Central actions of estrogens: effects on GnRH neurons

描述（由申请人提供）：兴奋影响许多中枢神经功能，但其机制尚不清楚。促性腺激素释放激素（GnRH）神经元形成生殖中枢调节的最终共同通路. 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力的影响已得到充分理解。通过使用GnRH神经元作为模型来确定雌二醇改变神经网络的机制，我们将为人类健康提供重要信息，并设计生育和避孕的新策略。这项工作也将与雌二醇对更复杂的神经系统的作用有关，这些神经系统对于研究来说并不容易接近，并且其输出也没有很好的定义，例如那些控制认知和记忆形成的神经系统。国家的最先进的电生理方法将被用来调查的神经生物学机制雌二醇反馈的GnRH神经元。雌性生殖周期中雌二醇的增加对GnRH的释放有双相作用。雌二醇最初通过负反馈抑制GnRH释放。然而，随着持续暴露于升高的雌二醇，对这种类固醇的反应从阴性转为阳性。正反馈诱导GnRH释放激增，这是排卵的神经先决条件。使用一个小鼠模型，产生每天的负反馈和正反馈之间的转换后，暴露于恒定的生理雌二醇水平，三个具体的目标有关的雌二醇的行动将得到解决。将与通过阉割打开反馈回路的动物的数据进行比较。目的1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动和GnRH神经元的反应性。在目标2中，将探讨雌二醇对GnRH神经元固有电导的影响，包括雌二醇诱导的变化是否是由于离子通道磷酸化的变化。在目标3中，将检查假设介导雌二醇反馈的三种选定的神经调节剂的作用。总之，这些研究将提供深入了解的直接和跨突触的机制，利用雌二醇带来的负反馈和正反馈调节GnRH的释放。

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.