Genetic regulation of basal and antidepressant-induced adult neurogenesis

描述（由申请人提供）：临床抑郁症是一种使人衰弱的情绪障碍，终生患病率为15-20%，死亡率高达20%。目前的抗抑郁药物治疗，所有这些目标在大脑中的单胺能系统，需要几个星期的治疗才能起效，并诱导缓解只有一半的患者。虽然抗抑郁作用的机制知之甚少，但最近有人提出抗抑郁药诱导的神经发生可能是临床反应的基础。为了检验这一假设，并确定是否有抗抑郁药的反应有遗传成分，我们建议定量成年海马细胞增殖和凋亡的20个近交系小鼠或无慢性抗抑郁药治疗。这些表型将用于单倍型作图，一种类型的数量性状基因座分析，以确定候选基因调节方面的基础和抗抑郁药诱导的神经发生。然后，我们将测量对照组和抗抑郁药治疗组小鼠在悬尾试验（一种行为绝望的测量方法）中的表现，以确定抗抑郁药对行为反应的程度是否与抗抑郁药影响神经发生的程度相关。公共卫生相关性：拟议实验的主要目标是：a）确定成年期调节新神经元产生的基因，B）确定与抗抑郁药的行为和神经源性反应相关的基因，以及c）确定抗抑郁药是否可能通过调节神经发生来影响行为。这些结果将帮助我们更好地了解抗抑郁药缓解抑郁症的最终机制。

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.