Computational modeling of the synergistic role of GCN2 and the HPA axis in regulating the integrated stress response in the central circadian timing system.

The circadian timing system and integrated stress response (ISR) systems are fundamental regulatory mechanisms that maintain body homeostasis. The central circadian pacemaker in the suprachiasmatic nucleus (SCN) governs daily rhythms through interactions with peripheral oscillators via the hypothalamus-pituitary-adrenal (HPA) axis. On the other hand, ISR signaling is pivotal for preserving cellular homeostasis in response to physiological changes. Notably, disrupted circadian rhythms are observed in cases of impaired ISR signaling. In this work, we examine the potential interplay between the central circadian system and the ISR, mainly through the SCN and HPA axis. We introduce a semimechanistic mathematical model to delineate SCN's capacity for indirectly perceiving physiological stress through glucocorticoid-mediated feedback from the HPA axis and orchestrating a cellular response via the ISR mechanism. Key components of our investigation include evaluating general control nonderepressible 2 (GCN2) expression in the SCN, the effect of physiological stress stimuli on the HPA axis, and the interconnected feedback between the HPA and SCN. Simulation revealed a critical role for GCN2 in linking ISR with circadian rhythms. Experimental findings have demonstrated that a Gcn2 deletion in mice leads to rapid re-entrainment of the circadian clock following jetlag as well as to an elongation of the circadian period. These phenomena are well replicated by our model, which suggests that both the swift re-entrainment and prolonged period can be ascribed to a reduced robustness in neuronal oscillators. Our model also offers insights into phase shifts induced by acute physiological stress and the alignment/misalignment of physiological stress with external light-dark cues. Such understanding aids in strategizing responses to stressful events, such as nutritional status changes and jetlag.NEW & NOTEWORTHY This study is the first theoretical work to investigate the complex interaction between integrated stress response (ISR) sensing and central circadian rhythm regulation, encompassing the suprachiasmatic nucleus (SCN) and hypothalamus-pituitary-adrenal (HPA) axis. The findings carry implications for the development of dietary or pharmacological interventions aimed at facilitating recovery from stressful events, such as jetlag. Moreover, they provide promising prospects for potential therapeutic interventions that target circadian rhythm disruption and various stress-related disorders.

The Physiological and Pharmacological Significance of the Circadian Timing of the HPA Axis: A Mathematical Modeling Approach.

As a potent endogenous regulator of homeostasis, the circadian time-keeping system synchronizes internal physiology to periodic changes in the external environment to enhance survival. Adapting endogenous rhythms to the external time is accomplished hierarchically with the central pacemaker located in the suprachiasmatic nucleus (SCN) signaling the hypothalamus-pituitary-adrenal (HPA) axis to release hormones, notably cortisol, which help maintain the body's circadian rhythm. Given the essential role of HPA-releasing hormones in regulating physiological functions, including immune response, cell cycle, and energy metabolism, their daily variation is critical for the proper function of the circadian timing system. In this review, we focus on cortisol and key fundamental properties of the HPA axis and highlight their importance in controlling circadian dynamics. We demonstrate how systems-driven, mathematical modeling of the HPA axis complements experimental findings, enhances our understanding of complex physiological systems, helps predict potential mechanisms of action, and elucidates the consequences of circadian disruption. Finally, we outline the implications of circadian regulation in the context of personalized chronotherapy. Focusing on the chrono-pharmacology of synthetic glucocorticoids, we review the challenges and opportunities associated with moving toward personalized therapies that capitalize on circadian rhythms.

The SCN-HPA-Periphery Circadian Timing System: Mathematical Modeling of Clock Synchronization and the Effects of Photoperiod on Jetlag Adaptation.

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.

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

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.

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

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.