Novel Actions of Estradiol that Influence Brain Function

描述（由申请人提供）：雌激素在性成熟和接受性中起关键作用。 这些作用的特点是：主要通过细胞内雌激素受体介导，雌二醇启动基因表达的变化，导致细胞兴奋性的改变。 但是雌二醇也通过在质膜上启动的快速作用影响神经元的可塑性。 雌二醇通过这种非常规的方法调节许多细胞内信号通路，影响各种脑功能，如学习和记忆，感觉运动控制和伤害感受。 然而，雌二醇作用于细胞膜的机制仍不清楚。 初步数据表明，雌二醇通过与膜定位受体的相互作用，激活I组和II组代谢型谷氨酸受体，导致几个主要信号级联的改变。 这种以前未定义的雌二醇作用机制在理论上可以解释类固醇激素的大多数无法解释的作用。 这个建议的中心假设是，通过激活代谢型谷氨酸受体，雌二醇对大脑功能有深远的影响。 具体目标1将描述雌二醇通过激活代谢型谷氨酸受体对CREB和NFATc4的影响，因为这两种转录因子是许多行为的重要调节因子。 此外，我们将定量雌二醇给药后CREB和NFATc4调控基因的mRNA表达。 具体目标2将描述雌二醇激活代谢型谷氨酸受体的机制。 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特异性差异，以及雌激素和谷氨酸受体之间的相互作用。 总之，这项研究将试图破译一个长期存在的谜，关于雌二醇的行动后，中枢神经系统。 它可能会提供一个统一的理论，详细说明雌二醇可以迅速引发细胞兴奋性变化的主要机制，并最终导致更好地了解雌二醇如何调节脑功能。

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.