Corrine K. Lutz

A Rhesus Monkey Model of Self-Injury: Effects of Relocation Stress on Behavior and Neuroendocrine Function

BACKGROUND Self-injurious behavior (SIB), a disorder that afflicts many individuals within both clinical and nonclinical populations, has been linked to states of heightened stress and arousal. However, there are no published longitudinal data on the relationship between increases in stress and changes in the incidence of SIB. This study investigated the short- and long-term behavioral and neuroendocrine responses of SIB and control monkeys to the stress of relocation. METHODS Twenty adult male rhesus macaques were exposed to the stress of relocation to a new housing arrangement in a newly constructed facility. Daytime behavior, sleep, and multiple measures of hypothalamic-pituitary-adrenocortical (HPA) axis function were investigated before and after the move. RESULTS Relocation induced a complex pattern of short- and long-term effects in the animals. The SIB animals showed a long-lasting increase in self-biting behavior, as well as evidence of sleep disturbance. Both groups exhibited elevated cortisol levels in saliva, serum, and hair, and also an unexpected delayed increase in circulating concentrations of corticosteroid binding globulin (CBG). CONCLUSIONS Our results indicate that relocation is a significant stressor for rhesus macaques and that this stressor triggers an increase in self-biting behavior as well as sleep disturbance in monkeys previously identified as suffering from SIB. These findings suggest that life stresses may similarly exacerbate SIB in humans with this disorder. The HPA axis results underscore the potential role of CBG in regulating long-term neuroendocrine responses to major stressors.

Techniques for collecting saliva from awake, unrestrained, adult monkeys for cortisol assay

Cortisol levels serve as an index of pituitary‐adrenal activity in nonhuman primates. In adult monkeys, cortisol is normally measured in blood (typically requiring restraint or sedation) or urine (reflecting a state rather than point estimate). In contrast, saliva collection is less invasive than drawing blood and allows for repeated sampling within a short period of time. Although protocols exist for collecting saliva from young monkeys, these procedures are inadequate for awake, unrestrained adult animals. Our laboratory has developed two methods for collecting saliva from adult rhesus monkeys: a “screen” method, which involves licking screen‐covered gauze, and a “pole” method, which involves sucking and chewing on an attached rope. Twenty‐three adult male rhesus monkeys were used to evaluate these two methods. After a period of adaptation, saliva samples were collected from 21 of 23 subjects. Saliva collection was faster with the pole than with the screen method (P < 0.01), but the pole method was not suitable for some animals because of their tendency to bite off the attached rope. An analysis of 19 saliva samples revealed a mean cortisol concentration of 0.84 μg/dl (range 0.27–1.77 μg/dl). There was no statistically significant difference in cortisol value between methods used (P > 0.22). The influence of the flavoring on the cortisol assay was tested, and was found to have no significant effect (P > 0.28). Our results indicate that either technique can be used to safely collect saliva from unrestrained adult monkeys. Choice of technique will depend on the proclivities of individual monkeys. Am. J. Primatol. 52:93–99, 2000.

The physiology and neurochemistry of self-injurious behavior: a nonhuman primate model.

Self-injurious behavior (SIB) is a serious behavioral condition that afflicts millions of individuals in the United States alone. The underlying factors contributing to the development of self-injury in people are poorly understood, and existing treatment strategies for this condition are limited. A low but persistent percentage of socially reared individually housed rhesus monkeys also spontaneously develop SIB. Data obtained from colony records suggest that the risk of developing SIB in socially reared rhesus monkeys is heightened by adverse early experience and subsequent stress exposure. The present review summarizes the physiological and neurochemical findings obtained in this nonhuman primate model of SIB, focusing on monoamine neurotransmitters, neuropeptides, and neuroendocrine systems. The results indicate that monkeys with SIB exhibit long-lasting disturbances in central and peripheral opioid and stress response systems, which lead to increased levels of anxiety. Based on these findings, we propose an integrated developmental-neurochemical hypothesis in which SIB arises from adverse life events in a subset of vulnerable monkeys, is maintained by a persisting dysregulation of several neurochemical and physiological systems, and functions to periodically reduce anxiety when the levels of anxiety become excessive. Implications of this hypothesis for understanding self-injury in patients with borderline personality disorder and members of the general population are discussed.

