxford University Press. these genetic changes await characterization by Preuss, T. M. 2004. What is it like to be a human? 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