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4.21 The Evolution of Neuron Types and Cortical
Histology in Apes and Humans
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C C Sherwood, Kent State University,
Kent, OH, USA
P R Hof, Mount Sinai School of Medicine,
New York, NY, USA
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ª 2007 Elsevier Inc. All rights reserved.
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4.21.1 Introduction
4.21.1.1 Evolutionary History of the Hominoids
4.21.1.2 History of Studies Concerning Hominoid Cortical Histology
4.21.2 Comparative Anatomy of the Cerebral Cortex
4.21.2.1 Topology of Cortical Maps
4.21.2.2 Architecture of the Cortex
4.21.2.3 Primary Visual Cortex
4.21.2.4 Auditory Cortex
4.21.2.5 Primary Motor Cortex
4.21.2.6 Inferior Frontal Cortex
4.21.2.7 Prefrontal Cortex
4.21.2.8 Anterior Cingulate Cortex
4.21.3 Patterns of Cortical Organization in Hominoids
4.21.3.1 The Emergence of Cell Types and their Distribution
4.21.3.2 The Evolution of Cortical Asymmetries
4.21.3.3 How much Variation in Cortical Architecture can be Attributed to Scaling
versus Specialization?
4.21.3.4 Genomic Data Provide Insights into Cortical Specializations
4.21.3.5 On the Horizon
Many biological traits scale with
overall size in a nonlinear fashion.
Such allometric scaling relationships can be expressed by the
power function: Y¼bXa. The logarithmic transformation of the
allometric scaling equation yields:
log Y¼log bþa log X. The exponent of the power function becomes
the slope of the log-transformed
function. The slope of this line can
then be interpreted in terms of a
biological scaling relationship
between the independent and
dependent variable. Positive allometry refers to a scaling
relationship with an exponent that
is greater than 1, which means that
the structure in question grows disproportionately larger or more
numerous with increases in the
size of the reference variable.
Negative allometry refers to a scaling relationship with an exponent
that is less than 1, which means that
Chemoarchitecture
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Glossary
Dysgranular
Cortex
Encephalization
Granular Cortex
Grey Level Index
(GLI)
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the structure in question becomes
proportionally smaller or less
numerous with increases in the
size of the reference variable.
The microanatomical organization
of the cerebral cortex revealed by
staining for biochemical substances
using techniques such as immunohistochemistry and enzyme or
lectin histochemistry.
A type of cortex that has a weakly
defined layer IV because it is variable in thickness. At points, layer
IV seems to disappear because neurons from layers IIIc and Va
intermingle.
A relative measure of a species’s
brain size that represents the degree
to which it is larger or smaller than
expected for a typical animal of its
body size.
A type of cortex that has a clearly
identifiable layer IV.
The proportion of an area of reference that is occupied by the
projected profiles of all Nisslstained elements. This value
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2 The Evolution of Neuron Types and Cortical Histology in Apes and Humans
Layers
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Apes and humans are members of the primate super- p0005
family Hominoidea (Figure 1). Molecular evidence
indicates that the hominoid lineage split from the
Old World monkeys about 25Ma (Wildman et al.,
2003). The extant representatives of this phylogenetic
group include two families. The Hylobatidae comprises gibbons and siamangs, and the Hominidae
includes great apes (i.e., orang-utans, gorillas, chimpanzees, and bonobos) and humans (Groves, 2001).
Living hominoids are distinguished by a suite of
shared derived traits that point to the key adaptations
of this clade. These characters include lack of an
external tail, modifications of the shoulder girdle and
wrist for greater mobility, and stabilization of the
lower back (Begun, 2003). These adaptations allow
hominoids to exploit resources in small branches of
trees by developing suspensory postures to distribute
their body weight. This form of locomotion may have
been particularly important in allowing certain species
to increase body size. In addition, compared to other
primates, hominoids have extended periods of growth
and development (Schultz, 1969), an increased complexity of social interactions (Potts, 2004), and larger
brains than would be expected for a monkey of the
same body size (Rilling and Insel, 1999). The
increased encephalization and associated life history
elongation of these species suggest that cognitive flexibility and learning were important aspects of the
hominoid adaptive complex, which allowed them to
deal with locating ephemeral resources from fruiting
trees and to negotiate more complicated relationships
in fission–fusion societies (Potts, 2004).
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Humans
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7 Ma
14 Ma
18 Ma
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4.21.1.1 Evolutionary History of the Hominoids
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4.21.1 Introduction
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provides an estimate of the fraction
of tissue that contains neuronal
somata, glial cell nuclei, and
endothelial nuclei versus neuropil.
GLI values are highly correlated
with the volume density occupied
by neurons since glial and endothelial cell nuclei contribute only a
very small proportion of the total
volume.
A phylogenetic clade that includes
lesser apes (gibbons and siamangs),
great apes (orang-utans, gorillas,
chimpanzees, and bonobos), and
humans.
Cortical layers that are deep to
granular layer IV, i.e., layers V
and VI.
Morphologically,
minicolumns
appear as a single vertical row of
neurons with strong vertical interconnections among layers, forming
a fundamental structural and functional unit. The core region of the
column contains the majority of the
neurons, their apical dendrites, and
both myelinated and unmyelinated
fibers. A cell-poor region, containing dendritic arbors, unmyelinated
axons, and synapses, surrounds
each column.
The
unstained
portion
of
Nissl-stained tissue, which is comprised of dendrites, axons, and
synapses.
Cortical layers that are superficial
to granular layer IV, i.e., layers I, II,
and III.
3 Ma
Bonobos
Chimpanzees
Gorillas
Orang-utans
25 Ma
Gibbons and simiangs
40 Ma
Old World monkeys
58 Ma
New World monkeys
63 Ma
Tarsiers
Lemurs and lorises
showing the phylogenetic relationships of living hominoids and other primates. Estimated divergence dates
f0005 Figure 1 Cladogram
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are taken from Goodman et al. (2005).
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s0015 4.21.1.2 History of Studies Concerning
Hominoid Cortical Histology
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At the beginning of the twentieth century, neuroanatomists applied new histological staining
techniques to reveal the architecture of the cerebral
cortex in numerous species, including apes and
humans (Campbell, 1905; Mauss, 1908;
Brodmann, 1909; Mauss, 1911; Beck, 1929;
Filimonoff, 1933; Strasburger, 1937a, 1937b). In
addition, with the advent of various techniques for
tracing neuronal connectivity based on intracellular
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pathological changes subsequent to ablation, some
studies also examined cortical projection systems in
apes (Walker, 1938; Lassek and Wheatley, 1945;
Kuypers, 1958; Jackson et al., 1969). After the
1950s, however, the amount of research directed
toward understanding variation in the hominoid
brain declined. There are three main reasons for
this. First, the development of molecular biological
techniques caused neuroscientists to focus on a
small number of model species under the implicit
assumption that many aspects of cortical structure
are evolutionarily conserved. These ideas were
further bolstered by claims of uniformity in the
basic columnar architecture of the cerebral cortex
(Rockel et al., 1980). Second, findings from the first
systematic studies of great ape behavior from the
field and laboratory were beginning to be appreciated (e.g., Kortlandt, 1962; Schaller, 1963; e.g.,
Yerkes and Learned, 1925; Yerkes and Yerkes,
1929). These studies contributed to a more sophisticated understanding of cognitive and emotional
complexity in great apes and suggested that they
deserve special protected status with respect to the
ethics of invasive neurobiological experimentation.
Third, the book Evolution of the Brain and
Intelligence (Jerison, 1973) had an enormous influence on the direction of later research in
comparative neuroanatomy. This book argued for
the predictability of neuroanatomical structure from
brain size and encephalization, suggesting that these
metrics form the most significant contribution to
species diversity in brain organization. Combined
with the ready availability of comparative brain
region volumetric data in primates and other mammals from the publications of Heinz Stephan, Heiko
Frahm, George Baron, and colleagues (e.g., Stephan
et al., 1981), a great deal of research effort has been
expended in studies of allometric scaling and covariance of large regions of the brain (Finlay and
Darlington, 1995; Barton and Harvey, 2000; de
Winter and Oxnard, 2001). In contrast, much less
attention has been paid to the possibility of phylogenetic variation in cortical histology (Preuss,
2000). Fortunately, advances in quantitative neuroanatomy and immunohistochemical staining
techniques have opened new avenues of research to
reveal interspecific diversity in the microstructure of
hominoid cerebral cortex.
The history of studies of hominoid cortical histol- p0025
ogy, therefore, has resulted in two eras of research.
