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 Because failures to replicate frequently remain unpublished, a survey methodology was used.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.
“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]
The induction of anhedonia has been the primary focus in the chronic unpredictable/mild/variable stress model.
“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]
Hypercortisolism is the most consistent biological abnormality in major depression.
“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]
Chronic unpredictable/mild/variable stress induces a myriad of behavioral, neurochemical, and neuroendocrine alterations that mirror changes mainly observed in human depression.
“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]
The chronic unpredictable/mild/variable stress model reproduces hypercortisolism found in 40-60% of patients with major depression.
“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
Willner, P. (2017) · Neurobiology of Stress · doi:10.1016/j.ynstr.2016.08.002 · Cited by 959 · see citing works
“An accompanying paper (Willner, 2016) describes a survey of users of these procedures (as discussed further below).”
BackgroundMethodInfluentialSelf-citationAntoniuk, S., Bijata, M., Ponimaskin, E., & Wlodarczyk, J. (2019) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2018.12.002 · Cited by 750 · see citing works
“…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).”
InfluentialOn the nature and use of models in network neuroscience
Bassett, D. S., Zurn, P., & Gold, J. I. (2018) · Nature reviews. Neuroscience · doi:10.1038/s41583-018-0038-8 · Cited by 367 · see citing works
Selecting an Appropriate Animal Model of Depression
Hao, Y., Ge, H., Sun, M., & Gao, Y. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20194827 · Cited by 247 · see citing works
“It also showed that the quality of a CMS model can be elevated by training laboratory operators to use sophisticated techniques [51].”
BackgroundMaking Sense of Rodent Models of Anhedonia
Scheggi, S., Montis, M. G. D., & Gambarana, C. (2018) · The International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyy083 · Cited by 209 · see citing works
“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.”
BackgroundMethodResultInfluentialCentral regulation of stress-evoked peripheral immune responses
Chan, K. L., Poller, W. C., Swirski, F. K., & Russo, S. J. (2023) · Nature Reviews Neuroscience · doi:10.1038/s41583-023-00729-2 · Cited by 207 · see citing works
Sucrose preference test: A systematic review of protocols for the assessment of anhedonia in rodents
Primo, M. J., Fonseca‐Rodrigues, D., Almeida, A., Teixeira, P., & Pinto‐Ribeiro, F. (2023) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2023.08.496 · Cited by 165 · see citing works
Chronic mild stress paradigm as a rat model of depression: facts, artifacts, and future perspectives
Strekalova, T. V., Liu, Y., Kiselev, D., Khairuddin, S., Chiu, J. L. Y., Lam, J., Chan, Y., Pavlov, D., Proshin, A. T., Lesch, K., et al. (2022) · Psychopharmacology · doi:10.1007/s00213-021-05982-w · Cited by 146 · see citing works
Sequeira‐Cordero, A., Salas-Bastos, A., Fornaguera, J., & Brenes, J. C. (2019) · Scientific Reports · doi:10.1038/s41598-019-53624-1 · Cited by 140 · see citing works
“An inter-laboratory survey conducted by Willner (2017) showed that at least 25% of laboratories have dealt with some problems of reproducibility on CUS-induced reduction in sucrose consumption or preference20.”
MethodCzéh, B., Vardya, I., Varga, Z., Febbraro, F., Csabai, D., Martis, L., Højgaard, K., Henningsen, K., Bouzinova, E. V., Miseta, A., et al. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00148 · Cited by 129 · see citing works
Markov, D. D. (2022) · Brain Sciences · doi:10.3390/brainsci12101287 · Cited by 125 · see citing works
“Of the 71 respondents who answered, 75% confirmed the reliability and stable reproducibility of the model, 21% of respondents mentioned that they had difficulties with reproducibility, and 4% admitted the inability to reproduce the effects of CUMS [53].”
BackgroundModels of Depression: Unpredictable Chronic Mild Stress in Mice
Nollet, M. (2021) · Current Protocols · doi:10.1002/cpz1.208 · Cited by 102 · see citing works
“Overall, these concerns highlight the importance of standardizing the procedure in each laboratory to ensure consistent and reproducible results, making UCMS models all the more reliable and robust (Willner, 2016).”
