We investigated the development of the HPA axis in group-living rhesus monkeys. Forty-three infants were studied from birth through their third year of life; 22 infants were physically abused by their mothers, while 21 infants were not abused. Plasma cortisol levels in basal conditions and in response to a novel environment test were assessed at 6-month intervals. Both basal and stress cortisol increased steadily from 6 to 24 months of age and then dropped. Across all ages, stress cortisol levels were significantly higher than the basal levels. The cortisol responses to stress at 30 and 36 months of age were significantly lower than the responses at all other ages. At most ages there was an inverse relationship between basal and stress cortisol levels. Individual differences in basal cortisol levels were generally stable in the first 2 years and more variable in the third year while the opposite for true for cortisol responses to stress. At the end of the first year, but not later in life, abused infants had higher cortisol levels than controls across the basal and stress conditions. Rates of social interactions with the mother and other group members were positively correlated with basal cortisol levels early in life, and with cortisol responses to stress later in life. Altogether, these results indicate that there are strong individual differences in HPA function, that there is a relationship between basal activity and stress reactivity, and that early abuse has the short-term effect of increasing both basal activity and stress reactivity.

Oxytocin (OXT) and its receptor (OXTR) are encoded by OXT and OXTR, respectively. Variable methylation of these genes has been linked to variability in sociability and neuroendophenotypes. Here we examine whether OXTR or OXT methylation in blood predicts concentrations of OXT in cerebrospinal fluid (CSF) (n = 166) and social behavior (n = 207) in socially-housed female rhesus macaques. We report a similarity between human and rhesus CpG sites for OXT and OXTR and a putative negative association between methylation of two OXTR CpG units with aggressive behavior (both P = 0.003), though this finding does not survive the most stringent correction for multiple comparison testing. We did not detect a statistically significant association between methylation of any CpG sites and CSF OXT concentrations, either. Because none of the tested associations survived statistical corrections, if there is any relationship between blood-derived methylation of these genes and the behavioral and physiological outcomes measured here, the effect size is too small to be detected reliably with this sample size. These results do not support the hypothesis that blood methylation of OXT or OXTR is robustly associated with CSF OXT concentration or social behavior in rhesus. It is possible, though, that methylation of these loci in the brain or in cheek epithelia may be associated with central OXT release and behavior. Finally, we consider the limitations of this exploratory study in the context of statistical power.

Background Early adverse experiences, especially those involving disruption of the mother-infant relationship, are detrimental for proper socioemotional development in primates. Humans with histories of childhood maltreatment are at high risk for developing psychopathologies including depression, anxiety, substance abuse, and behavioral disorders. However, the underlying neurodevelopmental alterations are not well understood. Here we used a nonhuman primate animal model of infant maltreatment to study the long-term effects of this early life stress on brain white matter integrity during adolescence, its behavioral correlates, and the relationship with early levels of stress hormones. Methods Diffusion tensor imaging and tract based spatial statistics were used to investigate white matter integrity in 9 maltreated and 10 control animals during adolescence. Basal plasma cortisol levels collected at one month of age (when abuse rates were highest) were correlated with white matter integrity in regions with group differences. Total aggression was also measured and correlated with white matter integrity. Results We found significant reductions in white matter structural integrity (measured as fractional anisotropy) in the corpus callosum, occipital white matter, external medullary lamina, as well as in the brainstem of adolescent rhesus monkeys that experienced maternal infant maltreatment. In most regions showing fractional anisotropy reductions, opposite effects were detected in radial diffusivity, without changes in axial diffusivity, suggesting that the alterations in tract integrity likely involve reduced myelin. Moreover, in most regions showing reduced white matter integrity, this was associated with elevated plasma cortisol levels early in life, which was significantly higher in maltreated than in control infants. Reduced fractional anisotropy in occipital white matter was also associated with increased social aggression. Conclusions These findings highlight the long-term impact of infant maltreatment on brain white matter structural integrity, particularly in tracts involved in visual processing, emotional regulation, and somatosensory and motor integration. They also suggest a relationship between elevations in stress hormones detected in maltreated animals during infancy and long-term brain white matter structural effects. Keywords: Early life stress; Adolescence; Rhesus monkeys; Diffusion tensor imaging