The early era comprises several qualitative comparative mapping studies of the cerebral cortex
based on cyto- and myeloarchitecture, with the
occasional comment regarding species differences
in the microstructure of homologous cortical areas
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Although only a small number of hominoid species persist today, the fossil record reveals a diverse
array of successive adaptive radiations of hominoids
in the past. During the Miocene epoch, global climates were warm and humid, supporting dense
forests and lush woodlands extending throughout
the tropics and into northern latitudes. These environmental conditions were favorable for the
diversification of arboreal specialists, such as the
hominoids. In fact, hominoids were the most abundant type of anthropoid primate throughout the
Miocene in Africa and Eurasia, occupying a range
of different ecological niches (Begun, 2003). The
earliest apes in the fossil record are characterized
by hominoidlike dental morphology, but monkeylike postcranial anatomy. The best known of these
early dental apes is the genus Proconsul from
the Early Miocene (20–18Ma) of East Africa.
Proconsul africanus endocasts show a frontal lobe
morphology that is similar to modern hominoids in
being gyrified and lacking the simple V-shaped arcuate sulcus that is characteristic of most Old World
monkeys (Radinsky, 1974). Furthermore, Proconsul
africanus had a relatively larger brain than extant
monkeys of comparable body size (Walker et al.,
1983). Thus, increased encephalization and perhaps
a greater degree of frontal lobe gyrification were
present early in the evolution of the hominoids.
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With the emergence of arid climates in the transition to the Pliocene and the replacement of forests
by mosaic habitats, the arboreal specializations of
hominoids were less successful. The relatively slow
reproductive rates of these taxa, moreover, made it
difficult for many to endure habitat loss resulting
from climate change and human encroachment in
recent times (Jablonski et al., 2000). In the context
of these dramatic environmental changes, one lineage adopted a new form of locomotion, upright
bipedal walking, which would give rise to modern
humans. Other hominoids, however, fared less well
and today apes are restricted to a small number of
endangered tropical forest species.
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4.21.2 Comparative Anatomy
of the Cerebral Cortex
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4.21.2.1 Topology of Cortical Maps
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Total brain weight in hominoids ranges from p0040
approximately 90g in Kloss’s gibbons (Hylobates
klossii) to 1,400g in humans (Homo sapiens)
(Table 1). While there is a large range of variation
among hominoids in total brain size, mapping studies of the cortex (Figure 2) generally agree that the
location of the primary sensory and motor areas are
similar across species (Grünbaum and Sherrington,
1903; Campbell, 1905; Mauss, 1908; Brodmann,
1909; Mauss, 1911; Leyton and Sherrington,
1917; Beck, 1929; Bailey et al., 1950; Preuss et al.,
1999; Hackett et al., 2001; Bush and Allman,
2004a, 2004b; Sherwood et al., 2004b). In particular, the primary visual cortex lies within the banks
of the calcarine sulcus. Primary auditory cortex is
located on the posterior superior plane of the superior temporal gyrus, usually comprising the
transverse gyrus of Heschl in great apes and
humans. Primary somatosensory cortex is found
within the posterior bank of the central sulcus and
extends on to the postcentral gyrus. Primary motor
cortex is located mostly on the anterior bank of the
central sulcus. One notable difference is the fact that
primary visual cortex extends to only a very small
portion of the lateral convexity of the occipital lobe
in humans, whereas a much larger part of the lateral
occipital lobe is comprised of striate cortex in apes
(Zilles and Rehkämper, 1988; Holloway et al.,
2003). This is because the primary visual cortex in
humans is 121% smaller than expected for a primate of the same brain size (Holloway, 1996).
Other higher-order areas, particularly within the
frontal cortex, have also been shown to occupy
similar locations across these species (Strasburger,
1937a, 1937b; Semendeferi et al., 1998;
Semendeferi et al., 2001; Sherwood et al., 2003a).
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cerebral cortex, highlighting evidence concerning
shared derived traits of hominoids in comparison
to other primates, as well as indicating possible
species-specific specializations. Hence, the studies
reviewed in this chapter provide the most direct
evidence currently available to delimit which
aspects of cortical histology are uniquely human,
which are derived for all hominoids, and which
reflect the specializations of each species.
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(Campbell, 1905; Mauss, 1908; Brodmann, 1909;
Mauss, 1911; Beck, 1929; Bailey et al., 1950). Later
studies from this era also contributed quantitative
data concerning the surface area of particular cortical areas, as well as cellular sizes and densities in a
few non-human hominoid species (Mayer, 1912;
Tilney and Riley, 1928; von Bonin, 1939; Lassek
and Wheatley, 1945; Shariff, 1953; Haug, 1956;
Glezer, 1958; Blinkov and Glezer, 1968). These
quantitative data, however, were rarely presented
in the context of a focused examination of variation
among hominoids.
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The modern era is characterized by studies that
use techniques such as design-based stereology,
computerized image analysis, and immunohistochemical and histochemical staining to identify
subpopulations of cortical cells. These new
approaches are especially appealing for investigations of phylogenetic variation in cortical histology
in species that are not common to the laboratory
because several enzymatic, cytoskeletal, and other
macromolecular constituents that are well preserved
in postmortem tissue can be used as reliable markers
for subpopulations of distinct neuron types, thereby
extending comparative studies of species for which
anatomical tracing, electrophysiological mapping,
or other experimental procedures would be either
unethical or impractical (see 00055). Subsets of pyramidal neurons, for example, can be distinguished
immunohistochemically by staining with an antibody (e.g., SMI-32) to nonphosphorylated epitopes
on the medium- and high-molecular-weight subunits of the neurofilament triplet protein. These
epitopes are particularly enriched in subpopulations
of large neurons of the neocortex that have a specific
laminar and regional distribution. Because nonphosphorylated neurofilament protein (NPNFP) is
involved in the maintenance and stabilization of
the axonal cytoskeleton, its expression is associated
with neurons that have thick myelinated axons
(Hoffman et al., 1987; Kirkcaldie et al., 2002). In
addition, the calcium-binding proteins–calbindin D28k (CB), calretinin (CR), and parvalbumin (PV)–
are useful markers for understanding the cortical
interneuron system because each of these molecules
is typically colocalized with GABA in morphologically and physiologically distinct nonoverlapping
populations (DeFelipe, 1997; Markram et al.,
2004).
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While the neuroanatomical structure of one
hominoid species in particular has been studied
most extensively, it is well beyond the scope of this
article to provide a comprehensive review of human
cortical architecture. Here we focus explicitly on
comparative studies of the histology of hominoid
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4.21.2.2 Architecture of the Cortex
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The general histological architecture of the neocor- p0045
tex in hominoids shares many features in common
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t0005 Table 1 Endocranial volumes of hominoids (in cc)
Species
Sex
Sample size
Mean
SD
Range
White-handed gibbon
Hylobates lar
Siamang
Symphalangus syndactylus
Orang-utan
Pongo pygmaeus
Gorilla
Gorilla gorilla
Chimpanzee
Pan troglodytes
Bonobo
Pan paniscus
Human
Homo sapiens
M
F
M
F
M
F
M
F
M
F
M
F
M
F
44
37
8
12
66
63
283
199
159
204
28
30
502
165
106.3
104.2
127.7
125.9
415.6
343.1
535.5
452.2
397.2
365.7
351.8
349.0
1457.2
1317.9
7.2
7.0
8.2
12.7
33.6
33.6
55.3
41.6
39.4
31.9
30.6
37.7
119.8
109.8
92–125
90–116
99–140
102–143
334–502
276–431
410–715
345–553
322–503
270–450
295–440
265–420
1160–1850
1040–1615
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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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on the basis of cytoarchitecture and topology, several studies have compared the microstructure of
these areas among different hominoid species
(reviewed below). On the whole, the cytoarchitecture of homologous cortical areas shows only subtle
differences across hominoid species. Indeed, an
early quantitative comparative analysis of the
cytoarchitecture of primary cortical areas (areas 3,
4, 17, and 41/42), found marked similarities among
species (orang-utans, gorillas, chimpanzees, and
humans) in terms of the relative thickness of different layers and the proportion of neuropil in each
layer (Zilles and Rehkämper, 1988). Only minor
differences were noted, such as greater relative
thickness of layer III in primary somatosensory cortex (area 3) in humans and gorillas, an increase in
the proportion of neuropil in layers V and VI of area
3 in orang-utans, and a relatively thicker layer IV of
primary auditory cortex (area 41/42) in orangutans. These results were interpreted to corroborate
the qualitative observations of Campbell (1905) and
Brodmann (1909), indicating that there are not any
substantial differences between humans and apes in
the cytoarchitecture of these primary cortical areas.
The study by Zilles and Rehkämper (1988), however, was based on small samples, which did not
permit statistical evaluation of species differences.
More recent studies using larger samples, different
staining techniques, and more refined quantitative
methods have revealed interesting phylogenetic differences among hominoids in cortical histological
structure.
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with other primates and mammals in general, such
as a fundamental six-layered and columnar organization (Mountcastle, 1998). Compared to other
mammals of similar brain size, however, the cerebral cortex of hominoids is reported to have a
relatively low density of glial cells and a greater
variety of neuron soma sizes (Haug, 1987).
