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Joint attention (JA) is an important milestone in human infant development and is predictive of the onset of language later in life. Clinically, it has been reported that children at risk for or with a diagnosis of autism spectrum disorder (ASD) perform more poorly on measures of JA compared to neurotypical controls. JA is not unique to humans but has also been reported in great apes and to a lesser extent in more distantly related monkeys. Further, individual differences in JA among chimpanzees are associated with polymorphisms in the vasopressin and oxytocin genes, AVPR1A and OXTR. Here, we tested whether individual variation in DNA methylation of OXTR and AVPR1A were associated with performance on JA tasks in chimpanzees. We found that individual differences in JA performance was associated with AVPR1A methylation, but not OXTR methylation in the chimpanzees. The collective results provide further evidence of the role of AVPR1A in JA abilities in chimpanzees. The results further suggest that methylation values for AVPR1A may be useful biomarkers for identifying individuals at risk for ASD or related neurodevelopmental disorders associated with impairments in JA abilities.

International audience; Abstract The superior temporal sulcus (STS) is a conserved fold that divides the middle and superior temporal gyri. In humans, there is considerable variation in the shape, folding pattern, lateralization, and depth of the STS that have been reported to be associated with social cognition and linguistic functions. We examined the role that genetic factors play on individual variation in STS morphology in chimpanzees. The surface area and depth of the STS were quantified in sample of 292 captive chimpanzees comprised of two genetically isolated population of individuals. The chimpanzees had been previously genotyped for AVPR1A and KIAA0319, two genes that play a role in social cognition and communication in humans. Single nucleotide polymorphisms in the KIAA0319 and AVPR1A genes were associated with average depth as well as asymmetries in the STS. By contrast, we found no significant effects of these KIA0319 and AVPR1A polymorphism on surface area and depth measures for the central sulcus. The overall findings indicate that genetic factors account for a small to moderate amount of variation in STS morphology in chimpanzees. These findings are discussed in the context of the role of the STS in social cognition and language in humans and their potential evolutionary origins.

A long-standing topic of interest in human neurosciences is the understanding of the neurobiology underlying human cognition. Less commonly considered is to what extent such systems may be shared with other species. We examined individual variation in brain connectivity in the context of cognitive abilities in chimpanzees ( n = 45) and humans in search of a conserved link between cognition and brain connectivity across the two species. Cognitive scores were assessed on a variety of behavioral tasks using chimpanzee- and human-specific cognitive test batteries, measuring aspects of cognition related to relational reasoning, processing speed, and problem solving in both species. We show that chimpanzees scoring higher on such cognitive skills display relatively strong connectivity among brain networks also associated with comparable cognitive abilities in the human group. We also identified divergence in brain networks that serve specialized functions across humans and chimpanzees, such as stronger language connectivity in humans and relatively more prominent connectivity between regions related to spatial working memory in chimpanzees. Our findings suggest that core neural systems of cognition may have evolved before the divergence of chimpanzees and humans, along with potential differential investments in other brain networks relating to specific functional specializations between the two species.

Detailed neuroscientific data from macaque monkeys have been essential in advancing understanding of human frontal cortex function, particularly for regions of frontal cortex without homologs in other model species. However, precise transfer of this knowledge for direct use in human applications requires an understanding of monkey to hominid homologies, particularly whether and how sulci and cytoarchitectonic regions in the frontal cortex of macaques relate to those in hominids. We combine sulcal pattern analysis with resting-state functional magnetic resonance imaging and cytoarchitectonic analysis to show that old-world monkey brains have the same principles of organization as hominid brains, with the notable exception of sulci in the frontopolar cortex. This essential comparative framework provides insights into primate brain evolution and a key tool to drive translation from invasive research in monkeys to human applications.

