Dynamic longitudinal relations between regional brain metabolism and stress-related blood cortisol during the first year of nonhuman primate life

Hypothalamic-pituitary-adrenal(HPA)-activation is critical to the stress response, promoting adaptation and survival. To further understand the developmental time-course of stress-related HPA-activation and its neural correlates in nonhuman primates (NHP), we longitudinally studied infant rhesus monkeys from birth to 1-year. 35 monkeys (24 F/11 M) were assessed 5 times during development (T1-T5; average ages: 11,43,84,168,365 days). At each timepoint, subjects were injected with 18flurodeoxyglucose (FDG) and exposed to 30 minutes of potential threat (No-eye-contact condition of Human Intruder Paradigm, NEC). Subjects were anesthetized, had blood drawn, and underwent a PET scan. We performed timepoint-specific voxel-wise correlations of plasma cortisol levels and FDG-PET metabolism. Threat-induced cortisol levels displayed logarithmic growth across the first year of life (p<0.0002). Cortisol at T1 predicted cortisol levels at T2 and T3 (p<0.001), but not at T4 or T5 (p>0.1). Cortisol levels related to metabolism in different brain regions at each age (p<0.005, uncorrected). At younger ages, higher cortisol levels following NEC were associated with decreased brain metabolism (T1: amygdala; T2: amygdala, anterior hippocampus). At older ages, higher cortisol levels were associated with increased brain metabolism (T4: sublenticular extended amygdala, T5: bed nucleus of stria terminalis, thalamus). These findings demonstrate that the developmental pattern of HPA-activation in young NHPs may be logarithmic in nature. Our findings also indicate changes to the relationship between individual differences in stress-related HPA-activation and regional brain metabolism during this time. Interestingly, cortisol has negative correlations with limbic regions in newborns, later transitioning to adult-like positive correlations with limbic regions.