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4.21a0005 The Evolution of Neuron Types and CorticalHistology in Apes and Humans

C C Sherwood, Kent State University,Kent, OH, USAP R Hof, Mount Sinai School of Medicine,New York, NY, USA

ª 2007 Elsevier Inc. All rights reserved.

4.21.1 Introduction 24.21.1.1 Evolutionary History of the Hominoids 24.21.1.2 History of Studies Concerning Hominoid Cortical Histology 3

4.21.2 Comparative Anatomy of the Cerebral Cortex 44.21.2.1 Topology of Cortical Maps 44.21.2.2 Architecture of the Cortex 44.21.2.3 Primary Visual Cortex 54.21.2.4 Auditory Cortex 84.21.2.5 Primary Motor Cortex 104.21.2.6 Inferior Frontal Cortex 124.21.2.7 Prefrontal Cortex 134.21.2.8 Anterior Cingulate Cortex 14

4.21.3 Patterns of Cortical Organization in Hominoids 154.21.3.1 The Emergence of Cell Types and their Distribution 154.21.3.2 The Evolution of Cortical Asymmetries 154.21.3.3 How much Variation in Cortical Architecture can be Attributed to Scaling

versus Specialization? 174.21.3.4 Genomic Data Provide Insights into Cortical Specializations 184.21.3.5 On the Horizon 19

Glossary

g0005 Allometry Many biological traits scale withoverall size in a nonlinear fashion.Such allometric scaling relation-ships can be expressed by thepower function: Y¼bXa. The loga-rithmic transformation of theallometric scaling equation yields:log Y¼log bþa log X. The expo-nent of the power function becomesthe slope of the log-transformedfunction. The slope of this line canthen be interpreted in terms of abiological scaling relationshipbetween the independent anddependent variable. Positive allo-metry refers to a scalingrelationship with an exponent thatis greater than 1, which means thatthe structure in question grows dis-proportionately larger or morenumerous with increases in thesize of the reference variable.Negative allometry refers to a scal-ing relationship with an exponentthat is less than 1, which means that

the structure in question becomesproportionally smaller or lessnumerous with increases in thesize of the reference variable.

g0010Chemoarchitecture The microanatomical organizationof the cerebral cortex revealed bystaining for biochemical substancesusing techniques such as immuno-histochemistry and enzyme orlectin histochemistry.

g0015DysgranularCortex

A type of cortex that has a weaklydefined layer IV because it is vari-able in thickness. At points, layerIV seems to disappear because neu-rons from layers IIIc and Vaintermingle.

g0020Encephalization A relative measure of a species’sbrain size that represents the degreeto which it is larger or smaller thanexpected for a typical animal of itsbody size.

g0025Granular Cortex A type of cortex that has a clearlyidentifiable layer IV.

g0030Grey Level Index(GLI)

The proportion of an area of refer-ence that is occupied by theprojected profiles of all Nissl-stained elements. This value

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provides an estimate of the fractionof tissue that contains neuronalsomata, glial cell nuclei, andendothelial nuclei versus neuropil.GLI values are highly correlatedwith the volume density occupiedby neurons since glial and endothe-lial cell nuclei contribute only avery small proportion of the totalvolume.

g0035 Hominoid A phylogenetic clade that includeslesser apes (gibbons and siamangs),great apes (orang-utans, gorillas,chimpanzees, and bonobos), andhumans.

g0040 InfragranularLayers

Cortical layers that are deep togranular layer IV, i.e., layers Vand VI.

g0045 Minicolumn Morphologically, minicolumnsappear as a single vertical row ofneurons with strong vertical inter-connections among layers, forminga fundamental structural and func-tional unit. The core region of thecolumn contains the majority of theneurons, their apical dendrites, andboth myelinated and unmyelinatedfibers. A cell-poor region, contain-ing dendritic arbors, unmyelinatedaxons, and synapses, surroundseach column.

g0050 Neuropil The unstained portion ofNissl-stained tissue, which is com-prised of dendrites, axons, andsynapses.

g0055 SupragranularLayers

Cortical layers that are superficialto granular layer IV, i.e., layers I, II,and III.

s00054.21.1 Introduction

s00104.21.1.1 Evolutionary History of the Hominoids

p0005Apes and humans are members of the primate super-family Hominoidea (Figure 1). Molecular evidenceindicates that the hominoid lineage split from theOld World monkeys about 25Ma (

b0860

Wildman et al.,2003). The extant representatives of this phylogeneticgroup include two families. The Hylobatidae com-prises gibbons and siamangs, and the Hominidaeincludes great apes (i.e., orang-utans, gorillas, chim-panzees, and bonobos) and humans (

b0300

Groves, 2001).Living hominoids are distinguished by a suite ofshared derived traits that point to the key adaptationsof this clade. These characters include lack of anexternal tail, modifications of the shoulder girdle andwrist for greater mobility, and stabilization of thelower back (

b0075

Begun, 2003). These adaptations allowhominoids to exploit resources in small branches oftrees by developing suspensory postures to distributetheir body weight. This form of locomotion may havebeen particularly important in allowing certain speciesto increase body size. In addition, compared to otherprimates, hominoids have extended periods of growthand development (

b0675

Schultz, 1969), an increased com-plexity of social interactions (

b0570

Potts, 2004), and largerbrains than would be expected for a monkey of thesame body size (

b0630

Rilling and Insel, 1999). Theincreased encephalization and associated life historyelongation of these species suggest that cognitive flex-ibility and learning were important aspects of thehominoid adaptive complex, which allowed them todeal with locating ephemeral resources from fruitingtrees and to negotiate more complicated relationshipsin fission–fusion societies (

b0570

Potts, 2004).

Humans

Bonobos

Chimpanzees

Gorillas

Orang-utans

Gibbons and simiangs

Old World monkeys

New World monkeys

Tarsiers

Lemurs and lorises

7 Ma

14 Ma

18 Ma

25 Ma

40 Ma

58 Ma

63 Ma

6 Ma

3 Ma

f0005 Figure 1 Cladogram showing the phylogenetic relationships of living hominoids and other primates. Estimated divergence dates

are taken fromb0295

Goodman et al. (2005).

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p0010 Although only a small number of hominoid spe-cies persist today, the fossil record reveals a diversearray of successive adaptive radiations of hominoidsin the past. During the Miocene epoch, global cli-mates were warm and humid, supporting denseforests and lush woodlands extending throughoutthe tropics and into northern latitudes. These envir-onmental conditions were favorable for thediversification of arboreal specialists, such as thehominoids. In fact, hominoids were the most abun-dant type of anthropoid primate throughout theMiocene in Africa and Eurasia, occupying a rangeof different ecological niches (

b0075

Begun, 2003). Theearliest apes in the fossil record are characterizedby hominoidlike dental morphology, but monkey-like postcranial anatomy. The best known of theseearly dental apes is the genus Proconsul fromthe Early Miocene (20–18Ma) of East Africa.Proconsul africanus endocasts show a frontal lobemorphology that is similar to modern hominoids inbeing gyrified and lacking the simple V-shaped arc-uate sulcus that is characteristic of most Old Worldmonkeys (

b0610

Radinsky, 1974). Furthermore, Proconsulafricanus had a relatively larger brain than extantmonkeys of comparable body size (

b0830

Walker et al.,1983). Thus, increased encephalization and perhapsa greater degree of frontal lobe gyrification werepresent early in the evolution of the hominoids.

p0015 With the emergence of arid climates in the transi-tion to the Pliocene and the replacement of forestsby mosaic habitats, the arboreal specializations ofhominoids were less successful. The relatively slowreproductive rates of these taxa, moreover, made itdifficult for many to endure habitat loss resultingfrom climate change and human encroachment inrecent times (

b0420

Jablonski et al., 2000). In the contextof these dramatic environmental changes, one line-age adopted a new form of locomotion, uprightbipedal walking, which would give rise to modernhumans. Other hominoids, however, fared less welland today apes are restricted to a small number ofendangered tropical forest species.

