recently, Mirsky et al. used a detailed model to predict the phenotype of 7 knockout and 2 double knockout mutations as well as concentration variations in clock genes in the respective scenarios. However, as it was noted in the work of Mirsky et al., in order to describe phenotypes observed in tissue or organ levels, additional dynamics such as entrainment and synchronization must be taken into consideration.
Recently, the mechanism of peripheral entrainment by systemic cues has been further elucidated. Single cell experiments of Nagoshi et al. in rat and mouse fibroblasts showed that single peripheral cells even in in vitro conditions independent of any entraining cue retain robust rhythmicity similar to SCN cells [10]. As a result, the dampening rhythms they observed in vitro at the population level emerge from robust single cell oscillations that fall out of phase and desynchronize in the absence of an entraining force. Based on this, we recently studied the synchronization properties of cortisol in a population of peripheral clock genes. We found that cortisol entrains the peripheral clocks in an amplitude and frequency dependent manner [11] (Table 1). Chronically stressed conditions, represented by blunted cortisol circadian amplitudes, lead to loss of peripheral clock gene entrainment and synchronization. Similarly, cortisol oscillatory frequencies largely deviating from a 24-h period, which have been experimentally found in rodent models of jet lag, fail to synchronize peripheral clocks resulting in high level of desynchronization and weaker ensemble average rhythm. Furthermore, Abraham et al. showed that the oscillator qualities that greatly determine entrainment efficiency, are the ratio between entrainer coupling strength and oscillator amplitude, and the rigidity of the oscillatory system as defined by the relaxation rate upon perturbation [12] (Table 1). This result can explain the evidence that peripheral tissues such as lung, can be entrained by a wider range of entrainer’s