Social stability influences the association between adrenal responsiveness and hair cortisol concentrations in rhesus macaques.

Hair cortisol concentrations are increasingly being used in both humans and nonhuman animals as a biomarker of chronic stress. However, many details regarding how hair cortisol concentrations relate to the dynamic activity and regulation of the HPA axis are still unknown. The current study explores 1) how the regulation of the HPA axis in infancy relates to hair cortisol concentrations (HCC) in infancy 2) whether this relationship persists into adulthood under conditions of social stability, and 3) how social instability impacts these relationships. All subjects were rhesus monkeys housed in large social groups at the California National Primate Research Center, and all had participated in a 25-hr. long BioBehavioral Assessment (BBA) at 3-4 months of age when four plasma samples were taken to assess HPA regulation, in particular cortisol responses to 1) 2-hour social separation and relocation, 2) sustained challenge, 3) dexamethasone and 4) ACTH administration. In Study 1, hair samples were collected at the end of the BBA testing from 25 infant rhesus monkeys from 2 different stable social groups. In Study 2, hair samples were obtained at three timepoints from 108 adults from 3 different stable social groups (1 in the Spring/Summer and 2 in the Fall/Winter) to examine the temporal stability of the relationship between HCC and HPA axis regulation. In Study 3, subjects included 31 infants and 33 adults from a single social group experiencing social instability following the same procedures as in Studies 1 and 2. Generalized linear models were used to determine if infants' HPA axis activity and regulation predicted HCC in infancy (Study 1), in adulthood with animals living in stable social conditions (Study 2) or in animals living in an unstable social group (Study 3). Results indicated that for both infants and adults living in stable social groups, HCC are associated with the adrenal response to ACTH in infancy. Samples collected in the winter also had higher HCC than those collected in summer. In the unstable social group, adult hair cortisol levels were higher than in the stable social groups. Additionally, there were no consistent relationships between HCC and infant HPA axis regulation among adults or infants living in a group experiencing social instability. These results suggest that the aspects of the HPA axis that drive HCC may differ depending on context. Under stable, non-stressed conditions there seems to be a trait-like association between adrenal responsivity and HCC in infancy and adulthood. However, this association may be reduced or eliminated under conditions of social stress.

Vandeleest JJ ，Capitanio JP ，Hamel A ，Meyer J ，Novak M ，Mendoza SP ，McCowan B ... -  《-》

Physiological and behavioral adaptation to relocation stress in differentially reared rhesus monkeys: hair cortisol as a biomarker for anxiety-related responses.

Increased hair cortisol concentrations have been associated with stress exposure in both human and nonhuman primates, and hair cortisol is now gaining attention as a biomarker for stress-related health problems. The present study examined the behavioral and physiological reactions of rhesus monkey (Macaca mulatta) infants reared in three different rearing environments to the major stressor of relocation. Infant monkeys (n=61) were studied from birth through 2 years of age. For the first 8 months of life, infants were either with their mothers and peers (MPR, n=21) or reared in a nursery using either peer-rearing (PR, n=20) or surrogate-peer-rearing (SPR, n=20). At approximately 8 months of age, infants were removed from their rearing group, simultaneously placed into a large social environment consisting of infants from all three rearing conditions, and observed for the next 16 months. Behavior was recorded twice per week from 1 to 24 months, and composite anxiety scores were calculated for each monkey. Monkeys were initially shaved at the nape of the neck on day 14 to remove any prenatal effects on hair cortisol deposition. Hair samples were then collected by re-shaving at 6, 12, 18 and 24 months and analyzed for cortisol content. MPR monkeys were the least affected by the stressor, showing smaller increases in anxious behavior than the other groups and more rapid physiological adaptation as assessed using hair cortisol. PR monkeys showed heightened and prolonged anxious behavior, had the highest cortisol levels prior to relocation, and their cortisol levels did not decline until more than a year later. SPR monkeys exhibited more rapid behavioral adaptation than PR monkeys, showing heightened but not prolonged anxious behavior. However, the SPR group showed a marked increase in cortisol in response to the relocation, and like the PR group, their physiological adaptation was slower than that of the MPR group as indicated by elevated cortisol levels at 18 months. By 24 months of age (16 months after relocation), all rearing groups were indistinguishable from one another physiologically and behaviorally. Spearman rank correlation revealed that hair cortisol taken at month 6 was not correlated with composite anxiety scores from months 6 to 8 (just before the relocation), but was positively correlated with composite anxiety scores between months 8 and 12 (immediately after relocation) for PR infants only (r(s)=0.75, p<0.001). Month 6-hair cortisol tended to positively correlate with composite anxiety scores for the following 6 months (months 12-18) for PR monkeys only (r(s)=0.47, p=0.037), which exhibited more anxious behavior than MPR and SPR infants during this period (ANOVA: F((2,60))=14.761, p<0.001) This is the first study to show that elevated hair cortisol early in life is a biomarker for the later development of anxious behavior in response to a major life stressor, particularly for infant monkeys exposed to early life adversity in the form of peer-rearing.

Dettmer AM ，Novak MA ，Suomi SJ ，Meyer JS ... -  《-》

The effects of birth timing and ambient temperature on the hypothalamic-pituitary-adrenal axis in 3-4 month old rhesus monkeys.

