Hedonic eating, obesity, and addiction result from increased neuropeptide Y in the nucleus accumbens during human brain evolution.

The nucleus accumbens (NAc) is central to motivation and action, exhibiting one of the highest densities of neuropeptide Y (NPY) in the brain. Within the NAc, NPY plays a role in reward and is involved in emotional behavior and in increasing alcohol and drug addiction and fat intake. Here, we examined NPY innervation and neurons of the NAc in humans and other anthropoid primates in order to determine whether there are differences among these various species that would correspond to behavioral or life history variables. We quantified NPY-immunoreactive axons and neurons in the NAc of 13 primate species, including humans, great apes, and monkeys. Our data show that the human brain is unique among primates in having denser NPY innervation within the NAc, as measured by axon length density to neuron density, even after accounting for brain size. Combined with our previous finding of increased dopaminergic innervation in the same region, our results suggest that the neurochemical profile of the human NAc appears to have rendered our species uniquely susceptible to neurophysiological conditions such as addiction. The increase in NPY specific to the NAc may represent an adaptation that favors fat intake and contributes to an increased vulnerability to eating disorders, obesity, as well as alcohol and drug dependence. Along with our findings for dopamine, these deeply rooted structural attributes of the human brain are likely to have emerged early in the human clade, laying the groundwork for later brain expansion and the development of cognitive and behavioral specializations.

Cortisol levels across the lifespan in common marmosets (Callithrix jacchus).

Human aging is associated with senescence of the hypothalamic-pituitary-adrenal (HPA) axis, leading to progressive dysregulation characterized by increased cortisol exposure. This key hormone is implicated in the pathogenesis of many age-related diseases. Common marmosets (Callithrix jacchus) display a wide spectrum of naturally occurring age-related pathologies that compare similarly to humans and are increasingly used as translational models of aging and age-related disease. Whether the marmoset HPA axis also shows senescence with increasing age is unknown. We analyzed hair cortisol concentration (HCC) across the lifespan of 50 captive common marmosets, ranging in age from approximately 2 months-14.5 years, via a cross-sectional design. Samples were processed and analyzed for cortisol using enzyme immunoassay. HCC ranged from 1416 to 15,343 pg/mg and was negatively correlated with age. We found significant main effects of age group (infant, adolescent, adult, aged, very aged) and sex on HCC, and no interaction effects. Infants had significantly higher levels of HCC compared with all other age groups. Females had higher HCC than males. There was no interaction between age and sex. These results suggest marmosets do not show dysregulation of the HPA axis with increasing age, as measured via HCC.

Age-related changes in hematological biomarkers in common marmosets.

Researchers and veterinarians often use hematology and clinical chemistry to evaluate animal health. These biomarkers are relatively easy to obtain, and understanding how they change across healthy aging is critical to clinical care and diagnostics for these animals. We aimed to evaluate how clinical biomarkers from a chemistry profile and complete blood count (CBC) change with age in common marmosets (Callithrix jacchus). We assessed blood samples collected during routine physical exams at the Southwest National Primate Research Center and the University of Texas Health San Antonio marmoset colonies from November 2020-November 2021. We found that chemistry and CBC profiles varied based on facility, sex, and age. Significant changes in albumin, phosphorus/creatinine ratio, albumin/globulin ratio, amylase, creatinine, lymphocyte percent, hematocrit, granulocytes percent, lymphocytes, hemoglobin, red cell distribution width, and platelet distribution width were all reported with advancing age. Aged individuals also demonstrated evidence for changes in liver, kidney, and immune system function compared with younger individuals. Our results suggest there may be regular changes associated with healthy aging in marmosets that are outside of the range typically considered as normal values for healthy young individuals, indicating the potential need for redefined healthy ranges for clinical biomarkers in aged animals. Identifying animals that exhibit values outside of this defined healthy aging reference will allow more accurate diagnostics and treatments for aging colonies.

Determination of dexamethasone dose for cortisol suppression in adult common marmosets (Callithrix jacchus).

We conducted a dose-response study of dexamethasone to investigate an optimal dexamethasone suppression test for common marmosets. Twelve marmosets received 0.1, 0.5, or 1.0 mg/kg dexamethasone. Doses of 0.5 and 1.0 mg/kg both suppressed endogenous cortisol for at least 18 h with greater individual variability in the lower 0.5 mg/kg dose.

The Development of Core Concepts for Neuroscience Higher Education: From Beginning to Summer Virtual Meeting Satellite Session.

