Central actions of estrogens: effects on GnRH neurons

说明(申请人提供)：雌二醇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途径。促性腺激素释放激素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是众所周知的。通过以促性腺激素释放激素神经元为模型确定雌激素改变神经网络的机制，我们将提供对人类健康至关重要的信息，并设计新的生育和避孕策略。这项工作也将与雌二醇在更复杂的神经系统上的作用有关，这些神经系统不太适合研究，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被用来研究雌激素反馈对GnRH神经元的神经生物学机制。在女性生殖周期中，雌二醇的增加对GnRH的释放有两方面的影响。最初，雌二醇通过负反馈抑制GnRH的释放。然而，随着持续暴露在升高的雌二醇中，对这种类固醇的反应从阴性转变为阳性。正反馈导致促性腺激素释放激素释放激增，这是排卵的神经先决条件。使用一个小鼠模型，在暴露于恒定的生理雌二醇水平时，每天产生负反馈和正反馈之间的转换，将解决与雌二醇的作用有关的三个具体目标。将与通过阉割打开反馈回路的动物的数据进行比较。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，将探讨雌二醇对促性腺激素释放激素神经元内源性电导的影响，包括雌二醇引起的变化是否源于离子通道磷酸化的变化。在目标3中，将检验三种选定的神经调节剂的作用，这些神经调节剂被假设为介导雌二醇反馈。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.