Human language is supported by a cortical network involving Broca’s area which comprises Brodmann Areas 44 and 45 (BA44, BA45). While cytoarchitectonic homolog areas have been identified in nonhuman primates, it remains unknown how these regions evolved to support human language. Here, we use histological data and advanced cortical registration methods to precisely compare the morphology of BA44 and 45 between humans and chimpanzees. We found a general expansion of Broca’s areas in humans, with the left BA44 enlarging the most, growing anteriorly into a region known to process syntax. Together with recent functional studies, our findings show that BA44 evolved from a purely action-related region to a more expanded region in humans, with a posterior portion supporting action and an anterior portion supporting syntactic processes. Furthermore, our findings provide a solution for the longstanding debate concerning the structural and functional evolution of Broca’s area and its role in action and language.

Recent studies have shown that great apes predict that other agents will search for objects of interest where the agents believe the objects are hidden. Little is understood about the cognitive process that apes undergo to make such predictions. According to prevailing models, great apes make such predictions by metarepresenting others’ beliefs or perceptual states. We investigated the simpler simulation model. In this model, apes predict where other agents will search for objects of interest by simulating believing what another agent believes about the location of the object. The simulation model predicts that simulating what another believes should manifest in altercentric biasing effects, such as behaving as if one shares another’s belief in cases where the other’s belief is false. We tested this by giving chimpanzees a novel search paradigm embedded in a change-of-location false-belief test and measured where they searched for a grape that they witnessed moved from its original location to a new location. In true-belief trials, chimpanzees were presented with an agent who knew (as they did) that the grape was hidden in the new location; in false-belief trials, the agent falsely believed the grape was still hidden in the original location while the chimpanzee knew it was hidden in the new location. As predicted by the simulation model, chimpanzees searched for the grape closer to its original location than to its new location in significantly more false-belief trials than true-belief trials. Results suggest that chimpanzees show a signature altercentric biasing effect of simulating believing what others believe and may use simulation, rather than metarepresentation, to predict where others will search for objects of interest.

Chimpanzees have consistent individual differences in behaviour, also referred to as personality. Similar to human personality structure, five dimensions are commonly found in chimpanzee studies that show evidence for convergent and predictive validity (Dominance, Openness, Extraversion, Agreeableness, and Reactivity/Undependability). These dimensions are to some extent heritable, indicating a genetic component that explains part of the variation in personality scores, but are also influenced by environmental factors, such as the early social rearing background of the individuals. In this study, we investigated the role of epigenetic modification of the dopamine receptor D2 gene (DRD2) as a potential mechanism underlying personality variation in 51 captive chimpanzees. We used previously collected personality trait rating data and determined levels of DRD2 CpG methylation in peripheral blood samples for these same individuals. Results showed that DRD2 methylation is most strongly associated with Extraversion, and that varying methylation levels at specific DRD2 sites are associated with changes in Extraversion in nursery-reared, but not mother-reared, individuals. These results highlight the role of dopaminergic signalling in chimpanzee personality, and indicate that environmental factors, such as social experiences early in life, can have long-lasting behavioural effects, potentially through modification of the epigenome. These findings add to the growing evidence demonstrating the importance of the experience-dependent methylome for the development of complex social traits like personality.

Varicose projection astrocytes (VP-As) are found in the cerebral cortex and have been described to be specific to humans and chimpanzees. To further examine the phylogenetic distribution of this cell type, we analyzed cortical tissue from several primates ranging from primitive primates to primates evolutionary closer to human such as apes. We specifically analyzed tissue from four strepsirrhine species, one tarsier, six species of platyrrhine monkeys, ten species of cercopithecoid monkeys, two hylobatid ape species, four to six cases each of chimpanzee, bonobo, gorilla, and orangutan, and thirteen human. We found that VP-As were present only in human and other apes (hominoids) and were absent in all other species. We showed that VP-As are localized to layer VI and the superficial white matter of the cortex. The presence of VP-As co-occured with interlaminar astrocytes that also had varicosities in their processes. Due to their location, their long tangential processes, and their irregular presence within species, we propose that VP-As are astrocytes that develop varicosities under specific conditions and that are not a distinct astrocyte type.

