{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T23:15:51Z","timestamp":1789341351193,"version":"build-2803163510"},"reference-count":86,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,7,27]],"date-time":"2021-07-27T00:00:00Z","timestamp":1627344000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"U.S. Army Medical Research and Material Command","award":["W911NF-17-2-0086"],"award-info":[{"award-number":["W911NF-17-2-0086"]}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["K24-HL105664"],"award-info":[{"award-number":["K24-HL105664"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01-HL128538"],"award-info":[{"award-number":["R01-HL128538"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P01-AG009975"],"award-info":[{"award-number":["P01-AG009975"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>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\u2013pituitary\u2013adrenal (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.<\/jats:p>","DOI":"10.3390\/metabo11080483","type":"journal-article","created":{"date-parts":[[2021,7,27]],"date-time":"2021-07-27T12:18:31Z","timestamp":1627388311000},"page":"483","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Modeling the Influence of Chronic Sleep Restriction on Cortisol Circadian Rhythms, with Implications for Metabolic Disorders"],"prefix":"10.3390","volume":"11","author":[{"given":"Rohit","family":"Rao","sequence":"first","affiliation":[{"name":"Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02139, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pramod","family":"Somvanshi","sequence":"additional","affiliation":[{"name":"Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02139, USA"},{"name":"Department of Systems and Computational Biology, School of Life Sciences, University of Hyderabad, Hyderabad 500046, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth B.","family":"Klerman","sequence":"additional","affiliation":[{"name":"Division of Sleep Medicine, Harvard Medical School, Boston, MA 02115, USA"},{"name":"Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles","family":"Marmar","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, New York Langone Medical School, New York, NY 10016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"III","given":"Francis J.","family":"Doyle","sequence":"additional","affiliation":[{"name":"Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02139, USA"},{"name":"Division of Sleep Medicine, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1016\/j.sleep.2014.01.018","article-title":"Prevalence and associated factors of DSM-V insomnia in Norway: The Nord-Trondelag Health Study (HUNT 3)","volume":"15","author":"Uhlig","year":"2014","journal-title":"Sleep Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.jsmc.2008.02.001","article-title":"Insomnia: Prevalence, Impact, Pathogenesis, Differential Diagnosis, and Evaluation","volume":"3","author":"Mai","year":"2008","journal-title":"Sleep Med. Clin."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1093\/sleep\/30.10.1245","article-title":"Sleep and mortality: A population-based 22-year follow-up study","volume":"30","author":"Hublin","year":"2007","journal-title":"Sleep"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1659","DOI":"10.1093\/sleep\/30.12.1659","article-title":"A prospective study of change in sleep duration: Associations with mortality in the Whitehall II cohort","volume":"30","author":"Ferrie","year":"2007","journal-title":"Sleep"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"564","DOI":"10.3109\/07853890.2011.586365","article-title":"Obesity and metabolic syndrome: Association with chronodisruption, sleep deprivation, and melatonin suppression","volume":"44","author":"Reiter","year":"2012","journal-title":"Ann. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1016\/j.sleep.2012.12.001","article-title":"Epidemiological evidence for the link between sleep duration and high blood pressure: A systematic review and meta-analysis","volume":"14","author":"Guo","year":"2013","journal-title":"Sleep Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1093\/sleep\/34.5.565","article-title":"Change in sleep duration and cognitive function: Findings from the Whitehall II Study","volume":"34","author":"Ferrie","year":"2011","journal-title":"Sleep"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.smrv.2011.05.001","article-title":"Immune, inflammatory and cardiovascular consequences of sleep restriction and recovery","volume":"16","author":"Faraut","year":"2012","journal-title":"Sleep Med. Rev."},{"key":"ref_9","unstructured":"Terjung, R. (2014). HPA Axis-Rhythms. Comprehensive Physiology, John Wiley & Sons, Inc."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"759234","DOI":"10.1155\/2010\/759234","article-title":"Impact of sleep and its disturbances on hypothalamo-pituitary-adrenal axis activity","volume":"2010","author":"Balbo","year":"2010","journal-title":"Int. J. Endocrinol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"207","DOI":"10.4093\/dmj.2012.36.3.207","article-title":"The role of cortisol in the pathogenesis of the metabolic syndrome","volume":"36","author":"Jeong","year":"2012","journal-title":"Diabetes Metab. J."