Stress In Nonhuman Primates Research Articles

Longitudinal Baboon (Papio anubis) Neutrophil to Lymphocyte Ratio (NLR), and Correlations with Monthly Sedation Rate and Within-Group Sedation Order.

Neutrophil to lymphocyte ratio (NLR) is a simple marker of stress and inflammation, but there is limited research regarding NLR in nonhuman primates (NHPs), with studies showing associations with longevity, certain medical conditions, and stressful circumstances. Here, we examined baboon NLR longitudinally, and as a function of health parameters. We also examined whether NLR was affected by sedation rate, as well as the order of sedation within a group, given that sedation events during clinical and research practices can induce stress in NHPs. While older adult and geriatric baboon NLR did not differ longitudinally, juvenile and young adult NLR tended to increase, primarily driven by increases in females. Additionally, baboons sedated later within a group showed significantly higher NLRs than those sedated earlier in the process. However, baboons with higher sedation rates per month showed lower NLRs. These data indicate that NLR may be dysregulated in different ways as a function of different types of stress, with sedation order (i.e., acute stress) causing pathological increases in NLR, and sedation rate over time (i.e., chronic stress) causing decreases. Importantly, we propose that NLR, a routinely obtained veterinary measure, has potential utility as a welfare indicator of stress resulting from clinical and research practices, as well as a measure that can inform behavioral management practices and interventions.

The effects of positive and negative experiences on subsequent behavior and cognitive performance in capuchin monkeys (Sapajus [Cebus] apella).

Our understanding of animals' affective processing is notably limited compared to the wealth of research on humans, largely due to difficulties in measurement. Moreover, despite a recent increase in the understanding of the interaction between affect and cognition in animals, most research has focused on negative affect, with the result that we continue to know little about the effects of positive affect. In this study, we tested 15 adult capuchin monkeys (Sapajus [Cebus] apella) using a novel methodology that took advantage of capuchins' species-typical behavior to engineer both a positive and negative experience, using the same apparatus to minimize extraneous impacts. Following a positive or negative experience (that presumably induced positive and negative affect, respectively), or a control with no manipulation, we assessed subjects' performance on a cognitive task, a computerized delayed match-to-sample. As predicted, behavior following the negative condition suggested a negative affective state, with increased rates of scratching (commonly used as an indicator of stress in nonhuman primates) compared to both the positive and control conditions. Cognitive performance was also impaired in the negative condition compared to the other two. Contrary to predictions, however, the positive condition did not have a facilitative effect on cognitive performance, but behavioral results indicate that we may not have induced a truly positive affective state. Although we add to evidence that a negative experience can influence subsequent behavior and cognitive performance in nonhuman primates, our work highlights our lack of knowledge about the impact of positive affect, if any, on behavior and cognition. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Gene-Specific and Genome-Wide Effects of Ancestral Maltreatment on DNA Methylation in Rhesus Macaques

Environmental stress in antecedent generations may influence molecular and behavioral phenotypes including the risk for mental disorders in offspring, leading. Here we present data on a model of early life stress in non-human primates investigating the biological transmission of stress from the parental generation to the offspring and its functional epigenetic implications in the offspring on the level of DNA methylation changes in stress-related genes and on the genome-wide level.

Behavioral and cortisol responses of adult marmoset monkeys (Callithrix penicillata) to different home-cage social disruption intervals

Social separation is an increasingly used strategy to experimentally assess psychogenic stress in nonhuman primates, yet it is also inherently required for captive management. Surprisingly, little is known on the effects of an individual left alone in a highly familiar place, compared to novel-environment isolation. Therefore, using stable heterosexual pairs of adult marmosets (Callithrix penicillata), we assessed in the individual left behind in the home-cage: (1) the behavior during and after a 5 and 15 min separation; (2) the behavior and cortisol levels before, during and after a 7-day separation; and (3) the relationship between these two components of the stress response. All conditions induced social contact calls and hyperlocomotion, with prolonged separation yielding a habituation effect (p < 0.05). How each parameter returned to baseline following the reunion depended on the duration of the preceding separation interval, with post-reunion affiliative behaviors increasing significantly only after longer intervals (experiment 1: p = 0.02; experiment 2: p = 0.001). Cortisol concentrations, which also increased during the 7-day separation (p = 0.04), were temporally dissociated from and not correlated with the marmosets’ behavioral response (p > 0.05). Interestingly, cortisol levels during the social separation phase were negatively correlated with post-reunion affiliative behavior (p = 0.05). Stress-induced cortisol may thus hinder putative behavioral coping strategies. However, post-reunion affiliative behavior was not correlated with the last cortisol measure (p = 0.21). Therefore, social disruption in a familiar environment – even if brief – induces stress-related responses and behavioral coping strategies. These findings bear important implication for captive management and research protocols using marmosets.