s0015 4.21.1.2 History of Studies ConcerningHominoid Cortical Histology

p0020 At the beginning of the twentieth century, neuroa-natomists applied new histological stainingtechniques to reveal the architecture of the cerebralcortex in numerous species, including apes andhumans (

b0135

Campbell, 1905;b0500

Mauss, 1908;b0100

Brodmann, 1909;b0505

Mauss, 1911;b0070

Beck, 1929;b0230

Filimonoff, 1933;b0745

Strasburger, 1937a,b0750

1937b). Inaddition, with the advent of various techniques fortracing neuronal connectivity based on intracellular

pathological changes subsequent to ablation, somestudies also examined cortical projection systems inapes (

b0835

Walker, 1938;b0470

Lassek and Wheatley, 1945;b0460

Kuypers, 1958;b0425

Jackson et al., 1969). After the1950s, however, the amount of research directedtoward understanding variation in the hominoidbrain declined. There are three main reasons forthis. First, the development of molecular biologicaltechniques caused neuroscientists to focus on asmall number of model species under the implicitassumption that many aspects of cortical structureare evolutionarily conserved. These ideas werefurther bolstered by claims of uniformity in thebasic columnar architecture of the cerebral cortex(

b0650

Rockel et al., 1980). Second, findings from the firstsystematic studies of great ape behavior from thefield and laboratory were beginning to be appre-ciated (e.g.,

b0445

Kortlandt, 1962;b0660

Schaller, 1963; e.g.,b0870

Yerkes and Learned, 1925;b0875

Yerkes and Yerkes,1929). These studies contributed to a more sophis-ticated understanding of cognitive and emotionalcomplexity in great apes and suggested that theydeserve special protected status with respect to theethics of invasive neurobiological experimentation.Third, the book Evolution of the Brain andIntelligence (

b0430

Jerison, 1973) had an enormous influ-ence on the direction of later research incomparative neuroanatomy. This book argued forthe predictability of neuroanatomical structure frombrain size and encephalization, suggesting that thesemetrics form the most significant contribution tospecies diversity in brain organization. Combinedwith the ready availability of comparative brainregion volumetric data in primates and other mam-mals from the publications of Heinz Stephan, HeikoFrahm, George Baron, and colleagues (e.g.,

b0740

Stephanet al., 1981), a great deal of research effort has beenexpended in studies of allometric scaling and covar-iance of large regions of the brain (

b0235

Finlay andDarlington, 1995;

b0065

Barton and Harvey, 2000;b0195

deWinter and Oxnard, 2001). In contrast, much lessattention has been paid to the possibility of phylo-genetic variation in cortical histology (

b0575

Preuss,2000). Fortunately, advances in quantitative neu-roanatomy and immunohistochemical stainingtechniques have opened new avenues of research toreveal interspecific diversity in the microstructure ofhominoid cerebral cortex.

p0025The history of studies of hominoid cortical histol-ogy, therefore, has resulted in two eras of research.The early era comprises several qualitative com-parative mapping studies of the cerebral cortexbased on cyto- and myeloarchitecture, with theoccasional comment regarding species differencesin the microstructure of homologous cortical areas

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(b0135

Campbell, 1905;b0500

Mauss, 1908;b0100

Brodmann, 1909;b0505

Mauss, 1911;b0070

Beck, 1929;b0055

Bailey et al., 1950). Laterstudies from this era also contributed quantitativedata concerning the surface area of particular corti-cal areas, as well as cellular sizes and densities in afew non-human hominoid species (

b0510

Mayer, 1912;b0765

Tilney and Riley, 1928;b0810

von Bonin, 1939;b0470

Lassekand Wheatley, 1945;

b0705

Shariff, 1953;b0325

Haug, 1956;b0290

Glezer, 1958;b0080

Blinkov and Glezer, 1968). Thesequantitative data, however, were rarely presentedin the context of a focused examination of variationamong hominoids.

p0030 The modern era is characterized by studies thatuse techniques such as design-based stereology,computerized image analysis, and immunohisto-chemical and histochemical staining to identifysubpopulations of cortical cells. These newapproaches are especially appealing for investiga-tions of phylogenetic variation in cortical histologyin species that are not common to the laboratorybecause several enzymatic, cytoskeletal, and othermacromolecular constituents that are well preservedin postmortem tissue can be used as reliable markersfor subpopulations of distinct neuron types, therebyextending comparative studies of species for whichanatomical tracing, electrophysiological mapping,or other experimental procedures would be eitherunethical or impractical (see 00055). Subsets of pyr-amidal neurons, for example, can be distinguishedimmunohistochemically by staining with an anti-body (e.g., SMI-32) to nonphosphorylated epitopeson the medium- and high-molecular-weight subu-nits of the neurofilament triplet protein. Theseepitopes are particularly enriched in subpopulationsof large neurons of the neocortex that have a specificlaminar and regional distribution. Because nonpho-sphorylated neurofilament protein (NPNFP) isinvolved in the maintenance and stabilization ofthe axonal cytoskeleton, its expression is associatedwith neurons that have thick myelinated axons(

b0365

Hoffman et al., 1987;b0440

Kirkcaldie et al., 2002). Inaddition, the calcium-binding proteins–calbindin D-28k (CB), calretinin (CR), and parvalbumin (PV)–are useful markers for understanding the corticalinterneuron system because each of these moleculesis typically colocalized with GABA in morphologi-cally and physiologically distinct nonoverlappingpopulations (

b0200

DeFelipe, 1997;b0495

Markram et al.,2004).

p0035 While the neuroanatomical structure of onehominoid species in particular has been studiedmost extensively, it is well beyond the scope of thisarticle to provide a comprehensive review of humancortical architecture. Here we focus explicitly oncomparative studies of the histology of hominoid

cerebral cortex, highlighting evidence concerningshared derived traits of hominoids in comparisonto other primates, as well as indicating possiblespecies-specific specializations. Hence, the studiesreviewed in this chapter provide the most directevidence currently available to delimit whichaspects of cortical histology are uniquely human,which are derived for all hominoids, and whichreflect the specializations of each species.

s00204.21.2 Comparative Anatomyof the Cerebral Cortex

s00254.21.2.1 Topology of Cortical Maps

p0040Total brain weight in hominoids ranges fromapproximately 90g in Kloss’s gibbons (Hylobatesklossii) to 1,400g in humans (Homo sapiens)(Table 1). While there is a large range of variationamong hominoids in total brain size, mapping stu-dies of the cortex (Figure 2) generally agree that thelocation of the primary sensory and motor areas aresimilar across species (

b0305

Grunbaum and Sherrington,1903;

b0135

Campbell, 1905;b0500

Mauss, 1908;b0100

Brodmann,1909;

b0505

Mauss, 1911;b0480

Leyton and Sherrington,1917;

b0070

Beck, 1929;b0055

Bailey et al., 1950;b0595

Preuss et al.,1999;

b0310

Hackett et al., 2001;b0110

Bush and Allman,2004a,

b0115

2004b;b0730

Sherwood et al., 2004b). In particu-lar, the primary visual cortex lies within the banksof the calcarine sulcus. Primary auditory cortex islocated on the posterior superior plane of the super-ior temporal gyrus, usually comprising thetransverse gyrus of Heschl in great apes andhumans. Primary somatosensory cortex is foundwithin the posterior bank of the central sulcus andextends on to the postcentral gyrus. Primary motorcortex is located mostly on the anterior bank of thecentral sulcus. One notable difference is the fact thatprimary visual cortex extends to only a very smallportion of the lateral convexity of the occipital lobein humans, whereas a much larger part of the lateraloccipital lobe is comprised of striate cortex in apes(

b0880

Zilles and Rehkamper, 1988;b0385

Holloway et al.,2003). This is because the primary visual cortex inhumans is 121% smaller than expected for a pri-mate of the same brain size (

b0375

Holloway, 1996).Other higher-order areas, particularly within thefrontal cortex, have also been shown to occupysimilar locations across these species (

b0745

Strasburger,1937a,

b0750

1937b;b0680

Semendeferi et al., 1998;b0690

Semendeferi et al., 2001;b0710

Sherwood et al., 2003a).

s00304.21.2.2 Architecture of the Cortex

p0045The general histological architecture of the neocor-tex in hominoids shares many features in common

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with other primates and mammals in general, suchas a fundamental six-layered and columnar organi-zation (

b0525

Mountcastle, 1998). Compared to othermammals of similar brain size, however, the cere-bral cortex of hominoids is reported to have arelatively low density of glial cells and a greatervariety of neuron soma sizes (

b0330

Haug, 1987).Astroglia of the cerebral cortex in great apes, asrevealed by immunohistochemistry for glial fibril-lary acidic protein (GFAP), resemble other primatesin forming long, radially oriented interlaminar pro-cesses spanning supragranular cortical layers(

b0180

Colombo et al., 2004). This configuration may beunique to primates, as GFAP staining in the cortexof other mammals appears distinctly different, com-prising a network of stellate astroglial somata withshort, branching processes (

b0165

Colombo, 1996;b0175

Colombo et al., 2000;b0170

Colombo and Reisin, 2004).p0050 Comparison of mammalian brains indicates that

the surface area of the cortical sheet can vary bymore than five orders of magnitude, while the thick-ness of the cortex varies by less than one order ofmagnitude (

b0010

Allman, 1990). Accordingly, evolution-ary changes in the size of the cerebral cortex haveoccurred primarily in the tangential dimension,while the vertical dimension of the cortex may bemore constrained by the development of columnarunits (

b0615

Rakic, 1988,b0620

1995). Nonetheless, the corticalsheet does tend to display increased thickness inmammals with larger brains (

b0370

Hofman, 1988). Dueto these scaling trends, hominoids have thicker cor-tices than other smaller-brained primates andhomologous cortical areas in humans tend to bethicker than in apes (Figure 3).

