Disrupted Reproduction, Estrous Cycle, and Circadian Rhythms in Female Mice Deficient in Vasoactive Intestinal Peptide

Sep 26, 2014Journal of biological rhythms

Disrupted reproduction, reproductive cycles, and daily rhythms in female mice lacking a key brain signaling molecule

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Abstract

Mutant female mice lacking vasoactive intestinal peptide (VIP) produce about half the offspring of their wild-type counterparts.

Loss of VIP leads to a disrupted estrous cycle characterized by less frequent ovulation and fewer released oocytes.
Circadian rhythms of wheel-running activity are altered in mutant females compared to controls.
Dorsal SCN neurons in VIP-deficient mice show decreased spontaneous electrical activity.
Molecular analysis reveals lower amplitude oscillations and altered phase relationships in SCN tissue lacking VIP.
The data suggest that the absence of VIP weakens the SCN oscillator, affecting synchronization within the female circadian system.

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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.

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Disrupted Reproduction, Estrous Cycle, and Circadian Rhythms in Female Mice Deficient in Vasoactive Intestinal Peptide

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