Are hair cortisol levels dependent on hair growth rate? A pilot study in rhesus macaques.

Research incorporating the analysis of glucocorticoids, specifically cortisol, in hair samples has exploded over the past 10-15 years, yet factors contributing to the accumulation of cortisol in hair are not yet fully characterized. In particular, it is not clear whether cortisol accumulation in hair is dependent on hair growth rate, a possibility raised by prior rodent studies reporting glucocorticoid-mediated inhibition of hair growth. Using rhesus macaque monkeys (Macaca mulatta), an extensively studied nonhuman primate species, the present pilot study evaluated the hypothesis that hair cortisol accumulation is inversely related to hair growth rate (i.e., slower hair growth leading to elevated cortisol levels). Hair samples were collected from 19 adult female macaques and 17 infants (9 males) 3 months apart using a shave-reshave procedure from the same site below the posterior vertex of the scalp. The second hair samples were measured to the nearest millimeter (mm) for growth rate over the previous 3 months and assayed for hair cortisol concentrations (HCCs) using enzyme immunoassay. Because of the possibility of age-related differences in hair growth rate, correlational analyses were performed separately for adults and infants to determine whether HCC values were associated with growth rate in each age group. These analyses revealed that neither group displayed a significant correlation of HCCs with hair growth. The results additionally showed that overall, adults had a faster hair growth rate than infants and, as expected from previous studies, had lower HCCs than infants. Our results suggest that higher HCCs within the non-stress range do not result from cortisol-mediated inhibition of hair growth. Moreover, similarities between humans and macaque monkeys in both HPA axis regulation and hair growth rates argue that these findings are relevant for human hair cortisol studies. Extrapolation to other species in which the features of hair growth and the relevant regulatory mechanisms are less well understood should be done with caution.

Nonhuman primate abnormal behavior: Etiology, assessment, and treatment.

Across captive settings, nonhuman primates may develop an array of abnormal behaviors including stereotypic and self-injurious behavior. Abnormal behavior can indicate a state of poor welfare, since it is often associated with a suboptimal environment. However, this may not always be the case as some behaviors can develop independently of any psychological distress, be triggered in environments known to promote welfare, and be part of an animal's coping mechanism. Furthermore, not all animals develop abnormal behavior, which has led researchers to assess risk factors that differentiate individuals in the display of these behaviors. Intrinsic risk factors that have been identified include the animal's species and genetics, age, sex, temperament, and clinical condition, while environmental risk factors include variables such as the animal's rearing, housing condition, husbandry procedures, and research experiences. To identify specific triggers and at-risk animals, the expression of abnormal behavior in captive nonhuman primates should be routinely addressed in a consistent manner by appropriately trained staff. Which behaviors to assess, what assessment methods to use, which primates to monitor, and the aims of data collection should all be identified before proceeding to an intervention and/or treatment. This article provides guidance for this process, by presenting an overview of known triggers and risk factors that should be considered, steps to design a comprehensive evaluation plan, and strategies that might be used for prevention or treatment. It also outlines the tools and processes for assessing and evaluating behavior in an appendix. This process will lead to a better understanding of abnormal behavior in captive primate colonies and ultimately to improved welfare.

A Rhesus Monkey Model of Non-suicidal Self-Injury.

Non-suicidal self-injury (NSSI) is a type of behavioral pathology seen not only in a variety of clinical conditions but also among non-clinical populations, particularly adolescents and young adults. With the exception of rare genetic conditions that give rise to self-harming behaviors, the etiology of NSSI and the events that trigger specific episodes of this behavior remain poorly understood. This review presents the features of an important, extensively studied animal model of NSSI, namely spontaneously occurring self-injurious behavior (SIB) in rhesus macaque monkeys. We compare and contrast rhesus monkey SIB with NSSI with respect to form, prevalence rates, environmental and biological risk factors, behavioral correlates, proposed functions, and treatment modalities. Many parallels between rhesus monkey SIB and NSSI are demonstrated, which supports the validity of this animal model across several domains. Determining the etiology of spontaneously occurring SIB in monkeys, its underlying biological mechanisms, and which pharmacological agents are most effective for treating the disorder may aid in identifying potential risk factors for the occurrence of NSSI in humans and developing medications for severe cases that are resistant to conventional psychotherapeutic approaches.

