Melissa K. Edler

Molecular and cellular reorganization of neural circuits in the human lineage

The makings of the primate brain Although nonhuman primate brains are similar to our own, the disparity between their and our cognitive abilities tells us that surface similarity is not the whole story. Sousa et al. overlaid transcriptome and histological analyses to see what makes human brains different from those of nonhuman primates. Various differentially expressed genes, such as those encoding transcription factors, could alter transcriptional programs. Others were associated with neuromodulatory systems. Furthermore, the dopaminergic interneurons found in the human neocortex were absent from the neocortex of nonhuman African apes. Such differences in neuronal transcriptional programs may underlie a variety of neurodevelopmental disorders. Science, this issue p. 1027 Comparing transcriptome and histology of human and nonhuman primate brains reveals changes that make humans unique. To better understand the molecular and cellular differences in brain organization between human and nonhuman primates, we performed transcriptome sequencing of 16 regions of adult human, chimpanzee, and macaque brains. Integration with human single-cell transcriptomic data revealed global, regional, and cell-type–specific species expression differences in genes representing distinct functional categories. We validated and further characterized the human specificity of genes enriched in distinct cell types through histological and functional analyses, including rare subpallial-derived interneurons expressing dopamine biosynthesis genes enriched in the human striatum and absent in the nonhuman African ape neocortex. Our integrated analysis of the generated data revealed diverse molecular and cellular features of the phylogenetic reorganization of the human brain across multiple levels, with relevance for brain function and disease.

Human-specific increase of dopaminergic innervation in a striatal region associated with speech and language: A comparative analysis of the primate basal ganglia

The dopaminergic innervation of the striatum has been implicated in learning processes and in the development of human speech and language. Several lines of evidence suggest that evolutionary changes in dopaminergic afferents of the striatum may be associated with uniquely human cognitive and behavioral abilities, including the association of the human‐specific sequence of the FOXP2 gene with decreased dopamine in the dorsomedial striatum of mice. To examine this possibility, we quantified the density of tyrosine hydroxylase‐immunoreactive axons as a measure of dopaminergic innervation within five basal ganglia regions in humans, great apes, and New and Old World monkeys. Our results indicate that humans differ from nonhuman primate species in having a significant increase in dopaminergic innervation selectively localized to the medial caudate nucleus. This region of the striatum is highly interconnected, receiving afferents from multiple neocortical regions, and supports behavioral and cognitive flexibility. The medial caudate nucleus also shows hyperactivity in humans lacking a functional FOXP2 allele and exhibits altered dopamine concentrations in humanized Foxp2 mice. Additionally, striatal dopaminergic input was not altered in chimpanzees that used socially learned attention‐getting sounds versus those that did not. This evidence indicates that the increase in dopamine innervation of the medial caudate nucleus in humans is a species‐typical characteristic not associated with experience‐dependent plasticity. The specificity of this increase may be related to the degree of convergence from cortical areas within this region of the striatum and may also be involved in human speech and language. J. Comp. Neurol. 524:2117–2129, 2016.

Humans and great apes share increased neocortical neuropeptide Y innervation compared to other haplorhine primates

Neuropeptide Y (NPY) plays a role in a variety of basic physiological functions and has also been implicated in regulating cognition, including learning and memory. A decrease in neocortical NPY has been reported for Alzheimers disease, schizophrenia, bipolar disorder, and depression, potentially contributing to associated cognitive deficits. The goal of the present analysis was to examine variation in neocortical NPY-immunoreactive axon and varicosity density among haplorhine primates (monkeys, apes, and humans). Stereologic methods were used to measure the ratios of NPY-expressing axon length density to total neuron density (ALv/Nv) and NPY-immunoreactive varicosity density to neuron density (Vv/Nv), as well as the mean varicosity spacing in neocortical areas 10, 24, 44, and 22 (Tpt) of humans, African great apes, New World monkeys, and Old World monkeys. Humans and great apes showed increased cortical NPY innervation relative to monkey species for ALv/Nv and Vv/Nv. Furthermore, humans and great apes displayed a conserved pattern of varicosity spacing across cortical areas and layers, with no differences between cortical layers or among cortical areas. These phylogenetic differences may be related to shared life history variables and may reflect specific cognitive abilities.