p0055 With the relative ease of establishing homologyamong the primary sensory and motor cortical areas

on the basis of cytoarchitecture and topology, sev-eral studies have compared the microstructure ofthese areas among different hominoid species(reviewed below). On the whole, the cytoarchitec-ture of homologous cortical areas shows only subtledifferences across hominoid species. Indeed, anearly quantitative comparative analysis of thecytoarchitecture of primary cortical areas (areas 3,4, 17, and 41/42), found marked similarities amongspecies (orang-utans, gorillas, chimpanzees, andhumans) in terms of the relative thickness of differ-ent layers and the proportion of neuropil in eachlayer (

b0880

Zilles and Rehkamper, 1988). Only minordifferences were noted, such as greater relativethickness of layer III in primary somatosensory cor-tex (area 3) in humans and gorillas, an increase inthe proportion of neuropil in layers V and VI of area3 in orang-utans, and a relatively thicker layer IV ofprimary auditory cortex (area 41/42) in orang-utans. These results were interpreted to corroboratethe qualitative observations of

b0135

Campbell (1905) andBrodmann (1909), indicating that there are not anysubstantial differences between humans and apes inthe cytoarchitecture of these primary cortical areas.The study by

b0880

Zilles and Rehkamper (1988), how-ever, was based on small samples, which did notpermit statistical evaluation of species differences.More recent studies using larger samples, differentstaining techniques, and more refined quantitativemethods have revealed interesting phylogenetic dif-ferences among hominoids in cortical histologicalstructure.

s00354.21.2.3 Primary Visual Cortex

p0060Important modifications of primary visual cortex(Brodmann’s area 17) histology, particularly of the

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.

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thalamic recipient layer IV, have taken place at severalpoints in the evolution of hominoids. Distinct parallelascending fiber systems arising from retinal ganglioncells project to the lateral geniculate nucleus (LGN) ofthe thalamus. The M-type retinal ganglion cells giverise to the magnocellular channel, which is involved in

the analysis of motion and gross spatial properties ofstimuli. The P-type ganglion cells process visual infor-mation with high acuity and color sensitivity, andproject to parvocellular layers of the LGN. In thegeniculostriate component of these parallel pathways,different systems derive from distinct portions of the

(a)

(c) (d)

(b)

f0010 Figure 2 Parcellation maps of the cerebral cortex of apes. Chimpanzee (Pan troglodytes) cortical maps reproduced from

(a)b0135

Campbell (1905) and (b)b0055

Bailey et al. (1950). Orang-utan (Pongo pygmaeus) cortical maps reproduced from (c)b0135

Campbell (1905)

and (d)b0500

Mauss (1908,b0505

1911) compiled inb0880

Zilles and Rekamper (1988).

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LGN and synapse within separate sublayers of layerIV in primary visual cortex. The complexity of segre-gated geniculostriate projects is reflected in thedevelopment of at least three subdivisions of layer IVin primates as demarcated by

b0100

Brodmann (1909). Twocell-rich layers, IVA and IVC, are separated by a cell-poor layer IVB, which contains a dense plexus ofmyelinated axons known as the stria of Gennari.Neurons in the magnocellular layers of the LGN pro-ject to the upper half of layer IVC. Neurons in theparvocellular layers of the LGN project to layer IVA.

p0065 The chemoarchitecture of layer IVA is markedlydifferent in hominoids compared to other primates(Figure 4). In most monkeys, except the nocturnalowl monkey, there is a dense band of cytochromeoxidase (CO)-rich staining in layer IVA (reviewed inb0595

Preuss et al., 1999), reflecting high levels of

metabolic activity within this sublayer. However,in the hominoid species examined to date (orang-utans, chimpanzees, and humans), intense CO stain-ing in layer IVA is absent, suggesting that the directparvocellular-geniculate projection to layer IVAwas either reduced or more dispersed to includeboth layers IVA and IVB in the last common ances-tor of this phylogenetic group (

b0595

Preuss et al., 1999;b0580

Preuss and Coleman, 2002). Primary visual cortexof great apes and humans is further distinguishedfrom monkeys in having increased staining of CB-immunoreactive (-ir) interneurons and neuropil inlayer IVA (

b0580

Preuss and Coleman, 2002).p0070Layer IVA of primary visual cortex in humans

exhibits additional modifications to the basic homi-noid plan described above. In humans, a meshworkpattern is observed in which compartments of neu-ropil that stain intensively for Cat-301 andnonpyramidal NPNFP-ir cells, and neurites alter-nate with bands of high densities of CB-irinterneurons (

b0580

Preuss and Coleman, 2002). Thesechanges in human primary visual cortex have beeninterpreted to reflect a closer association of thislayer to M-pathway inputs than observed in anyother primates. The functional implications ofthese histological changes are unclear; however, ithas been suggested that these alterations are relatedto specializations in humans for the visual percep-tion of rapid orofacial gestures in speech (

b0580

Preuss andColeman, 2002).

p0075Another distinctive feature of primary visual cor-tex organization in many primates is oculardominance columns, which correspond to the hor-izontal segregation of inputs from the two retinae to

Chimpanzee HumanLong-tailed macaque

wmwm wm

III

III

VVI

IV

I

III

V

VI

IV

I

III

V

VI

IV

II

II

wmwm wm

III

III

VVI

IV

I

III

V

VI

IV

I

III

V

VI

IV

II

II

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.

f0020 Figure 4 Comparative chemoarchitecture of layer IV in pri-

mary visual cortex of squirrel monkeys (Saimiri ), macaques

(Macaca), chimpanzees (Pan), and humans (Homo).

Reproduced fromb0580

Preuss and Coleman (2002).

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different compartments in layer IV of primary visualcortex. Ocular dominance columns have been ana-tomically demonstrated in Old World monkeys,humans, and some other primates, such as theNew World spider monkey and the strepsirrhinegalago (reviewed in

b0015

Allman and McGuinness,1988). A similar pattern of alternating patches ofocular representation within primary visual cortexhas been described in a chimpanzee after monocularinjection of a transneuronal tritiated tracer sub-stance (

b0760

Tigges and Tigges, 1979). It is worthnoting, however, that this study revealed geniculateprojections to layer IVC, but not to layer IVA, as isobserved in monkeys.

p0080 Large pyramidal neurons, which are found at theboundary between layers V and VI, called Meynertcells, are prominent in the primary visual cortex ofprimates, and their soma size displays interspecificvariation (Figure 5) (

b0720

Sherwood et al., 2003c). Thesecells can be distinguished as a unique subtype on thebasis of their morphology and connectivity. Theirthick axon collaterals project to both area MT/V5and the superior colliculus, suggesting that thesecells are involved in processing visual motion (

b0240

Frieset al., 1985;

b0530

Movshon and Newsome, 1996;b0490

Livingstone, 1998). In a comparative study,Meynert cell somata were found to be on average2.8 times lager than other layer V pyramidal neu-rons across a range of primates (

b0720

Sherwood et al.,2003c). Because the basal dendrites and axon col-laterals of Meynert cells extend horizontally inlayers V and VI to integrate information and facil-itate responses across widespread areas of visualspace, interspecific variation in Meynert cell sizeappears to be largely constrained by their functionin the repetitive stereotyped local circuits that repre-sent the retinal sheet in primary visual cortex. In the

context of the general scaling patterns of Meynertcells, it is interesting that soma volumes of theseneurons fit closely with predictions among humans(2.84 times larger than neighboring pyramidal cells)and gorillas (2.98 times), whereas they are relativelylarge in chimpanzees (3.78 times) and relativelysmall in orang-utans (1.94 times). These differencesin neural organization for the processing of visualmotion may relate to socioecological differencesamong these apes. Because wild chimpanzeesengage in aggressive incursions into the territory ofneighboring groups (

b0845

Watts and Mitani, 2001) andhunt highly mobile prey such as red colobus mon-keys (

b0850

Watts and Mitani, 2002), we speculate thatrelatively large Meynert cells evolved in this speciesto enhance detection of visual motion during bound-ary patrolling and hunting. In contrast, relativelysmall Meynert cells in orang-utans may relate tothe fact that these apes are solitary, large-bodied,committed frugivores (

b0805

van Schaik and van Hooff,1996), which allows them to maintain low levels ofvigilance for motions of predators, competitors, andfood items.

s00404.21.2.4 Auditory Cortex

p0085There are two parallel thalamocortical projectionsfrom the medial geniculate nucleus (MGN) to thesuperior temporal cortex of primates. Neurons inthe ventral division of the MGN supply a tonotopicprojection to the core region of auditory cortex(Brodmann’s areas 41 and 42). Neurons in the dor-sal and medial divisions of the MGN project toareas surrounding the core. The core region of audi-tory cortex has been identified in macaques,chimpanzees, and humans as a discrete architecturalzone as compared to the surrounding belt cortex(

b0310

Hackett et al., 2001). The core can be recognizedby a broad layer IV that receives a dense thalamicprojection, heavy myelination, and intense expres-sion of acetylcholinesterase (AChE), CO, and PV inthe neuropil of layer IV. In macaques, the relativelyhigh density of cells and fibers makes the auditorycortex core appear structurally homogeneous ascompared to the hominoids. In contrast, the medialand lateral domains of the core region of auditorycortex are more clearly differentiated in humans andchimpanzees because of the lower packing densityof structural elements. Additionally, the network ofsmall horizontal and tangential myelinated fibers inlayer III appears most complex in humans, inter-mediate in chimpanzees, and least elaborate inmacaques.

p0090The auditory core region is enveloped by severalhigher-order belt and parabelt fields (Figure 6). The

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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.

