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

描述(申请人提供)：重度抑郁症是一种影响全球1.21亿人的情绪障碍，是导致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(AD)药物于20世纪50年代问世，此后经过改进，副作用较少，但在提高疗效方面进展甚微，仅有约50%的患者完全缓解。此外，救济 从症状开始需要几周的慢性AD治疗，在此期间发生的治疗效果的变化仍不清楚。最近，在啮齿动物中看到的对ADS的一些积极行为反应需要神经发生，新生神经元的成熟与AD作用的延迟开始相一致。这项建议的研究部分的主要目的是了解慢性抗抑郁药物治疗后，成人产生的齿状回颗粒细胞(GC)在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，但尚不清楚是年轻神经元驱动了行为反应，还是它们对现有回路的长期修改导致了情绪的改变。因此，在这个建议中，我提供了一种在时间受限的情况下抑制成人GC的策略。 时尚，允许长期或短期沉默成人产生的GC。为了实现这一点，我表达了一种进化的G蛋白偶联受体(HM4Di)，它只被药理惰性药物氯氮平-N-氧化物(CNO)激活，在成人产生的GC中选择性地激活。被CNO激活后，hM4Di可引起迅速的膜超极化和神经元沉默。这一工具将使我能够调查急性或长期沉默的新生儿成人产生的GC对行为的影响。这些研究将首次检验成人产生的GC在行为中的急性贡献，以及确定慢性AD治疗对神经发生依赖的行为影响的潜在机制。

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.