The impact of sleep dysregulation on Autism Spectrum Disorder: Abstract As many as 80% of children with Autism Spectrum Disorder (ASD) experience sleep disruptions. These are among the most burdensome symptoms reported by parents of children with ASD. Insufficient subjective sleep quality is associated with exacerbated severity of core ASD symptoms, including repetitive behaviors, social and communication difficulties. However, the few objective sleep PSG studies have not found significant effects. This likely reflects the small number of studies that utilized PSG as an objective sleep measure, small sample sizes, or assessment in a laboratory setting rather than in the child's home environment. Our own investigation of a larger sample using sleep PSG in ASD subjects, in their home, found an increased SWS ratio in ASD and a lower REM sleep ratio compared to typically developing (TD) children and adolescents. To address the critical question of whether dysregulated sleep is central to the development and symptoms of ASD, we will test for differences in sleep fragmentation (actigraphy), sleep architecture (PSG) and daytime, awake, resting state EEG, in 150 individuals with ASD and 75 age and sex-matched TD controls, age 4-17. We will examine if any observed sleep dysregulation is associated with the core symptoms, repetitive behaviors, and cognitive function of ASD. We will also examine if sleep impairments are associated with dysregulated daytime, resting state EEG in ASD compared to TD. In collaboration with Project 2, we will examine if target engagement-induced normalization of sleep positively impacts these symptoms. In collaboration with Projects 3 and 4, we will examine if the hypothesized impairments in sleep fragmentation, sleep architecture and daytime awake, resting state EEG in ASD will be recapitulated in our animal experiments of sleep in genetic models of ASD and if normalization of sleep fragmentation, sleep architecture and daytime awake, resting EEG in our animal models of ASD will be associated with improved social communication and cognition, and reduced repetitive behaviors in these animal models. If we demonstrate that sleep fragmentation is responsible for the development of some ASD traits and sleep normalization alleviates them, we will have demonstrated the potential causality and importance of sleep in ASD.