Androgen Receptor Expression in Developing Rat Forebrain

本研究的总体目标是阐明睾酮对发育中的哺乳动物神经系统的影响的机制。 特徴塑造发育中的神经系统，确保大脑的性表现型与性腺的性表现型相匹配。 在啮齿类动物中，围产期的睾酮暴露不仅使中枢神经系统的形态、连接和化学永久男性化，而且使行为和神经内分泌功能永久男性化。睾酮和雌激素受体的雌激素代谢产物在前脑雄性化过程中的重要作用是无可争议的。 然而，令人信服的积累的数据，使我们假设，雄激素受体是睾酮对神经系统的组织作用的一个组成部分，雄激素受体的表达和调节的空间和时间的变化有助于雄激素在大脑发育的调制的具体行动。 一个综合的分子和解剖学的方法将被用来检查雄激素受体的表达在7个功能相关的区域的大鼠脑的发展和激素调节。 这些研究将成为行为实验的基础，这些实验将测试发育过程中雄激素受体的激活是否会改变性分化行为的发展。 四个具体的假设将被测试：一。睾丸激素通过雄激素受体作用的解剖学底物存在于产前前脑; II.产前睾酮雄性化雄激素受体mRNA和蛋白质水平在以后的发展; III。 雄激素受体表达的激素调节是特定的发育阶段; IV.雄激素暴露通过雄激素受体依赖机制使行为男性化。 将用特异性类固醇受体配体或拮抗剂处理大鼠，并使用原位杂交、免疫细胞化学和蛋白质印迹评估雄激素受体mRNA和蛋白质表达，或使用对激素的成年行为反应的标准测量分析行为。 这些研究将确定雄激素受体mRNA和蛋白质表达何时开始，雄激素受体蛋白表达细胞在发育过程中的细胞表型，出生前或出生后雄激素是否会改变随后的雄激素受体表达，以及雄激素受体调节的成人模式何时出现，最后，雄激素受体表达和调节的改变是否会影响对随后激素暴露的敏感性，并在成年性成熟中发挥作用，行为。 这些研究将为解剖大脑性别分化过程的复杂机制提供必要的数据，并有助于了解发育阶段对激素的特定反应。 此外，这些研究将阐明男性与女性相比更普遍的神经和精神疾病的病因。

The overall goal of this research is to elucidate the mechanisms underlying the impact of testosterone on the developing mammalian nervous system. Testosterone sculpts the developing nervous system, insuring that the sexual phenotype of the brain matches that of the gonads. In rodents, testosterone exposure during the perinatal period permanently masculinizes not only the morphology, connectivity, and chemistry of the central nervous system but also behavioral and neuroendocrine functions. The prominent role of both estrogenic metabolites of testosterone and estrogen receptors in the process of forebrain masculinization is undisputed. Compelling accumulated data, however, have led us to hypothesize that androgen receptors are an integral component of the organizational effects of testosterone on the nervous system, and that spatial and temporal shifts in androgen receptor expression and regulation contribute to specific actions of androgens in modulation of brain development. An integrated molecular and anatomical approach will be used to examine the development and hormonal regulation of androgen receptor expression in seven functionally relevant regions of the rat brain. These studies will form the basis for behavioral experiments that will test whether androgen receptor activation during development modifies the development of sexually differentiated behaviors. Four specific hypotheses will be tested: I. The anatomical substrate for testosterone action via androgen receptors exists prenatally in the forebrain; II. Prenatal testosterone masculinizes androgen receptor mRNA and protein levels during later development; III. Hormonal regulation of androgen receptor expression is specific to the developmental stage; IV. Androgen exposure masculinizes behaviors via androgen receptor dependent mechanisms. Rats will be treated with specific steroid receptor ligands or antagonists, and androgen receptor mRNA and protein expression will be assessed using in situ hybridization, immunocytochemistry and western blots, or behaviors will be analyzed using standard measures of adult behavioral responses to hormones. These studies will determine when androgen receptor mRNA and protein expression begins, the cellular phenotype of androgen receptor protein expressing cells through development, whether pre or postnatal androgen modifies subsequent androgen receptor expression, and when adult patterns of androgen receptor regulation arise, and finally, whether alterations in androgen receptor expression and regulation affect sensitivity to subsequent hormone exposure and play a role in maturation of adult sexual behaviors. The studies proposed will provide data essential to dissecting the complex mechanisms underlying the process of sexual differentiation of the brain, and contribute to an understanding of developmental stage-specific responses to hormones. Further, these studies will shed light on the etiology of neurologic and mental disorders that are more prevalent in men vs. women.