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.

PROJECT NARRATIVE Sensory hypersensitivity is a central issue in autism and autism-related disorders like Fragile X syndrome (FX), and relatively little is known about the underlying brain mechanisms. This proposal combines novel behavioral assays for assessing sound hypersensitivity in rodents with state-of-the-art electrophysiological, chemogenetic, and analytical techniques to determine the currently poorly understood nature of auditory perceptual and circuit abnormalities in FX. Results from this study will uncover fundamental neural disruptions at the core of FX and autism as well as provide a clinically translatable platform for screening potential therapies for auditory disturbances in these common and debilitating disorders.