Assessment of prenatal stress-related cortisol exposure: focus on cortisol accumulation in hair and nails.

Prenatal stress adversely affects offspring development. Although cortisol is hypothesized to be a key mediator of stress-induced developmental deficits, determining the amount of fetal cortisol exposure produced by maternal stress has proved challenging. Current approaches, such as measuring cortisol concentrations in maternal plasma, saliva, or urine, amniotic fluid, fetal plasma, or cord blood, all have significant limitations for assessing cumulative fetal cortisol exposure over time. A recently emerging approach is to measure cortisol concentrations in maternal hair and/or newborn hair or nail samples. Maternal hair cortisol potentially shows long-term production across each trimester of pregnancy, whereas neonatal hair or nail cortisol is thought to reflect mainly third trimester hormone accumulation. This review first describes fetal adrenocortical development, placental cortisol metabolism, and the various sources of fetal cortisol exposure across pregnancy. We then summarize the results obtained from "classical" methods of assessing prenatal cortisol exposure prior to the advent of hair and nail cortisol measurement. Lastly, we discuss the initial development and validation of the hair cortisol methodology, its subsequent application to studies of chronic stress, and recent findings regarding maternal and neonatal hair or nail cortisol concentrations in relation to prenatal stress and other variables of interest.

Self-Injurious behavior in rhesus macaques: Issues and challenges.

Some monkeys housed in research facilities develop abnormal behavior ranging from stereotypic to the more serious condition of self-injurious behavior (SIB). We initially sought to understand how and why monkeys engaged in SIB and more importantly why only a small percentage of laboratory monkeys, with seemingly similar housing and background, developed this disorder. Of particular importance was the recognition that different pathways might lead to SIB and that strong individual differences would affect the manifestation of this disorder and the response to treatment. We developed a comprehensive plan to identify effective treatment and prevention strategies. We started with characterizing the disorder in terms of prevalence and types of environments in which it was found. We then conducted observations on a cohort of SIB and control monkeys to identify conditions associated with SIB (e.g., disordered sleep) as well as clinical disease states and congenital defects that could be precipitating factors. We examined the environmental events that triggered episodes of SIB in monkeys with the disorder and evaluated three models that might explain the reinforcement contingencies associated with SIB, including tension reduction, self-stimulation, and social communication. Possible treatments for SIB such as environmental enrichment, social housing, and pharmacotherapy were tested by our group and others. To date, no single treatment has been found to abolish SIB, and each of these treatments is impacted by individual differences. To develop possible prevention strategies, we examined colony management and health records to find risk factors for SIB. These risk factors generalized to other facilities, and considerable effort was expended by all behavioral managers at these facilities to reduce early life stress exposure, to minimize the length of individual cage housing by emphasizing pair housing, and to reduce the possible stressfulness of various veterinary/medical procedures by implementing positive reinforcement training.

Hair cortisol in captive corral-housed baboons.

Hair cortisol concentrations (HCCs) are measures of long-term hypothalamic-pituitary-adrenocortical (HPA) activity and can be used as indicators of chronic stress. However, intrinsic factors such as an animal's age and sex can also have an impact on resulting HCCs. Although baboons are commonly studied in captivity, little is known about baseline HCC in this population. Here we measured HCC in two same-sex groups of captive olive (Papio hamadryas anubis) baboons and olive/yellow baboon (Papio hamadryas cynocephalus) crosses housed in large outdoor corrals, and we assessed the impact of age and sex on HCC as major variables of interest. Hair was gently shaved from the back of the neck when the animals were sedated for routine physicals. Subjects were divided into three age categories: juvenile (2-4 years), adult (9-12 years), and senior (13-19 years). The "senior" category contained only males. Results confirm an effect of sex and age on HCCs. Females had higher levels of hair cortisol than males, and juveniles had higher levels than adults. There was also a significant sex × age interaction. There were no sex differences in HCCs in juveniles, but there was a greater decline in HCCs in adult males than in adult females. Within males, there was a significant difference in levels of hair cortisol across the three age categories. Juveniles had higher levels than did adults and seniors, but adults and seniors were not significantly different from one another. These results provide baseline measures of hair cortisol in captive baboons and demonstrate effects of sex and age on HCCs.

