Sarcina sp. as a presumptive cause of fatal acute gastric dilation and gastric emphysema in rhesus macaques.

A 4-y-old female and 3-y-old male rhesus macaque (Macaca mulatta), both housed in the same facility, died unexpectedly within 2 wk. Postmortem examination revealed severe gastric dilation in both macaques and gastric emphysema in the female macaque. Histologically, bacteria consistent with Sarcina sp. were present in both macaques within the lungs and lumen of the trachea, esophagus, and gastrointestinal (GI) tract without associated inflammation. Additionally, in the female macaque, the bacteria were found in the gastric mucosa and associated with emphysematous spaces in the gastric wall without associated inflammation. PCR and Sanger sequencing of amplicons were subsequently performed on GI contents and non-alimentary tissues from the 2 affected monkeys and on comparative samples from unaffected rhesus monkeys in the same facility and an adjacent primate facility. The cases were compared using the 2-tailed Fisher exact test (p-value at 95% confidence). PCR identified Sarcina in GI contents of both affected and unaffected monkeys (p = 0.6084) and in non-alimentary tissues of affected monkeys only (p = 0.0083). These results suggest that the presence of Sarcina sp. in non-alimentary tissues is associated with gastric distension, gas accumulation, and unexpected death in nonhuman primates.

100 years of comparative psychology advancing practice, policy, and the public-And what the future requires.

This year marks the 100th anniversary since the inception of the original Journal of Comparative Psychology. This review highlights the evolution of Journal of Comparative Psychology and the field of comparative psychology over the past century through the lens of the field's contributions in the realms of science practice, science policy, and public opinion. The review culminates with a look ahead to the next 100 years, with both challenges that are likely to remain as well as potential paths to continue growth and success. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Predicting their past: Machine language learning can discriminate the brains of chimpanzees with different early-life social rearing experiences.

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.

Freestanding bipedal posture and coordinated bimanual manipulation significantly influence lateralized hand use in rhesus monkeys (Macaca mulatta) and chimpanzees (pan troglodytes).

Investigations of behavioral lateralization in nonhuman primates yield important insights into brain-behavior relationships. In turn, they provide clues about both proximal and distal factors that shape the development and expression of association between motor asymmetries and underlying neural substrates. Nonhuman primates afford unique comparative opportunities to evaluate potential routes for the evolution of handedness, as well as to uncover relationships between behavioral lateralization and underlying neural, genetic, and physiological correlates. We examined hand preference in 22 rhesus monkeys and 79 chimpanzees using unimanual reaching tasks varying in postural stability and in a coordinated bimanual task. The majority of rhesus monkeys and chimpanzees showed significant lateral biases when reaching from a freestanding posture and when engaged in a coordinated bimanual task. Population-level directional bias was not evident for any task for rhesus monkeys and was observed only in the bimanual task for chimpanzees. We did not find consistent relationships between an individual's hand preference for different types of tasks. Both freestanding bipedal posture and coordinated bimanual hand use elicited significantly stronger lateral biases in reaching when compared with quadrupedal reaching. These data support the hypothesis that both degrees of postural instability and complex manipulation, such as bimanual coordination, may influence the expression of behavioral asymmetries in primates. These results demonstrate robust lateralization occurs at the individual level. Our results also highlight the need for greater consideration of task type and descriptive data in studies aimed at evaluating brain-behavior relationships and individual differences associated with hand preference. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Animal Research in Neuroscience: A Duty to Engage.

Activists opposed to the use of animals in scientific research are increasingly dominating the public discourse and pressuring government officials to severely limit the scope of the work. Polls show that public support for animal research is in decline. Scientists must respond by engaging with the public and policymakers to explain their research and its importance and by addressing moral concerns and objections.

Moving evidence into practice: cost analysis and assessment of macaques' sustained behavioral engagement with videogames and foraging devices.

