Vasoactive intestinal peptide shapes photic communication across the circadian visual system

Circadian rhythms affect human health and well-being by temporally organizing biological processes and fitting them to a 24 hour period. In mammals, circadian rhythm generation and organization are regulated by oscillatory networks in the heterogeneous suprachiasmatic nucleus (SCN) of the hypothalamus. Acute light resets the phase of these networks at night by an incompletely understood mechanism that involves changes in the transcriptional status of the immediate early gene c-fos and the clock gene Per1 in individual SCN cells. Neuropeptides, which anatomically define the SCN's functionally distinct core and shell subregions, have also emerged as important players in this light response pathway. The following set of studies examines how one such neuropeptide, vasoactive intestinal peptide (VIP), contributes to the gene expression changes across the SCN network during a successful phase shift. Experiments show that in response to a phase shifting light pulse, mice genetically deficient in VIP: 1) have acute, blunted molecular responses of c-FOS and Per1 in the SCN, 2) do not sustain gene expression changes in c-FOS and Per1 across SCN cells over time, and 3) lack gene expression changes of c-FOS and Per1 specifically in the SCN shell. Because these effects of VIP may be either acute or chronic due to an organizational or developmental role for VIP, experiments were also carried out to identify anatomical changes in the SCN of mice genetically deficient in VIP. Results suggest that specific changes to the light-input side of the circuit are altered when VIP is absent, indicating an organizational role for this neuropeptide. These changes include increased retinal afferent terminal branching and decreased androgen receptor expression in the retino-recipient region of the SCN. Interestingly, there did not appear to be changes in intra-SCN connectivity in mice lacking VIP, as determined by analysis of Golgi impregnated neurons. These data together suggest that VIP acts not only acutely to affect photic signaling, but it also plays a role in the structuring of the SCN to allow for the efficient flow of photic phase resetting information from retinal inputs across the circadian system.