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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., Data was generated as part of the PsychENCODE Consortium, supported by MH103339, MH106934, and MH110926. Additional support was provided by NIH grants MH109904, MH106874, AG048918, DK111178, and NS092988 (National Chimpanzee Brain Resource), the Kavli Foundation, the James S. McDonnell Foundation, NSF grant BCS-1316829, MINECO BFU2014-55090-P (FEDER), Howard Hughes International Early Career, and Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement de la Generalitat de Catalunya.

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. © 2015 Wiley Periodicals, Inc.

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 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 Alzheimer's 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. © 2016 Wiley Periodicals, Inc.