Aging is associated with stable decline in the brain’s gray matter. This spatially specific, morphological change in humans has also recently been shown in chimpanzees. The correspondence between species-specific cortical expansion and the degree of brain structure deterioration in aging remains poorly understood. Here, we present a data-driven, cross-species comparative framework and apply it to explore the relationship between gray matter alterations with age and cross-species cerebral expansion in chimpanzees and humans. In humans, we found a positive relationship between cerebral aging and cortical expansion, whereas, in chimpanzees no such relationship was found between aging and cortical expansion. The greater aging and expansion effects in higher-order cognitive regions like the orbito-frontal cortex were observed to be unique to humans. This resembles the last-in, first out hypothesis for neurodevelopment on the evolutionary scale and may suggest a biological cost for recent evolutionary developments of human faculties.

Humans have unique cognitive abilities among primates, including language, but their molecular, cellular, and circuit substrates are poorly understood. We used comparative single nucleus transcriptomics in adult humans, chimpanzees, gorillas, rhesus macaques, and common marmosets from the middle temporal gyrus (MTG) to understand human-specific features of cellular and molecular organization. Human, chimpanzee, and gorilla MTG showed highly similar cell type composition and laminar organization, and a large shift in proportions of deep layer intratelencephalic-projecting neurons compared to macaque and marmoset. Species differences in gene expression generally mirrored evolutionary distance and were seen in all cell types, although chimpanzees were more similar to gorillas than humans, consistent with faster divergence along the human lineage. Microglia, astrocytes, and oligodendrocytes showed accelerated gene expression changes compared to neurons or oligodendrocyte precursor cells, indicating either relaxed evolutionary constraints or positive selection in these cell types. Only a few hundred genes showed human-specific patterning in all or specific cell types, and were significantly enriched near human accelerated regions (HARs) and conserved deletions (hCONDELS) and in cell adhesion and intercellular signaling pathways. These results suggest that relatively few cellular and molecular changes uniquely define adult human cortical structure, particularly by affecting circuit connectivity and glial cell function.

Dehydroepiandrosterone-sulfate is the most abundant circulating androgen in humans and other catarrhines. It is involved in several biological functions, such as testosterone production, glucocorticoid antagonist actions, neurogenesis and neuroplasticty. Although the role of dehydroepiandrosterone-sulfate (DHEAS) in cognition remains elusive, the DHEAS/cortisol ratio has been positively associated with a slower cognitive age-decline and improved mood in humans. Whether this relationship is found in nonhuman primates remains unknown.We measured DHEAS and cortisol levels in serum of 107 adult chimpanzees to investigate the relationship between DHEAS levels and age. A subset of 21 chimpanzees was used to test the potential associations between DHEAS, cortisol, and DHEAS/cortisol ratio in cognitive function, taking into account age, sex, and their interactions. We tested for cognitive function using the primate cognitive test battery (PCTB) and principal component analyses to categorize cognition into three components:DHEAS levels, but not the DHEAS/cortisol ratio, declined with age in chimpanzees. Our analyses for

Astrocytes are the main homeostatic cell of the brain involved in many processes related to cognition, immune response, and energy expenditure. It has been suggested that the distribution of astrocytes is associated with brain size, and that they are specialized in humans. To evaluate these, we quantified astrocyte density, soma volume, and total glia density in layer I and white matter in Brodmann's area 9 of humans, chimpanzees, baboons, and macaques. We found that layer I astrocyte density, soma volume, and ratio of astrocytes to total glia cells were highest in humans and increased with brain size. Overall glia density in layer I and white matter were relatively invariant across brain sizes, potentially due to their important metabolic functions on a per volume basis. We also quantified two transporters involved in metabolism through the astrocyte-neuron lactate shuttle, excitatory amino acid transporter 2 (EAAT2) and glucose transporter 1 (GLUT1). We expected these transporters would be increased in human brains due to their high rate of metabolic consumption and associated gene activity. While humans have higher EAAT2 cell density, GLUT1 vessel volume, and GLUT1 area fraction compared to baboons and chimpanzees, they did not differ from macaques. Therefore, EAAT2 and GLUT1 are not related to increased energetic demands of the human brain. Taken together, these data provide evidence that astrocytes play a unique role in both brain expansion and evolution among primates, with an emphasis on layer I astrocytes having a potentially significant role in human-specific metabolic processing and cognition.

