Project 2: Project Summary/Abstract Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social communication deficits, sensory abnormalities, and restricted/repetitive behaviors (RRB). Disrupted sleep is usually described as the one of the most burdensome symptoms in children and adolescents with ASD with rate of up to 80%. Animal studies demonstrate that sleep plays important roles in structural plasticity of synaptic networks, homeostatic rebalancing of synaptic strengths and the replay and consolidation of memories. In humans, sleep disruption is well documented to impair cognition and affect. In fact, parent reports have found insufficient sleep in individuals with ASD to exacerbate the severity of core symptoms, with increased RRB as well as worsening of social communication deficits. Therefore, increasing our understanding of sleep physiology and improving sleep in ASD is critical for the potential development of interventions that could benefit core autism features as well as in associated behaviors. While there is increased interest in the neurobiology of ASD, limited research has been conducted to elucidate the neurobiology of sleep disturbances. Recent investigations have provided evidence that children with ASD had shorter total sleep time, greater slow-wave sleep percentage, and much less rapid eye movement (REM) sleep percentage. However, despite the consistent findings of sleep abnormalities in ASD, limited studies have examined the effectiveness of pharmacological compounds on sleep physiology. Critically, there is a lack of investigations assessing the biologic effects of hypnotic agents on sleep architecture. The goal of the proposed project is to conduct a series of pilot trials to investigate the effect of three sleep-inducing agents with different mechanisms (diphenhydramine, zolpidem, and suvorexant) on sleep architecture in children and adolescents with ASD (age range 8-17 years). Diphenhydramine is an anti-histaminergic agent with strong hypnotic properties. Zolpidem is a nonbenzodiazepine Gamma Aminobutyric Acid-GABAa receptor agonist drug which acts as a sedative and hypnotic. Suvorexant is a selective, dual orexin receptor antagonist used for the treatment of sleep onset difficulties and/or sleep maintenance. We will use a randomized double-blind crossover placebo-controlled 8- week design to examine the effect of the 3 hypnotic compounds on sleep physiology and circadian rhythm as assessed by polysomnography, actigraphy, cortisol and melatonin saliva levels. These measures will be obtained before randomization, at week 4, and at week 8. Sleep measures will include slow wave sleep, Non- REM sleep, REM sleep, sleep efficiency, wake after sleep onset, and sleep latency. We will also compare the effect of the three agents on sleep parameters, circadian rhythm, and sleep quality. Finally, we will examine the relationship between these measures and changes in the clinical features of ASD, includin...