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.

项目总结/摘要 美国人口中约有3200万至3500万成年人（16%）经历过重大脑血管病发作。 抑郁症在他们的一生中，和常用的治疗，如选择性血清素再摄取抑制剂 SSRIs（选择性5-羟色胺再吸收抑制剂）并不理想，因为只有一部分患者（约33%）在初始治疗后达到缓解。的 有些人接受抗抑郁治疗而另一些人不接受的原因尚不清楚。鉴于 抗抑郁药如SSRIs也常用于治疗其他精神疾病，如 广泛性焦虑症和强迫症，这是至关重要的确定 抗抑郁治疗缓解者和非缓解者之间的差异。我们的整体研究计划 通过评估小鼠的抗抑郁治疗抗性来解决这个问题。初步数据显示 以分子和神经回路为基础的修饰齿状回的方法， 将氟西汀（一种SSRI）的行为无应答者转化为应答者。初步数据显示，这些 这些方法也可以作为其他几类抗抑郁药的增强策略。的 具体的目的是：1）测试基于激活素信号传导的齿状回修饰可以改变 氟西汀通过调节年轻成年出生的颗粒细胞的行为反应; 2）测试氟西汀对成年出生的颗粒细胞的影响。 假设基于回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 反应者和无反应者之间的差异; 3）检验DG颗粒细胞的改变是一种 行为对不同抗抑郁治疗无反应的共同特征。