Astroglia of the cerebral cortex in great apes, as
revealed by immunohistochemistry for glial fibrillary acidic protein (GFAP), resemble other primates
in forming long, radially oriented interlaminar processes spanning supragranular cortical layers
(Colombo et al., 2004). This configuration may be
unique to primates, as GFAP staining in the cortex
of other mammals appears distinctly different, comprising a network of stellate astroglial somata with
short, branching processes (Colombo, 1996;
Colombo et al., 2000; Colombo and Reisin, 2004).
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Comparison of mammalian brains indicates that
the surface area of the cortical sheet can vary by
more than five orders of magnitude, while the thickness of the cortex varies by less than one order of
magnitude (Allman, 1990). Accordingly, evolutionary changes in the size of the cerebral cortex have
occurred primarily in the tangential dimension,
while the vertical dimension of the cortex may be
more constrained by the development of columnar
units (Rakic, 1988, 1995). Nonetheless, the cortical
sheet does tend to display increased thickness in
mammals with larger brains (Hofman, 1988). Due
to these scaling trends, hominoids have thicker cortices than other smaller-brained primates and
homologous cortical areas in humans tend to be
thicker than in apes (Figure 3).
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With the relative ease of establishing homology
among the primary sensory and motor cortical areas
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4.21.2.3 Primary Visual Cortex
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Important modifications of primary visual cortex p0060
(Brodmann’s area 17) histology, particularly of the
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2 Parcellation maps
of the cerebral cortex of apes. Chimpanzee (Pan troglodytes) cortical maps reproduced
from
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(1905) and
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(1950). Orang-utan (Pongo pygmaeus) cortical maps reproduced from (c) Campbell (1905)
(a) Campbell
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and (d) Mauss (1908, 1911) compiled in Zilles and Rekämper (1988).
thalamic recipient layer IV, have taken place at several
points in the evolution of hominoids. Distinct parallel
ascending fiber systems arising from retinal ganglion
cells project to the lateral geniculate nucleus (LGN) of
the thalamus. The M-type retinal ganglion cells give
rise to the magnocellular channel, which is involved in
the analysis of motion and gross spatial properties of
stimuli. The P-type ganglion cells process visual information with high acuity and color sensitivity, and
project to parvocellular layers of the LGN. In the
geniculostriate component of these parallel pathways,
different systems derive from distinct portions of the
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Chimpanzee
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metabolic activity within this sublayer. However,
in the hominoid species examined to date (orangutans, chimpanzees, and humans), intense CO staining in layer IVA is absent, suggesting that the direct
parvocellular-geniculate projection to layer IVA
was either reduced or more dispersed to include
both layers IVA and IVB in the last common ancestor of this phylogenetic group (Preuss et al., 1999;
Preuss and Coleman, 2002). Primary visual cortex
of great apes and humans is further distinguished
from monkeys in having increased staining of CBimmunoreactive (-ir) interneurons and neuropil in
layer IVA (Preuss and Coleman, 2002).
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exhibits additional modifications to the basic hominoid plan described above. In humans, a meshwork
pattern is observed in which compartments of neuropil that stain intensively for Cat-301 and
nonpyramidal NPNFP-ir cells, and neurites alternate with bands of high densities of CB-ir
interneurons (Preuss and Coleman, 2002). These
changes in human primary visual cortex have been
interpreted to reflect a closer association of this
layer to M-pathway inputs than observed in any
other primates. The functional implications of
these histological changes are unclear; however, it
has been suggested that these alterations are related
to specializations in humans for the visual perception of rapid orofacial gestures in speech (Preuss and
Coleman, 2002).
Another distinctive feature of primary visual cor- p0075
tex organization in many primates is ocular
dominance columns, which correspond to the horizontal segregation of inputs from the two retinae to
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LGN and synapse within separate sublayers of layer
IV in primary visual cortex. The complexity of segregated geniculostriate projects is reflected in the
development of at least three subdivisions of layer IV
in primates as demarcated by Brodmann (1909). Two
cell-rich layers, IVA and IVC, are separated by a cellpoor layer IVB, which contains a dense plexus of
myelinated axons known as the stria of Gennari.
Neurons in the magnocellular layers of the LGN project to the upper half of layer IVC. Neurons in the
parvocellular layers of the LGN project to layer IVA.
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The chemoarchitecture of layer IVA is markedly
different in hominoids compared to other primates
(Figure 4). In most monkeys, except the nocturnal
owl monkey, there is a dense band of cytochrome
oxidase (CO)-rich staining in layer IVA (reviewed in
Preuss et al., 1999), reflecting high levels of
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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.
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f0020 Figure 4 Comparative chemoarchitecture of layer IV in primary visual cortex of squirrel monkeys (Saimiri ), macaques
(Macaca), chimpanzees
(Pan), and humans (Homo).
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IVA
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IVB
IVC
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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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context of the general scaling patterns of Meynert
cells, it is interesting that soma volumes of these
neurons fit closely with predictions among humans
(2.84 times larger than neighboring pyramidal cells)
and gorillas (2.98 times), whereas they are relatively
large in chimpanzees (3.78 times) and relatively
small in orang-utans (1.94 times). These differences
in neural organization for the processing of visual
motion may relate to socioecological differences
among these apes. Because wild chimpanzees
engage in aggressive incursions into the territory of
neighboring groups (Watts and Mitani, 2001) and
hunt highly mobile prey such as red colobus monkeys (Watts and Mitani, 2002), we speculate that
relatively large Meynert cells evolved in this species
to enhance detection of visual motion during boundary patrolling and hunting. In contrast, relatively
small Meynert cells in orang-utans may relate to
the fact that these apes are solitary, large-bodied,
committed frugivores (van Schaik and van Hooff,
1996), which allows them to maintain low levels of
vigilance for motions of predators, competitors, and
food items.
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different compartments in layer IV of primary visual
cortex. Ocular dominance columns have been anatomically demonstrated in Old World monkeys,
humans, and some other primates, such as the
New World spider monkey and the strepsirrhine
galago (reviewed in Allman and McGuinness,
1988). A similar pattern of alternating patches of
ocular representation within primary visual cortex
has been described in a chimpanzee after monocular
injection of a transneuronal tritiated tracer substance (Tigges and Tigges, 1979). It is worth
noting, however, that this study revealed geniculate
projections to layer IVC, but not to layer IVA, as is
observed in monkeys.
p0080
Large pyramidal neurons, which are found at the
boundary between layers V and VI, called Meynert
cells, are prominent in the primary visual cortex of
primates, and their soma size displays interspecific
variation (Figure 5) (Sherwood et al., 2003c). These
cells can be distinguished as a unique subtype on the
basis of their morphology and connectivity. Their
thick axon collaterals project to both area MT/V5
and the superior colliculus, suggesting that these
cells are involved in processing visual motion (Fries
et al., 1985; Movshon and Newsome, 1996;
Livingstone, 1998). In a comparative study,
Meynert cell somata were found to be on average
2.8 times lager than other layer V pyramidal neurons across a range of primates (Sherwood et al.,
2003c). Because the basal dendrites and axon collaterals of Meynert cells extend horizontally in
layers V and VI to integrate information and facilitate responses across widespread areas of visual
space, interspecific variation in Meynert cell size
appears to be largely constrained by their function
in the repetitive stereotyped local circuits that represent the retinal sheet in primary visual cortex. In the
4.21.2.4 Auditory Cortex
s0040
There are two parallel thalamocortical projections p0085
from the medial geniculate nucleus (MGN) to the
superior temporal cortex of primates. Neurons in
the ventral division of the MGN supply a tonotopic
projection to the core region of auditory cortex
(Brodmann’s areas 41 and 42). Neurons in the dorsal and medial divisions of the MGN project to
areas surrounding the core. The core region of auditory cortex has been identified in macaques,
chimpanzees, and humans as a discrete architectural
zone as compared to the surrounding belt cortex
(Hackett et al., 2001). The core can be recognized
by a broad layer IV that receives a dense thalamic
projection, heavy myelination, and intense expression of acetylcholinesterase (AChE), CO, and PV in
the neuropil of layer IV. In macaques, the relatively
high density of cells and fibers makes the auditory
cortex core appear structurally homogeneous as
compared to the hominoids. In contrast, the medial
and lateral domains of the core region of auditory
cortex are more clearly differentiated in humans and
chimpanzees because of the lower packing density
of structural elements. Additionally, the network of
small horizontal and tangential myelinated fibers in
layer III appears most complex in humans, intermediate in chimpanzees, and least elaborate in
macaques.
The auditory core region is enveloped by several p0090
higher-order belt and parabelt fields (Figure 6). The
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The Evolution of Neuron Types and Cortical Histology in Apes and Humans
41
Tpt
HG
auditory cortex are not well understood, but they
are likely to be important for higher-order processing of natural sounds, including those used in
communication. Neurons in the lateral belt cortex
areas of rhesus macaques, for example, respond better
to species-specific vocalizations than to energymatched pure tone stimuli (Rauschecker et al., 1995).
