BRAIN OXYTOCIN RECEPTORS--FUNCTION AND STRUCTURE

描述（改编自申请人摘要）：这是一份修订版 申请第一个奖项（R29）。 我的长期研究目标是 建立一个独立的多学科研究计划，以揭示 卵巢类固醇激素调节女性性行为的机制 对大鼠 这种行为长期以来一直是一个优秀的模型系统， 脑内类固醇激素作用的生物学基础。 先前的研究 表明下丘脑中的催产素受体（OTRs）有助于女性 雌激素和孕激素预处理后的性行为。 雌激素似乎对增强这种基因的mRNA水平很重要。 蛋白 然而，在没有孕酮的情况下，这些雌二醇诱导的 受体不足以使OT增强性行为。 的 孕酮的允许作用的机制尚不清楚。 拟议 实验将研究雌二醇和孕酮的机制， 大鼠脑中OTR表达和功能的调节。 第一 具体目标是从大鼠脑中克隆OTR。 预计这将使 研究者开发适当的试剂（例如，探针， 抗血清）用于后续研究。 第二个具体目标是测试 假设雌二醇和孕酮调节OTR转录， 调节转录的速率。 这项研究不仅将确定 雌二醇诱导OTR mRNA增加的机制，但也将 确定孕酮是否积极地共同调节雌二醇对 OTR转录。 第三个具体目标将检验以下假设： 类固醇激素诱导下丘脑OTR结合活性的变化 与第二信使产生的改变有关。 比如说， 假设将被测试，生物学基础 催产素依赖性促进性行为是 增强OTR信号转导。 最后的调查将决定 OTR信号转导的任何增加是否部分由 类固醇激素诱导的与OTR相关的G蛋白上调。 总之，拟议的实验将提供详细的分析， 类固醇激素对这种神经肽的多层次调节 受体，以允许可塑性的这一生物学上重要的行为。 从这些研究中获得的见解可能与其他例子有关， 类固醇与神经回路的相互作用，如压力反应和情绪 紊乱

DESCRIPTION (Adapted from applicant's abstract): This is a revised application for a FIRST award (R29). My long-term research goal is to establish an independent multidisciplinary research program to reveal the mechanisms whereby ovarian steroid hormones regulate female sexual behavior in rats. This behavior has long served as an excellent model system for the biological basis of steroid hormone actions in brain. Previous studies have shown that oxytocin receptors (OTRs) in the hypothalamus facilitate female sexual behavior after pretreatment with estradiol and progesterone. Estradiol appears important for enhancing the level of mRNA for this protein. In the absence of progesterone, however, these estradiol-induced receptors are not sufficient for OT to augment sexual behavior. The mechanism of progesterone's permissive effects are not known. The proposed experiments will examine the mechanisms of estradiol and progesterone regulation of OTR expression and function in the rat brain. The first specific aim is to clone OTRs from rat brain. This is expected to enable the investigators to develop the appropriate reagents (e.g., probes, antisera) for subsequent studies. The second specific aim is to test the hypothesis that estradiol and progesterone regulate OTR transcripts by modulating the rate of transcription. This study will not only determine the mechanism for estradiol-induced increases in OTR mRNA, but will also determine whether progesterone actively co-regulates estradiol's effects on OTR transcription. The third specific aim will test the hypothesis that steroid hormone-induced changes in OTR binding activity in the hypothalamus are associated with alteration in second messenger production. For example, the hypothesis will be tested that the biological basis for progesterone-dependent facilitation of sexual behavior by OT is the augmentation of OTR signal transduction. A final inquiry will determine whether any increases in OTR signal transduction are mediated in part by steroid hormone-induced upregulation of G proteins associated with OTRs. Taken together, the proposed experiments will provide a detailed analysis of the multiple levels of regulation by steroid hormones of this neuropeptide receptor to permit plasticity of this biologically important behavior. Insights gained from these studies may be relevant to other examples of steroid interactions with neural circuits, such as stress responses and mood disorders.