NEUROGENIC TARGETS OF ANTIDEPRESSANT THERAPIES

描述（由申请人提供）：最近的证据表明抗抑郁药的作用与成人海马神经发生增加之间存在联系；此外，这表明抗抑郁药的作用可能需要神经发生。然而，目前尚不清楚神经分化级联中的哪一类细胞是抗抑郁药物和治疗的目标。我们已经开发了一种新的方法来识别和分类神经元前体，并获得由神经源性药物引起的变化的精确定量。我们使用这种方法来证明抗抑郁药氟西汀影响成人海马体中早期祖细胞类的对称分裂。在这个探索性应用中，我们将使用这种方法来确定一系列抗抑郁药物和治疗的细胞和基因靶标。在第一个系列的实验中，我们将确定四个主要家族的抗抑郁药物（SSRIs、SNRIs、NRIs和TCAs）、电惊厥休克和深部脑刺激的神经源性细胞靶点。在第二个系列实验中，我们将使用激光捕获显微镜和微阵列转录谱来确定成人海马神经干和祖细胞中各种抗抑郁疗法的共同基因靶点。相关性：新出现的证据暗示成人神经发生在抑郁症的病理生理和抗抑郁药的作用。我们在此建议使用一种新的方法来识别一系列抗抑郁药物和治疗的细胞和基因靶点。我们的研究将对抗抑郁药的作用机制提出新的假设，并有助于设计更具体、更有效的抗抑郁治疗方法。新出现的证据暗示成人神经发生在抑郁症的病理生理和抗抑郁药的作用。我们在此建议使用一种新的方法来识别一系列抗抑郁药物和治疗的细胞和基因靶点。我们的研究将对抗抑郁药的作用机制提出新的假设，并有助于设计更具体、更有效的抗抑郁治疗方法。

DESCRIPTION (provided by applicant): Recent evidence demonstrates a link between the action of antidepressants and increased neurogenesis in the adult hippocampus; moreover, it suggests that neurogenesis may be required for the action of antidepressants. However, it is not known which class of cells within the neuronal differentiation cascade is targeted by the antidepressant drugs and treatments. We have developed a novel approach to identify and classify neuronal precursors and to obtain precise quantitation of changes induced by neurogenic agents. We used this approach to demonstrate that antidepressant fluoxetine affects symmetric division of an early progenitor cell class in the adult hippocampus. In this exploratory application we will use this approach to determine the cellular and gene targets of a range of antidepressant drugs and treatments. In the first series of experiments, we will determine the neurogenic cellular targets of antidepressants of four major families of the drugs (SSRIs, SNRIs, NRIs, and TCAs), of electroconvulsive shock, and of deep brain stimulation. In the second series of experiments we will use laser capture microscopy and transcriptional profiling with microarrays to determine the common gene targets of various antidepressant therapies in neural stem and progenitor cells in the adult hippocampus. Relevance: Emerging evidence implicates adult neurogenesis in the pathophysiology of depression and the action of antidepressants. We here propose to use a novel approach to identify cellular and gene targets for a range of antidepressant drugs and treatments. Our studies will lead to new hypotheses on the mechanisms of action of antidepressants and will help design more specific and effective antidepressant therapies. Emerging evidence implicates adult neurogenesis in the pathophysiology of depression and the action of antidepressants. We here propose to use a novel approach to identify cellular and gene targets for a range of antidepressant drugs and treatments. Our studies will lead to new hypotheses on the mechanisms of action of antidepressants and will help design more specific and effective antidepressant therapies.