Mechanisms of sound hypersensitivity in a rat model of autism

项目摘要 感觉过敏，特别是在听觉领域，是最常见的和衰弱的 自闭症谱系障碍（ASD）的特征。听觉超敏反应不仅是一个核心缺陷， ASD的临床问题，但它可能有助于并反映了基本的大脑病理学， 更复杂但更难理解的自闭症特征，如沟通障碍和异常的社交能力， 互动因此，确定ASD中异常声音感知的性质是一种易于处理的模型，用于确定ASD中异常声音感知的性质。 确定ASD中的核心细胞和电路改变，这也对独特的 障碍的方面。我开发了新颖的行为范例来测量响度、增长和声音 啮齿动物的不耐受性。利用这些工具，我确定了一个经过充分验证的脆性X综合征大鼠模型， (FX)，ASD的主要遗传原因之一，表现出夸大的响度感知和极端 声音回避行为，与在大多数FX个体中观察到的听觉超敏性一致。 该提议将联合收割机这些新的行为测定与高密度体内多电极、离体 全细胞电生理记录，和新的细胞类型特异性化学遗传操作， 确定改变的听觉网络活动如何引起异常的声音感知和响度 在Fmr 1 KO动物中的不耐受性。从这些目标的结果将：（1）提供洞察临床相关 FX和其他自闭症相关疾病的特征;（2）揭示核心的基本神经中断 ASD病理生理学;和（3）为筛选FX和ASD的潜在疗法提供了新的平台。 本文的研究是对我以前工作的一个逻辑延伸和新的方向。 神经发育障碍和经验依赖性可塑性的机制。为指导 我的导师，共同导师和合作者，我将开发实验和智力工具，解剖 神经回路涉及感觉信息的动态编码，以及这些过程如何被 自闭症和听觉过敏等神经系统疾病的患者技术和专业培训， 我在这里收到的信息将有助于我建立一个独立的学术实验室的最终目标 在那里我可以联合收割机结合上述技术来研究经验如何在多个不同的时间塑造功能性大脑回路。 分析的水平，使用听觉系统作为模型，也与直接的临床影响。

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.