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WIREs Syst Biol Med
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Circadian rhythms and the HPA axis: A systems view

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Abstract The circadian timing system comprises a network of time‐keeping clocks distributed across a living host whose responsibility is to allocate resources and distribute functions temporally to optimize fitness. The molecular structures generating these rhythms have evolved to accommodate the rotation of the earth in an attempt to primarily match the light/dark periods during the 24‐hr day. To maintain synchrony of timing across and within tissues, information from the central clock, located in the suprachiasmatic nucleus, is conveyed using systemic signals. Leading among those signals are endocrine hormones, and while the hypothalamic–pituitary–adrenal axis through the release of glucocorticoids is a major pacesetter. Interestingly, the fundamental units at the molecular and physiological scales that generate local and systemic signals share critical structural properties. These properties enable time‐keeping systems to generate rhythmic signals and allow them to adopt specific properties as they interact with each other and the external environment. The purpose of this review is to provide a broad overview of these structures, discuss their functional characteristics, and describe some of their fundamental properties as these related to health and disease. This article is categorized under: Immune System Diseases > Computational Models Immune System Diseases > Biomedical Engineering
The two major feedback loops driving the dynamics of the fundamental circadian oscillator: CLOCK/BMAL1 regulates the expression of two arms that eventually feed ack to its activity. On the one hand, it drives the expression of rep and cry which, ultimately inhibit CLOCK/BMAL1's activity, and on the other hand, it regulates Rev‐Erbα, which will eventually regulate the expression of Bmal1
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Evolution of HPA skeletal models. Top: minimal model expressing the sequential activation “CRH ➔ ACTH ➔ Cortisol” incorporating cortisol feedback to the hypothalamus and adrenal. Middle: semi‐mechanistic structure, including the receptor and cortisol‐receptor complex as the driver of the feedback regulation. Bottom: Model of increased detail incorporating the transcription and translation of the glucocorticoid receptor and the dynamics of the nuclear translocation of the activated complex inducing the negative feedback
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Left: Goodwin oscillator. Right: Goldbeter's PER model. Both represent essential regulatory structures generating sustainable oscillations. Both models have extensively explored in the literature and define the basis of model advanced and complex mathematical models of oscillatory biological systems
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A modular representation of the hierarchical nature of the timing system, not meant to reflect the actual physiology, but rather be used as a template for developing computational and mathematical models. The central pacemaker, located in the SCN, receives photic signals which entrain the local clock genes coordinating the firing of neuropeptides. These SCN‐derived signals either directly, or via the ANS, entrain the ultradian glucocorticoid release, which is established by the CRH‐ACTH‐GC feedback loops. GCs, in turn, coordinate the action of peripheral clock and GC‐responsive genes, thus propagating those rhythms across the host. It should be noted that the core clock genes (central and peripheral) contain GR elements, thus are GC responsive genes, whereas the action of glucocorticoids is inhibited by CLACK/BMAL. Thus a complex, layered structure emerges
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(left) Temporal profiles of core‐clock genes in 12 mouse tissues characteristic of the core‐clock coordination across multiple organs. Reprinted with permission from Zhang et al. (2014). Copyright 2014 PNAS
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