Prefrontal corticothalamic circuits in autism

自闭症的前额皮质丘脑回路

基本信息

批准号：
9145809
负责人：
Audrey Christine Brumback
金额：
$ 5.88万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-30 至 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9145809
关键词：
Acute Animal Behavior Anticonvulsants Area Autistic Disorder Basic Science Behavior Behavioral Behavioral Symptoms Binding Proteins Bioethics Biometry Brain Brain region CNTNAP1 gene Calcium Cell Adhesion Molecules Cells Child Clinical Clinical Management Communication Complement Contralateral Data Data Analyses Defect Development Development Plans Disease Doctor of Philosophy Dorsal Electrophysiology (science)Equilibrium Exhibits Exposure to FMR1 Fiber Fragile X Gene Fragile X Syndrome Funding Future Genes Genetic Goals Health High Prevalence Histone Deacetylase Inhibitor Image Implant In Vitro Individual International K-Series Research Career Programs Knock-out Leadership Learning Link Manuscripts Measures Medial Mentors Mentorship Messenger RNA Modeling Mus Mutation Neurobiology Neurodevelopmental Disorder Neurologist Neurology Neuronal Dysfunction Neurons Neurosciences Optics Photometry Physicians Physiology Play Population Prefrontal Cortex Publishing Research Research Personnel Rest Role Running Scientist Signal Transduction Slice Social Behavior Social Interaction Symptoms Synapses Synaptic Transmission Techniques Testing Thalamic structure Therapeutic Training Translating Work autism spectrum disorder autistic behaviour awake base brain electrical activity career career development clinically relevant computer program design disability experience hippocampal pyramidal neuron in vivo interest meetings mouse model nervous system disorder neural circuit neuronal circuitry neuropsychiatric disorder neuropsychiatry optogenetics patch clamp prenatal prenatal exposure research and development research clinical testing research study signal processing skills social cognition social communication tool valproate

项目摘要

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.

描述（由申请人提供）：自闭症谱系障碍是一种普遍且具有破坏性的神经精神疾病，其特征是社交沟通障碍以及重复、受限的兴趣和行为。尽管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自闭症。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回路水平上相互联系以驱动自闭症相关行为。神经科学。我在神经生物学以及神经系统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大脑，以便成为一名独立的研究者，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，有几个我需要掌握的内容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研究者开展职业生涯所需的培训、指导和经验。赤字前额皮质丘脑神经元的兴奋性是常见的三种自闭症小鼠模型（脆性 X 敲除、CNTNAP2 敲除和产前丙戊酸暴露）重要的是，丙戊酸暴露小鼠的社会行为可以通过这些前额皮质丘脑神经元的急性个体发育激活或失活来双向调节。我将使用这些自闭症小鼠模型来测试有关前额皮质丘脑回路如何参与自闭症相关行为的具体假设。我将进行体外脑切片电生理学，以测试自闭症的假设，即前额皮质和丘脑之间的突触传递存在缺陷。在目标 2 中，我将在社交过程中对前额皮质和丘脑进行体内电生理学和体内钙成像。最后，在目标 3 中，我将对清醒的行为小鼠进行个体发育操作，以测试前额叶如何相互作用。我组建了一支由神经生物学和自闭症专家组成的团队作为导师——Vikaas Sohal 博士、Mattew State 和另外两位世界知名专家将担任该项目的顾问。体内电生理学（Loren Frank 博士）和行为实验（Jacqueline Crawley 博士）我将通过信号处理、数据分析、计算机编程、生物统计学等课程来补充指导研究。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有关自闭症谱系障碍的正式课程来磨练我的专业技能。完成职业发展奖后，我将成功申请 R01 级资助。由于个性化的职业发展计划，我将能够开始我作为一名医生科学家的职业生涯。和独立调查员领导一个富有成效的团队的研究人员专注于发现自闭症谱系障碍的细胞和基于回路的机制。