Birth timing, a relative measure of the timing of births within a season, has been shown to be related to the ways mothers and infant interact as well as to infant behavior and physiology. Although effects of birth timing on the hypothalamic-pituitary-adrenal (HPA) axis have previously been associated with variation in social relationships, these effects could also be related to seasonal variation in climate conditions when the birth season is long. The current study examines the effects of birth timing and ambient temperature on the activity and regulation of the HPA axis in 3-4 month old rhesus monkeys (N=338). Subjects were part of a BioBehavioral Assessment in which infants were separated from their mothers and relocated to a novel testing environment for a period of 25h. Four blood samples were collected and assayed for cortisol concentrations and reflected HPA response to (1) 2h maternal separation and relocation, (2) 7h maternal separation and relocation (sustained challenge), (3) dexamethasone suppression, and (4) ACTH challenge. Nonlinear mixed modeling was used to examine the independent effects of birth timing and temperature on HPA axis activity and regulation over the study period. Results indicated that birth timing and ambient temperature both had significant, but opposing effects on the cortisol response to sustained challenge. Chronic exposure to low ambient temperatures was associated with higher cortisol levels. After controlling for the effect of ambient temperature, birth timing was positively associated with cortisol such that late-born infants exhibited higher cortisol concentrations than did early-born infants. These results highlight the fact that climate conditions, even mild, subtropical conditions, can have potentially important influences on the activity and development of the HPA axis.

Vandeleest JJ ，Blozis SA ，Mendoza SP ，Capitanio JP ... -  《-》

OPRM1 gene variation influences hypothalamic-pituitary-adrenal axis function in response to a variety of stressors in rhesus macaques.

The endogenous opioid system is involved in modulating a number of behavioral and physiological systems, including the hypothalamic-pituitary-adrenal (HPA) axis. In humans, a functional variant in the OPRM1 gene (OPRM1 A118G) is associated with a number of outcomes, including attenuated HPA axis responses to stress. A nonsynonymous variant (OPRM1 C77G) in the rhesus macaque has been shown to have similar effects in vivo to the human variant. The current study investigated whether OPRM1 C77G influences HPA axis response to stress in rhesus macaques. We analyzed plasma adrenocorticotropic hormone (ACTH) and cortisol levels measured in response to three different stressors: (1) maternal separation in infant subjects at 6 months of age, (2) acute ethanol administration in adolescent subjects at 4 years of age, and (3) postpartum HPA axis function in adult rhesus macaque females. For the maternal separation paradigm, ACTH and cortisol levels were determined at baseline as well as peak levels during each of 4 consecutive separation episodes. For the acute ethanol administration paradigm, hormone levels were determined at baseline and again at 5 min, 10 min, and 60 min following the ethanol infusion. For postpartum sampling, hormone levels were determined at postpartum days 7, 14, 21, 30, 60, 90, 120, and 150. Infants carrying the 77G allele exhibited lower levels of cortisol across all 4 separation episodes. Furthermore, adolescents carrying the 77G allele exhibited lower cortisol levels at 5 and 10 min following acute ethanol administration. Adult females with prior reproductive experience and who carry the 77G allele exhibited lower cortisol levels across the postpartum period. No significant genotype effects were found for ACTH, although there were some trends for lower ACTH levels in 77G allele carriers. These data are consistent with human studies that have demonstrated attenuated cortisol responses to stress among carriers of the OPRM1 118G allele, lending further support to the argument that the rhesus and human allelic variants are functionally similar. Our results also suggest that OPRM1 variation may influence coping style, as well as alcohol-induced and postpartum levels of HPA axis activity and, as such, may modify vulnerability to alcohol use disorders and postpartum depression.

Schwandt ML ，Lindell SG ，Higley JD ，Suomi SJ ，Heilig M ，Barr CS ... -  《-》

Age-related differences in stress responsiveness of the hypothalamic-pituitary-adrenal axis of nonhuman primates with various types of adaptive behavior.

Aging is characterized by disturbances in the functioning of the hypothalamic-pituitary-adrenal (HPA) axis, associated with disturbances in the adaptation processes and increase of the probability of the onset of post-stress syndrome. However, the individual features of age-related disorders stress reactivity of HPA axis have not been studied. The purpose was to study individual characteristics of the HPA axis responsiveness to acute psycho-emotional stress exposure (restraint, ASE) at different age periods on the model of the young adult and old physically healthy female rhesus monkeys that differ in their behavioral responses to stress, i.e., with depression-like and anxiety-like behavior (DAB) on the one hand and healthy standard (control) adaptive behavior (SB) on the other hand. No significant intergroup differences were observed in HPA axis responses to ASE in young animals. During aging the monkeys with SB showed reduced ACTH response to the ASE, whereas the monkeys with DAB demonstrated its increase. The old animals with DAB in response to ASE demonstrated the most pronounced HPA axis disorders, such as the highest levels of corticotrophin (ACTH), the lowest levels of dehydroepiandrosterone sulfate (DHEAS), reduced cortisol (F) levels and the highest values of the F/DHEAS molar ratio. The ratio F/DHEAS positively correlates with the malondialdehyde concentration in erythrocytes that is considered as the biomarker of oxidative stress. Thus, these data allow us to consider the old monkeys with DAB as individuals with higher vulnerability to the adverse effects of ASE. In addition, depression-like and anxiety-like behavior of aged primates under mild/moderate stress along with reduced DHEAS plasma concentration and increased values of F/DHEAS ratio can be used to identify individuals with increased vulnerability to ASE and accelerated aging.

Goncharova ND ，Oganyan TE 《-》