Androgen Receptor Expression in Developing Rat Forebrain

发育中的大鼠前脑中雄激素受体的表达

• 批准号: 6539202
• 负责人: Lydia L DonCarlos
• 金额: $ 29.6万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6539202
• 关键词: androgen inhibitor; androgen receptor; aromatase; behavior test; behavioral /social science research tag; brain mapping; developmental neurobiology; dihydrotestosterone; embryo /fetus; gender difference; hormone regulation /control mechanism; immunocytochemistry; laboratory rat; male; male castration; newborn animals; prosencephalon; protein localization; receptor expression; sex behavior; sex differentiation; steroid hormone metabolism; testosterone; western blottings

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.

这项研究的总体目标是阐明睾丸激素对发育中的哺乳动物神经系统的影响的基础机制。 睾丸激素雕刻了发育中的神经系统，确保大脑的性表型与性腺的性表型相匹配。 在啮齿动物中，围产期期间睾丸激素的暴露不仅会永久性地男性化，不仅在中枢神经系统的形态，连通性和化学中，而且行为和神经内分泌功能。在前脑男性化过程中，睾丸激素和雌激素受体的雌激素代谢产物的重要作用是无可争议的。 然而，引人注目的积累数据使我们假设雄激素受体是睾丸激素对神经系统的组织作用的组成部分，并且雄激素受体表达和调节的空间和时间变化有助于雄性大脑发育调节中雄激素的特定作用。 综合分子和解剖方法将用于检查大鼠脑的七个功能相关区域中雄激素受体表达的发育和激素调节。 这些研究将构成行为实验的基础，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别分化行为的发展。 将测试四个特定的假设：I。通过雄激素受体的睾丸激素作用的解剖学底物在前脑中存在于产前； ii。产前睾丸激素在以后发育期间使雄激素受体mRNA和蛋白质水平降低了男性化； iii。 雄激素受体表达的激素调节特定于发育阶段。 iv。通过雄激素受体依赖机制，雄激素暴露于男性化的行为。 将使用特定类固醇受体配体或拮抗剂治疗大鼠，并将使用原位杂交，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，或者将使用成人行为对激素的标准措施进行分析。 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行为。 提出的研究将为剖析大脑性别分化过程的复杂机制提供必不可少的数据，并有助于理解对激素的发展阶段特异性反应。 此外，这些研究将阐明在男性与女性中更普遍的神经系统和精神障碍的病因。