Cellular Mechanisms of Antidepressant Action

大多数抗抑郁药，如选择性5-羟色胺再摄取抑制剂（SSRIs）， 在整个大脑中。然而，目前还不清楚哪些特定的回路介导这些行为效应。 化合物.我们已经证明，缺乏5-羟色胺1A受体（5-HTIA）的小鼠，特别是在齿状回， 在几种焦虑和抑郁的动物模型中，脑回对SSRI没有反应（Samuels等人，2012, 附纸）。在另一组实验中，我们已经证明齿状回的神经发生是 抗抑郁药的某些但非全部行为效应所需的（大卫等人，2009年）。这两 一些独立的证据表明，齿状回在行为上起着重要的作用， 抗抑郁药的作用。 这些发现是令人惊讶的，因为海马的齿状回（DG）已经被广泛地 研究了它在学习和记忆中的作用，特别是在编码新信息和 消除相似信息的歧义，这一过程称为模式分离。然而，这一部分的作用 海马体在焦虑和抑郁相关行为中的作用知之甚少。在目前的提案中，我们 我建议通过检验一般假设来调和DG的这两个看似无关的功能 DG的功能沿着其背腹轴是不同的，背侧部分参与了 中性模式分离，而腹侧部分涉及情感模式分离，这是一个过程， 经常会因情绪和焦虑症而受损 这些研究将为调节腹侧DG兴奋性的新策略铺平道路， 治疗焦虑和情绪障碍 相关性（参见说明）： 超过20%的美国成年人在某个时候被诊断出患有情绪障碍或焦虑症， 巨大的个人、社会和经济成本。这些疾病最常见的治疗方法是 选择性5-羟色胺再摄取抑制剂（SSRIs）。然而，只有25-50%的患者获得缓解。 因此，非常需要新的治疗方法。这一提议将为一个全面的 这些疾病的新治疗策略。

Most antidepressants such as the selective serotonin reuptake inhibitors (SSRIs) increase serotonin levels throughout the brain. However it is still unclear which specific circuits mediate the behavioral effects of these compounds. We have shown that mice lacking the serotonin 1A receptor (5-HTIA) specifically in the dentate gyrus do not respond to SSRIs in several animal models of anxiety and depression (Samuels et al., 2012, appended paper). In a separate set of experiments we have shown that neurogenesis in the dentate gyrus is required for some but not all behavioral effects of antidepressants (David et al., 2009). These two independent lines of evidence point to the dentate gyrus as playing an important role in the behavioral effects of antidepressants. These findings are surprising because the dentate gyrus (DG) ofthe hippocampus has been extensively studied for its role in learning and memory and specifically in encoding new information and in disambiguating similar informations, a process termed pattern separation. However the role of this part ofthe hippocampus in anxiety and depression-related behaviors is poorly understood. In the current proposal we propose to reconcile these two seemingly unrelated functions ofthe DG by testing the general hypothesis that the functions ofthe DG are distinct along its dorso-ventral axis with the dorsal part being involved in neutral pattern separation while the ventral part is involved in emotional pattern separation, a process that is often impaired in mood and anxiety disorders. These studies will paveithe way for novel strategies aimed at modulating the excitability of the ventral DG for the treatment of anxiety and mood disorders. RELEVANCE (See instructions): Over 20% of adult Americans are, at some point, diagnosed with either mood or anxiety disorders, with enormous personal, societal and financial costs. The most common treatments for these disorders are the selective serotonin reuptake inhibitors (SSRIs). However, only 25-50% of patients achieve remission. Therefore, there is a considerable need for new therapies. This proposal will lay the groundwork for a totally novel treatment strateav for these disorders.