Alopecia in rhesus macaques (Macaca mulatta): Association with pregnancy and chronic stress.

BACKGROUND: Alopecia in captive non-human primates is often presented as a welfare issue. However, it is a complex condition with a number of possible causes. The purpose of this study was to assess the impact of pregnancy and hair cortisol concentrations on alopecia in rhesus macaques. METHODS: Subjects were 113 socially housed adult female rhesus macaques (27 pregnant, 35 nursing infants, 51 controls). During routine physicals, photographs were taken for alopecia assessment and hair samples were collected for cortisol assay. RESULTS: Alopecia was more prevalent in pregnant than in control females, but there was no association between alopecia and hair cortisol. However, there was a significant effect of pregnancy on hair cortisol. Nursing females had higher hair cortisol levels than pregnant females, which had higher levels than control females. CONCLUSIONS: Although alopecia does not appear to be associated with hair cortisol, both alopecia and hair cortisol were associated with pregnancy.

Cortisol in Neonatal Mother's Milk Predicts Later Infant Social and Cognitive Functioning in Rhesus Monkeys.

Milk provides not only the building blocks for somatic development but also the hormonal signals that contribute to the biopsychological organization of the infant. Among mammals, glucocorticoids (GCs) in mother's milk have been associated with infant temperament. This study extended prior work to investigate rhesus monkey (Macaca mulatta) mother-infant dyads (N = 34) from birth through 8 months postpartum. Regression analysis revealed that cortisol concentrations in milk during the neonatal period predicted impulsivity on a cognitive task, but not global social behaviors, months later. During this time period, sex-differentiated social behavior emerged. For female infants, milk cortisol concentrations predicted total frequency of play. Collectively, these findings support and extend the "lactational programming" hypothesis on the impact of maternal-origin hormones ingested via milk.

Rhesus macaques (Macaca mulatta) displaying self-injurious behavior show more sleep disruption than controls.

Self-injurious behavior (SIB) is a pathology observed in both humans and animals. In humans, SIB has been linked to various mental health conditions that are also associated with significant sleep disruption. In rhesus macaques, SIB consists of self-directed biting which can range from mild skin abrasions to wounds requiring veterinary care. However, only one study suggests possible sleep disruption in macaques with SIB. We evaluated sleep disruption using a noninvasive system (infra-red camera and a video surveillance program) which created videos for every movement over the nighttime hours. Nighttime activity was examined in 13 macaques (three females) of which six were classified as having SIB (one female). Each monkey was studied for a total of 6 nights spanning a period of 4 months. Measures included total movement time (TMT), time moving in the first hour (HR1), time moving in the last hour (HR11), and number of videos <10 secs, ≥10 secs, and ≥30 secs in length. Overall, SIB monkeys had higher TMT (p < 0.01), higher HR1 (p<0.001), and generated more videos ≥10 secs (p < 0.01) and ≥30 secs (p < 0.01). Thus, SIB monkeys showed significant sleep disruption. A four-fold difference between SIB and control monkeys in the ≥30 secs videos revealed many more significant awakenings in the SIB group. Overall higher nighttime activity, in the first hour but not in the last hour, is consistent with sleep-onset insomnia in humans. Whether increased nighttime activity contributes to the SIB condition during the day or, conversely, SIB causes higher nighttime activity remains undetermined.

Environmental Enrichment in the 21st Century.

More than a quarter of a century has elapsed since the Animal Welfare Act mandated that research facilities develop and follow a plan to promote the psychological well-being of captive primates. Since passage of this law, considerable effort and resources have been directed to designing environmental enrichment strategies in an effort to improve animal welfare. These plans typically consist of environmental enrichment and socialization efforts. While environmental enhancement has undergone a great deal of improvement in the past 25 years, it should be viewed as a continual work in progress, which takes advantage of emergent and future technologies. In this review, we discuss the objectives of the environmental enhancement plan along with relevant outcome measures, as well as ongoing challenges, costs, and benefits. We then review various enrichment strategies and assess their efficacy in meeting goals and objectives. Finally, we look forward to consider what the future might hold for environmental enrichment of nonhuman primates used in research.

