Gastrin-releasing peptide mediates light-like resetting of the Suprachiasmatic nucleus circadian pacemaker through cAMP response element-binding protein and Per1 activation

Circadian rhythmicity in the primary mammalian circadian pacemaker, the suprachiasmatic nucleus ( SCN) of the hypothalamus, is maintained by transcriptional and translational feedback loops among circadian clock genes. Photic resetting of the SCN pacemaker involves induction of the clock genes Period1 ( Per1) and Period2 ( Per2) and communication among distinct cell populations. Gastrin-releasing peptide ( GRP) is localized to the SCN ventral retinorecipient zone, from where it may communicate photic resetting signals within the SCN network. Here, we tested the putative role of GRP as an intra-SCN light signal at the behavioral and cellular levels, and we also tested whether GRP actions are dependent on activation of the cAMP response element-binding protein ( CREB) pathway and Per1. In vivo microinjections of GRP to the SCN regions of Per1:: green fluorescent protein ( GFP) mice during the late night induced Per1:: GFP throughout the SCN, including a limited population of arginine vasopressin-immunoreactive ( AVP-IR) neurons. Blocking spike-mediated communication with tetrodotoxin did not disrupt overall Per1::GFP induction but did reduce induction within AVP-IR neurons. In vitro GRP application resulted in persistent increases in the spike frequency of Per1:: GFP-induced neurons. Blocking endogenous Per1 with antisense oligodeoxynucleotides inhibited GRP-induced increases in spike frequency. Furthermore, inhibition of CREB-mediated gene activation with decoy oligonucleotides blocked GRP-induced phase shifts of PER2:: luciferase rhythms in SCN slices. Altogether, these results indicate that GRP communicates phase resetting signals within the SCN network via both spike-dependent and spike-independent mechanisms, and that activation of the CREB pathway and Per1 are key steps in mediating downstream events in GRP resetting of SCN neurons.