Hippocampal Neurogenesis: Mechanisms of Antidepressant Action

海马神经发生：抗抑郁作用机制

• 批准号: 7935618
• 负责人: Eduardo David Leonardo
• 金额: $ 6.78万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7935618
• 关键词: Ablation; Adult; Affect; Animal Model; Animals; Antidepressive Agents; Anxiety; Area; Behavior; Behavioral; Behavioral Paradigm; Brain Part; Breeding; Chronic; Cognitive; Cytoplasmic Granules; Dependence; Dissociation; Dorsal; Emotional; Etiology; Evaluation; Exposure to; Fluoxetine; Funding; Ganciclovir; Genetic; Glial Fibrillary Acidic Protein; Goals; Herpesviridae; Hippocampus (Brain); Human; Infusion procedures; Institutes; Investigation; Knowledge; Laboratories; Lead; Learning; Link; Maintenance; Mediating; Memory; Mental disorders; Mentors; Mentorship; Modification; Moods; Mus; Neurobiology; Neurons; Neurosciences Research; Neurotransmitters; New York; Newborn Infant; Parahippocampal Gyrus; Performance; Pharmacotherapy; Property; Recovery; Research; Research Personnel; Research Training; Resources; Role; Science; Specificity; TK Gene; Tamoxifen; Testing; Training; Transgenic Mice; Transgenic Organisms; behavior test; career; dentate gyrus; depression; design; experience; genetic manipulation; granule cell; irradiation; meetings; mouse model; nerve stem cell; nestin protein; neural circuit; neurogenesis; newborn neuron; novel; programs; promoter; recombinase; research study; response; restoration; segregation

DESCRIPTION (provided by applicant): This proposal will prepare the candidate for an independent career in neuroscience research and includes both a training and research plan. The training plan combines formal mentorship, didactics, seminars and meetings designed to provide: 1) expertise in the breeding, maintenance and behavioral characterization of mice that have been subjected to X-irradiation, pharmacologic manipulation and genetic modification; 2) a fund of knowledge in relevant neurobiological issues that will enhance the candidate's ability to think creatively about animal models of psychiatric illness; 3) exposure to issues in the responsible conduct of science; and 4) experience in effective laboratory management and mentoring. In pursuit of these goals the candidate will benefit from the extensive educational and research resources available at the Columbia Center for Neurobiology and Behavior and at the New York State Psychiatric Institute. The research plan involves a comprehensive evaluation of the requirement for newborn hippocampal dentate granule neurons in a variety of behavioral paradigms in mice. Previous studies have shown that disrupting hippocampal neurogenesis in the dentate gyrus results in animals' inability to respond to behavioral paradigms sensitive to chronic antidepressants and in deficits in spatial learning tasks. Separate lines of investigation reveal a functional dissociation across the dorsal-ventral axis of the hippocampus, with the ventral hippocampus modulating behavior in anxiety paradigms, and the dorsal hippocampus modulating performance on spatial learning tasks. The research plan proposed here aims to specifically test the hypothesis that neurogenesis in the ventral dentate gyrus, but not the dorsal dentate gyrus, is required for the behavioral response to antidepressants. A secondary hypothesis is that other paradigms sensitive to disruption of neurogenesis will also show differential dependence on dorsal or ventral areas. Completing these plans will further define the functional role of newborn neurons in the hippocampus, including a role in the response to antidepressants. By demonstrating regional specificity, these results will also provide clues to other components of the neural circuitry involved in the response to antidepressants. This could lead to novel targets for the pharmacotherapy of depression and anxiety. At completion of this project, the candidate will have the knowledge and experience to independently develop and characterize mouse models of psychiatric disease.

描述（由申请人提供）：该提案将为候选人在神经科学研究领域的独立职业做好准备，包括培训和研究计划。该培训计划结合了正式的指导、教学、研讨会和会议，旨在提供：1）经过 X 射线照射、药理操作和基因改造的小鼠的繁殖、维护和行为特征方面的专业知识； 2）相关神经生物学问题的知识储备，这将增强候选人创造性地思考精神疾病动物模型的能力； 3）接触负责任的科学行为的问题； 4) 有效实验室管理和指导的经验。为了实现这些目标，候选人将受益于哥伦比亚神经生物学和行为中心以及纽约州精神病学研究所提供的广泛教育和研究资源。该研究计划涉及对小鼠各种行为模式下新生海马齿状颗粒神经元的需求进行全面评估。先前的研究表明，破坏齿状回的海马神经发生会导致动物无法对慢性抗抑郁药敏感的行为模式做出反应，并导致空间学习任务的缺陷。不同的研究揭示了海马背腹轴的功能分离，腹侧海马在焦虑范式中调节行为，背侧海马调节空间学习任务的表现。这里提出的研究计划旨在专门测试这样的假设：抗抑郁药的行为反应需要腹侧齿状回的神经发生，而不是背侧齿状回的神经发生。第二个假设是，对神经发生破坏敏感的其他范式也将表现出对背侧或腹侧区域的不同依赖性。完成这些计划将进一步确定海马体中新生神经元的功能作用，包括在抗抑郁药反应中的作用。通过证明区域特异性，这些结果还将为参与抗抑郁药反应的神经回路的其他组成部分提供线索。这可能会导致抑郁症和焦虑症药物治疗的新靶点。该项目完成后，候选人将拥有独立开发和表征精神疾病小鼠模型的知识和经验。