TEMPORALLY RESTRICTED ROLE OF RETINAL PACAP: INTEGRATION OF THE PHASE-ADVANCING LIGHT SIGNAL TO THE SCN

摘要

Circadian rhythms in physiology and behavior are temporally synchronized to the day:night cycle through the action of light on the circadian clock. In mammals, transduction of the photic signal reaching the circadian oscillator in the suprachiasmatic nucleus (SCN) occurs through the release of glutamate and pituitary adenylate cyclase-activating peptide (PACAP). Our study aimed at clarifying the role played by PACAP in photic resetting and entrainment. We investigated the circadian response to light of PACAP-null mice lacking the 5^th exon of the PACAP coding sequence. Specifically, we examined free-running rhythms, entrainment to 12-h light:12-h dark (LD) cycles, the phase response curve (PRC) to single light pulses, entrainment to a 23-h T-cycle, re-entrainment to 6-h phase shifts in LD cycles, and light-induced c-Fos expression. PACAP-null and wild-type mice show similar free-running periods and similar entrainment to 12:12 LD cycles. However, the PRC of PACAP-null mice lacks a phase-advance portion. Surprisingly, despite the absence of phase advance to single light pulses, PACAP-null mice are able to entrain to a 23-h T-cycle, but with a significantly longer phase angle of entrainment than wild types. In addition, PACAP-null mice re-entrain more slowly to a 6-h phase advance of the LD cycle. Nevertheless, induction of c-Fos by light in late night is normal. In all experiments, PACAP-null mice show specific behavioral impairments in response to phase-advancing photic stimuli. These results suggest that PACAP is required for the normal integration of the phase-advancing light signal by the SCN.