Identification and characterization of the novel sleep regulatory pathways in Drosophila melanogaster

Abstract

Sleep is an important physiology for animals including mammals and insects. It shares many features like prolonged quiescence, reduced responsiveness and activity. Sleep is regulated by the circadian rhythm, which controls the time of sleep, and the homeostatic factor, which controls the amount of sleep needs. The fruit fly, Drosophila melanogaster, has proven useful in the search for the molecular mechanisms of sleep. Using Drosophila as a model system, we identified two novel sleep regulating signals, the histaminergic signaling and Mip-SPR signaling, and investigated their regulatory mechanisms using genetic and pharmacological means. Histamine is an important neurotransmitter known to control photoreception and temperature sensing in Drosophila. However, its role in sleep-wake regulation has not yet been established. Here, we obtained mutant flies exhibiting low expression of histidine decarboxylase (hdc) and two histamine receptors, histamine-gated chloride channel subunit 1 (hisCl1) and ora transientless (ort), and assayed them for baseline sleep phenotypes. The hdc and hisCl1 mutants exhibited increases in sleep duration. In contrast, ort mutants showed no change in sleep patterns. Increases in sleep parameters in the hdc and hisCl1 mutants were reversed by histamine treatment or expression of the histamine receptor, hisCl1, in pigment dispersing factor (PDF) neurons. Elevation of histamine levels decreased sleep in wild-type flies. Histamine treatment tests revealed that PDF neurons are important for histamine signaling-mediated wake activation. These data show that the histamine-HisCl1 receptor axis can activate and maintain the wakeful state in Drosophila, and that wake-activating signals may travel via the PDF neurons. Sex peptide receptor (SPR) mediates the post-mating switch in Drosophila reproductive behavior. Sex peptide (SP), the first known class of SPR ligands, activates the downstream signaling of SPR and evokes the post-mating behavioral sw...