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.
Highlights
Most organisms have evolved an endogenous circadian timing system to anticipate periodic variations in their environment
The hypothalamic paraventricular nucleus (PVN) releases a corticotrophin-releasing hormone (CRH) which activates the release of adrenocorticotropic hormone (ACTH) from the pituitary gland and in turn induces the secretion of GCs from the adrenal glands[14]
At the HPA axis level, we consider the corticosterone dynamics which are regulated by the arginine vasopressin (AVP) signal released from the shell
Summary
Most organisms have evolved an endogenous circadian timing system to anticipate periodic variations in their environment. A set of mutually regulated genes and proteins within the SCN neurons form a self-sustained regulatory network that oscillates with a circadian period (≈ 24 h ). This transcriptional-translational oscillator consists of positive and negative feedback loops. Our model reproduces a series of experimental observations including (1) the phase relation under 12 h/12 h light/dark entrainment; (2) temporal signal transient across the core, the shell, and the HPA axis; (3) a variety in individual’s ability to adapt to perturbed schedules such as jet lag and shift work. Our work provides insights into the individualized allostatic adaptation strategies and functional trade-offs by investigating complex physiological entrainment architectures between the SCN and the HPA axis
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