Vasoactive Intestinal Polypeptide Entrains Circadian Rhythms in Astrocytes

Abstract

Many mammalian cell types show daily rhythms in gene expression driven by a circadian pacemaker. For example, cultured astrocytes display circadian rhythms in Period1 and Period2 expression. It is not known, however, how or which intercellular factors synchronize and sustain rhythmicity in astrocytes. Because astrocytes are highly sensitive to vasoactive intestinal polypeptide (VIP), a neuropeptide released by neurons and important for the coordination of daily cycling, the authors hypothesized that VIP entrains circadian rhythms in astrocytes. They used astrocyte cultures derived from knock-in mice containing a bioluminescent reporter of PERIOD2 (PER2) protein, to assess the effects of VIP on the rhythmic properties of astrocytes. VIP induced a dose-dependent increase in the peak-to-trough amplitude of the ensemble rhythms of PER2 expression with maximal effects near 100 nM VIP and threshold values between 0.1 and 1 nM. VIP also induced dose- and phase-dependent shifts in PER2 rhythms and daily VIP administration entrained bioluminescence rhythms of astrocytes to a predicted phase angle. This is the first demonstration that a neuropeptide can entrain glial cells to a phase predicted by a phase-response curve. The authors conclude that VIP potently entrains astrocytes in vitro and is a candidate for coordinating daily rhythms among glia in the brain.