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.

严重抑郁症是一种情绪障碍，影响全球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。抗抑郁症（AD）药物于20世纪50年代引入，此后经过改进，副作用较少，但在提高疗效方面进展甚微，只有约50%的患者达到完全缓解。此外，救济 从症状中恢复需要几周的慢性AD治疗，并且在此期间发生的作为治疗效果基础的变化仍然未知。最近，神经发生已被证明是必要的一些积极的行为反应，在啮齿动物中看到的AD，和新生神经元的成熟与AD行动的延迟发作相一致。本研究的主要目标是了解成年人产生的齿状回颗粒细胞（GC）在慢性抗抑郁治疗后焦虑相关行为任务中的在线贡献。虽然成人神经发生与AD治疗的延迟疗效有关，但尚不清楚是否年轻的神经元驱动行为反应，或者是否是它们对现有回路的长期修饰导致情绪改变。因此，在本提案中，我提供了一种在时间限制的情况下抑制成人GC的策略。 方式，允许成人产生的GC的长期或短期沉默。为了实现这一目标，我表达了一种进化的G蛋白偶联受体（hM 4Di），它只被非生物活性药物氯氮平-N-氧化物（CNO）激活，选择性地在成人产生的GC中。在CNO激活后，hM 4Di可以诱导快速的膜超极化和神经元沉默。这个工具将使我能够研究急性或长期沉默的新生儿成人产生的GC对行为的影响。这些研究将是第一个检查成人产生的GC在行为中的急性贡献，以及确定慢性AD治疗的神经发生依赖性行为效应的机制。