A functional polymorphism in the promoter region of the serotonin transporter (5-HTTLPR) gene has been associated with variation in anxiety and hypothalamus-pituitary-adrenal (HPA) axis function in humans and rhesus macaques. Individuals carrying the short allele are at a higher risk for developmental psychopathology, and this risk is magnified in short allele carriers who have experienced early life stress. This study investigated the relationship between 5-HTTLPR allelic variation, infant abuse, and behavioral and hormonal responses to stress in rhesus macaques. Subjects were 10 abusive mothers and their infants, and 10 nonabusive mother-infant pairs. Mothers and infants were genotyped for the rh5-HTTLPR, and studied in the first 6 months of infant life. For mothers and infants, we measured social group behavior, behavioral responses to handling procedures, and plasma concentrations of ACTH and cortisol under basal conditions and in response to stress tests. The proportion of individuals carrying the short rh5-HTTLPR allele was significantly higher among abusive mothers than controls. Among mothers and infants, the short allele was associated with higher basal cortisol levels and greater hormonal stress responses in the infants. In addition, infants who carried the short rh5-HTTLPR allele had higher anxiety scores than infants homozygous for the long allele. The rh5-HTTLPR genotype also interacted with early adverse experience to impact HPA axis function in the infants. These results are consistent with those of previous studies which demonstrate associations between serotonergic activity and anxiety and stress reactivity, and add additional evidence suggesting that genetic variation in serotonergic function may contribute to the occurrence of abusive parenting in rhesus macaques and modulate emotional behavior and HPA axis function.

In this study we investigated the development of the hypothalamic- pituitary-adrenal (HPA) axis in 21 group-living rhesus monkeys infants that were physically abused by their mothers in the first few months of life and in 21 nonabused controls. Cortisol and adrenocorticotropin hormone (ACTH) responses to a corticotropin-releasing hormone (CRH) challenge were assessed at 6-month intervals during the subjects' first 3 years of life. Abused infants exhibited greater cortisol responses to CRH than controls across the 3 years. Abused infants also exhibited blunted ACTH secretion in response to CRH, especially at 6 months of age. Although there were no significant sex differences in abuse experienced early in life, females showed a greater cortisol response to CRH than males at all ages. There were no significant sex differences in the ACTH response to CRH, or significant interactions between sex and abuse in the ACTH or cortisol response. Our findings suggest that early parental maltreatment results in greater adrenocortical, and possibly also pituitary, responsiveness to challenges later in life. These long-term alterations in neuroendocrine function may be one the mechanisms through which infant abuse results in later psychopathologies. Our study also suggests that there are developmental sex differences in adrenal function that occur irrespective of early stressful experience. The results of this study can enhance our understanding of the long-term effects of child maltreatment as well as our knowledge of the development of the HPA axis in human and nonhuman primates.

Maternal presence has a potent buffering effect on infant fear and stress responses in primates. We previously reported that maternal presence is not effective in buffering the endocrine stress response in infant rhesus monkeys reared by maltreating mothers. We have also reported that maltreating mothers show low maternal responsiveness and permissiveness/secure-base behavior. Although still not understood, it is possible that this maternal buffering effect is mediated, at least partially, through deactivation of amygdala response circuits when mothers are present. Here, we studied rhesus monkey infants that differed in the quality of early maternal care to investigate how this early experience modulated maternal buffering effects on behavioral responses to novelty during the weaning period. We also examined the relationship between these behavioral responses and structural connectivity in one of the underlying regulatory neural circuits: amygdala-prefrontal pathways. Our findings suggest that infant exploration in a novel situation is predicted by maternal responsiveness and structural integrity of amygdala-prefrontal white matter depending on maternal presence (positive relationships when mother is absent). These results provide evidence that maternal buffering of infant behavioral inhibition is dependent on the quality of maternal care and structural connectivity of neural pathways that are sensitive to early life stress.