title: C. elegans Stress-Induced Sleep Emerges from the Collective Action of Multiple Neuropeptides.
abstract: The genetic basis of sleep regulation remains poorly understood. In C. elegans, cellular stress induces sleep through epidermal growth factor (EGF)-dependent activation of the EGF receptor in the ALA neuron. The downstream mechanism by which this neuron promotes sleep is unknown. Single-cell RNA sequencing of ALA reveals that the most highly expressed, ALA-enriched genes encode neuropeptides. Here we have systematically investigated the four most highly enriched neuropeptides: flp-7, nlp-8, flp-24, and flp-13. When individually removed by null mutation, these peptides had little or no effect on stress-induced sleep. However, stress-induced sleep was abolished in nlp-8; flp-24; flp-13 triple-mutant animals, indicating that these neuropeptides work collectively in controlling stress-induced sleep. We tested the effect of overexpression of these neuropeptide genes on five behaviors modulated during sleep-pharyngeal pumping, defecation, locomotion, head movement, and avoidance response to an aversive stimulus-and we found that, if individually overexpressed, each of three neuropeptides (nlp-8, flp-24, or flp-13) induced a different suite of sleep-associated behaviors. These overexpression results raise the possibility that individual components of sleep might be specified by individual neuropeptides or combinations of neuropeptides.
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA; Howard Hughes Medical Institute, Cornell University, Ithaca, NY 14853-2703, USA.
authors.forename: Ravi D
authors.initials: RD
authors.lastname: Nath
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA; Howard Hughes Medical Institute, Cornell University, Ithaca, NY 14853-2703, USA.
authors.forename: Elly S
authors.initials: ES
authors.lastname: Chow
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA; Howard Hughes Medical Institute, Cornell University, Ithaca, NY 14853-2703, USA.
authors.forename: Han
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Molecular Biology and Genetics, Biotechnology 351, Cornell University, Ithaca, NY 14853-2703, USA.
authors.forename: Erich M
authors.initials: EM
authors.lastname: Schwarz
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA; Howard Hughes Medical Institute, Cornell University, Ithaca, NY 14853-2703, USA. Electronic address: pws@caltech.edu.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Sternberg
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000378:metabolism; D009479:Neuropeptides / Q000235:genetics* / Q000378:metabolism; D012890:Sleep / Q000235:genetics*; D013312:Stress, Physiological
chemical_list: D029742:Caenorhabditis elegans Proteins; D009479:Neuropeptides
keywords: RFamides; genetic redundancy; neuropeptide modulation; single-neuron RNA-seq; sleep regulation