The long-term goals of this project are to determine the neurobiological mechanisms that underlie the sex differences in the function of the adult hypothalamo-pituitary-adrenal (HPA) axis. In humans and animals, sex differences in HPA reactivity are well established;females exhibit a more robust activation of the HPA axis following stress than do males. Our hypothesis is that sex differences in adult hormonal stress responses are primarily the result of the opposing actions of testosterone (T) and estrogen (E) on HPA function. Activation of the HPA axis is a basic response of animals to environmental perturbations that threaten homeostasis. These responses are regulated by neurons residing in the paraventricular nucleus of the hypothalamus (PVN) that synthesize and secrete corticotropin-releasing hormone (CRH). Other PVN neuropeptides, such as vasopressin (AVP) and oxytocin (OT), modulate activity of CRH neurons at the level of the PVN as well as enhancing CRH secretogogue activity at the anterior pituitary gland. The reproductive steroids, E and T can also modulate stress responses. Circulating E enhances stress activated ACTH and CORT secretion. In contrast, T decreases the gain of the HPA axis. Published and preliminary data show that androgens can act directly on PVN neurons in the male rat through a novel pathway that involves estrogen receptor beta (ERbeta), whereas E acts predominantly through ERalpha. Thus, we hypothesize that in males, T suppresses HPA function by androgen metabolites that bind ERbeta. Clues to the neurobiological mechanisms underlying such a novel action can be gleaned from studies showing extensive colocalization of ERbeta in OT-containing cells of the PVN. Hence, in this application we address the possibility that testosterone inhibits HPA reactivity by metabolizing to a compound that binds ERbeta and regulates OT containing neurons of the PVN. Furthermore, we hypothesize that this action is distinct from that found in females where estradiol is the ligand acting through ERalpha.
Five specific aims are proposed.
Aim 1 will identify the location and regulation of steroid metabolizing enzymes in neurons of the PVN that allow synthesis of 32-Diol.
Aim 2 will use mouse models to test the hypothesis that locally synthesized 32-Diol acts upon ERbeta neurons in the PVN to inhibit HPA reactivity.
Aim 3 will determine if ERbeta containing neurons regulate HPA axis function through local release of OT or extra-PVN oxytocinergic connections with limbic nuclei.
Aim 4 will test the hypothesis that 32 Diol and ERbeta functionally interact with the oxytocin promoter in a ligand dependent fashion.
Aim 5 will test the hypothesis that the nature of the ligand bound to ERbeta determines the assembly of co-regulatory factors recruited to target sites on the OT promoter.

Public Health Relevance

Sex differences exist in the hormonal response of animals to physical and psychological stressors. These sex differences arise as a result of the actions of estrogen and androgen acting upon neural circuits within the hypothalamus. In this application we will test the hypothesis that the actions of testosterone act to inhibit neuroendocrine responses to stress through metabolism to 32-Diol and subsequent binding to estrogen receptor beta found in oxytocin neurons of the hypothalamus.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IFCN-H (03))
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Gnadt, James W
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University of Arizona
Other Basic Sciences
Schools of Medicine
United States
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Hiroi, Ryoko; Lacagnina, Anthony F; Hinds, Laura R et al. (2013) The androgen metabolite, 5ýý-androstane-3ýý,17ýý-diol (3ýý-diol), activates the oxytocin promoter through an estrogen receptor-ýý pathway. Endocrinology 154:1802-12
Carbone, D L; Handa, R J (2013) Sex and stress hormone influences on the expression and activity of brain-derived neurotrophic factor. Neuroscience 239:295-303
Handa, Robert J; Mani, Shaila K; Uht, Rosalie M (2012) Estrogen receptors and the regulation of neural stress responses. Neuroendocrinology 96:111-8

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