Cerebellar-cerebro cortical circuits in ASD

ASD 中的小脑-大脑皮层回路

• 批准号: 10532753
• 负责人: Peter T. Tsai
• 金额: $ 50.57万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10532753
• 关键词: Address; Adult; Affect; Anatomy; Behavior; Behavior Disorders; Behavioral; Brain; Cell Culture Techniques; Cerebellar Diseases; Cerebellum; Child; Clinical; Clinical Research; Data; Decision Making; Deep Brain Stimulation; Defect; Development; Disease; Early treatment; Electrophysiology (science); Genes; Genetic; Healthcare; Impairment; Intervention; Lifestyle-related condition; Light; Literature; Medial; Mediating; Mus; Nature; Neurodevelopmental Disorder; Nuclear; Pathogenesis; Physiology; Prefrontal Cortex; Publishing; Purkinje Cells; Regulation; Role; Signal Transduction; Slice; Social Behavior; Techniques; Thalamic structure; Therapeutic; Therapeutic Uses; Time; Tuberous Sclerosis; Viral; Work; autism spectrum disorder; behavioral phenotyping; behavioral study; care burden; critical developmental period; critical period; defined contribution; effective therapy; experimental study; genetic manipulation; improved; in vivo; in vivo Model; mouse model; mutant; neural circuit; neuroregulation; optogenetics; pharmacologic; postnatal; pre-clinical; prevent; targeted treatment; therapeutic development; treatment duration; treatment strategy

Project Summary No targeted therapies exist for the treatment of Autism Spectrum Disorders (ASD), as the underlying mechanisms remain poorly understood. Recent studies have implicated the cerebellum in the pathogenesis of ASDs2-5, while we have recently shown that cerebellar dysfunction is sufficient to generate ASD-relevant behaviors6. Although abnormalities in specific cerebellar regions have been identified in clinical ASD studies, the exact functions of these cerebellar domains and the neural circuit basis by which these domains regulate ASD behaviors remains poorly understood. In this proposal, we present data demonstrating a critical role for the clinically-implicated, cerebellar domain right CrusI7 in the regulation of ASD-related behaviors. Moreover, we also show that modulation of this region during adulthood is able to partially rescue ASD-related behaviors in an ASD mouse model. However, important questions remain including whether critical periods contribute to this incomplete cerebellar-mediated rescue. We hypothesize that developmental critical time windows will impact rescue of ASD-related behaviors. To evaluate these hypotheses, we propose experiments in Aim 1 to establish the critical periods regulating ASD behaviors. In addition, considering a growing literature demonstrating the presence of cerebellar-cerebro cortical circuits5, another unanswered question is whether the cerebellum regulates ASD behaviors through modulation of cortical domains? We have generated preliminary data demonstrating connectivity between the cerebellum and the clinically-implicated medial prefrontal cortex (mPFC) as well as data supporting a role for the mPFC in cerebellar-regulated ASD behaviors. Based on these data, we hypothesize that cerebellar regulation of the mPFC will contribute to ASD behaviors and that thalamo-cortical circuits will provide an anatomic substrate for these cerebellar-regulated ASD behaviors. To address these hypotheses, we propose experiments in Aims 2 and 3 to further establish the functional relevance of cerebellar-mPFC connectivity, to determine the anatomic basis for this connectivity in the regulation of ASD-related behaviors, and to uncover whether modulation of these circuits can improve ASD-related behaviors. Thus, in this proposal, we will establish the developmental time windows during which rescue of cerebellar- mediated ASD behaviors can be achieved. We will additionally seek to identify and establish the role for cerebellar-mPFC circuits in ASD-related behaviors and define the therapeutic benefits of circuit modulation on these behaviors. Thus, these studies will not only further our understanding of basic mechanisms of ASD but will also evaluate the pre-clinical potential for therapeutics using circuit-based neuromodulation for the treatment of ASD.

项目概要 目前尚无治疗自闭症谱系障碍 (ASD) 的靶向疗法，因为其根本原因是 机制仍知之甚少。最近的研究表明小脑与疾病的发病机制有关 ASDs2-5，而我们最近表明小脑功能障碍足以产生 ASD 相关的 行为6.尽管临床 ASD 研究已发现特定小脑区域的异常， 这些小脑结构域的确切功能以及这些结构域调节的神经回路基础 自闭症谱系障碍（ASD）行为仍然知之甚少。 在本提案中，我们提供的数据证明了临床相关的小脑区域的关键作用 对CrusI7在ASD相关行为的调节中的作用。此外，我们还表明该区域的调制 在成年期能够部分挽救 ASD 小鼠模型中与 ASD 相关的行为。然而， 重要的问题仍然存在，包括关键时期是否导致这种不完全的小脑介导 救援。我们假设发育关键时间窗口将影响 ASD 相关行为的救援。 为了评估这些假设，我们在目标 1 中提出了实验来建立调节的关键时期 自闭症谱系障碍行为。 此外，考虑到越来越多的文献证明小脑-大脑皮层回路的存在5， 另一个悬而未决的问题是小脑是否通过调节 ASD 行为 皮质域？我们已经生成了初步数据，证明小脑之间的连接 和临床相关的内侧前额叶皮层 (mPFC) 以及支持 mPFC 在 小脑调节的 ASD 行为。根据这些数据，我们假设小脑调节 mPFC 将有助于 ASD 行为，而丘脑皮质回路将为 ASD 行为提供解剖学基础 这些小脑调节的 ASD 行为。为了解决这些假设，我们在目标 2 中提出了实验 3 进一步建立小脑-mPFC连接的功能相关性，以确定解剖学 调节 ASD 相关行为的这种连通性的基础，并揭示是否调节 这些电路可以改善 ASD 相关行为。 因此，在本提案中，我们将建立发育时间窗口，在此期间小脑的救援 介导的 ASD 行为是可以实现的。我们还将寻求确定并建立以下角色： 小脑-mPFC 回路在 ASD 相关行为中的作用，并定义了回路调制的治疗益处 这些行为。因此，这些研究不仅将加深我们对 ASD 基本机制的理解，而且 还将评估使用基于电路的神经调节进行治疗的临床前潜力 自闭症谱系障碍的治疗。