Prefrontal corticothalamic circuits in autism

 描述(由申请人提供)：自闭症谱系障碍是一种普遍和破坏性的神经精神疾病，其特征是社交障碍和重复的、受限的兴趣和行为。尽管许多基因变化与自闭症有关，但目前尚不清楚相关基因如何转化为临床症状。在拟议的研究中，我将使用尖端技术来发现自闭症的不同遗传原因如何在神经元电路水平上联系起来，以驱动与自闭症相关的行为。我是一名拥有神经科学博士学位的儿童神经科医生。我在神经生物学以及神经疾病的临床评估和管理方面接受过广泛的培训。我的长期目标是通过与临床相关的基础科学研究来了解自闭症患者的大脑。为了成为一名独立的研究员，管理着我自己富有成效的研究小组，阐明自闭症的神经生物学，我需要掌握几项技能。通过拟议的研究和职业发展计划，我将获得作为一名成功的独立调查员开始职业生涯所需的培训、指导和经验。我的初步研究显示，前额叶皮质丘脑神经元的兴奋性有一种特殊的缺陷，这种缺陷常见于 自闭症的三种小鼠模型(脆性X基因敲除、CNTNAP2基因敲除和产前丙戊酸盐暴露)。重要的是，暴露于丙戊酸盐的小鼠的社会行为可以通过这些前额叶皮质丘脑神经元的急性个体发育激活或失活来双向调节。在拟议的研究中，我将使用这些自闭症小鼠模型来测试有关前额叶皮质丘脑回路如何参与自闭症相关行为的特定假设。在目标1中，我将进行体外脑片电生理学来验证自闭症患者的假设，即前额叶皮质和丘脑之间的突触传递存在缺陷。在目标2中，我将对社会行为过程中的前额叶皮质和丘脑进行体内电生理学和体内钙成像，以确定这些区域在正常和自闭症大脑中是如何相互作用的。最后，在目标3中，我将在清醒、行为正常的小鼠身上进行个体发育操作，以测试前额叶皮质丘脑回路如何直接影响社会行为。我组建了一支神经生物学和自闭症方面的一流专家团队，担任导师--维卡斯·索哈尔博士、马修州立大学和伊莉莎·马尔科博士。另外两位世界知名的专家将担任体内电生理学(Loren Frank博士)和行为实验(Jacqueline Crawley博士)的顾问。我将用信号处理、数据分析、计算机编程、生物统计学和生物伦理学等课程来补充辅导性研究。通过State博士和Marco博士的指导，我将获得自闭症谱系障碍临床方面的专业知识。最后，我将通过发表原创研究手稿、在国际会议上展示我的工作，以及参加关于科学领导和管理的正式课程来磨练我的专业技能。到职业发展奖完成时，我将成功申请R01级资金。作为个性化护理人员发展计划的结果，我将能够开始我的职业生涯，作为一名内科科学家和独立调查员，领导一个富有成效的研究团队，专注于发现自闭症谱系障碍的细胞和电路机制。

 DESCRIPTION (provided by applicant): Autism spectrum disorder is a prevalent and devastating neuropsychiatric condition characterized by disabilities in social communication and repetitive, restricted interests and behaviors. Though many genetic changes have been linked to autism, it is unclear how the implicated genes translate into clinical symptoms. In the proposed studies, I will use cutting-edge techniques to discover how diverse genetic causes of autism connect at the level of neuronal circuits to drive autism-associated behaviors. I am a board-certified Child Neurologist with a PhD in Neuroscience. I have extensive training in neurobiology and the clinical evaluation and management of neurological diseases. My long-term goal is to understand the autistic brain through clinically-relevant basic science research. In order to become an independent investigator running my own productive research group elucidating the neurobiology of autism, there are several skills I need to master. Through the proposed research and career development plan, I will obtain the training, mentorship, and experience I need to launch my career as a successful independent investigator. My preliminary studies show a specific deficit in the excitability of prefrontal corticothalamic neurons that is common to three mouse models of autism (Fragile X knockout, CNTNAP2 knockout, and prenatal valproate exposure). Importantly, the social behavior of valproate-exposed mice can be bidirectionally modulated by acute ontogenetic activation or inactivation of these prefrontal corticothalamic neurons. In the proposed studies, I will use these mouse models of autism to test specific hypotheses about how the prefrontal corticothalamic circuit participates in autism-associated behaviors. In Aim 1, I will perform in vitro brain slice electrophysiology to test the hypothesis tat in autism, synaptic transmission is defective between the prefrontal cortex and thalamus. In Aim 2, I will perform in vivo electrophysiology and in vivo calcium imaging of the prefrontal cortex and thalamus during social behavior to determine how these regions interact in the normal and autistic brain. Finally, in Aim 3, I will perform ontogenetic manipulations in awake, behaving mice to test how the prefrontal corticothalamic circuit directly contributes to social behavior. I have assembled a stellar team of experts in neurobiology and autism to serve as mentors - Drs. Vikaas Sohal, Mattew State, and Elysa Marco. Two other world-renown experts will serve as advisors for the in vivo electrophysiology (Dr. Loren Frank) and behavioral experiments (Dr. Jacqueline Crawley). I will supplement the mentored research with coursework on signal processing, data analysis, computer programming, biostatistics, and bioethics. I will gain expertise in the clinical aspects of autism spectrum disorder through mentoring by Drs. State and Marco. Finally, I will hone my professional skills by publishing original research manuscripts, presenting my work at international meetings, and participating in formal courses on scientific leadership and management. By the completion of the career development award, I will have successfully applied for R01-level funding. As a result of the individually-tailored carer development plan, I will be able to launch my career as a physician- scientist and independent investigator leading a productive team of researchers focused on discovering the cellular and circuit-based mechanisms of autism spectrum disorder.