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

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belt areas of auditory cortex, which are less precisein their tonotopic organization, receive major inputsfrom the core and diffuse input from the dorsaldivision of the MGN. The belt region is borderedlaterally on the superior temporal gyrus by a para-belt region of two or more divisions that areactivated by afferents from the belt areas and thedorsal MGN, but not the ventral MGN or the core.Interestingly, AChE-stained pyramidal cells in layerIII and V of the belt region are more numerous inchimpanzees and humans compared to macaques(

b0310

Hackett et al., 2001). Neurons in the belt and para-belt project to auditory-related fields in thetemporal, parietal, and frontal cortex. Other typesof processing that occur in the other divisions of

auditory cortex are not well understood, but theyare likely to be important for higher-order proces-sing of natural sounds, including those used incommunication. Neurons in the lateral belt cortexareas of rhesus macaques, for example, respond betterto species-specific vocalizations than to energy-matched pure tone stimuli (

b0625

Rauschecker et al., 1995).p0095The comparative anatomy of one particular

region of auditory association cortex has been stu-died most extensively. In humans, Wernicke’s area,a region important for the comprehension of lan-guage and speech, is located in the posteriorsuperior temporal cortex. Gross anatomic observa-tions indicate that asymmetries similar to humansare present in the superior temporal lobe of non-human primates, such as leftward dominance of theplanum temporale in great apes (

b0275

Gannon et al.,1998;

b0400

Hopkins et al., 1998) and a longer left sylvianfissure in many anthropoid species (

b0475

LeMay andGeschwind, 1975;

b0865

Yeni-Komshian and Benson,1976;

b0350

Heilbroner and Holloway, 1988;b0405

Hopkinset al., 2000).

p0100Several investigations have examined the micro-structure of the cortical area most closely associatedwith Wernicke’s area. Area Tpt (

b0260

Galaburda et al.,1978) or area TA1 (

b0825

von Economo and Koskinas,1925) comprises a portion of posteriorBrodmann’s area 22 located on the upper bank ofthe superior temporal gyrus and sometimes extend-ing to part of the parietal operculum and theconvexities of the temporal and parietal lobes(

b0260

Galaburda et al., 1978). This area represents atransition between auditory association cortex andcortex of the inferior parietal lobule (

b0700

Shapleskeet al., 1999). Cortex with the cytoarchitectural char-acteristics of area Tpt has been described in galagos,macaques, chimpanzees, and humans (

b0255

Galaburdaand Pandya, 1982;

b0585

Preuss and Goldman-Rakic,1991;

b0120

Buxhoeveden et al., 2001a,b0125

2001b). Themicrostructure of area Tpt in these primates is dis-tinguished by a eulaminate appearance, with apoorly defined border of layer IV due to theencroachment of pyramidal cells in adjacent layersIIIc and Va, and an indistinct border between layersIV and V due to curvilinear columns of neurons thatbridge the two layers (

b0250

Galaburda and Sanides,1980).

p0105There are differences among rhesus monkeys,chimpanzees, and humans in the details of minicol-umn structure in area Tpt. In the left hemisphere,area Tpt of humans has wider minicolumns as com-pared to macaques or chimpanzees, whereas thewidth of minicolumns is similar in the non-humanspecies (

b0125

Buxhoeveden et al., 2001b). These findingssuggest that wider minicolumns in human area Tpt

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f0030 Figure 6 Cytoarchitecture of auditory cortex of an orang-utan

(Pongo pygmaeus). A parasagittal section of the superior tem-

poral 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.

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The Evolution of Neuron Types and Cortical Histology in Apes and Humans 9

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may be a species-specific specialization that allowsfor more extensive neuropil space containing inter-connections among neurons.

p0110 The microstructure of area Tpt has also beenshown to be asymmetric in humans, possibly as aneural substrate of hemispheric dominance in thecerebral representation of language. Long-rangeintrinsic connections within area Tpt labeled inpostmortem brains with lipophilic dyes haverevealed greater spacing between interconnectedpatches in the left hemisphere compared to theright (

b0270

Galuske et al., 2000). Furthermore, leftarea Tpt has a greater number of the largest pyr-amidal cells in layer III, known asmagnopyramidal cells, that give rise to long corti-cocortical association projections (

b0410

Hutsler, 2003).In addition, AChE-rich pyramidal cells displaygreater cell soma volumes in the left hemispheredespite lacking asymmetry in number (

b0415

Hutsler andGazzaniga, 1996). In humans, left area Tpt hasalso been shown to contain a greater amount ofneuropil and axons with thicker myelin sheaths(

b0035

Anderson et al., 1999). Of particular significance,a comparative analysis of area Tpt found thatonly humans, but not rhesus macaques or chim-panzees, exhibit left dominant asymmetry in areaTpt, with wider minicolumns and a greater pro-portion of neuropil (

b0120

Buxhoeveden et al., 2001a).

s0045 4.21.2.5 Primary Motor Cortex

p0115 The primary motor cortex (Brodmann’s area 4) hasa distinctive cytoarchitectural appearance in pri-mates (

b0285

Geyer et al., 2000;b0730

Sherwood et al., 2004b),containing giant Betz cells in the lower portion oflayer V, low cell density, large cellular sizes, anindistinct layer IV, and a diffuse border betweenlayer VI and the subjacent white matter(Figure 7a). In humans, the region of primarymotor cortex that corresponds to the representationof the hand exhibits interhemispheric asymmetry inits cytoarchitectural organization. Concomitantwith strong population-wide right handedness inhumans, most postmortem brains display a greaterproportion of neuropil volume in the left hemi-sphere of this part of primary motor cortex(

b0025

Amunts et al., 1996). Interestingly, brains of cap-tive chimpanzees (

b0390

Hopkins and Cantalupo, 2004)and capuchin monkeys (

b0565

Phillips and Sherwood,2005) show humanlike asymmetries of the handregion of the central sulcus that are correlated withthe direction of individual hand preference.However, the histology of primary motor cortex innon-human primates has not yet been examined forasymmetry (see 00021).

p0120While the cytoarchitectural organization of pri-mary motor cortex is generally similar acrossspecies, interspecific differences have beendescribed. The cytoarchitecture of the region corre-sponding to orofacial representation of primarymotor cortex in several catarrhine species (long-tailed macaques, anubis baboon, orang-utans, gor-illas, chimpanzees, and humans) was analyzed usingthe Grey Level Index (GLI) method (

b0730

Sherwoodet al., 2004b). Compared to Old World monkeys,great apes and humans displayed an increased rela-tive thickness of layer III and a greater proportion ofneuropil space. A stereologic investigation ofNPNFP and calcium-binding protein-ir neuronswas also conducted in this same comparative sample(

b0725

Sherwood et al., 2004a). Primary motor cortex ingreat apes and humans was characterized by agreater percentage of neurons enriched in NPNFPand PV compared to the Old World monkeys(Figure 8). Conversely, the percentage of CB- andCR-ir neuron subtypes did not significantly differamong these species. These modifications of parti-cular subsets of neuron types might contribute to thevoluntary dexterous control of orofacial musclesexhibited in the vocal and gestural communicationof great apes and humans. Enhancement of PV-irinterneuron-mediated lateral inhibition of cell col-umns may enhance specificity in the recruitment of

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f0035Figure 7 Cytoarchitecture of primary motor cortex and mor-

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 coun-

terstain is shown (b). Scale bar (a)¼250mm. Scale bar

(b)¼50mm.

