Modulating plasticity in adult-born neurons of the dentate gyrus

描述（由申请人提供）：抑郁症是世界上导致残疾的主要原因，开发新的治疗方法对其治疗至关重要。最近的研究表明，对情绪有有益影响的干预措施，如运动和慢性抗抑郁治疗，会增加海马神经的发生。此外，海马神经发生是慢性抗抑郁治疗的一些行为效果所必需的。DG中的成体颗粒细胞（GC）在其发育的关键窗口期表现出增强的突触可塑性，这种增强的可塑性是由NR2B亚基介导的NMDA受体。然而，尚不清楚成年出生的GCs中这种增加的兴奋性在行为中起什么作用。这一提议将验证一种假设，即阻止成年出生的巨噬细胞促进巨噬细胞可塑性的能力对小鼠的认知功能和抗抑郁功效有不利影响。具体来说，我们提出的实验将测试NR2B亚基在成年GCs中特异性缺失对DG生理、情境恐惧学习和抗抑郁药行为反应的影响。

DESCRIPTION (provided by applicant): Depression is a major cause of disability in the world, and developing novel therapeutic approaches for its treatment is of utmost importance. Recent studies have suggested that interventions that have beneficial effects on mood such as exercise and chronic antidepressant treatment increase hippocampal neurogenesis. In addition, hippocampal neurogenesis is required for some of the behavioral effects of chronic antidepressant treatment. Adult-born granule cells (GC) in the DG exhibit a heightened synaptic plasticity during a critical window of their development, an enhanced plasticity mediated by the NR2B subunit-containing NMDA receptors. Yet, it remains unknown what role this increased excitability in adult-born GCs plays in behavior. This proposal will test the hypothesis that blocking the ability for adult-born GCs to contribute to plasticity in the DG has detrimental effects on cognitive function and antidepressant efficacy in mice. Specifically, the experiments proposed will test the effect of deletion of the NR2B subunit specifically in adult-born GCs on DG physiology, contextual fear learning and behavioral response to antidepressants. PUBLIC HEALTH RELEVANCE: This proposal is the first attempt to assess the impact of strategies aimed at modulating plasticity in adult born neurons. A potential application of these findings would be that pharmacological interventions aimed at modulating hippocampal neurogenesis might be beneficial for the treatment of mood or cognitive disorders.