Environmental enrichment plans for captive nonhuman primates often include provision of foraging devices. The rationale for using foraging devices is to promote species-typical activity patterns that encourage physical engagement and provide multi-sensory stimulation. However, these devices have been shown to be ineffective at sustaining manipulation over long periods of time, and often produce minimal cognitive engagement. Here we use an evidence-based approach to directly compare the amount of object-directed behavior with a foraging device and a computer-based videogame system. We recorded 11 adult male rhesus monkeys' interactions with a foraging device and two tasks within a joystick videogame cognitive test battery. Both techniques successfully produced high levels of engagement during the initial 20 min of observation. After 1 hr the monkeys manipulated the foraging device significantly less than the joystick, F(2,10) = 43.93, P < 0.0001. Subsequent testing showed that the monkeys engaged in videogame play for the majority of a 5 hr period, provided that they received a 94 mg chow pellet upon successful completion of trials. Using a model approach, we developed previously as a basis for standardized cost:benefit analysis to inform facility decisions, we calculated the comprehensive cost of incorporating a videogame system as an enrichment strategy. The videogame system has a higher initial cost compared to widely-used foraging devices, however, the ongoing labor and supply costs are relatively low. Our findings add to two decades of empirical studies by a number of laboratories that have demonstrated the successful use of videogame-based systems to promote sustained non-social cognitive engagement for macaques. The broader significance of the work lies in the application of a systematic approach to compare and contrast enrichment strategies and encourage evidence-based decision making when choosing an enrichment strategy in a manner that promotes meaningful cognitive enrichment to the animals.

Broader impacts: international implications and integrative ethical consideration of policy decisions about US chimpanzee research.

Recent decisions and unprecedented evaluative processes about research with chimpanzees (Pan troglodytes) by the US National Institutes of Health (NIH) continue to attract widespread attention by the public, media, and scientific community. Over the past 5 years, actions by the NIH and the United States Fish and Wildlife Services, have significantly truncated valuable scientific research and jeopardized future research. From a global perspective, the decisions have broad consequences for research aimed not only at human health, but also the conservation and welfare of other species. Full consideration of the role that research plays in improving animal welfare in captivity and in the wild, and the impact of the loss of access to chimpanzees for research, remains largely unexamined. At the same time, legal initiatives aimed at protecting chimpanzees by granting them "personhood" status have increasingly raised questions about equity in standards, oversight, and transparency for chimpanzees in other captive settings. Together, the decisions, subsequent actions, and public discussion put the growing need for a more integrative and global approach to decision-making about the future of captive chimpanzees into sharp relief. In this paper, we outline an expansive framework for ethical consideration to guide dialogue and decisions about animal research, welfare, and equitable treatment of nonhuman animals across settings. Regardless of the setting in which animals live, science plays an indispensable role in informing decisions about individual, species, societal, and environmental health. Thus, the scientific community and broader public need to engage in serious and thoughtful deliberations to weigh the harms and benefits of conducting (or failing to conduct) research that transcends geographic borders and that can guide responsible and informed decisions about the future of chimpanzees.

Behavioral response inhibition and maturation of goal representation in prefrontal cortex after puberty.

Executive functions including behavioral response inhibition mature after puberty, in tandem with structural changes in the prefrontal cortex. Little is known about how activity of prefrontal neurons relates to this profound cognitive development. To examine this, we tracked neuronal responses of the prefrontal cortex in monkeys as they transitioned from puberty into adulthood and compared activity at different developmental stages. Performance of the antisaccade task greatly improved in this period. Among neural mechanisms that could facilitate it, reduction of stimulus-driven activity, increased saccadic activity, or enhanced representation of the opposing goal location, only the latter was evident in adulthood. Greatly accentuated in adults, this neural correlate of vector inversion may be a prerequisite to the formation of a motor plan to look away from the stimulus. Our results suggest that the prefrontal mechanisms that underlie mature performance on the antisaccade task are more strongly associated with forming an alternative plan of action than with suppressing the neural impact of the prepotent stimulus.

New era for chimpanzee research: broad implications of chimpanzee research decisions.

The unprecedented recent decision-making about chimpanzees supported for biomedical science by the US National Institutes of Health attracted international attention and significantly changed many dimensions of chimpanzee research. Many public and media portrayals incorrectly generalized the NIH findings to conclude that chimpanzee research itself was no longer necessary. In fact, the broader question of the necessity and value of the full range of chimpanzee research was never asked, evaluated, or within the NIH's primary charge. The Institute of Medicine evaluative panel found that research with chimpanzees was necessary for some, but not all, purposes. The panel's findings also led the NIH to introduce new standards for the care and management of NIH-supported chimpanzees and a new mechanism for ethical review of grant proposals involving chimpanzees. The NIH evaluation and decisions could not address all captive chimpanzees and all types of research. However, the process did underscore the need for a more expansive framework for continued ethical review and decision-making to responsibly address the future of captive chimpanzee management and research. Among the broader considerations are extension of evidence-informed standards to ensure equitable care and treatment of all chimpanzees; determining the global impact of limited captive populations; and balancing benefit and harm at individual, species, societal, and environmental levels. The breadth and longevity of impact from the current US decisions suggest the need for many voices, disciplines, and stakeholders to address the complex interplay between science, animal welfare, and global health.

