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：培训候选人成为一名独立的临床研究人员，并解决主要但被忽视的自闭症谱系障碍（ASD）的限制性重复症状的大脑（和遗传）基础。长期目标包括：开发一个综合研究模型，让我们了解ASD的原因，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ASD中涉及限制性、重复性行为和兴趣症状的大脑区域和基因。认知灵活性是研究这一症状群的一个窗口，提出的研究通过仔细地将灵活性解析为自闭症儿童的核心组成部分，解决了过去工作的局限性。患有和不患有ASD的儿童将对涉及ASD和认知灵活性的血清素转运基因进行基因分型，并将参与功能性MRI和心理测试，以评估认知灵活性和ASD症状。据预测，患有ASD和血清素转运基因风险等位基因的儿童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上表现出更大的偏差。职业发展计划包括高级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；培训来自正式教学，指导阅读和实验室经验，由一组杰出的专家共同导师组成，神经学家作为主要导师。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城大学的一个新兴的合作自闭症研究项目中进行，他将接受来自费城儿童医院和斯坦福大学的科学家建立的机构和个人合作的深入高级培训。

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.