Regulation of Hippocampal Neurogenesis by Antidepressants

抗抑郁药对海马神经发生的调节

• 批准号: 8267123
• 负责人: IRWIN LUCKI
• 金额: $ 39.6万
• 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/8267123
• 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）：该提案研究了小鼠重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的遗传倾向和环境压力的共同作用造成的。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，这种变化是随着抗抑郁药物的长期治疗而出现的，并可作为产生治疗效果的模型。大多数研究都是在常规饲养条件下使用啮齿类动物来测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。我们已经鉴定出一种小鼠品系（MRL/MpJ），其在长期服用氟西汀后神经发生显着增加。此外，添加应激激素可增强氟西汀对无反应小鼠品系 (C57BL/6) 神经发生的影响。该拨款提案的中心假设是，遗传倾向和压力在揭示长期抗抑郁治疗对海马神经发生的影响方面发挥着关键作用。使用流式细胞术作为本实验室快速开发的测量神经发生的技术，将能够完成神经发生药理学研究所需的大量研究。该提案的主要目标是：1）证明暴露于皮质酮（CORT）在增强抗抑郁药物长期治疗对有反应和无反应小鼠品系的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着类似的作用； 3) 确定海马 BDNF 是否是长期抗抑郁药物治疗产生这些作用的潜在机制。 公共健康相关性：该项目研究了小鼠模型中遗传倾向和环境应激暴露的聚合作用，这些模型调节长期抗抑郁药物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，因为它具有严重的经济影响和其他疾病的发病率。该项目的结果将有助于确定压力脆弱性和恢复力的机制，并导致发现新颖且更有效的抗抑郁治疗方法。