Influence of dominance rank and affiliation relationships on self-directed behavior in female Tibetan macaques (Macaca thibetana).

Self-directed behavior (SDB) is characterized as an indicator of anxiety, frustration and stress in nonhuman primates. In this study, we collected self-directed behavior data from one group of free-ranging Tibetan macaques (Macaca thibetana) at Mt. Huangshan, China (September 2012-May 2013) using a combination of behavioral sampling methods including focal animal sampling, behavioral sampling, continuous sampling and instantaneous sampling. Our results showed that females engaged in significantly higher rates of self-directed behavior when they were in proximity to dominant individuals compared to subordinate ones. Conflict losers significantly increased their SDB rates after agonistic episodes, indicating that SDB might also serve as an index of anxiety in M. thibetana. We further found that females significantly increased their SDB rates when focal individual was proximity to weakly affiliation relationship higher rank members than to strongly affiliation relationship higher rank members. If conflicts were not reconciled, the postconflict SDB rates of losers were higher when they stayed with strongly affiliation opponents; if conflicts were reconciled, victims of strongly affiliation relationships opponents engaged in more SDB rates before reconciliation than after reconciliation, while victims of moderately affiliation relationships opponents did not engaged in more SDB rates before reconciliation than after reconciliation. We conclude that both of dominance rank and affiliation relationships might both influence the SDB rates of female Tibetan macaques significantly, suggesting that SDB is not only an index of anxiety in Tibetan macaques, but also can provide a new insight into evaluation of social relationships between individuals.

Models of stress in nonhuman primates and their relevance for human psychopathology and endocrine dysfunction.

Stressful life events have been linked to the onset of severe psychopathology and endocrine dysfunction in many patients. Moreover, vulnerability to the later development of such disorders can be increased by stress or adversity during development (e.g., childhood neglect, abuse, or trauma). This review discusses the methodological features and results of various models of stress in nonhuman primates in the context of their potential relevance for human psychopathology and endocrine dysfunction, particularly mood disorders and dysregulation of the hypothalamic-pituitary-adrenocortical (HPA) system. Such models have typically examined the effects of stress on the animals' behavior, endocrine function (primarily the HPA and hypothalamic-pituitary-gonadal systems), and, in some cases, immune status. Manipulations such as relocation and/or removal of an animal from its current social group or, alternatively, formation of a new social group can have adverse effects on all of these outcome measures that may be either transient or more persistent depending on the species, sex, and other experimental conditions. Social primates may also experience significant stress associated with their rank in the group's dominance hierarchy. Finally, stress during prenatal development or during the early postnatal period may have long-lasting neurobiological and endocrine effects that manifest in an altered ability to cope behaviorally and physiologically with later challenges. Whereas early exposure to severe stress usually results in deficient coping abilities, certain kinds of milder stressors can promote subsequent resilience in the animal. We conclude that studies of stress in nonhuman primates can model many features of stress exposure in human populations and that such studies can play a valuable role in helping to elucidate the mechanisms underlying the role of stress in human psychopathology and endocrine dysfunction.

Hair as a long-term retrospective cortisol calendar in orang-utans (Pongo spp.): New perspectives for stress monitoring in captive management and conservation

This study examined whether the method of hair cortisol analysis is applicable to orang-utans (Pongo spp.) and can help to advance the objective monitoring of stress in non-human primates. Specifically, we examined whether fundamental prerequisites for hair cortisol analysis are given in orang-utans and, subsequently, whether segmental hair analysis may provide a retrospective calendar of long-term cortisol levels. For this, hair samples were examined from 71 zoo-living orang-utans (38 males, mean age=22.5years; 33 females, mean age=24years) for which detailed records of past living conditions were available. Hair samples were cut from defined body regions and were analyzed either in full length or in segments. Results showed that hair cortisol concentrations (HCC) were unrelated to age or sex of the individual animal. HCC were found to be higher in orang-utans, with perceived long-term stressful periods (mean HCC=43.6±26.5pg/mg, n=13) compared to animals without perceived stressful periods (19.3±5.5pg/mg, n=55, P<0.001). In non-stressed animals, segmental hair analyses revealed that HCC was stable along the hair shaft even when hair reached >40cm. The possibility of obtaining a retrospective calendar of stress-related cortisol changes through hair analysis was further supported by data of three case studies showing close correspondence between the segmental HCC results and keeper reports of stress exposure during the respective time periods. Finally, low within-animal variation in HCC from different body regions (CV%: 14.3) suggested that this method may also be applicable to naturally shed hair, e.g., as found in nests of wild orang-utans and other great apes. Therefore, using HCC may provide an ideal non-invasive tool for both captive management as well as conservation in orang-utans and potentially other great apes.

