Regulation of Hippocampal Neurogenesis by Antidepressants

描述(由申请人提供)：这项建议研究了通过反复抗抑郁药物治疗在小鼠身上产生的成年神经发生的调节如何有助于从应激和抑郁中恢复行为。严重的抑郁障碍是由潜在的遗传倾向和暴露在环境压力下的趋同引起的。成年海马齿状回神经再生增加的证据是抗抑郁药物慢性治疗后神经可塑性变化的模型，也是产生治疗效果的模型。大多数研究都是在常规居住条件下使用啮齿动物来衡量抗抑郁药物的效果，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品系(MRL/MPJ)，该品系在慢性氟西汀后显示出更大的神经发生增加。此外，应激激素的添加增加了氟西汀对无反应小鼠品系(C57BL/6)神经发生的影响。这项拨款提案的中心假设是，遗传易感性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。使用流式细胞术作为一种由该实验室快速开发的测量神经发生的技术，将使研究神经发生的药理学所需的大量研究得以完成。该建议的主要目标是：1)证明暴露于皮质酮(CORT)在增强对慢性抗抑郁药物治疗的反应对有反应和无反应小鼠品系的神经发生和行为的关键作用；2)证明环境应激在导致抗抑郁药物改变神经发生和行为方面是否扮演类似的角色；以及3)确定海马区BDNF是否作为慢性抗抑郁药物治疗产生这些影响的机制。 公共卫生相关性：该项目在调节慢性抗抑郁药物治疗对海马神经发生和行为的影响的小鼠模型中，检验了遗传易感性和环境应激暴露的汇聚作用。严重的抑郁症是一个重要的公共卫生问题，因为它对经济造成严重影响，并导致其他医学疾病的发病率。该项目的结果将有助于确定应对压力的脆弱性和恢复力的机制，并导致发现新的、更有效的抗抑郁药物治疗。

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.