The Role of Central Gain Control in Hyperacusis of Diverse Origin

 描述（由申请人提供）：听觉过敏是一种普遍的感觉障碍，其中中等强度的声音被认为是难以忍受的响亮甚至疼痛。尽管听觉过敏症对社会和经济有重大影响，但缺乏对这种疾病的治疗。虽然听力损失一直被认为是听觉过敏的主要危险因素，但许多其他疾病也与响度不耐受有关，这表明听觉过敏的原因可能是多种多样的。听觉过敏在几种神经发育障碍中特别普遍，例如威廉姆斯综合征、脆性X综合征（FX）和自闭症谱系障碍（ASD）。该建议的目的是直接比较不同起源的听觉过敏的潜在机制，以确定是否有一个共同的神经中断，表现出听觉超敏反应。具体来说，拟议的工作将测试这样的假设，即改变的中央增益控制是两种不同的听觉过敏模型中常见的病理生理机制：长期听力损失和FX的动物模型，FX是ASD的主要遗传原因。电生理学和行为测量的组合将用于表征这些模型中中枢听觉过度活跃和听觉过度样行为之间的关系，以：（1）确定由于听力损失引起的听觉过度的神经相关性;（2）表征FX动物模型中的听觉过度和潜在的神经相关性;以及（3）确定可以改善听力损失和FX模型中的听觉过敏测量的药物。了解这些不同形式的听觉过敏是如何相似和/或不同的，将提供与理解和治疗听觉过敏相关的临床和基础科学见解。

 DESCRIPTION (provided by applicant): Hyperacusis is a prevalent sensory disorder in which sounds of moderate intensity are perceived as intolerably loud or even painful. Despite the significant societal and economic impact of hyperacusis, treatments for this disorder are lacking. While hearing loss has consistently been identified as the primary risk factor for hyperacusis, many other disorders are also associated with loudness intolerance, suggesting the causes of hyperacusis can be varied. Hyperacusis is particularly prevalent in several neurodevelopmental disorders, such as Williams Syndrome, Fragile X Syndrome (FX), and autism spectrum disorders (ASD). The aim of this proposal is to directly compare the mechanisms underlying hyperacusis of distinct origin to determine if there is a shared neural disruption that manifests a auditory hypersensitivity. Specifically, the proposed work will test the hypothesis that altered central gain control is a common pathophysiological mechanism in two distinct models of hyperacusis: long-term hearing loss and an animal model of FX, the leading inherited cause of ASD. A combination of electrophysiological and behavioral measures will be used to characterize the relationship between central auditory hyperactivity and hyperacusis-like behavior in these models to: (1) determine the neural correlates of hyperacusis due to hearing loss; (2) characterize hyperacusis and the potential neural correlates in an animal model of FX; and (3) identify drugs that may ameliorate measures of hyperacusis in both hearing loss and FX models. Understanding how these distinct forms of hyperacusis are similar and/or different will provide both clinical and basic science insights relevant to understanding and treating hyperacusis.