Self-injurious behavior in male rhesus macaques does not reflect externally directed aggression

Self-injurious behaviors (SIB), such as self-biting and self-wounding, have been observed in a small percentage of captive nonhuman primates. Because rhesus monkeys that exhibit SIB also tend to be more aggressive, it was hypothesized that SIB is related to externally directed aggression and is associated with contexts in which physical contact between participants is prevented. The purpose of this study was to test the hypothesized relationship between SIB and outward aggression. Subjects were first presented with videotapes of conspecifics, scenery and a blank screen, and their behavior was recorded. Levels of salivary cortisol, an indicator of stress, were also measured before and after presentation of the videos. Although aggression increased when subjects viewed tapes containing conspecifics, neither cortisol levels nor self-biting behavior varied as a function of tape content. The subjects were then placed in two additional test situations: an empty room and the same room containing an unfamiliar conspecific. Aggression was significantly higher in the stranger condition compared to the empty room condition. The two situations yielded parallel increases in cortisol, suggesting that being alone was just as stressful as being paired with an unfamiliar conspecific. Self-biting rates were also similar in these two conditions. Thus, contrary to our prediction, increases in aggression did not correlate with increases in SIB. These results suggest that under similarly stressful conditions, SIB and externally directed aggression are unrelated.

IACUC review of nonhuman primate research.

This article will detail some of the issues that must be considered as institutional animal care and use committees (IACUCs) review the use of nonhuman primates (NHPs) in research. As large, intelligent, social, long-lived, and non-domesticated animals, monkeys are amongst the most challenging species used in biomedical research and the duties of the IACUC in relation to reviewing research use of these species can also be challenging. Issues of specific concern for review of NHP research protocols that are discussed in this article include scientific justification, reuse, social housing requirements, amelioration of distress, surgical procedures, and humane endpoints. Clear institutional policies and procedures as regards NHP in these areas are critical, and the discussion of these issues presented here can serve as a basis for the informed establishment of such policies and procedures.

Stereotypic Behavior in Nonhuman Primates as a Model for the Human Condition

Stereotypies that develop spontaneously in nonhuman primates can provide an effective model for repetitive stereotyped behavior in people with neurodevelopmental or obsessive-compulsive disorders. The behaviors are similar in form, are similarly affected by environmental conditions, and are improved with similar treatment methods such as enrichment, training, and drug therapy. However, because of a greater number of commonalities in these factors, nonhuman primates may serve as a better model for stereotyped behavior in individuals with autism or intellectual disability than for compulsions in individuals with obsessive-compulsive disorder. Because animal models may not be exact in all features of the disorder being studied, it is important to investigate the strengths and weaknesses of using a nonhuman primate model for stereotyped behavior in people with psychological disorders.

Responses to the Human Intruder Test are related to hair cortisol phenotype and sex in rhesus macaques (Macaca mulatta)

Measurement of cortisol in hair provides a chronic index of hypothalamic–pituitary–adrenal (HPA) axis activity and has been applied to assessments of temperament (stable behavioral differences between individuals). However, the extent to which chronically high HPA axis activity relates to a correspondingly high degree of behavioral reactivity is as yet unknown. Therefore, the goal of the present experiment was to assess the relationship between hair cortisol and a reactive temperament. We administered the Human Intruder Test (HIT) twice to 145 (80 male) rhesus macaques (Macaca mulatta) in order to assess behavioral reactivity. The HIT presents monkeys with an unfamiliar experimenter and is composed of a Baseline phase (no intruder) followed by three experimental phases in which the orientation of the intruder changes (Profile, Stare, Back). Behavioral responses to the test were videotaped and behaviors thought to reflect a reactive response to the intruder were scored for duration. Hair samples collected within ±1 month of the first HIT session were analyzed for cortisol by enzyme immunoassay. Subjects were assigned to three groups based on hair cortisol concentration: high, intermediate, and low cortisol phenotypes. Monkeys with the high cortisol phenotype were more reactive to the presence of the intruder than those with the low cortisol phenotype: they were more aggressive, scratched more, and spent more time in the back half of the cage. Males yawned significantly more while females spent more time immobile and in the back of the cage. Overall, monkeys with higher hair cortisol demonstrated an exaggerated response to the presence of the human intruder, supporting a relationship between high levels of chronic HPA axis activity and a reactive temperament. These results indicate that high levels of HPA axis activity, which may result from either genetic variation or environmental stress, correspond with heightened behavioral responses to a stressful experience. Am. J. Primatol. 79:e22526, 2017.