The effect of short-term stress on serotonin gene expression in high and low resilient macaques.

Female cynomolgus monkeys exhibit different degrees of reproductive dysfunction with moderate metabolic and psychosocial stress. When stressed with a paradigm of relocation and diet for 60 days, or 2 menstrual cycles, highly stress resilient monkeys continue to ovulate during both stress cycles (HSR); medium stress resilient monkeys ovulate once (MSR) and stress sensitive monkeys do not ovulate for the entire 60 days (SS). This study examines serotonin-related gene expression in monkeys with different sensitivity to stress and exposed to 5 days of moderate stress. Monkeys were first characterized as HSR, MSR or SS. After resumption of menstrual cycles, each monkey was re-stressed for 5 days in the early follicular phase. The expression of 3 genes pivotal to serotonin neural function was assessed in the 3 groups of monkeys (n=4-5/group). Tryptophan hydroxylase 2 (TPH2), the serotonin reuptake transporter (SERT), and the 5HT1A autoreceptor mRNAs expression were determined at 4 morphological levels of the dorsal raphe nucleus with in situ hybridization (ISH) using digoxigenin-incorporated riboprobes. In addition, cFos was examined with immunohistochemistry. Positive pixel area and/or cell number were measured. All data were analyzed with ANOVA (3 groups) and with a t-test (2 groups). After 5 days of stress, TPH2, SERT, 5HT1A and cFos were significantly lower in the SS group than the HSR group (p<0.05, all). This pattern of expression was the same as the pattern observed in the absence of stress in previous studies. Therefore, the ratio of the HSR/SS expression of each serotonergic gene was calculated in the presence and absence of stress. There was little or no difference in the ratio of HSR/SS gene expression in the presence or absence of stress. Moreover, cFos expression indicates that overall, cell activation in the dorsal raphe nucleus and periaquaductal gray is lower in SS than HSR animals. These data suggest that the serotonin system may set the sensitivity or resilience of the individual, but serotonin-related gene expression may not rapidly respond to moderate stress in nonhuman primates.

Linear enamel hypoplasia as an indicator of physiological stress in great apes: Reviewing the evidence in light of enamel growth variation

Physiological stress, such as malnutrition or illness, can disrupt normal enamel growth, resulting in linear enamel hypoplasias (LEHs). Although ecological factors may contribute to LEH expression, other factors, such as surface abrasion and enamel growth variables, are also likely to be involved. Attention to these other factors is necessary before we can begin to understand what LEH might signify in terms of ecological sources of physiological stress in non-human primates. This study focuses on assessing the contribution of these other factors to variation in LEH expression within and across great ape taxa. Here, we present LEH data from unabraded crown regions in samples of seven great ape species. We analyze these data with respect to lateral enamel formation time and the angles that striae of Retzius make with the enamel surface, as these variables are expected to affect variation in LEH expression. We find that although the duration of enamel formation is associated with sex differences in LEH expression, it is not clearly related to taxonomic variation in LEH expression, and does not explain the low frequency of LEH in mountain gorillas found in this and a previous study. Our data on striae of Retzius angles suggest that these influence LEH expression along the tooth crown and may contribute to the consistently high frequencies of LEH seen in Pongo in this and previous studies. We suggest that future work aimed at understanding species variation in these angles is crucial to evaluating taxonomic patterns of LEH expression in great apes.

