ABSTRACT: The long-term goal of this project is to determine the neurobiological mechanisms that underlie the effects of estrogens on the adult hypothalamo-pituitary-adrenal (HPA) axis. HPA axis activation in mammals is a basic response to environmental perturbations that threaten homeostasis and such responses, although beneficial in the short-term, have deleterious consequences under chronic conditions. Prolonged elevations of adrenal glucocorticoids (GCs) are neuroendangering and alter feeding and autonomic functions. Moreover, a dysregulation of the HPA activity accompanies these disorders. In rodents, females show a more robust HPA axis response to stress than do males, partly because of sex-differences in circulating estradiol (E2) levels. Thus, the overarching postulate of this application is that individual differences in adult stress-responses arise from differential E2 actions on the stress-circuitry. Our studies focus predominantly on estrogen receptor beta (ERβ). Rodent studies show that the alpha form of ER (ERα) increases adrenal corticosterone (CORT) and the pituitary adrenocorticotropic hormone (ACTH) response to stressors whereas activation of ERβ inhibits HPA activity. Importantly, ERβ is highly expressed in neurons of the PVN of both male and female mice to allow integration of gonadal hormone levels with stress-related inputs. Using novel transgenic mouse models, we will identify stress responsive ERβ-ergic neural circuitry of the mouse hypothalamus and determine how activation of PVN ERβ reduces HPA drive and energy balance. Specific aim 1 will determine if OT is required for ERβ regulation of PVN function using a novel Oxytocin:cre recombinase mouse line and an ERβ-cre mouse line to genetically manipulate OT and ERβ neurons. Aim 2 will assess the function of ERβ neurons that are incorporated into the stress circuitry of the mouse brain following multimodal stress and chronic unpredictable mild stressors. Aim 3 will elucidate molecular changes and sex differences that occur in PVN ERβ neurons in response to MMS and to glucocorticoids. In all cases we are highly cognizant of the presence of sex differences in these physiological pathways and will explore the role that estradiol or 5α-androstan 3β,17β diol (3β diol), a metabolite of the androgen, dihydrotestosterone that binds and activates ERβ, have on HPA axis activation and feeding behaviors. The results of these studies will provide novel insight into the role played by PVN ERβ neurons in controlling hypophysiotrophic function and metabolism with hopes of identifying novel targets for therapeutic approaches to treating stress and associated neurological deficits.