Center for Sleep in Autism Spectrum Disorder

自闭症谱系障碍睡眠中心

• 批准号: 10698028
• 负责人: JOACHIM F HALLMAYER
• 金额: $ 194.59万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-06 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10698028
• 关键词: Age; Animal Genetics; Animal Model; Animals; Basic Science; Behavior; Behavioral Symptoms; Biological; Brain; Caregivers; Clinical; Cognition; Comparative Biology; Consensus; Development; Diphenhydramine; Disease; Double-Blind Method; Electroencephalography; Etiology; Experimental Animal Model; Foundations; Functional disorder; Genes; Genetic Models; Genetic study; Goals; Home; Human; Impairment; Link; Measures; Mission; Mus; Mutation; Neurobehavioral Manifestations; Neuronal Plasticity; Neurons; Participant; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Phenotype; Physiological; Pilot Projects; Placebo Control; Polysomnography; Public Health; REM Sleep; Randomized; Research; Research Personnel; Rest; Role; Sleep; Sleep Architecture; Sleep Fragmentations; Sleep disturbances; Stereotyped Behavior; Structure; Symptoms; Synapses; Synaptic plasticity; System; Translations; Zebrafish; actigraphy; adolescent with autism spectrum disorder; aged; animal data; associated symptom; autism spectrum disorder; autistic children; awake; behavioral phenotyping; cognitive function; comorbidity; experience; gene function; human subject; improved; individuals with autism spectrum disorder; multimodality; neurodevelopment; neuron development; non rapid eye movement; programs; reduce symptoms; repetitive behavior; sex; sleep abnormalities; sleep onset; sleep physiology; sleep quantity; social communication; trait; translational approach; zolpidem

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.

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症状发展和恶化的中心。动物数据表明，睡眠是 对于大脑基本结构的成熟、神经元的发育和突触的可塑性是必不可少的。 睡眠失调是自闭症患者最沉重的症状之一。入睡晚了， 夜间频繁觉醒、睡眠碎片化和睡眠质量异常是ASD的睡眠特征。沉睡 EEG研究表明，快速眼动睡眠减少，非快速眼动睡眠增加。尽管它在大脑中起着核心作用 在发育和功能方面，睡眠障碍通常被认为是次要的。我们的主要目标是 ASD的睡眠中心是确定睡眠障碍是否反映了汇聚通路，这些通路可以起到 ASD核心、行为和认知症状的原因和/或共同加重因素。我们提出了一个 多模式、人体和动物模型方案，包括四个协同项目，旨在 在表征睡眠碎片和生理在ASD核心症状中的作用。我们会 对150例4~17岁自闭症患者进行睡眠脑电、日间清醒、静息脑电和活动描记检查。 与75个年龄和性别匹配的典型发育中(TD)对照组进行比较，并确定这些影响 睡眠参数对核心症状的影响(项目1)。使用目标接洽方法，我们将确定 睡眠正常化与核心症状的改善有关(项目2)。我们将检查是否 这些发现在ASD的遗传动物模型(小鼠：项目3；斑马鱼：项目4)中得到了概括。这个 睡眠脑电特征和行为的进化守恒使其成为一种强大的翻译方法 作为相同的生理参数，生物终点和行为表型可以进行比较 跨物种，揭示睡眠表型在不同基因之间的影响是否存在趋同性 ASD的模型，或者从睡眠表型到核心症状的不同途径。 具体目标1：在患有自闭症、对照和互补疾病的人类中利用比较生物学 ASD和野生型的遗传动物模型，以检查跨物种的多系统睡眠测量 集中于ASD中睡眠碎片和结构的共同表型；或b)捕获不同的亚型 睡眠失调的表型和跨物种的睡眠结构。具体目标2：检查a)是否 睡眠表型与睡眠障碍的核心、行为和认知症状有不同的相关性。 ASD在患有ASD和ASD互补遗传动物模型的人类中的分布；b)如果睡眠正常化 患有ASD的人类和ASD的互补基因动物模型可以缓解核心、行为和 自闭症的认知症状；以及c)这些影响是否因年龄和/或性别而减轻。具体目标3：提供 为自闭症领域的初级和老牌研究人员提供研究和合作机会，或 在自闭症领域成立，但对ACE中心的研究重点来说是新的。