Localization of relaxin‐3 in brain of Macaca fascicularis: Identification of a nucleus incertus in primate

Relaxin-3 (RLN3) is a highly conserved, ancestral member of the insulin/relaxin peptide family. RLN3 mRNA is highly expressed in rat, mouse, and human brain and molecular genetic and pharmacological studies suggest that RLN3 is the cognate ligand for the relaxin family peptide-3 receptor (RXFP3). The distribution of RLN3/RXFP3 networks has been determined in rat and mouse brain, but not in higher species. In this study we describe the distribution of RLN3 neurons in the brain of macaque (Macaca fascicularis) using in situ hybridization histochemistry and immunohistochemistry. RLN3 mRNA and high levels of RLN3-like immunoreactivity (-LI) were observed in neurons within a ventromedial region of the central gray of the pons and medulla that appears to represent the primate analog of the nucleus incertus (NI) described in lower species. Nerve fibers and terminals containing RLN3-LI were observed throughout brain regions identical to those known to receive afferents from the NI in the rat, including the septum, hippocampus, entorhinal cortex, lateral, dorsomedial and ventromedial hypothalamus, supramammillary and interpeduncular nuclei, anterodorsal, paraventricular and reuniens thalamic nuclei, lateral habenula, central gray, and dorsal raphe, solitary tract, and ambiguus nuclei. Experimental studies in the rat strongly implicate a role of this neuropeptide-receptor system in arousal, feeding, and metabolism, learning and memory, and central responses to psychological stressors. These new anatomical findings support the proposition that the RLN3 system is similarly involved in the integration and modulation of behavioral activation and arousal and responses to stress in nonhuman primates and humans.

Assessment of stress in non-human primates: application of the neutrophil activation test

AbstractA technique measuring leukocyte (neutrophil) activity was used to examine differences between stress levels in a breeding colony of rhesus macaques housed in either a traditional caging system or open-rooms. The leukocyte activation test measured the degree to which blood from the two treatment groups could launch a further neutrophil response (superoxide production) to anin vitrochallenge. Animals housed in a traditional caging system produced a significantly lower leukocyte response than animals housed in open-rooms, indicating that there was a higher level of stress associated with caged housing than open-room housing. This was not influenced by whether animals were physically restrained or trained to stand for a sedating injection. No differences were found between treatment groups in leukocyte numbers or composition. This study validates the use of the leukocyte activation test to assess physiological stress levels in non-human primates and demonstrates the animal welfare benefits of open-room housing over traditional laboratory caging systems.

Neurobiology of early life stress: nonhuman primate models.

Numerous studies have shown that early life stress in nonhuman primates produces profound and long-lasting changes in behavior and biological function. We review several aspects of the neurobiology of early life stress, focusing on nonhuman primate experimental paradigms. There is experimental evidence that even prenatal stress can produce profound alterations in biological factors such as regulation of the hypothalamic-pituitary-adrenal (HPA) axis, biogenic amines, and immune function, as well as in behavioral measures of attention and sociability. An ongoing struggle in research studies is defining the relative contributions of nature and nurture in mediating the long-term effects of stress. Studies of social support contend that this has the capacity to buffer the deleterious effects of stressful early rearing environments, whereas social deprivations appear to have negative behavioral and medical outcomes, most notably deficits in immune function. From studies involving variable foraging demand (VFD)-reared nonhuman primates and other models, we suggest that many of the behavioral and biochemical changes produced resemble those seen in humans who suffer from depressive and anxiety conditions. Finally, there appears to be remarkable consistency of key neurobiological findings across species.

Displacement Activities as a Behavioral Measure of Stress in Nonhuman Primates and Human Subjects

Traditionally, research on human stress has relied mostly on physiological and psychological measures with a relatively minor emphasis on the behavioral aspects of the phenomenon. Such an approach makes it difficult to develop valid animal models of the human stress syndrome. A promising approach to the study of the behavioral correlates of stress is to analyze those behavior patterns that ethologists have named displacement activities and that, in primates, consist mostly of self-directed behaviors. In both nonhuman primates and human subjects, displacement behavior appears in situations characterized by social tension and is likely to reflect increased autonomic arousal. Pharmacological studies of nonhuman primates have shown that the frequency of occurrence of displacement behavior is increased by anxiogenic compounds and decreased by anxiolytic drugs. Ethological studies of healthy persons and psychiatric patients during interviews have found that increased displacement behavior not only correlates with a subjective feeling state of anxiety and negative affect but also gives more veridical information about the subject's emotional state than verbal statements and facial expression. The measurement of displacement activities may be a useful complement to the physiological and psychological studies aimed at analyzing the correlates and consequences of stress.

What can developmental defects of enamel reveal about physiological stress in nonhuman primates?

