Serine metabolism in the brain regulates starvation-induced sleep suppression in <i>Drosophila melanogaster</i>.

Abstract

Sleep and metabolism are physiologically and behaviorally intertwined; however, the molecular basis for their interaction remains poorly understood. Here, we identified a serine metabolic pathway as a key mediator for starvation-induced sleep suppression. Transcriptome analyses revealed that enzymes involved in serine biosynthesis were induced upon starvation in <i>Drosophila melanogaster</i> brains. Genetic mutants of <i>astray</i> (<i>aay</i>), a fly homolog of the rate-limiting phosphoserine phosphatase in serine biosynthesis, displayed reduced starvation-induced sleep suppression. In contrast, a hypomorphic mutation in a serine/threonine-metabolizing enzyme, <i>serine/threonine dehydratase</i> (<i>stdh</i>), exaggerated starvation-induced sleep suppression. Analyses of double mutants indicated that <i>aay</i> and <i>stdh</i> act on the same genetic pathway to titrate serine levels in the head as well as to adjust starvation-induced sleep behaviors. RNA interference-mediated depletion of <i>aay</i> expression in neurons, using cholinergic Gal4 drivers, phenocopied <i>aay</i> mutants, while a nicotinic acetylcholine receptor antagonist selectively rescued the exaggerated starvation-induced sleep suppression in <i>stdh</i> mutants. Taken together, these data demonstrate that neural serine metabolism controls sleep during starvation, possibly via cholinergic signaling. We propose that animals have evolved a sleep-regulatory mechanism that reprograms amino acid metabolism for adaptive sleep behaviors in response to metabolic needs.