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. © 2016 Wiley Periodicals, Inc.

The correlation between alopecia and temperament in rhesus macaques (Macaca mulatta) at four primate facilities.

Alopecia is a ubiquitous, multifaceted problem at facilities caring for captive rhesus macaques. There is a wide range of potential etiologies for the hair loss, including compromised immune function, dermatological pathologies, and environmental factors. However, few studies have examined whether various temperamental traits affect vulnerability to develop alopecia. We examined the correlation between alopecia and temperament in 101 (51M) indoor-housed rhesus macaques at four national primate centers. We utilized a cage side version of the Human Intruder test (HIT) to assess response to four conditions: no human present (Alone), human intruder standing next to the cage without making eye contact (Profile), intruder making direct eye contact (Stare) and intruder with back turned (Back). Behavior from all videos was quantified at one facility. We used generalized linear modeling to examine the relationship between behavior on the HIT and alopecia, controlling for facility, age, and sex. There was a significant negative correlation between alopecia and various behaviors associated with an inhibited or anxious temperament, including self-directed behavior (ß = -0.15, P < 0.001) and freeze in the Profile period (ß = -0.0092, P < 0.001), and defensive behaviors (ß = -0.0094, P < 0.001) and time spent in the back of the cage in the Stare period (ß = -0.0023, P = 0.015). Individuals with an inhibited or anxious temperament had less alopecia than others. Further, there were facility differences with respect to several variables on the HIT, including defensive behavior in Stare and freeze in Profile. These results suggest that temperament can influence the development of alopecia in rhesus macaques. Our results also highlight the degree to which facility differences can affect outcomes on standardized behavioral tests. Am. J. Primatol. 79:e22504, 2017. © 2015 Wiley Periodicals, Inc.

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. © 2016 Wiley Periodicals, Inc.

Rhesus macaques (Macaca mulatta) with self-injurious behavior show less behavioral anxiety during the human intruder test.

Self-injurious behavior (SIB) has been linked to anxiety in the human literature, but relatively few studies have explored this link in rhesus macaques. A widely used behavioral assessment of anxiety, the human intruder test (HIT), employs the mildly stressful stimulus of an unfamiliar experimenter to assess anxious behavior in macaques. The HIT was conducted on 59 (20 male) laboratory housed rhesus macaques, 30 with a record of SIB (10 male). If monkeys with SIB have a more anxious phenotype, they should show stronger reactions to the HIT. However, contrary to our predictions, monkeys with SIB did not show higher levels of anxious behavior compared to controls. They spent significantly less time showing anxious behavior and displayed little aggression in response to the stare of the intruder. SIB and control monkeys did not differ in a range score (number of unique behaviors expressed per phase); however, SIB monkeys had a lower change score (total number of behaviors expressed including repetitions) than controls. In general, monkeys that paced regardless of SIB status, showed a reduction in pacing when the intruder entered the room. Possible explanations for the failure of SIB monkeys to show increased anxiety in the HIT include greater exposure of SIB monkeys to unfamiliar humans because of their condition, evidence for a subtype of SIB which is not anxiety related, and/or the presence of comorbid depressive-like symptoms. Am. J. Primatol. 79:e22569, 2017. © 2016 Wiley Periodicals, Inc.

Associations between early life experience, chronic HPA axis activity, and adult social rank in rhesus monkeys.