Evolutionary Anthropology: Issues, News, and ReviewsVolume 10, Issue 4 p. 138-151 Research Article What can developmental defects of enamel reveal about physiological stress in nonhuman primates? Debbie Guatelli-Steinberg, Debbie Guatelli-Steinberg Debbie Guatelli-Steinberg is an Assistant Professor in the Department of Anthropology at The Ohio State University. Her research focuses primarily on the use of developmental defects of enamel to understand patterns of stress in human and nonhuman primates.Search for more papers by this author Debbie Guatelli-Steinberg, Debbie Guatelli-Steinberg Debbie Guatelli-Steinberg is an Assistant Professor in the Department of Anthropology at The Ohio State University. Her research focuses primarily on the use of developmental defects of enamel to understand patterns of stress in human and nonhuman primates.Search for more papers by this author First published: 22 August 2001 https://doi.org/10.1002/evan.1027Citations: 59 AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume10, Issue42001Pages 138-151 RelatedInformation

Response of fecal cortisol to stress in captive chimpanzees (Pan troglodytes)

This study examined whether fecal cortisol could be used as an index of stress responses. The stress responsiveness of fecal cortisol was tested with a stressor known to stimulate adrenal activity, the stress of anesthesia. Daily fecal and urine samples were collected from four captive chimpanzees (Pan troglodytes) before and after anesthetizations with Telazol®/Ketasat®. Tests of assay validity indicated that cortisol was measurable in chimpanzee fecal extracts. Fecal cortisol concentrations were significantly elevated 2 days after anesthetization, with elevations in seven of the eight treatments. The posttreatment peak was significantly greater than baseline values in three of the four subjects. Both fecal concentrations and proportionate increases in response to stress were significantly correlated with the corresponding values in urinary cortisol, confirming the stressfulness of these procedures and the stress responsiveness of fecal cortisol. These findings provide evidence for the application of fecal cortisol as a noninvasive index of physiologic stress in nonhuman primates. Am. J. Primatol. 44:57–69, 1998. © 1998 Wiley-Liss, Inc.

Response of fecal cortisol to stress in captive chimpanzees (Pan troglodytes).

This study examined whether fecal cortisol could be used as an index of stress responses. The stress responsiveness of fecal cortisol was tested with a stressor known to stimulate adrenal activity, the stress of anesthesia. Daily fecal and urine samples were collected from four captive chimpanzees (Pan troglodytes) before and after anesthetizations with Telazol/Ketasat. Tests of assay validity indicated that cortisol was measurable in chimpanzee fecal extracts. Fecal cortisol concentrations were significantly elevated 2 days after anesthetization, with elevations in seven of the eight treatments. The posttreatment peak was significantly greater than baseline values in three of the four subjects. Both fecal concentrations and proportionate increases in responses to stress were significantly correlated with the corresponding values in urinary cortisol, confirming the stressfulness of these procedures and the stress responsiveness of fecal cortisol. These findings provide evidence for the application of fecal cortisol as a noninvasive index of physiologic stress in nonhuman primates.

Catecholamine-glucocorticoid interactions during surgical stress

The stress response involves activation of the hypothalamic-pituitary adrenal axis and the sympathetic nervous system. To study the relative contributions of glucocorticoids, epinephrine, norepinephrine, and dopamine to homeostasis, we examined the effects of cortisol and epinephrine deficiency on the norepinephrine and dopamine responses to surgical stress in nonhuman primates. Adult male cynomolgus monkeys ( n = 7–8/group)underwent bilateral or sham adrenalectomy and were maintained for 4 months on physiologic glucocorticoid (hydrocortisone phosphate, 32 mg/M 2/day) and mineralocorticoid (DOCA pivalate, 1 mg/day) replacement, or placebo injections, respestively. The adrenalectomized monkeys were then stratified into three groups receiving subphysiologic (× 1 10 ), physiologic (×1), or supraphysiologic (×10) glucocorticoid replacement. A cholecystectomy was performed 4 days later and the pre-, intra-, and postoperative plasma catecholamine levels were measured. Adrenalectomized animals had markedly decreased plasma epinephrine concentrations and accentuated plasma norepinephrine and dopamine responses to cholecystectomy, when compared to shamadrenalectomized controls. The magnitude of the norepinephrine accentuation was inversely related to the dose of cortisol administered preceding surgery. Norepinephrine and dopamine failed to completely normalize even at the high dose of glucocorticoid replacement which had been calculated to be similar to the cortisol production rate during maximal stress. Thus, surgical stress in the setting of inadequate glucocorticoid (cortisol) replacement and epinephrine deficiency, stimulates additional sympathetic activity, probably as an adaptive mechanism to maintain homeostasis. Both norepinephrine and dopamine are recruited to compensate for the glucocorticoid and epinephrine deficiency. Glucocorticoid administration decreases but does not normalize this compensatory sympathetic activity.