MethodCsabai, D., Wiborg, O., & Czéh, B. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00024 · Cited by 100 · see citing works
Gáll, Z., Farkas, S., Albert, Á., Ferencz, E., Vancea, S., Urkon, M., & Kolcsár, M. (2020) · Biomolecules · doi:10.3390/biom10050801 · Cited by 99 · see citing works
“The chronic unpredictable mild stress (CUMS) model is a widely used and well-established animal model of depression [22], whose supposed underlying mechanisms include stress-induced neural reorganization, neurotransmitter alterations in brain regions associated with depression, and microglial activation leading to alt…”
MethodFang, X., Jiang, S., Wang, J., Bai, Y., Kim, C. S., Blake, D., Weintraub, N. L., Lei, Y., & Lu, X.-Y. (2021) · Molecular Psychiatry · doi:10.1038/s41380-020-01004-x · Cited by 95 · see citing works
Ohmura, Y., Tsutsui‐Kimura, I., Sasamori, H., Nebuka, M., Nishitani, N., Tanaka, K. F., Yamanaka, A., & Yoshioka, M. (2019) · Neuropharmacology · doi:10.1016/j.neuropharm.2019.107703 · Cited by 92 · see citing works
Handling method alters the hedonic value of reward in laboratory mice
Clarkson, J. M., Dwyer, D. M., Flecknell, P. A., Leach, M. C., & Rowe, C. (2018) · Scientific Reports · doi:10.1038/s41598-018-20716-3 · Cited by 91 · see citing works
Brimson, J. M., Brimson, S. J., Prasanth, M. I., Thitilertdecha, P., Malar, D. S., & Tencomnao, T. (2021) · Scientific Reports · doi:10.1038/s41598-020-80045-2 · Cited by 90 · see citing works
Perspectives for therapy of treatment‐resistant depression
Papp, M., Cubała, W. J., Święcicki, Ł., Newman‐Tancredi, A., & Willner, P. (2021) · British Journal of Pharmacology · doi:10.1111/bph.15596 · Cited by 92 · see citing works
“…(measured by a decrease in consumption of a palatable sweet solution) and display a wide range of further behavioural and physiological changes characteristic of depression, which respond to chronic but not acute treatment with antidepressant drugs (Hill et al., 2012; Willner, 1997, 2017a).”
BackgroundMethodSelf-citationMarkov, D. D., & Novosadova, E. V. (2022) · Biology · doi:10.3390/biology11111621 · Cited by 95 · see citing works
“The feedback was received from 71 respondents, which is 42% [7].”
BackgroundSex differences in the blood–brain barrier: Implications for mental health
Dion‐Albert, L., Binder, L. B., Daigle, B., Hong-Minh, A., Lebel, M., & Ménard, C. (2022) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2022.100989 · Cited by 89 · see citing works
“CMS involves continuous exposure to a variety of mild stressors, such as periods of food and water deprivation, changes in social hierarchy, cage tilt, etc. (Willner, 2017).”
BackgroundJoffe, M. E., Santiago, C. I., Oliver, K. H., Maksymetz, J., Harris, N. A., Engers, J. L., Lindsley, C. W., Winder, D. G., & Conn, P. J. (2019) · Neuron · doi:10.1016/j.neuron.2019.09.044 · Cited by 75 · see citing works
Lee, Y.-J., Kim, H. R., Lee, C. Y., Hyun, S., Ko, M. Y., Lee, B., Hwang, D. Y., & Ka, M. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21239103 · Cited by 71 · see citing works
“The sucrose preference test was performed as described previously [47] to assess anhedonia in mice.”
BackgroundMethodTchekalarova, J., Stoynova, T., Ilieva, K., Mitreva, R., & Atanasova, M. (2018) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2018.05.016 · Cited by 67 · see citing works
“The extended survey aiming to identify experimental variables for validation of the procedure suggest that the concentration-intake curve for sucrose is bellshaped (Willner, 2017) while loss of sucrose preference (two-bottle choice procedure) rather than decreased sucrose intake represent a reliable measure to assess…”
InfluentialHuijuan, G., Liu, X., Chen, T., Wang, X., & Zhang, X. (2023) · Molecular Neurobiology · doi:10.1007/s12035-023-03602-6 · Cited by 66 · see citing works
Zhang, Z., Cai, X., Yao, Z., Wen, F., Fu, Z., Zhang, J., Zheng, Z., Huang, Y., & Qu, S. (2020) · Neural Plasticity · doi:10.1155/2020/8860968 · Cited by 57 · see citing works
Jiang, N., ZHANG, B., Dong, L., Lv, J., Lü, C., Wang, Q., Fan, L.-X., Zhang, H., Pan, R., & Liu, X. (2018) · Phytotherapy Research · doi:10.1002/ptr.6040 · Cited by 55 · see citing works
“The CUMS model is a validated and widely adopted behavioral model of depression, based on the loss of responsiveness to rewards by animals subjected to a varying schedule of minor stressors (Willner, 2016; Willner, Towell, Sampson, Sophokleous, & Muscat, 1987).”
