Neural Mechanisms of Predictive Impairments in Autism

自闭症预测性障碍的神经机制

• 批准号: 10198668
• 负责人: Alexander Chubykin
• 金额: $ 37.33万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-20 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10198668
• 关键词: Address; Area; Behavior; Biological Models; Brain; Code; Development; Disease; Electrophysiology (science); Environment; Event; FMR1; Fragile X Syndrome; Functional Magnetic Resonance Imaging; Future; Gene Mutation; Goals; Impairment; In Vitro; Inherited; Knockout Mice; Knowledge; Lead; Learning; Link; Maps; Measures; Modeling; Mus; Mutant Strains Mice; Neurons; Perception; Process; Reporting; Research; Rewards; Short-Term Memory; Silicon; Structure; Synapses; Synaptic plasticity; System; Testing; Time; Visual Cortex; Visual Perception; area striata; autism spectrum disorder; autistic children; base; cholinergic; evidence base; expectation; experience; extracellular; image guided; in vivo; information processing; insight; mouse model; neocortical; neuromechanism; novel; optogenetics; patch clamp; prospective; relating to nervous system; response; sensory stimulus; synaptogenesis; theories; therapeutic target; visual learning

Project Summary Autism Spectrum Disorders (ASDs) are characterized by a range of reported deficits and impairments. However, detailed knowledge about their underlying mechanisms and explanatory models is currently lacking. A novel concept, supported by growing evidence, is that autism may well be primarily a disorder of prediction. Impairments of structural and functional connectivity reported in children with ASD are entirely consistent with this concept. The brain processes information by constantly making predictions about future developments in the surrounding environment, based on information from previous experience. Violations of expectations are used by the brain to adjust and make future more accurate predictions as part of the learning process. Impairments in this function may be among the key underlying core deficits in ASD. Of direct relevance to this concept, we have recently discovered a new mechanism for predictive learning in the visual cortex, which acts through modulation of persistent activity (neuronal activity, which lasts beyond the time of initial sensory stimulus). Persistent activity functions to encode information about the timing of prospective salient events, and is hypothesized to be the underlying cellular basis of working memory. Since Fragile X Syndrome, like other forms of ASDs, is characterized by impairment of structural and functional circuit connectivity, there is a critical need to establish how these aberrations of circuit connectivity lead to impaired neural activity and predictive learning in ASDs. To address this need, we will first identify impaired synaptic connections within the cortical microcircuit of Fragile X mice. Second, we will test the hypothesis that predictive coding is impaired in Fragile X mice. Finally, we will establish a causal link between impaired persistent activity and aberrant visual perception and learning in Fragile X mice. The results of these studies are expected to help establish a strong evidence- based framework for systematic characterization of additional single gene mutations associated with ASD, which may ultimately lead to potential development of targeted circuit-specific therapies for successful treatment of autism.

项目摘要 自闭症谱系障碍（ASD）的特征是一系列报告的缺陷和损伤。 然而，目前缺乏关于其基本机制和解释模型的详细知识。 越来越多的证据支持了一个新的概念，即自闭症很可能主要是一种预测障碍。 ASD儿童报告的结构和功能连接受损完全符合 这个概念.大脑通过不断预测未来的发展来处理信息， 周围环境，根据以往的经验。违反期望是 作为学习过程的一部分，大脑使用它来调整和做出未来更准确的预测。 这一功能的损害可能是ASD的关键核心缺陷之一。与此直接相关的 概念，我们最近在视觉皮层中发现了一种新的预测学习机制， 通过调节持续活动（神经元活动，其持续超过初始感觉的时间， 刺激）。持续性活动的功能是编码关于预期显著事件的时间的信息， 被认为是工作记忆的细胞基础。由于脆性X综合征，像其他 ASD的形式，其特征是结构和功能电路连接受损， 需要确定这些电路连接的异常如何导致神经活动受损， 学习ASD。为了解决这一需要，我们将首先确定皮层内受损的突触连接， 脆性X小鼠的微电路。第二，我们将检验预测编码在脆性X染色体中受损的假设， 小鼠最后，我们将建立一个因果关系之间的损害持续活动和异常的视觉感知 和学习能力。这些研究的结果预计将有助于建立一个强有力的证据- 用于系统表征与ASD相关的其他单基因突变的基于框架， 这可能最终导致靶向回路特异性治疗的潜在发展， 自闭症的治疗