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: 10626742
• 负责人: Ashley Grace Anderson
• 金额: $ 7.18万
• 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/10626742
• 关键词: Address; Adult; Affect; Agonist; Alleles; Animal Model; Animals; Area; Automobile Driving; Behavior; Behavioral; Biology; Brain; Cell Nucleus; Cells; Cognitive; Cognitive deficits; Cytoplasmic Granules; Data; Deep Brain Stimulation; Disease; Event; Exhibits; Female; Gene Expression; Genetic; Genetic Transcription; Goals; Harvest; Hippocampus; Human; Immunofluorescence Immunologic; Impaired cognition; Impairment; In Situ Hybridization; Injections; Intellectual functioning disability; Label; Laboratory Finding; 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; Proliferating; Regulator Genes; Research; Rett Syndrome; Seizures; Sorting; Syndrome; Tamoxifen; Techniques; Testing; Therapeutic; Therapeutic Intervention; Tissues; Work; X-linked intellectual disability; adult neurogenesis; antibody conjugate; cell type; cognitive enhancement; cognitive function; cognitive performance; dentate gyrus; girls; improved; loss of function mutation; male; memory process; mosaic; mouse model; mutant; nerve stem cell; nervous system disorder; neural; neurogenesis; newborn neuron; programs; single nucleus RNA-sequencing; 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（MECP 2）。RTT主要影响女孩，是X连锁智力残疾的常见原因。 目前还没有治愈RTT的方法，也没有可用的治疗方法可以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 学习和记忆。这些动物是重要的工具，可以促进我们对基本的 RTT综合征的生物学和测试潜在的治疗方法。Zoghbi的突破性发现， Tang实验室发现，RTT小鼠海马体的深部脑刺激拯救了学习和记忆 损伤这种刺激也显著增加了成年海马神经发生（AHN）， 这个过程与RTT小鼠的记忆形成密切相关。单独刺激AHN是否能改善认知功能 RTT中的函数未知。已知MeCP 2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颗粒神经元的成熟。然而，分子 在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上的问题， 我们对MeCP 2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，我集中在两个问题：1）在RTT中破坏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MeCP 2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，我建议识别关键的转录变化， 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- 测序以鉴定对照与RTT小鼠中的分子和细胞差异。在目标2中，我建议 通过刺激TLR-核受体增加AHN，TLR-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挽救。总之，这些目标将有助于建立一个 全面了解MeCP 2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基于治疗的策略，以改善 RTT中的学习和记忆功能以及潜在的其他MECP 2相关疾病。