title: Disrupted reproduction, estrous cycle, and circadian rhythms in female mice deficient in vasoactive intestinal peptide.
abstract: The female reproductive cycle is gated by the circadian timing system and may be vulnerable to disruptions in the circadian system. Prior work suggests that vasoactive intestinal peptide (VIP)-expressing neurons in the suprachiasmatic nucleus (SCN) are one pathway by which the circadian clock can influence the estrous cycle, but the impact of the loss of this peptide on reproduction has not been assessed. In the present study, we first examine the impact of the genetic loss of the neuropeptide VIP on the reproductive success of female mice. Significantly, mutant females produce about half the offspring of their wild-type sisters even when mated to the same males. We also find that VIP-deficient females exhibit a disrupted estrous cycle; that is, ovulation occurs less frequently and results in the release of fewer oocytes compared with controls. Circadian rhythms of wheel-running activity are disrupted in the female mutant mice, as is the spontaneous electrical activity of dorsal SCN neurons. On a molecular level, the VIP-deficient SCN tissue exhibits lower amplitude oscillations with altered phase relationships between the SCN and peripheral oscillators as measured by PER2-driven bioluminescence. The simplest explanation of our data is that the loss of VIP results in a weakened SCN oscillator, which reduces the synchronization of the female circadian system. These results clarify one of the mechanisms by which disruption of the circadian system reduces female reproductive success.
authors.affiliation: Laboratory of Circadian and Sleep Medicine, Department of Psychiatry and Biobehavioral Sciences, University of California-Los Angeles, California HLoh@ucla.edu.
authors.forename: D H
authors.initials: DH
authors.lastname: Loh
authors.affiliation: Laboratory of Circadian and Sleep Medicine, Department of Psychiatry and Biobehavioral Sciences, University of California-Los Angeles, California Department of Neurobiology, University of California-Los Angeles.
authors.forename: D A
authors.initials: DA
authors.lastname: Kuljis
authors.affiliation: Laboratory of Circadian and Sleep Medicine, Department of Psychiatry and Biobehavioral Sciences, University of California-Los Angeles, California.
authors.forename: L
authors.initials: L
authors.lastname: Azuma
authors.affiliation: Laboratory of Circadian and Sleep Medicine, Department of Psychiatry and Biobehavioral Sciences, University of California-Los Angeles, California.
authors.forename: Y
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Laboratory of Circadian and Sleep Medicine, Department of Psychiatry and Biobehavioral Sciences, University of California-Los Angeles, California.
authors.forename: D
authors.initials: D
authors.lastname: Truong
authors.affiliation: Laboratory of Circadian and Sleep Medicine, Department of Psychiatry and Biobehavioral Sciences, University of California-Los Angeles, California.
authors.forename: H B
authors.initials: HB
authors.lastname: Wang
authors.affiliation: Laboratory of Circadian and Sleep Medicine, Department of Psychiatry and Biobehavioral Sciences, University of California-Los Angeles, California.
authors.forename: C S
authors.initials: CS
authors.lastname: Colwell
mesh_terms: D000818:Animals; D002940:Circadian Rhythm / Q000502:physiology*; D030762:Estrous Cycle / Q000502:physiology*; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000502:physiology; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D009479:Neuropeptides / Q000378:metabolism; D056950:Period Circadian Proteins / Q000378:metabolism; D012098:Reproduction / Q000502:physiology*; D013493:Suprachiasmatic Nucleus / Q000378:metabolism / Q000502:physiology; D014660:Vasoactive Intestinal Peptide / Q000378:metabolism*
chemical_list: D009479:Neuropeptides; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D014660:Vasoactive Intestinal Peptide
keywords: circadian rhythms; estrous cycle; female; mouse; ovulation; reproduction; vasoactive intestinal peptide