Assessment of foraging devices as a model for decision-making in nonhuman primate environmental enrichment.

Continued progress to move evidence-based best practices into community and regulatory animal welfare standards depends in part on developing common metrics to assess cost, benefit, and relative value. Here we describe a model approach to evidence-based evaluation and an example of comprehensive cost-benefit assessment for a common element of environmental enrichment plans for laboratory-housed nonhuman primates. Foraging devices encourage a species-typical activity that dominates the time budget of primates outside captivity and provide inherent cognitive challenges, physical activity demands, and multi-sensory stimulation. However, their implementation is not standard, and is challenged by perception of high costs and labor; nutritional and health concerns; and identification of best practices in implementation (that is, device types, food type, frequency of delivery and rotation). To address these issues, we directly compared monkeys' engagement with different foraging devices and the comprehensive cost of implementing foraging opportunities. We recorded 14 adult male cynomolgus monkeys' interactions with 7 types of devices filled with a range of enrichment foods. All devices elicited foraging behavior, but there were significant differences among them both initially and over subsequent observations. Devices that afforded opportunity for extraction of small food items and that posed manipulative challenge elicited greater manipulation. The cost of providing a foraging opportunity to a single monkey is roughly US$1, with approximately 80% attributable to labor. This study is the first to perform a rigorous cost-benefit analysis and comparison of common foraging devices included in environmental enrichment. Its broader significance lies in its contribution to the development of methods to facilitate improvement in evidence-based practices and common standards to enhance laboratory animal welfare.

Evolution of the central sulcus morphology in primates.

The central sulcus (CS) divides the pre- and postcentral gyri along the dorsal-ventral plane of which all motor and sensory functions are topographically organized. The motor-hand area of the precentral gyrus or KNOB has been described as the anatomical substrate of the hand in humans. Given the importance of the hand in primate evolution, here we examine the evolution of the motor-hand area by comparing the relative size and pattern of cortical folding of the CS surface area from magnetic resonance images in 131 primates, including Old World monkeys, apes and humans. We found that humans and great apes have a well-formed motor-hand area that can be seen in the variation in depth of the CS along the dorsal-ventral plane. We further found that great apes have relatively large CS surface areas compared to Old World monkeys. However, relative to great apes, humans have a small motor-hand area in terms of both adjusted and absolute surface areas.

Age-dependent changes in prefrontal intrinsic connectivity.

The prefrontal cortex continues to mature after puberty and into early adulthood, mirroring the time course of maturation of cognitive abilities. However, the way in which prefrontal activity changes during peri- and postpubertal cortical maturation is largely unknown. To address this question, we evaluated the developmental stage of peripubertal rhesus monkeys with a series of morphometric, hormonal, and radiographic measures, and conducted behavioral and neurophysiological tests as the monkeys performed working memory tasks. We compared firing rate and the strength of intrinsic functional connectivity between neurons in peripubertal vs. adult monkeys. Notably, analyses of spike train cross-correlations demonstrated that the average magnitude of functional connections measured between neurons was lower overall in the prefrontal cortex of peripubertal monkeys compared with adults. The difference resulted because negative functional connections (indicative of inhibitory interactions) were stronger and more prevalent in peripubertal compared with adult monkeys, whereas the positive connections showed similar distributions in the two groups. Our results identify changes in the intrinsic connectivity of prefrontal neurons, particularly that mediated by inhibition, as a possible substrate for peri- and postpubertal advances in cognitive capacity.

Different early rearing experiences have long-term effects on cortical organization in captive chimpanzees (Pan troglodytes).

