Hugin ⁺ neurons provide a link between sleep homeostat and circadian clock neurons

Abstract

Sleep is controlled by homeostatic mechanisms, which drive sleep after wakefulness, and a circadian clock, which confers the 24-h rhythm of sleep. These processes interact with each other to control the timing of sleep in a daily cycle as well as following sleep deprivation. However, the mechanisms by which they interact are poorly understood. We show here that hugin+ neurons, previously identified as neurons that function downstream of the clock to regulate rhythms of locomotor activity, are also targets of the sleep homeostat. Sleep deprivation decreases activity of hugin+ neurons, likely to suppress circadian-driven activity during recovery sleep, and ablation of hugin+ neurons promotes sleep increases generated by activation of the homeostatic sleep locus, the dorsal fan-shaped body (dFB). Also, mutations in peptides produced by the hugin+ locus increase recovery sleep following deprivation. Transsynaptic mapping reveals that hugin+ neurons feed back onto central clock neurons, which also show decreased activity upon sleep loss, in a Hugin peptide–dependent fashion. We propose that hugin+ neurons integrate circadian and sleep signals to modulate circadian circuitry and regulate the timing of sleep.

Insect PRXamides: Evolutionary Divergence, Novelty, and Loss in a Conserved Neuropeptide System

“…The hugin peptide sequence of Orthorrapha and Eremoneura is also highly conserved (SVPFKPRL) although single amino acid substitutions characterize some taxa (e.g., SVQFKPRL in the higher Calyptratae). In Drosophila melanogaster the hugin peptide plays a potentially novel role in regulation of circadian locomotor rhythms and feeding behaviors ( Sun et al 2014 , Schoofs et al 2014 , King et al 2017 , Schwarz et al 2021 ). Given the conserved sequence motif of the hugin peptide it is likely that these functions are supported by the hugin peptide throughout the Brachycera.…”

“…The genomic model organism Drosophila melanogaster has an unusual modification to the pk/pban gene: loss of the PBAN coding sequence, which is present in all other insects investigated to date including basal Diptera. and acquisition of the hugin peptide that functions in feeding and circadian locomotor activity ( Schoofs et al 2014 , Choi et al 2015 , Schwarz et al 2021 ). The Diptera are a diverse and speciose insect Order that has undergone three rapid bursts of diversification: the first in the most basal clades (i.e., the former ‘Nematocera’), the second in the early Brachycera, and the third in the Schizophora, a group contained within the modern Cyclorrhapha.…”

“…Recently, a novel population of hugin producing interneurons (Hugin TS in the third thoracic segment) was found to respond to rising glucose levels by inhibiting diuretic hormone 44 (DH44) producing neurons and promoting cessation of feeding behavior ( Oh et al 2021 ). Median neurosecretory cells in the PI produce (DH44) and send descending processes to the ventrolateral esophageal foramen neuropil where they overlap with the dendrites of GNG hugin neurons expressing the DH44 receptor ( McKellar 2016 , King et al 2017 , Schwarz et al 2021 ). Circadian release of DH44 is an important regulator of neurons that control sleep: activity rhythms suggesting that hugin neurons also contribute to daily behavioral rhythms ( Cavanaugh et al 2014 ).…”

“…Drosophila hugin efferents projecting to the CA of the ring gland also express the receptor for DH44 and thus are likely to participate in circadian functions of this neuroendocrine gland ( Mizuno et al 2021 ). Finally, GNG hugin neurons decrease activity and suppress circadian activity under sleep deprivation conditions, possibly via direct connections between ascending hugin interneurons and sleep homeostasis regulating neurons in the protocerebrum ( Schwarz et al 2021 ).…”

Single-cell transcriptomics reveals that glial cells integrate homeostatic and circadian processes to drive sleep-wake cycles

“…In flies, recent studies suggest a model where the sleep homeostat and the circadian clock interact indirectly with each other through neuronal circuit connections. Several circuits have been shown to convey the circadian time information from clock neurons to the sleep homeostat centres EB and dFB 48, 49, 53 . Reciprocally, hugin+ neurons act downstream of dFB neurons and modulate clock neurons 50 .…”