Novel Actions of Estradiol that Influence Brain Function

雌激素在性成熟和接受性中起着关键作用。这些影响的特点是： 雌二醇主要通过细胞内雌激素受体介导，启动基因表达的变化， 导致细胞兴奋性的改变。但雌二醇也通过快速作用影响神经元的可塑性 从质膜开始。许多细胞内信号传导途径是由雌二醇通过这一途径调节的。 非传统的方法，影响各种大脑功能，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，导致几个主要信号传导的改变， 瀑布这种以前未明确的雌二醇作用机制在理论上可以解释大多数 类固醇激素无法解释的作用这一建议的核心假设是，通过 雌二醇激活代谢型谷氨酸受体，对脑功能有深远的影响。 具体目标1将通过激活代谢型谷氨酸来表征雌二醇的作用 受体，CREB和NFATc4，因为这两个转录因子是许多重要的调节因子， 行为。此外，我们将定量CREB和NFATc4调控基因的mRNA表达， 雌二醇给药。 具体目标2将阐明雌二醇激活代谢型谷氨酸的机制 受体。实验将详细说明雌激素受体的特异性，雌二醇的性别特异性差异 敏感性以及雌激素和谷氨酸受体之间的相互作用。 总之，这项研究将试图解开一个长期存在的谜团，关于雌二醇的作用， 中枢神经系统它可能提供一个统一的理论，详细说明一个主要的机制， 雌二醇可以迅速引发细胞兴奋性的变化，并最终导致更好地了解如何 雌二醇调节大脑功能。

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.