Cellular Mechanisms of Antidepressant Action.

抗抑郁作用的细胞机制。

• 批准号: 10320435
• 负责人: Rene Hen
• 金额: $ 40.5万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-07 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10320435
• 关键词: Affect; Amygdaloid structure; Animal Model; Animals; Anti-Anxiety Agents; Antidepressive Agents; Anxiety; Anxiety Disorders; Behavior; Behavioral; Brain region; Calcium; Cells; Chronic; Cognitive; Disease; Environment; Exposure to; Generations; Goals; Growth; Hippocampus (Brain); Hypothalamic structure; Image; Interneurons; Knowledge; Lead; Limbic System; Mental Depression; Modeling; Mus; Neurons; Output; Patients; Pattern; Persons; Population; Predisposition; Production; Pyramidal Cells; Selective Serotonin Reuptake Inhibitor; Serotonin; Serotonin Receptor 5-HT1A; Sexual Dysfunction; Stress; Structure; Testing; Treatment Efficacy; Work; antidepressant effect; brain cell; cognitive function; common treatment; conditioned fear; dentate gyrus; experience; flexibility; granule cell; neurogenesis; novel; novel therapeutic intervention; response; serotonin transporter; side effect; social defeat; tool

Depression and anxiety disorders are debilitating illnesses that affect more than 350 million people wordwide. The most common treatments for these disorders are SSRIs (selective serotonin reuptake inhibitors) which block the serotonin transporter and thereby increase serotonin levels in many brain regions. However, about 50% of patients who take SSRIs do not fully respond and among those who respond a significant fraction experiences various side effects such as sexual dysfunction. In addition, SSRIs have a delayed onset of therapeutic efficacy of several weeks. There is therefore a considerable need for better and faster acting antidepressants. One way to develop novel antidepressants is to understand how SSRIs work and why they take so long to be effective and then to target directly the underlying mechanisms. One of the dominant hypothesis in this field is that downstream of the increase in serotonin elicited by SSRIs there are a number of growth related changes such as an increase in hippocampal neurogenesis and a rewiring of limbic circuits that are responsible for the delayed onset of efficacy of SSRIs. We have discovered several lines of evidence pointing to the ventral hippocampus and specifically the ventral dentate gyrus (DG) as being critical for many of the antidepressant and anxiolytic-like effects of chronic SSRIs in animal models. In the current application, we propose to build on these results to understand how a chronic exposure to SSRIs modifies the activity of the ventral DG and consequently of the ventral hippocampus and the limbic structures it influences, to generate an antidepressant response. To achieve this goal, we propose to assess the activity of the ventral hippocampus in response to chronic SSRIs with calcium imaging and miniscopes in freely moving mice. Our overarching hypothesis is that the concerted action of SSRIs on young and mature granule cells of the ventral DG results in a decrease in the activity of the DG and consequently a decrease in the activity of “anxiety cells” located in the ventral portion of CA1 and projecting to the limbic system, ultimately resulting in antidepressant and anxiolytic-like effects. These studies will therefore enable us to identify changes in the function of the ventral hippocampus that are produced by a chronic treatment with SSRIs and that are critical for the antidepressant response in animal models. Such knowledge will in turn inform novel therapeutic approaches aimed at targeting directly specific cells in the ventral hippocampus in order to develop faster and more efficacious antidepressants. !

抑郁症和焦虑症是使人衰弱的疾病，影响着全球超过 3.5 亿人。 这些疾病最常见的治疗方法是 SSRI（选择性血清素再摄取抑制剂）， 阻断血清素转运蛋白，从而增加许多大脑区域的血清素水平。 50% 服用 SSRI 的患者没有完全缓解，其中有相当一部分患者出现缓解 此外，SSRIs 还具有起效延迟的作用。 因此，非常需要更好和更快的作用。 开发新型抗抑郁药的一种方法是了解 SSRI 的作用及其原因。 需要很长时间才能发挥作用，然后直接针对主要机制之一。 该领域的假设是，在 SSRI 引起的血清素增加的下游，存在许多 与生长相关的变化，例如海马神经发生的增加和边缘回路的重新布线， SSRIs 起效延迟的原因。 我们发现了多条证据指向腹侧海马体，特别是腹侧海马体。 齿状回 (DG) 对于慢性 SSRI 的许多抗抑郁和抗焦虑样作用至关重要 在当前的应用中，我们建议以这些结果为基础来了解慢性病是如何发生的。 暴露于 SSRIs 会改变腹侧 DG 的活性，从而改变腹侧海马的活性， 它影响边缘系统，产生抗抑郁反应。为了实现这一目标，我们建议： 通过钙成像评估腹侧海马对慢性 SSRIs 的反应 我们的总体假设是 SSRIs 对幼鼠的协同作用。 腹侧 DG 的成熟颗粒细胞导致 DG 活性降低，从而导致 位于 CA1 腹侧部分并投射到边缘系统的“焦虑细胞”活性降低 系统，最终产生抗抑郁和抗焦虑样作用。 因此，这些研究将使我们能够识别腹侧海马功能的变化，这些变化是 由 SSRIs 长期治疗产生，对于动物的抗抑郁反应至关重要 这些知识反过来将为旨在直接针对特定目标的新治疗方法提供信息。 腹侧海马体的细胞，以便开发出更快、更有效的抗抑郁药物。 ！