HORMONAL MODULATION OF CA2+ SOURCES IN HIPPOCAMPAL AGING AND VULNERABILITY

该项目源于研究表明糖皮质激素(GC) 荷尔蒙似乎加速了大脑衰老的各个方面，神经元 能见度和可能的阿尔茨海默病(AD)。此外，以前的 该项目中的电生理学研究发现，GC增加 钙介导的电位和电流(GC也已知为 影响长时程增强和突触电位)。在最近的几年里 发现另一种类固醇，骨化三醇，似乎也会影响 电生理学，具有神经保护作用。雌激素也是已知的 具有神经保护作用。因此，这个项目将集中于确定 电生理和钙介导的机制是基础 糖皮质激素、骨化三醇和雌激素对脑老化、神经元的影响 脆弱，可能还有阿尔茨海默氏症。这个项目将 利用两种模型系统，大鼠海马片研究衰老 和大鼠海马神经元培养的影响，以研究神经元 脆弱性。在三个具体目标中，项目将确定 电生理学和药理学定义的电流和 钙的来源受到类固醇的影响，我们将确定 类固醇的作用随着年龄的增长而变化，并将检验这一假说 这些类固醇效应对海马神经元有重要作用 易受谷氨酸诱导的细胞死亡。在另外两个目标中， 该项目将尝试识别分子和细胞内 调节类固醇的通路，包括那些由激动酶激活的通路 对电生理特性和钙调节的影响。 总而言之，这些研究的目的是既识别潜在的 机制，并清楚地测试功能与衰老和 神经退行性变，类固醇对大脑特性的作用 神经元。因此，这些研究应该在很大程度上澄清我们的 对脑老化和脑损伤的机制的理解 内分泌环境增加患阿尔茨海默病的风险 其他神经退行性疾病。

This project developed out of studies showing that glucocorticoid (GC) hormones appeared to accelerate aspects of brain aging, neuron visibility and possibly Alzheimer's disease (AD). In addition, previous electrophysiological studies in this project found that GCs increase calcium-mediated potentials and currents (GCs are also known to influence long-term potentiation and synaptic potentials). In recent we have found that another steroid, calcitriol, also appears to influence electrophysiology and is neuroprotective. Estrogens are also known to be neuroprotective. Thus, this project will focus on identifying the electrophysiological and calcium-mediated mechanisms that underlie the effects of GCs, calcitriol and estrogens on brain aging, neuronal vulnerability and possibly Alzheimer's disease. This project will utilize two model systems, the rat hippocampal slice to study aging effects, and rat hippocampal cultured neurons, to study neuronal vulnerability. In three of the specific aims, the project will determine which electrophysiologically and pharmacologically defined currents and calcium sources are affected by the steroids, we will determine whether the effects of steroids change with aging, and will test the hypothesis that these steroid effects contribute importantly to hippocampal neuron vulnerability to glutamate-induced cell death. In two other aims, the project will attempt to identify the molecular and intracellular pathways, including those activated by kinases, that mediate steroid effects on electrophysiological properties and calcium regulation. Together, these studies are aimed at both identifying the underlying mechanisms and at clearly testing the functional relevance for aging and neurodegeneration, of steroid actions on the properties of brain neurons. These studies, therefore, should substantially clarify our understanding of the mechanisms through which brain aging and the endocrine environment increase the risk for Alzheimer's disease and other neurodegenerative disorders.