Neuroscience curricula vary widely across higher education institutions due to the lack of an accrediting body or a set of unified educational concepts or outcomes. Each institution has developed a unique set of fundamental knowledge, topical subdisciplines, and core competencies to be delivered in a neuroscience program. Core concepts would provide neuroscience departments and programs with a generally agreed upon set of overarching principles that organize knowledge and can be applied to all sub-disciplines of the field, providing a useful framework from which to approach neuroscience education. We set out to develop a consensus set of neuroscience core concepts to aid in higher education curricular development and assessment. Suggestions for neuroscience core concepts were solicited from neuroscience faculty in a nationwide survey and analyzed using an inductive, independent coding model to identify eight core concepts based upon survey responses. Accompanying explanatory paragraphs for each core concept were developed through an iterative process. We presented the resulting core concepts to 134 neuroscience educators at a satellite session of the Faculty for Undergraduate Neuroscience 2020 Summer Virtual Meeting (SVM). Individuals and groups of faculty provided feedback regarding the accuracy, comprehensiveness, and clarity of each concept and explanatory paragraph, as well as the structure of the document as a whole. We continue to refine the core concepts based upon this feedback and will distribute the final document in a subsequent publication. Following publication of the finalized list of core concepts, we will develop tools to help educators incorporate the core concepts into their curricula.

Invariant Synapse Density and Neuronal Connectivity Scaling in Primate Neocortical Evolution.

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.

Cortical Afferents of Area 10 in Cebus Monkeys: Implications for the Evolution of the Frontal Pole.

Area 10, located in the frontal pole, is a unique specialization of the primate cortex. We studied the cortical connections of area 10 in the New World Cebus monkey, using injections of retrograde tracers in different parts of this area. We found that injections throughout area 10 labeled neurons in a consistent set of areas in the dorsolateral, ventrolateral, orbital, and medial parts of the frontal cortex, superior temporal association cortex, and posterior cingulate/retrosplenial region. However, sites on the midline surface of area 10 received more substantial projections from the temporal lobe, including clear auditory connections, whereas those in more lateral parts received >90% of their afferents from other frontal areas. This difference in anatomical connectivity reflects functional connectivity findings in the human brain. The pattern of connections in Cebus is very similar to that observed in the Old World macaque monkey, despite >40 million years of evolutionary separation, but lacks some of the connections reported in the more closely related but smaller marmoset monkey. These findings suggest that the clearer segregation observed in the human frontal pole reflects regional differences already present in early simian primates, and that overall brain mass influences the pattern of cortico-cortical connectivity.

Brain Connectivity in Ateles geoffroyi: Resting-State Functional Magnetic Resonance Imaging of Working Memory and Executive Control.

The objective of this research was to describe the organization and connectivity of the working memory (WM) and executive control (EC) networks in Ateles geoffroyi in resting-state conditions. Recent studies have shown that resting-state activity may underlie rudimentary brain functioning, showing that several brain regions can be tonically active at rest, maximizing the efficiency of information transfer while preserving a low physical connection cost. Whole-brain resting-state images were acquired from three healthy adult Ateles monkeys (2 females, 1 male; mean age 10.5 ± SD 2.5 years). Data were analyzed with independent component analysis, and results were grouped together using the GIFT software. The present study compared the EC and WM networks obtained with human data and with results found in the literature in other primate species. Nine resting-state networks were found, which were similar to resting networks found in healthy human adults in the prefrontal basal portion and frontopolar area. Additionally, components of the WM network were found to be extending into the hypothalamus and the olfactory areas. A key finding was the discovery of connections in the WM and EC networks to the hypothalamus, the motor cortex, and the entorhinal cortex, suggesting that information is integrated from larger brain areas. The correlated areas suggest that many elements of WM and EC may be conserved across primate species. Characterization of these networks in resting-state conditions in nonhuman primate brains is a fundamental prerequisite for understanding of the neural bases underlying the evolution and function of this cognitive system.

Age-related changes in myelin of axons of the corpus callosum and cognitive decline in common marmosets.