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1016\/j.bbadis.2011.02.003","article-title":"Circadian rhythm of adrenal glucocorticoid: Its regulation and clinical implications","volume":"1812","author":"Chung","year":"2011","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1210\/er.2015-1080","article-title":"The Functional and Clinical Significance of the 24-Hour Rhythm of Circulating Glucocorticoids","volume":"38","author":"Oster","year":"2017","journal-title":"Endocr. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1435","DOI":"10.1016\/S0140-6736(99)01376-8","article-title":"Impact of sleep debt on metabolic and endocrine function","volume":"354","author":"Spiegel","year":"1999","journal-title":"Lancet"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1007\/BF03348519","article-title":"Multifactorial control of the 24-hour secretory profiles of pituitary hormones","volume":"8","author":"Refetoff","year":"1985","journal-title":"J. Endocrinol. Investig."},{"key":"ref_16","first-page":"97","article-title":"Circadian and sleep-dependent regulation of hormone release in humans","volume":"54","author":"Czeisler","year":"1999","journal-title":"Recent Prog. Horm. Res."},{"key":"ref_17","first-page":"549","article-title":"Comparative effect of night and daytime sleep on the 24-hour cortisol secretory profile","volume":"18","author":"Weibel","year":"1995","journal-title":"Sleep"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/0006-3223(91)90093-2","article-title":"Sleep disruption alters nocturnal ACTH and cortisol secretory patterns","volume":"29","author":"Gofferje","year":"1991","journal-title":"Biol. Psychiatry"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1016\/S0013-4694(97)00013-1","article-title":"Temporal relationships between pulsatile cortisol secretion and electroencephalographic activity during sleep in man","volume":"103","author":"Gronfier","year":"1997","journal-title":"Electroencephalogr. Clin. Neurophysiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1159\/000262524","article-title":"Role of sleep and sleep loss in hormonal release and metabolism","volume":"17","author":"Leproult","year":"2010","journal-title":"Endocr. Dev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2861","DOI":"10.1210\/jc.2013-4254","article-title":"Adverse effects of two nights of sleep restriction on the hypothalamic-pituitary-adrenal axis in healthy men","volume":"99","author":"Guyon","year":"2014","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2126","DOI":"10.2337\/db09-0699","article-title":"Sleep restriction for 1 week reduces insulin sensitivity in healthy men","volume":"59","author":"Buxton","year":"2010","journal-title":"Diabetes"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.smrv.2007.01.002","article-title":"The metabolic consequences of sleep deprivation","volume":"11","author":"Knutson","year":"2007","journal-title":"Sleep Med. Rev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.sleep.2015.01.007","article-title":"Reducing health disparities: The role of sleep deficiency and sleep disorders","volume":"18","author":"Laposky","year":"2016","journal-title":"Sleep Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1016\/j.sleep.2016.08.006","article-title":"Short sleep duration and health outcomes: A systematic review, meta-analysis, and meta-regression","volume":"32","author":"Itani","year":"2017","journal-title":"Sleep Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1210\/er.2013-1051","article-title":"The effects of light at night on circadian clocks and metabolism","volume":"35","author":"Fonken","year":"2014","journal-title":"Endocr. Rev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1785","DOI":"10.1016\/j.jand.2012.07.032","article-title":"Partial sleep deprivation and energy balance in adults: An emerging issue for consideration by dietetics practitioners","volume":"112","author":"Shlisky","year":"2012","journal-title":"J. Acad. Nutr. Diet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1038\/nrendo.2009.23","article-title":"Effects of poor and short sleep on glucose metabolism and obesity risk","volume":"5","author":"Spiegel","year":"2009","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.slsci.2015.09.002","article-title":"Interactions between sleep, stress, and metabolism: From physiological to pathological conditions","volume":"8","author":"Hirotsu","year":"2015","journal-title":"Sleep Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.metabol.2018.02.010","article-title":"Sleep influences on obesity, insulin resistance, and risk of type 2 diabetes","volume":"84","author":"Reutrakul","year":"2018","journal-title":"Metabolism"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"E1190","DOI":"10.1152\/ajpendo.00271.2012","article-title":"A phenomenological model for circadian and sleep allostatic modulation