title: A neuropeptide speeds circadian entrainment by reducing intercellular synchrony.
abstract: Shift work or transmeridian travel can desynchronize the body's circadian rhythms from local light-dark cycles. The mammalian suprachiasmatic nucleus (SCN) generates and entrains daily rhythms in physiology and behavior. Paradoxically, we found that vasoactive intestinal polypeptide (VIP), a neuropeptide implicated in synchrony among SCN cells, can also desynchronize them. The degree and duration of desynchronization among SCN neurons depended on both the phase and the dose of VIP. A model of the SCN consisting of coupled stochastic cells predicted both the phase- and the dose-dependent response to VIP and that the transient phase desynchronization, or "phase tumbling", could arise from intrinsic, stochastic noise in small populations of key molecules (notably, Period mRNA near its daily minimum). The model also predicted that phase tumbling following brief VIP treatment would accelerate entrainment to shifted environmental cycles. We tested this using a prepulse of VIP during the day before a shift in either a light cycle in vivo or a temperature cycle in vitro. Although VIP during the day does not shift circadian rhythms, the VIP pretreatment approximately halved the time required for mice to reentrain to an 8-h shifted light schedule and for SCN cultures to reentrain to a 10-h shifted temperature cycle. We conclude that VIP below 100 nM synchronizes SCN cells and above 100 nM reduces synchrony in the SCN. We show that exploiting these mechanisms that transiently reduce cellular synchrony before a large shift in the schedule of daily environmental cues has the potential to reduce jet lag.
authors.affiliation: Department of Biology, Washington University in St. Louis, Saint Louis, MO 63130.
authors.forename: Sungwon
authors.initials: S
authors.lastname: An
authors.forename: Rich
authors.initials: R
authors.lastname: Harang
authors.forename: Kirsten
authors.initials: K
authors.lastname: Meeker
authors.forename: Daniel
authors.initials: D
authors.lastname: Granados-Fuentes
authors.forename: Connie A
authors.initials: CA
authors.lastname: Tsai
authors.forename: Cristina
authors.initials: C
authors.lastname: Mazuski
authors.forename: Jihee
authors.initials: J
authors.lastname: Kim
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Doyle
authors.forename: Linda R
authors.initials: LR
authors.lastname: Petzold
authors.forename: Erik D
authors.initials: ED
authors.lastname: Herzog
mesh_terms: D000818:Animals; D001683:Biological Clocks / Q000187:drug effects / Q000502:physiology*; D002940:Circadian Rhythm / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D008163:Luminescent Measurements; D008297:Male; D051379:Mice; D008954:Models, Biological; D009043:Motor Activity / Q000502:physiology; D056950:Period Circadian Proteins / Q000378:metabolism; D017440:Photoperiod; D015398:Signal Transduction / Q000502:physiology*; D013493:Suprachiasmatic Nucleus / Q000502:physiology*; D013696:Temperature; D014660:Vasoactive Intestinal Peptide / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D056950:Period Circadian Proteins; D014660:Vasoactive Intestinal Peptide
keywords: biological clock; circadian oscillator; period gene; vasoactive intestinal peptide; vasopressin