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With rates of psychiatric illnesses such as depression continuing to rise, additional preclinical models are needed to facilitate translational neuroscience research. In the current study, the raccoon (Procyon lotor) was investigated due to its similarities with primate brains, including comparable proportional neuronal densities, cortical magnification of the forepaw area, and cortical gyrification. Specifically, we report on the cytoarchitectural characteristics of raccoons profiled as high, intermediate, or low solvers in a multi-access problem-solving task. Isotropic fractionation indicated that high-solvers had significantly more cells in the hippocampus (HC) than the other solving groups; further, a nonsignificant trend suggested that this increase in cell profile density was due to increased non-neuronal (e.g., glial) cells. Group differences were not observed in the cellular density of the somatosensory cortex. Thionin-based staining confirmed the presence of von Economo neurons (VENs) in the frontoinsular (FI) cortex, although no impact of solving ability on VEN cell profile density levels was observed. Elongated fusiform cells were quantified in the hippocampus dentate gyrus where high-solvers were observed to have higher levels of this cell type than the other solving groups. In sum, the current findings suggest that varying cytoarchitectural phenotypes contribute to cognitive flexibility. Additional research is necessary to determine the translational value of cytoarchitectural distribution patterns on adaptive behavioral outcomes associated with cognitive performance and mental health. This article is protected by copyright. All rights reserved.

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.

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.

The genus Macaca is an ideal model for investigating the biological basis of primate social behavior from an evolutionary perspective. A significant amount of behavioral diversity has been reported among the macaque species, but little is known about the neural substrates that support this variation. The present study compared neural cell density and serotonergic innervation of the amygdala among four macaque species using histological and immunohistochemical methods. The species examined included rhesus (Macaca mulatta), Japanese (M. fuscata), pigtailed (M. nemestrina), and moor macaques (M. maura). We anticipated that the more aggressive rhesus and Japanese macaques would have lower serotonergic innervation within the amygdala compared to the more affiliative pigtailed and moor macaques. In contrast to our prediction, pigtailed macaques had higher serotonergic innervation than Japanese and moor macaques in the basal and central amygdala nuclei when controlling for neuron density. Our analysis of neural cell populations revealed that Japanese macaques possess significantly higher neuron and glia densities relative to the other three species, however we observed no glia-to-neuron ratio differences among species. The results of this study revealed serotonergic innervation and cell density differences among closely related macaque species, which may play a role in modulating subtle differences in emotional processing and species-typical social styles.

Several primate species have been shown to exhibit age-related changes in cognition, brain, and behavior. However, severe neurodegenerative illnesses, such as Alzheimer's disease (AD), were once thought to be uniquely human. Recently, some chimpanzees naturally were documented to develop both neurofibrillary tangles and amyloid plaques, the main characteristics of AD pathology. In addition, like humans and other primates, chimpanzees show similar declines in cognition and motor function with age. Here, we used voxel-based morphometry to examine the relationships among gray matter volume, age, and cognition using magnetic resonance imaging scans previously acquired from chimpanzees (N = 216). We first determined the relationship between age and gray matter volume, identifying the regions that declined with age. With a subset of our sample (N = 103), we also determined differences in gray matter volume between older chimpanzees with higher cognition scores than expected for their age, and older chimpanzees with lower than expected scores. Finally, we ran a conjunction analysis to determine any overlap in brain regions between these two analyses. We found that as chimpanzees age, they lose gray matter in regions associated with cognition. In addition, cognitively healthy older chimpanzees (those performing better for their age) have greater gray matter volume in many brain regions compared with chimpanzees who underperform for their age. Finally, the conjunction analysis revealed that regions of age-related decline overlap with the regions that differ between cognitively healthy chimpanzees and those who underperform. This study provides further evidence that chimpanzees are an important model for research on the neurobiology of aging. Future studies should investigate the effects of cognitive stimulation on both cognitive performance and brain structure in aging nonhuman primates.

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 pro-sociality 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 andfavors 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.

Although rodents are the primary animal model used for biomedical research, neurological and evolutionary differences from humans have contributed to a high failure rate of Alzheimer’s disease clinical trials. Nonhuman primates are a viable model of aging and neurodegeneration and can help address this major concern. Aging in primates is associated with gene expression changes, volumetric atrophy, cerebrovascular dysfunction, neuroinflammation, and mild cognitive decline. Moreover, primates exhibit the pathologic hallmarks of Alzheimer’s disease, amyloid-beta and tau lesions, in association with glial activation. In contrast, primates do not experience the extensive neuronal loss and dementia symptoms seen in Alzheimer’s disease patients. Understanding similarities and differences between humans and primates can contribute to a greater understanding of normal aging and neurodegenerative processes as well as improve the efficacy of models and therapeutics for Alzheimer’s disease.

