ESTROGEN-REGULATED PLASTICITY OF HIPPOCAMPAL NEURONS

为了充分了解大脑功能在衰老过程中的变化，有必要了解随着年龄增长而下降的激素如何正常调节和维持成年大脑的结构和功能可塑性和弹性。E2（E）是关于认知能力下降和阿尔茨海默病的最佳研究激素。然而，即使如此，我们在很大程度上仍然不知道衰老的大脑如何在细胞、分子和解剖学水平上对E做出反应，以及E调节的可塑性和神经保护作用如何随着年龄的增长而变化。此外，我们需要知道E是否具有神经保护作用，这些作用与它们调节结构和功能可塑性的能力有关，并抑制大脑中产生潜在的破坏性分子，如随着年龄的增长而增加的细胞因子。本项目的主要目的是在细胞和分子水平上对E引起突触的信号通路进行体外研究 在海马和皮质神经元中形成，并且还保护细胞免受损伤和死亡。主要假设是树突棘的E-诱导是一种不仅增强神经功能和记忆过程，而且还赋予神经元免受兴奋性毒性损伤的保护的机制，部分原因是两者涉及相同信号通路的操作。合作研究将确定这些机制的相关性的假设年龄相关的下降，在E-诱导的突触形成在老龄大鼠和灵长类动物的大脑正在研究的其他组成部分，这个程序项目的研究。E调节 信号通路增加了雌激素或修饰雌激素干预的选择。 由于激素治疗（HT）是在密切的临床审查，这是至关重要的，以获得更详细的，雌激素如何影响大脑的机制的理解，以提供更明智的方法HT和促进成功的大脑老化的理解。从这个项目和PPG作为一个整体的结果应该有助于识别特定的类似物和其他药理学分子的治疗价值的老化过程。

In order to fully understand changes in brain function during aging, it is necessary to understand how hormones that decline with age normally regulate and maintain structural and functional plasticity and resilience of the adult brain. Estradiol (E) is the best studied hormone with respect to cognitive decline and Alzheimer's disease. Yet, even then, we are largely ignorant about how the aging brain responds to E at the cellular, molecular and anatomical levels and how E regulated plasticity and neuroprotective actions may change with age. Moreover, we need to know whether E has neuroprotective actions that are related to their ability to regulate structural and functional plasticity and to contain the production in brain of potentially damaging molecules such as cytokines that rises with age. The main objective of this project is to carry out in vitro studies of the signaling pathways at the cellular and molecular level by which E causes synapse formation in hippocampal and cortical neurons and also protects cells against damage and death. The main hypothesis is that E-induction of dendritic spines is a mechanism that not only enhances neural function and memory processes but also confers protection of neurons from excitotoxic damage, in part because both involve operation of the same signaling pathways. Collaborative studies will determine the relevance of these mechanisms to the studies of the hypothesized age-related decline in E-induced synapse formation in the aging rat and primate brain which are being studied in other components of this program project. The E-regulated signaling pathways increase the options for intervention by estrogens or modified estrogens. Because hormone therapy (HT) is under close clinical scrutiny, it is critical to obtain a more detailed, mechanistic understanding of how estrogens affect the brain in order to provide for more informed approaches to HT and to promote an understanding of successful brain aging. Results from this project and from the PPG as a whole should facilitate identification of specific analogs and other pharmacologic molecules of therapeutic value to the aging process.