REGULATION OF HIPPOCAMPAL NEUROGENESIS BY ANTIDEPRESSANTS

抗抑郁药对海马神经发生的调节

基本信息

批准号：
7914988
负责人：
IRWIN LUCKI
金额：
$ 39.32万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-08 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7914988
关键词：
Adult Affect Antidepressive Agents Applications Grants Behavior Behavioral Brain-Derived Neurotrophic Factor C57BL/6 Mouse Chronic Chronic stress Citalopram Corticosterone Disease Emotional Exposure to Flow Cytometry Fluoxetine Functional disorder Genetic Genetic Predisposition to Disease Goals Hippocampus (Brain)Hormones Housing Intraventricular Infusion Investigation Laboratories Lead Major Depressive Disorder Measures Mediator of activation protein Medical Modeling Morbidity - disease rate Mouse Strains Mus Neuronal Plasticity Parahippocampal Gyrus Patients Pharmaceutical Preparations Pharmacology Play Procedures Production Public Health Recovery Regulation Rodent Role Stress Techniques Testing Therapeutic Effect adult neurogenesis dentate gyrus depression depressive symptoms economic impact hypothalamic-pituitary-adrenal axis mouse model neurogenesis neurotrophic factor novel reboxetine resilience response treatment effect

项目摘要

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 predispositons and exposure to environmental stress. Evidence for increases of neurogenesis in the adult dentate gyrus of the hippocampus are 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 nonresponder 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 nonresponder 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

该提案研究了成人神经发生的调节如何产生小鼠重复抗抑郁药物治疗可能有助于行为恢复来自压力和抑郁。重度抑郁症是由收敛引起的潜在的遗传倾向和环境压力的暴露。证据海马体齿状回神经发生的增加是一个模型抗抑郁药物长期治疗引起的神经可塑性变化并作为产生治疗效果的模型。大多数研究都有在常规饲养条件下使用啮齿动物测量抗抑郁药的效果并且忽视了遗传和压力在药物治疗中的关键作用影响。我们已经鉴定出一种小鼠品系 (MRL/MpJ)，其显示出较大的增加慢性氟西汀后的神经发生。另外，添加应激激素增强氟西汀对无反应小鼠品系神经发生的影响 (C57BL/6)。该拨款提案的中心假设是遗传倾向和压力对于揭示慢性抗抑郁药的作用发挥着关键作用海马神经发生的治疗。使用流式细胞术作为一种技术测量该实验室快速开发的神经发生将能够完成研究神经发生的药理学需要大量的研究。该提案的主要目标是：1）展示接触的关键作用皮质酮 (CORT) 增强抗抑郁药长期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有影响的药物； 2）表明环境压力是否在导致抗抑郁药物的产生中起着类似的作用改变神经发生和行为； 3) 确定海马 BDNF 是否起作用作为基础机制