Role of neonatal testosterone in shaping the adult male hypothalamic-pituitary-adrenal axis response to stress

Testosterone exposure during critical periods of development exerts major organizing effects on the hypothalamic-pituitary-adrenal (HPA) axis. The aim of this thesis was to determine how HPA axis activity is altered by neonatal testosterone, and where and how this might occur in the adult brain. In chapter two, I demonstrate that neonatal gonadectomy increased plasma corticosterone and Fos activation in the ACTH-regulating zone of the paraventricular nucleus of the hypothalamus under basal conditions and following restraint exposure. These responses were normalized with postnatal, but not adult testosterone replacement. Neonatal gonadectomized rats also had decreased numbers of AR and arginine vasopressin-positive cells in the bed nucleus of the stria terminalis and medial amygdala. This suggests that testosterone exposure during the neonatal period may prime adult HPA response to testosterone by altering AR levels and function within afferent mediators of HPA axis activity. Testosterone in the brain can be converted to estradiol by the aromatase enzyme, and estradiol usually impacts brain development directly. In chapter 3, I demonstrate that animals neonatally exposed to aromatase, or AR blockade fail to show a normal decline in corticosterone, or habituate, in response to repeat restraint exposure. By contrast, males castrated as adults show a significant reduction in corticosterone after repeated stress. These findings suggest an organizing influence of both ARs and estrogen conversion on HPA habituation, which occurs independently of activational effects of testosterone. The immediate early gene c-fos is rapidly induced in many brain regions following acute restraint stress and is an excellent tool for mapping functional differences in brain activation by stress. In chapter 4, we used c-fos mRNA as a tool to map changes in cellular activation in acutely stressed adult animals that received aromatase blockade neonatally. This treatment enhanced stress-induced c-fos expression in several limbic regions, including within the anterior cingulate and medial prefrontal cortex, lateral septum, anterior hypothalamic area, dorsal medial hypothalamus and medial amygdala, as well as at multiple levels of somatosensation. Based on these results, I propose estrogens exert effects during the neonatal period that result in systems-wide differences in adult neuroendocrine responses to homeostatic threat.Medicine, Faculty ofGraduat