Early life experience and socioeconomic status (SES) are well-established predictors of health outcomes in people. Both factors likely influence health outcomes via hypothalamic-pituitary-adrenal (HPA) axis regulation. However, it is unclear how early experience and HPA axis activity influence adult social status. We studied differentially reared female rhesus monkeys (Macaca mulatta, N = 90) as models to test the hypothesis that chronic HPA axis activity assessed via hair cortisol concentrations (HCCs) mediated the relationship between early life experience and adult social rank. We found that mother-peer-reared (MPR) monkeys acquired higher social ranks than either of the two nursery-reared (NR) groups (peer-reared, PR, or surrogate-peer-reared, SPR monkeys) (ß = -0.07, t(89) = -2.16, p = 0.034). We also found that MPR HCCs were lower during the juvenile period at 18 months (F(2,25) = 3.49, p = 0.047). Furthermore, for MPR but not NR monkeys, changes in HCCs from 18 to 24 months (r(s) = -0.627, p = 0.039) and adult HCCs (r(s) = -0.321, p = 0.03) were negatively correlated with adult social rank. These findings suggest that chronic HPA axis regulation in juvenility, and perhaps in adulthood, may influence adult social status for primates that experience typical early rearing. However, early life adversity may result in dissociation between neuroendocrine stress regulation and adult social competence, which may be risk factors for adverse health outcomes.

A longitudinal study of hair cortisol concentrations in Macaca nemestrina mothers and infants.

Cortisol is a well-known glucocorticoid that can be used as a biomarker of hypothalamic-pituitary-adrenocortical activity. To explore basal cortisol physiology during pregnancy and infancy in Macaca nemestrina monkeys, hair was collected from a convenience sample of 22 healthy mother-infant dyads. Adult females were housed in pairs as part of a small breeding colony at the Washington National Primate Research Center and infants were reared in a specialized nursery. Maternal samples were collected from females during a pregnancy-detection ultrasound and immediately following labor and delivery. Infant samples were collected at birth, 20 days, 4, 6, 8, and 10 months of age. Hair cortisol concentrations (HCCs) were determined using an enzyme immunoassay in washed and ground hair samples. Like human mothers, macaque HCCs rose during pregnancy (paired t = 5.8, df = 16, P < 0.001). Maternal HCCs at pregnancy-detection (114.2 ± 12.07 picogram/milligram [pg/mg]) were highly predictive of maternal HCCs at delivery (144.8 ± 13.60 pg/mg), suggesting a trait-like quality (r = 0.90, P < 0.001). When maternal HCCs were viewed on a continuum, the absolute rise in cortisol over the course of pregnancy was significantly related to newborn HCCs (r = 0.55, P = 0.02). Infant birth HCCs (1,027.43 ± 97.95 pg/mg) were seven times higher than maternal HCCs at delivery (paired t = 19.1, df = 16, P < 0.001). Higher birth HCCs were strongly associated with larger decreases in infant hair cortisol until 6 months of postnatal age when infant HCCs converged on values indistinguishable from adults. Overall, study results demonstrate a marked degree of fetal cortisol exposure during the latter part of gestation and suggest that the rise in maternal cortisol over pregnancy may play an influential role on HCCs in the newborn.

Factors influencing alopecia and hair cortisol in rhesus macaques (Macaca mulatta).

BACKGROUND: Alopecia can occur in captive non-human primates, but its etiology is poorly understood. The purpose of this study was to assess alopecia and hair cortisol in rhesus monkeys and to identify the potential risk factors. METHODS: Subjects were 117 rhesus monkeys at two National Primate Research Centers. Photographs and hair samples were obtained during routine physicals. Photographs were analyzed using Image J software to calculate hair loss, and hair samples were assayed for cortisol. RESULTS: Age, days singly housed, and their interactions contributed to the alopecia model for both facilities. Sex and location changes contributed to the hair cortisol model for Facility 1; sedations contributed for Facility 2. Alopecia and hair cortisol were associated at Facility 1. CONCLUSIONS: Captive management practices can affect alopecia and hair cortisol. However, there are facility differences in the relationship between alopecia and hair cortisol and in the effect of intrinsic variables and management procedures.

Associations between Parity, Hair Hormone Profiles during Pregnancy and Lactation, and Infant Development in Rhesus Monkeys (Macaca mulatta).

