Elucidating Molecular Mediators of Environmentally Induced Neurogenesis

 描述(由申请人提供)：(修订正文)本提案寻求识别和研究调节成人神经发生对环境刺激的反应的分子途径。在早期发育的形成期之后，持续的神经发生持续在海马齿状回(DG)，并有助于学习、记忆和情绪调节。成人神经发生可以受到环境影响和经验的调节，包括电惊厥(ECS)和自愿跑步。在轮子跑的啮齿动物模型中已经证明了增强的学习能力，而电惊厥疗法在人类中被用于有效地治疗抑郁障碍。以前的工作已经涉及到少量的分子将外部刺激转化为神经源性效应，但在已经确立的神经源性因子之外的新途径很少被从功能上确定。此外，一个主要的障碍是无法研究神经源性细胞类型内的生物途径。因此，促进环境诱导的成年DG神经发生的分子机制仍然很大程度上是未知的。为了解决DG中的分子机制，特别是新形成的神经元中的分子机制如何促进神经发生对外部信号的反应的问题，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，以便有针对性地筛选可能有助于环境诱导神经发生的候选基因。我将描述在ECS和/或车轮运行后DG中发现表达改变的候选基因的功能角色。其次，我将利用一种新的Nestin-CreERT2/RiboTag小鼠系来捕获和表征在自愿车轮运行范式中成熟的丰富的新生神经元群体的翻译图谱，并将从功能上评估通过这一分析确定的感兴趣的基因。这项研究将产生对内在的重大洞察 发育中的神经元在环境和神经可塑性交界处的工作原理。此外，新发现的机制和途径可能为未来脑损伤和中枢神经系统疾病的再生治疗提供有价值的靶点。

 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.