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

• 批准号: 10425463
• 负责人: Benjamin D Auerbach
• 金额: $ 14.29万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 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/10425463
• 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

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.

项目摘要 感觉超敏反应，尤其是在听觉领域，是最常见和令人衰弱的一种 自闭症谱系障碍的特征（ASD）。听觉超敏反应不仅是核心赤字和重要 ASD中的临床问题，但它可能会导致并反映基本的大脑病理，这将扩展到 自闭症的更复杂但易于访问的特征，例如沟通障碍和异常社交 相互作用。因此，确定ASD中异常声音感知的性质是一个可寓言的模型 识别ASD中核心细胞和电路变化，这也对唯一具有直接的临床意义 该疾病的方面。我已经开发了新颖的行为范式来衡量响度的增长和声音 啮齿动物不耐受。使用这些工具，我确定了脆弱X综合征的验证良好的大鼠模型 （FX）是ASD的主要继承原因之一，表现出夸张的响度和极端 声音回避行为，与大多数FX个体中观察到的听觉超敏反应一致。 该建议将将这些新型行为测定与体内多电极中的高密度结合在一起 全细胞电生理记录和新型的细胞类型特异性化学遗传操作 确定听觉网络活动变化如何引起异常的声音感知和响度 FMR1 KO动物的不耐受。这些目标的结果将：（1）提供有关临床相关的见解 FX和其他与自闭症有关的疾病的特征； （2）发现基本神经干扰的核心 ASD病理生理学； （3）提供了一个新颖的平台，用于筛选FX和ASD的潜在疗法。 拟议的研究既是我以前的工作的逻辑扩展和新颖的方向 神经发育障碍和经验依赖性可塑性的机制。在指导 我的导师，联合官员和合作者，我将开发实验和智力工具，以剖析 神经回路涉及感官信息的动态编码，以及这些过程如何是 在自闭症和HyperAcusis等神经系统疾病中受到干扰。我会的技术和专业培训 在这里接收将有助于我建立独立学术实验室的最终目标 我可以在其中结合上述技术来研究体验如何在多个以上的功能性脑电路 分析级别，使用听觉系统作为与直接临床意义相关的模型。