Examining adult hippocampal neurogenesis and cognitive function in Rett syndrome

检查雷特综合征成人海马神经发生和认知功能

• 批准号: 10425703
• 负责人: Ashley Grace Anderson
• 金额: $ 6.76万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10425703
• 关键词: Address; Adult; Affect; Agonist; Alleles; Animal Model; Animals; Area; Automobile Driving; Behavior; Behavioral; Biology; Brain; Cell Maturation; Cell Nucleus; Cells; Cognitive; Cognitive deficits; Cytoplasmic Granules; Data; Deep Brain Stimulation; Disease; Event; Exhibits; Female; Gene Expression; Genetic; Genetic Transcription; Goals; Harvest; Hippocampus (Brain); Immunofluorescence Immunologic; Impaired cognition; Impairment; In Situ Hybridization; Injections; Intellectual functioning disability; Label; Learning; Link; Measures; Mediating; Memory; Memory impairment; Methyl-CpG-Binding Protein 2; Molecular; Mosaicism; Motor; Mus; Mutation; Neurodevelopmental Disorder; Neurons; Nuclear Receptors; Outcome; Pathway interactions; Patients; Performance; Phenotype; Process; Regulator Genes; Research; Rett Syndrome; Seizures; Syndrome; Tamoxifen; Techniques; Testing; Therapeutic; Therapeutic Intervention; Tissues; Work; X-linked intellectual disability; adult neurogenesis; antibody conjugate; base; cell type; cognitive enhancement; cognitive function; cognitive performance; dentate gyrus; girls; improved; loss of function mutation; male; memory process; mouse model; mutant; nerve stem cell; nervous system disorder; neurogenesis; newborn neuron; programs; relating to nervous system; stem cell proliferation; symptom treatment; targeted treatment; therapeutic development; tool; transcriptome sequencing

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.

项目概要 Rett 综合征 (RTT) 是一种进行性神经系统疾病，由甲基 CpG- 功能缺失突变引起 结合蛋白 2 (MECP2)。 RTT 主要影响女孩，并且是 X 连锁智力障碍的常见原因。 目前还没有治疗 RTT 的方法，也没有可以改善学习和记忆功能的治疗方法。 这些病人。 RTT 突变小鼠模型概括了该疾病的许多方面，包括损伤 的学习和记忆。这些动物是增进我们对基本知识的理解的重要工具。 RTT 综合征的生物学和测试潜在的治疗方法。 Zoghbi 的突破性发现和 Tang 实验室发现，RTT 小鼠海马体的深部脑刺激可挽救学习和记忆 损伤。这种刺激还显着增加了成人海马神经发生（AHN），这是一种神经元 在 RTT 小鼠中，这一过程与记忆形成密切相关。单独刺激 AHN 是否可以改善认知能力 RTT 中的功能未知。 MeCP2 已知可调节 AHN 级联的重要特征，例如 成体神经干细胞的增殖和成体出生的颗粒神经元的成熟。然而，分子 RTT 中破坏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 实时传输时间。在我的提案中，我关注两个问题：1）RTT 中破坏 AHN 的分子机制是什么？ 2) 提高 AHN 是否可以挽救 RTT 中的学习和记忆缺陷？我假设 MeCP2 调节细胞- 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并使用单核 RNA- 测序以确定对照小鼠与 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（海马神经发生的主要调节因子）增加 AHN RTT 小鼠并测量学习和记忆行为是否得到挽救。这些目标共同将有助于建立一个 全面了解 MeCP2 如何影响 RTT 背景下的 AHN 和认知行为。 这些数据的最终目标将是确定和制定有针对性的治疗策略，以改善 RTT 和其他潜在 MECP2 相关疾病中的学习和记忆功能。