- Awarded: 2019
- Award Type: Pilot
- Award #: 611534
Converging evidence from human and animal studies have identified cellular and molecular disruptions that are central to the pathophysiology of autism spectrum disorders (ASDs). 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. Sensory hypersensitivity, particularly in the auditory realm, is one of the most common and debilitating features of ASD. Not only is auditory hypersensitivity a pressing clinical problem in ASD, but it also likely reflects and contributes to fundamental brain pathology that extends to more complex but less accessible features of ASD, such as communication impairment and abnormal social interaction. Thus, understanding the nature of aberrant sound perception in ASD is a tractable model for identifying core circuit- and systems-level alterations in ASD that also has direct clinical implications.
Richard Salvi and his colleagues, Benjamin D. Auerbach and Kelly Radziwon, of the Center for Hearing and Deafness at the University at Buffalo, have developed novel behavioral paradigms for assessing auditory sensitivity and sound tolerance in rodents1 and propose to utilize these tools to assess circuit- and systems-level auditory deficits in a rat model of ASD. Fragile X syndrome (FXS) is one of the leading inherited causes of ASD, and, using the auditory tools their group has developed, Salvi and colleagues have determined that an Fmr1 knockout rat model of FXS exhibits exaggerated loudness perception and extreme sound avoidance behavior. These findings are consistent with auditory hypersensitivity observed in a majority of FXS individuals. Based on these preliminary findings, Salvi and colleagues propose to combine these novel behavioral assays with high-density in vivo electrophysiological recordings from multiple brain areas to determine how altered auditory network activity gives rise to aberrant sound perception and loudness intolerance in Fmr1 knockouts. This novel symptoms-to-circuit approach will: (1) offer insight into clinically relevant features of FXS and other autism-related disorders, (2) uncover fundamental neural disruptions central to ASD pathophysiology and (3) provide a new platform for screening potential therapies for FXS and other ASDs.