A neurochemical hypothesis for the origin of hominids

Significance Two factors vital to the human clade are our unique demographic success and our social facilities including language, empathy, and altruism. These have always been difficult to reconcile with individual reproductive success. However, the striatum, a region of the basal ganglia, modulates social behavior and exhibits a unique neurochemical profile in humans. The human signature amplifies sensitivity to social cues that encourage social conformity and affiliative behavior and could have favored provisioning and monogamy in emergent hominids, consilient with the simultaneous origin of upright walking and elimination of the sectorial canine. Such exceptional neurochemistry would have favored individuals especially sensitive to social cues throughout later human evolution and may account for cerebral cortical expansion and the emergence of language. It has always been difficult to account for the evolution of certain human characters such as language, empathy, and altruism via individual reproductive success. However, the striatum, a subcortical region originally thought to be exclusively motor, is now known to contribute to social behaviors and “personality styles” that may link such complexities with natural selection. We here report that the human striatum exhibits a unique neurochemical profile that differs dramatically from those of other primates. The human signature of elevated striatal dopamine, serotonin, and neuropeptide Y, coupled with lowered acetylcholine, systematically favors externally driven behavior and greatly amplifies sensitivity to social cues that promote social conformity, empathy, and altruism. We propose that selection induced an initial form of this profile in early hominids, which increased their affiliative behavior, and that this shift either preceded or accompanied the adoption of bipedality and elimination of the sectorial canine. We further hypothesize that these changes were critical for increased individual fitness and promoted the adoption of social monogamy, which progressively increased cooperation as well as a dependence on tradition-based cultural transmission. These eventually facilitated the acquisition of language by elevating the reproductive advantage afforded those most sensitive to social cues.

Cholinergic innervation of the basal ganglia in humans and other anthropoid primates.

Cholinergic innervation of the basal ganglia is important in learning and memory. Striatal cholinergic neurons integrate cognitive and motivational states with behavior. Given these roles, it is not surprising that deficits in cortical cholinergic innervation have been correlated with loss of cognitive function in Alzheimers disease and schizophrenia. Such evidence suggests the potential significance of subcortical cholinergic innervation in the evolution of the human brain. To compare humans with other closely related primates, the present study quantified axons and interneurons immunoreactive for choline acetyltransferase (ChAT) in regions of the executive and motor loops of the basal ganglia of humans, great apes, and monkeys. We also compared ChAT‐immunoreactive (ir) interneuron morphological types among species within striatal regions. The results indicate that humans and great apes differ from monkeys in having a preponderance of multipolar ChAT‐ir interneurons in the caudate nucleus and putamen, whereas monkeys have a more heterogeneous representation of multipolar, bipolar, and unipolar interneurons. Cholinergic innervation, as measured by axon and interneuron densities, did not differ across species in the medial caudate nucleus. Differences were detected in the dorsal caudate nucleus, putamen, and globus pallidus but the observed variation did not associate with the phylogenetic structure of the species in the sample. However, combining the present results with previously published data for dopamine revealed a unique pattern of innervation for humans, with higher amounts of dopamine compared with acetylcholine in the striatum. Taken together, these findings indicate a potential evolutionary shift in basal ganglia neurotransmission in humans that may favor increased synaptic plasticity. J. Comp. Neurol. 525:319–332, 2017.

Microglia changes associated to Alzheimer's disease pathology in aged chimpanzees

In Alzheimers disease (AD), the brains primary immune cells, microglia, become activated and are found in close apposition to amyloid beta (Aβ) protein plaques and neurofibrillary tangles (NFT). The present study evaluated microglia density and morphology in a large group of aged chimpanzees (n = 20, ages 37–62 years) with varying degrees of AD‐like pathology. Using immunohistochemical and stereological techniques, we quantified the density of activated microglia and morphological variants (ramified, intermediate, and amoeboid) in postmortem chimpanzee brain samples from prefrontal cortex, middle temporal gyrus, and hippocampus, areas that show a high degree of AD pathology in humans. Microglia measurements were compared to pathological markers of AD in these cases. Activated microglia were consistently present across brain areas. In the hippocampus, CA3 displayed a higher density than CA1. Aβ42 plaque volume was positively correlated with higher microglial activation and with an intermediate morphology in the hippocampus. Aβ42‐positive vessel volume was associated with increased hippocampal microglial activation. Activated microglia density and morphology were not associated with age, sex, pretangle density, NFT density, or tau neuritic cluster density. Aged chimpanzees displayed comparable patterns of activated microglia phenotypes as well as an association of increased microglial activation and morphological changes with Aβ deposition similar to AD patients. In contrast to human AD brains, activated microglia density was not significantly correlated with tau lesions. This evidence suggests that the chimpanzee brain may be relatively preserved during normal aging processes but not entirely protected from neurodegeneration as previously assumed.