Methylation of OXT and OXTR genes, central oxytocin, and social behavior in female macaques.

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.

Effects of early life stress on cocaine intake in male and female rhesus macaques.

RATIONALE: It is critical to identify potential risk factors, such as a history of early life stress (ELS), that may confer specific vulnerabilities to increased drug intake. OBJECTIVE: In this study, we examined whether male and female rhesus monkeys with a history of ELS (infant maltreatment; MALT) demonstrated significantly greater cocaine intake compared with controls. METHODS: Monkeys were trained to self-administer cocaine during 4-h sessions at a peak dose (0.003-0.1 mg/kg/infusion; extended access, "EA peak") and a dose of 0.1 mg/kg/infusion (EA 0.1) of cocaine. These data were compared with data obtained previously in monkeys trained during 1-h limited access (LA) sessions at the same peak dose of cocaine used here (Wakeford et al. Psychopharmacology, 236:2785-2796, 2019). RESULTS: Monkeys significantly increased total number of infusions earned in EA compared with LA, but total session response rates significantly decreased in EA compared with LA. There was no evidence of escalation in drug intake when we compared response rates to obtain the first 20 cocaine infusions between LA and EA peak conditions. Moreover, there was no evidence of escalation in drug intake during an additional 7 weeks of self-administration at 0.1 mg/kg/injection. CONCLUSIONS: The current study expands on previous reports demonstrating that rhesus macaques did not escalate cocaine intake under the experimental conditions employed and extended these findings by using a unique population of nonhuman primates with a history of infant MALT to test the hypothesis that ELS is a risk factor for escalation of cocaine intake in nonhuman primates. There was no clear evidence of escalation in cocaine intake as a consequence of ELS.

Effects of early life stress on cocaine self-administration in post-pubertal male and female rhesus macaques.

RATIONALE: Early life stress (ELS), including childhood maltreatment, is a predictive factor for the emergence of cocaine use disorders (CUDs) in adolescence. OBJECTIVE: Accordingly, we examined whether post-pubertal male and female rhesus macaques that experienced infant maltreatment (maltreated, n = 7) showed greater vulnerability to cocaine self-administration in comparison with controls (controls, n = 7). METHODS: Infant emotional reactivity was measured to assess differences in behavioral distress between maltreated and control animals as a result of early life caregiving. Animals were then surgically implanted with indwelling intravenous catheters and trained to self-administer cocaine (0.001-0.3 mg/kg/infusion) under fixed-ratio schedules of reinforcement. Days to acquisition, and sensitivity to (measured by the EDMax dose of cocaine) and magnitude (measured by response rates) of the reinforcing effects of cocaine were examined in both groups. RESULTS: Maltreated animals demonstrated significantly higher rates of distress (e.g., screams) in comparison with control animals. When given access to cocaine, control males required significantly more days to progress through terminal performance criteria compared with females and acquired cocaine self-administration slower than the other three experimental groups. The dose that resulted in peak response rates did not differ between groups or sex. Under 5-week, limited-access conditions, males from both groups had significantly higher rates of responding compared with females. CONCLUSIONS: In control monkeys, these data support sex differences in cocaine self-administration, with females being more sensitive than males. These findings also suggest that ELS may confer enhanced sensitivity to the reinforcing effects of cocaine, especially in males.

Maternal buffering beyond glucocorticoids: impact of early life stress on corticolimbic circuits that control infant responses to novelty.

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.

Social buffering of stress responses in nonhuman primates: Maternal regulation of the development of emotional regulatory brain circuits.

Social buffering, the phenomenon by which the presence of a familiar individual reduces or even eliminates stress- and fear-induced responses, exists in different animal species and has been examined in the context of the mother-infant relationship, in addition to adults. Although it is a well-known effect, the biological mechanisms that underlie it as well as its developmental impact are not well understood. Here, we provide a review of evidence of social and maternal buffering of stress reactivity in nonhuman primates, and some data from our group suggesting that when the mother-infant relationship is disrupted, maternal buffering is impaired. This evidence underscores the critical role that maternal care plays for proper regulation and development of emotional and stress responses of primate infants. Disruptions of the parent-infant bond constitute early adverse experiences associated with increased risk for psychopathology. We will focus on infant maltreatment, a devastating experience not only for humans, but for nonhuman primates as well. Taking advantage of this naturalistic animal model of adverse maternal caregiving, we have shown that competent maternal care is critical for the development of healthy attachment, social behavior, and emotional and stress regulation, as well as of the neural circuits underlying these functions.

Early adverse experience increases emotional reactivity in juvenile rhesus macaques: relation to amygdala volume.

This study investigated the impact of infant maltreatment on juvenile rhesus monkeys' behavioral reactivity to novel stimuli and its associations with amygdala volume. Behavioral reactivity to novel stimuli of varying threat intensity was measured using Approach/Avoidance (AA) and Human Intruder (HI) tasks. In vivo magnetic resonance imaging (MRI) was used to measure amygdala volume. Interestingly, group behavioral differences were context-dependent. When exposed to a human intruder, maltreated subjects displayed more anxious behaviors than controls; however, when presented with fear-evoking objects, maltreated animals exhibited increased aggression and a shorter latency to inspect the objects. Finally, under testing conditions with the lowest levels of threat (neutral novel objects) maltreated animals also showed shorter latencies to inspect objects, and reduced avoidance and increased exploration compared to controls. This suggests alterations in threat assessment and less behavioral inhibition in animals with early adverse experience compared to controls. Some of these behavioral responses were associated with amygdala volume, which was positively correlated with abuse rates received during infancy, particularly reflecting a relationship with exploration, consistent with previous studies.

Brain white matter microstructure alterations in adolescent rhesus monkeys exposed to early life stress: associations with high cortisol during infancy.

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.

Early maternal rejection affects the development of monoaminergic systems and adult abusive parenting in rhesus macaques (Macaca mulatta).

This study investigated the effects of early exposure to variable parenting style and infant abuse on cerebrospinal fluid (CSF) concentrations of monoamine metabolites and examined the role of monoaminergic function in the intergenerational transmission of infant abuse in rhesus monkeys (Macaca mulatta). Forty-three infants reared by their biological mothers and 15 infants that were cross-fostered at birth and reared by unrelated mothers were followed longitudinally through their first 3 years of life or longer. Approximately half of the infants were reared by abusive mothers and half by nonabusive controls. Abused infants did not differ from controls in CSF concentrations of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), or 3-methoxy-4-hydroxyphenylgycol (MHPG). Abused infants, however, were exposed to higher rates of maternal rejection, and highly rejected infants had lower CSF 5-HIAA and HVA than low-rejection infants. The abused females who became abusive mothers in adulthood had lower CSF 5-HIAA than the abused females who did not. A similar trend was also observed among the cross-fostered females, suggesting that low serotonergic function resulting from early exposure to high rates of maternal rejection plays a role in the intergenerational transmission of infant abuse.