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）：本提案研究了小鼠反复抗抑郁药物治疗产生的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。重度抑郁症是由潜在遗传易感性和环境压力的聚集引起的。成年海马齿状回神经发生增加的证据是神经可塑性变化的模型，这种变化是抗抑郁药物长期治疗的结果，并可作为产生治疗效果的模型。大多数研究都测量了抗抑郁药在常规饲养条件下使用啮齿动物的效果，忽略了遗传学和压力在促进药物治疗效果方面的关键作用。我们已经确定了一种小鼠品系（MRL/MpJ），在慢性氟西汀治疗后神经发生增加更大。此外，在无应答小鼠品系（C57 BL/6）中，添加应激激素增强了氟西汀对神经发生的影响。这项拨款建议的中心假设是，遗传倾向和压力产生的关键作用，揭示慢性抗抑郁药治疗对海马神经发生的影响。使用流式细胞术作为一种技术来衡量神经发生迅速发展的实验室将能够完成大量的研究所需的调查神经发生的药理学。本研究的主要目的是：1）证明皮质酮（CORT）暴露在抗抑郁药物慢性治疗对应答和非应答小鼠品系神经发生和行为的增强反应中的关键作用; 2）显示环境应激是否在引起抗抑郁药物改变神经发生和行为中起类似作用;以及3）确定海马BDNF是否作为慢性抗抑郁药物治疗产生这些作用的潜在机制。 公共卫生相关性：该项目研究了遗传倾向和暴露于环境应激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的会聚作用。重度抑郁症是一个重要的公共卫生问题，因为它严重的经济影响和其他医学疾病的发病率。该项目的结果将有助于确定脆弱性和抗压力能力的机制，并导致发现新的和更有效的抗抑郁治疗方法。