Executive control is a higher-level cognitive function that involves a range of different processes that are involved in the planning, coordination, execution, and inhibition of responses. Many of the processes associated with executive control, such as response inhibition and mental flexibility, decline with age. Degeneration of white matter architecture is considered to be the one of the key factors underlying cognitive decline associated with aging. Here we investigated how white matter changes of the corpus callosum were related to cognitive aging in common marmosets (Callithrix jacchus). We hypothesized that reduction in myelin thickness, myelin density, and myelin fraction of axonal fibers in the corpus callosum would be associated with performance on a task of executive function in a small sample of geriatric marmosets (n = 4) and young adult marmosets (n = 2). Our results indicated declines in myelin thickness, density, and myelin fraction with age. Considerable variability was detected on these characteristics of myelin and cognitive performance assessed via the detoured reach task. Age-related changes in myelin in Region II of the corpus callosum were predictive of cognitive performance on the detoured reach task. Thus the detoured reach task appears to also measure aspects of corticostriatal function in addition to prefrontal cortical function.

Cross-sectional comparison of health-span phenotypes in young versus geriatric marmosets.

The development of the marmoset as a translational model for healthspan and lifespan studies relies on the characterization of health parameters in young and geriatric marmosets. This cross-sectional study examined health phenotypes in marmosets for five domains of interest for human health and aging: mobility, cognition, metabolism, homeostasis, and immune function. Geriatric marmosets were found to have significant executive function impairment when compared to young animals. While geriatric animals did not show gross abnormalities in mobility and measures of locomotion, their types of movement were altered from young animals. Geriatric marmosets had alterations in cardiac function, with significantly increased mean arterial pressures; metabolism, with significantly lower VO2 ; and suppressed immune function. Further, this study sought to characterize and describe histopathology for both young and geriatric healthy marmosets. Overall this study provides a characterization of health parameters for young and geriatric marmosets which will greatly enhance future aging and interventional testing in marmosets.

Quantification of hair cortisol concentration in common marmosets (Callithrix jacchus) and tufted capuchins (Cebus apella).

Quantifying cortisol concentration in hair is a non-invasive biomarker of long-term hypothalamic-pituitary-adrenal (HPA) activation, and thus can provide important information on laboratory animal health. Marmosets (Callithrix jacchus) and capuchins (Cebus apella) are New World primates increasingly used in biomedical and neuroscience research, yet published hair cortisol concentrations for these species are limited. Review of the existing published hair cortisol values from marmosets reveals highly discrepant values and the use of variable techniques for hair collection, processing, and cortisol extraction. In this investigation we utilized a well-established, standardized protocol to extract and quantify cortisol from marmoset (n = 12) and capuchin (n = 4) hair. Shaved hair samples were collected from the upper thigh during scheduled exams and analyzed via methanol extraction and enzyme immunoassay. In marmosets, hair cortisol concentration ranged from 2,710 to 6,267 pg/mg and averaged 4,070 ± 304 pg/mg. In capuchins, hair cortisol concentration ranged from 621 to 2,089 pg/mg and averaged 1,092 ± 338 pg/mg. Hair cortisol concentration was significantly different between marmosets and capuchins, with marmosets having higher concentrations than capuchins. The incorporation of hair cortisol analysis into research protocols provides a non-invasive measure of HPA axis activity over time, which offers insight into animal health. Utilization of standard protocols across laboratories is essential to obtaining valid measurements and allowing for valuable future cross-species comparisons.

Insightful problem solving and emulation in brown capuchin monkeys.

We investigated problem solving abilities of capuchin monkeys via the "floating object problem," a task in which the subject must use creative problem solving to retrieve a favored food item from the bottom of a clear tube. Some great apes have solved this problem by adding water to raise the object to a level at which it can be easily grabbed. We presented seven capuchins with the task over eight trials (four "dry" and four "wet"). None of the subjects solved the task, indicating that no capuchin demonstrated insightful problem solving under these experimental conditions. We then investigated whether capuchins would emulate a solution to the task. Seven subjects observed a human model solve the problem by pouring water from a cup into the tube, which brought the object to the top of the tube, allowing the subject to retrieve it. Subjects were then allowed to interact freely with an unfilled tube containing the object in the presence of water and objects that could be used to solve the task. While most subjects were unable to solve the task after viewing a demonstrator solve it, one subject did so, but in a unique way. Our results are consistent with some previous results in great ape species and indicate that capuchins do not spontaneously solve the floating object problem via insight.

The corpus callosum in primates: processing speed of axons and the evolution of hemispheric asymmetry.

