title: Calcitonin gene-related peptide neurons mediate sleep-specific circadian output in Drosophila.
abstract: BACKGROUND
  Imbalances in amount and timing of sleep are harmful to physical and mental health. Therefore, the study of the underlying mechanisms is of great biological importance. Proper timing and amount of sleep are regulated by both the circadian clock and homeostatic sleep drive. However, very little is known about the cellular and molecular mechanisms by which the circadian clock regulates sleep. In this study, we describe a novel role for diuretic hormone 31 (DH31), the fly homolog of the vertebrate neuropeptide calcitonin gene-related peptide, as a circadian wake-promoting signal that awakens the fly in anticipation of dawn.
  
  
  RESULTS
  Analysis of loss-of-function and gain-of-function Drosophila mutants demonstrates that DH31 suppresses sleep late at night. DH31 is expressed by a subset of dorsal circadian clock neurons that also express the receptor for the circadian neuropeptide pigment-dispersing factor (PDF). PDF secreted by the ventral pacemaker subset of circadian clock neurons acts on PDF receptors in the DH31-expressing dorsal clock neurons to increase DH31 secretion before dawn. Activation of PDF receptors in DH31-positive DN1 specifically affects sleep and has no effect on circadian rhythms, thus constituting a dedicated locus for circadian regulation of sleep.
  
  
  CONCLUSIONS
  We identified a novel signaling molecule (DH31) as part of a neuropeptide relay mechanism for circadian control of sleep. Our results indicate that outputs of the clock controlling sleep and locomotor rhythms are mediated via distinct neuronal pathways.
authors.affiliation: Department of Cellular and Molecular Physiology, Yale School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Kunst
authors.affiliation: Department of Cellular and Molecular Physiology, Yale School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Hughes
authors.affiliation: Department of Cellular and Molecular Physiology, Yale School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
authors.forename: Davide
authors.initials: D
authors.lastname: Raccuglia
authors.affiliation: Department of Cellular and Molecular Physiology, Yale School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
authors.forename: Mario
authors.initials: M
authors.lastname: Felix
authors.affiliation: Department of Cellular and Molecular Physiology, Yale School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Cellular and Molecular Physiology, Yale School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Barnett
authors.affiliation: Department of Cellular and Molecular Physiology, Yale School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
authors.forename: Janelle
authors.initials: J
authors.lastname: Duah
authors.affiliation: Department of Cellular and Molecular Physiology, Yale School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA; Department of Genetics, Yale School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA; Program in Cellular Neuroscience, Neurodegeneration, and Repair, Yale School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA. Electronic address: michael.nitabach@yale.edu.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Nitabach
mesh_terms: D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism / Q000502:physiology*; D002940:Circadian Rhythm / Q000235:genetics*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D004331:Drosophila melanogaster / Q000235:genetics* / Q000502:physiology; D007301:Insect Hormones / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D012890:Sleep / Q000235:genetics*
chemical_list: C434606:Dh31 protein, Drosophila; D029721:Drosophila Proteins; D007301:Insect Hormones; D015740:Calcitonin Gene-Related Peptide