Central actions of estrogens: effects on GnRH neurons

描述（申请人提供）：雌二醇影响许多中枢神经功能，但机制尚不清楚。促性腺激素释放激素（GnRH）神经元形成了生殖中枢调控的最终共同途径。GnRH神经元是中枢神经系统的输出神经元，雌二醇对整个动物生育能力的影响已经很清楚。通过以GnRH神经元为模型，确定雌二醇改变神经网络的机制，我们将为人类健康和设计新的生育和避孕策略提供重要信息。这项工作也将与雌二醇对更复杂的神经系统的作用有关，这些神经系统不太容易研究，其输出也没有很好的定义，比如那些控制认知和记忆形成的神经系统。最先进的电生理学方法将用于研究雌二醇对GnRH神经元反馈的神经生物学机制。雌二醇的增加发生在女性生殖周期中，对GnRH的释放有双相影响。最初雌二醇通过负反馈抑制GnRH的释放。然而，随着持续暴露于高水平的雌二醇，对这种类固醇的反应从阴性转变为阳性。正反馈诱导GnRH释放激增，这是排卵的神经先决条件。使用小鼠模型，在暴露于恒定的生理雌二醇水平时产生每日负反馈和正反馈之间的转换，将解决有关雌二醇作用的三个具体目标。将与通过阉割打开反馈回路的动物的数据进行比较。在Aim 1中，将研究雌二醇对GnRH神经元快速突触传递的影响，包括传入神经元的活性和GnRH神经元的反应性。在Aim 2中，我们将探讨雌二醇对GnRH神经元内在电导的影响，包括雌二醇诱导的变化是否由于离子通道磷酸化的改变。在Aim 3中，三种选定的神经调节剂的作用假设介导雌二醇反馈将被检查。总之，这些研究将深入了解雌二醇对GnRH释放的负反馈和正反馈调节的直接和跨突触机制。

DESCRIPTION (provided by applicant): Estradiol affects many central neural functions but the mechanisms are not well understood. Gonadotropin- releasing hormone (GnRH) neurons form the final common pathway for the central regulation of reproduction. GnRH neurons are output neurons of the central nervous system and the effects of estradiol on fertility in the whole animal are well understood. By determining the mechanisms by which estradiol alters neural networks using GnRH neurons as a model, we will provide information vital for human health and designing new strategies for fertility and contraception. The work will also be relevant to estradiol action on more complex neural systems that are not as approachable for study and for which the output is not well defined, such as those governing cognition and memory formation. State-of-the-art electrophysiological approaches will be used to investigate the neurobiological mechanisms underlying estradiol feedback on GnRH neurons. The increase in estradiol that occurs during the female reproductive cycle has a biphasic effect on GnRH release. Initially estradiol inhibits GnRH release via negative feedback. With sustained exposure to elevated estradiol, however, the response to this steroid switches from negative to positive. Positive feedback induces a surge in GnRH release that is the neural prerequisite for ovulation. Using a mouse model that generates daily transitions between negative and positive feedback upon exposure to constant physiological estradiol levels, three specific aims concerning the actions of estradiol will be addressed. Comparisons will be made with data from animals in which the feedback loop was opened by castration. In Aim 1, the effects of estradiol on fast synaptic transmission to GnRH neurons will be studied, including activity of afferent neurons and responsiveness of GnRH neurons. In Aim 2, the effects of estradiol on intrinsic conductances of GnRH neurons will be explored, including whether estradiol-induced changes are due to changes in phosphorylation of ion channels. In Aim 3, the effects of three selected neuromodulators hypothesized to mediate estradiol feedback will be examined. Together these studies will provide insight into the direct and transsynaptic mechanisms utilized by estradiol to bring about negative and positive feedback regulation of GnRH release.