Molecular and Neural Circuitry Mechanisms Underlying Antidepressant Treatment Resistance

抗抑郁药治疗耐药性的分子和神经回路机制

• 批准号: 9288517
• 负责人: BENJAMIN A SAMUELS
• 金额: $ 38.75万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-16 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9288517
• 关键词: Activin Receptor; Activins; Address; Adult; Affect; Alpha Cell; Antidepressive Agents; Anxiety; Behavior; Behavioral; Chronic; Complex; Data; Disease remission; Effexor; Fluoxetine; Funding; Future; Gene Expression; Generalized Anxiety Disorder; Goals; Growth Factor; Individual; Infusion procedures; Lead; Learning; Major Depressive Disorder; Maps; Mediating; Mediator of activation protein; Memory; Mental disorders; Modernization; Modification; Molecular; Mus; Obsessive-Compulsive Disorder; Parahippocampal Gyrus; Pharmaceutical Preparations; Population; Reporting; Research; Selective Serotonin Reuptake Inhibitor; Serotonin Receptor 5-HT1A; Signal Transduction; Stress; Techniques; Testing; Transforming Growth Factor beta; Work; activin A; adult neurogenesis; base; behavior test; behavioral response; dentate gyrus; depressive symptoms; design; designer receptors exclusively activated by designer drugs; emotional behavior; experience; granule cell; hypothalamic-pituitary-adrenal axis; improved; neural circuit; neuropsychiatry; patient subsets; programs; responders and non-responders; response; therapy resistant; venlafaxine; young adult

PROJECT SUMMARY/ABSTRACT Approximately 32-35 million adults in the US population (16%) experience an episode of major depression in their lifetime, and commonly used treatments, such as selective serotonin reuptake inhibitors (SSRIs), are not ideal since only a subset of patients (~33%) achieves remission with initial treatment. The reasons why some individuals remit to antidepressant treatments while others do not are unknown. Given that antidepressants such as SSRIs are also commonly used to treat other psychiatric disorders, such as generalized anxiety disorder and obsessive-compulsive disorder, it is of critical importance to determine the differences between remitters and non-remitters to antidepressant treatment. Our overall research program addresses this question by assessing antidepressant treatment resistance in mice. Preliminary data indicate that both molecular and neural-circuit based approaches to modifying the dentate gyrus may be able to convert behavioral non-responders to fluoxetine (a SSRI) into responders. Further preliminary data indicate that these approaches may also work as augmentation strategies for several other classes of antidepressants. The Specific Aims are: 1) Test the hypothesis that Activin signaling based modifications of dentate gyrus can alter the behavioral response to fluoxetine through modulation of young adult-born granule cells; 2) To test the hypothesis that circuit-based approaches to silencing mature dentate gyrus granule cells can alter the behavioral response to fluoxetine and to determine whether there are functional differences in DG inputs between responders and non-responders; and 3) Test the hypothesis that alterations in DG granule cells are a common feature of behavioral non-response to different antidepressant treatments.

项目概要/摘要 美国人口中大约有 32-3500 万成年人 (16%) 经历过重大疾病发作 一生中的抑郁症以及常用的治疗方法，例如选择性血清素再摄取抑制剂 （SSRIs）并不理想，因为只有一部分患者（约 33%）通过初始治疗获得缓解。这 有些人接受抗抑郁治疗而另一些人却没有接受治疗的原因尚不清楚。鉴于 SSRIs 等抗抑郁药也常用于治疗其他精神疾病，例如 广泛性焦虑症和强迫症，确定其症状至关重要 汇款人和非汇款人在抗抑郁治疗方面的差异。我们的总体研究计划 通过评估小鼠抗抑郁治疗的抵抗力来解决这个问题。初步数据表明 基于分子和神经回路的方法来修改齿状回可能能够将 将氟西汀（一种 SSRI）行为无反应者转变为反应者。进一步的初步数据表明，这些 这些方法也可以作为其他几种抗抑郁药的增强策略。这 具体目标是： 1) 检验基于激活素信号传导的齿状回修饰可以改变的假设 通过调节年轻成年颗粒细胞对氟西汀的行为反应； 2) 测试 假设基于电路的方法沉默成熟的齿状回颗粒细胞可以改变 对氟西汀的行为反应并确定 DG 输入是否存在功能差异 响应者和非响应者之间； 3) 检验 DG 颗粒细胞的改变是一个假设 对不同抗抑郁治疗行为无反应的共同特征。