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，睡眠问题深刻影响生活质量， 神经发育结果。该中心提出了一个模式研究项目，重点是机制 使用包括临床部分的多学科方法， 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 建立在我们以前的IDDRC模型项目和细胞和电路核心的发现基础上，灵感来自两个惊人的 研究结果：（1）在Dup15q综合征中，我们的研究人员发现了严重的睡眠异常 在患者中，以异常睡眠纺锤波和衰减的慢波睡眠（SWS）为特征的生理学 这些EEG异常的程度与患者的 智力残疾和（2）在Rett综合征类器官模型中，我们的研究人员量化了异常振荡 在发展的最早阶段。在这个项目中，我们采用完全翻译的方法来研究 Dup15q和Rett综合征的神经振荡和睡眠机制在目标1（临床）中，我们 验证患有以下疾病的幼儿的临床脑电图中睡眠生理学（SWS和睡眠梭形密度）的异常 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 小鼠睡眠生理学（SWS和纺锤波）及其对海马和前额叶整体活动影响 Dup15q和Rett综合征模型，进行EEG和同步电生理记录， 钙成像使用一种新型的微型显微镜。在目标3（临床前模型）中，我们研究了早期 人类皮质、皮质下和海马类器官中的神经网络功能源自Dup15q 和Rett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的临床和临床前研究方面的优势， IDDs和利用我们中心的基础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IDDs中一个基本的未充分研究的问题。通过验证关系 NREM睡眠异常与这些综合征儿童的行为之间的关系， 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，该项目将直接通知及时，有效的治疗发展的下一步 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.