Epigenetic age has emerged as an important biomarker of biological ageing. It has revealed that some tissues age faster than others, which is vital to understanding the complex phenomenon of ageing and developing effective interventions. Previous studies have demonstrated that humans exhibit heterogeneity in pace of epigenetic ageing among brain structures that are consistent with differences in structural and microanatomical deterioration. Here, we add comparative data on epigenetic brain ageing for chimpanzees, humans' closest relatives. Such comparisons can further our understanding of which aspects of human ageing are evolutionarily conserved or specific to our species, especially given that humans are distinguished by a long lifespan, large brain, and, potentially, more severe neurodegeneration with age. Specifically, we investigated epigenetic ageing of the dorsolateral prefrontal cortex and cerebellum, of humans and chimpanzees by generating genome-wide CpG methylation data and applying established epigenetic clock algorithms to produce estimates of biological age for these tissues. We found that both species exhibit relatively slow epigenetic ageing in the brain relative to blood. Between brain structures, humans show a faster rate of epigenetic ageing in the dorsolateral prefrontal cortex compared to the cerebellum, which is consistent with previous findings. Chimpanzees, in contrast, show comparable rates of epigenetic ageing in the two brain structures. Greater epigenetic change in the human dorsolateral prefrontal cortex compared to the cerebellum may reflect both the protracted development of this structure in humans and its greater age-related vulnerability to neurodegenerative pathology.

Recent evidence suggests that increased dopaminergic signaling within the dorsal striatum played a central role in the evolution of the human brain. This increase has been linked to human prosociality and language in what has been described as a dopamine-dominated striatum personality style. Increased striatal dopamine is associated with an increase in ventral striatal activity and promotes externally driven behaviors, including cooperation and social conformity. In contrast, decreased striatal dopamine is associated with increased dorsal striatal activity and favors internally driven and goal-oriented behaviors. Previous comparative studies have focused on the dorsal striatum, measuring dopaminergic innervation in the dorsal and medial caudate nucleus and putamen. Here, we add to this knowledge by examining regions of the ventral striatum. We quantified the density of tyrosine hydroxylase-immunoreactive axons, as a measure of dopaminergic innervation, in the nucleus accumbens and ventral pallidum of humans, great apes, platyrrhine and cercopithecid monkeys. Our data show that humans have a significantly greater dopaminergic innervation in both structures, supporting the hypothesis that selection for a prosocial neurochemistry in the human basal ganglia may have contributed to the evolution of our uniquely social behavior profile.

SummaryThere has been an immense research focus on the topic of cortical reorganization in human evolution, but much less is known regarding the reorganization of subcortical circuits which are intimate working partners of the cortex. Here, by combining advanced image analysis techniques with comparative neuroimaging data, we systematically map organizational differences in striatal, pallidal and thalamic anatomy between humans and chimpanzees. We relate interspecies differences, a proxy for evolutionary changes, to genetics and behavioral correlates. We show that highly heritable morphological measures are significantly expanded across species, in contrast to previous findings in the cortex. The identified morphological-cognitive latent variables were associated with striatal expansion, and affective latent variables were associated with more evolutionarily-conserved areas in the thalamus and globus pallidus. These findings provide new insight into the architecture of these subcortical hubs and can provide greater information on the role of these structures in health and illness.

The human corpus callosum exhibits substantial atrophy in old age, which is stronger than what would be predicted from parallel changes in overall brain anatomy. To date, however, it has not been conclusively established whether this accentuated decline represents a common feature of brain aging across species, or whether it is a specific characteristic of the aging human brain. In the present cross-sectional study, we address this question by comparing age-related difference in corpus callosum morphology of chimpanzees and humans. For this purpose, we measured total midsagittal area and regional thickness of the corpus callosum from T1-weighted MRI data from 213 chimpanzees, aged between 9 and 54 years. The results were compared with data drawn from a large-scale human sample which was age-range matched using two strategies: (a) matching by chronological age (human sample size: n = 562), or (b) matching by accounting for differences in longevity and various maturational events between the species (i.e., adjusted human age range: 13.6 to 80.9 years; n = 664). Using generalized additive modeling to fit and compare aging trajectories, we found significant differences between the two species. The chimpanzee aging trajectory compared with the human trajectory was characterized by a slower increase from adolescence to middle adulthood, and by a lack of substantial decline from middle to old adulthood, which, however, was present in humans. Thus, the accentuated decline of the corpus callosum found in aging humans is not a universal characteristic of the aging brain, and appears to be human-specific.

