REGULATION OF HIPPOCAMPAL NEUROGENESIS BY ANTIDEPRESSANTS

本研究旨在探讨成年神经发生的调节是如何通过 小鼠反复抗抑郁药物治疗可能有助于行为恢复 从压力和抑郁中解脱出来重度抑郁症是由于 潜在的遗传倾向和暴露于环境压力。证据 成年海马齿状回神经发生的增加是一个模型， 抗抑郁药物长期治疗后出现的神经可塑性变化 并作为产生治疗效果的模型。大多数研究 在常规饲养条件下， 忽视了遗传和压力在药物治疗中的关键作用 方面的影响.我们已经确定了一种小鼠品系（MRL/MpJ）， 慢性氟西汀后的神经发生。另外，压力荷尔蒙的加入 增强氟西汀对无应答小鼠品系神经发生的作用 （C57BL/6）。这项拨款提案的核心假设是， 和应激对揭示慢性抗抑郁药的作用起关键作用 海马神经发生的治疗。使用流式细胞术作为一种技术， 这个实验室快速开发的神经发生测量将使完成 需要大量的研究来调查神经发生的药理学。 本提案的主要目标是：1）展示暴露于以下方面的关键作用： 皮质酮（CORT）增强抗抑郁药长期治疗的反应 药物对应答和非应答小鼠品系的神经发生和行为的影响; 2） 显示环境压力是否在抗抑郁药物中起着类似的作用， 改变神经发生和行为; 3）确定海马BDNF是否 作为一种潜在机制

This proposal examines how the regulation of adult neurogenesis produced by repeated antidepressant drug treatment in mice may contribute to behavioral recovery from stress and depression. Major depressive disorder results from convergent underlying genetic predispositons and exposure to environmental stress. Evidence for increases of neurogenesis in the adult dentate gyrus of the hippocampus are a model for changes in neuroplasticity that emerge with chronic treatment with antidepressant drugs and serve as a model for the production of therapeutic effects. Most studies have measured the effects of antidepressants using rodents under routine housing conditions and have ignored the critical role of genetics and stress in contributing to drug treatment effects. We have identified a mouse strain (MRL/MpJ) that shows larger increases in neurogenesis following chronic fluoxetine. Also, the addition of stress hormones augments the effects of fluoxetine on neurogenesis in a nonresponder mouse strain (C57BL/6). The central hypothesis of this grant proposal is that genetic predispositions and stress produce a critical role for revealing the effects of chronic antidepressant treatments on hippocampal neurogenesis. The use of flow cytometry as a technique to measure neurogenesis rapidly developed by this laboratory will enable completion of the large number of studies required for investigation of the pharmacology of neurogenesis. The primary goals of this proposal are: 1) demonstrate the critical role of exposure to corticosterone (CORT) in augmenting responses to chronic treatment with antidepressant drugs on neurogenesis and behavior in a responder and nonresponder mouse strain; 2) show whether environmental stress plays a similar role in causing antidepressant drugs to alter neurogenesis and behavior; and 3) determine whether hippocampal BDNF serves as a mechanism underlying