The Neural Substrates of Higher-Level Learning in Autism

描述（由申请人提供）：ASD患者在学习和记忆方面表现出独特的能力和残疾模式。他们对项目、事实、细节和惯例表现出完整的低级学习。然而，他们在抽象、解决问题、使用必须由自我生成的概念图式组织的信息和概括学习等高级学习方面表现出障碍。这种不均衡的、以情境为中心的学习状况对自闭症患者的学业、社会和适应功能产生了深远的影响。此外，尽管与ASD的其他神经认知理论一致，但基于学习的方法提供了与动物和计算模型系统更清晰的联系，从而增强了其阐明病理生理机制的潜力。在这项应用中，我试图阐明高级学习缺陷的神经机制，并帮助确定它们对ASD青少年日常功能的确切影响。实验将包括行为和功能磁共振成像研究，研究对象是年龄在12-17岁、11个月大的ASD青少年（n=40），以及年龄、智商和性别匹配的典型发展对照组（TYP; n=40）。第一个目的是利用功能磁共振成像和传递推理范式研究青少年ASD高水平学习缺陷的神经回路，包括测试低水平训练和高水平抽象刺激之间的关系。本研究采用快速事件相关的功能磁共振成像研究，在我们最近对年轻人传递推理学习的行为研究背景下进行解释，以及两种突出的机械学习模型。我们预测，在高层次的推理过程中，患有ASD的个体将表现出额叶功能和功能连接的减少。在第二个目标中，我们研究了低水平和高水平学习的行为和神经指标如何与学习成绩、社会问题解决以及限制性和重复性行为相关，使用回归分析来检验阅读、写作、数学和社会问题解决能力以及限制性兴趣和重复性行为如何被抽象推理和概括的神经认知测量和传递推理的神经指标预测。本研究提出了一种新的ASD发病机制模型；试图将神经认知与现实生活中的问题联系起来；在潜在的有效干预窗口期间，关注未被充分研究的青少年人群；为这些非常有能力，但经历了限制其人类潜力的高级学习问题的个体推进精神药理学，社会心理和神经再训练补救策略的研究；使用贝叶斯状态空间定量方法仔细研究学习的产生；并通过在ASD小鼠模型中开发并行任务，为未来研究小鼠学习泛化奠定概念基础，该模型可用于多巴胺能和其他认知缺陷药物治疗的临床前试验。

DESCRIPTION (provided by applicant): Individuals with ASD display a unique pattern of abilities and disabilities in learning and memory. They exhibit intact lower-level learning of item, facts, details, and routines. However, they manifest impairments in higher- level learning involving abstraction, problem solving, using information that must be organized with self- generated conceptual schemas, and generalizing learning. This uneven and situation-focused learning profile has a profound impact on the academic, social, and adaptive functioning of those with ASD. Furthermore, while consistent with other neurocognitive theories of ASD, a learning-based approach offers clearer links to animal and computational model systems, thus enhancing its potential to illuminate pathophysiological mechanisms. In this application, I attempt to clarify the neural mechanisms underlying higher-level learning deficits, and help identify their precise effects on the day-to-day functioning of adolescents with ASD. Experiments will include behavioral and fMRI studies in a well-characterized group of adolescents aged 12-17 years, 11 months with ASD (n=40), and age, IQ, and gender-matched control participants with typical development (TYP; n=40).The first Aim, investigates the neural circuitry underlying higher-level learning deficits in adolescents with ASD using fMRI and a transitive inference paradigm which includes testing on lower-level trained and higher-level abstracted relationships between stimuli. This Aim employs a rapid event- related fMRI study which is interpreted in the context of our recent behavioral study of transitive inference learning in young adults, and two prominent mechanistic learning models. We predict that individuals with ASD will demonstrate reduced frontal functioning and functional connectivity during higher-level inferences. In the second Aim, we investigate how behavioral and neural indices of lower and higher-level learning relate to academic performance, social problem solving, and restricted and repetitive behaviors using regression analyses to examine how reading, writing, math, and social problem solving abilities, and restricted interests and repetitive behaviors, are predicted by neurocogntive measures of abstract reasoning and generalization, and neural indices of transitive inference. This work proposes a new mechanistic model of ASD; attempts to link neurocognition to real life problems; focuses on the understudied adolescent population during a potentially effective window for intervention; advances the search for psychopharmacological, psychosocial, and neural retraining remediation strategies for these individuals who are extremely able, but experience higher-level learning problems that limit their human potential; uses Bayesian state-space quantitative methods to closely examine the emergence of learning; and establishes a conceptual basis for future investigation of generalization of learning in mice through the development of parallel tasks in mouse models of ASD that can be used as preclinical assays for dopaminergic and other pharmacological treatments for cognitive deficits.