Mechanisms of sound hypersensitivity in a rat model of autism

项目总结 感觉过敏，尤其是在听觉领域，是最常见和最令人衰弱的疾病之一 自闭症谱系障碍(ASD)的特点听觉过敏症不仅是一种核心缺陷和重要 ASD的临床问题，但它可能有助于并反映基本的大脑病理，这些病理将延伸到 自闭症更复杂但更难接近的特征，如沟通障碍和社交异常 互动。因此，确定ASD中异常声音知觉的性质是一个容易处理的模型 确定ASD的核心细胞和电路改变，这些改变也对独特的 精神障碍的各个方面。我开发了新的行为模式来测量响度、生长和声音 啮齿动物的不耐受性。使用这些工具，我确定了一个经过良好验证的脆性X综合征大鼠模型 (FX)是ASD的主要遗传原因之一，表现出夸张的响度感知和极端 声音回避行为，与在大多数外汇个体中观察到的听觉过敏症一致。 这一建议将把这些新的行为分析与体内高密度多电极、体外 全细胞电生理记录和新的细胞类型特异性化学发生操作 确定听觉网络活动改变如何导致声音感知和响度异常 Fmr1KO动物的不耐受。这些目标的结果将：(1)提供对临床相关的洞察 FX和其他与自闭症相关的障碍的特征；(2)发现核心的基本神经障碍 ASD的病理生理学；以及(3)为筛选FX和ASD的潜在治疗方法提供了一个新的平台。 建议的研究既是逻辑上的扩展，也是我在 神经发育障碍和经验依赖性可塑性的机制。在…的指导下 我的导师，共同导师和合作者，我将开发实验和智力工具来解剖 神经回路涉及感官信息的动态编码，以及这些过程是如何进行的 患有自闭症和听力过敏症等神经障碍。我将接受的技术和专业培训 在这里接受将有助于我建立一个独立的学术实验室的最终目标 在那里我可以结合上面的技术来研究体验是如何在多个 分析水平，使用听觉系统作为模型，也与直接的临床意义相关。

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.