Consequences of rearing history in chimpanzees (Pan troglodytes) have been explored in relation to behavioral abnormalities and cognition; however, little is known about the effects of rearing conditions on anatomical brain development. Human studies have revealed that experiences of maltreatment and neglect during infancy and childhood can have detrimental effects on brain development and cognition. In this study, we evaluated the effects of early rearing experience on brain morphology in 92 captive chimpanzees (ages 11-43) who were either reared by their mothers (n = 46) or in a nursery (n = 46) with age-group peers. Magnetic resonance brain images were analyzed with a processing program (BrainVISA) that extracts cortical sulci. We obtained various measurements from 11 sulci located throughout the brain, as well as whole brain gyrification and white and grey matter volumes. We found that mother-reared chimpanzees have greater global white-to-grey matter volume, more cortical folding and thinner grey matter within the cortical folds than nursery-reared animals. The findings reported here are the first to demonstrate that differences in early rearing conditions have significant consequences on brain morphology in chimpanzees and suggests potential differences in the development of white matter expansion and myelination.

Working memory performance and neural activity in prefrontal cortex of peripubertal monkeys.

The dorsolateral prefrontal cortex matures late into adolescence or early adulthood. This pattern of maturation mirrors working memory abilities, which continue to improve into adulthood. However, the nature of the changes that prefrontal neuronal activity undergoes during this process is poorly understood. We investigated behavioral performance and neural activity in working memory tasks around the time of puberty, a developmental event associated with the release of sex hormones and significant neurological change. The developmental stages of male rhesus monkeys were evaluated with a series of morphometric, hormonal, and radiographic measures. Peripubertal monkeys were trained to perform an oculomotor delayed response task and a variation of this task involving a distractor stimulus. We found that the peripubertal monkeys tended to abort a relatively large fraction of trials, and these were associated with low levels of task-related neuronal activity. However, for completed trials, accuracy in the delayed saccade task was high and the appearance of a distractor stimulus did not impact performance significantly. In correct trials delay period activity was robust and was not eliminated by the presentation of a distracting stimulus, whereas in trials that resulted in errors the sustained cue-related activity was significantly weaker. Our results show that in peripubertal monkeys the prefrontal cortex is capable of generating robust persistent activity in the delay periods of working memory tasks, although in general it may be more prone to stochastic failure than in adults.

The influences of perinatal challenge persist into the adolescent period in socially housed bonnet macaques (Macaca radiata).

Social challenges during the perinatal period influence the mother-infant relationship in nonhuman primates and may affect the offspring's response to later social challenge(s). Relocation of a breeding colony of monkeys (Macaca radiata) created two groups of infants: one group experienced social group relocation to a new housing facility during the perinatal period (ATYPICAL) and the second group developed within a constant environment (TYPICAL). At a mean age of 25 months, all animals were removed from their natal group and placed in same sex adolescent social groups. Behavioral observations were collected after group formation or introduction to a new group. ATYPICAL subjects showed increased aggression and reduced affiliation compared to TYPICAL subjects. Hair cortisol in male subjects collected 6 months after introduction was elevated in the ATYPICAL subjects compared to TYPICAL subjects. These findings demonstrate that early life challenges affect behavior as well as stress hormone responses to social challenge in adolescence.

The signature of maternal rearing in the methylome in rhesus macaque prefrontal cortex and T cells.

Early-life adversity is associated with a broad scope of life-long health and behavioral disorders. Particularly critical is the role of the mother. A possible mechanism is that these effects are mediated by "epigenetic" mechanisms. Studies in rodents suggest a causal relationship between early-life adversity and changes in DNA methylation in several "candidate genes" in the brain. This study examines whether randomized differential rearing (maternal vs surrogate-peer rearing) of rhesus macaques is associated with differential methylation in early adulthood. The data presented here show that differential rearing leads to differential DNA methylation in both prefrontal cortex and T cells. These differentially methylated promoters tend to cluster by both chromosomal region and gene function. The broad impact of maternal rearing on DNA methylation in both the brain and T cells supports the hypothesis that the response to early-life adversity is system-wide and genome-wide and persists to adulthood. Our data also point to the feasibility of studying the impact of the social environment in peripheral T-cell DNA methylation.

Chronic treatment with extended release methylphenidate does not alter dopamine systems or increase vulnerability for cocaine self-administration: a study in nonhuman primates.

