Atypical sensory processing is widely observed in individuals with autism spectrum disorder (ASD) although the underlying biological mechanisms are unknown. Previous work has largely focused on alterations in neural processing at early stages, such as sensory neurons in the periphery and primary sensory areas in the brain. However, the relative contributions of areas outside these pathways to perceptual dysfunction in ASD has not been evaluated. he locus coeruleus – norepinephrine (LC-NE) system has been hypothesized to play a role in several ASD comorbidities, including deficits in motor learning, attention, and arousal. This project will extend this work to determine whether LC-NE dysregulation plays a role in perceptual deficits in ASD. Experiments will use a perceptual integration task in which sensory information is presented in brief, randomly timed pulses. This task was developed to distinguish the relative contribution of sensory and cognitive deficits to perceptual decisions and to facilitate cross-species (human-animal) analysis.

Preliminary studies funded by a SFARI Human Cognitive and Behavioral Science Award have validated the task in individuals with ASD. This project will extend the task to a mouse model of ASD (Shank3 KO). Behavioral data from Shank3 KO mice, human individuals with ASD and unaffected individuals will be analyzed and quantitatively compared using sequential sampling models, which provide individual-specific estimates of latent parameters that govern perception. Cellular resolution calcium imaging of the LC-NE neurons will be used to evaluate the potential role of LC-NE system dysregulation in perceptual symptoms in Shank3 KO mice performing the perceptual integration task. Finally, chemogenetic manipulation of LC-NE neurons will test the causal role of LC-NE in ASD-related perceptual phenotypes. Together, these experiments will evaluate the potential role of the LC-NE system in altered sensory processing in a rodent model of ASD.