Ovarian Steroid Hormones and Hippocampal Plasticity

描述：（改编自申请人摘要） 海马的功能是通过改变卵巢类固醇的水平来调节的， 雌二醇和孕酮，在成年女性。这里特别感兴趣的是 观察到：1）雌二醇调节长时程增强（LTP）， CA 3-CA 1突触的长期抑制（LTD）和2）雌二醇增加 CA 1锥体神经元的兴奋性。我们假设这两个人 观察结果不是独立的，增加的神经元兴奋性 是突触可塑性中雌二醇依赖性变化的基础。因此 这个新的R 01应用程序的长期目标是了解如何改变水平 雌二醇调节海马CA 1区的兴奋性， 因此，发生在CA 3-CA 1的长期突触修饰 突触这里研究的重点是假设雌二醇增加 CA 1-CA 1循环连通性。使用电生理学和 药理学方法在成人海马CA 1区小切片中， 用雌二醇或溶剂预处理的卵巢切除（OVX）大鼠，目的1 描述了这种变化的兴奋性的大小，并测试假设 关于这种兴奋性增强的近端原因。目标2地址 使用CA 1增强兴奋性的生理意义 正常发情周期大鼠的小切片。我们还将 确定是否在整个兴奋性增加的时间过程中， 动情周期与突触变化的时间进程有关， 可塑性（LTP和LTD）在CA 3-CA 1突触。目标3使用形态学 方法来探讨这一假设，雌二醇依赖性增加， CA 1锥体神经元的兴奋性涉及复发性神经元的形成。 兴奋性CA 1-CA 1突触。我们将确定局部轴突 CA 1锥体的分支随着OVX大鼠的雌二醇治疗而增加。 目的4检验了这种雌二醇依赖性增加的假设， 海马兴奋性需要基因组雌激素受体的作用。 这些研究将有助于我们更好地了解雌激素如何调节 海马功能，从而其认知功能在女性。此外，委员会认为， 这些可能为理解生物学提供重要的见解， 更年期可能出现的记忆问题的基础。

DESCRIPTION:(adapted from applicant's abstract) Hippocampal function is modulated by changing levels of the ovarian steroids, estradiol and progesterone, in adult females. Of particular interest here are the observations that 1) estradiol modulates long-term potentiation (LTP) and long-term depression (LTD) of the CA3-CA1 synapses and 2) estradiol increases the excitability of CAl pyramidal neurons. We hypothesize that these two observations are not independent and that the increased neuronal excitability underlies the estradiol-dependent changes in synaptic plasticity. Thus the long-term goal of this new R01 application is to understand how changing levels of estradiol modulate the excitability of the hippocampal CA1 region and thereby the long-term synaptic modification that occurs at the CA3-CA1 synapses. Here the focus of study is the hypothesis that estradiol increases recurrent CA 1-CA 1 connectivity. Using electrophysiological and pharmacological methods in hippocampal CA1 mini-slices from adult, ovariectomized (OVX) rats pretreated with estradiol or vehicle, Aim 1 characterizes the magnitude of this changed excitability and tests hypotheses concerning the proximal causes of this enhanced excitability. Aim 2 addresses the physiological significance of this enhanced excitability using CAl mini-slices from normally cycling rats across the estrous cycle. We will also determine whether the time course of the increase in excitability across the estrous cycle correlates with the time course of the changes of synaptic plasticity (LTP and LTD) at the CA3-CA 1 synapses. Aim 3 uses morphological methods to explore the hypothesis that this estradiol-dependent increase in the excitability of CAl pyramidal neurons involves the formation of recurrent excitatory CAl-CAl synapses. We will determine if the local axonal arborizations of CAl pyramids increase with estradiol treatment of OVX rats. Aim 4 tests the hypothesis that this estradiol-dependent increase in hippocampal excitability requires the action of genomic estrogen receptors. These studies will help us to understand better how estrogens modulate the hippocampal function and thus its cognitive functions in females. Moreover, these are likely to provide important insights for understanding the biological basis of memory problems that can occur with menopause.