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)，会增加5-羟色胺水平 贯穿整个大脑。然而，目前还不清楚哪些特定的回路介导了这些行为的影响 化合物。我们已经证明，缺乏5-HTIA受体(5-HTIA)的小鼠在齿状回具有特异性 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，我们已经证明了齿状回中的神经发生是 抗抑郁药的部分但非全部行为效应所需(David等人，2009年)。这两个 独立的证据表明，齿状回在行为中起着重要作用。 抗抑郁药的效果。 这些发现令人惊讶，因为海马齿状回(DG)已广泛分布于 研究了它在学习和记忆中的作用，特别是在编码新信息和在 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还知之甚少。在目前的提案中，我们 建议通过检验一般假设来调和DG的这两个看似无关的职能 DG的功能在其背腹轴上是不同的，背部参与了 中性模式分离，而腹侧部分参与情绪模式分离，这是一个 通常在情绪和焦虑症方面受损。 这些研究将为旨在调节腹侧DG兴奋性的新策略铺平道路 焦虑和情绪障碍的治疗。 相关性(请参阅说明)： 超过20%的美国成年人在某种程度上被诊断出患有情绪或焦虑症， 巨大的个人、社会和经济代价。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，有相当大的需要新的治疗方法。这项提议将为一项 针对这些疾病的新的治疗策略。

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.