The comparative anatomy of one particular p0095
region of auditory association cortex has been studied most extensively. In humans, Wernicke’s area,
a region important for the comprehension of language and speech, is located in the posterior
superior temporal cortex. Gross anatomic observations indicate that asymmetries similar to humans
are present in the superior temporal lobe of nonhuman primates, such as leftward dominance of the
planum temporale in great apes (Gannon et al.,
1998; Hopkins et al., 1998) and a longer left sylvian
fissure in many anthropoid species (LeMay and
Geschwind, 1975; Yeni-Komshian and Benson,
1976; Heilbroner and Holloway, 1988; Hopkins
et al., 2000).
Several investigations have examined the micro- p0100
structure of the cortical area most closely associated
with Wernicke’s area. Area Tpt (Galaburda et al.,
1978) or area TA1 (von Economo and Koskinas,
1925) comprises a portion of posterior
Brodmann’s area 22 located on the upper bank of
the superior temporal gyrus and sometimes extending to part of the parietal operculum and the
convexities of the temporal and parietal lobes
(Galaburda et al., 1978). This area represents a
transition between auditory association cortex and
cortex of the inferior parietal lobule (Shapleske
et al., 1999). Cortex with the cytoarchitectural characteristics of area Tpt has been described in galagos,
macaques, chimpanzees, and humans (Galaburda
and Pandya, 1982; Preuss and Goldman-Rakic,
1991; Buxhoeveden et al., 2001a, 2001b). The
microstructure of area Tpt in these primates is distinguished by a eulaminate appearance, with a
poorly defined border of layer IV due to the
encroachment of pyramidal cells in adjacent layers
IIIc and Va, and an indistinct border between layers
IV and V due to curvilinear columns of neurons that
bridge the two layers (Galaburda and Sanides,
1980).
There are differences among rhesus monkeys, p0105
chimpanzees, and humans in the details of minicolumn structure in area Tpt. In the left hemisphere,
area Tpt of humans has wider minicolumns as compared to macaques or chimpanzees, whereas the
width of minicolumns is similar in the non-human
species (Buxhoeveden et al., 2001b). These findings
suggest that wider minicolumns in human area Tpt
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f0030 Figure 6 Cytoarchitecture of auditory cortex of an orang-utan
(Pongo pygmaeus). A parasagittal section of the superior temporal gyrus shows the location of regions detailed below
(a). Higher-power micrographs show cytoarchitecture in (b) the
core of primary auditory cortex (Brodmann’s area 41 or von
Economo and Koskinas’ area TC) and (c) area Tpt (posterior
Brodmann’s area 22 or von Economo and Koskinas’ area TA1).
HG¼Heschl’s gyrus; PT¼planum temporale; S¼superior;
P¼posterior. Scale bar¼500mm.
EL
belt areas of auditory cortex, which are less precise
in their tonotopic organization, receive major inputs
from the core and diffuse input from the dorsal
division of the MGN. The belt region is bordered
laterally on the superior temporal gyrus by a parabelt region of two or more divisions that are
activated by afferents from the belt areas and the
dorsal MGN, but not the ventral MGN or the core.
Interestingly, AChE-stained pyramidal cells in layer
III and V of the belt region are more numerous in
chimpanzees and humans compared to macaques
(Hackett et al., 2001). Neurons in the belt and parabelt project to auditory-related fields in the
temporal, parietal, and frontal cortex. Other types
of processing that occur in the other divisions of
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may be a species-specific specialization that allows
for more extensive neuropil space containing interconnections among neurons.
p0110
The microstructure of area Tpt has also been
shown to be asymmetric in humans, possibly as a
neural substrate of hemispheric dominance in the
cerebral representation of language. Long-range
intrinsic connections within area Tpt labeled in
postmortem brains with lipophilic dyes have
revealed greater spacing between interconnected
patches in the left hemisphere compared to the
right (Galuske et al., 2000). Furthermore, left
area Tpt has a greater number of the largest pyramidal
cells
in
layer
III,
known
as
magnopyramidal cells, that give rise to long corticocortical association projections (Hutsler, 2003).
In addition, AChE-rich pyramidal cells display
greater cell soma volumes in the left hemisphere
despite lacking asymmetry in number (Hutsler and
Gazzaniga, 1996). In humans, left area Tpt has
also been shown to contain a greater amount of
neuropil and axons with thicker myelin sheaths
(Anderson et al., 1999). Of particular significance,
a comparative analysis of area Tpt found that
only humans, but not rhesus macaques or chimpanzees, exhibit left dominant asymmetry in area
Tpt, with wider minicolumns and a greater proportion of neuropil (Buxhoeveden et al., 2001a).
OO
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The primary motor cortex (Brodmann’s area 4) has
a distinctive cytoarchitectural appearance in primates (Geyer et al., 2000; Sherwood et al., 2004b),
containing giant Betz cells in the lower portion of
layer V, low cell density, large cellular sizes, an
indistinct layer IV, and a diffuse border between
layer VI and the subjacent white matter
(Figure 7a). In humans, the region of primary
motor cortex that corresponds to the representation
of the hand exhibits interhemispheric asymmetry in
its cytoarchitectural organization. Concomitant
with strong population-wide right handedness in
humans, most postmortem brains display a greater
proportion of neuropil volume in the left hemisphere of this part of primary motor cortex
(Amunts et al., 1996). Interestingly, brains of captive chimpanzees (Hopkins and Cantalupo, 2004)
and capuchin monkeys (Phillips and Sherwood,
2005) show humanlike asymmetries of the hand
region of the central sulcus that are correlated with
the direction of individual hand preference.
However, the histology of primary motor cortex in
non-human primates has not yet been examined for
asymmetry (see 00021).
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Figure 7 Cytoarchitecture of primary motor cortex and mor- f0035
phology of Betz cells in an orang-utan (Pongo pygmaeus). Betz
cells can be seen in the bottom of layer V, as indicated by the
arrow in the Nissl-stained section (a). The morphology of Betz
cells as revealed by immunostaining for NPNFP with Nissl counterstain is shown (b). Scale bar (a)¼250mm. Scale bar
(b)¼50mm.
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While the cytoarchitectural organization of pri- p0120
mary motor cortex is generally similar across
species, interspecific differences have been
described. The cytoarchitecture of the region corresponding to orofacial representation of primary
motor cortex in several catarrhine species (longtailed macaques, anubis baboon, orang-utans, gorillas, chimpanzees, and humans) was analyzed using
the Grey Level Index (GLI) method (Sherwood
et al., 2004b). Compared to Old World monkeys,
great apes and humans displayed an increased relative thickness of layer III and a greater proportion of
neuropil space. A stereologic investigation of
NPNFP and calcium-binding protein-ir neurons
was also conducted in this same comparative sample
(Sherwood et al., 2004a). Primary motor cortex in
great apes and humans was characterized by a
greater percentage of neurons enriched in NPNFP
and PV compared to the Old World monkeys
(Figure 8). Conversely, the percentage of CB- and
CR-ir neuron subtypes did not significantly differ
among these species. These modifications of particular subsets of neuron types might contribute to the
voluntary dexterous control of orofacial muscles
exhibited in the vocal and gestural communication
of great apes and humans. Enhancement of PV-ir
interneuron-mediated lateral inhibition of cell columns may enhance specificity in the recruitment of
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The Evolution of Neuron Types and Cortical Histology in Apes and Humans 11
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(a)
(b)
PV
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Specializations of biochemical phenotypes are p0130
known for certain regionally restricted subsets of
pyramidal neurons. Although calcium-binding proteins are expressed transiently during prenatal and
early postnatal development (Moon et al., 2002;
Ulfig, 2002), their expression in pyramidal neurons
of adult mammals is more limited. Neurons expressing the calcium-binding proteins – CB, CR, and PV –
are thought to have relatively high metabolic rates
associated with fast repolarization for multiple
action potentials (Baimbridge et al., 1992). While
such calcium buffering mechanisms are most commonly associated with GABAergic interneurons,
the presence of calcium-binding proteins in pyramidal cells might reflect a neurochemical
specialization for higher rates of activity. In this
context, it is interesting that faint CR immunoreactivity is observed in isolated medium- and large-size
layer V pyramidal neurons in primary motor cortex
of great apes and humans, but not in macaques or
baboons (Hof et al., 1999; Sherwood et al.,
2004a). PV-ir pyramidal neurons are also very
rarely observed in the neocortex of mammals (see
00055). However, large layer V pyramidal neurons, including Betz cells, have been reported to
express PV immunoreactivity in primary motor
cortex of humans (Nimchinsky et al., 1997;
Sherwood et al., 2004a). Evidence concerning the
existence of PV-ir pyramidal neurons in other nonhuman primates is somewhat contradictory. In one
study, PV-ir pyramidal neurons were observed in
primary motor and somatosensory cortices of galagos and macaques (Preuss and Kaas, 1996).
