Adult mice lacking VIP SCN neurons retain circadian locomotor behavior but exhibit dampened daily glucocorticoid rhythms

The suprachiasmatic nucleus (SCN) drives circadian rhythms in locomotion through coupled, single-cell oscillations. Global genetic deletion of the neuropeptide, Vip or its receptor Vipr2, results in profound deficits in daily synchrony among SCN cells and daily rhythms in locomotor behavior and glucocorticoid secretion. To test whether this phenotype depends on VIP neurons in the SCN, we ablated VIP SCN neurons in vivo in adult mice through Caspase3-mediated induction of the apoptotic pathway in cre-expressing VIP neurons. We found that ablation of VIP SCN neurons in adult mice caused a phenotype distinct from Vip- and Vipr2- null mice. Mice lacking VIP neurons retained rhythmic locomotor activity with a shortened circadian period, more variable onsets and decreased duration of daily activity. Circadian hormonal outputs, specifically corticosterone rhythms were severely dampened. In contrast, deletion of neonatal SCN VIP neurons dramatically reduced circadian gene expression in the cultured SCN, mimicking the effects of global deletion of Vip or Vipr2. These results suggest that SCN VIP neurons play a role in lengthening circadian period and stimulating the daily surge in glucocorticoids in adults and in synchronizing and sustaining daily rhythms among cells in the developing SCN. Significance StatementThe importance of the neuropeptide, VIP, for circadian rhythms has been described in mice lacking the gene for Vip or its receptor, Vipr2. This study found that ablation of VIP neurons only in the adult SCN reproduced the loss of circadian rhythms in glucocorticoids, but not the loss of circadian locomotor behavior, seen with global loss of VIP signaling. We conclude that VIP SCN neurons play two roles: one in adulthood lengthening circadian period and regulating circadian outputs, and one in development coordinating synchrony among circadian cells.