Monoamine oxidase enzymes are responsible for the degredation of serotonin, dopamine, and norepinephrine in the central neurvous system. Although it has been nearly 100 years since they were first described, we are still learning about their role in the healthy brain and how they are altered in various disease states. The present review provides a survey of our current understanding of monoamine oxidases, with a focus on their contributions to neuropsychiatric, neurodevelopmental, and neurodegenerative disease. Important species differences in monoamine oxidase function and development in the brain are highlighted. Sex-specific monoamine oxidase regulatory mechanisms and their implications for various neurological disorders are also discussed. While our understanding of these critical enzymes has expanded over the last century, gaps exist in our understanding of sex and species differences and the roles monoamine oxidases may play in conditions often comorbid with neurological disorders.

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.

In the absence of disease, ageing in the human brain is accompanied by mild cognitive dysfunction, gradual volumetric atrophy, a lack of significant cell loss, moderate neuroinflammation, and an increase in the amyloid beta (A β ) and tau proteins. Conversely, pathologic age-related conditions, particularly Alzheimer's disease (AD), result in extensive neocortical and hippocampal atrophy, neuron death, substantial A β plaque and tau-associated neurofibrillary tangle pathologies, glial activation and severe cognitive decline. Humans are considered uniquely susceptible to neurodegenerative disorders, although recent studies have revealed A β and tau pathology in non-human primate brains. Here, we investigate the effect of age and AD-like pathology on cell density in a large sample of postmortem chimpanzee brains ( n = 28, ages 12–62 years). Using a stereologic, unbiased design, we quantified neuron density, glia density and glia:neuron ratio in the dorsolateral prefrontal cortex, middle temporal gyrus, and CA1 and CA3 hippocampal subfields. Ageing was associated with decreased CA1 and CA3 neuron densities, while AD pathologies were not correlated with changes in neuron or glia densities. Differing from cerebral ageing and AD in humans, these data indicate that chimpanzees exhibit regional neuron loss with ageing but appear protected from the severe cell death found in AD. This article is part of the theme issue ‘Evolution of the primate ageing process’.

Synapses are involved in the communication of information from one neuron to another. However, a systematic analysis of synapse density in the neocortex from a diversity of species is lacking, limiting what can be understood about the evolution of this fundamental aspect of brain structure. To address this, we quantified synapse density in supragranular layers II–III and infragranular layers V–VI from primary visual cortex and inferior temporal cortex in a sample of 25 species of primates, including humans. We found that synapse densities were relatively constant across these levels of the cortical visual processing hierarchy and did not significantly differ with brain mass, varying by only 1.9-fold across species. We also found that neuron densities decreased in relation to brain enlargement. Consequently, these data show that the number of synapses per neuron significantly rises as a function of brain expansion in these neocortical areas of primates. Humans displayed the highest number of synapses per neuron, but these values were generally within expectations based on brain size. The metabolic and biophysical constraints that regulate uniformity of synapse density, therefore, likely underlie a key principle of neuronal connectivity scaling in primate neocortical evolution.

Background : Primate species differ drastically from most other mammals in how they visually perceive their environments, which is important for foraging, predator avoidance, and detection of social cues. Although it is well established that primates display diversity in color vision and various ecological specializations, it is not understood how visual system characteristics and ecological adaptations may be associated with gene expression levels within the primary visual cortex (V1). Results : We performed RNA-Seq on V1 tissue samples from 28 individuals, representing 13 species of anthropoid primates, including hominoids, cercopithecoids, and platyrrhines. We explored trait-dependent differential expression (DE) by contrasting species with different visual system phenotypes and ecological traits. Between 4-25% of genes were determined to be differentially expressed in primates that varied in type of color vision (trichromatic or polymorphic di/trichromatic), habitat use (arboreal or terrestrial), group size (large or small), and primary diet (frugivorous, folivorous, or omnivorous). DE analyses revealed that humans and chimpanzees showed the most marked differences between any two species, despite the fact that they are only separated by 6-8 million years of independent evolution. Pathway enrichment analyses of DE genes demonstrated that changes in cellular metabolic pathways (e.g. glycolysis) contribute to altered gene expression in primate V1 more than neuron-specific processes (e.g. synaptic signaling). The exception to this trend is between human and chimpanzee, which exhibited DE for a number of processes related to cholinergic and GABAergic synaptic signaling. Conclusions : Our data significantly expand the number of primate species for which V1 expression data exists. These results show a combination of species-specific and trait-dependent differences in the evolution of gene expression in primate V1. We also show that human-specific changes in brain gene expression extend to the primary visual cortex in a manner similar to that reported of other brain regions.

