Light entrainment of the SCN circadian clock and implications for personalized alterations of corticosterone rhythms in shift work and jet lag

Abstract

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.

Principles of Endocrine Regulation: Reconciling Tensions Between Robustness in Performance and Adaptation to Change

“…While there is no universal definition of resilience, patterns of resilience have been discussed for different systems ( 60 ). While the thyroid stress response is less dynamic, recent insights into the stress response of the hypothalamic-pituitary-adrenal (HPA) axis have linked chronic disruption of circadian rhythms to the accumulation of allostatic load ( 61 , 62 ). Adaptation of the HPA axis has been modeled as a trade-off between its stress-responsiveness and its time-keeping ability, and individualized allostatic adaptation strategies have emerged ( 63 ).…”

Light-induced synchronization of the SCN coupled oscillators and implications for entraining the HPA axis

“…In the negative feedback loop, nucleus PER/CRY protein inhibits their own mRNA’s transcription by binding to the E box enhancer of the CLOCK/BMAL1 heterocomplex (Equations 2 and 10). As included in Supplementary Table 1 , the parameters for the core and the shell are adapted from our previous work ( 45 ), the suffix “m” denotes parameters in the core compartment, and the suffix “e” denotes parameters in the shell compartment.…”

“…The inter-subpopulation coupling is introduced by an additional term in Equation 10, which accounts for an independent neurotransmitter-driven transcription process apart from the CLOCK/BMAL1 driven transcription ( 49 ). Light entrainment of the core is modeled by an additional term in Equation 2 to describe the independent photic activation effects on Per/Cry mRNA transcription ( 45 ). Although light signals are mainly transduced by the core, it is strongly speculated that the core is not the only light-responsive subregion.…”

“…The model of the HPA axis is adapted from our prior works ( 43 , 45 , 54 ), where its entraining effects are achieved as AVP’s (ensemble average secreted from the SCN shell, Equation 18) down-regulation on the CRH secretion (Equation 19). CRH further regulates the release of ACTH (Equation 20) and eventually induces glucocorticoid (CORT) secretion (corticosterone in this work, Equation 21).…”

DataSheet_1.pdf

“…While there is no universal definition of resilience, patterns of resilience have been discussed for different systems (60). While the thyroid stress response is less dynamic, recent insights into the stress response of the hypothalamicpituitary-adrenal (HPA) axis have linked chronic disruption of circadian rhythms to the accumulation of allostatic load (61,62). Adaptation of the HPA axis has been modeled as a trade-off between its stress-responsiveness and its time-keeping ability, and individualized allostatic adaptation strategies have emerged (63).…”