of plasma cortisol concentration","volume":"303","author":"Thorsley","year":"2012","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"S36","DOI":"10.1055\/s-0033-1333763","article-title":"A minimal physiologically based model of the HPA axis under influence of the sleep-wake cycles","volume":"46","author":"Postnova","year":"2013","journal-title":"Pharmacopsychiatry"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1111\/j.1365-2869.1992.tb00013.x","article-title":"Concepts and models of sleep regulation: An overview","volume":"1","author":"Borbely","year":"1992","journal-title":"J. Sleep Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"45158","DOI":"10.1038\/srep45158","article-title":"The effects of self-selected light-dark cycles and social constraints on human sleep and circadian timing: A modeling approach","volume":"7","author":"Skeldon","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1177\/0748730416658806","article-title":"Sleep Propensity under Forced Desynchrony in a Model of Arousal State Dynamics","volume":"31","author":"Postnova","year":"2016","journal-title":"J. Biol. Rhythms"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"70","DOI":"10.3389\/fendo.2017.00070","article-title":"Stress-Related and Circadian Secretion and Target Tissue Actions of Glucocorticoids: Impact on Health","volume":"8","author":"Nicolaides","year":"2017","journal-title":"Front. Endocrinol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1256","DOI":"10.1046\/j.1523-1755.2000.00959.x","article-title":"Specificity in mineralocorticoid versus glucocorticoid action","volume":"57","author":"Fuller","year":"2000","journal-title":"Kidney Int."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1016\/j.psyneuen.2012.08.007","article-title":"Mineralocorticoid and glucocorticoid receptor balance in control of HPA axis and behaviour","volume":"38","author":"Harris","year":"2013","journal-title":"Psychoneuroendocrinology"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1040","DOI":"10.1093\/infdis\/174.5.1040","article-title":"Diurnal variations in the human host response to endotoxin","volume":"174","author":"Pollmacher","year":"1996","journal-title":"J. Infect. Dis."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"5762","DOI":"10.1210\/jc.2004-1003","article-title":"Leptin levels are dependent on sleep duration: Relationships with sympathovagal balance, carbohydrate regulation, cortisol, and thyrotropin","volume":"89","author":"Spiegel","year":"2004","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_41","first-page":"1431","article-title":"Nocturnal adrenocorticotropin and cortisol secretion depends on sleep duration and decreases in association with spontaneous awakening in the morning","volume":"75","author":"Scholler","year":"1992","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"4801","DOI":"10.1210\/jc.2009-0555","article-title":"Self-reported sleep duration and sleep disturbance are independently associated with cortisol secretion in the Whitehall II study","volume":"94","author":"Kumari","year":"2009","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_43","first-page":"865","article-title":"Sleep loss results in an elevation of cortisol levels the next evening","volume":"20","author":"Leproult","year":"1997","journal-title":"Sleep"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.brainresbull.2008.07.013","article-title":"Effects of sleep restriction periods on serum cortisol levels in healthy men","volume":"77","author":"Wu","year":"2008","journal-title":"Brain Res. Bull."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Reynolds, A.C., Dorrian, J., Liu, P.Y., Van Dongen, H.P., Wittert, G.A., Harmer, L.J., and Banks, S. (2012). Impact of five nights of sleep restriction on glucose metabolism, leptin and testosterone in young adult men. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0041218"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.smrv.2019.02.002","article-title":"Effects of sleep restriction on metabolism-related parameters in healthy adults: A comprehensive review and meta-analysis of randomized controlled trials","volume":"45","author":"Zhu","year":"2019","journal-title":"Sleep Med. Rev."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"E105","DOI":"10.1002\/oby.20083","article-title":"Cortisol, obesity, and the metabolic syndrome: A cross-sectional study of obese subjects and review of the literature","volume":"21","author":"Abraham","year":"2013","journal-title":"Obesity"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"689","DOI":"10.3945\/ajcn.112.037192","article-title":"Effect of a phase advance and phase delay of the 24-h cycle on energy metabolism, appetite, and related hormones","volume":"96","author":"Gonnissen","year":"2012","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2754","DOI":"10.1210\/en.2014-1048","article-title":"From receptor balance to rational glucocorticoid therapy","volume":"155","year":"2014","journal-title":"Endocrinology"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1677\/JOE-09-0292","article-title":"The