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Reliability of the chronic mild stress model of depression: A user survey
Open accessAbstract
The chronic mild stress (CMS) model of depression is considered by many to be the animal model of depression that has the greatest validity and translational potential, but it has often been criticized for a perceived lack of reliability. The aims of this study were to establish the extent to which the procedure is reproducible, and to identify experimental variables relevant to its reliability. Because failures to replicate frequently remain unpublished, a survey methodology was used. A questionnaire was circulated to 170 labs identified from a PubMed search as having published a CMS study in the years 2010 or 2015 (with no selection in respect of the results reported). Responses were returned by 71 (42%) of the recipients, followed by further correspondence with some of them. Most of the respondents (n = 53: 75%) reported that the CMS procedure worked reliably in their hands. Of the others, 15 (21%) reported that the procedure was usually reliable, but not always (n = 9: 13%) or not for all measures (n = 6: 8%). Only three respondents (4%) reported being unable to reproduce the characteristic effects, two of whom may be using an insufficient duration of CMS exposure. A series of analyses compared the 75% of 'reliable' labs with the 25% of 'less reliable' labs on a range of experimenter, subject, stress and outcome variables. Few if any significant differences between these two samples were identified, possibly because of the small size and diversity of the 'less reliable' sample. Two other limitations of the study include the (unavoidable) omission of labs that may have worked with the model but not published their data, and the use of ad hoc measures to compare the severity of different stress regimes. The results are discussed in relation to relevant published observations. It is concluded that CMS is in fact a rather robust model, but the factors that result in a less effective implementation in a minority of laboratories remain to be firmly established.
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“Chronic unpredictable/mild/variable stress and chronic social defeat stress are the two most commonly used animal models of depression [31, 34–38].”
From Chronic unpredictable stress induces depression-related behaviors by suppressing AgRP neuron activity (2021) · cites this paper as [38]
In the citing paper
“The induction of anhedonia has been the primary focus in this model”
From Chronic unpredictable stress induces depression-related behaviors by suppressing AgRP neuron activity (2021) · cites this paper as [38]
In the citing paper
“has been the most consistent biological abnormality in this disorder [38, 40].”
From Chronic unpredictable stress induces depression-related behaviors by suppressing AgRP neuron activity (2021) · cites this paper as [38]
In the citing paper
“chronic unpredictable/mild/variable stress induces a myriad of behavioral, neurochemical, and neuroendocrine alterations that mirror changes mainly observed in human depression [38].”
From Chronic unpredictable stress induces depression-related behaviors by suppressing AgRP neuron activity (2021) · cites this paper as [38]
In the citing paper
“along with its important feature reproducing hypercortisolism, which is found in 40–60% of patients with major depression”
From Chronic unpredictable stress induces depression-related behaviors by suppressing AgRP neuron activity (2021) · cites this paper as [38]
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The chronic mild stress (CMS) model of depression: History, evaluation and usage
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“An accompanying paper (Willner, 2016) describes a survey of users of these procedures (as discussed further below).”
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“…CUMS paradigm to evaluate depressive-like behavior in rodents and identify strain-specific susceptibility to stress based on one of the main end points of this model, “anhedonia,” assessed by the sucrose preference test (Willner et al., 1987; Willner, 2017b) and sucrose intake (Papp et al., 1994).”
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“It also showed that the quality of a CMS model can be elevated by training laboratory operators to use sophisticated techniques [51].”
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“A recent review shows that different names of the model do not strictly relate to the severity of the stressors used or predictability of the stressors (Willner, 2017a), and they usually yield similar results than the original protocol.”
BackgroundMethodResultInfluential
Metadata
- Authors
- Willner, P.
- Affiliations
- Swansea University (GB)
- Corresponding author
- Willner, Paul
- ORCID
- Willner, Paul
- Venue
- Neurobiology of Stress
- Publisher
- Elsevier BV
- Published
- 2017-02
- Volume
- 6
- Pages
- 68-77
- ISSN
- 2352-2895 (ISSN-L)
- PMC
- PMC5314419
- OpenAlex
- W2510666910
- Cited by
- 198
- References
- 91
- Citations by year
- 2026: 14 · 2025: 16 · 2024: 27 · 2023: 22 · 2022: 31 · 2021: 25 · 2020: 17 · 2019: 20 · 2018: 19 · 2017: 5
- FWCI
- 9.79
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Neurobiology of Stress (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Veterinary › Small Animals › Animal testing and alternatives
- Keywords
- chronic mild stress, animal models of depression, reproducibility, reliability statistics, replication failure, stressor severity, translational validity
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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