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

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different muscle groups for dynamic modulation offine orofacial movements (Scheiber, 2001).Increased proportions of NPNFP-ir pyramidalcells, on the other hand, may be a correlate ofgreater descending cortical innervation of brainstemcranial motor nuclei by heavily myelinated axons toallow for more voluntary control (

b0460

Kuypers, 1958).p0125 The giant Betz cells are found in the lower half of

layer V of primary motor cortex and possess a largenumber of primary dendritic shafts that leave thesoma at several locations around its surface(Figure 7b) (

b0095

Braak and Braak, 1976;b0670

Scheibel andScheibel, 1978;

b0515

Meyer, 1987). They are largest andmost numerous in the cortical representation of theleg, where axons project farther along the corticosp-inal tract to reach large masses of muscles (

b0465

Lassek,1948;

b0640

Rivara et al., 2003). Betz cells are stronglyimmunoreactive for NPNFP among humans, greatapes, and Old World monkeys (

b0725

Sherwood et al.,2004a). An analysis of scaling of Betz cell somatavolumes in the region of hand representation ofprimates revealed that these cell subtypes becomerelatively enlarged with increases in brain and bodysize (

b0720

Sherwood et al., 2003c). At larger sizes, there isan increase in the distance to the spinal representa-tion of target muscles and a greater number of lessdensely distributed corticospinal neurons (

b0545

Nudoet al., 1995). In larger brains and bodies, Betz cellaxons need to become thicker to maintain conduc-tion speed to reach more distant targets in the spinalcord. Accordingly, Betz cells are scaled to globalconnectivity constraints and therefore increase insomatic volume in a manner that is correlated withbrain size. Due to these scaling trends, among homi-noids Betz cells are relatively largest in humans(10.96 times larger than neighboring pyramidalcell), then gorillas (8.37 times), chimpanzees (7.02times), and orang-utans (6.51 times).

p0130Specializations of biochemical phenotypes areknown for certain regionally restricted subsets ofpyramidal neurons. Although calcium-binding pro-teins are expressed transiently during prenatal andearly postnatal development (

b0520

Moon et al., 2002;b0800

Ulfig, 2002), their expression in pyramidal neuronsof adult mammals is more limited. Neurons expres-sing the calcium-binding proteins – CB, CR, and PV –are thought to have relatively high metabolic ratesassociated with fast repolarization for multipleaction potentials (

b0060

Baimbridge et al., 1992). Whilesuch calcium buffering mechanisms are most com-monly associated with GABAergic interneurons,the presence of calcium-binding proteins in pyra-midal cells might reflect a neurochemicalspecialization for higher rates of activity. In thiscontext, it is interesting that faint CR immunoreac-tivity is observed in isolated medium- and large-sizelayer V pyramidal neurons in primary motor cortexof great apes and humans, but not in macaques orbaboons (

b0355

Hof et al., 1999;b0725

Sherwood et al.,2004a). PV-ir pyramidal neurons are also veryrarely observed in the neocortex of mammals (see00055). However, large layer V pyramidal neu-rons, including Betz cells, have been reported toexpress PV immunoreactivity in primary motorcortex of humans (

b0535

Nimchinsky et al., 1997;b0725

Sherwood et al., 2004a). Evidence concerning theexistence of PV-ir pyramidal neurons in other non-human primates is somewhat contradictory. In onestudy, PV-ir pyramidal neurons were observed inprimary motor and somatosensory cortices of gala-gos and macaques (

b0590

Preuss and Kaas, 1996).Another study, however, failed to label PV-ir pyr-amidal cells in macaques (

b0205

DeFelipe et al., 1989),probably due to methodological discrepanciesamong experiments. A comparative study of pri-mary motor cortex using the same

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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.

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The Evolution of Neuron Types and Cortical Histology in Apes and Humans 11

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immunohistochemical procedures across speciesfound that PV-ir pyramidal neurons were eithernot present or sparse in Old World monkeys,whereas they were considerably more numerousin great apes and humans (

b0725

Sherwood et al., 2004a).

s0050 4.21.2.6 Inferior Frontal Cortex

p0135 The microstructure of the inferior frontal cortex, theregion that contains Broca’s area in humans, hasbeen described in hominoids on the basis on cyto-,myelo-, and NPNFP-architecture (

b0820

von Economo,1929;

b0050

Bailey and von Bonin, 1951;b0090

Braak, 1980;b0030

Amunts et al., 1999;b0340

Hayes and Lewis, 1995;b0710

Sherwood et al., 2003a). Cytoarchitectural studiesof chimpanzee and orang-utan frontal cortexdescribe a dysgranular region anterior to the inferiorprecentral sulcus comprising a part of pars opercu-laris and designated Brodmann’s area 44 (

b0815

vonBonin, 1949;

b0710

Sherwood et al., 2003a), FCBm(

b0055

Bailey et al., 1950), or areas 56 and 57 (b0455

Kreht,1936). In chimpanzees, this region has been shownto receive projections from the mediodorsal nucleusof the thalamus (

b0835

Walker, 1938). In macaques, a fieldwith similar cytoarchitectural characteristics in thecaudal bank of the inferior limb of the arcuate sul-cus has been denoted area 44, with area 45 locatedrostrally (

b0255

Galaburda and Pandya, 1982;b0560

Petridesand Pandya, 1994). The cytoarchitecture of area44 is characterized by a columnar organization simi-lar to ventral premotor area 6, but it is distinguishedby the development of a thin layer IV and clusteredmagnopyramidal neurons in the deep part of layerIII. Layer IV in area 44 has an undulating appear-ance due to the invasion of pyramidal cells fromlayer III and layer V. Nonphosphorylated neurofila-ment protein staining in area 44 of chimpanzees andhumans displays clusters of large pyramidal neuronsat the bottom of layer III and a lower band of immu-noreactive layer V cells and neuropil (Figure 9)(

b0340

Hayes and Lewis, 1995;b0710

Sherwood et al., 2003a).p0140 The cytoarchitecture of area 45 is distinguished

from area 44 by the presence of a more prominentlayer IV, a more homogeneous distribution ofpyramidal cells in the deep portion of layer III,and the absence of conspicuous cell columns.Nonphosphorylated neurofilament protein stainingin area 45 is characterized by a clearer separation ofimmunoreactive neurons into upper (layer III) andlower (layer V) populations and by the absence ofthe intensely stained magnopyramidal clusters, asseen in area 44.

p0145 Considering the preponderance of left hemispheredominant control of language in humans, severalstudies have examined the cortex of the inferior

frontal gyrus in humans for microstructural asymme-tries. Using GLI profile analysis methods to quantifyregional variation in cytoarchitecture, area 44 hasbeen shown to display left dominance in terms ofvolume and an increased proportion of neuropilspace, whereas area 45 does not show a consistentdirection of asymmetry (

b0030

Amunts et al., 1999). Inaddition, the total length of pyramidal cell dendritesis longer in the left opercular region of the inferiorfrontal gyrus due to a selective increase in the lengthof higher-order segments (

b0665

Scheibel et al., 1985).Using different methods, another study examinedasymmetries in only magnopyramidal cells in layerIII of area 45 and found total dendritic length, den-dritic complexity (numbers of branches and maximalbranch order), and spine densities to be greater in theright (

b0345

Hayes and Lewis, 1996). In area 45, AChE-positive layer III magnopyramidal cells have largersomata in the left hemisphere, despite lacking asym-metry in their density (

b0340

Hayes and Lewis, 1995;b0280

Garcia et al., 2004).p0150While asymmetries of the inferior frontal cortex

are well established in humans, the condition ofnon-human primates is less clear. Although popula-tion-level leftward asymmetry of the fronto-orbitalsulcus, a portion of the inferior frontal gyrus, hasbeen reported in great apes (

b0145

Cantalupo andHopkins, 2001), it remains to be known whetherhumanlike microstructural asymmetries are present

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f0045Figure 9 The architecture of areas 44 and 45 in a chimpanzee

(Pan troglodytes). Area 44 is shown stained for Nissl substance

(a) and NPNFP (b). Area 45 is shown stained for Nissl sub-

stance (c) and NPNFP (d). Scale bar¼500mm.

