Cheryl D. Stimpson

Prolonged myelination in human neocortical evolution

Nerve myelination facilitates saltatory action potential conduction and exhibits spatiotemporal variation during development associated with the acquisition of behavioral and cognitive maturity. Although human cognitive development is unique, it is not known whether the ontogenetic progression of myelination in the human neocortex is evolutionarily exceptional. In this study, we quantified myelinated axon fiber length density and the expression of myelin-related proteins throughout postnatal life in the somatosensory (areas 3b/3a/1/2), motor (area 4), frontopolar (prefrontal area 10), and visual (areas 17/18) neocortex of chimpanzees (N = 20) and humans (N = 33). Our examination revealed that neocortical myelination is developmentally protracted in humans compared with chimpanzees. In chimpanzees, the density of myelinated axons increased steadily until adult-like levels were achieved at approximately the time of sexual maturity. In contrast, humans displayed slower myelination during childhood, characterized by a delayed period of maturation that extended beyond late adolescence. This comparative research contributes evidence crucial to understanding the evolution of human cognition and behavior, which arises from the unfolding of nervous system development within the context of an enriched cultural environment. Perturbations of normal developmental processes and the decreased expression of myelin-related molecules have been related to psychiatric disorders such as schizophrenia. Thus, these species differences suggest that the human-specific shift in the timing of cortical maturation during adolescence may have implications for vulnerability to certain psychiatric disorders.

Evolution of increased glia–neuron ratios in the human frontal cortex

Evidence from comparative studies of gene expression and evolution suggest that human neocortical neurons may be characterized by unusually high levels of energy metabolism. The current study examined whether there is a disproportionate increase in glial cell density in the human frontal cortex in comparison with other anthropoid primate species (New World monkeys, Old World monkeys, and hominoids) to support greater metabolic demands. Among 18 species of anthropoids, humans displayed the greatest departure from allometric scaling expectations for the density of glia relative to neurons in layer II/III of dorsolateral prefrontal cortex (area 9L). However, the human glia–neuron ratio in this prefrontal region did not differ significantly from allometric predictions based on brain size. Further analyses of glia–neuron ratios across frontal areas 4, 9L, 32, and 44 in a sample of humans, chimpanzees, and macaque monkeys showed that regions involved in specialized human cognitive functions, such as “theory of mind” (area 32) and language (area 44) have not evolved differentially higher requirements for metabolic support. Taken together, these findings suggest that greater metabolic consumption of human neocortical neurons relates to the energetic costs of maintaining expansive dendritic arbors and long-range projecting axons in the context of an enlarged brain.

Cortical dopaminergic innervation among humans, chimpanzees, and macaque monkeys: A comparative study

In this study, we assessed the possibility that humans differ from other primate species in the supply of dopamine to the frontal cortex. To this end, quantitative comparative analyses were performed among humans, chimpanzees, and macaques using immunohistochemical methods to visualize tyrosine hydroxylase-immunoreactive axons within the cerebral cortex. Axon densities and neuron densities were quantified using computer-assisted stereology. Prefrontal areas 9 and 32 were chosen for evaluation due to their roles in higher-order executive functions and theory of mind, respectively. Primary motor cortex (area 4) was also evaluated because it is not directly associated with cognition. We did not find an overt quantitative increase in cortical dopaminergic innervation in humans relative to the other primates examined. However, several differences in cortical dopaminergic innervation were observed among species which may have functional implications. Specifically, humans exhibited a sublaminar pattern of innervation in layer I of areas 9 and 32 that differed from that of macaques and chimpanzees. Analysis of axon length density to neuron density among species revealed that humans and chimpanzees together deviated from macaques in having increased dopaminergic afferents in layers III and V/VI of areas 9 and 32, but there were no phylogenetic differences in area 4. Finally, morphological specializations of axon coils that may be indicative of cortical plasticity events were observed in humans and chimpanzees, but not macaques. Our findings suggest significant modifications of dopamines role in cortical organization occurred in the evolution of the apes, with further changes in the descent of humans.