Another study, however, failed to label PV-ir pyramidal cells in macaques (DeFelipe et al., 1989),
probably due to methodological discrepancies
among experiments. A comparative study of primary
motor
cortex
using
the
same
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different muscle groups for dynamic modulation of
fine orofacial movements (Scheiber, 2001).
Increased proportions of NPNFP-ir pyramidal
cells, on the other hand, may be a correlate of
greater descending cortical innervation of brainstem
cranial motor nuclei by heavily myelinated axons to
allow for more voluntary control (Kuypers, 1958).
p0125
The giant Betz cells are found in the lower half of
layer V of primary motor cortex and possess a large
number of primary dendritic shafts that leave the
soma at several locations around its surface
(Figure 7b) (Braak and Braak, 1976; Scheibel and
Scheibel, 1978; Meyer, 1987). They are largest and
most numerous in the cortical representation of the
leg, where axons project farther along the corticospinal tract to reach large masses of muscles (Lassek,
1948; Rivara et al., 2003). Betz cells are strongly
immunoreactive for NPNFP among humans, great
apes, and Old World monkeys (Sherwood et al.,
2004a). An analysis of scaling of Betz cell somata
volumes in the region of hand representation of
primates revealed that these cell subtypes become
relatively enlarged with increases in brain and body
size (Sherwood et al., 2003c). At larger sizes, there is
an increase in the distance to the spinal representation of target muscles and a greater number of less
densely distributed corticospinal neurons (Nudo
et al., 1995). In larger brains and bodies, Betz cell
axons need to become thicker to maintain conduction speed to reach more distant targets in the spinal
cord. Accordingly, Betz cells are scaled to global
connectivity constraints and therefore increase in
somatic volume in a manner that is correlated with
brain size. Due to these scaling trends, among hominoids Betz cells are relatively largest in humans
(10.96 times larger than neighboring pyramidal
cell), then gorillas (8.37 times), chimpanzees (7.02
times), and orang-utans (6.51 times).
PR
OO
f0040 Figure 8 Calcium-binding protein-immunoreactive neurons in layer III of primary motor cortex of a chimpanzee (Pan troglodytes).
Neurons stained for calbindin (CB) (a), calretinin (CR) (b), and parvalbumin (PV) (c) are shown. Morphologically, CR-ir interneurons
correspond mostly to double-bouquet cells. They are predominantly found in layers II and III, and have narrow vertically oriented
axonal arbors that span several layers. CB-ir neurons are morphologically more varied, including double-bouquet and bipolar types,
with many showing a predominantly vertical orientation of axons. In contrast, the morphology of PV-ir interneurons includes large
multipolar types, such as large basket cells and chandelier cells, which have horizontally spread axonal arbors spanning across
cortical columns within the same layer as the parent soma. Scale bar¼50mm.
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The Evolution of Neuron Types and Cortical Histology in Apes and Humans
immunohistochemical procedures across species
found that PV-ir pyramidal neurons were either
not present or sparse in Old World monkeys,
whereas they were considerably more numerous
in great apes and humans (Sherwood et al., 2004a).
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Figure 9 The architecture of areas 44 and 45 in a chimpanzee f0045
(Pan troglodytes). Area 44 is shown stained for Nissl substance
(a) and NPNFP (b). Area 45 is shown stained for Nissl substance (c) and NPNFP (d). Scale bar¼500mm.
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The microstructure of the inferior frontal cortex, the
region that contains Broca’s area in humans, has
been described in hominoids on the basis on cyto-,
myelo-, and NPNFP-architecture (von Economo,
1929; Bailey and von Bonin, 1951; Braak, 1980;
Amunts et al., 1999; Hayes and Lewis, 1995;
Sherwood et al., 2003a). Cytoarchitectural studies
of chimpanzee and orang-utan frontal cortex
describe a dysgranular region anterior to the inferior
precentral sulcus comprising a part of pars opercularis and designated Brodmann’s area 44 (von
Bonin, 1949; Sherwood et al., 2003a), FCBm
(Bailey et al., 1950), or areas 56 and 57 (Kreht,
1936). In chimpanzees, this region has been shown
to receive projections from the mediodorsal nucleus
of the thalamus (Walker, 1938). In macaques, a field
with similar cytoarchitectural characteristics in the
caudal bank of the inferior limb of the arcuate sulcus has been denoted area 44, with area 45 located
rostrally (Galaburda and Pandya, 1982; Petrides
and Pandya, 1994). The cytoarchitecture of area
44 is characterized by a columnar organization similar to ventral premotor area 6, but it is distinguished
by the development of a thin layer IV and clustered
magnopyramidal neurons in the deep part of layer
III. Layer IV in area 44 has an undulating appearance due to the invasion of pyramidal cells from
layer III and layer V. Nonphosphorylated neurofilament protein staining in area 44 of chimpanzees and
humans displays clusters of large pyramidal neurons
at the bottom of layer III and a lower band of immunoreactive layer V cells and neuropil (Figure 9)
(Hayes and Lewis, 1995; Sherwood et al., 2003a).
p0140
The cytoarchitecture of area 45 is distinguished
from area 44 by the presence of a more prominent
layer IV, a more homogeneous distribution of
pyramidal cells in the deep portion of layer III,
and the absence of conspicuous cell columns.
Nonphosphorylated neurofilament protein staining
in area 45 is characterized by a clearer separation of
immunoreactive neurons into upper (layer III) and
lower (layer V) populations and by the absence of
the intensely stained magnopyramidal clusters, as
seen in area 44.
p0145
Considering the preponderance of left hemisphere
dominant control of language in humans, several
studies have examined the cortex of the inferior
p0135
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s0050 4.21.2.6 Inferior Frontal Cortex
frontal gyrus in humans for microstructural asymmetries. Using GLI profile analysis methods to quantify
regional variation in cytoarchitecture, area 44 has
been shown to display left dominance in terms of
volume and an increased proportion of neuropil
space, whereas area 45 does not show a consistent
direction of asymmetry (Amunts et al., 1999). In
addition, the total length of pyramidal cell dendrites
is longer in the left opercular region of the inferior
frontal gyrus due to a selective increase in the length
of higher-order segments (Scheibel et al., 1985).
Using different methods, another study examined
asymmetries in only magnopyramidal cells in layer
III of area 45 and found total dendritic length, dendritic complexity (numbers of branches and maximal
branch order), and spine densities to be greater in the
right (Hayes and Lewis, 1996). In area 45, AChEpositive layer III magnopyramidal cells have larger
somata in the left hemisphere, despite lacking asymmetry in their density (Hayes and Lewis, 1995;
Garcia et al., 2004).
While asymmetries of the inferior frontal cortex p0150
are well established in humans, the condition of
non-human primates is less clear. Although population-level leftward asymmetry of the fronto-orbital
sulcus, a portion of the inferior frontal gyrus, has
been reported in great apes (Cantalupo and
Hopkins, 2001), it remains to be known whether
humanlike microstructural asymmetries are present
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The Evolution of Neuron Types and Cortical Histology in Apes and Humans 13
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Area 13 is a dysgranular field located in the pos- p0160
terior orbitofrontal cortex (Figure 10). This cortical
area is remarkably integrative, receiving inputs from
olfactory, gustatory, and visceral centers, as well as
premotor, somatosensory, auditory, visual, and
parahippocampal cortices (Carmichael and Price,
1995; Cavada et al., 2000). Damage to this region
disrupts performance on tasks that require behavioral inhibition and causes impairments in
emotional control (Fuster, 1998; Roberts and
Wallis, 2000). In a study of the cytoarchitecture of
area 13 across macaques and hominoids, several
similarities were observed that suggest homology
among these species (Semendeferi et al., 1998).
This cortical area is distinguished by a poorly
defined layer IV, horizontal striations of cells in
layers V and VI, large pyramidal cells in layer V,
relatively thick infragranular layers as compared
with supragranular layers, and greater neuropil
space in supragranular layers as compared with deeper layers. Among hominoids, area 13 is located in
the posterior portion of the medial orbital and posterior orbital gyri. This concords with the earlier
description of an area labeled FF in the posterior
orbitofrontal cortex of chimpanzees that seems to
correspond to these cytoarchitectural features
(Bailey et al., 1950).
While general similarities are found in the p0165
cytoarchitecture of area 13 of hominoids, quantitative analyses have identified some interspecific
differences. For example, layer IV in orang-utans
is relatively wide, making this cortex appear more
similar to granular prefrontal cortex. Compared
to other hominoids, area 13 in humans and bonobos occupies a small proportion of total brain
b0150
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While it has been a popular notion that human
cognitive abilities are associated with disproportionate enlargement of the frontal or prefrontal
cortex, recent data show that the human frontal
cortex is no larger than expected for a hominoid
of the same brain size (Semendeferi et al., 1997;
2002). Furthermore, progressive increase in the
relative size of the frontal cortex accompanies
enlarging brain size for primates in general, with
hominoids simply continuing this scaling trend
(Bush and Allman, 2004a) (see 00061, 00066,
00081). At present, the comparative quantitative
data available concerning the volume of specific
prefrontal cortical areas in hominoids are scanty,
representing only areas 10 and 13 in one individual per species (Semendeferi et al., 1998, 2001).
