UC San Diego

The mammalian circadian system is regulated by an internal oscillator that has evolved to keep time in a very predictable rhythmic environment, and is generally considered not flexible enough to adjust to rapidly changing sleep schedules in shiftworkers. This inability to quickly adjust leads to circadian disruption, which is associated with increased risk for chronic disease. Increasing the flexibility of the circadian system could enhance adaptation to irregular cycles, and thereby alleviate negative consequences. This dissertation examines a mouse model for enhanced circadian entrainment, its mechanisms, and its utility for human shiftworkers.

Chapter 2 describes that with the addition of dim night time illumination, mice can behaviorally adapt to 18 hour days (T18). T18 entrainment is remarkable and unprecedented in any mammalian system, which typically can only entrain to a narrow range of day-lengths (i.e 22-26 hours). Chapter 3 expands the characterization of this state of enhanced circadian plasticity by describing oscillator characteristics. After demonstrating the lack of circadian oscillator-typical behavior in T18, we conclude that control of behavior in this condition must not derive from entrainment of a conventional circadian oscillator as explained by classical entrainment theories. In Chapter 4, clock gene expression rhythms in the suprachiasmatic nucleus -- a small area in the hypothalamus that orchestrates rhythms in mammals -- and liver and kidney further support the hypothesis that canonical circadian drivers are not involved in control of behavior in T18. While behavior displays 18 hours rhythms, clock gene expression is 24 hours in all tissues. Lastly, Chapter 5 demonstrates that the temporal organization of control of female reproductive function is altered in T18, without any negative impact on reproductive efficacy.

Together, this work demonstrates that the rodent circadian system can be markedly more flexible than traditional circadian entrainment theory predicts, but that this flexibility might rely on mechanisms that do not fit with the classical understanding of entrainment systems. Flexible entrainment has translational potential for human shiftworkers to adapt to irregular and sometimes unpredictable work schedules; and does not lead to negative health consequences seen in other non-24h paradigms.