Prefrontal corticothalamic circuits in autism

 描述（由申请人提供）：自闭症谱系障碍是一种流行的和毁灭性的神经精神疾病，其特征是社会沟通和重复性的残疾，限制的兴趣和行为。虽然许多基因变化与自闭症有关，但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回路水平上连接，以驱动自闭症相关行为。我是一名获得委员会认证的儿童神经学家，拥有神经科学博士学位。我在神经生物学和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调查员，管理我自己的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，我将获得培训，指导和经验，我需要启动我的职业生涯作为一个成功的独立调查员。我的初步研究表明，前额叶皮质丘脑神经元的兴奋性有一个特定的缺陷，这是常见的， 三种自闭症小鼠模型（脆性X基因敲除、CNTNAP 2敲除和产前丙戊酸盐暴露）。重要的是，这些前额叶皮质丘脑神经元的急性个体发育激活或失活可双向调节丙戊酸盐暴露小鼠的社会行为。在拟议的研究中，我将使用这些自闭症小鼠模型来测试关于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。在目的1中，我将进行体外脑切片电生理学测试自闭症的假设达特即前额叶皮层和丘脑之间的突触传递是有缺陷的。在目标2中，我将在社会行为过程中对前额叶皮层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如何相互作用。最后，在目标3中，我将在清醒的行为小鼠中进行个体发育操作，以测试前额叶皮质丘脑回路如何直接影响社会行为。我组建了一个由神经生物学和自闭症专家组成的优秀团队，他们是Vikaas Sohal博士、Mattew State博士和Elysa Marco博士。另外两名世界知名的专家将担任顾问的体内电生理学（博士罗兰弗兰克）和行为实验（博士杰奎琳克劳利）。我将补充辅导的研究与课程的信号处理，数据分析，计算机编程，生物统计学和生物伦理学。我将通过State和Marco博士的指导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，并参加科学领导和管理的正式课程来磨练我的专业技能。通过职业发展奖的完成，我将成功申请R 01级资助。由于个人定制的护理人员发展计划，我将能够开始我的职业生涯，作为一名医生-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.