Taken together, however, it does not seem that
these prefrontal areas are disproportionately
enlarged in human beyond what is expected for
a hominoid of the same brain size (Holloway,
2002). Nonetheless, quantitative cytoarchitectural
analyses have shown that some prefrontal cortical
areas differ in their histological organization
among hominoid species.
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in the inferior frontal cortex of these species. In
humans and chimpanzees, the borders of areas 44
and 45 have been shown to correspond poorly with
external sulcal landmarks (Amunts et al., 1999;
Sherwood et al., 2003a). Thus, determination of
whether asymmetries are evident in regional
volumes and intrinsic circuitry of areas 44 and 45
of great apes will require histological studies.
IV
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f0050 Figure 10 The cytoarchitecture of area 13 in hominoids. Scale bar¼500mm. Modified from Semendeferi et al. (1998).
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The Evolution of Neuron Types and Cortical Histology in Apes and Humans
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In layer Vb of anterior cingulate cortex (subareas p0175
24a, 24b, and 24c), large spindle-shaped cells are
found only in great apes and humans, to the exclusion of hylobatids and other primates (Nimchinsky
et al., 1999). These neurons have a very elongate,
gradually tapering, large soma that is symmetrical
about its vertical and horizontal axes (Figure 12).
This distinctive somatic morphology arises from the
presence of a large apical dendrite that extends
toward the pial surface, as well as a single large
basal dendrite that extends toward the underlying
white matter, without any other dendrites branching from the basal aspect of the cell. These unique
neurons are also substantially larger in size than
other neighboring pyramidal cells. Interestingly,
spindle neurons increase in soma size, density, and
clustering from orang-utans to gorillas, chimpanzees, bonobos, and humans. Furthermore, spindleshaped neurons have been observed in layer Vb of
area 24b in a fetal chimpanzee (E 224), indicating
that this specialized projection cell type differentiates early in development (Hayashi et al., 2001).
Notably, neurons with a spindle phenotype also
have a phylogenetically restricted distribution
within another region, the frontoinsular cortex.
Spindle cells are found in layer V in the frontoinsular cortex only in humans and African great apes
(i.e., gorillas, chimpanzees, and bonobos), being far
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raise uncertainty regarding whether a homolog of
area 10 is present in gorillas. In particular, the
cortex of the frontal pole in gorillas has a prominent layer II and Va, features that are not found
in macaques or other hominoids.
PR
volume and more cytoarchitectonic subdivisions
occupy the orbitofrontal cortex adjacent to area
13. In contrast, area 13 of orang-utans is relatively large and thus occupies the majority of the
orbitofrontal region.
p0170
Area 10 is a granular cortex that forms a part
of the frontal pole in most hominoid species,
including humans, chimpanzees, bonobos, orangutans, and gibbons (Figure 11) (Semendeferi et al.,
2001). This cortical area is involved in planning
and decision-making (Fuster, 1998). Area 10
receives highly processed sensory afferents from
corticocortical connections in addition to inputs
from the mediodorsal nucleus of the thalamus,
striatum, and many limbic structures (Öngür and
Price, 2000). In hominoids, the cytoarchitecture of
area 10 is characterized by a distinct layer II, a
wide layer III with large pyramidal cells in its
deep portion, a clearly differentiated granular
layer IV, large pyramidal cells in layer Va, and a
sharp boundary between layer VI and the white
matter. Quantitative analyses reveal a similar pattern of relative laminar widths among humans,
chimpanzees, and bonobos, such that the supragranular layers are relatively thick compared to
the infragranular layers (Semendeferi et al.,
2001). In contrast, the infragranular layers comprise a greater proportion of cortical thickness in
the other hominoids. When GLI profile curves
describing laminar variation in neuron volume
densities are compared among taxa, apes and
macaques follow a similar pattern with roughly
equal GLI throughout the cortical depth. The proportion of neuropil space in layers II and III
relative to infragranular layers, however, is greater
in humans. Notably, Semendeferi et al. (2001)
T
14
I
II
I
II
III
III
III
I
II
IV
III
IV
V
V
VI
VI
I
II
IV
V
IV
IV
III
V
V
IV
VI
VI
VI
V
VI
wm
Human
wm
Bonobo
wm
Chimpanzee
wm
Gorilla
wm
Orang-utan
b0690
wm
Gibbon
f0055 Figure 11 The cytoarchitecture of area 10 in hominoids. Scale bar¼500mm. Modified from Semendeferi et al. (2001).
NRVS 00022
The Evolution of Neuron Types and Cortical Histology in Apes and Humans 15
4.21.3 Patterns of Cortical
Organization in Hominoids
s0065
4.21.3.1 The Emergence of Cell Types
and their Distribution
s0070
f0060 Figure 12 Morphology of spindle-shaped neurons in layer Vb
of anterior cingulate cortex in a bonobo (Pan paniscus) (a) and
gorilla
(Gorilla gorilla) (b). Scale bar¼80mm. Modified from
b0540
Nimchinsky et al. (1999).
more numerous in humans compared to the apes
(see 00165; Hakeem et al., 2004).
p0180
In addition to spindle-shaped neurons, the anterior cingulate cortex of great apes and humans
contains another unique pyramidal cell phenotype.
A survey of the anterior cingulate cortex of several
primate species revealed a small subpopulation of
CR-containing layer V pyramidal neurons that are
only found in great apes and humans (Hof et al.,
2001). These neurons are located in the superficial
part of layer V in areas 24 and 25. In orang-utans,
they comprise 0.5% of all layer V pyramidal cells in
the anterior cingulate, 2% in gorillas, 4.1% in chimpanzees, and 5.3% in humans. The occurrence of
these cells decreases sharply at the boundary
between anterior and posterior cingulate cortex,
suggesting that they are not directly involved in the
somatic motor functions associated with the posterior cingulate motor areas.
p0185
The restricted phylogenetic distribution of spindle-shaped cells and CR-ir pyramidal neurons in
layer V of anterior cingulate cortex may reflect specializations of projection neurons in this region for a
role in the control of vocalization, facial expression,
attention, the expression and interpretation of emotions, and autonomic functions (Nimchinsky et al.,
1999; Allman et al., 2001; Hof et al., 2001). Of
particular interest, in humans, CR-immunoreactive
layer V pyramidal neurons are also present in the
anterior paracingulate cortex (area 32) (Hof et al.,
2001). The presence of this distinctive projection
cell type in area 32 of humans is intriguing, considering that this cortical area has been found to be
recruited in tasks that require theory of mind
(Gallagher et al., 2000), which is the capacity to
attribute mental states such as attention, intention,
and beliefs to others and may be a cognitive capacity
that is exclusive to humans (Tomasello et al., 2003).
SE
VI
ER
FI
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RS
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EL
b0020
PR
(b)
T
(a)
OO
F
Particular cellular subtypes appear to have phylo- p0190
genetically restricted distributions. It is interesting
that among hominoids, the presence of these unique
neuron phenotypes accords with the hierarchical
nested structure of monophyletic taxa, suggesting
that they are indicators of phylogenetic relationships (Table 2). For example, in all great apes and
humans, spindle-shaped neurons are found in layer
V of anterior cingulate cortex. Also in these taxa,
CR-ir pyramidal cells are found in layer V of anterior cingulate cortex and primary motor cortex. In
just African great apes and humans, layer V spindleshaped neurons are found in frontoinsular cortex.
And only in humans, CR-ir pyramidal neurons in
layer V are found in anterior paracingulate cortex.
Thus, novel neuron phenotypes have appeared at
several different times in hominoid evolution.
It is tempting to speculate that the evolution of p0195
each unique neuron type marks specializations of
the cortical areas involved. In particular, the morphomolecular characteristics of these novel neuron
types suggest that there have been modifications of
specific efferent projections to facilitate high levels
of activity or higher conduction velocity for outputs.
The possibility that the great ape and human clade is
distinguished by such specializations of projection
cells is especially intriguing in light of recent hypotheses that intelligence among mammals is correlated
with the rate of information processing capacity as
represented by axonal conduction speed (Roth and
Dicke, 2005). The presence of unique neuron classes
in great apes and humans extends this hypothesis to
suggest that specific cortical efferents located within
behaviorally relevant circuits may be selectively
modified. It is also significant that a common feature of these novel projection cells is their
localization in layer V. This laminar distribution
indicates that evolutionary modifications have
been focused upon descending cortical control over
targets in the brainstem and spinal cord.
b0655
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b0265
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4.21.3.2 The Evolution of Cortical Asymmetries
s0075
A substantial body of evidence shows that the p0200
human cerebral cortex expresses lateralization in
the control of language and fine motor actions of
the hand (Toga and Thompson, 2003). Asymmetries
in histological structure have been demonstrated
across cortical areas implicated in these processes
in humans, including Broca’s area (areas 44 and 45),
b0770
NRVS 00022
16
The Evolution of Neuron Types and Cortical Histology in Apes and Humans
t0010 Table 2 Phylogenetic distribution of some cortical histological traits
Primary visual cortexb
Primary visual cortexb
Primary visual cortexb
Auditory belt cortexc
a
þ
þ
þ
?
