Molecular and Neural Circuitry Mechanisms Underlying Antidepressant Treatment Resistance

项目摘要/摘要 在美国人口中，大约有3200-3500万成年人(16%)经历了一次重大的 终生抑郁，以及常用的治疗方法，如选择性5-羟色胺再摄取抑制剂 (SSRI)是不理想的，因为只有一小部分患者(~33%)在最初的治疗中获得缓解。这个 为什么有些人可以接受抗抑郁药物治疗，而另一些人则不能，原因不明。考虑到 抗抑郁药，如SSRIs，也通常用于治疗其他精神疾病，如 对于广泛性焦虑症和强迫症来说，确定 汇款患者与非汇款患者抗抑郁药物治疗的差异。我们的整体研究计划 通过评估小鼠的抗抑郁剂治疗耐药性来解决这个问题。初步数据显示 基于分子和神经回路的修饰齿状回的方法可能都能将 行为无应答者对氟西汀(一种SSRI)转为应答者。进一步的初步数据表明，这些 这些方法也可以作为其他几类抗抑郁药的强化策略。这个 具体目标是：1)测试基于激活素信号的齿状回修饰可以改变 氟西汀对幼年出生的颗粒细胞的调节作用；2)检测 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和确定DG输入是否存在功能差异 应答者和无应答者之间的差异；以及3)检验DG颗粒细胞的改变是一种 对不同抗抑郁药物治疗的行为无反应的共同特征。

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.