Chronic mild stress paradigm as a rat model of depression: facts, artifacts, and future perspectives

Tatyana Strekalova,Sharafuddin Khairuddin,Lee Wei Lim,Andrey Proshin,Justin Lam,Ying-Shing Chan,Jennifer Lok Yu Chiu,Daniel C Anthony,Dmitrii Pavlov,Klaus-Peter Lesch,Yanzhi Liu,Daniel Kiselev

doi:10.1007/s00213-021-05982-w

Abstract

RationaleThe chronic mild stress (CMS) paradigm was first described almost 40 years ago and has become a widely used model in the search for antidepressant drugs for major depression disorder (MDD). It has resulted in the publication of almost 1700 studies in rats alone. Under the original CMS procedure, the expression of an anhedonic response, a key symptom of depression, was seen as an essential feature of both the model and a depressive state. The prolonged exposure of rodents to unpredictable/uncontrollable mild stressors leads to a reduction in the intake of palatable liquids, behavioral despair, locomotor inhibition, anxiety-like changes, and vegetative (somatic) abnormalities. Many of the CMS studies do not report these patterns of behaviors, and they often fail to include consistent molecular, neuroanatomical, and physiological phenotypes of CMS-exposed animals.ObjectivesTo critically review the CMS studies in rats so that conceptual and methodological flaws can be avoided in future studies.ResultsAnalysis of the literature supports the validity of the CMS model and its impact on the field. However, further improvements could be achieved by (i) the stratification of animals into ‘resilient’ and ‘susceptible’ cohorts within the CMS animals, (ii) the use of more refined protocols in the sucrose test to mitigate physiological and physical artifacts, and (iii) the systematic evaluation of the non-specific effects of CMS and implementation of appropriate adjustments within the behavioral tests.ConclusionsWe propose methodological revisions and the use of more advanced behavioral tests to refine the rat CMS paradigm, which offers a valuable tool for developing new antidepressant medications.

Highlights

Major depressive disorder (MDD) is a common psychiatric illness that has an enormous impact on quality of life
This phenomenon could be partly due to the limited accuracy of behavioral tests, inter-individual variability of stress response, and the development of general hyperlocomotion that were previously described in murine Chronic mild stress (CMS) models (Strekalova et al 2005; Schweizer et al 2009; Boulle et al 2014), which are discussed further below
Seventeen studies utilizing CMS procedures on male rats described a stratification of stressed animals to "susceptible" and "resilient" upon signs of anhedonia in the sucrose test

Summary

Results

Analysis of the literature supports the validity of the CMS model and its impact on the field. Further improvements could be achieved by (i) the stratification of animals into ‘resilient’ and ‘susceptible’ cohorts within the CMS animals, (ii) the use of more refined protocols in the sucrose test to mitigate physiological and physical artifacts, and (iii) the systematic evaluation of the non-specific effects of CMS and implementation of appropriate adjustments within the behavioral tests

Conclusions

Introduction

15 Duration of

Conclusions and future perspectives