Mechanisms of Loudness Intolerance in a Rat Model of Fragile X

脆性 X 大鼠模型的响度不耐受机制

• 批准号: 9978352
• 负责人: RICHARD J SALVI
• 金额: $ 23.93万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9978352
• 关键词: Address; Aggressive behavior; Amygdaloid structure; Animals; Area; Attenuated; Auditory; Auditory Perception; Auditory area; Automobile Driving; Behavior; Behavioral; Behavioral Assay; Behavioral Paradigm; Biological Assay; Brain; Brain region; Catabolism; Clinic; Clinical; Clinical Assessment Tool; Complex; Defect; Development; Diagnostic; Disease; Electrophysiology (science); Equilibrium; Exhibits; FMR1; Fragile X Syndrome; Functional disorder; Goals; Growth; Human; Human Genetics; Hyperactive behavior; Hyperacusis; Hypersensitivity; Impairment; Individual; Inherited; Intervention; Lateral; Lead; Link; Loudness; Loudness Perception; Measures; Methods; Modeling; Molecular; Nature; Neurons; Outcome Measure; Pharmacology; Pharmacotherapy; Prevalence; Process; Quality of life; Rattus; Research; Rodent; Role; Self-Injurious Behavior; Sensory; Social Behavior; Social Interaction; Structure; Symptoms; Synapses; System; Techniques; Testing; Translating; Translations; Vigabatrin; autism spectrum disorder; autistic; avoidance behavior; behavioral phenotyping; cellular pathology; clinically relevant; density; endophenotype; experimental study; in vivo; insight; metabotropic glutamate receptor 5; molecular pathology; neural circuit; neurophysiology; novel; relating to nervous system; response; screening; sound; tool

Abstract Converging evidence from human and animal studies have identified cellular and molecular disruptions that are central to the pathophysiology of autism spectrum disorders (ASD). Connecting this molecular pathology to behavioral phenotypes in ASD has been limited by our understanding of how these disruptions manifest at the neural circuit level, which in turn has impeded development of ASD therapies. Aberrant sensory processing is a key diagnostic criterion for ASD that is likely related to fundamental circuit deficits underlying more complex but less accessible features of the disorder, such as communicative impairment and abnormal social behavior. Sensory hypersensitivity, particularly in the auditory realm, also profoundly impacts the quality of life for autistic individuals and is associated with self-harm and aggression. Thus, determining the nature of aberrant sound perception in ASD is a tractable model for identifying core circuit and system level alterations in ASD that also has direct clinical implications for unique aspects of the disorder. We have developed novel behavioral paradigms to measure loudness growth and sound intolerance in rodents. Using these tools, we found 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. Here we propose to combine these novel behavioral assays with high-density in vivo electrophysiological recordings and local pharmacological manipulation of multiple brain areas to determine how altered auditory network activity gives rise to aberrant sound perception in Fmr1 KO animals. In addition, we will test several distinct pharmacological therapies aimed at reversing these sensory disturbances. 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.

抽象的 来自人类和动物研究的综合证据已经确定了细胞和分子的破坏 是自闭症谱系障碍 (ASD) 病理生理学的核心。连接这种分子病理学 对 ASD 行为表型的认识受到我们对这些干扰如何在 神经回路水平，这反过来又阻碍了 ASD 疗法的发展。感觉处理异常 是 ASD 的一个关键诊断标准，可能与更多潜在的基本电路缺陷有关 该疾病的复杂但不易理解的特征，例如沟通障碍和异常的社交 行为。感觉过敏，特别是听觉领域，也深刻影响生活质量 对于自闭症患者来说，这与自残和攻击行为有关。因此，确定性质 ASD 中的异常声音感知是一个易于处理的模型，用于识别 ASD 中的核心电路和系统级更改 自闭症谱系障碍 (ASD) 对该疾病的独特方面也具有直接的临床意义。我们开发了新颖的 测量啮齿动物响度增长和声音不耐受的行为范式。使用这些工具，我们 发现一种经过充分验证的脆性 X 综合征 (FX) 大鼠模型，这是自闭症谱系障碍 (ASD) 的主要遗传原因之一， 表现出夸张的响度感知和极端的声音回避行为，与听觉一致 在大多数 FX 个体中观察到超敏反应。在这里，我们建议将这些新颖的行为结合起来 高密度体内电生理记录和局部药理学操作的测定 多个大脑区域以确定听觉网络活动的改变如何引起异常的声音感知 在 Fmr1 KO 动物中。此外，我们将测试几种不同的药物疗法，旨在逆转 这些感觉障碍。这些目标的结果将：（1）深入了解临床相关特征 FX 和其他自闭症相关疾病； (2) 揭示 ASD 核心的基本神经破坏 病理生理学； (3) 提供一个新的平台来筛选 FX 和 ASD 的潜在疗法。