Few studies exist of the bowhead whale brain and virtually nothing is known about its cortical cytoarchitecture or how it compares to other cetaceans. Bowhead whales are one of the least encephalized cetaceans and occupy a basal phylogenetic position among mysticetes. Therefore, the bowhead whale is an important specimen for understanding the evolutionary specializations of cetacean brains. Here, we present an overview of the structure and cytoarchitecture of the bowhead whale cerebral cortex gleaned from Nissl-stained sections and magnetic resonance imaging (MRI) in comparison with other mysticetes and odontocetes. In general, the cytoarchitecture of cetacean cortex is consistent in displaying a thin cortex, a thick, prominent layer I, and absence of a granular layer IV. Cell density, composition, and width of layers III, V, and VI vary among cortical regions, and cetacean cortex is cell-sparse relative to that of terrestrial mammals. Notably, all regions of the bowhead cortex possess high numbers of von Economo neurons and fork neurons, with the highest numbers observed at the apex of gyri. The bowhead whale is also distinctive in having a significantly reduced hippocampus that occupies a space below the corpus callosum within the lateral ventricle. Consistent with other balaenids, bowhead whales possess what appears to be a blunted temporal lobe, which is in contrast to the expansive temporal lobes that characterize most odontocetes. The present report demonstrates that many morphological and cytoarchitectural characteristics are conserved among cetaceans, while other features, such as a reduced temporal lobe, may characterize balaenids among mysticetes. Anat Rec, 2018. © 2018 Wiley Periodicals, Inc. Anat Rec, 302:745-760, 2019. © 2018 Wiley Periodicals, Inc.

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.

Alzheimer's disease (AD) is a uniquely human brain disorder characterized by the accumulation of amyloid-beta protein (Aβ) into extracellular plaques, neurofibrillary tangles (NFT) made from intracellular, abnormally phosphorylated tau, and selective neuronal loss. We analyzed a large group of aged chimpanzees (n = 20, age 37–62 years) for evidence of Aβ and tau lesions in brain regions affected by AD in humans. Aβ was observed in plaques and blood vessels, and tau lesions were found in the form of pretangles, NFT, and tau-immunoreactive neuritic clusters. Aβ deposition was higher in vessels than in plaques and correlated with increases in tau lesions, suggesting that amyloid build-up in the brain's microvasculature precedes plaque formation in chimpanzees. Age was correlated to greater volumes of Aβ plaques and vessels. Tangle pathology was observed in individuals that exhibited plaques and moderate or severe cerebral amyloid angiopathy, a condition in which amyloid accumulates in the brain's vasculature. Amyloid and tau pathology in aged chimpanzees suggests these AD lesions are not specific to the human brain.

Common marmosets (Callithrix jacchus) have been suggested as a new model for analysis of age-related changes and neurodegenerative diseases. However, the effects of age on learning and memory processes are not well defined within this species. Therefore, we employed visual discrimination and reversal learning tasks to evaluate learning and memory in four aged common marmosets relative to a younger cohort. We found that aged marmosets commit significantly more errors in initial stages of visual discrimination and more perseverative errors in reversal learning, indicating prefrontal dysfunction. However, they showed comparable performance with younger marmosets in the later stages of both tasks.

Although it has been claimed that marsupials possess a lower density of isocortical neurons compared with other mammals, little is known about cross-cortical variation in neuron distributions in this diverse taxonomic group. We quantified upper-layer (layers II-IV) and lower-layer (layers V-VI) neuron numbers per unit of cortical surface area in three diprotodont marsupial species (two macropodiformes, the red kangaroo and the parma wallaby, and a vombatiform, the koala) and compared these results to eutherian mammals (e.g., xenarthrans, rodents, primates). In contrast to the notion that the marsupial isocortex contains a low density of neurons, we found that neuron numbers per unit of cortical surface area in several marsupial species overlap with those found in eutherian mammals. Furthermore, neuron numbers vary systematically across the isocortex of the marsupial mammals examined. Neuron numbers under a unit of cortical surface area are low toward the frontal cortex and high toward the caudo-medial (occipital) pole. Upper-layer neurons (i.e., layers II-IV) account for most of the variation in neuron numbers across the isocortex. The variation in neuron numbers across the rostral to the caudal pole resembles primates. These findings suggest that diprotodont marsupials and eutherian mammals share a similar cortical architecture despite their distant evolutionary divergence.

In the effort to understand the evolution of mammalian brains, we have found that common relationships between brain structure mass and numbers of nonneuronal (glial and vascular) cells apply across eutherian mammals, but brain structure mass scales differently with numbers of neurons across structures and across primate and nonprimate clades. This suggests that the ancestral scaling rules for mammalian brains are those shared by extant nonprimate eutherians - but do these scaling relationships apply to marsupials, a sister group to eutherians that diverged early in mammalian evolution? Here we examine the cellular composition of the brains of 10 species of marsupials. We show that brain structure mass scales with numbers of nonneuronal cells, and numbers of cerebellar neurons scale with numbers of cerebral cortical neurons, comparable to what we have found in eutherians. These shared scaling relationships are therefore indicative of mechanisms that have been conserved since the first therians. In contrast, while marsupials share with nonprimate eutherians the scaling of cerebral cortex mass with number of neurons, their cerebella have more neurons than nonprimate eutherian cerebella of a similar mass, and their rest of brain has fewer neurons than eutherian structures of a similar mass. Moreover, Australasian marsupials exhibit ratios of neurons in the cerebral cortex and cerebellum over the rest of the brain, comparable to artiodactyls and primates. Our results suggest that Australasian marsupials have diverged from the ancestral Theria neuronal scaling rules, and support the suggestion that the scaling of average neuronal cell size with increasing numbers of neurons varies in evolution independently of the allocation of neurons across structures.