Studies examining hormones throughout pregnancy and lactation in women have been limited to single, or a few repeated, short-term measures of endocrine activity. Furthermore, potential differences in chronic hormonal changes across pregnancy/lactation between first-time and experienced mothers are not well understood, especially as they relate to infant development. Hormone concentrations in hair provide long-term assessments of hormone production, and studying these measures in non-human primates allows for repeated sampling under controlled conditions that are difficult to achieve in humans. We studied hormonal profiles in the hair of 26 female rhesus monkeys (Macaca mulatta, n=12 primiparous), to determine the influences of parity on chronic levels of cortisol (hair cortisol concentration, HCC) and progesterone (hair progesterone concentration, HPC) during early- to mid-pregnancy (PREG1), in late pregnancy/early lactation (PREG2/LACT1), and in peak lactation (LACT2). We also assessed infants' neurobehavioral development across the first month of life. After controlling for age and stage of pregnancy at the first hair sampling period, we found that HCCs overall peaked in PREG2/LACT1 (p=0.02), but only in primiparous monkeys (p<0.001). HPCs declined across pregnancy and lactation for all monkeys (p<0.01), and primiparous monkeys had higher HPCs overall than multiparous monkeys (p=0.02). Infants of primiparous mothers had lower sensorimotor reflex scores (p=0.02) and tended to be more irritable (p=0.05) and less consolable (p=0.08) in the first month of life. Moreover, across all subjects, HCCs in PREG2/LACT1 were positively correlated with irritability (r(s)=0.43, p=0.03) and negatively correlated with sensorimotor scores (r(s)=-0.41, p=0.04). Together, the present results indicate that primiparity influences both chronic maternal hormonal profiles and infant development. These effects may, in part, reflect differential reproductive and maternal effort in mothers with varied caretaking experience. In addition, infant exposure to relatively higher levels of maternal cortisol during the late fetal and early postnatal periods is predictive of poorer developmental outcomes.

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

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

Short-term testosterone manipulations do not affect cognition or motor function but differentially modulate emotions in young and older male rhesus monkeys.

Human aging is characterized by declines in cognition and fine motor function as well as improved emotional regulation. In men, declining levels of testosterone (T) with age have been implicated in the development of these age-related changes. However, studies examining the effects of T replacement on cognition, emotion and fine motor function in older men have not provided consistent results. Rhesus monkeys (Macaca mulatta) are excellent models for human cognitive aging and may provide novel insights on this issue. We tested 10 aged intact male rhesus monkeys (mean age=19, range 15-25) on a battery of cognitive, motor and emotional tasks at baseline and under low or high T experimental conditions. Their performance was compared to that of 6 young males previously tested in the same paradigm (Lacreuse et al., 2009; Lacreuse et al., 2010). Following a 4-week baseline testing period, monkeys were treated with a gonadotropin releasing hormone agonist (Depot Lupron, 200 µg/kg) to suppress endogenous T and were tested on the task battery under a 4-week high T condition (injection of Lupron+T enanthate, 20 mg/kg, n=8) or 4-week low T condition (injection of Lupron+oil vehicle, n=8) before crossing over to the opposite treatment. The cognitive tasks consisted of the Delayed Non-Matching-to-Sample (DNMS), the Delayed Response (DR), and the Delayed Recognition Span Test (spatial-DRST). The emotional tasks included an object Approach-Avoidance task and a task in which monkeys were played videos of unfamiliar conspecifics in different emotional context (Social Playbacks). The fine motor task was the Lifesaver task that required monkeys to remove a Lifesaver candy from rods of different complexity. T manipulations did not significantly affect visual recognition memory, working memory, reference memory or fine motor function at any age. In the Approach-Avoidance task, older monkeys, but not younger monkeys, spent more time in proximity of novel objects in the high T condition relative to the low T condition. In both age groups, high T increased watching time of threatening social stimuli in the Social Playbacks. These results suggest that T affects some aspects of emotional processing but has no effect on fine motor function or cognition in young or older male macaques. It is possible that the duration of T treatment was not long enough to affect cognition or fine motor function or that T levels were too high to improve these outcomes. An alternative explanation for the discrepancies of our findings with some of the cognitive and emotional effects of T reported in rodents and humans may be the use of a chemical castration, which reduced circulating gonadotropins in addition to T. Further studies will investigate whether the luteinizing hormone LH mediates the effects of T on brain function in male primates.