Despite the widespread use of stimulant medications for the treatment of attention deficit hyperactivity disorder, few studies have addressed their long-term effects on the developing brain or susceptibility to drug use in adolescence. Here, we determined the effects of chronic methylphenidate (MPH) treatment on brain dopamine (DA) systems, developmental milestones, and later vulnerability to substance abuse in juvenile nonhuman primates. Male rhesus monkeys (approximately 30 months old) were treated daily with either a sustained release formulation of MPH or placebo (N=8 per group). Doses were titrated to achieve initial drug blood serum levels within the therapeutic range in children and adjusted throughout the study to maintain target levels. Growth, including measures of crown-rump length and weight, was assessed before and after 1 year of treatment and after 3-5 months washout. In addition, positron emission tomography scans were performed to quantify binding availability of D2/D3 receptors and dopamine transporters (DATs). Distribution volume ratios were calculated to quantify binding of [¹8F]fluoroclebopride (DA D2/D3) and [¹8F]-(+)-N-(4-fluorobenzyl)-2ß-propanoyl-3ß-(4-chlorophenyl)tropane (DAT). Chronic MPH did not differentially alter the course of weight gain or other measures of growth, nor did it influence DAT or D2/D3 receptor availability after 1 year of treatment. However, after washout, the D2/D3 receptor availability of MPH-treated animals did not continue to decline at the same rate as control animals. Acquisition of intravenous cocaine self-administration was examined by first substituting saline for food reinforcement and then cocaine doses (0.001-0.1 mg/kg per injection) in ascending order. Each dose was available for at least five consecutive sessions. The lowest dose of cocaine that maintained response rates significantly higher than saline-contingent rates was operationally defined as acquisition of cocaine reinforcement. There were no differences in rates of acquisition, overall response rates, or cocaine intake as a function of cocaine dose between groups. In an animal model that closely mimics human development; chronic treatment with therapeutic doses of sustained release MPH did not have a significant influence on the regulation of DATs or D2/D3 receptors, or on standard measures of growth. Furthermore, this treatment regimen and subsequent drug washout did not have an impact on vulnerability to cocaine abuse.

Cortical sulci asymmetries in chimpanzees and macaques: a new look at an old idea.

Functional and neuroanatomical asymmetries are an important characteristic of the human brain. The evolution of such specializations in the human cortex has provoked great interest in primate brain evolution. Most research on cortical sulci has revolved around linear measurements, which represent only one dimension of sulci organization. Here, we used a software program (BrainVISA) to quantify asymmetries in cortical depth and surface area from magnetic resonance images in a sample of 127 chimpanzees and 49 macaques. Population brain asymmetries were determined from 11 sulci in chimpanzees and seven sulci in macaques. Sulci were taken from the frontal, temporal, parietal, and occipital lobes. Population-level asymmetries were evident in chimpanzees for several sulci, including the fronto-orbital, superior precentral, and sylvian fissure sulci. The macaque population did not reveal significant population-level asymmetries, except for surface area of the superior temporal sulcus. The overall results are discussed within the context of the evolution of higher order cognition and motor functions.

Effects of early life stress on drinking and serotonin system activity in rhesus macaques: 5-hydroxyindoleacetic acid in cerebrospinal fluid predicts brain tissue levels.

Early childhood stress is a risk factor for the development of substance-abuse disorders. A nonhuman primate model of early life stress, social impoverishment through nursery-rearing rather than mother-rearing, has been shown to produce increased impulsive and anxiety-like behaviors, cognitive and motor deficits, and increased alcohol consumption. These behavioral changes have been linked to changes in cerebrospinal fluid (CSF) levels of 5-hydroxyindoleacetic acid (5-HIAA), a serotonin (5-HT) metabolite. The effects of different rearing conditions on ethanol drinking and three measures of 5-HT function in the central nervous system were evaluated, including CSF 5-HIAA levels and tissue levels of 5-HT and 5-HIAA in brain samples. Brain samples were taken from the dorsal caudate, putamen, substantia nigra (SN) pars reticulata, SN pars compacta and hippocampus. There was a clear effect of rearing condition on the 5-HT system. Overall 5-HIAA and 5-HIAA/5-HT ratio measures of 5-HT turnover were significantly lower in nursery reared compared to mother-reared animals. In addition, there was a strong within-subject correlation between CSF and brain tissue 5-HIAA levels. Ethanol drinking was greater in nursery reared monkeys, consistent with previous results. These findings show that CSF 5-HIAA measurements can be used to predict brain 5-HT activity that may be involved in behavioral outcomes such as anxiety and alcohol consumption. Thus, CSF sampling may provide a minimally invasive test for neurochemical risk factors related to alcohol abuse.