Genetic and neural pathways for the sleep-regulatory function of ornithine metabolism in Drosophila sleep

Abstract

Sleep is essential physiology conserved across animal species. Evolutionary-development analyses of Drosophila and Hydra sleep have identified ornithine metabolism as a part of the ancestral sleep-regulatory pathways. Here we demonstrate genetic and neural mechanisms underlying sleep-promoting effects of ornithine (SPEO) in Drosophila. Dietary ornithine induced sleep more evidently in wild-type females, consistent with long-sleep phenotypes caused by pan-neuronal depletion or genomic deletion of ornithine aminotransferase that metabolizes ornithine and alpha-ketoglutarate into glutamate and glutamate-5-semialdehyde. Short-sleep mutants of the voltage-gated K+ channel Shaker, but not of the dopamine transporter, were sensitized to the dietary SPEO. By contrast, oral administration of the wake-promoting carbamazepine potently masked the dietary SPEO, whereas an arousing dopamine precursor showed additive effects. Genetic and pharmacological manipulations of Drosophila sleep further supported the implication of GABA transmission in SPEO. Finally, we identified a specific neural locus in the fly brain that controls the dietary SPEO. These data together propose that a key metabolite from the urea cycle may have established sleep-regulatory function in primitive brain-less organisms and then acquired its dedicated genetic and neural pathways during the evolution of the central nervous system.