Acute Inhibition of Adult-born Granule Cells and its Effect on Antidepressant Act

成体颗粒细胞的急性抑制及其抗抑郁作用

• 批准号: 8734273
• 负责人: Lindsay Elsa Tannenholz
• 金额: $ 4.14万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8734273
• 关键词: Ablation; Accounting; Acute; Address; Adult; Adverse effects; Affect; Antidepressive Agents; Anxiety; Bathing; Behavior; Behavioral; Brain; Cells; Chronic; Clozapine; Conflict (Psychology); Disease remission; G-Protein-Coupled Receptors; Genetic; Goals; Hippocampus (Brain); Intervention; Knowledge; Lead; Learning; Major Depressive Disorder; Mediating; Membrane; Methods; Modification; Mood Disorders; Moods; Mus; Neurons; Newborn Infant; Oxides; Patients; Pharmaceutical Preparations; Population; Process; Research; Rodent; Role; Site; Symptoms; Tamoxifen; Techniques; Testing; Therapeutic Effect; Time; Work; adult neurogenesis; behavior test; burden of illness; dentate gyrus; design; disability; efficacy testing; feeding; granule cell; improved; insight; irradiation; nerve stem cell; nestin protein; neurogenesis; newborn neuron; olfactory bulb; public health relevance; receptor; response; selective expression; subventricular zone; tool

DESCRIPTION (provided by applicant): Major depression is a mood disorder affecting 121 million people worldwide and is among the leading causes of disability making it a main contributor to the global burden of disease. Antidepressant (AD) drugs were introduced in the 1950s and have since been refined to have fewer side effects, but little advancement has been made in improving efficacy with only ~50% of patients achieving full remission. In addition, relief from symptoms requires several weeks of chronic AD treatment and the changes occurring during this time that underlie the therapeutic effects are still unknown. Recently, neurogenesis has been shown to be necessary for some of the positive behavioral responses to ADs seen in rodents, and maturation of newborn neurons coincide with the delayed onset of AD action. The primary goal of the research component of this proposal is to understand the on-line contribution of adult-generated dentate gyrus granule cells (GCs) in anxiety-related behavioral tasks after chronic antidepressant treatment. While adult neurogenesis has been implicated in the delayed efficacy of AD treatment, it remains unknown if young neurons drive the behavioral response, or if it is their long-term modification of existing circuitry that contributes to alterations in mood Thus, in this proposal, I provide a strategy for inhibition of adult GCs in a temporally restricted fashion, allowing for either long-term or short-term silencing of adult-generated GCs. To achieve this, I have expressed an evolved G-protein coupled receptor (hM4Di), which is exclusively activated by the pharmacologically inert drug clozapine-N-oxide (CNO), selectively in adult-generated GCs. Upon activation by CNO, hM4Di can induce rapid membrane hyperpolarization and neuronal silencing. This tool will allow me to investigate the consequence of acute or long-term silencing of the population of newborn adult-generated GCs on behavior. These studies will be the first to examine the acute contribution of adult-generated GCs in behavior, as well as determine the mechanism underlying the neurogenesis-dependent behavioral effects of chronic AD treatment.

描述（由申请人提供）：严重抑郁症是一种情绪障碍，影响了全球1.21亿人，是残疾的主要原因之一，使其成为全球疾病负担的主要贡献者。在1950年代引入了抗抑郁药（AD）药物，此后进行了精致的副作用，但在提高疗效方面几乎没有进步，只有约50％的患者达到了完全缓解。另外，解脱 从症状出发需要数周的长期AD治疗，并且在此期间发生的变化仍然是尚不清楚的。最近，已经证明神经发生对于某些对啮齿动物中的广告的积极行为反应是必要的，而新生儿神经元的成熟与AD作用的延迟开始相吻合。该提案的研究组成部分的主要目标是了解长期抗抑郁药治疗后，在与焦虑相关的行为任务中，成人生成的齿状回和颗粒细胞（GCS）的在线贡献。尽管成人神经发生与AD治疗的延迟疗效有关，但尚不清楚年轻的神经元是否驱动行为反应，或者是否是他们对现有电路的长期修改，导致情绪改变有助于改变，因此，在此提案中，我为成人GC在时间限制的策略中提供了一种策略 时尚，允许成人生成的GC的长期或短期沉默。为了实现这一目标，我表达了进化的G蛋白偶联受体（HM4DI），该受体仅由成人生成的GC选择性地被药理学惰性药物氯氮平-N-氧化物（CNO）激活。 CNO激活后，HM4DI会诱导快速的膜超极化和神经元沉默。该工具将使我能够调查新生成人生成的GC对行为的急性或长期沉默的后果。这些研究将是第一个研究成人生成的GC在行为中的急性贡献，并确定慢性AD治疗的神经发生依赖性行为效应的机制。