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The Journal of Neuroscience, November 30, 2005, 25(48):11155-11164; doi:10.1523/JNEUROSCI.3821-05.2005

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Behavioral/Systems/Cognitive
Gastrin-Releasing Peptide Promotes Suprachiasmatic Nuclei Cellular Rhythmicity in the Absence of Vasoactive Intestinal Polypeptide-VPAC₂ Receptor Signaling

Timothy M. Brown, Alun T. Hughes, and Hugh D. Piggins

Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom

Vasoactive intestinal polypeptide (VIP) and gastrin-releasing peptide (GRP) acting via the VPAC₂ receptor and BB₂ receptors, respectively, are key signaling pathways in the suprachiasmatic nuclei (SCN) circadian clock. Transgenic mice lacking the VPAC₂ receptor (Vipr2^-/-) display a continuum of disrupted behavioral rhythms with only a minority capable of sustaining predictable cycles of rest and activity. However, electrical or molecular oscillations have not yet been detected in SCN cells from adult Vipr2^-/- mice. Using a novel electrophysiological recording technique, we found that in brain slices from wild-type and behaviorally rhythmic Vipr2^-/- mice, the majority of SCN neurons we detected displayed circadian firing patterns with estimated periods similar to the animals' behavior. In contrast, in slices from behaviorally arrhythmic Vipr2^-/- mice, only a small minority of the observed SCN cells oscillated. Remarkably, exogenous GRP promoted SCN cellular rhythms in Vipr2^-/- mouse slices, whereas blockade of BB₂ receptors suppressed neuronal oscillations. In wild-type mice, perturbation of GRP-BB₂ signaling had few effects on SCN cellular rhythms, except when VPAC₂ receptors were blocked pharmacologically. These findings establish that residual electrical oscillations persist in the SCN of Vipr2^-/- mice and reveal a potential new role for GRP-BB₂ signaling within the circadian clock.

Key words: VIP; electrophysiology; hypothalamus; circadian; BB₂ receptor; entrainment

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Received April 20, 2005; revised October 20, 2005; accepted October 21, 2005.

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