ESTROGEN REGULATED PLASTICITY OF HIPPOCAMPAL NEURONS

雌激素调节海马神经元的可塑性

• 批准号: 6299414
• 负责人: Bruce S. McEwen
• 金额: $ 32.12万
• 依托单位: MOUNT SINAI SCHOOL OF MEDICINE OF CUNY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2001-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6299414
• 关键词: NMDA receptors; aging; biological signal transduction; cAMP response element binding protein; dehydroepiandrosterone; estradiol; excitatory aminoacid; female; gene expression; glia; hippocampus; hormone regulation /control mechanism; immunocytochemistry; in situ hybridization; laboratory rat; neural plasticity; neurons; neuroprotectants; neuroregulation; neurotoxicology; polymerase chain reaction; protein kinase; protein structure function; reproductive development; synaptogenesis; tissue /cell culture

In order to fully understand changes in brain function during aging, it is necessary to understand how hormones that decline with age, such as estradiol (E) and dehydroepiandrosterone (DHEA) maintain the normal plasticity and resilience of the adult brain. Estradiol 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 and at anatomical levels, or whether E (and DHEA) have neuroprotective actions that are related to their ability to regulate plasticity. This project utilizes cell culture of embryonic hippocampal neurons that are allowed to mature for at least 10d in vitro to differentiate and establish connections among neurons with an environment of glial cells. It uses not only cell culture, with immunocytochemistry and in situ hybridization, but also employs the technique of differential display to identify novel and known genes that are activated during the induction of resilience and synapse formation. The project has a three-fold objective: First, to study the processes at the cellular and molecular level by which estradiol (E) causes synapse formation in hippocampal neurons; this will be relevant to the studies of the hypothesized age-related decline in E- induced hippocampal synapse formation in the aging rat and primate brain which are being studied in other components of this program project; Second, to study how the conditions of E treatment that results in synapse formation alter the response of the hippocampus to excitotoxic damage, and , in this connection, Third, to investigate the possible synergistic neuroprotective effects of another steroid that declines with age, dehydroepiandrosterone (DHEA). DHEA has been reported to block NMDA-induced excitotoxicity and to do so, at least in part, by acting on glial cells, which are also responsive to estrogens. Glial cells also participate in E-induced synapse formation and the information gained in these studies will illuminate this aspect as well.

为了充分了解衰老过程中大脑功能的变化，有必要了解随着年龄的增长的激素，例如雌二醇（E）和脱氢表雄酮（DHEA）如何保持成人大脑的正常可塑性和弹性。雌二醇是关于认知能力下降和阿尔茨海默氏病的最佳研究激素。然而，即便如此，我们在很大程度上对衰老的大脑在细胞和解剖学水平上的响应方式不了解，或者E（和DHEA）是否具有与调节可塑性的能力相关的神经保护作用。该项目利用了胚胎海马神经元的细胞培养物，这些细胞在体外至少10天被允许成熟，以区分与神经胶质细胞环境之间的神经元之间的连接。它不仅使用细胞培养，具有免疫细胞化学和原位杂交，而且还采用差异显示技术来识别在诱导弹性和突触形成期间被激活的新颖基因和已知基因。该项目具有三个倍的目标：首先，在细胞和分子水平上研究雌二醇（E）在海马神经元中导致突触形成的过程；这将与对衰老大鼠和灵长类动物大脑中的诱导的海马突触形成的假设年龄相关的研究有关，该研究在该计划项目的其他组件中正在研究；其次，为了研究导致突触形成的E治疗状况如何改变海马对兴奋毒性损伤的反应，在这方面，第三，为了研究另一种随着年龄增长的类固醇的可能协同神经保护作用，脱氧核糖核酸（DHEA）。据报道，DHEA可以阻止NMDA诱导的兴奋性毒性，并至少部分地通过作用于神经胶质细胞，这些细胞也对雌激素有反应。神经胶质细胞还参与电子诱导的突触形成，这些研究中获得的信息也将阐明这一方面。