Mechanisms of Loudness Intolerance in a Rat Model of Fragile X

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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.