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

摘要 睡眠障碍在IDDS中普遍存在，睡眠问题深刻影响着人们的生活质量和生活质量 神经发育结果。该中心提出了一个模型研究项目，重点是机制 使用包括临床部分的多学科方法对IDDS的潜在睡眠障碍进行研究， 动物模型，以及使用患者来源的诱导多能干细胞的脑器官模型。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基础上，灵感来自两个引人注目的 发现：(1)在Dup15q综合征中，我们的研究人员发现了严重的睡眠异常 患者的生理特征是睡眠纺锤波异常和慢波睡眠(SWS)减弱 曾接受过夜临床的患者，这些脑电异常的程度与其程度相关 智力障碍和(2)在Rett综合征器质性模型中，我们的研究人员量化了异常振荡 处于发展早期阶段的活动。对于这个项目，我们采取了完全翻译的方法来研究 Dup15q和Rett综合征患者神经振荡和睡眠的潜在机制。在目标1(临床)中，我们 证实青少年儿童睡眠生理异常(SWS和睡眠纺锤体密度) Dup15q综合征及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(SWS和纺锤波)及其对小鼠海马区和前额叶系膜活动的影响 Dup15q和Rett综合征模型，进行脑电和同步电生理记录 使用新型微型显微镜进行钙成像。在AIM 3(临床前模型)中，我们早期调查 来源于Dup15q的人脑皮质、皮质下和海马区有机体的神经网络功能 和Rett综合征IPSC使用钙成像、电生理记录技术和转录 分析。该项目利用了我们中心在临床和临床前综合征研究方面的优势 IDDS，并利用我们中心基础和临床研究人员之间积极的科学合作 了解睡眠生理学，这是IDDS的一个基本和未被研究的问题。通过验证关系 这些综合征儿童的NREM睡眠异常和行为之间的关系，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，这个项目将直接通知下一步制定及时、有效的治疗方法 这可能会调节睡眠，进而改善神经发育结果。

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.