Identification Of A Molecular Basis For The Juvenile Sleep State

Sleep is a highly conserved behavior critical to nervous system function. Across species, sleep amounts are highest in young animals and taper with maturity. These ontogenetic changes to sleep have long been thought to facilitate brain maturation. Indeed, developmental sleep abnormalities are highly prevalent across neuropsychiatric disorders. However, knowledge of the genetic and molecular factors controlling early life sleep is lacking. Here, we use Drosophila to investigate the juvenile sleep state. Detailed behavioral characterization supports the idea that juvenile sleep represents a distinct behavioral state, uniquely evolved for the needs of a developing nervous system. Consistent with this, we find that sleep ontogenetic change is preserved in all studied short and long sleeping Drosophila mutants, suggesting that the molecular determinants of adult sleep duration do not regulate developmental sleep transitions. Through an RNAi-based screen, we identified the transcription factor pdm3 as the first known genetic regulator of sleep ontogeny. Increased sleep in young flies is normally driven by elevated activity of the sleep-promoting dorsal fan shaped body (dFSB). Loss of PDM3 leads to a premature increase in inhibitory wake-promoting dopaminergic (DA) synapses in the dFSB, reducing dFSB activity and preventing young flies from achieving the high sleep amounts normally observed. Pdm3 acts during the mid-pupal developmental stage to control DA projection ingrowth to this sleep region. Transcriptional analysis indicated that pdm3-mediated repression of the synaptogenesis gene Msp300 controls sleep ontogeny. Overall, this work demonstrates that juvenile sleep is a unique behavior subject to distinct genetic regulation, and provides the first insight into molecular cues governing sleep ontogeny. Further, our findings support the existence of a new class of developmentally-expressed sleep genes that orchestrate sleep circuit formation, raising the possibility that some primary sleep disorders are of neurodevelopmental origin.