þþ
?
þþ
?
þþ
?
þ
þþ
?
þþ
þþ
þþ
?
þ
þ
?
þ
þ
?
þ
þ
?
?
þ
?
?
þ
?
?
?
þþ
?
þþ
?
?
?
þ
þþ
þþ
þþ
þ
þ
þþ
?
þþ
þ
þ
?
þ
?
?
þþ
þ
þ
þ
ER
Anterior cingulate
cortexd
Anterior cingulate
cortexe
Anterior paracingulate
cortexe
Frontoinsular cortexf
?
F
Primary motor cortexa
þ
FI
Primary motor cortexa
CR-ir pyramidal
neurons
Layer V PV-ir pyramidal
neurons
Layers NPNFP-ir
III and
neurons
V
Layer
Loss of COIVA
dense band
Layer
Dense CB-ir
IVA
neurons and
neuropil
Layer
Meshwork with
IVA
dense
NPNFP and
Cat-301
staining in
mesh bands
alternating
with dense
CB in
interstitial
zones
Layers AchE-stained
III and
pyramidal
V
cells
Layer
Spindle-shaped
Vb
neurons
Layer
CR-ir pyramidal
Vb
neurons
Layer
CR-ir pyramidal
Vb
neurons
Layer
Spindle-shaped
Vb
neurons
Gorilla Pongo
Hylobates Macaca
gorilla pygmaeus sp.
sp.
OO
Layer V
Homo
Pan
Pan
sapiens paniscus troglodytes
PR
Primary motor cortexa
Trait
T
Layer
RS
Cortical area
b0725
(Sherwood
et al., 2004a)
b0580
(b0310
Preuss and Coleman, 2002)
c
(Hackett
et al., 2001)
b0540
d
(Nimchinsky
et al., 1999)
b0360
e
(b0315
Hof et al., 2001)
f
(Hakeem et al., 2004)
þ¼present; þþ¼present and abundant in comparison to other species; ¼absent
SE
VI
b
EL
Wernicke’s area (area Tpt), and the hand representation of primary motor cortex (area 4). Some
authors have hypothesized that these anatomical
asymmetries are exclusive adaptations of the
human brain that are encoded genetically and comprise the chief evolutionary novelty in the speciation
of modern humans (Crow, 2000; Annett, 2002).
p0205
An alternative view is that functional and anatomical lateralization may be a byproduct of increases
in overall brain size (Ringo et al., 1994; Hopkins
and Rilling, 2000). One cost of increasing brain size
is that axons must propagate action potentials over
a greater distance to communicate between the
hemispheres (Harrison et al., 2002). While these
b0190
b0635
b0320
b0040
b0395
delays in conduction can be overcome to some
extent by increasing axon cross-sectional area and
myelination (Changizi, 2001), the design problems
associated with large brains ultimately may necessitate increased modularity of processing and more of
an emphasis on local network connectivity (Kaas,
2000). In particular, as brains grow in size, the
efficiency of interhemispheric transfer of information by long connections diminishes because costs,
in terms of wiring space, dictate that axons cannot
increase cross-sectional area sufficiently to keep
pace with demands for processing speed (Aboitiz
and Montiel, 2003). Hence, it is expected that cortical processes in large brains, especially those that
b0160
b0435
b0005
NRVS 00022
The Evolution of Neuron Types and Cortical Histology in Apes and Humans 17
F
b0185
ER
FI
RS
b0120
OO
b0395
PR
b0635
b0550
b0310
hominoids (Hackett et al., 2001) is of functional
importance until we have developed a clearer understanding of the scaling principles that govern the
distribution of AChE-enriched neurons in general?
Hence, whenever possible it is best to evaluate phylogenetic variation in cortical histology from the
perspective of allometric scaling. Accordingly, the
case for declaring that a trait is a phylogenetic specialization is strengthened when it can be
demonstrated that individual species depart from
allometric expectations or that an entire clade scales
along a different trajectory (i.e., grade shift).
It is well established that cortical neuron density p0220
varies among mammalian species. Across a large
sample of mammals ranging from mouse to elephant, there is a negative correlation between
cortical neuron density and brain size (Tower,
1954; Cragg, 1967; Haug, 1987; Prothero, 1997).
Despite this broad trend, however, some evidence
suggests that neuron densities may be higher in
hominoids (gorilla, chimpanzee, and human) than
expected for their brain size (Haug, 1987). It has
also been shown that the fraction of the cortex that
is comprised by neuropil space versus cell somata
increases in a negative allometric fashion with
greater brain size (Shariff, 1953; Tower, 1954;
Bok, 1959; Tower and Young, 1973; Zilles et al.,
1982; Armstrong et al., 1986; Haug, 1987). These
empirical findings fit with a model predicting that a
constant average percent interconnectedness among
neurons cannot feasibly be maintained in the face of
increasing gray matter volume, so the reach of processing networks cannot keep pace with brain size
variation (Changizi, 2001).
Many of these theories concerning the scaling of p0225
network connectedness across brain size, however,
were developed to explain variation in mouse to
elephant comparisons. Are these predicted allometric relationships between neuron density,
neuropil space, and brain size maintained when
comparisons are restricted to the hominoids? AU2
Table 3 shows the results of stereologic estimates
of neuron density and GLI from recent comparative studies of areas 4, 10, and 13 in hominoids.
In each of these cortical areas, there is not a
correlation between neuron densities or GLI and
brain size. Therefore, the mammal-wide relationship between these parameters and brain size may
not explain interspecific variance in interconnectedness within cortical areas of hominoids. This
raises the interesting possibility that differences
among hominoid species in these variables might
instead correspond to functionally significant
modifications in the organization of cortical
interconnections.
s0080 4.21.3.3 How much Variation in Cortical
SE
Interpretation of interspecific differences in the histological structure of the cortex in hominoids
requires parsing the source of this variation.
Certainly a portion of it can be attributed to specific
alterations of circuitry that generate behavioral differences among species. Another cause, however,
may be the effects of allometric scaling. That is, as
overall brain size changes, predictable changes
occur in cell sizes, cell packing density, dendritic
geometries, and other aspects of microstructure
(Jerison, 1973; Striedter, 2005). Thus, with variation in brain size among hominoids, some of the
observed interspecific differences may simply be
the result of scaling to maintain functional equivalence and may not indicate any significant
differences in computational capacities. For example, how can we know whether greater densities of
AChE-stained neurons in the auditory belt of
EL
p0215
VI
Architecture can be Attributed to Scaling
versus Specialization?
b0430
b0755
b0780
b0330
T
depend on rapid computations, will come to rely on
specialized processing that is dominant in one hemisphere. Indeed, it has been shown that increasing
brain size is accompanied by reduced hemispheric
interconnectivity via the corpus callosum (Ringo
et al., 1994; Olivares et al., 2001) and the development of more pronounced gross cerebral
asymmetries among anthropoid primates (Hopkins
and Rilling, 2000).
p0210
One consequence of lateralized hemispheric specialization of function may be divergence in the
histological organization of homotopic cortical
areas. Unfortunately, there is a surprising absence
of data from non-humans concerning microstructural asymmetries in the homologues of Broca’s
area, Wernicke’s area, and primary motor cortex.
At present, the sole study of such histological asymmetry indicates that lateralization is not present in
area Tpt of chimpanzees or macaques, while asymmetry of neuropil space and minicolumn widths are
observed in humans (Buxhoeveden et al., 2001a).
Although this is an important finding, it should be
kept in mind that there are many other aspects of
microstructural organization that have been demonstrated to be asymmetric in the human cortex, such
as distributions of cell volumes and dendritic geometry, which have yet to be investigated in other
species. Thus, at the present time, there are still
insufficient data to adequately resolve whether
many of the observed microstructural asymmetries
of the human cerebral cortex are unique speciesspecific adaptations that are related to language
and handedness.
b0605
b0330
b0705
b0085
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b0885
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NRVS 00022
18
The Evolution of Neuron Types and Cortical Histology in Apes and Humans
t0015 Table 3 Neuron densities (in neurons per mm3) and Grey Level Index (GLI) values for different cortical areas in hominoids and Old
World monkeys
Area 4a
Area 10 b
Area 13 c
GLI
Neuron density
GLI
Neuron density
GLI
Neuron density
Homo sapiens
Pan troglodytes
Pan paniscus
Gorilla gorilla
Pongo pygmaeus
Hylobates lar
Macaca sp.
