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

Abstract

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.

Investigating the Synergistic Role of GCN2 and HPA Axis in Regulating Integrated Stress Response in the Central Circadian Timing System

“…To capture the inherent oscillatory behavior of the HPA, we utilized an established HPA axis model from prior works (Mavroudis et al 2014). This model was further refined by integrating synchronization cues originating from the SCN, as detailed in (Li and Androulakis 2021, 2022). The exact mechanism through which the SCN receives ISR signals and activates GCN2 pathways within its neurons remains unclear.…”

“…Our model also highlights the interconnected reliance of this master clock’s response to metabolic stress signals on feedback from the hypothalamic-pituitary-adrenal (HPA) axis. This relationship is framed within the SCN topology-HPA axis model established in our previous work [1, 2]. Distinctively, the model differently represents the SCN as a heterogeneous collection of GCN2-eIF2α-ATF4 pathway-mediated, damped neuronal oscillators and further incorporates the hypothetic, indirect effect of glucocorticoids (CORT), which is output from the HPA axis, on upregulating the neurotransmitter expression within SCN neurons ( Figure 1 ).…”

“…A single cell (cell i) in the SCN: Similar to our prior works [1, 2], the SCN in this study is represented as a single compartment that consists of a population of neurons with heterogeneity, where the component SCN neurons release neurotransmitters ( V ) ( Equation 4 ) for both self-coupling at the cellular level and inter-neuronal communication at the tissue level. The secretion of neurotransmitters to the extracellular medium are assumed to be induced upon the activity of PER/CRY proteins ( Equation 4 ) and their functions as inter-cellular coupling signals are distance-dependent, implying that the adjacent neurons of the neurotransmitter-releasing neuron are more affected ( Equation 5-7 ).…”

“…The intrinsic dynamics of the clock genes and proteins network is modeled using the same gene regulatory network [4, 5] as our previous works [1, 2, 6, 7], which consists of interacted positive and negative transcriptional translational feedback loops. The positive branch is constituted by a sequence of indirect activation of Bmal1 transcription by nuclear PER/CRY protein ( Equation 12 ), translation of Bmal1 mRNA ( Equation 13 ), nuclear translocation of cytoplasmic BMAL1 protein ( Equation 14 ), and heterodimerization to CLOCK/BMAL1 complex ( Equation 15 ).…”

“…Built upon our previous models [1, 2, 7], the neurotransmitter V released from the SCN downregulates the secretion of CRH [10] ( Equation 16 ), driving the circadian rhythm of the HPA axis. Besides, a closed CORT-dependent negative feedback loop that inhibits the production of CRH and ACTH is reserved, which is essential to maintain the homeostasis and terminate the stress response of the HPA axis.…”