Center for Sleep in Autism Spectrum Disorder

自闭症谱系障碍睡眠中心

• 批准号: 10531469
• 负责人: JOACHIM F HALLMAYER
• 金额: $ 194.92万
• 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/10531469
• 关键词: Age; Animal Genetics; Animal Model; Animals; Architecture; Basic Science; Behavior; Behavioral Symptoms; Biological; Brain; Caregivers; Child; Clinical; Cognition; Comparative Biology; Consensus; Development; Diphenhydramine; Disease; Double-Blind Method; Electroencephalography; Etiology; 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; Translations; Zebrafish; actigraphy; adolescent with autism spectrum disorder; aged; animal data; associated symptom; autism spectrum disorder; autistic children; awake; base; behavioral phenotyping; cognitive function; comorbidity; disorder control; experience; experimental study; 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会导致 ASD 症状的发展和恶化的核心。动物数据表明睡眠 对于基本大脑结构的成熟、神经元发育和突触可塑性至关重要。 睡眠失调是自闭症谱系障碍患者最严重的症状之一。入睡晚， 夜间频繁醒来、睡眠碎片化和睡眠量异常是自闭症谱系障碍 (ASD) 睡眠的标志。睡觉 脑电图研究表明快速眼动睡眠减少，非快速眼动睡眠增加。尽管它在大脑中发挥着核心作用 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 自闭症谱系障碍 (ASD) 睡眠中心旨在确定睡眠障碍是否反映了可以充当 ASD 核心、行为和认知症状的因果因素和/或共同加重因素。我们提出一个 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 描述睡眠碎片化和生理学对 ASD 核心症状的作用。我们将 检查 150 名 4 至 17 岁 ASD 患者的睡眠脑电图、白天清醒、静息脑电图和体动记录仪， 与 75 个年龄和性别匹配的典型发育 (TD) 对照进行比较，并确定这些对照的影响 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相关（项目 2）。我们将检查是否 这些发现在 ASD 遗传动物模型中得到了概括（小鼠：项目 3；斑马鱼：项目 4）。这 睡眠脑电图特征和行为的进化保守性使其成为一种强大的转化方法 由于相同的生理参数、生物学终点和行为表型可以进行比较 跨物种，揭示不同遗传的睡眠表型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：利用自闭症谱系障碍 (ASD) 和对照以及互补的人类比较生物学 ASD 和野生型遗传动物模型，用于检查跨物种的多系统睡眠测量 a) 集中于自闭症谱系障碍 (ASD) 睡眠碎片化和结构的共同表型；或b）捕获不同的子 跨物种睡眠失调和睡眠结构的表型。具体目标 2：检查是否 a) 确定的睡眠表型与核心、行为和认知症状有不同的相关性 患有自闭症谱系障碍的人类和自闭症谱系障碍的互补遗传动物模型； b) 如果睡眠正常化 患有 ASD 的人类和 ASD 的互补遗传动物模型，减轻了核心、行为和 自闭症谱系障碍（ASD）的认知症状； c) 这些影响是否因年龄和/或性别而减弱。具体目标 3：提供 为自闭症领域的初级和成熟研究人员提供研究和合作机会，或 该研究是在自闭症领域建立的，但对于 ACE 中心的研究重点来说是新的。