Exercise and circadian rhythms: A new role for VIP

Physical exercise has numerous beneficial effects for brain and body and is known to influence the activity of the brain’s circadian clock in the suprachiasmatic nuclei (SCN). Vasoactive intestinal polypeptide (VIP) signalling via the VPAC2 receptor is important for the SCN to generate normal (~24h) rhythms. Mice lacking VIP or the VPAC2 receptor have weakened SCN clocks and typically exhibit altered periods (~22h) or arrhythmia in behaviour and physiology. Recently we showed that scheduled voluntary exercise (SVE) in a running-wheel markedly improved circadian rhythms in behaviour of these neuropeptide signalling deficient mice, Intriguingly, this effect of SVE was most pronounced in those mice lacking the VPAC2 receptor (VPAC2RKO; 90% of these mice expressed ~24h rhythms post-SVE), whereas most mice lacking VIP showed only transient improvements that were not sustained following SVE. Since VPAC2KO mice have VIP, this suggests that VIP signalling through a non-VPAC2 receptor is necessary for SVE to promote rhythms in VPAC2KO mice. To test this, we generated mice lacking both VPAC2 receptor and VIP and assessed their rhythms in behaviour pre- and post-SVE. In constant dark, ~45% of VPAC2xVIP deficient mice expressed rhythms with a period of ~22h. During SVE, all VPAC2xVIP deficient mice synchronised to the stimulus and showed ~24h rhythms. Following SVE, ~50% of VPAC2xVIP deficient mice expressed ~24h rhythms, while the rest were arrhythmic. Since 90% of VPAC2KO mice are rhythmic post-SVE, these results establish that VIP signalling through a non-VPAC2 receptor is necessary for SVE to reorganize the neural circadian system of these mice. Overall, this study reveals new actions of VIP in the brain and reveals extensive plasticity in the circadian system of neuropeptide-signalling deficient mice.