MethodGuo, J., Zhang, F., Gao, J., Guan, X., Liu, B., Wang, X., Qin, Z., Tang, K., & Liu, S. (2019) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.14695 · Cited by 55 · see citing works
The role of allopregnanolone in depressive-like behaviors: Focus on neurotrophic proteins
Almeida, F. B., Nin, M. S., & Barros, H. M. T. (2020) · Neurobiology of Stress · doi:10.1016/j.ynstr.2020.100218 · Cited by 55 · see citing works
“Though some uncertainty regarding the reproducibility of the CUS model has been frequently raised over the years, a significant portion of this apparent problem might derive from factors such as excessively short exposures (two weeks or less) (Willner, 2017b).”
BackgroundMethodMorató, L., Astori, S., Zalachoras, I., Rodrigues, J., Ghosal, S., Huang, W., de Suduiraut, I. G., Grosse, J., Zanoletti, O., Cao, L., et al. (2022) · Science Advances · doi:10.1126/sciadv.abj9109 · Cited by 51 · see citing works
“On the contrary, CUS involves exposure to daily stressors, lasting for at least 4 weeks (up to 8 weeks in some studies) ( 68 ).”
InfluentialPre-clinical investigations of β-carboline alkaloids as antidepressant agents: A systematic review
Ferraz, C. A. A., Júnior, R. G. D. O., Picot, L., Almeida, J. R. G. D. S., & Nunes, X. P. (2019) · Fitoterapia · doi:10.1016/j.fitote.2019.104196 · Cited by 53 · see citing works
Fee, C., Prévot, T. D., Misquitta, K. A., Banasr, M., & Sibille, E. L. (2020) · Neuroscience · doi:10.1016/j.neuroscience.2020.05.034 · Cited by 48 · see citing works
The Eph receptor A4 plays a role in demyelination and depression-related behavior
Li, Y., Su, P., Chen, Y., Nie, J., Yuan, T.-F., Wong, A. H. C., & Liu, F. (2022) · Journal of Clinical Investigation · doi:10.1172/jci152187 · Cited by 52 · see citing works
“CUMS was applied as previously described (7, 35).”
BackgroundMethodSöderlund, J., & Lindskog, M. (2018) · The International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyy037 · Cited by 50 · see citing works
“Although this model has a reputation of being unreliable, a recent survey suggested that the unreliability may not be worse in this model compared with other depression models (Willner, 2017).”
ResultMaramis, M. M., Mahajudin, M. S., & Khotib, J. (2020) · Neuropsychobiology · doi:10.1159/000508682 · Cited by 48 · see citing works
The hippocampus in stress susceptibility and resilience: Reviewing molecular and functional markers
Larosa, A., & Wong, T. P. (2022) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2022.110601 · Cited by 47 · see citing works
Fee, C., Prévot, T. D., Misquitta, K. A., Knutson, D. E., Li, G., Mondal, P., Cook, J. M., Banasr, M., & Sibille, E. L. (2021) · The International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyab002 · Cited by 45 · see citing works
“However, the well-noted replicability challenges of individual behavioral tests (Willner, 2017) justified development of the PhenoTyper Test (a fully automated test with higher reproducibility than EPM and OFT; Prevot et al., 2019b) and Z-scoring methods that increase the power and reliability of…”
MethodInfluentialPrévot, T. D., Misquitta, K. A., Fee, C., Newton, D. F., Chatterjee, D., Nikolova, Y. S., Sibille, E. L., & Banasr, M. (2019) · Neuropharmacology · doi:10.1016/j.neuropharm.2019.05.005 · Cited by 45 · see citing works
Depression and Anxiety in the Epilepsies: from Bench to Bedside
Krishnan, V. (2020) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-020-01065-z · Cited by 47 · see citing works
Rojas‐Carvajal, M., Sequeira‐Cordero, A., & Brenes, J. C. (2021) · European Journal of Neuroscience · doi:10.1111/ejn.15160 · Cited by 44 · see citing works
“Because there is only a small room for further deterioration, stress models have come to exhibit weak or moderate effects with sometimes lack of consistency within and among labs despite using severe stress protocols (Willner, 2017a).”
