Dissecting Estrogen Control of Sexual Differentiation of the Brain

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DESCRIPTION (provided by applicant): In this proposal, I will investigate the cellular and molecular mechanisms utilized by steroid hormones to masculinize the bed nucleus of the stria terminalis (BNST), an important node in the neural circuits that generate sexually dimorphic behaviors such as mating and aggression. The BNST is reciprocally connected with the hypothalamus and amygdala, and its structure is sexually dimorphic, with more neurons in males. Both classic endocrine studies, and genetic loss-of-function experiments indicate that steroid hormones and their receptors are also required for male-typical behaviors. Androgen receptor (AR) is expressed in more cells in the male BNST. My findings indicate that estrogen acts in a male-specfic manner during the first few days of life to direct sexual differentiation of the BNST, in part through male-specific regulation of AR. I propose to investigate two questions relating to the role of estrogen in generating sexual dimorphism in the BNST. 1) What are the mechanisms by which estrogen generates sexual dimorphism in AR expression in the brain? 2) What is the genetic program mediated by estrogen to masculinize the BNST? By answering these questions, I hope to define the mechanisms which generate a sex-specific cell population in the brain. The goal of Aim 1 is to demonstrate a direct role for estrogen in activating a male-specific expression pattern of AR in the BNST. I will utilize the previously published AR-IPIN reporter mice, which express LacZ in all AR-positive cells, to evaluate the requirement for estrogen in AR expression. Through chromatin immunoprecipitation analysis (ChIP), I will demonstrate the direct recruitment of estrogen receptor alpha (ERa) to the AR locus in the neonatal BNST of males. These studies will reveal the mechanisms for generating sexual dimorphism in AR expression in the BNST I hypothesize that, in addition to regulating AR expression, estrogen signaling controls the sex-specific expression of many genes in the BNST. The goal of Aim 2 is to identify additional sexually dimorphic genes regulated by ERcx in the developing BNST through microarray analysis. These genes will provide important insight into the role of hormones in regulating sexual differentiation of the brain. My experiments will elucidate the fundamental mechanisms that control sexual differentiation of an important brain region, the BNST. Many psychiatric conditions such as autism and depression present with sex-biased ratios. Understanding how the brain undergoes sexual differentiation is likely to advance our understanding of the basic mechanisms that lead to many of these disorders.