Mechanisms underlying non-REM sleep and neural oscillation abnormalities in Dup15q and Rett Syndrome: Effects on Intellectual Disability

Dup15q 和 Rett 综合征中非快速眼动睡眠和神经振荡异常的机制：对智力障碍的影响

• 批准号: 10686876
• 负责人: BENNETT G NOVITCH
• 金额: $ 37.34万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10686876
• 关键词: Address; Affect; Age; Animal Model; Attenuated; Biological Models; Brain; Calcium; Cells; Child; Clinical; Clinical Trials; Cognition; Cognitive; Collaborations; Data; Defect; Development; Electroencephalography; Electrophysiology (science); Event; Fostering; Funding; Future; Generations; Genetic; Genomics; Hippocampus; Human; Image; Impaired cognition; Impairment; Informatics; Intellectual and Developmental Disabilities Research Centers; Intellectual functioning disability; Intervention; Investigation; Learning; Measures; Memory; Microscope; Modeling; Molecular; Neurons; Organoids; Outcome; Pathway interactions; Patients; Play; Pre-Clinical Model; Process; Quality of life; Research Personnel; Research Project Grants; Rett Syndrome; Role; Severities; Sleep; Sleep Architecture; Sleep Disorders; Sleep Fragmentations; Sleep disturbances; Slow-Wave Sleep; Syndrome; System; Techniques; Visualization; behavioral impairment; behavioral outcome; biomarker development; clinical investigation; cognitive development; cognitive function; comparison control; density; effective therapy; imaging modality; improved; induced pluripotent stem cell; interdisciplinary approach; interest; memory consolidation; miniaturize; mouse model; network dysfunction; neural; neural network; non rapid eye movement; non-verbal; novel; pre-clinical; recruit; skills; sleep abnormalities; sleep behavior; sleep physiology; sleep spindle; therapeutic target; transcriptome; transcriptomics; translational approach; verbal

ABSTRACT Sleep impairments are ubiquitous in IDDs, and sleep problems profoundly impact quality of life and neurodevelopmental outcomes. The Center proposes a model research project, focused on the mechanisms underlying sleep impairments in IDDs using a multidisciplinary approach that includes a clinical component, animal models, and brain organoid models using patient-derived induced pluripotent stem cells. This project builds on findings from our previous IDDRC model project and the cells and circuits core, inspired by two striking findings: (1) in Dup15q syndrome, our investigators discovered profoundly abnormal sleep physiology, characterized by abnormal sleep spindles and attenuated slow-wave sleep (SWS), among patients who had undergone overnight clinical, with magnitude of these EEG abnormalities correlated with the degree of intellectual disability and (2) in Rett syndrome organoid models, our investigators quantified abnormal oscillatory activity in the earliest stages of development. For this project, we take a fully translational approach to study mechanisms underlying neural oscillations and sleep in Dup15q and Rett syndrome. In Aim 1 (Clinical), we verify abnormalities in sleep physiology (SWS and sleep spindle density) in clinical EEGs of young children with Dup15q syndrome and examine their relation to cognitive function. In Aim 2 (Preclinical model), we examine sleep physiology (SWS and spindles) and its effect on hippocampal and prefrontal ensemble activity in mouse models of Dup15q and Rett syndrome, performing EEG and simultaneous electrophysiological recordings and calcium imaging using a novel miniaturized microscope. In Aim 3 (Preclinical model), we investigate early neural network function in human cortical, subcortical, and hippocampal organoids from derived from Dup15q and Rett Syndrome iPSC using calcium imaging, electrophysiological recordings techniques, and transcriptomic analyses. This project leverages our center's strengths in both clinical and preclinical investigation of syndromic IDDs and capitalizes on active scientific collaborations between basic and clinical researchers in our center to understand sleep physiology, a fundamental and understudied problem in IDDs. By verifying the relationship between NREM sleep abnormalities and behavior in children with these syndromes and then, in model systems, determining the network and cellular basis of abnormal neural oscillations that are critical for memory formation and learning, this project will directly inform next steps for development of timely, effective treatments that may modulate sleep and, in turn, improve neurodevelopmental outcomes.

抽象的 睡眠障碍在 IDD 中普遍存在，睡眠问题深刻影响生活质量和 神经发育结果。该中心提出了一个模型研究项目，重点关注机制 使用包括临床成分在内的多学科方法来识别 IDD 的潜在睡眠障碍， 动物模型和使用患者来源的诱导多能干细胞的脑类器官模型。这个项目 建立在我们之前的 IDDRC 模型项目以及单元和电路核心的发现之上，受到两个引人注目的启发 研究结果：(1) 在 Dup15q 综合征中，我们的研究人员发现睡眠严重异常 患者的生理学特点是睡眠纺锤波异常和慢波睡眠（SWS）减弱 接受过过夜临床检查的患者，这些脑电图异常的程度与脑电图异常的程度相关 智力障碍和（2）在雷特综合征类器官模型中，我们的研究人员量化了异常振荡 发展最早阶段的活动。对于这个项目，我们采取完全转化的方法来研究 Dup15q 和 Rett 综合征神经振荡和睡眠的潜在机制。在目标 1（临床）中，我们 验证患有以下疾病的幼儿的临床脑电图的睡眠生理学异常（SWS 和睡眠纺锤波密度） Dup15q 综合征并检查其与认知功能的关系。在目标 2（临床前模型）中，我们检查 睡眠生理学（SWS 和纺锤体）及其对小鼠海马和前额叶整体活动的影响 Dup15q 和 Rett 综合征模型，进行脑电图和同步电生理记录， 使用新型微型显微镜进行钙成像。在目标 3（临床前模型）中，我们尽早进行调查 Dup15q 衍生的人类皮质、皮质下和海马类器官中的神经网络功能 和雷特综合征 iPSC 使用钙成像、电生理记录技术和转录组学 分析。该项目利用了我们中心在综合征临床和临床前研究方面的优势 IDD 并利用我们中心的基础研究人员和临床研究人员之间的积极科学合作， 了解睡眠生理学，这是 IDD 中一个基本且未被充分研究的问题。通过验证关系 NREM 睡眠异常与患有这些综合征的儿童的行为之间的关系，然后在模型中 系统，确定对记忆至关重要的异常神经振荡的网络和细胞基础 形成和学习，该项目将直接为下一步开发及时、有效的治疗方法提供信息 这可能会调节睡眠，进而改善神经发育结果。