Novel Actions of Estradiol that Influence Brain Function

描述(由申请人提供)：雌二醇对性成熟和接受性起关键作用。这些效应有很好的特征：雌二醇主要通过细胞内的雌激素受体介导，启动基因表达的变化，导致细胞兴奋性的变化。但雌二醇也通过启动质膜的快速反应来影响神经元的可塑性。许多细胞内的信号通路都是由雌二醇通过这种非常规的方式来调节的，从而影响到学习和记忆、感觉运动控制和伤害性感受等多种大脑功能。然而，雌二醇作用于细胞膜的机制尚不清楚。初步数据表明，雌二醇通过与膜上定位的受体相互作用，激活第一组和第二组代谢性谷氨酸受体，导致几个主要信号级联反应的改变。从理论上讲，这一以前未明确的雌激素作用机制可以解释类固醇激素大部分未解释的作用。这一建议的中心假设是，通过激活代谢性谷氨酸受体，雌二醇对大脑功能有深远的影响。具体目标1将表征雌二醇通过激活代谢性谷氨酸受体对CREB和NFATc4的影响，因为这两个转录因子是许多行为的重要调节因子。此外，我们将量化雌激素给药后受CREB和NFATc4调控的基因的mRNA表达。具体目标2将描述雌二醇激活代谢性谷氨酸受体的机制。实验将详细说明雌激素受体的特异性，雌二醇敏感性的性别差异，以及雌激素和谷氨酸受体之间的相互作用。总之，这项研究将试图破解一个长期存在的关于雌二醇对中枢神经系统的作用的谜团。它可能会提供一个统一的理论，详细说明雌激素可以迅速引发细胞兴奋性变化的主要机制，并最终导致更好地理解雌激素如何调节大脑功能。

DESCRIPTION (provided by applicant): Estradiol plays a critical role in sexual maturation and receptivity. These effects are well characterized: primarily mediated through intracellular estrogen receptors, estradiol initiates changes in gene expression, leading to alterations in cell excitability. But estradiol also influences neuronal plasticity via rapid actions initiated at the plasma membrane. Many intracellular signaling pathways are modulated by estradiol via this unconventional method, influencing various brain functions such as learning and memory, sensorimotor control and nociception. Yet, the mechanism by which estradiol acts at the membrane remains unknown. Preliminary data suggest that estradiol, through interactions with a membrane localized receptor, activates both group I and group II metabotropic glutamate receptors, leading to alterations in several major signaling cascades. This previously undefined mechanism of estradiol action can theoretically account for the majority of unexplained actions of the steroid hormone. The central hypothesis of this proposal is that through activation of metabotropic glutamate receptors, estradiol has profound influences upon brain function. Specific Aim 1 will characterize the effects of estradiol, through activation of metabotropic glutamate receptors, upon CREB and NFATc4, as these two transcription factors are essential regulators of many behaviors. Moreover, we will quantify mRNA expression for genes regulated by CREB and NFATc4 following estradiol administration. Specific Aim 2 will delineate the mechanism by which estradiol activates metabotropic glutamate receptors. Experiments will detail estrogen receptor specificity, gender specific differences in estradiol sensitivity, and interactions between estrogen and glutamate receptors. In sum, this study will attempt to decipher a long standing mystery regarding the actions of estradiol upon the central nervous system. It will potentially provide a unifying theory detailing a principal mechanism by which estradiol can rapidly trigger changes in cell excitability and ultimately lead to a better understanding of how estradiol modulates brain function.