Yerkes National Primate Research Center Research Articles

The Minimal Information about MHC Multimers (MIAMM)

Abstract The Minimal Information about MHC Multimers (MIAMM, miamm.lji.org) is a recently established data standard to be applied to publications utilizing these reagents. Available at miamm.lji.org, we explain how to easily represent multimer reagents in a standardized format using ontology terminology. Additionally, we provide a free, publicly available Multimer Validation Tool. This tool helps users adopt this new data standard and was proven to be generally applicable to real life use cases by its validation of the data present in the NIH Tetramer Core Facility and the nearly 18,500 multimer assays in the Immune Epitope Database (IEDB). As the scientific public adopts MIAMM, the quality, reproducibility, and annotatability of MHC multimer reagent data in the scientific literature will be improved. Funding: JDA, RAW, and DLL acknowledge support from the contract for the NIH Tetramer Facility (75N93020D00005) from the Yerkes National Primate Research Center (P51OD011132), and the Emory Center for AIDS Research (P30AI050409). RV, JAO, AM, and BP acknowledge support from National Institutes of Health grant R24 HG010032. RV, JAO, AM, BP, and AS acknowledge support from National Institutes of Health contract 75N93019C00001

Weight management towards physiological and behavioral wellbeing for chimpanzees living under human care

Across a period of 54 months, several changes were made to the feeding protocols of 32 adult chimpanzees living at the Yerkes National Primate Research Center Field Station. Before implementing any changes in diet, baseline data were collected for 6 months. During Baseline (BS), the chimpanzees received unlimited amounts of primate biscuits twice a day and a limited amount of produce as enrichment. Treatment One (T1) dietary modifications included an increased amount of vegetables, primarily leafy greens, and biscuit feedings scheduled to occur an hour after vegetables were provided to the chimpanzees. T1 lasted for 1 year. At the end of T1, most of the chimpanzees had gained weight. Treatment Two (T2) occurred over the span of 3 years, during which all the chimpanzees were switched from unlimited, group-distributed primate biscuits to individually prescribed amounts of biscuits, fed in\dividually, and increased daily feedings of leafy greens. By the end of T2, 10 of 15 chimpanzees who were overweight or obese at the start of the project were within range of ideal body condition, and 4 of the remaining 5 were improved. All the chimpanzees who started the project within ideal range were still within ideal range. Significantly more time was invested in eating, foraging, and processing food during T2 (p < .05), more appropriately replicating the natural time budget for a chimpanzee. There were not any increases in abnormal, stress-related, or agonistic behaviors as a function of dietary modifications. Inactivity, however, was significantly higher (p < .05) during the later protocol, and locomotion was concurrently lower (p < .05).

Contribution of adult sex ratio to trauma and reproductive output in large breeding groups of rhesus macaques (Macaca mulatta).

Maintaining stable breeding groups of rhesus macaques (Macaca mulatta) can be challenging due to the complex social dynamics and despotic nature of the species. Trauma from aggression is a common problem in rhesus colonies and can cause social disruption, strain veterinary and animal management resources, and potentially affect reproduction. Previous research has shown that increasing the number of non-natal adult males in a breeding group can improve group stability, reduce trauma, and increase reproduction. Here, we used mixed-effects regression models to examine the effects of sex ratio and other factors on trauma and reproduction at the Yerkes National Primate Research Center using a historical dataset made up of four large rhesus groups over an eleven-year period (2003-2013). As expected, sex ratio was a significant predictor for both trauma and reproduction. However, group age since formation was a stronger predictor of trauma frequency and the amount of space available was a slightly better predictor of reproduction than sex ratio or trauma. These results indicate that improving sex ratios can be a viable management strategy to reduce trauma and improve reproduction, particularly when it is difficult to manipulate the group compositions and/or their housing situations. Reducing trauma is a primary goal for rhesus breeding colonies, as it directly impacts the monkeys' health and psychological well-being. Such improvements are necessary for the ethical treatment and care of the animals themselves, but also to reduce financial burdens and maintain a healthy colony for research purposes.

Science and the Good: The Tragic Quest for the Foundations of Morality

Science and the Good: The Tragic Quest for the Foundations of Morality

Factors influencing the success of male introductions into groups of female rhesus macaques: Introduction technique, male characteristics and female behavior.