Wernicke's area homologue in chimpanzees (Pan troglodytes) and its relation to the appearance of modern human language

Human language is distinctive compared with the communication systems of other species. Yet, several questions concerning its emergence and evolution remain unresolved. As a means of evaluating the neuroanatomical changes relevant to language that accompanied divergence from the last common ancestor of chimpanzees, bonobos and humans, we defined the cytoarchitectonic boundaries of area Tpt, a component of Wernickes area, in 12 common chimpanzee brains and used design-based stereologic methods to estimate regional volumes, total neuron number and neuron density. In addition, we created a probabilistic map of the location of area Tpt in a template chimpanzee brain coordinate space. Our results show that chimpanzees display significant population-level leftward asymmetry of area Tpt in terms of neuron number, with volume asymmetry approaching significance. Furthermore, asymmetry in the number of neurons in area Tpt was positively correlated with asymmetry of neuron numbers in Brodmanns area 45, a component of Brocas frontal language region. Our findings support the conclusion that leftward asymmetry of Wernickes area originated prior to the appearance of modern human language and before our divergence from the last common ancestor. Moreover, this study provides the first evidence of covariance between asymmetry of anterior and posterior cortical regions that in humans are important to language and other higher order cognitive functions.

Synaptogenesis and development of pyramidal neuron dendritic morphology in the chimpanzee neocortex resembles humans

Neocortical development in humans is characterized by an extended period of synaptic proliferation that peaks in mid-childhood, with subsequent pruning through early adulthood, as well as relatively delayed maturation of neuronal arborization in the prefrontal cortex compared with sensorimotor areas. In macaque monkeys, cortical synaptogenesis peaks during early infancy and developmental changes in synapse density and dendritic spines occur synchronously across cortical regions. Thus, relatively prolonged synapse and neuronal maturation in humans might contribute to enhancement of social learning during development and transmission of cultural practices, including language. However, because macaques, which share a last common ancestor with humans ∼25 million years ago, have served as the predominant comparative primate model in neurodevelopmental research, the paucity of data from more closely related great apes leaves unresolved when these evolutionary changes in the timing of cortical development became established in the human lineage. To address this question, we used immunohistochemistry, electron microscopy, and Golgi staining to characterize synaptic density and dendritic morphology of pyramidal neurons in primary somatosensory (area 3b), primary motor (area 4), prestriate visual (area 18), and prefrontal (area 10) cortices of developing chimpanzees (Pan troglodytes). We found that synaptogenesis occurs synchronously across cortical areas, with a peak of synapse density during the juvenile period (3–5 y). Moreover, similar to findings in humans, dendrites of prefrontal pyramidal neurons developed later than sensorimotor areas. These results suggest that evolutionary changes to neocortical development promoting greater neuronal plasticity early in postnatal life preceded the divergence of the human and chimpanzee lineages.

Cholinergic innervation of the frontal cortex: differences among humans, chimpanzees, and macaque monkeys.

Cholinergic innervation of the frontal cortex is important in higher cognitive functions and may have been altered in humans relative to other species to support human‐specific intellectual capacities. To evaluate this hypothesis we conducted quantitative comparative analyses of choline acetyltransferase‐immunoreactive axons in cortical areas 9, 32, and 4 among humans, chimpanzees, and macaque monkeys. Area 9 of the dorsolateral prefrontal cortex is involved in inductive reasoning and specific components of working memory processes, while area 32 of the medial prefrontal cortex has been implicated in theory of mind. Area 4 (primary motor cortex) was also evaluated because it is not directly associated with higher cognitive functions. The findings revealed no quantitative species differences in the three cortical areas examined, indicating that human cognitive specializations are not related to a quantitative increase in cortical cholinergic input. However, species‐specific morphological specializations were observed. Clusters of cholinergic fibers that may be indicative of cortical plasticity events were present in chimpanzees and humans, but not in macaques. The other significant morphology noted was the common and distinctive oval or ovoid perisomatic staining in macaque cortices. This feature was also sporadically observed in chimpanzee cortex. Our findings suggest a potential alteration of cortical cholinergic afferents within the prefrontal cortex of humans and chimpanzees, to the exclusion of macaque monkeys. J. Comp. Neurol. 506:409–424, 2008.

Scaling of inhibitory interneurons in areas V1 and V2 of anthropoid primates as revealed by calcium-binding protein immunohistochemistry

Inhibitory GABAergic interneurons are important for shaping patterns of activity in neocortical networks. We examined the distributions of inhibitory interneuron subtypes in layer II/III of areas V1 and V2 in 18 genera of anthropoid primates including New World monkeys, Old World monkeys, and hominoids (apes and humans). Interneuron subtypes were identified by immunohistochemical staining for calbindin, calretinin, and parvalbumin and densities were quantified using the optical disector method. In both V1 and V2, calbindin-immunoreactive neuron density decreased disproportionately with decreasing total neuronal density. Thus, V1 and V2 of hominoids were occupied by a smaller percentage of calbindin-immunoreactive interneurons compared to monkeys who have greater overall neuronal densities. At the transition from V1 to V2 across all individuals, we found a tendency for increased percentages of calbindin-immunoreactive multipolar cells and calretinin-immunoreactive interneurons. In addition, parvalbumin-immunoreactive cell soma volumes increased from V1 to V2. These findings suggest that modifications of specific aspects of inhibition might be critical to establishing the receptive field properties that distinguish visual areas. Furthermore, these results show that phylogenetic variation exists in the microcircuitry of visual cortex that could have general implications for sensory processing.

