| 著者 |
Rossi L, Amoako K, Busack I, Golinelli L, Courtney A, Besseling J, Schafer W, Beets I, Bringmann H.
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| Abstract |
Sleep is caused by the depolarization of sleep-active neurons, which secrete gamma-aminobutyric acid (GABA) and neuropeptides such as conserved RFamide (c-terminal Arg-Phe-NH2 motif) neuropeptides to dictate when an organism falls asleep and when it wakes up.1,2,3,4,5,6,7,8,9,10 However, the mechanisms by which neurotransmission from sleep-active neurons induces sleep and determines the duration of sleep remain poorly understood. Sleep in Caenorhabditis elegans crucially requires the single sleep-active RIS neuron, which induces sleep via the release of FLP-11 RFamide neuropeptides.8,11 However, how RIS and FLP-11 control sleep is not well understood, as the receptor through which FLP-11 acts has yet to be identified. In this study, we discovered that RIS and FLP-11 control sleep through the Gi/o-protein coupled receptor DroMyoSuppressin receptor related 1 (DMSR-1).12,13 Using cell-specific knockdowns,14 we demonstrate that dmsr-1 induces sleep by acting in cholinergic neurons downstream of RIS activation. Pharmacological intervention indicates that inhibiting cholinergic signaling is necessary for sleep. Consistently, DMSR-1 expression in cholinergic neurons is essential for core sleep functions, including protective gene expression and survival. In contrast, we found that dmsr-1 in RIS mediates negative feedback control during sleep that limits RIS calcium activation and the duration of sleep. Consequently, dmsr-1 in RIS inhibits protective gene expression and survival. Thus, DMSR-1 controls both the initiation and limitation of sleep, effectively coupling sleep induction with a sleep-stop signal. RFamide neuropeptide-GPCR signaling might underlie similar dual mechanisms of sleep control in other species, and self-inhibition of sleep-active neurons might represent a conserved mechanism for limiting the duration of sleep. VIDEO ABSTRACT.
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