Williams syndrome (WS) is a rare neurodevelopmental disorder caused by the hemideletion of approximately 25-28 genes at 7q11.23. Its unusual social and cognitive phenotype is most strikingly characterized by the disinhibition of social behavior, in addition to reduced global IQ, with a relative sparing of language ability. Hypersociality and increased social approach behavior in WS may represent a unique inability to inhibit responses to specific social stimuli, which is likely associated with abnormalities of frontostriatal circuitry. The striatum is characterized by a diversity of interneuron subtypes, including inhibitory parvalbumin-positive interneurons (PV+) and excitatory cholinergic interneurons (Ch+). Animal model research has identified an important role for these specialized cells in regulating social approach behavior. Previous research in humans identified a depletion of interneuron subtypes associated with neuropsychiatric disorders. Here, we examined the density of PV+ and Ch+ interneurons in the striatum of 13 WS and neurotypical (NT) subjects. We found a significant reduction in the density of Ch+ interneurons in the medial caudate nucleus and nucleus accumbens, important regions receiving cortical afferents from the orbitofrontal and ventromedial prefrontal cortex, and circuitry involved in language and reward systems. No significant difference in the distribution of PV+ interneurons was found. The pattern of decreased Ch+ interneuron densities in WS differs from patterns of interneuron depletion found in other disorders.

Significance Dogs were shaped during the course of domestication both in their behavior and in their anatomical features. Here we show that domestication transformed the facial muscle anatomy of dogs specifically for facial communication with humans. A muscle responsible for raising the inner eyebrow intensely is uniformly present in dogs but not in wolves. Behavioral data show that dogs also produce the eyebrow movement significantly more often and with higher intensity than wolves do, with highest-intensity movements produced exclusively by dogs. Interestingly, this movement increases paedomorphism and resembles an expression humans produce when sad, so its production in dogs may trigger a nurturing response. We hypothesize that dogs’ expressive eyebrows are the result of selection based on humans’ preferences., Domestication shaped wolves into dogs and transformed both their behavior and their anatomy. Here we show that, in only 33,000 y, domestication transformed the facial muscle anatomy of dogs specifically for facial communication with humans. Based on dissections of dog and wolf heads, we show that the levator anguli oculi medialis, a muscle responsible for raising the inner eyebrow intensely, is uniformly present in dogs but not in wolves. Behavioral data, collected from dogs and wolves, show that dogs produce the eyebrow movement significantly more often and with higher intensity than wolves do, with highest-intensity movements produced exclusively by dogs. Interestingly, this movement increases paedomorphism and resembles an expression that humans produce when sad, so its production in dogs may trigger a nurturing response in humans. We hypothesize that dogs with expressive eyebrows had a selection advantage and that “puppy dog eyes” are the result of selection based on humans’ preferences.

Monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B) are enzymes that degrade several monoamines of the central nervous system and have long been implicated in the modulation of social behavior. Macaque monkeys are a suitable model for investigating the role of functional monoamine oxidase polymorphisms in behavior modulation given the high amount of social diversity among the nearly two dozen species. The present study reports allele frequencies for two polymorphisms, MAOA-LPR and MBin2, in samples of rhesus (Macaca mulatta) and Japanese (M. fuscata) macaques. Our results suggest that the two species may differ in high- and low-activity MAOA-LPR allele frequencies. Specifically, 89% of the Japanese macaque alleles in our sample were the low-activity variant, whereas only 41% of the rhesus macaque alleles were of this sort. In our samples, the two species possessed similar allelic variation at the MBin2 locus, with each possessing some species-specific alleles. We also tested for associations between MAOA-LPR genotype and plasma serotonin (5-HT) and dopamine (DA) concentrations in a subset of rhesus macaques, which revealed no association with genotype. Our findings point toward potential differences in the monoaminergic system of two closely related macaque species. Discussion of our results are centered on implications for future investigations that aim to better understand the functionality of monoamine oxidase polymorphisms in the context of primate social behavior.

