Functional Imaging of Flexibility in Autism: Informed by SLC6A4

描述（由申请人提供）：本申请的直接目标包括：培训候选人成为独立的临床研究人员，并解决自闭症谱系障碍（ASD）的主要但被忽视的限制性重复症状的大脑（和遗传）基础。长期目标包括：开发一个综合研究的模型，告知我们对ASD原因的理解，并提高我们测试和靶向治疗ASD的能力。该研究项目使用成熟的神经科学方法（功能性MRI和基因分型）来研究与ASD中的受限，重复行为和兴趣症状有关的大脑区域和基因。认知灵活性是了解这一症状群的一个窗口，拟议的研究通过仔细分析ASD儿童的核心组成部分来解决过去工作的局限性。患有和不患有ASD的儿童将进行与ASD和认知灵活性有关的5-羟色胺转运体基因的基因分型，并将参加功能性MRI和心理电池，评估认知灵活性和ASD症状。患有ASD和5-羟色胺转运体基因风险等位基因的儿童预计在灵活性任务中会犯更多错误，并且在激活的大脑区域的结构和功能中表现出更大的偏差。职业发展计划包括先进的MRI技术，神经解剖学，神经生物学，遗传学，神经心理学和成像基因组学的跨学科培训;培训来自正式的教学法，指导性阅读和实验室经验，由一位神经学家担任首席导师的杰出专家共同导师小组。研究环境：候选人的主要培训和研究将在儿童国家医学中心和乔治敦大学的一个新兴的自闭症合作研究项目中进行，他将接受来自费城儿童医院和斯坦福大学科学家的机构和个人合作的深入高级培训。 公共卫生相关性：根据疾病控制中心的数据，美国每150名儿童中就有1名患有自闭症。重复的行为和僵化，僵化的思维是这种疾病的主要症状，并阻止许多其他高功能的人成为主流社会的有能力的成员。然而，我们对这些症状的理解仍然局限于认知，大脑和遗传水平的分析。这项拟议中的工作旨在确定这组自闭症症状的神经和遗传因素，以帮助我们寻找这些核心自闭症缺陷的原因，并采取针对性干预措施。

DESCRIPTION (provided by applicant): The immediate goals of this application include: training the candidate to become an independent clinical- researcher, and to addressing the brain (and genetic) basis of a cardinal, but neglected restricted, repetitive symptoms of autism spectrum disorders (ASD). Long term goals include: developing a model for integrative research, informing our understanding of the causes of ASD, and advancing our ability to test and target treatments for ASD. The research project uses well established neuroscience methods (functional MRI and genotyping) to investigate brain regions and genes involved in restricted, repetitive behavior and interest symptoms in ASD. Cognitive flexibility serves as a window into this symptom cluster, and the proposed studies address a limitation of past work by carefully parsing flexibility into its core components in children with ASD. Children with and without ASD will be genotyped for a serotonin transporter gene implicated in both ASD and cognitive flexibility and will participate in functional MRI and psychological batteries that assess cognitive flexibility and ASD symptoms. Children with ASD and the risk allele for the serotonin transporter gene are predicted to make more errors on flexibility tasks and show greater deviance in the structure and function of brain regions activated. The career development plan includes cross-disciplinary training in advanced MRI techniques, neuroanatomy, neurobiology, genetics, neuropsychology, and imaging genomics; training comes from formal didactics, directed readings and laboratoryexperiences with a distinguished panel of expert co-mentors with a neurologist as lead mentor. Research environment: The candidate's main training and research will occur in a burgeoning, collaborative autism research program at Children's National Medical Center and Georgetown University, and he will receive in-depth advanced training from established institutional and personal collaborations with scientists at the Children's Hospital of Philadelphia and Stanford University. PUBLIC HEALTH RELEVANCE: According to the Center for Disease Control, 1 in 150 children in the US has autism. Repetitive behaviors and rigid, inflexible thinking are cardinal symptoms of the disorder and prevent many otherwise high funcitoning people from being poductive members of main stream society. Yet our understanding of these symptoms remains limited at cognitive, brain, and genetic levels of analysis. The proposed work seeks to define neural and genetic contributors to this cluster of autism symptoms in order to help us pursue the causes of, and target interventions to treat, these core autism deficits.