Genetic regulation of basal and antidepressant-induced adult neurogenesis

基础和抗抑郁药物诱导的成人神经发生的基因调控

• 批准号: 7619114
• 负责人: BROOKE H MILLER
• 金额: $ 5.17万
• 依托单位: SCRIPPS FLORIDA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7619114
• 关键词: Adult; Affect; Antidepressive Agents; Apoptosis; Behavior; Behavioral; Brain; Candidate Disease Gene; Cell Proliferation; Chronic; Clinical; Disease remission; Endogenous depression; Genes; Genetic; Goals; Haplotypes; Hippocampus (Brain); Inbred Strains Mice; Maps; Measures; Mood Disorders; Mus; Neurons; Patients; Performance; Phenotype; Prevalence; Production; Quantitative Trait Loci; Regulation; System; Tail Suspension; Testing; adult neurogenesis; behavior measurement; depression; mortality; neurogenesis; public health relevance; research study; response

DESCRIPTION (provided by applicant): Clinical depression is a debilitating mood disorder with a lifetime prevalence rate of 15-20% and a mortality rate of up to 20%. Current antidepressant drug treatments, all of which target monoaminergic systems in the brain, require several weeks of treatment before the onset of efficacy, and induce remission in only half of patients. Although the mechanism of antidepressant action is poorly understood, it has recently been suggested that antidepressant-induced neurogenesis may underlie clinical response. In order to test this hypothesis, and to determine whether the response to antidepressants has a genetic component, we propose to quantitate adult hippocampal cell proliferation and apoptosis in twenty inbred strains of mice with or without chronic antidepressant treatment. These phenotypes will be used for haplotype mapping, a type of quantitative trait locus analysis, in order to identify candidate genes regulating aspects of both basal and antidepressant-induced neurogenesis. We will then measure the performance of control and antidepressant-treated mice 'on the tail suspension test, a measure of behavioral despair, to determine whether the magnitude of the behavioral response to antidepressants is associated with the extent to which antidepressants affect neurogenesis. PUBLIC HEALTH RELEVANCE: The primary goals of the proposed experiments are: a) to identify genes that regulate the production of new neurons during adulthood, b) to identify genes associated with the behavioral and neurogenic response to antidepressants, and c) to determine whether antidepressants may affect behavior via the regulation of neurogenesis. The results will help us to better understand the ultimate mechanism by which antidepressants provide relief from depression.

描述(申请人提供)：临床抑郁症是一种衰弱的情绪障碍，终生患病率为15%-20%，死亡率高达20%。目前的抗抑郁药物治疗都是针对大脑中的单胺类系统，需要几周的治疗才能起效，而且只有一半的患者会得到缓解。尽管抗抑郁作用的机制尚不清楚，但最近有研究表明，抗抑郁药诱导的神经发生可能是临床反应的基础。为了验证这一假说，并确定对抗抑郁药物的反应是否具有遗传成分，我们建议对20个近交系小鼠的成年海马细胞增殖和凋亡进行量化，无论是否接受慢性抗抑郁药物治疗。这些表型将用于单倍型作图，这是一种数量性状基因座分析，以确定调控基础和抗抑郁诱导的神经发生的候选基因。然后，我们将测量对照组和抗抑郁剂治疗组小鼠在尾部悬挂试验中的表现，以确定对抗抑郁剂的行为反应的幅度是否与抗抑郁剂影响神经发生的程度有关。公共卫生相关性：拟议的实验的主要目标是：a)确定成年期间调节新神经元产生的基因，b)确定与抗抑郁剂的行为和神经性反应相关的基因，以及c)确定抗抑郁剂是否可能通过调节神经发生来影响行为。结果将帮助我们更好地理解抗抑郁剂缓解抑郁的最终机制。