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Vasoactive intestinal polypeptide mediates circadian rhythmicity and synchrony in mammalian clock neurons

Nature Neuroscience volume 8, pages 476–483 (2005)Cite this article

Abstract

The mammalian suprachiasmatic nucleus (SCN) is a master circadian pacemaker. It is not known which SCN neurons are autonomous pacemakers or how they synchronize their daily firing rhythms to coordinate circadian behavior. Vasoactive intestinal polypeptide (VIP) and the VIP receptor VPAC2 (encoded by the gene Vipr2) may mediate rhythms in individual SCN neurons, synchrony between neurons, or both. We found that Vip−/− and Vipr2−/− mice showed two daily bouts of activity in a skeleton photoperiod and multiple circadian periods in constant darkness. Loss of VIP or VPAC2 also abolished circadian firing rhythms in approximately half of all SCN neurons and disrupted synchrony between rhythmic neurons. Critically, daily application of a VPAC2 agonist restored rhythmicity and synchrony to VIP−/− SCN neurons, but not to Vipr2−/− neurons. We conclude that VIP coordinates daily rhythms in the SCN and behavior by synchronizing a small population of pacemaking neurons and maintaining rhythmicity in a larger subset of neurons.

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Figure 1: Mice with disrupted VIP/VPAC2 signaling express multiple circadian periods.
Figure 2: A reduced proportion of Vip−/− and Vipr2−/− SCN neurons fires rhythmically in vitro.
Figure 3: Genetic knockout of Vip or Vipr2 abolishes synchrony among rhythmic SCN neurons in the same culture (a) Representative rhythmic firing rate records from wild-type, Vipr2−/− or Vip−/− SCN neurons in the same high density culture.
Figure 4: The distributions of circadian periods of locomotor activity in mice (left) are similar to those of firing rate rhythms in SCN neurons (right) for the three genotypes.
Figure 5: Daily application of VPAC2 agonist Ro 25-1553 restores rhythmicity to Vip−/− SCN neurons.

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Acknowledgements

We thank P. Taghert, R. Van Gelder, D. Granados-Fuentes, and U. Abraham for helpful discussions; D. Piatchek and J. Diani of the Washington University Hilltop animal facility; H. Dave, T. Fadelu, and L. Prolo for expert technical assistance and animal care; and P. Robberecht (University of Brussels) for providing VPAC2 agonist Ro 25-1553. This work was supported by a US National Science Foundation graduate research fellowship (S.J.A.) and by the National Institutes of Health (grants MH63104, MH62517 and MH073302).

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Authors and Affiliations

  1. Department of Biology, One Brookings Drive, Washington University, St. Louis, 63130, Missouri, USA

    Sara J Aton & Erik D Herzog

  2. Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, 10920 Wilshire Blvd., Suite 1200, Los Angeles, 90024, California, USA

    Christopher S Colwell & James Waschek

  3. Division of Neuroscience and Centre for Neuroscience Research, University of Edinburgh, 1 George Square, Edinburgh, EH8 9JZ, UK

    Anthony J Harmar

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Correspondence to Erik D Herzog.

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Aton, S., Colwell, C., Harmar, A. et al. Vasoactive intestinal polypeptide mediates circadian rhythmicity and synchrony in mammalian clock neurons. Nat Neurosci 8, 476–483 (2005). https://doi.org/10.1038/nn1419

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