In humans, neutrophil to lymphocyte ratio (NLR) has been used as a clinical tool in diagnosis and/or prognosis of a variety of cancers and medical conditions, as well as in measuring physiological stress over time. Given the close phylogenetic relationship and physical similarities between humans and apes, NLR may similarly be a useful diagnostic tool in assessing chimpanzee health. Only one study has examined NLR in apes, reporting that NLR increased with age and was affected by body-mass index and sex. In the current study, we examined changes in NLR data from longitudinal health records for 443 chimpanzees in two captive chimpanzee populations. Using these data, we analyzed intra-individual changes and inter-individual differences in NLR as a function of age, rearing history, and sex. Contrary to previous studies in humans and the one previous study in chimpanzees, NLR values did not change over a 10-year timespan within individual chimpanzees. However, cross-sectional comparisons revealed a significant quadratic relationship between age and NLR with the highest values during mid-life (20-30 years of age) and the lowest values in younger and older individuals. Additionally, males and mother-reared individuals had higher NLR than females and nursery-reared chimpanzees, respectively. Lastly, males and those with higher NLR values died at younger ages. These findings may suggest that NLR can be used a predictor of longevity in chimpanzees. However, given the complexities of these relationships, more research is needed to determine the utility of NLR as a diagnostic health tool for use in chimpanzees.

The isocortex of primates is disproportionately expanded relative to many other mammals, yet little is known about what the expansion of the isocortex entails for differences in cellular composition and connectivity patterns in primates. Across the depth of the isocortex, neurons exhibit stereotypical patterns of projections. Upper-layer neurons (i.e., layers II-IV) project within and across cortical areas, whereas many lower-layer pyramidal neurons (i.e., layers V-VI) favor connections to subcortical regions. To identify evolutionary changes in connectivity patterns, we quantified upper (i.e., layers II-IV)- and lower (i.e., layers V-VI)-layer neuron numbers in primates and other mammals such as rodents and carnivores. We also used MR tractography based on high-angular resolution diffusion imaging and diffusion spectrum imaging to compare anterior-to-posterior corticocortical tracts between primates and other mammals. We found that primates possess disproportionately more upper-layer neurons as well as an expansion of anterior-to-posterior corticocortical tracts compared with other mammals. Taken together, these findings demonstrate that primates deviate from other mammals in exhibiting increased cross-cortical connectivity. J. Comp. Neurol. 525:1075-1093, 2017. © 2016 Wiley Periodicals, Inc.

Over evolutionary time, light from the sun, moon, and stars has provided organisms with reliable information about the passage of time; but modern artificial lighting has drastically altered these cues. Evidence is accumulating that exposure to light at night—particularly blue wavelengths—from computer screens, urban light pollution, or as an occupational hazard of night-shift work has major implications for human health. Nocturnal animals in zoos are generally housed on reversed light cycles and are illuminated by blue or red artificial light so that daytime visitors can observe their active behaviors. However, previous research suggests that exposure to light all 24 h of the day and exposure to blue light during the dark phase can be harmful to human and animal health. Information about the consequences of lighting design for animal health and behavior is needed to formulate evidence-based guidelines for the exhibition of nocturnal animals in zoos. This study was conducted with nocturnal strepsirrhines at two facilities, one where the standard practice was to house nocturnal primates under blue light, and the other red. We experimentally changed the color of light illuminating habitats during the dark phase using an ABA study design and recorded continuous behavior data. We hypothesized that activity levels and time allocated to specific active behaviors would be lower under blue light compared to red. The overall percent of time spent performing active behaviors was lower when subjects were housed under blue light compared to red (generalized linear mixed models: pottos (N = 4), F 1,1169 = 54.0, p 1,689 = 26.4, p 1,482 = 99.1, p 1,312 = 8.4, p = 0.005). These changes were largely due to increased time spent moving around exhibits and examining objects under red light. We were also able to measure concentrations of the timekeeping hormone melatonin in the saliva of the aye-aye and found that levels were significantly lower in blue light compared to red (F 1,85 = 18.0, p

Despite extensive investigations of the neocortex in the domestic cat, little is known about neuronal morphology in larger felids. To this end, the present study characterized and quantified the somatodendritic morphology of neocortical neurons in prefrontal, motor, and visual cortices of the Siberian tiger (Panthera tigris altaica) and clouded leopard (Neofelis nebulosa). After neurons were stained with a modified Golgi technique (N = 194), dendritic branching and spine distributions were analyzed using computer-assisted morphometry. Qualitatively, aspiny and spiny neurons in both species appeared morphologically similar to those observed in the domestic cat. Although the morphology of spiny neurons was diverse, with the presence of extraverted, inverted, horizontal, and multiapical pyramidal neurons, the most common variant was the typical pyramidal neuron. Gigantopyramidal neurons in the motor cortex were extremely large, confirming the observation of Brodmann ([1909] Vergleichende Lokalisationlehre der Grosshirnrinde in ihren Prinzipien dargestellt auf Grund des Zellenbaues. Leipzig, Germany: J.A. Barth), who found large somata for these neurons in carnivores in general, and felids in particular. Quantitatively, a MARSplines analysis of dendritic measures differentiated typical pyramidal neurons between the Siberian tiger and the clouded leopard with 93% accuracy. In general, the dendrites of typical pyramidal neurons were more complex in the tiger than in the leopards. Moreover, dendritic measures in tiger pyramidal neurons were disproportionally large relative to body/brain size insofar as they were nearly as extensive as those observed in much larger mammals (e.g., African elephant). Comparison of neuronal morphology in a more diverse collection of larger felids may elucidate the comparative context for the relatively large size of the pyramidal neurons observed in the present study. J. Comp. Neurol. 524:3641-3665, 2016. © 2016 Wiley Periodicals, Inc.

