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） 海马功能是通过卵巢类固醇水平变化来调节的 成年女性的雌二醇和孕酮。这里特别感兴趣的是 1）雌二醇调节长期增强（LTP）和 CA3-CA1突触的长期抑郁（LTD）和2）雌二醇增加 Cal锥体神经元的兴奋性。我们假设这两个 观察并非独立，而神经元兴奋性提高 是突触可塑性的雌二醇依赖性变化的基础。因此 该新的R01应用程序的长期目标是了解如何变化的水平 雌二醇调节海马CA1区和 因此在CA3-CA1上发生的长期突触修饰 突触。在这里，研究的重点是雌二醇增加的假设 复发Ca 1-CA 1连接。使用电生理和 来自成人的海马CA1迷你切片的药理方法， 用雌二醇或车辆预处理的卵巢切除（OVX）大鼠AIM 1 表征了这种改变兴奋性的大小，并测试了假设 关于这种增强兴奋性的近端原因。 AIM 2地址 使用CAL的这种增强兴奋性的生理意义 从通常骑自行车大鼠穿越整个发情循环的小型切片。我们也会 确定兴奋性增加的时间过程是否 发情循环与突触变化的时间过程相关 CA3-CA 1突触的可塑性（LTP和LTD）。 AIM 3使用形态学 探索雌二醇依赖性增加的假设的方法 Cal锥体神经元的兴奋性涉及复发的形成 兴奋性Cal-Cal突触。我们将确定本地轴突是否 CAL金字塔的树木随着OVX大鼠的雌二醇治疗而增加。 AIM 4检验了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。 这些研究将帮助我们更好地了解雌激素如何调节 海马功能及其在女性中的认知功能。而且， 这些可能会为了解生物学提供重要的见解 绝经可能发生的记忆问题的基础。