In captive populations of rhesus macaques, novel adult males are commonly introduced to female groups every few years to prevent inbreeding, which mimics male dispersal in wild macaque populations. However, introducing adult males is challenging because macaques are aggressive to newcomers, which can result in serious injuries. Efforts to reduce trauma risk during the introduction process and increase the probability of success are needed. Here we investigate the impact of multiple factors, including male attributes (e.g., age, weight, rank, and experience), introduction method (punctuated vs. continual exposure to females), and female behavior, on males' trauma risk and integration success. We studied eight introductions of multimale cohorts (3-7 males each; N = 36 total) into existing female groups of rhesus macaques at the Yerkes National Primate Research Center. Four cohorts were introduced using the punctuated exposure method where adult males were moved each morning from run housing to the females' indoor enclosure and returned to run housing in the afternoon, and four cohorts were introduced using the continual exposure method where adult males were moved to an introduction enclosure attached to the females' outdoor compound, allowing males to live in protected contact next to the female group continuously. Generalized linear mixed models fitted to trauma risk (e.g., latency to first trauma; total trauma count) and success or failure to integrate (i.e., continual residence within the female group for greater than 53% of days within a 28-day window after first overnight stay) showed that continual exposure to females in the introduction enclosure reduced male trauma risk and increased the likelihood of successful integration compared to punctuated exposure. Males received less trauma when they received a higher rate of grooming from females. Male attributes had no effect. These findings highlight the importance of introduction technique and female behavior in the process of males' social integration into female groups.

Validation of the Social Responsiveness Scale (SRS) to screen for atypical social behaviors in juvenile macaques.

Primates form strong social bonds and depend on social relationships and networks that provide shared resources and protection critical for survival. Social deficits such as those present in autism spectrum disorder (ASD) and other psychiatric disorders hinder the individual’s functioning in communities. Given that early diagnosis and intervention can improve outcomes and trajectories of ASD, there is a great need for tools to identify early markers for screening/diagnosis, and for translational animal models to uncover biological mechanisms and develop treatments. One of the most widely used screening tools for ASD in children is the Social Responsiveness Scale (SRS), a quantitative measure used to identify individuals with atypical social behaviors. The SRS has been adapted for use in adult rhesus monkeys (Macaca mulatta)–a species very close to humans in terms of social behavior, brain anatomy/connectivity and development–but has not yet been validated or adapted for a necessary downward extension to younger ages matching those for ASD diagnosis in children. The goal of the present study was to adapt and validate the adult macaque SRS (mSRS) in juvenile macaques with age equivalent to mid-childhood in humans. Expert primate coders modified the mSRS to adapt it to rate atypical social behaviors in juvenile macaques living in complex social groups at the Yerkes National Primate Research Center. Construct and face validity of this juvenile mSRS (jmSRS) was determined based on well-established and operationalized measures of social and non-social behaviors in this species using traditional behavioral observations. We found that the jmSRS identifies variability in social responsiveness of juvenile rhesus monkeys and shows strong construct/predictive validity, as well as sensitivity to detect atypical social behaviors in young male and female macaques across social status. Thus, the jmSRS provides a promising tool for translational research on macaque models of children social disorders.

