Modeling the Influence of Chronic Sleep Restriction on Cortisol Circadian Rhythms, with Implications for Metabolic Disorders.

Rohit Rao,Pramod Somvanshi,Francis J Doyle,Charles Marmar,Elizabeth B Klerman

doi:10.3390/metabo11080483

Abstract

Chronic sleep deficiency is prevalent in modern society and is associated with increased risk of metabolic and other diseases. While the mechanisms by which chronic sleep deficiency induces pathophysiological changes are yet to be elucidated, the hypothalamic–pituitary–adrenal (HPA) axis may be an important mediator of these effects. Cortisol, the primary hormone of the HPA axis, exhibits robust circadian rhythmicity and is moderately influenced by sleep and wake states and other physiology. Several studies have explored the effects of acute or chronic sleep deficiency (i.e., usually from self-selected chronic sleep restriction, CSR) on the HPA axis. Quantifying long-term changes in the circadian rhythm of cortisol under CSR in controlled conditions is inadequately studied due to practical limitations. We use a semi-mechanistic mathematical model of the HPA axis and the sleep/wake cycle to explore the influence of CSR on cortisol circadian rhythmicity. In qualitative agreement with experimental findings, model simulations predict that CSR results in physiologically relevant disruptions in the phase and amplitude of the cortisol rhythm. The mathematical model presented in this work provides a mechanistic framework to further explore how CSR might lead to HPA axis disruption and subsequent development of chronic metabolic complications.

Highlights

We present a prototype mathematical model that accounts for the dual influence of both circadian and sleep/wake processes on HPA axis activity, thereby enabling a more physiologically relevant description of the effects of Chronic sleep restriction (CSR) on cortisol
The mathematical model used in this work to explore the influence of sleep and wake timing and duration on the circadian activity of the HPA axis encompasses four physiologic elements: (i) a model composed of a phenomenological sleep/wake switch that captures the mutual inhibition of sleep-promoting ventrolateral preoptic area (VLPO) and wake-promoting monoaminergic neuronal populations leading to the emergence of sleep and wake states; (ii) the endogenous circadian drive and a homeostatic sleep drive, which are integrated in the VLPO and thereby influence the sleep/wake switch; (iii) a self-regulatory negative feedback loop incorporating the interactions among the major hormones of the HPA axis, namely
We subsequently modeled the dynamics of the receptor–glucocorticoid complex during habitual and CSR conditions

Summary

Introduction

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Adequate sleep is essential to the maintenance of metabolic homeostasis [1,2]. Epidemiological studies have implicated sleep disruption and changes in sleep duration and sleep disturbances in the development of numerous health disorders. Shorter sleep duration and disrupted sleep have been associated with increased all-cause mortality [3,4]; increased risk of cardiovascular death [4], Type II diabetes, metabolic syndrome [5], obesity, and hypertension [6]; accelerated aging-associated cognitive function decline [7]; vulnerability to infection [8]

Methods

Results

Conclusion