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

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in the inferior frontal cortex of these species. Inhumans and chimpanzees, the borders of areas 44and 45 have been shown to correspond poorly withexternal sulcal landmarks (

b0030

Amunts et al., 1999;b0710

Sherwood et al., 2003a). Thus, determination ofwhether asymmetries are evident in regionalvolumes and intrinsic circuitry of areas 44 and 45of great apes will require histological studies.

s0055 4.21.2.7 Prefrontal Cortex

p0155 While it has been a popular notion that humancognitive abilities are associated with dispropor-tionate enlargement of the frontal or prefrontalcortex, recent data show that the human frontalcortex is no larger than expected for a hominoidof the same brain size (

b0685

Semendeferi et al., 1997;b0695

2002). Furthermore, progressive increase in therelative size of the frontal cortex accompaniesenlarging brain size for primates in general, withhominoids simply continuing this scaling trend(

b0110

Bush and Allman, 2004a) (see 00061, 00066,00081)AU1 . At present, the comparative quantitativedata available concerning the volume of specificprefrontal cortical areas in hominoids are scanty,representing only areas 10 and 13 in one indivi-dual per species (

b0680

Semendeferi et al., 1998,b0690

2001).Taken together, however, it does not seem thatthese prefrontal areas are disproportionatelyenlarged in human beyond what is expected fora hominoid of the same brain size (

b0380

Holloway,2002). Nonetheless, quantitative cytoarchitecturalanalyses have shown that some prefrontal corticalareas differ in their histological organizationamong hominoid species.

p0160Area 13 is a dysgranular field located in the pos-terior orbitofrontal cortex (Figure 10). This corticalarea is remarkably integrative, receiving inputs fromolfactory, gustatory, and visceral centers, as well aspremotor, somatosensory, auditory, visual, andparahippocampal cortices (

b0150

Carmichael and Price,1995;

b0155

Cavada et al., 2000). Damage to this regiondisrupts performance on tasks that require beha-vioral inhibition and causes impairments inemotional control (

b0245

Fuster, 1998;b0645

Roberts andWallis, 2000). In a study of the cytoarchitecture ofarea 13 across macaques and hominoids, severalsimilarities were observed that suggest homologyamong these species (

b0680

Semendeferi et al., 1998).This cortical area is distinguished by a poorlydefined layer IV, horizontal striations of cells inlayers V and VI, large pyramidal cells in layer V,relatively thick infragranular layers as comparedwith supragranular layers, and greater neuropilspace in supragranular layers as compared with dee-per layers. Among hominoids, area 13 is located inthe posterior portion of the medial orbital and pos-terior orbital gyri. This concords with the earlierdescription of an area labeled FF in the posteriororbitofrontal cortex of chimpanzees that seems tocorrespond to these cytoarchitectural features(

b0055

Bailey et al., 1950).p0165While general similarities are found in the

cytoarchitecture of area 13 of hominoids, quanti-tative analyses have identified some interspecificdifferences. For example, layer IV in orang-utansis relatively wide, making this cortex appear moresimilar to granular prefrontal cortex. Comparedto other hominoids, area 13 in humans and bono-bos occupies a small proportion of total brain

Orang-utanBonobo Chimpanzee GorillaHuman Gibbon

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f0050 Figure 10 The cytoarchitecture of area 13 in hominoids. Scale bar¼500mm. Modified fromb0680

Semendeferi et al. (1998).

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The Evolution of Neuron Types and Cortical Histology in Apes and Humans 13

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volume and more cytoarchitectonic subdivisionsoccupy the orbitofrontal cortex adjacent to area13. In contrast, area 13 of orang-utans is rela-tively large and thus occupies the majority of theorbitofrontal region.

p0170 Area 10 is a granular cortex that forms a partof the frontal pole in most hominoid species,including humans, chimpanzees, bonobos, orang-utans, and gibbons (Figure 11) (

b0690

Semendeferi et al.,2001). This cortical area is involved in planningand decision-making (

b0245

Fuster, 1998). Area 10receives highly processed sensory afferents fromcorticocortical connections in addition to inputsfrom the mediodorsal nucleus of the thalamus,striatum, and many limbic structures (

b0555

Ongur andPrice, 2000). In hominoids, the cytoarchitecture ofarea 10 is characterized by a distinct layer II, awide layer III with large pyramidal cells in itsdeep portion, a clearly differentiated granularlayer IV, large pyramidal cells in layer Va, and asharp boundary between layer VI and the whitematter. Quantitative analyses reveal a similar pat-tern of relative laminar widths among humans,chimpanzees, and bonobos, such that the supra-granular layers are relatively thick compared tothe infragranular layers (

b0690

Semendeferi et al.,2001). In contrast, the infragranular layers com-prise a greater proportion of cortical thickness inthe other hominoids. When GLI profile curvesdescribing laminar variation in neuron volumedensities are compared among taxa, apes andmacaques follow a similar pattern with roughlyequal GLI throughout the cortical depth. The pro-portion of neuropil space in layers II and IIIrelative to infragranular layers, however, is greaterin humans. Notably,

b0690

Semendeferi et al. (2001)

raise uncertainty regarding whether a homolog ofarea 10 is present in gorillas. In particular, thecortex of the frontal pole in gorillas has a promi-nent layer II and Va, features that are not foundin macaques or other hominoids.

s00604.21.2.8 Anterior Cingulate Cortex

p0175In layer Vb of anterior cingulate cortex (subareas24a, 24b, and 24c), large spindle-shaped cells arefound only in great apes and humans, to the exclu-sion of hylobatids and other primates (

b0540

Nimchinskyet al., 1999). These neurons have a very elongate,gradually tapering, large soma that is symmetricalabout its vertical and horizontal axes (Figure 12).This distinctive somatic morphology arises from thepresence of a large apical dendrite that extendstoward the pial surface, as well as a single largebasal dendrite that extends toward the underlyingwhite matter, without any other dendrites branch-ing from the basal aspect of the cell. These uniqueneurons are also substantially larger in size thanother neighboring pyramidal cells. Interestingly,spindle neurons increase in soma size, density, andclustering from orang-utans to gorillas, chimpan-zees, bonobos, and humans. Furthermore, spindle-shaped neurons have been observed in layer Vb ofarea 24b in a fetal chimpanzee (E 224), indicatingthat this specialized projection cell type differenti-ates early in development (

b0335

Hayashi et al., 2001).Notably, neurons with a spindle phenotype alsohave a phylogenetically restricted distributionwithin another region, the frontoinsular cortex.Spindle cells are found in layer V in the frontoinsu-lar cortex only in humans and African great apes(i.e., gorillas, chimpanzees, and bonobos), being far

Human Bonobo Chimpanzee Gorilla Orang-utan Gibbon

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f0055 Figure 11 The cytoarchitecture of area 10 in hominoids. Scale bar¼500mm. Modified fromb0690

Semendeferi et al. (2001).

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

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more numerous in humans compared to the apes(see 00165;

b0315

Hakeem et al., 2004).p0180 In addition to spindle-shaped neurons, the ante-

rior cingulate cortex of great apes and humanscontains another unique pyramidal cell phenotype.A survey of the anterior cingulate cortex of severalprimate species revealed a small subpopulation ofCR-containing layer V pyramidal neurons that areonly found in great apes and humans (

b0360

Hof et al.,2001). These neurons are located in the superficialpart of layer V in areas 24 and 25. In orang-utans,they comprise 0.5% of all layer V pyramidal cells inthe anterior cingulate, 2% in gorillas, 4.1% in chim-panzees, and 5.3% in humans. The occurrence ofthese cells decreases sharply at the boundarybetween anterior and posterior cingulate cortex,suggesting that they are not directly involved in thesomatic motor functions associated with the poster-ior cingulate motor areas.

p0185 The restricted phylogenetic distribution of spin-dle-shaped cells and CR-ir pyramidal neurons inlayer V of anterior cingulate cortex may reflect spe-cializations of projection neurons in this region for arole in the control of vocalization, facial expression,attention, the expression and interpretation of emo-tions, and autonomic functions (

b0540

Nimchinsky et al.,1999;

b0020

Allman et al., 2001;b0360

Hof et al., 2001). Ofparticular interest, in humans, CR-immunoreactivelayer V pyramidal neurons are also present in theanterior paracingulate cortex (area 32) (

b0360

Hof et al.,2001). The presence of this distinctive projectioncell type in area 32 of humans is intriguing, consid-ering that this cortical area has been found to berecruited in tasks that require theory of mind(

b0265

Gallagher et al., 2000), which is the capacity toattribute mental states such as attention, intention,and beliefs to others and may be a cognitive capacitythat is exclusive to humans (

b0775

Tomasello et al., 2003).

s00654.21.3 Patterns of CorticalOrganization in Hominoids

s00704.21.3.1 The Emergence of Cell Typesand their Distribution

p0190Particular cellular subtypes appear to have phylo-genetically restricted distributions. It is interestingthat among hominoids, the presence of these uniqueneuron phenotypes accords with the hierarchicalnested structure of monophyletic taxa, suggestingthat they are indicators of phylogenetic relation-ships (Table 2). For example, in all great apes andhumans, spindle-shaped neurons are found in layerV of anterior cingulate cortex. Also in these taxa,CR-ir pyramidal cells are found in layer V of ante-rior cingulate cortex and primary motor cortex. Injust African great apes and humans, layer V spindle-shaped neurons are found in frontoinsular cortex.And only in humans, CR-ir pyramidal neurons inlayer V are found in anterior paracingulate cortex.Thus, novel neuron phenotypes have appeared atseveral different times in hominoid evolution.

p0195It is tempting to speculate that the evolution ofeach unique neuron type marks specializations ofthe cortical areas involved. In particular, the mor-phomolecular characteristics of these novel neurontypes suggest that there have been modifications ofspecific efferent projections to facilitate high levelsof activity or higher conduction velocity for outputs.The possibility that the great ape and human clade isdistinguished by such specializations of projectioncells is especially intriguing in light of recent hypoth-eses that intelligence among mammals is correlatedwith the rate of information processing capacity asrepresented by axonal conduction speed (

b0655

Roth andDicke, 2005). The presence of unique neuron classesin great apes and humans extends this hypothesis tosuggest that specific cortical efferents located withinbehaviorally relevant circuits may be selectivelymodified. It is also significant that a common fea-ture of these novel projection cells is theirlocalization in layer V. This laminar distributionindicates that evolutionary modifications havebeen focused upon descending cortical control overtargets in the brainstem and spinal cord.

s00754.21.3.2 The Evolution of Cortical Asymmetries

p0200A substantial body of evidence shows that thehuman cerebral cortex expresses lateralization inthe control of language and fine motor actions ofthe hand (

b0770

Toga and Thompson, 2003). Asymmetriesin histological structure have been demonstratedacross cortical areas implicated in these processesin humans, including Broca’s area (areas 44 and 45),

(a) (b)

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 fromb0540

Nimchinsky et al. (1999).

