Light-induced Desynchrony of a Multi-oscillatory Circadian System in Per2 -deficient Mice

Abstract

The Period (Per) gene was first identified in Drosophila as a key regulator of circadian rhythms, with mutations that altered or abolished behavioral rhythmicity. Mammals possess 3 homologs, Per1, Per2, and Per3. Here, we systematically compared the circadian properties of mice deficient in each Per gene, singly and in combination, under constant darkness (DD). We analyzed their free-running periods (τ) and phase response curves (PRCs) to 6-h light pulses (6-h LPs). Each Per-deficient line exhibited distinct circadian characteristics. Per1-deficient mice (including Per1^−/− Per3^−/− double mutants) showed high-amplitude PRCs with large phase shifts near CT18, consistent with Type 0 resetting. Per2-deficient mice displayed shorter τ and Type 1 PRCs with crossover points near CT17. Remarkably, some Per2-deficient mice lost circadian rhythmicity after a single 6-h LP delivered near the crossover but regained rhythmicity following a second pulse 12 days later. In contrast, Per1^−/− Per2^−/− mice, which retain Per3, failed to maintain stable rhythms in DD yet transiently reestablished a short-period (~19.5 h) rhythm in response to a 6-h LP. These findings indicate that rhythm loss in Per2-deficient mice does not represent oscillation stop but rather light-induced desynchrony among multiple oscillators that constitute the circadian pacemaker. Collectively, our results demonstrate that Per1 sustains oscillator strength, Per2 maintains inter-oscillator coupling, and together they ensure the robustness of the mammalian circadian system against strong photic perturbation.