Analysis of the role of hippocampal adult-born neurons in behavior and physiology

描述(由申请人提供)：本项目的主要目标是确定成年海马区神经发生在海马区依赖学习和记忆中的作用。已有研究表明，海马齿状回有能力在成年后产生新的神经元。这些新生细胞中的许多成熟为具有功能突触的齿状颗粒神经元。以往的文献表明，去除啮齿动物的海马神经发生抑制了对抗抑郁药物的行为反应，并导致了抗抑郁药物的治疗作用需要神经发生的假说。相反，阻止神经发生会损害几种形式的海马体依赖学习。我们已经证明，使用x射线或可诱导的基因消融方法阻止海马神经发生会损害背景恐惧条件反射，但会改善工作记忆任务，即新对象识别。此外，使用这些方法阻止神经再生消除了内侧穿支通路中的一种形式的长时程增强(LTP)，称为ACSF-LTP。考虑到有证据表明，发育中的成年神经元表现出独特的生理特性，拟议的研究将使用情景恐惧条件反射、新对象识别和电生理学(ACSF-LTP)来确定这些海马依赖任务需要多大年龄的成年神经元。公共卫生相关性：海马区神经发生已被证明影响特定的学习范式以及抗抑郁反应。旨在刺激海马神经发生的策略可以为认知和情绪障碍的治疗提供新的途径。

DESCRIPTION (provided by applicant): The broad goal of this project is to determine the involvement of adult hippocampal neurogenesis in hippocampal-dependent learning and memory. It has been shown that the dentate gyrus of the hippocampus has the ability to produce new neurons into adulthood. Many of these newborn cells mature into dentate granule neurons with functional synapses. Previous literature showed that ablation of hippocampal neurogenesis in rodents inhibits the behavioral response to antidepressant drugs and led to the hypothesis that neurogenesis is required for the therapeutic action of antidepressant drugs. Conversely, arresting neurogenesis impairs several forms of hippocampus-dependent learning. We have shown that blocking hippocampal neurogenesis using x-irradiation or an inducible genetic ablation method impairs contextual fear conditioning but improves a working memory task, novel object recognition. Furthermore, arrest of neurogenesis using these methods eliminates a form of long term potentiatioh (LTP) in the medial perforant path, termed ACSF-LTP. In consideration of evidence that developing adult-born neurons exhibit unique physiological properties, the proposed research will use contextual fear conditioning, novel object recognition, and electrophysiology (ACSF-LTP) to determine at what age adult-bom neurons become necessary for these hippocampal-dependent tasks. PUBLIC HEALTH RELEVANCE: Hippocampal neurogenesis has been shown to influence specific learning paradigms as well as antidepressant responses. Strategies aimed at stimulating hippocampal neurogenesis could provide novel avenues for the treatment of cognitive and mood disorders.