Role of sFRP3-Dependent Regulation of Adult Neurogenesis in Antidepressant Action

项目负责人/主要研究者（最后，第一，中间）：Jang，Mi-Hyeon 项目总结/摘要 抑郁症是最常见的精神疾病之一，影响着全球超过1.21亿人。是 现在普遍认为，新的神经元是在海马齿状回中不断产生的， 成年哺乳动物的大脑，这种神经发生被认为是抑郁症的治疗靶点 治疗抑郁症最常见的处方治疗之一，氟西汀，一种选择性的 已知5-羟色胺再摄取抑制剂增强海马齿状回中的成年神经发生。 然而，抗抑郁作用机制的分子和细胞基础对成人 海马神经发生尚未完全了解。最近，Wnt信号转导被牵连到调节 成年海马神经发生过程中神经元命运特化和成神经细胞增殖。分泌 卷曲受体蛋白（sFRP）3作为Wnt信号传导的分泌抑制剂，在人乳腺癌组织中高度表达。 成年小鼠齿状回。有趣的是，我们的初步研究表明，sFRP 3作为一种 抗抑郁药如电惊厥药治疗引起活性依赖性调节底物 治疗（ECT）和氟西汀在成人大脑中的作用。它的下调导致我们关注的机制， 抗抑郁作用和sFRP 3的参与。本提案工作的指导阶段将 表征sFRP 3和抗抑郁药的特定细胞和分子机制 神经发生在成年海马使用免疫组织化学，双光子共聚焦深度成像， 以及在特定目的1和2中使用sFRP 3 KO和TOPGAL转基因小鼠的单细胞遗传方法。的 这项工作的意义将提供对调节成人发育的机制的理解。 神经发生和抗抑郁作用，这将是治疗策略的关键。在独立 sFRP 3作为成年海马抗抑郁作用的中介的功能作用 将通过具体目标3和4中的电生理方法和行为分析进行识别。这套 的实验将使我们能够区分sFRP 3在神经发生独立的突触可塑性中的作用， 行为反应虽然啮齿动物模型已被证明是了解基因的重要工具， 功能和疾病，还报道了啮齿动物模型中对药物的反应差异， 在人类身上。具体来说，我们将根据成人的情况定义sFRP 3和抗抑郁药的功能作用。 非人灵长类绒猴的神经发生在特定目标5中。拟议的工作至关重要 由于在成人中基于Wnt/β-连环蛋白信号传导的抗抑郁药的机制仍然难以捉摸， 海马神经发生这些发现将提供一个强有力的证据， 成人神经发生在抗抑郁作用中起作用，这将是进一步临床研究的基础， 开发新的治疗干预措施。 PHS 398（Rev. 11/07）第1页

Program Director/Principal Investigator (Last, First, Middle): Jang, Mi-Hyeon Project Summary/Abstract Depression is one of the most prevalent mental illnesses, affecting more than 121 million people worldwide. It is now generally accepted that new neurons are continuously generated in the dentate gyrus of the hippocampus in the adult mammalian brain, and this neurogenesis has been implicated as a therapeutic target for depression treatment. One of the most commonly prescribed treatments of major depression, fluoxetine, a selective serotonin reuptake inhibitor, is known to enhance adult neurogenesis in the dentate gyrus of the hippocampus. However, the molecular and cellular basis of mechanisms underlying antidepressant action on adult hippocampal neurogenesis is not fully understood. Recently, Wnt signaling has been implicated in regulating neuronal fate specification and neuroblast proliferation during adult hippocampal neurogenesis. Secreted frizzled receptor protein (sFRP) 3 serves as a secreted inhibitor of Wnt signaling, and is highly expressed in the dentate gyrus of adult mouse. Interestingly, our preliminary studies have suggested that sFRP3 serves as a substrate for activity-dependent modulation caused by treatment of antidepressant such as electroconvulsive therapy (ECT) and fluoxetine in adult brain. Its down-regulation led us to focus on the mechanisms of antidepressant actions and involvement of sFRP3 in it. The mentored phase of this proposal work will characterize specific cellular and molecular mechanisms of sFRP3 and antidepressants underlying neurogenesis in the adult hippocampus using the immunohistochemistry, two photon confocal deep imaging, and single cell genetic approach with sFRP3 KO and TOPGAL transgenic mice in Specific Aims 1 and 2. The significance of work will provide understanding of the mechanisms that regulate development of adult neurogenesis and antidepressant action, which will be critical for the therapeutic strategies. In the independent phase of proposals, the functional role of sFRP3 as a mediation of antidepressant action in adult hippocampus will be identified with an electrophysiological approach and behavioral analysis in Specific Aims 3 and 4. This set of experiments will allow us to differentiate roles of sFRP3 in neurogenesis-independent synaptic plasticity and behavioral response. While rodent animal models have been proven to be great tools to understand gene function and diseases, there are also reported differences in the response to drugs in rodent animal models and in humans. Specifically, we will define the functional role of sFRP3 and antidepressant based on adult neurogenesis in nonhuman primate marmoset monkey in Specific Aim 5. The proposed work is of critical importance due to the still elusive mechanism of antidepressant based on Wnt/¿-catenin signaling in adult hippocampal neurogenesis. These discoveries will provide a strong body of evidence to the essential role that adult neurogenesis plays in antidepressant action which will be a foundation for further clinical studies and developing new therapeutic interventions. PHS 398 (Rev. 11/07) Page 1 Continuation Format Page