Steroid Hormones Regulatory Mechanisms and Behavior

描述(申请人提供)：卵巢类固醇激素，雌二醇 和黄体酮，调节中枢神经系统的细胞功能 导致各种动物的生理和生殖行为的变化 物种。黄体酮对性行为的影响不仅通过 涉及细胞内核的“经典”基因组作用机制 受体，但也通过涉及核外的快速“非经典”途径 信号转导级联反应。而细胞和分子机制 涉及这两种机制衔接的机制还不是很清楚，它 可能涉及蛋白激酶依赖的信号转导之间的“串扰” 级联起始于膜和核转录因子。 由蛋白激酶级联实现的显著信号放大可能 改变神经细胞内的磷酸化动态以实现加性， 协同或多余的效果产生多个成分，但协调一致 分子反应，最终形成统一的行为结果。这项建议 重点是确定黄体酮的作用机制 超出经典的细胞内类固醇受体介导的途径。 特别是，我们建议确定生化和分子事件 黄体酮启动的信号转导通路(S)。 具体目标1将确定快速、 黄体酮在与前凸相关的区域发出信号。我们会 检验孕酮启动的cAMP增加激活的假设 丝裂原活化蛋白激酶(MAPK)通路在下丘脑和 视前区(POA)，已知与前凸有关的区域 电路。我们将确定MAPK通路的激活是否会导致 下游核转录靶标如钙/cAMP的磷酸化 反应元件结合蛋白(CREB)。具体目标2将决定 通过检测激活的MAPK级联信号通路的细胞内定位 P-MAPK及其下游效应因子在细胞水平的分布。 《特定目标3》将检验黄体酮激活的假设 MAPK介导的级联及其转录靶点介导性行为 在活体内。识别这种串扰信号机制将有助于 对于我们对环境和内部决定因素的理解 荷尔蒙-大脑-行为机制。

DESCRIPTION (provided by applicant): The ovarian steroid hormones, estradiol and progesterone, regulate cellular functions in the central nervous system resulting in changes in physiology and reproductive behavior in a variety of species. Progesterone effects on sexual behavior are mediated not only through the "classical" genomic mechanism of action involving the intracellular nuclear receptors, but also via rapid "non-classical" pathways involving extra-nuclear signal transduction cascades. While the cellular and molecular mechanisms involved in the convergence of these two mechanisms are not well understood, it could involve "cross-talk" between protein kinase-dependent signal transduction cascades initiated at the membrane and the nuclear transcription factors. Pronounced signal amplification achieved by the protein kinase cascades could alter phosphorylation dynamics within the neuronal cells to achieve additive, synergistic or redundant effects producing a multi-component, but coordinated molecular response, culminating in an unified behavioral outcome. This proposal focuses on the determination of the mechanisms of progesterone action that extend beyond the classical intracellular steroid receptor-mediated pathways. In particular, we propose to determine the biochemical and molecular events underlying the rapid progesterone-initiated signal transduction pathway(s). Specific aim 1 will determine the mechanism underlying the rapid, progesterone-initiated signaling in areas associated with lordosis. We will test the hypothesis that the progesterone-initiated increases in cAMP activate mitogen activated protein kinase (MAPK) pathway in the hypothalamus and preoptic area (POA), the regions known to be associated with lordosis circuitry. We will determine whether activation of MAPK pathway results in the phosphorylation of downstream nuclear transcriptional targets like Ca+2/cAMP response element binding protein (CREB). Specific aim 2 will determine the intracellular localization of the activated MAPK cascade by examining the distribution of p-MAPK and its down-stream effectors at the cellular level. Specific aim 3 will test the hypothesis that the progesterone-activated MAPK-mediated cascade and its transcriptional targets mediate sexual behavior in vivo. Identification of such cross-talk signaling mechanisms will contribute to our understanding of the environmental and internal determinants of hormone-brain-behavior mechanisms.