Circadian Phase Resetting via Single and Multiple Control Targets

Circadian entrainment is necessary for rhythmic physiological functions to be appropriately timed over the 24-hour day. Disruption of circadian rhythms has been associated with sleep and neuro-behavioral impairments as well as cancer. To date, light is widely accepted to be the most powerful circadian synchronizer, motivating its use as a key control input for phase resetting. Through sensitivity analysis, we identify additional control targets whose individual and simultaneous manipulation (via a model predictive control algorithm) out-perform the open-loop light-based phase recovery dynamics by nearly 3-fold. We further demonstrate the robustness of phase resetting by synchronizing short- and long-period mutant phenotypes to the 24-hour environment; the control algorithm is robust in the presence of model mismatch. These studies prove the efficacy and immediate application of model predictive control in experimental studies and medicine. In particular, maintaining proper circadian regulation may significantly decrease the chance of acquiring chronic illness.Author Summary: The robust timing, or phase, of the circadian clock is critical in directing and synchronizing molecular, cellular, and organismal behaviors. The clock's failure to maintain precision and adaption is associated with sleeping disorders, depression, and cancer. To better study and control the timing of circadian rhythms, we make use of systems theoretic tools such as sensitivity analysis and model predictive control (MPC). Sensitivity analysis is used to identify key driving mechanisms without having to fully understand or investigate the detailed mechanistic interconnections of the large complex circadian network. Contrary to intuition, sensitivity analysis of the circadian model highlights several non-photic control inputs (such as transcriptional regulation) that outperform light-based circadian phase resetting – light is known to accelerate protein degradation. Aside from targeting individual parameters as control inputs, our methods identify combinations of control targets that may further the efficiency of entrainment. We compare the phase resetting performance of our MPC algorithm among cases involving individual and multiple simultaneous control targets (in wild-type simulations). We then tailor the algorithm to correct continuously the phase mismatch that occurs in short and long period mutant phenotypes. Through use of the presented tools, our algorithm is robust in the presence of model mismatch and outperforms the natural in silico sun-cycle–based phase recovery strategy by nearly 3-fold.