Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

A new model for the HPA axis explains dysregulation of stress hormones on the timescale of weeks

Omer Karin, Moriya Raz, Avichai Tendler, Alon Bar, Yael Korem Kohanim, Tomer Milo, Uri Alon
doi: https://doi.org/10.1101/2020.01.01.892596
Omer Karin
Dept. Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel 76100
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Moriya Raz
Dept. Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel 76100
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Avichai Tendler
Dept. Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel 76100
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Alon Bar
Dept. Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel 76100
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yael Korem Kohanim
Dept. Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel 76100
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Tomer Milo
Dept. Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel 76100
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Uri Alon
Dept. Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel 76100
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: uri.alon@weizmann.ac.il
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Supplementary material
  • Preview PDF
Loading

Abstract

Stress activates a complex network of hormones known as the Hypothalamic-Pituitary-Adrenal (HPA) axis. The HPA axis is dysregulated in chronic stress and psychiatric disorders, but the origin of this dysregulation is unclear and cannot be explained by current HPA models. To address this, we developed a new mathematical model for the HPA axis that incorporates changes in the total functional mass of the HPA hormone-secreting glands. The mass changes are caused by the HPA hormones which act as growth factors for the glands in the axis. We find that the HPA axis shows the property of dynamical compensation, where gland masses adjust over weeks to buffer variation in physiological parameters. These mass changes explain the experimental findings on dysregulation of cortisol and ACTH dynamics in alcoholism, anorexia and postpartum. Dysregulation occurs for a wide range of parameters, and is exacerbated by impaired glucocorticoid receptor (GR) feedback, providing an explanation for the implication of GR in mood disorders. These findings suggest that gland-mass dynamics may play an important role in the pathophysiology of stress-related disorders.

Author Summary The HPA axis is a neuroendocrine axis that is activated in response to stressors. The classical description of this axis includes three hormones that act in a cascade, with the final hormone cortisol inhibiting the two upstream hormones, ACTH and CRH. This classical picture has timescales of hours due to hormone half-lives, and cannot explain phenomena on the scale of weeks to months associated with this axis, such as the dysregulation observed in depression, alcohol addiction, postpartum, and other conditions. Here, we use a minimal-model approach to add to the classical model two known interactions in which CRH and ACTH not only regulate downstream hormones, but also act as growth factors for the cells that secrete these hormones. This creates a physiological circuit that can maintain total cell mass and buffer parameter changes. It has a fragility in which after prolonged stress, the total cell functional masses grow and take weeks to return to baseline. This is sufficient to explain the specific dynamics of hormone dysregulation found in several contexts. It also quantifies the effect of the cortisol (glucocorticoid) receptor on resilience to prolonged stress. Our findings suggest that interactions between hormones and cell functional mass may play an important role in HPA axis regulation on the timescale of weeks to months.

Figure

The HPA axis helps the body adapt to stress, but becomes dysregulated after prolonged activation, with clinical consequences. The origin of this dysregulation is unclear. We provide a mechanism for dysregulation based on the effect of the HPA hormones as growth factors for their downstream glands.

  • A mathematical model that includes gland functional mass dynamics, introduces a new slow timescale of weeks to the HPA axis; previous models had only fast timescales of hours.

  • The gland masses grow during prolonged activation, providing dynamical compensation, and recover with overshoots over weeks after withdrawal of activation.

  • These overshoots are sufficient to explain the observed HPA dysregulation in pathological conditions, and clarify the role of glucocorticoid receptors in resilience to prolonged stress.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
Back to top
PreviousNext
Posted March 22, 2020.
Download PDF

Supplementary Material

Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
A new model for the HPA axis explains dysregulation of stress hormones on the timescale of weeks
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
A new model for the HPA axis explains dysregulation of stress hormones on the timescale of weeks
Omer Karin, Moriya Raz, Avichai Tendler, Alon Bar, Yael Korem Kohanim, Tomer Milo, Uri Alon
bioRxiv 2020.01.01.892596; doi: https://doi.org/10.1101/2020.01.01.892596
Digg logo Reddit logo Twitter logo Facebook logo Google logo LinkedIn logo Mendeley logo
Citation Tools
A new model for the HPA axis explains dysregulation of stress hormones on the timescale of weeks
Omer Karin, Moriya Raz, Avichai Tendler, Alon Bar, Yael Korem Kohanim, Tomer Milo, Uri Alon
bioRxiv 2020.01.01.892596; doi: https://doi.org/10.1101/2020.01.01.892596

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Physiology
Subject Areas
All Articles
  • Animal Behavior and Cognition (3589)
  • Biochemistry (7552)
  • Bioengineering (5498)
  • Bioinformatics (20741)
  • Biophysics (10300)
  • Cancer Biology (7958)
  • Cell Biology (11623)
  • Clinical Trials (138)
  • Developmental Biology (6594)
  • Ecology (10175)
  • Epidemiology (2065)
  • Evolutionary Biology (13584)
  • Genetics (9525)
  • Genomics (12822)
  • Immunology (7909)
  • Microbiology (19518)
  • Molecular Biology (7646)
  • Neuroscience (42009)
  • Paleontology (307)
  • Pathology (1254)
  • Pharmacology and Toxicology (2195)
  • Physiology (3260)
  • Plant Biology (7027)
  • Scientific Communication and Education (1294)
  • Synthetic Biology (1948)
  • Systems Biology (5420)
  • Zoology (1113)