β1 Integrins Are Necessary for Medial Prefrontal Cortex Development and Function

Proper development and maturation of the brain relies on periods of structural remodeling. These structural adaptations require coordinated signaling between the extracellular environment and the intracellular actin cytoskeleton. Composed of an α subunit responsible for extracellular ligand binding and a β subunit that activates intracellular signaling, integrin receptors provide such a link. Here we tested the hypothesis that the β1 subunit, localized to neuronal synapses and abundant in the mammalian prefrontal cortex, would be essential to prefrontal cortical development, which extends well into adolescence. We used viral‐mediated gene silencing to reduce β1‐integrins in the medial prefrontal cortex (mPFC), delivering viral vectors just prior to the onset of adolescence or in adulthood. Early‐life, but not adult‐onset, β1‐integrin silencing eliminated dendritic spines, the primary sites of excitatory plasticity in the brain. To assess functional consequences, we focused on goal‐directed decision making. The mPFC is necessary for acquiring and consolidating associations between actions and their outcomes, such that mPFC inactivation causes organisms to defer to habitual behavior, which is insensitive to outcomes. We trained mice to nose poke for food reinforcers, then decreased either: 1) the predictive contingency between nose poking and food, or 2) food value. Early‐life β1‐integrin silencing occluded behavioral sensitivity to action‐outcome associations in both conditions, causing habits. Meanwhile, depression‐ and anxiety‐like behaviors were intact. Our findings suggest that developmental β1‐integrins are necessary for mPFC maturation and function.Support or Funding InformationThe work in the SLG lab was supported by NIH F31MH109208 and R01MH117103. The Yerkes National Primate Research Center was supported by the Office of Research Infrastructure Programs/OD P51 OD011132.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Effect of Chronic Social Stress on Prenatal Transfer of Antitetanus Immunity in Captive Breeding Rhesus Macaques (Macaca mulatta).

Because tetanus can cause significant morbidity and mortality in NHP, colonywide vaccination with tetanus toxoid is recommended for outdoor breeding colonies of rhesus macaques, with primary immunizations commonly given to infants at 6 mo of age followed by booster vaccines every 10 y. Maternal antibodies are thought to offer protective immunity to infants younger than 6 mo. However, historical colony data from the Yerkes National Primate Research Center show a higher incidence of tetanus among infants (≤ 6 mo old) born to subordinate dams. Whether this higher incidence of infantile tetanus is due to a higher incidence of trauma among subordinate animals or is a stress-induced impairment of maternal antibody protection is unknown. Studies in other NHP species suggest that chronic exposure to social stressors interferes with the receptor-mediated transplacental transfer of IgG. Therefore, the primary aim of this study was to determine whether chronic stress associated with social subordination impairs prenatal transfer of antitetanus immunity in breeding female rhesus macaques. Subjects included 26 high- and 26 low-ranking adult female rhesus macaques that were nearly 5 or 10 y after their initial immunization and their nonimmunized infants. We hypothesized that infants born to subordinate dams that were nearly 10 y after immunization would have the lowest infant-to-dam antibody ratios and thus would be at greatest risk for infection. Results revealed no significant intergroup differences in infant antitetanus IgG levels. However, infant-to-dam IgG ratios against tetanus were significantly lower among subordinate animals compared with dominant macaques, after accounting for the number of years since the dam's initial vaccination. In addition, higher maternal hair cortisol levels predicted lower infantto-dam tetanus toxoid IgG ratios. Together, these findings suggest that chronic social stress in female rhesus macaques may hamper the prenatal transfer of antitetanus immunity to offspring.

Diversity in Myosin Heavy Chain Composition of the Papionin Masseter Muscle Indicates the Importance of Hybrid Phenotypes for Feeding

The contractile performance of a muscle fiber is directly related to fiber type. Variation in fiber type within and among muscles leads to a diversity of phenotypes, providing the flexibility needed to perform an assortment of behaviors with varying functional demands. Previous analyses have demonstrated variation in fiber phenotype of the chewing muscles in a number of primates and nonprimate mammals. Some of this variation has been linked to species‐specific feeding behaviors. To further evaluate the relationship between fiber phenotype and feeding behavior, we compare the distribution of masseter muscle fiber types in four papionin species: the hard‐object feeding sooty mangabey (Cercocebus atys) and three papionin species that do not specialize on hard objects.Immunohistological staining was used to determine the presence of slow (MyHC‐1 and MyHC α –cardiac) and fast (MyHC‐2 and MyHC‐M) isoforms. Samples were taken from the anterior superficial masseter of C. atys (n=8), M. mulatta (n=2), M. fascicularis (n=2), and P. anubis (n=2). Histological sections were subsequently digitized to determine the relative proportions of MyHC types and fiber phenotype in each specimen.The presence of MyHC α‐cardiac was ubiquitous throughout the sample (C. atys=99%; M. mulatta=76%; M. fascicularis=77%; P. anubis=79%). MyHC α‐cardiac maintains fatigue resistance while producing twitch tension more rapidly than MyHC‐1, thus providing an advantage for animals that require a fiber phenotype combining fatigue resistance and intermediate speed of contraction. Previously, we reported high proportions of MyHC α‐cardiac in C. atys, which we functionally linked to the need for sustained and repetitive high bite forces required for crushing hard seeds. Our finding that C. atys consistently express a higher percentage of MyHC α‐cardiac in comparison to the other papionins further supports this interpretation. The presence of hybrid fibers in all four papionin species was notable. Slow types MyHC‐1 and MyHC α‐cardiac were co‐expressed in nearly 100% of fibers sampled in each of the species. Hybrid fibers co‐expressing slow and fast‐type phenotypes were also prevalent. The abundance of hybrid fibers across papionins suggests a shared fiber phenotype that provides for versatility in the contractile properties of the anterior superficial masseter, a muscular region that must meet diverse performance requirements. This initial work is part of a larger ongoing study to assess jaw‐muscle fiber phenotype in non‐human primates. Future analyses will include larger samples and a greater diversity of species to enable us to test key functional hypotheses about fiber type diversity in primates.Support or Funding InformationFunded in part by National Science Foundation Grants (BCS 1719743, BCS 0962677, BCS 0095522) and Yerkes National Primate Research Center Base Grant ORIP/OD P51OD011132 and the Comparative AIDS CoreThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Adult chimps are less consoling