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The Evolution of Neuron Types and Cortical Histology in Apes and Humans 15

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Wernicke’s area (area Tpt), and the hand represen-tation of primary motor cortex (area 4). Someauthors have hypothesized that these anatomicalasymmetries are exclusive adaptations of thehuman brain that are encoded genetically and com-prise the chief evolutionary novelty in the speciationof modern humans (

b0190

Crow, 2000;b0040

Annett, 2002).p0205 An alternative view is that functional and anato-

mical lateralization may be a byproduct of increasesin overall brain size (

b0635

Ringo et al., 1994;b0395

Hopkinsand Rilling, 2000). One cost of increasing brain sizeis that axons must propagate action potentials overa greater distance to communicate between thehemispheres (

b0320

Harrison et al., 2002). While these

delays in conduction can be overcome to someextent by increasing axon cross-sectional area andmyelination (

b0160

Changizi, 2001), the design problemsassociated with large brains ultimately may necessi-tate increased modularity of processing and more ofan emphasis on local network connectivity (

b0435

Kaas,2000). In particular, as brains grow in size, theefficiency of interhemispheric transfer of informa-tion by long connections diminishes because costs,in terms of wiring space, dictate that axons cannotincrease cross-sectional area sufficiently to keeppace with demands for processing speed (

b0005

Aboitizand Montiel, 2003). Hence, it is expected that cor-tical processes in large brains, especially those that

t0010 Table 2 Phylogenetic distribution of some cortical histological traits

Cortical area Layer Trait

Homo

sapiens

Pan

paniscus

Pan

troglodytes

Gorilla

gorilla

Pongo

pygmaeus

Hylobates

sp.

Macaca

sp.

Primary motor cortexa Layer V CR-ir pyramidal

neurons

þ ? þ þ þ ? �

Primary motor cortexa Layer V PV-ir pyramidal

neurons

þþ ? þþ ? þþ ? þ

Primary motor cortexa Layers

III and

V

NPNFP-ir

neurons

þþ ? þþ þþ þþ ? þ

Primary visual cortexb Layer

IVA

Loss of CO-

dense band

þ ? þ ? þ ? �

Primary visual cortexb Layer

IVA

Dense CB-ir

neurons and

neuropil

þ ? þ ? þ ? �

Primary visual cortexb Layer

IVA

Meshwork with

dense

NPNFP and

Cat-301

staining in

mesh bands

alternating

with dense

CB in

interstitial

zones

þ ? � ? � ? �

Auditory belt cortexc Layers

III and

V

AchE-stained

pyramidal

cells

þþ ? þþ ? ? ? þ

Anterior cingulate

cortexdLayer

Vb

Spindle-shaped

neurons

þþ þþ þþ þ þ � �

Anterior cingulate

cortexeLayer

Vb

CR-ir pyramidal

neurons

þþ ? þþ þ þ ? �

Anterior paracingulate

cortexeLayer

Vb

CR-ir pyramidal

neurons

þ ? � � � ? �

Frontoinsular cortexf Layer

Vb

Spindle-shaped

neurons

þþ þ þ þ � � �

a(b0725

Sherwood et al., 2004a)b(

b0580

Preuss and Coleman, 2002)c(

b0310

Hackett et al., 2001)d(

b0540

Nimchinsky et al., 1999)e(

b0360

Hof et al., 2001)f(

b0315

Hakeem et al., 2004)

þ¼present; þþ¼present and abundant in comparison to other species; �¼absent

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

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depend on rapid computations, will come to rely onspecialized processing that is dominant in one hemi-sphere. Indeed, it has been shown that increasingbrain size is accompanied by reduced hemisphericinterconnectivity via the corpus callosum (

b0635

Ringoet al., 1994;

b0550

Olivares et al., 2001) and the develop-ment of more pronounced gross cerebralasymmetries among anthropoid primates (

b0395

Hopkinsand Rilling, 2000).

p0210 One consequence of lateralized hemispheric spe-cialization of function may be divergence in thehistological organization of homotopic corticalareas. Unfortunately, there is a surprising absenceof data from non-humans concerning microstruc-tural asymmetries in the homologues of Broca’sarea, Wernicke’s area, and primary motor cortex.At present, the sole study of such histological asym-metry indicates that lateralization is not present inarea Tpt of chimpanzees or macaques, while asym-metry of neuropil space and minicolumn widths areobserved in humans (

b0120

Buxhoeveden et al., 2001a).Although this is an important finding, it should bekept in mind that there are many other aspects ofmicrostructural organization that have been demon-strated to be asymmetric in the human cortex, suchas distributions of cell volumes and dendritic geo-metry, which have yet to be investigated in otherspecies. Thus, at the present time, there are stillinsufficient data to adequately resolve whethermany of the observed microstructural asymmetriesof the human cerebral cortex are unique species-specific adaptations that are related to languageand handedness.

s0080 4.21.3.3 How much Variation in CorticalArchitecture can be Attributed to Scalingversus Specialization?

p0215 Interpretation of interspecific differences in the his-tological structure of the cortex in hominoidsrequires parsing the source of this variation.Certainly a portion of it can be attributed to specificalterations of circuitry that generate behavioral dif-ferences among species. Another cause, however,may be the effects of allometric scaling. That is, asoverall brain size changes, predictable changesoccur in cell sizes, cell packing density, dendriticgeometries, and other aspects of microstructure(

b0430

Jerison, 1973;b0755

Striedter, 2005). Thus, with varia-tion in brain size among hominoids, some of theobserved interspecific differences may simply bethe result of scaling to maintain functional equiva-lence and may not indicate any significantdifferences in computational capacities. For exam-ple, how can we know whether greater densities ofAChE-stained neurons in the auditory belt of

hominoids (b0310

Hackett et al., 2001) is of functionalimportance until we have developed a clearer under-standing of the scaling principles that govern thedistribution of AChE-enriched neurons in general?Hence, whenever possible it is best to evaluate phy-logenetic variation in cortical histology from theperspective of allometric scaling. Accordingly, thecase for declaring that a trait is a phylogenetic spe-cialization is strengthened when it can bedemonstrated that individual species depart fromallometric expectations or that an entire clade scalesalong a different trajectory (i.e., grade shift).

p0220It is well established that cortical neuron densityvaries among mammalian species. Across a largesample of mammals ranging from mouse to ele-phant, there is a negative correlation betweencortical neuron density and brain size (

b0780

Tower,1954;

b0185

Cragg, 1967;b0330

Haug, 1987;b0605

Prothero, 1997).Despite this broad trend, however, some evidencesuggests that neuron densities may be higher inhominoids (gorilla, chimpanzee, and human) thanexpected for their brain size (

b0330

Haug, 1987). It hasalso been shown that the fraction of the cortex thatis comprised by neuropil space versus cell somataincreases in a negative allometric fashion withgreater brain size (

b0705

Shariff, 1953;b0780

Tower, 1954;b0085

Bok, 1959;b0785

Tower and Young, 1973;b0885

Zilles et al.,1982;

b0045

Armstrong et al., 1986;b0330

Haug, 1987). Theseempirical findings fit with a model predicting that aconstant average percent interconnectedness amongneurons cannot feasibly be maintained in the face ofincreasing gray matter volume, so the reach of pro-cessing networks cannot keep pace with brain sizevariation (

b0160

Changizi, 2001).p0225Many of these theories concerning the scaling of

network connectedness across brain size, however,were developed to explain variation in mouse toelephant comparisons. Are these predicted allo-metric relationships between neuron density,neuropil space, and brain size maintained whencomparisons are restricted to the AU2hominoids?Table 3 shows the results of stereologic estimatesof neuron density and GLI from recent compara-tive studies of areas 4, 10, and 13 in hominoids.In each of these cortical areas, there is not acorrelation between neuron densities or GLI andbrain size. Therefore, the mammal-wide relation-ship between these parameters and brain size maynot explain interspecific variance in interconnect-edness within cortical areas of hominoids. Thisraises the interesting possibility that differencesamong hominoid species in these variables mightinstead correspond to functionally significantmodifications in the organization of corticalinterconnections.