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.

In Alzheimer's disease (AD), the brain's 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.

Astrocytes are the main homeostatic cell of the central nervous system. In addition, astrocytes mediate an inflammatory response when reactive to injury or disease known as astrogliosis. Astrogliosis is marked by an increased expression of glial fibrillary acidic protein (GFAP) and cellular hypertrophy. Some degree of astrogliosis is associated with normal aging and degenerative conditions such as Alzheimer's disease (AD) and other dementing illnesses in humans. The recent observation of pathological markers of AD (amyloid plaques and neurofibrillary tangles) in aged chimpanzee brains provided an opportunity to examine the relationships among aging, AD-type pathology, and astrocyte activation in our closest living relatives. Stereologic methods were used to quantify GFAP-immunoreactive astrocyte density and soma volume in layers I, III, and V of the prefrontal and middle temporal cortex, as well as in hippocampal fields CA1 and CA3. We found that the patterns of astrocyte activation in the aged chimpanzee brain are distinct from humans. GFAP expression does not increase with age in chimpanzees, possibly indicative of lower oxidative stress loads. Similar to humans, chimpanzee layer I astrocytes in the prefrontal cortex are susceptible to AD-like changes. Both prefrontal cortex layer I and hippocampal astrocytes exhibit a high degree of astrogliosis that is positively correlated with accumulation of amyloid beta and tau proteins. However, unlike humans, chimpanzees do not display astrogliosis in other cortical layers. These results demonstrate a unique pattern of cortical aging in chimpanzees and suggest that inflammatory processes may differ between humans and chimpanzees in response to pathology.

All domesticated mammals exhibit marked reductions in overall brain size, however, it is unknown whether the corpus callosum, an integral white matter fiber pathway for interhemispheric cortical communication, is affected by domestication differentially or strictly in coordination with changes in brain size. To answer this question, we used quantitative magnetic resonance imaging to compare the mid‐sagittal cross‐sectional areas of the corpus callosum in 35 carnivore species, including eight wild canids and 13 domestic dogs. We segmented rostro‐caudal regions of interest for the corpus callosum and evaluated correlations with brain mass. The results of this study indicate that under the influence of domestication in canids, the corpus callosum scales to brain size in an allometric relationship that is similar to that of wild canids and other carnivores, with relatively high correlation coefficients observed for all regions, except the rostrum. These results indicate that architectural and energetic considerations are likely to tightly constrain variation in caudal components of the corpus callosum relative to overall brain size, however fibers passing through the rostrum, putatively connecting prefrontal cortex, are less constrained and therefore may contribute more towards species‐specific differences in connectivity. Given the species diversity of the Canidae and the resurgence of interest in the brain of the domestic dog, further studies aimed at characterizing the neural architecture in domesticated species is likely to provide new insights into the effects of domestication, or artificial selection, on the brain.

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.

Although neocortical neuronal morphology has been documented in the adult giraffe (Giraffa camelopardalis tippelskirchi) and African elephant (Loxodonta africana), no research has explored the cortical architecture in newborns of these species. To this end, the current study examined the morphology of neurons from several cortical areas in the newborn giraffe and elephant. After cortical neurons were stained with a modified Golgi technique (N = 153), dendritic branching and spine distributions were analyzed by using computer-assisted morphometry. The results showed that newborn elephant neurons were considerably larger in terms of all dendritic and spine measures than newborn giraffe neurons. Qualitatively, neurons in the newborns appeared morphologically comparable to those in their adult counterparts. Neurons in the newborn elephant differed considerably from those observed in other placental mammals, including the giraffe, particularly with regard to the morphology of spiny projection neurons. Projection neurons were observed in both species, with a much larger variety in the elephant (e.g., flattened pyramidal, nonpyramidal multipolar, and inverted pyramidal neurons). Although local circuit neurons (i.e., interneurons, neurogliaform, Cajal–Retzius neurons) resembled those observed in other eutherian mammals, these were usually spiny, which contrasts with their adult, aspiny equivalents. Newborn projection neurons were smaller than the adult equivalents in both species, but newborn interneurons were approximately the same size as their adult counterparts. Cortical neuromorphology in the newborn giraffe is thus generally consistent with what has been observed in other cetartiodactyls, whereas newborn and adult elephant morphology appears to deviate substantially from what is commonly observed in other placental mammals. J. Comp. Neurol. 524:257–287, 2016. © 2015 Wiley Periodicals, Inc.