Papio anubis
11.65
13.19
–
8.76
10.61
–
15.58
14.85
18,048
22,177
–
24,733
18,825
–
50,798
33,661
15.17
17.52
18.17
15.87
20.10
19.80
20.34
–
34,014
60,468
55,690
47,300
78,182
86,190
–
–
14.18
18.63
16.98
14.62
18.55
13.33
18.36
–
30,351
50,686
44,111
54,783
42,400
53,830
–
–
OO
b0735
RS
b0785
ir neurons scale against total neuron density with
positive allometry in areas V1 and V2, resulting in a
smaller percentage of CB-ir interneurons in apes
compared to monkeys in these areas (Sherwood
et al., 2005). Further studies using allometric
approaches to examine the scaling of different neuron subtypes will be necessary to elucidate
phylogenetic specializations of cortical circuitry.
T
Other aspects of network scaling in the cerebral
cortex are less well understood. For example, there
does not appear to be a correlation between brain
size and the density of glial cells (Tower and Young,
1973; Haug, 1987). However, phylogenetic differences in glial cell densities have not yet been
systematically examined using modern immunohistochemical markers to identify astrocytes and
oligodendrocytes separately. Furthermore, questions regarding the scaling of subpopulations of
interneurons and pyramidal cells have only begun
to be addressed. Evidence suggests that the proportion of pyramidal neurons that are enriched in
NPNFP may increase with brain size. In the orofacial representation of primary motor cortex, there is
a striking increase in the percentage of neurons
stained for NPNFP in larger-brained great apes
and humans in comparison to smaller-brained Old
World monkeys (Sherwood et al., 2004a). Tsang
and colleagues (2000) also found increasing
NPNFP labeling in primary motor cortex across a
sample including rats, marmosets, rhesus macaques,
and humans. In addition, Campbell and Morrison
(1989) found a larger proportion of NPNFP-ir pyramidal neurons, particularly in supragranular
layers, in humans compared to macaque monkeys
across several different cortical areas.
p0235
Interneuron subtypes, as revealed by labeling for
calcium-binding proteins, appear to adhere to different scaling trends in anthropoid primates depending
on the cortical area. For example, when regressed on
total neuron density, the density of PV-ir neurons
scales with negative allometry in the primary motor
cortex and thus a greater proportion of PV-ir neurons
is observed in hominoids compared to Old World
monkeys (Sherwood et al., 2004a). In contrast, CBp0230
PR
Inb0715
all studies, neuron densities
were estimated by the optical dissector method.
b0730
a
(Sherwood
et al., 2003b; Sherwood et al., 2004b)
b0690
b
(b0680
Semendeferi et al., 2001)
c
(Semendeferi et al., 1998)
F
Species
VI
ER
FI
b0330
EL
SE
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b0725
b0140
b0790
4.21.3.4 Genomic Data Provide Insights
into Cortical Specializations
s0085
Recent studies of phylogenetic variation in gene p0240
sequences and expression provide additional
insights into cortical specializations among hominoids. While most of these studies have been
directed at determining the genetic basis for human
neural uniqueness (Enard et al., 2002a; 2002b;
Caceres et al., 2003; Dorus et al., 2004; Uddin
et al., 2004), some molecular data point to changes
that occurred at earlier times in the hominoid radiation. For instance, all hominoids have evolved a
novel biochemical mechanism to support high levels
of glutamate flux in neurotransmission through the
retroposition of the gene GLUD1 (Burki and
Kaessmann, 2004). This duplicated gene, GLUD2,
which is unique to hominoids, encodes an isotype of
the enzyme glutamate dehydrogenase that is
expressed in astrocytes. All hominoid GLUD2
sequences contain two key amino acid substitutions
that allow the GLUD2 enzyme to be activated in
astrocytes during conditions of high glutamatergic
neurotransmitter flux. Concordant with this evidence for alterations in the molecular machinery
necessary for enhanced neuronal activity in apes, it
has been shown that the gene encoding the
b0215
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NRVS 00022
The Evolution of Neuron Types and Cortical Histology in Apes and Humans 19
s0090
OO
F
There remains an extraordinary amount to learn p0260
regarding the microstructure of the cerebral cortex
of hominoids. Even the basic cytoarchitecture of
many cortical areas, such as the posterior parietal
cortex, inferior temporal cortex, posterior cingulate
cortex, and premotor cortex, has not yet been
explored using the methods of modern quantitative
neuroanatomy. Moreover, there is not a single
recent study of parcellation for any part of the cerebral cortex using chemoarchitectural staining
techniques in apes. It will also be important to
examine the scaling patterns that govern the distribution of neurochemically identified subsets of
pyramidal neurons, interneurons, and glia across
different cortical areas from a broad phylogenetic
perspective in order to clearly distinguish network
allometric scaling from phylogenetic specialization.
Finally, determination of whether humanlike histological asymmetries of cortical areas important in
language and control of the hand are present in
other apes still requires systematic study. By taking
seriously the task of understanding such speciesspecific neural adaptations, we stand to learn an
extraordinary amount about the underlying substrates of the cognitive abilities of humans and our
closest relatives.
FI
RS
b0485
4.21.3.5 On the Horizon
PR
b0855
is any hope of understanding how such molecular
differences translate into modifications of the computational capacities of cortical circuits.
T
cytochrome c oxidase subunit 4-1 underwent rapid
nonsynonymous evolution in the hominoid stem,
followed by purifying selection in descendent
lineages (Wildman et al., 2002). Because these
nucleotide substitutions have functional consequences for the manner and rate at which electrons
are transferred from cytochrome c to oxygen, it is
likely that these modifications were selected to serve
the needs of cells with high aerobic energy demands,
such as neurons.
p0245
Also of significance, an alternative splice variant of
neuropsin (type II) has originated in recent hominoid
evolution (Li et al., 2004). Neuropsin is expressed in
hippocampal pyramidal neurons and is involved in
neuronal plasticity. The high incidence of polymorphisms in the coding region of this protein in
gibbons and orang-utans, however, suggests that it
may not be functional in these species. In contrast,
the coding region of the type II splice form of neuropsin shows relatively little variation in gorillas,
chimpanzees, and humans, signifying that it is maintained by functional constraint and that it might be
involved in a molecular pathway important for learning and memory in these hominoids.
p0250
With respect to brain size, several genes that are
involved in controlling the development of cerebral
cortex size have undergone accelerated rates of
sequence evolution in the hominoid lineage. The
microcephalin gene shows an upsurge of nonsynonymous amino acid substitutions in a protein-coding
domain of the last common ancestor of great apes
and humans (Wang and Su, 2004). Additionally, the
ASPM gene shows evidence of adaptive sequence
evolution in all African hominoids (i.e., gorillas,
chimpanzees, bonobos, and humans) (Kouprina
et al., 2004).
p0255
These data put into phylogenetic context evidence
that, in the lineage leading to humans, several genes
important in the development, physiology, and
function of the cerebral cortex show positive selection (Enard et al., 2002b; Dorus et al., 2004; Evans
et al., 2004). Furthermore, findings from studies
that have compared human and chimpanzee transcriptomes indicate that the human cerebral cortex
is distinguished by elevated expression levels of
many genes associated with energy metabolism
(Caceres et al., 2003; Uddin et al., 2004), suggesting
that levels of neuronal activity might be higher in
humans compared to chimpanzees (Preuss et al.,
2004). While the phenotypic correlates of many of
these genetic changes await characterization by
in situ hybridization and immunohistochemical studies, it is clear that intensified efforts at analyzing
variation in the histological organization of the
hominoid cerebral cortex will be necessary if there
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Acknowledgements
This work was supported by the National Science p0265
Foundation (BCS-0515484 and BCS-0549117), the
Wenner-Gren Foundation for Anthropological
Research, and the James S. McDonnell Foundation
(22002078). The great ape brain materials were
available from the Great Ape Aging Project,
Cleveland Metroparks Zoo, and the Foundation
for Comparative and Conservation Biology.
Further Reading
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Holloway, R. L. 1996. Evolution of the human brain.
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Preuss, 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.
Zilles, K. 2005. Evolution of the human brain and comparative
cyto- and receptor architecture. In: From Monkey
Brain to Human Brain: a Fyssen Foundation Symposium
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b0005 Aboitiz, F. and Montiel, J. 2003. One hundred million years of
interhemispheric communication: the history of the corpus
callosum. Braz. J. Med. Biol. Res. 36, 409–420.
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Hof, P. 2001. The anterior cingulate cortex. The evolution of
an interface between emotion and cognition. Ann. N. Y. Acad.
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b0025 Amunts, K., Schlaug, G., Schleicher, A., et al. 1996. Asymmetry
in the human motor cortex and handedness. Neuroimage 4,
216–222.
b0030 Amunts, K., Schleicher, A., Burgel, U., Mohlberg, H.,
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asymmetries of the posterior superior temporal lobes: a postmortem study. Neuropsychiatry Neuropsychol. Behav.
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b0055 Bailey, P., von Bonin, G., and McCulloch, W. S. 1950. The
Isocortex of the Chimpanzee. University of Illinois Press.
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