Adult chimpanzees are less likely than young ones to console companions in times of distress. The finding raises questions about how the capacity for empathy changes with age in people's closest relatives--and them. When a chimpanzee gets upset, companions often sit with them and offer reassurance by kissing, grooming or embracing them. They know chimpanzees have personalities: lasting individual features in their behavior. But it was unclear whether their empathetic tendencies are part of their personality, and whether they change over time. Christine Webb at Emory University in Atlanta, Georgia, and her colleagues studied eight years of observations of a group of 44 chimpanzees at Yerkes National Primate Research Center.

The Macaque Social Responsiveness Scale (mSRS): A Rapid Screening Tool for Assessing Variability in the Social Responsiveness of Rhesus Monkeys (Macaca mulatta).

Understanding the biological mechanisms underlying human neuropsychiatric disorders, such as autism spectrum disorder (ASD), has been hindered by the lack of a robust, translational animal model. Rhesus monkeys (Macaca mulatta) display many of the same social behaviors that are affected in ASD, making them an excellent animal species in which to model social impairments. However, the social impairments associated with ASD may reflect extreme ends of a continuous distribution of traits. Thus, to validate the rhesus monkey as an animal model for studying social impairments that has strong translational relevance for ASD, researchers need an easily-implemented measurement tool that can quantify variation in social behavior dimensionally. The Social Responsiveness Scale (SRS) is a 65-item survey that identifies both typical and atypical social behaviors in humans that covary with ASD symptom severity. A chimpanzee SRS has already been validated and the current study adapted this tool for use in the rhesus monkey (mSRS). Fifteen raters completed the mSRS for 105 rhesus monkeys living at the Yerkes National Primate Research Center. The mSRS scores showed a unimodal distribution with a positive skew that identified 6 statistical outliers. Inter-rater reliability was very strong, but only 17 of the 36 questions showed positive intra-item reliability. The results of an exploratory factor analysis identified 3 factors that explained over 60% of the variance, with 12 items significantly loading onto the primary factor. These items reflected behaviors associated with social avoidance, social anxiety or inflexibility and social confidence. These initial findings are encouraging and suggest that variability in the social responsiveness of rhesus monkeys can be quantified using the mSRS: a tool that has strong translational relevance for human disorders. With further modification, the mSRS may provide an promising new direction for research on the biological mechanisms underlying social impairments.

Pair housing of Macaques: A review of partner selection, introduction techniques, monitoring for compatibility, and methods for long-term maintenance of pairs.

Pair housing of macaques has become a widely implemented compromise between meeting the social needs of the monkeys and allowing for their use in biomedical research. While beneficial to the animals, pair housing can provide challenges for those caring for them. Drawing from both scientific literature and direct experience, this paper provides a review of practical aspects of pair housing including partner selection, pairing methodologies, staff education, and equipment considerations. Recommendations include selecting a pairing method appropriate to the facility and the individual animals being paired, educating staff on social behavior, and establishing a pair monitoring program to facilitate long-term pair maintenance. Assessment of behavior is essential in determining the compatibility of new pairs and in identifying established pairs that may need interventions to enhance their long-term compatibility. The pair housing program at the Yerkes National Primate Research Center is described as one model of a successful program. Am. J. Primatol. 79:e22485, 2017. © 2015 Wiley Periodicals, Inc.

