Examining adult hippocampal neurogenesis and cognitive function in Rett syndrome

项目摘要 Rett综合征(RTT)是一种进行性神经系统疾病，由甲基-CpG-1基因功能缺失突变引起。 结合蛋白2(MECP2)。RTT主要影响女孩，是X连锁智力残疾的常见原因。 目前还没有治疗RTT的方法，也没有可用的治疗方法来改善学习和记忆功能 这些病人。RTT突变的小鼠模型概括了这种疾病的许多方面，包括损害 学习和记忆的能力。这些动物是促进我们对基本的 RTT综合征的生物学和测试潜在的治疗方法。佐格比的一个突破性发现和 唐实验室发现，刺激RTT小鼠海马区的深部大脑可以挽救学习和记忆 减损。这种刺激也显著增加了成年海马神经发生(Ahn)，一种神经 在RTT小鼠中，与记忆形成密切相关的过程。单独刺激Ahn是否能改善认知能力 RTT中的函数未知。已知MeCP2调节Ahn级联反应的重要特征，例如 成体神经干细胞的增殖和成体颗粒神经元的成熟。然而，分子 在RTT中扰乱这一过程的机制仍不清楚。我的项目的目标是解决这个概念 我们对MeCP2如何调节AHN以及AHN如何促进认知功能的理解存在差距 RTT.在我的建议中，我关注两个问题：1)RTT中扰乱AHN的分子机制是什么？ 2)增强AHN是否能挽救RTT中的学习和记忆缺陷？我假设MeCP2调节一个细胞- 类型特异性转录程序对成人神经发生很重要，增强AHN将得到改善 RTT动物的学习和记忆表现。在目标1中，我建议确定关键的转录变化 在AHN的关键阶段，通过跟踪新生神经元的发育和使用单核RNA- 测序以确定对照和RTT小鼠的分子和细胞差异。在目标2中，我建议 通过刺激TLX核受体增加Ahn，TLX核受体是海马神经发生的主要调节因子 RTT小鼠，并测量学习和记忆行为是否被拯救。总之，这些目标将有助于建立一个 全面了解MeCP2如何在RTT背景下影响AHN和认知行为。 这些数据的最终目标将是确定和开发基于治疗的有针对性的战略，以改善 RTT和其他潜在的MECP2相关疾病的学习和记忆功能。

Project Summary Rett syndrome (RTT) is a progressive neurological disorder caused by loss-of-function mutations in methyl-CpG- binding protein 2 (MECP2). RTT primarily affects girls and is a frequent cause of X-linked intellectual disability. There are currently no cures for RTT and no available treatments that improve learning and memory function in these patients. Mouse models of RTT mutations recapitulate many aspects of the disorder, including impairments of learning and memory. These animals are critical tools for advancing our understanding of both the basic biology of RTT syndrome and for testing potential treatments. A breakthrough discovery from the Zoghbi and Tang labs found that deep brain stimulation in the hippocampus of RTT mice rescued learning and memory impairments. This stimulation also significantly increased adult hippocampal neurogenesis (AHN), a neural process strongly linked to memory formation, in RTT mice. Whether stimulating AHN alone can improve cognitive function in RTT is unknown. MeCP2 is known to regulate important features of the AHN cascade, such as the proliferation of adult neural stem cells and maturation of adult-born granule neurons. However, the molecular mechanisms disrupting this process in RTT remain unclear. The goal of my project is to address this conceptual gap in our understanding of the how MeCP2 regulates AHN and how AHN contributes to cognitive function in RTT. In my proposal, I focus on two questions: 1) what are the molecular mechanisms disrupting AHN in RTT? 2) Does boosting AHN rescue learning and memory deficits in RTT? I hypothesize that MeCP2 regulates a cell- type-specific transcriptional program important for adult neurogenesis and that enhancing AHN will improve learning and memory performance in RTT animals. In Aim 1, I propose to identify key transcriptional changes during critical stages of AHN by tracking newborn neurons as they develop and using single-nuclei RNA- sequencing to identify the molecular and cellular differences in control vs RTT mice. In Aim 2, I propose to increase AHN via stimulation of the TLX-nuclear receptor, a master regulator of hippocampal neurogenesis, in RTT mice and measure if learning and memory behaviors are rescued. Together, these Aims will help build a comprehensive understanding of how MeCP2 influences AHN and cognitive behaviors in the context of RTT. The ultimate goal of these data will be to identify and develop targeted treatment-based strategies to improve learning and memory function in RTT and potentially other MECP2-related disorders.