Interhemispheric communication may be constrained as brain size increases because of transmission delays in action potentials over the length of axons. Although one might expect larger brains to have progressively thicker axons to compensate, spatial packing is a limiting factor. Axon size distributions within the primate corpus callosum (CC) may provide insights into how these demands affect conduction velocity. We used electron microscopy to explore phylogenetic variation in myelinated axon density and diameter of the CC from 14 different anthropoid primate species, including humans. The majority of axons were less than 1 µm in diameter across all species, indicating that conduction velocity for most interhemispheric communication is relatively constant regardless of brain size. The largest axons within the upper 95th percentile scaled with a progressively higher exponent than the median axons towards the posterior region of the CC. While brain mass among the primates in our analysis varied by 97-fold, estimates of the fastest cross-brain conduction times, as conveyed by axons at the 95th percentile, varied within a relatively narrow range between 3 and 9 ms across species, whereas cross-brain conduction times for the median axon diameters differed more substantially between 11 and 38 ms. Nonetheless, for both size classes of axons, an increase in diameter does not entirely compensate for the delay in interhemispheric transmission time that accompanies larger brain size. Such biophysical constraints on the processing speed of axons conveyed by the CC may play an important role in the evolution of hemispheric asymmetry.

Comparative analysis of Meissner's corpuscles in the fingertips of primates.

Meissner's corpuscles (MCs) are tactile mechanoreceptors found in the glabrous skin of primates, including fingertips. These receptors are characterized by sensitivity to light touch, and therefore might be associated with the evolution of manipulative abilities of the hands in primates. We examined MCs in different primate species, including common marmoset (Callithrix jacchus, n = 5), baboon (Papio anubis, n = 2), rhesus macaque (Macaca mulatta, n = 3), chimpanzee (Pan troglodytes, n = 3), bonobo (Pan paniscus, n = 1) and human (Homo sapiens, n = 8). Fingertips of the first, second and fourth digits were collected from both hands of specimens, dissected and histologically stained using hematoxylin and eosin. The density (MCs per 1 mm(2) ) and the size (cross-sectional diameter of MCs) were quantified. Overall, there were no differences in the densities of MCs or their size among the digits or between the hands for any species examined. However, MCs varied across species. We found a trend for higher densities of MCs in macaques and humans compared with chimpanzees and bonobos; moreover, apes had larger MCs than monkeys. We further examined whether the density or size of MCs varied as a function of body mass, measures of dexterity and dietary frugivory. Among these variables, only body size accounted for a significant amount of variation in the size of MCs.

Handedness influences intermanual transfer in chimpanzees (Pan troglodytes) but not rhesus monkeys (Macaca mulatta).

Intermanual transfer refers to an effect, whereby training one hand to perform a motor task improves performance in the opposite untrained hand. We tested the hypothesis that handedness facilitates intermanual transfer in two nonhuman primate species: rhesus monkeys (N = 13) and chimpanzees (N = 52). Subjects were grouped into one of four conditions: (1) left-handers trained with the left (dominant) hand; (2) left-handers trained with the right (nondominant) hand; (3) right-handers trained with the left (nondominant) hand; and (4) right-handers trained with the right (dominant) hand. Intermanual transfer was measured using a task where subjects removed a Life Savers(®) candy (monkeys) or a washer (chimpanzees) from metal shapes. Transfer was measured with latency by comparing the average time taken to solve the task in the first session with the trained hand compared to the first session with the untrained hand. Hypotheses and predictions were derived from three models of transfer: access: benefit training with nondominant hand; proficiency: benefit training with dominant hand; and cross-activation: benefit irrespective of trained hand. Intermanual transfer (i.e., shorter latency in untrained hand) occurred regardless of whether monkeys trained with the dominant hand or nondominant hand, supporting the cross-activation model. However, transfer was only observed in chimpanzees that trained with the dominant hand. When handedness groups were examined separately, the transfer effect was only significant for right-handed chimpanzees, partially supporting the proficiency model. Findings may be related to neurophysiological differences in motor control as well as differences in handedness patterning between rhesus monkeys and chimpanzees.

Why primate models matter.

Research involving nonhuman primates (NHPs) has played a vital role in many of the medical and scientific advances of the past century. NHPs are used because of their similarity to humans in physiology, neuroanatomy, reproduction, development, cognition, and social complexity-yet it is these very similarities that make the use of NHPs in biomedical research a considered decision. As primate researchers, we feel an obligation and responsibility to present the facts concerning why primates are used in various areas of biomedical research. Recent decisions in the United States, including the phasing out of chimpanzees in research by the National Institutes of Health and the pending closure of the New England Primate Research Center, illustrate to us the critical importance of conveying why continued research with primates is needed. Here, we review key areas in biomedicine where primate models have been, and continue to be, essential for advancing fundamental knowledge in biomedical and biological research.