Novel MHC class I full-length allele and haplotype characterization in sooty mangabeys.

Sooty mangabeys (Cercocebus atys) are natural SIV hosts and the presumed source of HIV-2 and SIVmac, which makes them a valuable model for HIV/SIV research. However, like other African primates, little is known about their major histocompatibility complex (MHC) genetics. In this study, we used Roche/454 and Illumina MiSeq deep sequencing in order to determine the MHC class I transcripts in a cohort of 165 sooty mangabeys from the Yerkes National Primate Research Center (YNPRC). We have characterized 121 functionally full-length classical (Ceat-A and Ceat-B) and non-classical (Ceat-F and Ceat-I) alleles and have also identified 22 Ceat-A/Ceat-B haplotype chromosomal combinations. We correlated these Ceat-A/Ceat-B haplotype combinations to recently described microsatellite haplotypes from the YNPRC colony. These newly identified alleles and haplotypes establish a resource for studying cellular immunity in sooty mangabeys and provide a framework for rapidly cataloging MHC class I sequences in an understudied, yet important, nonhuman primate species.

Immunogenetic characterization of a captive colony of sooty mangabeys (Cercocebus atys) used for SIV research.

African non-human primates are SIV natural hosts and do not develop disease following infection. Understanding disease avoidance mechanisms in these species is important for HIV vaccine development. The largest captive population of sooty mangabeys, a SIV natural host species, resides at the Yerkes National Primate Research Center. Thirteen primer sets that amplify polymorphic microsatellite loci within the MHC region were used to genotype 144 animals. Immunogenetic Management Software (IMS) was used to identify MHC haplotypes and organize data. Seventy-three haplotypes were identified. Limited haplotype diversity was observed in this population with 88.2% of included animals carrying one of 18 haplotypes. Differences in haplotype frequency were observed between SIV (+) and SIV (-) populations. We have developed a novel tool for others to use in the analysis of the role of the MHC in a natural host non-human primate model species used for SIV research.

Influence of methamphetamine self-administration on sleep in rhesus monkeys using actigraphy

Introduction Sleep disorders and substance abuse are highly comorbid. Although methamphetamine is a very commonly abused drug, to the best of our knowledge, no study has evaluated its effects on sleep during drug use and abstinence under well- controlled conditions in laboratory animals. The objective of this study was to examine the effects of methamphetamine self-administration on sleep-like measures in nonhuman primates. Materials and methods Adult male rhesus monkeys (Macaca mulatta; n = 4) self-administered methamphetamine (0.01 and 0.03 mg/kg/injection, i.v.) under a fixed- ratio 20 schedule of reinforcement (60-min sessions once a day, 5 days per week) for 5 weeks. Sleep-like measures were evaluated with Actiwatch monitors before, during, and after each period of drug self- administration. Results Both doses of methamphetamine reliably maintained self- administration. Methamphetamine (0.03 mg/kg) increased derived measures of latency to sleep onset and sleep fragmentation, and decreased sleep efficiency compared to abstinence, and higher methamphetamine intake predicted worse sleep quality. However, sleep normalized immediately after the discontinuation of methamphetamine self-administration. Conclusion Methamphetamine markedly disrupted sleep-like measures; however, methamphetamine self-administration did not disrupt sleep quality during subsequent periods of drug abstinence. Acknowledgements This research was supported by USPHS Grants DA10344 (LLH), DA31246 (LLH), P51OD11132 (Yerkes National Primate Research Center), and by AFIP and CNPq (MLA).