balance between gluco- and mineralo-corticoid action critically determines inflammatory adipocyte responses","volume":"204","author":"Hoppmann","year":"2010","journal-title":"J. Endocrinol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.biopsych.2015.05.014","article-title":"Sleep Disturbance, Sleep Duration, and Inflammation: A Systematic Review and Meta-Analysis of Cohort Studies and Experimental Sleep Deprivation","volume":"80","author":"Irwin","year":"2016","journal-title":"Biol. Psychiatry"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1038\/s41577-019-0190-z","article-title":"Sleep and inflammation: Partners in sickness and in health","volume":"19","author":"Irwin","year":"2019","journal-title":"Nat. Rev. Immunol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.bbi.2017.04.007","article-title":"Chronic sleep restriction promotes brain inflammation and synapse loss, and potentiates memory impairment induced by amyloid-beta oligomers in mice","volume":"64","author":"Kincheski","year":"2017","journal-title":"Brain Behav. Immun."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"998","DOI":"10.1176\/appi.ajp.162.5.998","article-title":"Circadian rhythm of salivary cortisol in Holocaust survivors with and without PTSD","volume":"162","author":"Yehuda","year":"2005","journal-title":"Am. J. Psychiatry"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"567","DOI":"10.2165\/00023210-200620070-00003","article-title":"Sleep disturbances in patients with post-traumatic stress disorder: Epidemiology, impact and approaches to management","volume":"20","author":"Maher","year":"2006","journal-title":"CNS Drugs"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"111","DOI":"10.2147\/JIR.S155903","article-title":"Systemic low-grade inflammation in post-traumatic stress disorder: A systematic review","volume":"11","author":"Speer","year":"2018","journal-title":"J. Inflamm. Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"E48","DOI":"10.1152\/ajpendo.00398.2019","article-title":"Role of enhanced glucocorticoid receptor sensitivity in inflammation in PTSD: Insights from computational model for circadian-neuroendocrine-immune interactions","volume":"319","author":"Somvanshi","year":"2020","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.ynstr.2016.09.001","article-title":"Interaction between circadian rhythms and stress","volume":"6","author":"Koch","year":"2017","journal-title":"Neurobiol. Stress"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.neubiorev.2009.12.011","article-title":"The cortisol awakening response: More than a measure of HPA axis function","volume":"35","author":"Clow","year":"2010","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_60","first-page":"1177625017702393","article-title":"The Synergistic Role of Light-Feeding Phase Relations on Entraining Robust Circadian Rhythms in the Periphery","volume":"11","author":"Bae","year":"2017","journal-title":"Gene Regul. Syst. Biol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"R98","DOI":"10.1152\/ajpregu.00230.2018","article-title":"Mathematical modeling informs the impact of changes in circadian rhythms and meal patterns on insulin secretion","volume":"317","author":"Bae","year":"2019","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.1016\/j.celrep.2016.09.060","article-title":"A Mathematical Model of the Liver Circadian Clock Linking Feeding and Fasting Cycles to Clock Function","volume":"17","author":"Woller","year":"2016","journal-title":"Cell Rep."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"E879","DOI":"10.1152\/ajpendo.00065.2019","article-title":"Mechanistic inferences on metabolic dysfunction in posttraumatic stress disorder from an integrated model and multiomic analysis: role of glucocorticoid receptor sensitivity","volume":"317","author":"Somvanshi","year":"2019","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1177\/0748730406297512","article-title":"A quantitative model of sleep-wake dynamics based on the physiology of the brainstem ascending arousal system","volume":"22","author":"Phillips","year":"2007","journal-title":"J. Biol. Rhythms"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1177\/074873099129000867","article-title":"A simpler model of the human circadian pacemaker","volume":"14","author":"Forger","year":"1999","journal-title":"J. Biol. Rhythms"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1177\/074873099129001073","article-title":"Quantifying human circadian pacemaker response to brief, extended, and repeated light stimuli over the phototopic range","volume":"14","author":"Kronauer","year":"1999","journal-title":"J. Biol. Rhythms"},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Serkh, K., and Forger, D.B. (2014). Optimal schedules of light exposure for rapidly correcting circadian misalignment. PLoS Comput. Biol., 10.","DOI":"10.1371\/journal.pcbi.1003523"},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Postnova, S., Robinson, P.A., and Postnov, D.D. (2013). Adaptation to shift work: Physiologically based modeling of the effects of lighting and shifts\u2019 start time. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0053379"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1177\/0748730411414163","article-title":"Revisiting spontaneous internal desynchrony using a quantitative model of sleep physiology","volume":"26","author":"Phillips","year":"2011","journal-title":"J. Biol. Rhythms"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1016\/S0166-2236(00)02002-6","article-title":"The sleep switch: Hypothalamic control of sleep and wakefulness","volume":"24","author":"Saper","year":"2001","journal-title":"Trends Neurosci."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1038\/nature04284","article-title":"Hypothalamic regulation of sleep and circadian rhythms","volume":"437","author":"Saper","year":"2005","journal-title":"Nature"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1177\/0748730410369208","article-title":"Probing the mechanisms of chronotype using quantitative modeling","volume":"25","author":"Phillips","year":"2010","journal-title":"J. Biol. Rhythms"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1554","DOI":"10.1016\/j.cub.2013.06.039","article-title":"Entrainment of the human circadian clock to the natural light-dark cycle","volume":"23","author":"Wright","year":"2013","journal-title":"Curr. Biol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1016\/0065-2571(65)90067-1","article-title":"Oscillatory behavior in enzymatic control processes","volume":"3","author":"Goodwin","year":"1965","journal-title":"Adv. Enzyme Regul."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Sriram, K., Rodriguez-Fernandez, M., and Doyle, F.J. (2012). Modeling Cortisol Dynamics in the Neuro-endocrine Axis Distinguishes Normal, Depression, and Post-traumatic Stress Disorder (PTSD) in Humans. PLoS Comput. Biol., 8.","DOI":"10.1371\/journal.pcbi.1002379"},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Rao, R.T., and Androulakis, I.P. (2017). Modeling the Sex Differences and Inter-individual Variability in the Activity of the Hypothalamic-Pituitary-Adrenal Axis. Endocrinology.","DOI":"10.1210\/en.2017-00544"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"E310","DOI":"10.1152\/ajpendo.00006.2016","article-title":"Mathematical modeling of the circadian dynamics of the neuroendocrine-immune network in experimentally induced arthritis","volume":"311","author":"Rao","year":"2016","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1152\/physiolgenomics.00026.2014","article-title":"Mathematical modeling of light-mediated HPA axis activity and downstream implications on the entrainment of peripheral clock genes","volume":"46","author":"Mavroudis","year":"2014","journal-title":"Physiol. Genom."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1038\/sj.npp.1300014","article-title":"Action of three ectopeptidases on corticotropin-releasing factor: Metabolism and functional aspects","volume":"28","author":"Ritchie","year":"2003","journal-title":"Neuropsychopharmacology"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1210\/er.2003-0031","article-title":"11beta-hydroxysteroid dehydrogenase type 1: A tissue-specific regulator of glucocorticoid response","volume":"25","author":"Tomlinson","year":"2004","journal-title":"Endocr. Rev."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.mce.2011.06.042","article-title":"Circadian rhythms in the hypothalamo-pituitary-adrenal (HPA) axis","volume":"349","author":"Kalsbeek","year":"2012","journal-title":"Mol. Cell Endocrinol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1023\/A:1015765201129","article-title":"Fifth-generation model for corticosteroid pharmacodynamics: Application to steady-state receptor down-regulation and enzyme induction patterns during seven-day continuous infusion of methylprednisolone in rats","volume":"29","author":"Ramakrishnan","year":"2002","journal-title":"J. Pharmacokinet. Pharmacodyn."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/S0955-0674(03)00017-6","article-title":"Sniffers, buzzers, toggles and blinkers: Dynamics of regulatory and signaling pathways in the cell","volume":"15","author":"Tyson","year":"2003","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_84","first-page":"55","article-title":"How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions","volume":"21","author":"Sapolsky","year":"2000","journal-title":"Endocr. Rev."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"2177","DOI":"10.1126\/science.284.5423.2177","article-title":"Stability, precision, and near-24-hour period of the human circadian pacemaker","volume":"284","author":"Czeisler","year":"1999","journal-title":"Science"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1152\/physiolgenomics.00006.2016","article-title":"The role of the hypothalamic-pituitary-adrenal axis in modulating seasonal changes in immunity","volume":"48","author":"Pierre","year":"2016","journal-title":"Physiol. 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