CREB in the mouse SCN: A molecular interface coding the phase-adjusting stimuli light, glutamate, PACAP, and melatonin for clockwork access

The suprachiasmatic nucleus (SCN) is a central pacemaker in mammals, drivin g many endogenous circadian rhythms. An important pacemaker target is the r egulation of a hormonal message for darkness, the circadian rhythm in melat onin synthesis. The endogenous clock within the SCN is synchronized to envi ronmental light/dark cycles by photic information conveyed via the retinohy pothalamic tract (RHT) and by the nocturnal melatonin signal that acts with in a feedback loop. We investigated how melatonin intersects with the tempo rally gated resetting actions of two RHT transmitters, pituitary adenylate cyclase-activating polypeptide (PACAP) and glutamate. We analyzed immunocyt ochemically the inducible phosphorylation of the transcription factor Ca2+/ cAMP response element-binding protein (CREB) in the SCN of a melatonin-prof icient (C3H) and a melatonin-deficient (C57BL) mouse strain. In vivo, light -induced phase shifts in locomotor activity were consistently accompanied b y CREB phosphorylation in the SCN of both strains. However, in the middle o f subjective nighttime, light induced larger phase delays in C57BL than in C3H mice. In vitro, PACAP and glutamate induced CREB phosphorylation in the SCN of both mouse strains, with PACAP being more effective during late sub jective daytime and glutamate being more effective during subjective nightt ime. Melatonin suppressed PACAP- but not glutamate-induced phosphorylation of CREB. The distinct temporal domains during which glutamate and PACAP ind uce CREB phosphorylation imply that during the light/dark transition the SC N switches sensitivity between these two RHT transmitters. Because these te mporal domains are not different between C3H and C57BL mice, the sensitivit y windows are set independently of the rhythmic melatonin signal.