Drug could stop PTSD before it starts

Researchers investigating the genetic basis of posttraumatic stress disorder (PTSD) have found a drug that could stop the condition from developing if given shortly after a traumatic experience. Kerry Ressler, a psychiatrist at Yerkes National Primate Research Center in Atlanta, Georgia, wanted to

Size isn't everything, comparatively speaking

Size isn't everything, comparatively speaking

Population Genetics of the Washington National Primate Research Center's (WaNPRC) Captive Pigtailed Macaque (Macaca nemestrina) Population

Pigtailed macaques (Macaca nemestrina) provide an important model for biomedical research on human disease and for studying the evolution of primate behavior. The genetic structure of captive populations of pigtailed macaques is not as well described as that of captive rhesus (M. mulatta) or cynomolgus (M. fascicularis) macaques. The Washington National Primate Research Center houses the largest captive colony of pigtailed macaques located in several different housing facilities. Based on genotypes of 18 microsatellite (short tandem repeat [STR]) loci, these pigtailed macaques are more genetically diverse than captive rhesus macaques and exhibit relatively low levels of inbreeding. Colony genetic management facilitates the maintenance of genetic variability without compromising production goals of a breeding facility. The periodic introduction of new founders from specific sources to separate housing facilities at different times influenced the colony's genetic structure over time and space markedly but did not alter its genetic diversity significantly. Changes in genetic structure over time were predominantly due to the inclusion of animals from the Yerkes National Primate Research Center in the original colony and after 2005. Strategies to equalize founder representation in the colony have maximized the representation of the founders' genomes in the extant population. Were exchange of animals among the facilities increased, further differentiation could be avoided. The use of highly differentiated animals may confound interpretations of phenotypic differences due to the inflation of the genetic contribution to phenotypic variance of heritable traits.

Benefits of pair housing are consistent across a diverse population of rhesus macaques

Introducing singly housed rhesus macaques (Macaca mulatta) into isosexual pairs is widely considered to improve welfare. The population of laboratory rhesus macaques is heterogeneous on a variety of factors and there is little literature available to directly evaluate the influence of many of these factors on the benefits of pair housing. Subjects were 46 adult female and 18 adult male rhesus macaques housed at the Tulane National Primate Research Center and the Yerkes National Primate Research Center. Behavioral data totalling 859h and serum cortisol levels derived from 312 serum samples were analyzed for main effects of housing condition, comparing single housing to pair housing. In addition, a series of analyses were performed to test for interactions between housing condition and seven independent variables: sex, age, prior duration of single housing, presence or absence of a history of self-injurious behavior, and dominance rank, levels of affiliation and agonism in the paired setting. After the collection of 4–8h of baseline data and three serum cortisol samples, pairs of individuals were introduced to one another and data collection was repeated, no earlier than 4 weeks after introduction. In pair housing both female and male subjects showed decrease in abnormal behavior (females: 54% reduction; P=0.001; males: 18% reduction; P=0.0007) and anxiety-related behavior (females: 35% reduction; P=0.0001; males: 41% reduction; P=0.0001), and increases in locomotion (females: 41% increase; P=0.0001; males: 76% increase: P=0.002). In pair housing, there were no significant sex differences in social behavior. Descriptively, paired females spent 12% of samples engaged in affiliative behavior and 0.5% engaged in agonistic behavior (backtransformed arcsin square root means). The corresponding values for males were 12% and 0.3%. No interaction effects were detected with any of the independent variables tested in this study. Cortisol values varied with sex but did not differ between housing conditions; no differences were detected when any of the above variables were included in the statistical model. Results support the general consensus among those studying the welfare of captive primates that social housing is a potent means for promoting behavioral indicators of the psychological well-being of laboratory primates. These results are of considerable practical significance and include information that refutes common perceptions about the unsuitability of males as socialization candidates, perceived negative consequences of subordinate rank within a pair, or variation in social dynamics observed in particular pairs. The population of singly housed rhesus macaques that will derive benefit from pair housing is diverse and findings of improved welfare can be broadly applied.

Erratum to: An inversion effect modified by expertise in capuchin monkeys

J. J. Pokorny (&) C. E. Webb F. B. M. de Waal Department of Psychology, Living Links, Yerkes National Primate Research Center, Emory University, 954 Gatewood Road, Atlanta, GA 30329, USA e-mail: jpokorn@emory.edu Fig. 2 a Example of an upright trial for capuchin face stimuli. The odd individual, and correct response, is the top right position. b Example of an inverted trial for capuchin face stimuli. The odd individual is depicted in the bottom left position