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.

摘要