The field of paleoneurology emerged as an independ-ent discipline in the early years of the twentieth centuryand was directed at systematically analyzing the brainsof fossil species within an evolutionary framework. Thepioneer of this effort was Tilly (Johanna Gabrielle Ottilie)Edinger (1897–1967), a German-born vertebrate paleon-tologist, who combined her interests in both paleontol-ogy and comparative neuroanatomy to add a newdimension to evolutionary studies of the brain (Buch-holtz and Seyfarth, 1999, 2001). Her father, LudwigEdinger (1855–1917), was a prominent and pioneeringcomparative neuroanatomist and served as an editorialboard member of the Journal of Comparative Neurology(JCN) beginning with its eighth volume (Herrick, 1954).The 25th volume of JCN was dedicated to LudwigEdinger in honor of his 60th birthday (April 13, 1915),and his brain was the object of study for a 1950 JCNreport (Riese and Goldstein, 1950).Paleoneurologists generally depend on endocasts tostudy the external features of brains because brains them-selves do not fossilize (Edinger, 1927). Endocasts aremade by creating a cast of the interior surface of the skullto reveal external features that left impressions on thebones. Natural endocasts occur when the cranial cavity ofa deceased animal is filled with sediment that is solidifiedby calciferous solutions (Kochetkova, 1978). Prior to the1920s, endocasts had been documented for a variety ofspecies, but these existed as independent observationsthat were purely descriptive. Tilly Edinger compiled allaccounts of natural brain casts that were distributedthroughout the paleontology literature and compiled theminto one volume (Edinger, 1929). Edinger’s unique contri-bution to the study of brain evolution was to add a“longitudinal” view wherein changes in patterns and struc-ture could be reconstructed through evolutionary time(Edinger, 1949). This is in contrast to the necessarily“horizontal”’ comparisons that are made when studyingneuroanatomical features of extant species. She appliedher methods to well-represented fossil sequences, includ-ing those of reptiles (Edinger, 1955b), amphibians (Romerand Edinger, 1942), bats (Edinger, 1926), cetaceans(Edinger, 1955a), and sirenians (Edinger, 1933, 1948),among others. Through her work, Edinger discountedsome prevalent ideas of her time, including the notion thatan increase in brain size was necessary for a species toavoid extinction (Edinger, 1962), and she also developed aconcept of mosaic evolution, that changes in one func-tional system, in this case the central nervous system,were independent of changes in other systems, includingthe postcranial skeleton (Edinger, 1958). Edinger changedour approaches and understanding of comparative neurol-ogy by providing the important additional element of evolu-tionary time with recognition of the sequence of changesthat led to modern species.JCN has had a tradition of presenting the findingsfrom paleoneurological research, including one articlefrom Tilly Edinger (Romer and Edinger, 1942). Theearliest endocast articles in JCN were reporting featuresof the brains of early cetaceans, the archeocetes (Fig.1; Elliot Smith, 1903), and fossil fish, amphibian, andreptile species (Case, 1921, 1928; Moodie, 1915a,b,1920). In the same years, many studies on the endo-cranial and brain anatomy of fossil mammals, includinga hominin, in comparison with their extant relatives(Black, 1915, 1920; Dempster, 1935; Moodie, 1922)were published in JCN, as well as, in more recent years,some of the earliest evolutionary interpretations ofstructure in the context of systems neuroscience in thepioneering work of Leonard Radinsky (Radinsky, 1968),which recently culminated in a review of olfaction inthe evolution of the mammalian cerebral cortex (Roweand Shepherd, 2015).Although natural endocasts are rare, it is almostunheard of to have a naturally preserved brain (i.e., mum-mified) with external and internal structures maintained(but see Papageorgopoulou et al., 2010, for an accountof a remarkably preserved human brain). Our Journal is

Black rhinoceros (rhinos) living in zoos express a host of unusual disease syndromes that are associated with increased morbidity and mortality, including hemolytic anemia, rhabdomyolysis, hepatopathy and ulcerative skin disease, hypophosphatemia and iron overload. We hypothesized that iron overload is a consequence and indicator of disturbances related to inflammation and insulin/glucose metabolism. The objectives of this study were to: (1) generate the first baseline information on biomarkers of inflammation (tumor necrosis factor alpha [TNFα], serum amyloid A [SAA]), insulin sensitivity (insulin, glucose and proxy calculations of insulin sensitivity), phosphate and iron stores (ferritin) using banked serum from free-ranging black rhinos; and (2) then compare serum biomarkers between zoo-managed (n=86 individuals) and free-ranging (n=120) animals. Enzyme immunoassays were validated for serum and then biomarker levels analyzed using mixed models while controlling for sex, age and year of sample collection. Concentrations of TNFα, SAA, insulin and insulin-to glucose ratio were higher (P0.05) in black rhinos managed in ex situ conditions compared to free-living counterparts. Findings indicate that the captive environment is contributing to increased inflammation and decreased insulin sensitivity in this endangered species.

