Prefrontal corticothalamic circuits in autism

自闭症的前额皮质丘脑回路

基本信息

批准号：
9303467
负责人：
Audrey Christine Brumback
金额：
$ 17.86万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
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 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9303467
关键词：
Acute Alpha Cell 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 Heritability 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 Pathologic Photometry Physicians Physiology Play Population Prefrontal Cortex Pregnancy 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 associated symptom autism spectrum disorder autistic behaviour awake base career career development clinically relevant computer program design disability experience experimental study hippocampal pyramidal neuron in vivo in vivo calcium imaging interest meetings mouse model nervous system disorder neural circuit neuronal circuitry neuropsychiatric disorder neuropsychiatry optogenetics patch clamp prenatal prenatal exposure public health relevance research and development research clinical testing 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（由适用提供）：自闭症谱系障碍是一种流行而毁灭性的神经精神病学疾病，其特征是社会交流和重复性，受限制的利益和行为中的疾病。尽管许多遗传变化已与自闭症有关，但尚不清楚所涉及的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遗传原因如何在神经元电路级别连接以推动自闭症相关行为。我是董事会认证的儿童神经科医生，拥有神经科学博士学位。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了广泛的培训。我的长期目标是通过临床上相关的基础科学研究来了解加速的大脑。为了成为一名独立研究者，经营着自己的生产研究小组，阐明了自闭症的神经生物学，我需要掌握几种技能。通过拟议的研究和职业发展计划，我将获得培训，心态和经验，我需要启动作为成功的独立调查员的职业。我的初步研究表明，前额叶皮质丘脑神经元的兴奋中存在特定的缺陷，这是常见的自闭症的三种小鼠模型（脆弱的X敲除，CNTNAP2敲除和产前丙戊酸盐暴露）。重要的是，可以通过急性个体遗传激活或这些前额叶皮质丘脑神经元的急性种植激活或灭活来调节丙戊酸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的这些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AIM 1中，我将进行体外脑切片电生理学以测试自闭症中的假设TAT，突触传播在前额叶皮层和丘脑之间是有缺陷的。在AIM 2中，我将在社会行为过程中对前额叶皮层和丘脑的体内电生理学和体内钙成像，以确定这些区域如何在正常和加速的大脑中相互作用。最后，在AIM 3中，我将在清醒中执行构造操作，表现小鼠以测试前额叶皮质丘脑回路如何直接有助于社会行为。我已经组建了一支由神经生物学和自闭症专家组成的出色团队，以担任导师-DR。 Vikaas Sohal，Mattew State和Elysa Marco。另外两位世界著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。我将通过信号的课程来补充指导的研究，我将通过DRS的心理来获得自闭症谱系障碍的临床方面的专业知识。州和马可。最后，我将通过出版原始的研究手稿，在国际会议上介绍我的作品，并参加有关科学领导力和管理的正式课程，以尊重自己的专业技能。通过完成职业发展奖，我将成功申请R01级资金。由于个人量身定制的载体开发计划，我将能够启动自己的职业生涯，领导着一支富有生产力的研究人员的研究人员，致力于发现基于细胞和电路的自闭症谱系障碍机制。