Regulation of Hippocampal Neurogenesis by Antidepressants

抗抑郁药对海马神经发生的调节

• 批准号: 7987729
• 负责人: IRWIN LUCKI
• 金额: $ 40万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7987729
• 关键词: Adult; Affect; Antidepressive Agents; Applications Grants; Behavior; Behavioral; Brain-Derived Neurotrophic Factor; C57BL/6 Mouse; Chronic; Chronic stress; Citalopram; Corticosterone; Development; Disease; Emotional; Endocrine; Exposure to; Flow Cytometry; Fluoxetine; Functional disorder; Genetic; Genetic Predisposition to Disease; Goals; Hippocampus (Brain); Hormones; Housing; Intraventricular Infusion; Investigation; Laboratories; Lead; MRL/MpJ Mouse; Major Depressive Disorder; Measures; Mediator of activation protein; Medical; Mental Depression; Modeling; Morbidity - disease rate; Mouse Strains; Mus; Neuronal Plasticity; Neurotransmitters; Parahippocampal Gyrus; Patients; Pharmaceutical Preparations; Pharmacology; Play; Procedures; Production; Public Health; Recovery; Regulation; Rodent; Role; Stress; Techniques; Testing; Therapeutic Effect; Variant; adult neurogenesis; dentate gyrus; depressive symptoms; drug discovery; drug testing; economic impact; hypothalamic-pituitary-adrenal axis; mouse model; neurogenesis; neurotransmitter release; neurotrophic factor; novel; public health relevance; reboxetine; resilience; response; treatment effect

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.

描述（由申请人提供）：该提案研究了小鼠反复抗抑郁药治疗产生的成年神经发生的调节可能会导致压力和抑郁症的行为恢复。主要的抑郁障碍导致融合的潜在遗传易感性和暴露于环境压力。海马成年齿状回的神经发生增加的证据是神经可塑性变化的模型，该模型用抗抑郁药慢性治疗出现，并作为产生治疗作用的模型。大多数研究都在常规外壳条件下使用啮齿动物测量了抗抑郁药的作用，并且忽略了遗传学和压力在促进药物治疗效应中的关键作用。我们已经确定了小鼠菌株（MRL/MPJ），该菌株显示出慢性氟西汀后神经发生的增加。同样，增加应力激素增强了氟西汀对无反应小鼠菌株（C57BL/6）中神经发生的影响。该批准建议的中心假设是遗传易感性和压力在揭示慢性抗抑郁治疗对海马神经发生的影响方面产生了关键作用。该实验室迅速开发的流式细胞仪作为一种测量神经发生的技术，将能够完成研究神经发生药理所需的大量研究。该提案的主要目标是：1）证明暴露于皮质酮（CORT）在增强抗抑郁药对响应者和无反应小鼠菌株中神经发生和行为的慢性治疗的反应中的关键作用； 2）表明环境压力在引起抗抑郁药改变神经发生和行为方面是否起着相似的作用； 3）确定海马BDNF是否是通过慢性抗抑郁药治疗产生这些作用的机制。 公共卫生相关性：该项目研究了遗传易感性和暴露于环境压力的小鼠模型中的收敛作用，这些模型调节了慢性抗抑郁药治疗对海马神经发生和行为的影响。重度抑郁症是一个重要的公共卫生问题，因为其经济严重影响和对其他医学疾病发病的贡献。该项目的结果将有助于确定脆弱性和韧性的机制，并导致发现新颖和更有效的抗抑郁治疗。