Elucidating Molecular Mediators of Environmentally Induced Neurogenesis

 描述（由申请人提供）：（修订文本）本提案旨在确定和研究调节成人神经发生的分子通路，以响应环境刺激。在早期发育的形成期之后，持续的神经发生持续存在于海马的齿状回（DG）中，并且有助于学习、记忆和情绪调节。成人神经发生可以通过环境影响和经历来调节，包括电休克（ECS）和自主跑步。增强的学习已经在啮齿动物的车轮运行模型中得到证明，而电休克疗法被用于人类有效地治疗抑郁症。以前的工作已经涉及少量的分子在转导外部刺激到神经原性的影响，但很少有新的途径以外的已经确立的神经原性因素已被功能性确定。此外，一个主要的障碍一直是无法研究生物学途径，特别是在神经源性细胞类型。因此，促进环境诱导的成年DG神经发生的分子机制在很大程度上仍然未知。 为了解决DG中的分子机制，特别是在新形成的神经元内如何促进神经发生的问题，我将利用两种互补的方法。首先，我建议可以整合表观遗传学和神经发育疾病领域的独立数据来源，以提供可能有助于环境诱导神经发生的候选基因的靶向筛选信息。我将描述候选基因的功能作用，发现有改变表达后，在DG ECS和/或车轮运行。其次，我将利用一种新的Nestin-CreERT 2/RiboTag小鼠系来捕获和表征新生神经元富集群体的翻译谱，因为它们在自愿轮运行模式中成熟，并且通过这种分析鉴定的感兴趣的基因将进行功能评估。这项研究将产生重要的洞察力， 发育中的神经元在环境和神经可塑性的界面上的工作。此外，发现的新机制和途径可能代表未来脑损伤和CNS疾病再生治疗的有价值的目标。

 DESCRIPTION (provided by applicant): (Revised text) This proposal seeks to identify and investigate molecular pathways that modulate adult neurogenesis in response to environmental stimuli. Following formative periods of early development, ongoing neurogenesis persists in the dentate gyrus (DG) of the hippocampus and contributes to learning, memory, and regulation of emotion. Adult neurogenesis can be modulated by environmental influences and experiences, including electroconvulsive shock (ECS) and voluntary running. Enhanced learning has been demonstrated in rodent models of wheel running, while electroconvulsive therapy is used in humans to effectively treat depressive disorders. Previous work has implicated a small number of molecules in transducing external stimuli into neurogenic effects, but few novel pathways outside of already well-established neurogenic factors have been functionally identified. Additionally, a major obstacle has been an inability to investigate biological pathways specifically within neurogenic cell types. Therefore, molecular mechanisms that facilitate environmentally induced neurogenesis in adult DG remain largely unknown. To address the question of how molecular machinery in DG and specifically within newly formed neurons facilitates neurogenesis in response to extrinsic signals, I will utilize two complementary methods. Firstly, I propose that independent sources of data in the fields of epigenetics and neurodevelopmental disease can be integrated to inform a targeted screening of candidate genes likely to contribute to environmentally induced neurogenesis. I will characterize functional roles for candidate genes found to have altered expression in DG after ECS and/or wheel running. Secondly, I will utilize a novel Nestin-CreERT2/RiboTag mouse line to capture and characterize the translational profiles of enriched populations of newborn neurons as they mature in a voluntary wheel running paradigm, and genes of interest identified through this analysis will be functionally assessed. This research will yield significant insight into the inner workings of developing neurons at the interface of environment and neuroplasticity. Additionally, novel mechanisms and pathways discovered may represent valuable targets for future regenerative treatments of brain injury and CNS disorders.