Within afrotherians, sirenians are unusual due to their aquatic lifestyle, large body size and relatively large lissencephalic brain. However, little is known about the neuron type distributions of the cerebral cortex in sirenians within the context of other afrotherians and aquatic mammals. The present study investigated two cortical regions, dorsolateral cortex area 1 (DL1) and cluster cortex area 2 (CL2), in the presumptive primary somatosensory cortex (S1) in Florida manatees (Trichechus manatus latirostris) to characterize cyto- and chemoarchitecture. The mean neuron density for both cortical regions was 35,617 neurons/mm3 and fell within the 95% prediction intervals relative to brain mass based on a reference group of afrotherians and xenarthrans. Densities of inhibitory interneuron subtypes labeled against calcium-binding proteins and neuropeptide Y were relatively low compared to afrotherians and xenarthrans and also formed a small percentage of the overall population of inhibitory interneurons as revealed by GAD67 immunoreactivity. Nonphosphorylated neurofilament protein-immunoreactive (NPNFP-ir) neurons comprised a mean of 60% of neurons in layer V across DL1 and CL2. DL1 contained a higher percentage of NPNFP-ir neurons than CL2, although CL2 had a higher variety of morphological types. The mean percentage of NPNFP-ir neurons in the two regions of the presumptive S1 were low compared to other afrotherians and xenarthrans but were within the 95% prediction intervals relative to brain mass, and their morphologies were comparable to those found in other afrotherians and xenarthrans. Although this specific pattern of neuron types and densities sets the manatee apart from other afrotherians and xenarthrans, the manatee isocortex does not appear to be explicitly adapted for an aquatic habitat. Many of the features that are shared between manatees and cetaceans are also shared with a diverse array of terrestrial mammals and likely represent highly conserved neural features. A comparative study across manatees and dugongs is necessary to determine whether these traits are specific to one or more of the manatee species, or can be generalized to all sirenians.

Gigantopyramidal neurons, referred to as Betz cells in primates are characterized by large somata and extensive basilar dendrites. Although there have been morphological descriptions and drawings of gigantopyramidal neurons in a limited number of species, quantitative investigations have typically been limited to measures of soma size. The current study thus employed two separate analytical approaches: a morphological investigation using the Golgi technique to provide qualitative and quantitative somatodendritic measures of gigantopyramidal neurons across 19 mammalian species from 7 orders; and unbiased stereology to compare the soma volume of layer V pyramidal and gigantopyramidal neurons in primary motor cortex between 11 carnivore and 9 primate species. Of the 617 neurons traced in the morphological analysis, 181 were gigantopyramidal neurons, with deep (primarily layer V) pyramidal (n = 203) and superficial (primarily layer III) pyramidal (n = 233) neurons quantified for comparative purposes. Qualitatively, dendritic morphology varied considerably across species, with some (sub)orders (e.g., artiodactyls, perissodactyls, feliforms) exhibiting bifurcating, V-shaped apical dendrites. Basilar dendrites exhibited idiosyncratic geometry across and within taxonomic groups. Quantitatively, most dendritic measures were significantly greater in gigantopyramidal neurons than in superficial and deep pyramidal neurons. Cluster analyses revealed that most taxonomic groups could be discriminated based on somatodendritic morphology for both superficial and gigantopyramidal neurons. Finally, in agreement with Brodmann, gigantopyramidal neurons in both the morphological and stereological analyses were larger in feliforms (especially in the Panthera species) than in other (sub)orders, possibly due to specializations in muscle fiber composition and musculoskeletal systems. This article is protected by copyright. All rights reserved.

The adaptive significance of human brain evolution has been frequently studied through comparisons with other primates. However, the evolution of increased brain size is not restricted to the human lineage but is a general characteristic of primate evolution. Whether or not these independent episodes of increased brain size share a common genetic basis is unclear. We sequenced and de novo assembled the transcriptome from the neocortical tissue of the most highly encephalized nonhuman primate, the tufted capuchin monkey ($\textit{Cebus apella}$). Using this novel data set, we conducted a genome-wide analysis of orthologous brain-expressed protein coding genes to identify evidence of conserved gene-phenotype associations and species-specific adaptations during three independent episodes of brain size increase. We identify a greater number of genes associated with either total brain mass or relative brain size across these six species than show species-specific accelerated rates of evolution in individual large-brained lineages. We test the robustness of these associations in an expanded data set of 13 species, through permutation tests and by analyzing how genome-wide patterns of substitution co-vary with brain size. Many of the genes targeted by selection during brain expansion have glutamatergic functions or roles in cell cycle dynamics. We also identify accelerated evolution in a number of individual capuchin genes whose human orthologs are associated with human neuropsychiatric disorders. These findings demonstrate the value of phenotypically informed genome analyses, and suggest at least some aspects of human brain evolution have occurred through conserved gene-phenotype associations. Understanding these commonalities is essential for distinguishing human-specific selection events from general trends in brain evolution.