UC San Diego

Over time, the mammalian circadian system has evolved to anticipate a 24 hour day. These rhythms are robust and not easily perturbed, but as a consequence, are also difficult to reset. Until the modernization of society and the advent of artificial light, the inability to reset rhythms has not been a problem. This inflexibility has the potential to induce health complications like mental illness and metabolic dysfunction when there is desynchrony between internal rhythms and the outside world is chronic, such as in shift workers whose schedules do not align with a normal day. Studies on the flexibility of circadian rhythms have mainly focused on standard 24 hour entrainment paradigms, but few have considered how plasticity may change under non-standard environmental conditions. Chapter 2 introduces the idea that bifurcation of circadian waveforms in peripheral tissues induces extraordinary flexibility in clock gene expression rhythms when challenged with simulated jet-lag. Bifurcated clock gene expression rhythms are low amplitude, which may enable such rapid resetting in peripheral tissues. Chapter 3 describes that the implementation of an 18 hour light and food restricted schedule can, remarkably, entrain low amplitude hepatic clock gene expression rhythms to an 18 hour day (T18). Entrainment to T18 is well beyond the established limits of entrainment for the liver (T=22-26 hours), and was not achieved in previous studies on T18 photoperiod without time restricted eating. Together, this thesis demonstrates increased circadian plasticity of mammalian peripheral clock gene expression rhythms beyond what was previously thought to be possible under standard environmental conditions. Enhanced flexibility of entrainment may be due to low amplitude clock gene expression rhythms, but the mechanism remains unknown. These results broaden the understanding of circadian flexibility and provide insight on mitigation of circadian disruption.