The NFκBDifis required for behavioral and molecular correlates of sleep homeostasis inDrosophila

Abstract

AbstractThe nuclear factor binding the κ light chain in B-cells (NFκB) is involved in a wide range of cellular processes including development, growth, innate immunity, and sleep. However, efforts have been limited toward understanding how specific NFκB transcription factors function in sleep.Drosophilafruit flies carry three genes encoding NFκB transcription factors,Dorsal,Dorsal Immunity Factor(Dif), andRelish. We previously found that loss of theRelishgene from fat body suppressed daily nighttime sleep, and abolished infection-induced sleep. Here we show thatDifregulates daily sleep and recovery sleep following prolonged wakefulness. Mutants ofDifshowed reduced daily sleep and suppressed recovery in response to sleep deprivation. Pan-neuronal knockdown ofDifstrongly suppressed daily sleep, indicating that in contrast toRelish,Diffunctions from the central nervous system to regulate sleep.Based on the distribution of aDif-associated GAL4 driver, we hypothesized that its effects on sleep were mediated by the pars intercerebralis (PI). While RNAi knock-down ofDifin the PI reduced daily sleep, it had no effect on the recovery response to sleep deprivation. However, recovery sleep was suppressed when RNAi knock-down ofDifwas distributed across a wider range of neurons. Induction of thenemuri(nur) antimicrobial peptide by sleep deprivation was suppressed inDifmutants and pan-neuronal over-expression ofnuralso suppressed theDifmutant phenotype. Together, these findings indicate thatDiffunctions from brain to targetnemuriand to promote sleep.Statement of SignificanceNFκB transcription factors drive inflammatory processes that underly a multitude of human diseases that are accompanied by sleep disturbance. However, genetic studies in mammals that investigate a function of NFκB in sleep have been limited. Using genetic approaches in theDrosophilafruit fly, we show that theDifNFκB, homologous to theRelfamily of NFκBs in humans, functions from neuronal tissue to regulate daily sleep and to mediate responses to sleep loss. These findings enhance our understanding of the role of a specific NFκB gene in sleep regulation.