The Role of Central Gain Control in Hyperacusis of Diverse Origin

 描述(申请人提供)：听力过敏症是一种普遍存在的感觉障碍，中等强度的声音被认为是无法忍受的响声，甚至是疼痛。尽管听力过敏症对社会和经济产生了重大影响，但对这种疾病的治疗仍然缺乏。虽然听力损失一直被认为是听力亢进的主要危险因素，但许多其他疾病也与响度不耐受有关，这表明听力亢进的原因可能是多种多样的。听力亢进在几种神经发育障碍中尤其普遍，如威廉姆斯综合征、脆性X综合征(FX)和自闭症谱系障碍(ASD)。这项建议的目的是直接比较不同起源的听觉过敏的潜在机制，以确定是否存在共同的神经紊乱，表现为听觉过敏。具体地说，这项拟议的工作将检验这一假说，即中枢增益控制改变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。在这些模型中，将使用电生理和行为测量相结合的方法来表征中枢听觉多动和类听觉过敏症行为之间的关系，以：(1)确定听力损失引起的听觉过敏症的神经相关性；(2)在FX动物模型中表征听觉过敏症和潜在的神经相关性；以及(3)识别可以改善听力损失和FX模型中的听觉过敏症措施的药物。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.