Rhythmic expression ofNeurofibromin 1in mushroom body neurons mediates circadian wake drive through activating cAMP−PKA signaling

SUMMARY Various behavioral and cognitive states exhibit circadian variations in animals across phyla including Drosophila , in which only ∼0.1% of the entire brain neurons contain circadian clocks. This suggests that clock neurons communicate with a plethora of non-clock neurons to transmit the timing information to gate various behavioral outputs in Drosophila . Here, we address the molecular underpinning of this phenomenon by performing circadian RNA-seq analysis of non-clock neurons that constitute the mushroom body (MB), the center of information processing and sleep regulation. We identify hundreds of genes rhythmically expressed in the MB, including the Drosophila ortholog of Neurofibromin 1 ( Nf1 ), the gene responsible for neurofibromatosis type 1 (NF1). Rhythmic expression of Nf1 promotes daytime wakefulness by activating cAMP−PKA signaling and increasing excitability of the MB. These findings reveal the pervasive, non-cell-autonomous circadian regulation of gene expression in the brain and its role in sleep, with implications in the pathology of NF1.