A systemic clock brake: Period1 stabilizes the circadian network under environmental stress

Abstract

Precise alignment between internal circadian clocks and environmental light cycles is essential for physiological homeostasis and survival. However, the molecular mechanisms that preserve this synchrony across central and peripheral tissues remain poorly defined. Here, we uncover an unexpected role for the core clock gene Period1 (Per1) as a systemic modulator of circadian stability, regulating light-induced re-entrainment across the brain and body. In Per1-deficient mice, we show that loss of Per1 accelerates clock realignment, influencing transcriptomic, metabolic, hormonal, and behavioral indicators of circadian realignment across multiple organ systems, including the suprachiasmatic nucleus (SCN) and peripheral tissues such as the liver, adipose tissue, and adrenal glands. Notably, this accelerated adaptation confers protection against jetlag-induced sleep disturbances, weight gain, and metabolic imbalance, underscoring a systemic role for Per1 in maintaining circadian network stability. Mechanistically, unbiased spatial transcriptomics identified reduced expression of the arginine vasopressin (AVP), a key neuropeptide mediating SCN intercellular coupling, as the driver of circadian network instability. Weakened SCN synchrony permits enhanced flexibility of peripheral oscillator responses, expediting whole-body adaptation to shifted light-dark schedules. These findings position Per1 as a critical regulator of circadian robustness, a buffer against light over-responsiveness, identifying a potential molecular target for mitigating circadian misalignment in contexts such as jetlag, shift work, and metabolic disease. TeaserWhat if beating jetlag was as simple as switching off a gene? Researchers show that disabling Per1, a core circadian regulator, accelerates body clock realignment and protects against sleep and metabolic disruption--highlighting new therapeutic possibilities for jetlag and shift work.