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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.