Ovarian Steroid Hormones and Hippocampal Plasticity

描述：(改编自申请者摘要) 海马体功能受到卵巢类固醇水平变化的调节， 雌二醇和黄体酮，在成年女性。这里特别值得关注的是 观察到：1)雌二醇调节长时程增强(LTP)和 CA3-CA1突触的长期抑制(LTD)和2)雌二醇的增加 CA1区锥体神经元的兴奋性我们假设这两个人 观察并不是独立的，神经元兴奋性的增加 这是雌激素依赖性突触可塑性变化的基础。因此， 此新R01应用程序的长期目标是了解如何更改级别 雌二醇对海马CA1区兴奋性的调节 因此，在CA3-CA1发生的长期突触修改 突触。在这里，研究的焦点是雌激素增加的假设 反复出现的CA1-CA1连接。使用电生理学和 成年大鼠海马CA1区小脑片的药理学方法 去卵巢(OVX)大鼠用雌二醇预处理或赋形剂，目标1 描述了这种变化的兴奋性的大小，并检验了假设 关于这种兴奋性增强的近端原因。AIM 2的地址 使用CAL增强兴奋性的生理意义 正常周期大鼠整个发情周期的小切片。我们还将 确定整个国家兴奋性增加的时间进程 动情周期与突触变化的时程相关 CA3-CA1突触的可塑性(LTP和LTD)。AIM 3使用形态学 方法探讨这样一种假设，即这种雌激素依赖的增加在 CA1区锥体神经元的兴奋性与复发性神经元的形成有关 兴奋性CAL-CAL突触。我们将确定局部轴突是否 雌二醇组去卵巢大鼠海马齿状回锥体分支增多。 目的4测试的假设是，这种雌激素依赖的增加 海马区的兴奋性需要基因组雌激素受体的作用。 这些研究将帮助我们更好地理解雌激素是如何调节 女性的海马体功能及其认知功能。此外， 这些很可能为理解生物学上的 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.