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The Evolution of Neuron Types and Cortical Histology in Apes and Humans 17

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p0230 Other aspects of network scaling in the cerebralcortex are less well understood. For example, theredoes not appear to be a correlation between brainsize and the density of glial cells (

b0785

Tower and Young,1973;

b0330

Haug, 1987). However, phylogenetic differ-ences in glial cell densities have not yet beensystematically examined using modern immunohis-tochemical markers to identify astrocytes andoligodendrocytes separately. Furthermore, ques-tions regarding the scaling of subpopulations ofinterneurons and pyramidal cells have only begunto be addressed. Evidence suggests that the propor-tion of pyramidal neurons that are enriched inNPNFP may increase with brain size. In the orofa-cial representation of primary motor cortex, there isa striking increase in the percentage of neuronsstained for NPNFP in larger-brained great apesand humans in comparison to smaller-brained OldWorld monkeys (

b0725

Sherwood et al., 2004a).b0790

Tsangand colleagues (2000) also found increasingNPNFP labeling in primary motor cortex across asample including rats, marmosets, rhesus macaques,and humans. In addition,

b0140

Campbell and Morrison(1989) found a larger proportion of NPNFP-ir pyr-amidal neurons, particularly in supragranularlayers, in humans compared to macaque monkeysacross several different cortical areas.

p0235 Interneuron subtypes, as revealed by labeling forcalcium-binding proteins, appear to adhere to differ-ent scaling trends in anthropoid primates dependingon the cortical area. For example, when regressed ontotal neuron density, the density of PV-ir neuronsscales with negative allometry in the primary motorcortex and thus a greater proportion of PV-ir neuronsis observed in hominoids compared to Old Worldmonkeys (

b0725

Sherwood et al., 2004a). In contrast, CB-

ir neurons scale against total neuron density withpositive allometry in areas V1 and V2, resulting in asmaller percentage of CB-ir interneurons in apescompared to monkeys in these areas (

b0735

Sherwoodet al., 2005). Further studies using allometricapproaches to examine the scaling of different neu-ron subtypes will be necessary to elucidatephylogenetic specializations of cortical circuitry.

s00854.21.3.4 Genomic Data Provide Insightsinto Cortical Specializations

p0240Recent studies of phylogenetic variation in genesequences and expression provide additionalinsights into cortical specializations among homi-noids. While most of these studies have beendirected at determining the genetic basis for humanneural uniqueness (

b0215

Enard et al., 2002a;b0220

2002b;b0130

Caceres et al., 2003;b0210

Dorus et al., 2004;b0795

Uddinet al., 2004), some molecular data point to changesthat occurred at earlier times in the hominoid radia-tion. For instance, all hominoids have evolved anovel biochemical mechanism to support high levelsof glutamate flux in neurotransmission through theretroposition of the gene GLUD1 (

b0105

Burki andKaessmann, 2004). This duplicated gene, GLUD2,which is unique to hominoids, encodes an isotype ofthe enzyme glutamate dehydrogenase that isexpressed in astrocytes. All hominoid GLUD2sequences contain two key amino acid substitutionsthat allow the GLUD2 enzyme to be activated inastrocytes during conditions of high glutamatergicneurotransmitter flux. Concordant with this evi-dence for alterations in the molecular machinerynecessary for enhanced neuronal activity in apes, ithas been shown that the gene encoding the

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.a(

b0715

Sherwood et al., 2003b;b0730

Sherwood et al., 2004b)b(

b0690

Semendeferi et al., 2001)c(

b0680

Semendeferi et al., 1998)

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

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cytochrome c oxidase subunit 4-1 underwent rapidnonsynonymous evolution in the hominoid stem,followed by purifying selection in descendentlineages (

b0855

Wildman et al., 2002). Because thesenucleotide substitutions have functional conse-quences for the manner and rate at which electronsare transferred from cytochrome c to oxygen, it islikely that these modifications were selected to servethe needs of cells with high aerobic energy demands,such as neurons.

p0245 Also of significance, an alternative splice variant ofneuropsin (type II) has originated in recent hominoidevolution (

b0485

Li et al., 2004). Neuropsin is expressed inhippocampal pyramidal neurons and is involved inneuronal plasticity. The high incidence of poly-morphisms in the coding region of this protein ingibbons and orang-utans, however, suggests that itmay not be functional in these species. In contrast,the coding region of the type II splice form of neu-ropsin shows relatively little variation in gorillas,chimpanzees, and humans, signifying that it is main-tained by functional constraint and that it might beinvolved in a molecular pathway important for learn-ing and memory in these hominoids.

p0250 With respect to brain size, several genes that areinvolved in controlling the development of cerebralcortex size have undergone accelerated rates ofsequence evolution in the hominoid lineage. Themicrocephalin gene shows an upsurge of nonsynon-ymous amino acid substitutions in a protein-codingdomain of the last common ancestor of great apesand humans (

b0840

Wang and Su, 2004). Additionally, theASPM gene shows evidence of adaptive sequenceevolution in all African hominoids (i.e., gorillas,chimpanzees, bonobos, and humans) (

b0450

Kouprinaet al., 2004).

p0255 These data put into phylogenetic context evidencethat, in the lineage leading to humans, several genesimportant in the development, physiology, andfunction of the cerebral cortex show positive selec-tion (

b0220

Enard et al., 2002b;b0210

Dorus et al., 2004;b0225

Evanset al., 2004). Furthermore, findings from studiesthat have compared human and chimpanzee tran-scriptomes indicate that the human cerebral cortexis distinguished by elevated expression levels ofmany genes associated with energy metabolism(

b0130

Caceres et al., 2003;b0795

Uddin et al., 2004), suggestingthat levels of neuronal activity might be higher inhumans compared to chimpanzees (

b0600

Preuss et al.,2004). While the phenotypic correlates of many ofthese genetic changes await characterization byin situ hybridization and immunohistochemical stu-dies, it is clear that intensified efforts at analyzingvariation in the histological organization of thehominoid cerebral cortex will be necessary if there

is any hope of understanding how such moleculardifferences translate into modifications of the com-putational capacities of cortical circuits.

s00904.21.3.5 On the Horizon

p0260There remains an extraordinary amount to learnregarding the microstructure of the cerebral cortexof hominoids. Even the basic cytoarchitecture ofmany cortical areas, such as the posterior parietalcortex, inferior temporal cortex, posterior cingulatecortex, and premotor cortex, has not yet beenexplored using the methods of modern quantitativeneuroanatomy. Moreover, there is not a singlerecent study of parcellation for any part of the cere-bral cortex using chemoarchitectural stainingtechniques in apes. It will also be important toexamine the scaling patterns that govern the distri-bution of neurochemically identified subsets ofpyramidal neurons, interneurons, and glia acrossdifferent cortical areas from a broad phylogeneticperspective in order to clearly distinguish networkallometric scaling from phylogenetic specialization.Finally, determination of whether humanlike histo-logical asymmetries of cortical areas important inlanguage and control of the hand are present inother apes still requires systematic study. By takingseriously the task of understanding such species-specific neural adaptations, we stand to learn anextraordinary amount about the underlying sub-strates of the cognitive abilities of humans and ourclosest relatives.

Acknowledgements

p0265This work was supported by the National ScienceFoundation (BCS-0515484 and BCS-0549117), theWenner-Gren Foundation for AnthropologicalResearch, and the James S. McDonnell Foundation(22002078). The great ape brain materials wereavailable from the Great Ape Aging Project,Cleveland Metroparks Zoo, and the Foundationfor Comparative and Conservation Biology.

Further Reading

b0890Bailey, P., von Bonin, G., and McCulloch, W. S. 1950. The

Isocortex of the Chimpanzee. University of Illinois Press.

b0895Holloway, R. L. 1996. Evolution of the human brain.In: Handbook of Human Symbolic Evolution (eds. A. Lock

and C. R. Peters), pp. 74–114. Oxford University Press.

b0900Preuss, T. M. 2004. What is it like to be a human? In: The

Cognitive Neurosciences III (ed. M. S. Gazzaniga), pp. 5–22.MIT Press.

b0905Zilles, K. 2005. Evolution of the human brain and comparative

cyto- and receptor architecture. In: From MonkeyBrain to Human Brain: a Fyssen Foundation Symposium

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(eds. S. Dehaene, J. R. Duhamel, M. D. Hauser, and G.

Rizzolatti), pp. 41–56. MIT Press.

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NRVS 00022

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