EFFECTS OF ESTRADIOL & ANTIDEPRESSANTS IN HIPPOCAMPAL NEUROGENESIS

雌二醇的作用

• 批准号: 7959497
• 负责人: LOTHAR H JENNES
• 金额: $ 24.3万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7959497
• 关键词: Antidepressive Agents; Brain-Derived Neurotrophic Factor; Centers of Research Excellence; Computer Retrieval of Information on Scientific Projects Database; Depressive disorder; Disease; Economics; Estradiol; Estrogens; Frequencies; Funding; Goals; Grant; Health; Hippocampus (Brain); Incidence; Institution; Medial; Neurons; Parahippocampal Gyrus; Postmenopause; Prefrontal Cortex; Research; Research Personnel; Resources; Selective Serotonin Reuptake Inhibitor; Serotonin; Severities; Site; Source; Synaptic Cleft; Testing; Transcript; United States; United States National Institutes of Health; Untranslated Regions; Woman; Women' s Health; cholinergic neuron; dentate gyrus; depression; depressive symptoms; neurogenesis; promoter; social

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Depressive disorders are a major health issue in the United States and cause severe social and economic problems. Currently, most of these disorders are treated with Selective Serotonin Reuptake Inhibitors (SSRIs) which cause an increase in serotonin levels in the synaptic cleft. How this increased availability of serotonin causes beneficial effects is not clear, however, it appears that it stimulates the synthesis of Brain-Derived Neurotrophic Factor (BDNF) which in turn enhances neurogenesis in the dentate gyrus of the hippocampus. It is thought that the formation of new connectivities of these neurons is, at least in part, responsible for successful treatment of depression. Thus, one goal is to identify the sites of actions as well as the mechanisms by which SSRIs cause an enhancement of BDNF levels in the hippocampus thereby stimulating neurogenesis. Many studies have shown that the frequency of depressive incidences increases in post-menopausal women and estrogen reduces depressive symptoms. Thus, a second goal is to identify the estrogen-sensitive neurons that project to the hippocampus and are regulated by serotonin and to reveal the mechanisms by which estrogen reduces the frequency and severity of depressive episodes. Aim 1: test the hypothesis that SSRIs and estrogen act on medial septal-diagonal band cholinergic neurons, the prefrontal cortex as well as directly on the hippocampus to enhance BDNF synthesis and neurogenesis in an additive or synergistic fashion. Aim 2: test the hypothesis that medial septal-diagonal band cholinergic neurons and cortical GABAergic neurons are necessary for estradiol and SSRIs to stimulate BDNF synthesis and neurogenesis in the hippocampus. Aim 3: test the hypothesis that the transcript-specific BDNF promoters and the untranslated regions regulate the expression, localization and function of BDNF.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 抑郁症是美国的一个主要健康问题，会造成严重的社会和经济问题。目前，大多数此类疾病都采用选择性血清素再摄取抑制剂（SSRI）进行治疗，该抑制剂会导致突触间隙中血清素水平增加。血清素可用性的增加如何产生有益效果尚不清楚，但它似乎会刺激脑源性神经营养因子（BDNF）的合成，从而增强海马齿状回的神经发生。人们认为，这些神经元新连接的形成至少在一定程度上是成功治疗抑郁症的原因。因此，我们的目标之一是确定 SSRI 的作用位点以及机制，从而提高海马 BDNF 水平，从而刺激神经发生。许多研究表明，绝经后女性抑郁发生的频率增加，而雌激素可以减轻抑郁症状。因此，第二个目标是识别投射到海马并受血清素调节的雌激素敏感神经元，并揭示雌激素降低抑郁发作频率和严重程度的机制。 目标 1：检验 SSRI 和雌激素作用于内侧隔对角带胆碱能神经元、前额皮质以及直接作用于海马体的假设，以相加或协同的方式增强 BDNF 合成和神经发生。 目标 2：检验内侧间隔对角带胆碱能神经元和皮质 GABA 能神经元对于雌二醇和 SSRI 刺激海马 BDNF 合成和神经发生所必需的假设。 目标 3：检验转录特异性 BDNF 启动子和非翻译区的假设 调节 BDNF 的表达、定位和功能。