Advanced light-entrained activity onsets and restored free-running suprachiasmatic nucleus circadian rhythms in...

Many behavioral and physiological processes display diurnal (24-h) rhythms controlled by an internal timekeeping system?the circadian clock. In mammals, a circadian pacemaker is located in the suprachiasmatic nucleus (SCN) of the hypothalamus and synchronizes peripheral oscillators found in most other tissues with the external light-dark (LD) cycle. At the molecular level, circadian clocks are regulated by transcriptional translational feedback loops (TTLs) involving a set of clock genes. The mammalian core TTL includes the transcriptional modulators PER?(1?3) and CRY?(1/2) that inhibit their own expression by interaction with CLOCK/NPAS2 and BMAL1 (ARNTL). The basic helix-loop-helix transcription factors DEC1 (BHLHE40) and DEC2 (BHLHE41) can interact with this core TTL, forming an accessory feedback mechanism. The authors measured circadian locomotor behavior and clock gene expression in the SCN of Per2/Dec double- and triple-mutant mice to analyze the functional interaction of PER2 and DEC feedback on circadian pacemaker function in the SCN. The data suggest a synergistic interaction of Per2 and Dec1/2 in activity entrainment to a standard LD cycle, correlating with a cumulative deficiency in negative-masking capacities in Per2/Dec double- and triple-mutant mice and suggesting an involvement of Per2-Dec1/2 interactivity in activity-onset regulation and masking under LD, but not under constant conditions. In contrast, under constant darkness (DD) conditions, a deletion of either Dec1 or Dec2 partially rescued the Per2 mutant short-period/arrhythmicity phenotype, accompanied by a restoration of time-of-day effects on clock gene expression in the SCN. Together, these results show an interaction of Per2 and Dec1/2 feedback processes in the SCN with differential modes of interactivity under entrained and free-run conditions. (Author correspondence: henrik.oster@mpibpc.mpg.de ).