Assessing significant (>30%) alopecia as a possible biomarker for stress in captive rhesus monkeys (Macaca mulatta)

Hair loss is common in macaque colonies. Very little is known about the relationship between psychological stress and hair loss. We initially examined alopecia and hair cortisol concentrations in 198 (89 male) rhesus macaques from three primate centers and demonstrated replicability of our previous finding that extensive alopecia (>30% hair loss) is associated with increased chronic cortisol concentrations and significantly affected by facility. A subset of these monkeys (142 of which 67 were males) were sampled twice approximately 8 months apart allowing us to examine the hypotheses that gaining hair should be associated with decreases in cortisol concentrations and vice versa. Hair loss was digitally scored using ImageJ software for the first sample. Then visual assessment was used to examine the second sample, resulting in three categories of coat condition: (i) monkeys that remained fully haired; (ii) monkeys that remained alopecic (with more than 30% hair loss); or (iii) monkeys that showed more than a 15% increase in hair. The sample size for the group that lost hair was too small to be analyzed. Consistent with our hypothesis, monkeys that gained hair showed a significant reduction in hair cortisol concentrations but this effect only held for females. Coat condition changed little across sampling periods with only 25 (11 male) monkeys showing a greater than 15% gain of hair. Twenty (7 male) monkeys remained alopecic, whereas 97 (49 males) remained fully haired. Hair cortisol was highly correlated across samples for the monkeys that retained their status (remained alopecic or retained their hair). Am. J. Primatol. 79:e22547, 2017.

The Effect of a Feeding Schedule Change and the Provision of Forage Material on Hair Eating in a Group of Captive Baboons (Papio hamadryas sp.)

Hair eating in nonhuman primates is thought to result from a frustrated appetitive drive produced by an inappropriate diet. To investigate whether hair eating could be reduced through changes in diet, a 2-part study was conducted with a group of baboons (Papio hamadryas sp.). The 1st part involved changing to a twice-daily feeding routine, thus providing prolonged access to an appropriate food source. The 2nd part involved scattering a grain mix to encourage more foraging while maintaining a once-daily feeding routine. Changing the feeding routine unexpectedly resulted in a significant increase in hair manipulation and ingestion. Providing additional grain did not significantly decrease hair manipulation and ingestion, but several individuals did show a reduction in these behaviors. Prolonged access to biscuits and the provision of a grain mix may have failed to satisfy the urge to forage because little effort was needed for their collection prior to consumption. Although the current study failed to significantly decrease hair eating, it provides valuable insight into further avenues of research on the behavior.

Abnormal behavior and associated risk factors in captive baboons (Papio hamadryas spp.)

Abnormal behavior, ranging from motor stereotypies to self‐injurious behavior, has been documented in captive nonhuman primates, with risk factors including nursery rearing, single housing, and veterinary procedures. Much of this research has focused on macaque monkeys; less is known about the extent of and risk factors for abnormal behavior in baboons. Because abnormal behavior can be indicative of poor welfare, either past or present, the purpose of this study was to survey the presence of abnormal behavior in captive baboons and to identify potential risk factors for these behaviors with an aim of prevention. Subjects were 144 baboons (119 females, 25 males) aged 3–29 (median = 9.18) years temporarily singly housed for research or clinical reasons. A 15‐min focal observation was conducted on each subject using the Noldus Observer® program. Abnormal behavior was observed in 26% of the subjects, with motor stereotypy (e.g., pace, rock, swing) being the most common. Motor stereotypy was negatively associated with age when first singly housed (P < 0.005) while self‐directed behavior (e.g., hair pull, self‐bite) was positively associated with the lifetime number of days singly housed (P < 0.05) and the average number of blood draws per year (P < 0.05). In addition, abnormal appetitive behavior was associated with being male (P < 0.05). Although the baboons in this study exhibited relatively low levels of abnormal behavior, the risk factors for these behaviors (e.g., social restriction, routine veterinary procedures, and sex) appear to remain consistent across primate species. Am. J. Primatol. 76:355–361, 2014.