Molecular Factors Governing Sleep Circuit Maturation And Neurodevelopmental Disorders

Early life sleep is critical for normal development of neural circuits. Despite the diversity in presentation of neurodevelopmental disorders (NDDs), sleep disruptions are among the most commonly-reported symptoms, suggesting sleep deficits may contribute to the severity of other symptoms. In this thesis, we used Drosophila melanogaster to interrogate the link between development and sleep in the context of pathology and normal physiology. We set out first to identify mechanisms underlying sleep disturbances in NDDs. From a reverse-genetic screen of Drosophila orthologs of human NDD-related genes, we found brain-specific knockdown of the chromatin remodeler Imitation SWItch/SNF (ISWI) resulted in dramatically reduced sleep duration. ISWI knockdown during a pre-adult developmental stage led to sleep deficits and morphologic and functional disruptions in adult sleep-promoting neurons. In the setting of ISWI loss, expressing the human ortholog of ISWI, SMARCA5, rescued sleep, while patient variants of SMARCA5 did not rescue sleep behavior. These results support the hypothesis that NDD-related sleep deficits are primary phenotypes of developmental origin. In the second part of this thesis, we investigated how maturation of sleep output neurons contributes to changes in sleep architecture changes across the lifespan. Excess sleep duration in juvenile flies was driven by a decreased probability of transitioning to wake. Hidden Markov modeling revealed juvenile flies spend more time in the deepest sleep stages compared to mature flies. Functional manipulations of the sleep output neurons in the dorsal fan-shaped body (dFB) revealed differential control of sleep between juvenile and mature flies. Transcriptomic profiling of these neurons revealed dynamic molecular landscapes between juvenile and mature flies. A subsequent RNAi-based screen of differentially-expressed genes in the dFB between juvenile and mature flies identified specific genes involved in distinct processes in the maturation of sleep architecture. These results establish a model for investigating the molecular mechanisms underlying the unique sleep architecture in juveniles, and have implications for developing targeted therapies for sleep deficits in early life