Interlaminar astrocytes (ILAs) are a subset of cortical astrocytes that reside in layer I, express GFAP, have a soma contacting the pia, and contain long interlaminar processes that extend through several cortical layers. We studied the prenatal and postnatal development of ILAs in three species of primates (rhesus macaque, chimpanzee, and human). We found that ILAs are generated prenatally likely from radial glial (RG) cells, that ILAs proliferate locally during gestation, and that ILAs extend interlaminar processes during postnatal stages of development. We showed that the density and morphological complexity of ILAs increase with age, and that ILAs express multiple markers that are expressed by RG cells (Pax6, Sox2, and Nestin), specific to inner and outer RG cells (Cryab and Hopx), and astrocyte markers (S100β, Aqp4, and GLAST) in prenatal stages and in adult. Finally, we demonstrated that rudimentary ILAs in mouse also express the RG markers Pax6, Sox2, and Nestin, but do not express S100β, Cryab, or Hopx, and that the density and morphological complexity of ILAs differ between primate species and mouse. Together these findings contribute new information on astrogenesis of this unique class of cells and suggest a lineal relationship between RG cells and ILAs.

The corpus callosum (CC) is the major white matter tract connecting the left and right cerebral hemispheres. It has been hypothesized that individual variation in CC morphology is negatively associated with forebrain volume (FBV) and this accounts for variation in behavioral and brain asymmetries as well as sex differences. To test this hypothesis, CC surface area and thickness as well as FBV was quantified in 221 chimpanzees with known pedigrees. CC surface area, thickness and FBV were significantly heritable and phenotypically associated with each other; however, no significant genetic association was found between FBV, CC surface area and thickness. The CC surface area and thickness measures were also found to be significantly heritable in both chimpanzee cohorts as were phenotypic associations with variation in asymmetries in tool use skill, suggesting that these findings are reproducible. Finally, significant phenotypic and genetic associations were found between hand use skill and region-specific variation in CC surface area and thickness. These findings suggest that common genes may underlie individual differences in chimpanzee tool use skill and interhemispheric connectivity as manifest by variation in surface area and thickness within the anterior region of the CC.

While low serotonergic activity is often associated with psychological disorders such as depression, anxiety, mood, and personality disorders, variations in serotonin also contribute to normal personality differences. In this study, we investigated the role of blood DNA methylation levels at individual CpG sites of two key serotonergic genes (serotonin receptor gene 1A, HTR1A; serotonin transporter gene, SLC6A4) in predicting the personalities of captive chimpanzees. We found associations between methylation at 9/48 CpG sites with four personality dimensions: Dominance, Reactivity/Dependability, Agreeableness, and Openness. Directionality of effects were CpG location-dependent and confirmed a role of serotonergic methylation in reducing anxiety (Dominance) and aggression-related personality (Reactivity/Undependability) while simultaneously promoting prosocial (Agreeableness) and exploratory personalities (Openness). Although early-life adversity has been shown to impact serotonergic methylation patterns in other species, here, atypical early social rearing experiences only had a modest impact on CpG methylation levels in this chimpanzee sample. The precise environmental factors impacting serotonergic methylation in chimpanzees remain to be identified. Nevertheless, our study suggests a role in shaping natural variation in animal personalities. The results of this study offer a basis for future hypothesis-driven testing in additional populations and species to better understand the impact of ecology and evolution on complex behavioral traits.

