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中无处不在，睡眠问题深远影响生活质量和 神经发育结果。该中心提出了一个模型研究项目，专注于机制 使用包括临床成分的多学科方法，IDD中的潜在睡眠障碍， 动物模型和使用患者衍生的多能干细胞的脑器官模型。这个项目 建立在我们以前的IDDRC模型项目和电池和电路核心的发现的基础上，灵感来自两个引人注目 调查结果：（1）在DUP15Q综合征中，我们的研究人员发现睡眠异常异常 生理学，其特征在于睡眠异常的纺锤体和慢波睡眠（SWS）的特征。 经历了一夜临床的人，这些脑电图异常的幅度与 智力障碍和（2）在Rett综合征器官模型中，我们的研究人员量化了异常振荡 在最早发展阶段的活动。对于这个项目，我们采用完全翻译的方法来学习 DUP15Q和RETT综合征中神经振荡和睡眠的机制。在AIM 1（临床）中，我们 验证睡眠生理学异常（SWS和睡眠主轴密度）的临床脑电图 DUP15Q综合征并检查其与认知功能的关系。在AIM 2（临床前模型）中，我们检查 睡眠生理（SWS和纺锤体）及其对小鼠海马和前额外合奏活动的影响 DUP15Q和RETT综合征的模型，进行脑电图和同时电生理记录以及 使用新型的微型显微镜进行钙成像。在AIM 3（临床前模型）中，我们提早研究 来自DUP15Q的人类皮质，皮层和海马类器官的神经网络功能 使用钙成像，电生理记录技术和转录组的RETT综合征IPSC 分析。该项目利用我们中心在综合症的临床和临床前研究中的优势 IDD并利用我们中心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中的一个基本和研究的问题。通过验证关系 NREM睡眠异常和这些综合症儿童的行为之间，然后在模型中 系统，确定异常神经振荡的网络和细胞基础，这对于记忆至关重要 该项目的形成和学习将直接为开发及时，有效治疗的下一步提供信息 这可能会调节睡眠，进而改善神经发育结果。