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Mechanisms of sound hypersensitivity in a rat model of autism

自闭症大鼠模型声音超敏反应的机制

基本信息

批准号：
10377540
负责人：
Benjamin D Auerbach
金额：
$ 14.51万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-10 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10377540
关键词：
Animals Area Auditory Auditory Perception Auditory area Auditory system Automobile Driving Behavioral Behavioral Assay Behavioral Paradigm Brain Brain Pathology Brain region Cells Chronic Clinical Closure by clamp Communication impairment Complex Disease Electrodes Electrophysiology (science)Equilibrium Etiology Exhibits FMR1 Fragile X Syndrome Functional disorder Funding Goals Growth Hyperactivity Hyperacusis Hypersensitivity Impairment Individual Inherited Interneurons Ion Channel Laboratories Lead Loudness Loudness Perception Measures Mentors Modeling Nature Neurodevelopmental Disorder Neurons Pathology Perception Population Positioning Attribute Postdoctoral Fellow Preparation Prevalence Process Rattus Research Rodent Role Sensory Severities Shapes Slice Social Interaction Symptoms Synapses System Techniques Testing Thalamic structure Training Viral Work autism spectrum disorder avoidance behavior awake behavioral phenotyping cell type clinically relevant clinically translatable density excitatory neuron experience gamma-Aminobutyric Acid genetic manipulation hearing impairment in vivo inhibitory neuron insight nervous system disorder neural circuit neuronal excitability neurophysiology novel patch clamp programs relating to nervous system response screening sound synaptic function tool voltage clamp

项目摘要

PROJECT SUMMARY Sensory hypersensitivity, particularly in the auditory realm, is one of the most common and debilitating features of autism spectrum disorders (ASD). Not only is auditory hypersensitivity a core deficit and important clinical problem in ASD, but it likely contributes to and reflects fundamental brain pathology that will extend to more complex but less accessible features of autism, such as communication impairment and abnormal social interaction. Thus, determining the nature of aberrant sound perception in ASD is a tractable model for identifying core cellular and circuit alterations in ASD that also has direct clinical implications for unique aspects of the disorder. I have developed novel behavioral paradigms to measure loudness growth and sound intolerance in rodents. Using these tools, I determined that a well-validated rat model of Fragile X Syndrome (FX), one of the leading inherited causes of ASD, exhibits exaggerated loudness perception and extreme sound avoidance behavior, consistent with auditory hypersensitivity observed in a majority of FX individuals. This proposal will combine these novel behavioral assays with high-density in vivo multi-electrode, ex vivo whole-cell electrophysiological recordings, and novel cell-type specific chemogenetic manipulations to determine how altered auditory network activity gives rise to aberrant sound perception and loudness intolerance in Fmr1 KO animals. The results from these aims will: (1) offer insight into clinically relevant features of FX and other autism-related disorders; (2) uncover fundamental neural disruptions at the core of ASD pathophysiology; and (3) provide a novel platform for screening potential therapies for FX and ASD. The proposed research is both a logical extension and novel direction from my previous work in neurodevelopmental disorders and the mechanisms of experience-dependent plasticity. With the guidance of my mentor, co-mentors and collaborator, I will develop the experimental and intellectual tools for dissecting the neural circuits involved the dynamic encoding of sensory information, and how these processes may be disturbed in neurological disorders like autism and hyperacusis. The technical and professional training I would receive here will be instrumental towards my ultimate goal of establishing an independent academic laboratory where I can combine the above techniques to study how experience shapes functional brain circuits at multiple levels of analysis, using the auditory system as a model that is also associated with direct clinical implications.

项目总结