Mathematical modeling of light-mediated HPA axis activity and downstream implications on the entrainment of peripheral clock genes.

In this work we propose a semimechanistic model that describes the photic signal transduction to the hypothalamic-pituitary-adrenal (HPA) axis that ultimately regulates the synchronization of peripheral clock genes (PCGs). Our HPA axis model predicts that photic stimulation induces a type-1 phase response curve to cortisol's profile with increased cortisol sensitivity to light exposure in its rising phase, as well as the shortening of cortisol's period as constant light increases (Aschoff's first rule). Furthermore, our model provides insight into cortisol's phase and amplitude dependence on photoperiods and reveals that cortisol maintains highest amplitude variability when it is entrained by a balanced schedule of light and dark periods. Importantly, by incorporating the links between HPA axis and PCGs we were able to investigate how cortisol secretion impacts the entrainment of a population of peripheral cells and show that disrupted light schedules, leading to blunted cortisol secretion, fail to synchronize a population of PCGs which further signifies the loss of circadian rhythmicity in the periphery of the body.