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，可以增加海马神经发生。此外，海马神经发生是慢性抗抑郁药治疗的一些行为效应所必需的。成年出生的颗粒细胞（GC）在DG中表现出高度的突触可塑性，在其发展的关键窗口，增强的可塑性介导的NR2B亚基含有NMDA受体。然而，它仍然是未知的成年出生的GC中的这种增加的兴奋性在行为中起着什么作用。这项提议将检验这样一个假设，即阻断成年出生的GC促进DG可塑性的能力对小鼠的认知功能和抗抑郁疗效有不利影响。具体而言，所提出的实验将测试NR2B亚基的删除，特别是在成年出生的GC DG生理学，上下文的恐惧学习和抗抑郁药的行为反应的影响。 公共卫生相关性：该提案是首次尝试评估旨在调节成人出生神经元可塑性的策略的影响。这些发现的一个潜在应用是，旨在调节海马神经发生的药物干预可能有利于治疗情绪或认知障碍。

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.