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Sex differences in the chronic mild stress model of depression

Franceschelli, Anthonya; Herchick, Samanthaa; Thelen, Connora; Papadopoulou-Daifoti, Zetab; Pitychoutis, Pothitos M.a

doi: 10.1097/FBP.0000000000000062
Review Articles

A large volume of clinical and experimental evidence documents sex differences in brain anatomy, chemistry, and function, as well as in stress and drug responses. The chronic mild stress model (CMS) is one of the most extensively investigated animal models of chronic stress. However, only a limited number of studies have been conducted in female rodents despite the markedly higher prevalence of major depression among women. Herein, we review CMS studies conducted in rats and mice of both sexes and further discuss intriguing sex-dependent behavioral and neurobiological findings. The PubMed literature search engine was used to find and collect all relevant articles analyzed in this review. Specifically, a multitermed search was performed with ‘chronic mild stress’, ‘chronic unpredictable stress’ and ‘chronic variable stress’ as base terms and ‘sex’, ‘gender’, ‘females’ and ‘depression’ as secondary terms in various combinations. Male and female rodents appear to be differentially affected by CMS application, depending on the behavioral, physiological, and neurobiological indices that are being measured. Importantly, the CMS paradigm, despite its limitations, has been successfully used to assess a constellation of interdisciplinary research questions in the sex differences field and has served as a ‘silver bullet’ in assessing the role of sex in the neurobiology of major depression.

aDepartment of Biology, Center for Tissue Regeneration and Engineering (TREND), University of Dayton, Dayton, Ohio, USA

bDepartment of Pharmacology, Medical School, National & Kapodistrian University of Athens, Athens, Greece

Correspondence to Pothitos M. Pitychoutis, PhD, Department of Biology, Center for Tissue Regeneration and Engineering (TREND), University of Dayton, 300 College Park, Dayton, OH 45469-2320, USA E-mail:

Received February 26, 2014

Accepted May 27, 2014

© 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins