EFFECTS OF ESTRADIOL & ANTIDEPRESSANTS IN HIPPOCAMPAL NEUROGENESIS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 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5-羟色胺再摄取抑制剂（SSRI）治疗的，这会导致突触间隙中5-羟色胺水平的增加。血清素的这种增加的可用性如何导致有益的效果尚不清楚，然而，似乎它刺激脑源性神经营养因子（BDNF）的合成，这反过来又增强了海马齿状回的神经发生。据认为，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引起海马中BDNF水平增强从而刺激神经发生的作用部位以及机制。许多研究表明，绝经后妇女抑郁发生率增加，雌激素可减少抑郁症状。因此，第二个目标是确定投射到海马体并受5-羟色胺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：验证SSRIs和雌激素作用于内侧隔-斜角带胆碱能神经元、前额叶皮质以及直接作用于海马以相加或协同方式增强BDNF合成和神经发生的假设。 目标二：验证内侧隔-斜角带胆碱能神经元和皮质GABA能神经元是雌二醇和SSRI刺激海马中BDNF合成和神经发生所必需的假设。 目的3：验证转录特异性BDNF启动子和非翻译区 调节BDNF的表达、定位和功能。

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.