Center for Sleep in Autism Spectrum Disorder

我们提议的自闭症卓越中心（ACE）的使命是检查睡眠失调是否是 ASD症状发展和恶化的核心。动物实验表明，睡眠是 对于基本脑结构的成熟、神经元发育和突触可塑性至关重要。 睡眠失调是ASD患者最严重的症状之一。晚睡， ASD患者的睡眠特点是夜间频繁觉醒、睡眠碎片化和睡眠量异常。睡眠 EEG研究表明，REM睡眠减少，非REM睡眠增加。尽管它在大脑中的核心作用 睡眠障碍通常被认为是继发性的。我们的主要目标是 ASD睡眠中心是为了确定睡眠障碍是否反映了可以作为 ASD中的核心、行为和认知症状的因果和/或共同加重因素。我们提出了一个 多模式，人类受试者和动物模型计划，其中包括四个协同项目，旨在 在描述睡眠片段和生理学对ASD核心症状的作用方面。我们将 检查150名4至17岁ASD患者的睡眠EEG、白天清醒、静息EEG和活动记录， 与75名年龄和性别匹配的典型发育（TD）对照进行比较，并确定这些因素的影响。 核心症状的睡眠参数（项目1）。使用目标参与方法，我们将确定是否 睡眠正常化与核心症状的改善有关（项目2）。我们将研究是否 这些发现在ASD的遗传动物模型（小鼠：项目3;和斑马鱼：项目4）中被概括。的 睡眠EEG特征和行为的进化保守性使其成为一种强大的转化方法 由于生理参数相同，生物学终点和行为表型可以进行比较 在不同的物种中，揭示了睡眠表型对不同遗传因素的影响是否存在趋同性。 ASD模型，或者从睡眠表型到核心症状的差异途径。 具体目标1：利用ASD患者和对照人群的比较生物学， ASD和野生型的遗传动物模型，以检查是否跨物种的多系统睡眠测量a） 会聚于ASD中睡眠片段化和结构的共同表型;或B）捕获不同的亚表型， 睡眠失调的表型和跨物种的睡眠结构。具体目标2：检查a） 所鉴定的睡眠表型与以下疾病的核心、行为和认知症状有差异性相关： 在患有ASD的人类和ASD的互补遗传动物模型中的ASD; B）如果在患有ASD的人类中睡眠正常化， 患有ASD的人和ASD的互补遗传动物模型，减轻了核心、行为和 ASD的认知症状;以及c）这些影响是否受年龄和/或性别的调节。具体目标3：提供 研究和合作的机会，初级和建立研究人员新的自闭症领域，或 在自闭症领域建立，但新的ACE中心的研究重点。

The mission of our proposed Autism Center of Excellence (ACE) is to examine if dysregulation of sleep is central to the development and exacerbation of symptoms in ASD. Animal data demonstrate that sleep is essential for the maturation of fundamental brain structures, neuronal development and synaptic plasticity. Sleep dysregulation is one of the most burdensome symptoms in individuals with ASD. Late sleep onset, frequent nighttime awakening, sleep fragmentation and abnormal sleep quantity hallmark sleep in ASD. Sleep EEG studies indicate less REM sleep and increased Non-REM Sleep. Despite its central role in brain development and function, sleep impairments are frequently considered as secondary. The main goal of our Center for Sleep in ASD is to determine if sleep disturbances reflect convergent pathways that can act as causal for, and/or co-aggravating factors of, core, behavioral and cognitive symptoms in ASD. We propose a multi-modal, human subjects and animal models program which encompasses four synergistic projects aimed at characterizing the role of sleep fragmentation and physiology on the core symptoms of ASD. We will examine Sleep EEG, daytime awake, resting EEG, and actigraphy in 150 individuals with ASD, 4 to 17 years, compared to 75 age- and sex-matched Typical Developing (TD) controls and determine the impact of these sleep parameters on core symptoms (Project 1). Using a target engagement approach, we will determine if normalization of sleep is associated with improvements in the core symptoms (Project 2). We will examine if these findings are recapitulated in genetic animal models of ASD (Mice: Project 3; & Zebrafish: Project 4). The evolutionary conservation of Sleep EEG signatures and behavior makes this a powerful translational approach as the same physiological parameters, biological endpoints and behavioral phenotypes can be compared across species, revealing if there is a convergence of the impact of sleep phenotypes across different genetic models of ASD, or alternatively differential pathways from sleep phenotypes to core symptoms. Specific Aim 1: To leverage comparative biology across humans with ASD and controls and complementary genetic animal models of ASD and wild type to examine if multisystem sleep measurements across species a) converge on a common phenotype of sleep fragmentation and architecture in ASD; or b) capture different sub- phenotypes of sleep dysregulation and sleep architecture across species. Specific Aim 2: Examine if a) the sleep phenotypes identified are differentially associated with the core, behavioral and cognitive symptoms of ASD across humans with ASD and complementary genetic animal models of ASD; b) if sleep normalization in humans with ASD and in complementary genetic animal models of ASD, alleviate the core, behavioral and cognitive symptoms of ASD; and c) if these effects are moderated by age and/or sex. Specific Aim 3: Provide research and collaborative opportunities to junior and established researchers new to the field of autism, or established in the field of autism but new to the research emphases of the ACE Center.