EFFECTS OF ESTRADIOL & ANTIDEPRESSANTS IN HIPPOCAMPAL NEUROGENESIS

雌二醇的作用

• 批准号: 7381196
• 负责人: LOTHAR H JENNES
• 金额: $ 25.05万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7381196
• 关键词: EFFECTS; ESTRADIOL; ANTIDEPRESSANTS; HIPPOCAMPAL; NEUROGENESIS

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.

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，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，并导致严重的社会和经济问题。目前，大多数这些疾病都是用选择性血清素再摄取抑制剂（SSRIs）治疗的，它会导致突触间隙中血清素水平的增加。血清素的增加如何产生有益的影响尚不清楚，然而，它似乎刺激了脑源性神经营养因子（BDNF）的合成，而BDNF反过来又促进了海马齿状回的神经发生。人们认为，这些神经元的新连接的形成，至少在一定程度上，是成功治疗抑郁症的原因。因此，一个目标是确定SSRIs的作用位点和机制，通过这些作用位点和机制，SSRIs会导致海马中BDNF水平的增强，从而刺激神经发生。许多研究表明，绝经后妇女患抑郁症的频率增加，雌激素可减轻抑郁症状。因此，第二个目标是确定投射到海马体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。目的1：验证SSRIs和雌激素作用于内侧间隔-对角带胆碱能神经元、前额皮质以及直接作用于海马的假设，以相加或协同的方式增强BDNF的合成和神经发生。目的2：验证雌二醇和SSRIs刺激海马BDNF合成和神经发生所必需的内侧间隔-对角带胆碱能神经元和皮质gaba能神经元的假设。目的3：验证转录特异性BDNF启动子和非翻译区调控BDNF的表达、定位和功能的假设。