The suprachiasmatic nucleus (SCN) functions as the central pacemaker aligning physiological and behavioral oscillations to day/night (activity/inactivity) transitions. The light signal entrains the molecular clock of the photo-sensitive ventrolateral (VL) core of the SCN which in turn entrains the dorsomedial (DM) shell via the neurotransmitter vasoactive intestinal polypeptide (VIP). The shell converts the VIP rhythmic signals to circadian oscillations of arginine vasopressin (AVP), which eventually act as a neurotransmitter signal entraining the hypothalamic–pituitary–adrenal (HPA) axis, leading to robust circadian secretion of glucocorticoids. In this work, we discuss a semi-mechanistic mathematical model that reflects the essential hierarchical structure of the photic signal transduction from the SCN to the HPA axis. By incorporating the interactions across the core, the shell, and the HPA axis, we investigate how these coupled systems synchronize leading to robust circadian oscillations. Our model predicts the existence of personalized synchronization strategies that enable the maintenance of homeostatic rhythms while allowing for differential responses to transient and permanent light schedule changes. We simulated different behavioral situations leading to perturbed rhythmicity, performed a detailed computational analysis of the dynamic response of the system under varying light schedules, and determined that (1) significant interindividual diversity and flexibility characterize adaptation to varying light schedules; (2) an individual’s tolerances to jet lag and alternating shift work are positively correlated, while the tolerances to jet lag and transient shift work are negatively correlated, which indicates trade-offs in an individual’s ability to maintain physiological rhythmicity; (3) weak light sensitivity leads to the reduction of circadian flexibility, implying that light therapy can be a potential approach to address shift work and jet lag related disorders. Finally, we developed a map of the impact of the synchronization within the SCN and between the SCN and the HPA axis as it relates to the emergence of circadian flexibility.
The suprachiasmatic nucleus (SCN) synchronizes the physiological rhythms to the external light-dark cycle and tunes the dynamics of circadian rhythms to photoperiod fluctuations. Changes in the neuronal network topologies are suggested to cause adaptation of the SCN in different photoperiods, resulting in the broader phase distribution of neuron activities in long photoperiods (LP) compared to short photoperiods (SP). Regulated by the SCN output, the level of glucocorticoids is elevated in short photoperiod, which is associated with peak disease incidence. The underlying coupling mechanisms of the SCN and the interplay between the SCN and the HPA axis have yet to be fully elucidated. In this work, we propose a mathematical model including a multiple-cellular SCN compartment and the HPA axis to investigate the properties of the circadian timing system under photoperiod changes. Our model predicts that the probability-dependent network is more energy-efficient than the distance-dependent network. Coupling the SCN network by intra-subpopulation and inter-subpopulation forces, we identified the negative correlation between robustness and plasticity of the oscillatory network. The HPA rhythms were predicted to be strongly entrained to the SCN rhythms with a pro-inflammatory high-amplitude glucocorticoid profile under SP. The fast temporal topology switch of the SCN network was predicted to enhance synchronization when the synchronization is not complete. These synchronization and circadian dynamics alterations might govern the seasonal variation of disease incidence and its symptom severity.
Synchronizing the circadian timing system (CTS) to external light/dark cycles is crucial for homeostasis maintenance and environmental adaptation. The CTS is organized hierarchically, with the central pacemaker located in the suprachiasmatic nuclei (SCN) generating coherent oscillations that are entrained to light/dark cycles. These oscillations regulate the release of glucocorticoids by the hypothalamus-pituitary-adrenal (HPA) axis, which acts as a systemic entrainer of peripheral clocks throughout the body. The SCN adjusts its network plasticity in response to variations in photoperiod, leading to changes in the rhythmic release of glucocorticoids and ultimately impacting peripheral clocks. However, the effects of photoperiod-induced variations of glucocorticoids on the synchronization of peripheral clocks are not fully understood, and the interaction between jetlag adaption and photoperiod changes is unclear. This study presents a semi-mechanistic mathematical model to investigate how the CTS responds to changes in photoperiod. Specifically, the study focuses on the entrainment properties of a system composed of the SCN, HPA axis, and peripheral clocks. The results show that high-amplitude glucocorticoid rhythms lead to a more coherent phase distribution in the periphery. In addition, our study investigates the effect of photoperiod exposure on jetlag recovery time and phase shift, proposing different interventional strategies for eastward and westward jetlag. The findings suggest that decreasing photic exposure before jetlag during eastward traveling and after jetlag during westward traveling can accelerate jetlag readaptation. The study provides insights into the mechanisms of CTS organization and potential recovery strategies for transitions between time zones and lighting zones.
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