Early life experiences, including separation from caregivers, can result in substantial, persistent effects on neural, behavioral, and physiological systems as is evidenced in a long-standing literature and consistent findings across species, populations, and experimental models. In humans and other animals, differential rearing conditions can affect brain structure and function. We tested for whole brain patterns of morphological difference between 108 chimpanzees reared typically with their mothers (MR; N = 54) and those reared decades ago in a nursery with peers, human caregivers, and environmental enrichment (NR; N = 54). We applied support vector machine (SVM) learning to archival MRI images of chimpanzee brains to test whether we could, with any degree of significant probability, retrospectively classify subjects as MR and NR based on variation in gray matter within the entire brain. We could accurately discriminate MR and NR chimpanzee brains with nearly 70% accuracy. The combined brain regions discriminating the two rearing groups were widespread throughout the cortex. We believe this is the first report using machine language learning as an analytic method for discriminating nonhuman primate brains based on early rearing experiences. In this sense, the approach and findings are novel, and we hope they stimulate application of the technique to studies on neural outcomes associated with early experiences. The findings underscore the potential for infant separation from caregivers to leave a long-term mark on the developing brain.

Serotonin is a neurotransmitter that plays an important role in regulating behavior and personality in humans and other mammals. Polymorphisms in genes coding for the serotonin receptor subtype 1A (HTR1A), the serotonin transporter (SLC6A4), and the serotonin degrading enzyme monoamine oxidase A (MAOA) are associated with anxiety, impulsivity, and neurotic personality in humans. In primates, previous research has largely focused on SLC6A4 and MAOA, with few studies investigating the role of HTR1A polymorphic variation on behavior. Here, we examined variation in the coding region of HTR1A across apes, and genotyped polymorphic coding variation in a sample of 214 chimpanzees with matched measures of personality and behavior. We found evidence for positive selection at three amino acid substitution sites, one in chimpanzees-bonobos (Thr26Ser), one in humans (Phe33Val), and one in orangutans (Ala274Gly). Investigation of the HTR1A coding region in chimpanzees revealed a polymorphic site, where a C/A single nucleotide polymorphism changes a proline to a glutamine in the amino acid sequence (Pro248Gln). The substitution is located in the third intracellular loop of the receptor, a region important for serotonin signal transduction. The derived variant is the major allele in this population (frequency 0.67), and is associated with a reduction in anxiety, decreased rates of male agonistic behavior, and an increase in socio-positive behavior. These results are the first evidence that the HTR1A gene may be involved in regulating social behavior in chimpanzees and encourage further systematic investigation of polymorphic variation in other primate populations with corresponding data on behavior.

Previous studies found associations between autism-related phenotypes and both rearing and V1A arginine vasopressin receptor (AVPR1A) genotypes. We tested whether these exposures as well as their interaction were associated with autism-related phenotypes in 121 laboratory-housed chimpanzees. We used expert-derived weights to obtain autism scores from ratings on the 43-item Chimpanzee Personality Questionnaire; higher scores indicated more autistic-like traits. The first model included fixed effects for sex, age, and rearing, and a random effect that addressed the relatedness of subjects. The second model was the same except that it also included the rearing × AVPR1A genotype interaction as a fixed effect. Both models indicated that the phenotype was moderately heritable and that chimpanzees reared by their mothers had lower scores on the scale. The effect of genotype in both models indicated that chimpanzees with an indel deletion had higher scores on the scale, although the credible interval included zero. Moreover, the rearing × genotype interaction in the second model indicated that chimpanzees who possessed the non-deletion genotype and who were reared by their mother were at even greater risk. The credible interval for this effect did not include zero, but fit statistics indicated that the model without the interaction was marginally better, and the interaction was in the opposite direction than we expected based on previous work. These findings highlight the importance of rearing effects in the typical social development of our closet-living nonhuman relative. LAY SUMMARY: We tested whether, in chimpanzees, scores on a scale comprising traits that resembled aspects of autism were related to a gene associated with autism in prior research and/or early rearing. Human-reared chimpanzees had higher scores (indicating more autistic-like traits). Chimpanzees that possessed the gene also had higher scores, but we could not exclude the possibility that there was no effect of genotype. These findings suggest that we can measure autism-like characteristics in chimpanzees, and so study it in this species.