Neuropil Distribution in the Cerebral Cortex Differs Between Humans and Chimpanzees

Increased connectivity of high‐order association regions in the neocortex has been proposed as a defining feature of human brain evolution. At present, however, there are limited comparative data to examine this claim fully. We tested the hypothesis that the distribution of neuropil across areas of the neocortex of humans differs from that of one of our closest living relatives, the common chimpanzee. The neuropil provides a proxy measure of total connectivity within a local region because it is composed mostly of dendrites, axons, and synapses. Using image analysis techniques, we quantified the neuropil fraction from both hemispheres in six cytoarchitectonically defined regions including frontopolar cortex (area 10), Brocas area (area 45), frontoinsular cortex (area FI), primary motor cortex (area 4), primary auditory cortex (area 41/42), and the planum temporale (area 22). Our results demonstrate that humans exhibit a unique distribution of neuropil in the neocortex compared to chimpanzees. In particular, the human frontopolar cortex and the frontoinsular cortex had a significantly higher neuropil fraction than the other areas. In chimpanzees these prefrontal regions did not display significantly more neuropil, but the primary auditory cortex had a lower neuropil fraction than other areas. Our results support the conclusion that enhanced connectivity in the prefrontal cortex accompanied the evolution of the human brain. These species differences in neuropil distribution may offer insight into the neural basis of human cognition, reflecting enhancement of the integrative capacity of the prefrontal cortex. J. Comp. Neurol. 520:2917–2929, 2012.

Biochemical specificity of von Economo neurons in hominoids

Objectives: Von Economo neurons (VENs) are defined by their thin, elongated cell body and long dendrites projecting from apical and basal ends. These distinctive neurons are mostly present in anterior cingulate (ACC) and fronto‐insular (FI) cortex, with particularly high densities in cetaceans, elephants, and hominoid primates (i.e., humans and apes). This distribution suggests that VENs contribute to specializations of neural circuits in species that share both large brain size and complex social cognition, possibly representing an adaptation to rapidly relay socially‐relevant information over long distances across the brain. Recent evidence indicates that unique patterns of protein expression may also characterize VENs, particularly involving molecules that are known to regulate gut and immune function.

Neocortical neuron types in Xenarthra and Afrotheria: implications for brain evolution in mammals

Interpreting the evolution of neuronal types in the cerebral cortex of mammals requires information from a diversity of species. However, there is currently a paucity of data from the Xenarthra and Afrotheria, two major phylogenetic groups that diverged close to the base of the eutherian mammal adaptive radiation. In this study, we used immunohistochemistry to examine the distribution and morphology of neocortical neurons stained for nonphosphorylated neurofilament protein, calbindin, calretinin, parvalbumin, and neuropeptide Y in three xenarthran species—the giant anteater (Myrmecophaga tridactyla), the lesser anteater (Tamandua tetradactyla), and the two-toed sloth (Choloepus didactylus)—and two afrotherian species—the rock hyrax (Procavia capensis) and the black and rufous giant elephant shrew (Rhynchocyon petersi). We also studied the distribution and morphology of astrocytes using glial fibrillary acidic protein as a marker. In all of these species, nonphosphorylated neurofilament protein-immunoreactive neurons predominated in layer V. These neurons exhibited diverse morphologies with regional variation. Specifically, high proportions of atypical neurofilament-enriched neuron classes were observed, including extraverted neurons, inverted pyramidal neurons, fusiform neurons, and other multipolar types. In addition, many projection neurons in layers II–III were found to contain calbindin. Among interneurons, parvalbumin- and calbindin-expressing cells were generally denser compared to calretinin-immunoreactive cells. We traced the evolution of certain cortical architectural traits using phylogenetic analysis. Based on our reconstruction of character evolution, we found that the living xenarthrans and afrotherians show many similarities to the stem eutherian mammal, whereas other eutherian lineages display a greater number of derived traits.