MECHANISMS BY WHICH GONADAL STEROIDS MODULATE NEURONAL ACTIVITY

性腺类固醇调节神经元活动的机制

• 批准号: 3756076
• 负责人: SYLVIA ANN VEREGGE
• 金额: --
• 依托单位: SAN JOSE STATE UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3756076
• 关键词: brain electrical activity; cerebellum; disease /disorder model; epilepsy; estradiol; estrogens; hippocampus; hormone regulation /control mechanism; laboratory rat; membrane potentials; neural transmission; neurons; neuropharmacology; neurophysiology; steroid hormone; voltage /patch clamp

Although it has become increasingly evident in the last decade that steroid hormones can modulate neuronal activity via non-genomic, short-latency effects, little is known about the mechanisms underlying these effects. The goal of this project is to investigate the cellular mechanisms by which gonadal steroids produce direct, short-latency changes in neuronal activity. We will study these mechanisms in the hippocampus and the cerebellum, two regions of the brain in which steroid hormones have been demonstrated to produce rapid alterations (within minutes) in neuronal activity. Our major objectives will be to investigate the mechanisms by which: a) estrone-3-sulfate, an estradiol metabolite, produces epileptiform activity in the hippocampal slice and b) estradiol-17-beta and estrone modulate glutamate-mediated neurotransmission in the cerebellar slice. The first objective expands our current studies of the mechanism of action of estrone-3-sulfate, and the second objective extends our investigations into other regions of the brain which have been shown to be directly influenced by estrogens. We will use intracellular and whole-cell patch clamp techniques and the in vitro brain slice to: 1) determine if physiological or pharmacological doses of estrone-3-sulfate suppress gamma-aminobutyric acid-mediated inhibition of CA1 pyramidal neurons in the hippocampal slice, 2) determine if physiological and pharmacological doses of estrone-3-sulfate suppress glutamate-mediated excitation of CA1 pyramidal cells in the hippocampal slice, 3) investigate the mechanisms by which estrone-3-sulfate alters the resting membrane potential of CA1 pyramidal cells, and 4) investigate the mechanisms by which estradiol-17-beta and estrone potentiate glutamate- mediated excitation of cerebellar Purkinje cells in the cerebellar slice. The results of these studies should provide us with further insight into the means by which gondal steroids modulate both normal and pathological processes in the central nervous system.

尽管在过去的十年中，它变得越来越明显 激素可以通过非基因组，短期来调节神经元活性 影响，对这些效果的基础机制知之甚少。 该项目的目的是研究细胞机制 性腺类固醇会产生直接的，短暂的神经元变化 活动。 我们将研究海马和 小脑，类固醇激素已经是大脑的两个区域 被证明会在神经元中产生快速改变（几分钟之内） 活动。 我们的主要目标是调查 这是：a）雌二醇代谢产物的雌二醇3-硫酸盐，产生 海马切片和b）雌二醇-17-beta和 雌酮调节小脑中的谷氨酸介导的神经传递 片。 第一个目标扩展了我们目前关于该机制的研究 Estrone-3-Sulfate的作用，第二个目标扩展了我们 对大脑其他区域的调查已被证明是 直接受雌激素的影响。 我们将使用细胞内和全细胞贴片夹技术以及IN 体外大脑切片至：1）确定生理或药理 雌激素-3-硫酸盐的剂量抑制γ-氨基丁酸介导的 在海马切片中抑制CA1锥体神经元，2）确定 如果生理和药理剂量的雌酮-3-硫酸盐抑制 海马中CA1锥体细胞的谷氨酸介导的激发 切片，3）研究雌酮-3-硫酸盐改变的机制 CA1锥体细胞的静息膜电位，4）研究 雌二醇17-β和雌酮增强谷氨酸的机制 小脑切片中小脑Purkinje细胞的介导的激发。 这些研究的结果应为我们提供进一步的了解 Gondal类固醇调节正常和病理的方式 中枢神经系统中的过程。