Ovarian Steroid Hormones and Hippocampal Plasticity

卵巢类固醇激素和海马可塑性

• 批准号: 6722884
• 负责人: WILLIAM B LEVY
• 金额: $ 22.2万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-15 至 2006-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6722884
• 关键词: NMDA receptors; estradiol; estrogen inhibitor; estrogen receptors; estrus; gap junctions; hippocampus; hormone regulation /control mechanism; laboratory rat; long term potentiation; neural plasticity; neuropharmacology; ovariectomy; radioimmunoassay

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.

描述：（改编自申请人的摘要） 海马功能通过改变卵巢类固醇的水平来调节， 成年女性中的雌二醇和黄体酮。这里特别感兴趣的是 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) 雌二醇增加 CA1 锥体神经元的兴奋性。我们假设这两个 观察结果不是独立的，神经元兴奋性增加 是雌二醇依赖性突触可塑性变化的基础。因此 这个新 R01 应用程序的长期目标是了解水平如何变化 雌二醇调节海马CA1区的兴奋性 从而在 CA3-CA1 处发生长期突触修饰 突触。这里研究的重点是雌二醇增加的假设 循环 CA 1-CA 1 连接。利用电生理学和 成人海马 CA1 迷你切片的药理学方法， 用雌二醇或媒介物预处理的卵巢切除 (OVX) 大鼠，目标 1 表征这种兴奋性变化的程度并测试假设 关于这种兴奋性增强的近端原因。目标2地址 使用 CAl 增强兴奋性的生理意义 正常大鼠发情周期的迷你切片。我们还将 确定兴奋性增加的时间过程是否 动情周期与突触变化的时间进程相关 CA3-CA 1 突触的可塑性（LTP 和 LTD）。目标 3 使用形态学 方法探讨了这种雌二醇依赖性增加的假设 CA1锥体神经元的兴奋性涉及复发性神经元的形成 兴奋性CAl-CAl突触。我们将确定局部轴突是否 CA1 金字塔的树枝化随着雌二醇治疗 OVX 大鼠的增加而增加。 目标 4 检验以下假设：雌二醇依赖性增加 海马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了解雌激素如何调节 女性的海马功能及其认知功能。而且， 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。