Prenatal alcohol exposure and chronic stress in adulthood : effects on anxiety- and depressive-like behavior and central regulation of the neuroendocrine stress response

Individuals prenatally exposed to alcohol show higher rates of mental health problems than unexposed individuals, with depression and anxiety being among the more commonly encountered disorders. Depression and anxiety are often observed in the context of stress and/or a dysregulated stress response system (the hypothalamic-pituitary-adrenal [HPA] axis). Prenatal alcohol exposure (PAE) can dysregulate the HPA axis, resulting in hyperresponsivity to stress, which in turn may predispose exposed individuals to the adverse effects of stress compared to unexposed individuals. With the overarching aim to examine the role of PAE-induced HPA hyperresponsivity to stress in depression and anxiety, and how sex differences may influence outcome, I examined the effects of PAE and chronic unpredictable stress (CUS) on multiple aspects of HPA regulation and behavioral output. I found that PAE alone altered, in a sex-dependent manner, baseline anxiety-/depressive-like behavior as well as neural activation and stress-related receptor expression in brain regions involved with both stress and emotional regulation compared to control animals. Additionally, PAE animals show differential sensitivity to the effects of chronic stress compared to unexposed animals. Furthermore, I demonstrate that several effects of CUS may have a delayed onset. Following the findings of these studies, I more directly examined the role of hypersecretion of corticosterone in mediating the effects of PAE and CUS on brain and behavior, by clamping corticosterone at basal physiological levels via adrenalectomy and hormone replacement in drinking water (ADXR). Our results suggest that while HPA hyperreactivity to stress is a robust consequence of PAE, corticosterone levels may be relevant for behavioral outcome and HPA regulation of PAE females but not males. Overall, our findings have important implications for understanding the role of stress and hormone secretion in the adverse effects of PAE, which has clinical relevance as individuals prenatally exposed to alcohol are at a higher risk than unexposed individuals of encountering stressful environments during their lifetimes.Medicine, Faculty ofGraduat