Aging of the cerebral cortex differs between humans and chimpanzees.

Several biological changes characterize normal brain aging in humans. Although some of these age-associated neural alterations are also found in other species, overt volumetric decline of particular brain structures, such as the hippocampus and frontal lobe, has only been observed in humans. However, comparable data on the effects of aging on regional brain volumes have not previously been available from our closest living relatives, the chimpanzees. In this study, we used MRI to measure the volume of the whole brain, total neocortical gray matter, total neocortical white matter, frontal lobe gray matter, frontal lobe white matter, and the hippocampus in a cross-sectional sample of 99 chimpanzee brains encompassing the adult lifespan from 10 to 51 y of age. We compared these data to brain structure volumes measured in 87 adult humans from 22 to 88 y of age. In contrast to humans, who showed a decrease in the volume of all brain structures over the lifespan, chimpanzees did not display significant age-related changes. Using an iterative age-range reduction procedure, we found that the significant aging effects in humans were because of the leverage of individuals that were older than the maximum longevity of chimpanzees. Thus, we conclude that the increased magnitude of brain structure shrinkage in human aging is evolutionarily novel and the result of an extended lifespan.

Serum biomarkers associated with aging and neurodegeneration in common marmosets (Callithrix jacchus).

The common marmoset (Callithrix jacchus), a small South American monkey, is an important nonhuman primate model in the study of aging and age-related neurodegenerative disease, including Alzheimer's disease, Parkinson's disease, and related dementias. Thorough characterization of the wild type marmoset brain agingmodel, including biomarkers of aging and neural degeneration, will further the marmoset's utility in translational research. We measured serum concentration of four key biomarkers of neural degeneration [total tau (T-tau), glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and ubiquitin C-terminal hydrolase-L1 (UCH-L1)] via single molecule array from 24 marmosets (female n = 13, male n = 11) ranging in age from 1.3 to 18.7 years. Aged marmosets (>7 years) had significantly higher GFAP, NfL, UCH-L1, and T-tau than adult marmosets. Sex differences were not detected for any of these biomarker concentrations. These data provide an important initial range of reference values for GFAP, NfL, T-tau, and UCH-L1 to evaluate aging and neural health in marmosets, as well as evaluation of therapeutics in clinical models of disease.

Hand preference for tool-use in capuchin monkeys (Cebus apella) is associated with asymmetry of the primary motor cortex.

Skilled motor actions are associated with handedness and neuroanatomical specializations in humans. Recent reports have documented similar neuroanatomical asymmetries and their relationship to hand preference in some nonhuman primate species, including chimpanzees and capuchin monkeys. We investigated whether capuchins displayed significant hand preferences for a tool-use task and whether such preferences were associated with motor-processing regions of the brain. Handedness data on a dipping tool-use task and high-resolution 3T MRI scans were collected from 15 monkeys. Capuchins displayed a significant group-level left-hand preference for this type of tool use, and handedness was associated with asymmetry of the primary motor cortex. Left-hand preferent individuals displayed a deeper central sulcus in the right hemisphere. Our results suggest that capuchins show an underlying right-hemisphere bias for skilled movement.

Community-Derived Core Concepts for Neuroscience Higher Education.

Core concepts provide a framework for organizing facts and understanding in neuroscience higher education curricula. Core concepts are overarching principles that identify patterns in neuroscience processes and phenomena and can be used as a foundational scaffold for neuroscience knowledge. The need for community-derived core concepts is pressing, because both the pace of research and number of neuroscience programs are rapidly expanding. While general biology and many subdisciplines within biology have identified core concepts, neuroscience has yet to establish a community-derived set of core concepts for neuroscience higher education. We used an empirical approach involving more than 100 neuroscience educators to identify a list of core concepts. The process of identifying neuroscience core concepts was modeled after the process used to develop physiology core concepts and involved a nationwide survey and a working session of 103 neuroscience educators. The iterative process identified eight core concepts and accompanying explanatory paragraphs. The eight core concepts are abbreviated as communication modalities, emergence, evolution, gene-environment interactions, information processing, nervous system functions, plasticity, and structure-function. Here, we describe the pedagogical research process used to establish core concepts for the neuroscience field and provide examples on how the core concepts can be embedded in neuroscience education.