Regulation of Hippocampal Neurogenesis by Antidepressants

描述（由申请人提供）：本提案探讨了反复抗抑郁药物治疗对小鼠成年神经发生的调节如何有助于从压力和抑郁中恢复行为。重度抑郁症是由趋同的潜在遗传倾向和暴露于环境压力引起的。成年海马齿状回神经发生增加的证据是抗抑郁药物慢性治疗中出现的神经可塑性变化的模型，并作为产生治疗效果的模型。大多数研究都是在常规的住房条件下使用啮齿动物来测量抗抑郁药的效果，而忽略了遗传和压力在药物治疗效果中的关键作用。我们已经确定了一种小鼠菌株（MRL/MpJ），在慢性氟西汀后显示出更大的神经发生增加。此外，应激激素的添加增强了氟西汀对无反应小鼠品系神经发生的影响（C57BL/6）。这项拨款提案的中心假设是，遗传倾向和压力在揭示慢性抗抑郁药物治疗对海马神经发生的影响方面发挥了关键作用。利用流式细胞术作为一种测量神经发生的技术，该实验室正在迅速发展，这将使神经发生药理学研究所需的大量研究得以完成。本提案的主要目标是：1)证明皮质酮（CORT）暴露在增强抗抑郁药物慢性治疗对神经发生和行为的反应中的关键作用；2)表明环境压力是否在导致抗抑郁药物改变神经发生和行为方面起类似作用；3)确定海马BDNF是否作为慢性抗抑郁药物治疗产生这些效应的机制。

DESCRIPTION (provided by applicant): 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 predispositions and exposure to environmental stress. Evidence for increases of neurogenesis in the adult dentate gyrus of the hippocampus is 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 non-responder 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 non-responder 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 the production these effects by chronic antidepressant drug treatments. PUBLIC HEALTH RELEVANCE: This project examines the convergent role of genetic predispositions and exposure to environmental stress in mouse models regulating the effects of chronic antidepressant drug treatments on hippocampal neurogenesis and behavior. Major depression is an important public health problem because of its severe economic impact and contribution to morbidity from other medical disorders. The results of this project will contribute to identifying mechanisms of vulnerability and resilience to stress and lead to the discovery of novel and more effective antidepressant treatments.