BackgroundInfluentialKolář, D., Kletečková, L., Brožka, H., & Valeš, K. (2021) · Neuroscience Letters · doi:10.1016/j.neulet.2021.136003 · Cited by 43 · see citing works
Berrio, J. P., Hestehave, S., & Kalliokoski, O. (2024) · Translational Psychiatry · doi:10.1038/s41398-024-02742-0 · Cited by 49 · see citing works
“A recent user survey [11] found that 83 – 86% of CUS protocols in rats use food and water deprivations as a stressor, and 32 out of 57 labs use more than 12 h of fasting to incentivize consumption in the SPT. Food or water deprivation, while stressful [19], are not necessary to make rodents consume…”
BackgroundDadomo, H., Gioiosa, L., Cigalotti, J., Ceresini, G., Parmigiani, S., & Palanza, P. (2017) · Hormones and Behavior · doi:10.1016/j.yhbeh.2017.11.013 · Cited by 40 · see citing works
“…resulting in behavioral changes, such as decreased response to rewards (considered a behavioral correlate of the core symptom of depression, anhedonia), decreased locomotor and explorative behavior, impairment of feeding, drinking and sexual behavior (Willner et al., 1987, 1992; Willner, 2017b).”
BackgroundMethodThe Effects of Chronic Stress on Migraine Relevant Phenotypes in Male Mice
Kaufmann, D., & Brennan, K. C. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00294 · Cited by 42 · see citing works
“The stressors employed were: rat encounter, predator odor, restrained stress, tail suspension, wet bedding, food and water deprivation, and cage tilt (Gamaro et al., 2003; Willner, 2017).”
BackgroundMethodResultInfluentialElhussiny, M. E. A., Carini, G., Mingardi, J., Tornese, P., Sala, N., Bono, F., Fiorentini, C., Via, L. L., Popoli, M., Musazzi, L., et al. (2020) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2020.110033 · Cited by 41 · see citing works
“In this study we used the classical CMS model of depression in rats (Willner, 2017; Tornese et al., 2019) to investigate the modifications induced by chronic stress and acute ketamine injection on AMPA/ NMDA ionotropic and metabotropic glutamate receptors at the transcriptional, post…”
BackgroundMethodInfluentialPapp, M., Gruca, P., Łasoń, M., Tota-Glowczyk, K., Niemczyk, M., Litwa, E., & Willner, P. (2018) · Journal of Psychopharmacology · doi:10.1177/0269881118791737 · Cited by 40 · see citing works
“(2013) used mice and a behavioural endpoint commonly used in mouse CMS studies (Willner, 2017), degradation of the state of their fur.”
Self-citationVega‐Rivera, N. M., Ortíz‐López, L., Granados-Juárez, A., Estrada-Camarena, E. M., & Ramírez-Rodríguez, G. B. (2020) · Neuroscience · doi:10.1016/j.neuroscience.2020.05.014 · Cited by 39 · see citing works
Pazini, F. L., Rosa, J. M., Camargo, A., Fraga, D. B., Moretti, M., Siteneski, A., & Rodrigues, A. L. S. (2020) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2020.109281 · Cited by 39 · see citing works
Fitzgerald, E., Parent, C. I., Kee, M. Z. L., & Meaney, M. J. (2021) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2021.635304 · Cited by 39 · see citing works
“…models are used for several weeks (Wang et al., 2017) and variability in results using this model has been ascribed to shorter paradigm durations (Willner, 2017), indicating a longer period of exposure is needed to reproducibly induce depressive and anxiety-like behaviors in adult animals.”
MethodResultFoyet, H. S., Defo, S. H. T., Yewo, P. K., Antioch, I., Zingue, S., Asongalem, E. A., Kamtchouing, P., & Ciobica, A. S. (2017) · BMC Complementary and Alternative Medicine · doi:10.1186/s12906-017-2012-9 · Cited by 39 · see citing works
“We thus used the unpredictable chronic mild stress model which is considered by many laboratories to be the animal model of depression that has the greatest validity and translational potential [24, 25].”
MethodBloch, S., Holleran, K. M., Kash, T. L., Vazey, E. M., Rinker, J. A., Lebonville, C. L., O’Hara, K., Lopez, M. F., Jones, S. R., Grant, K. A., et al. (2022) · Alcohol · doi:10.1016/j.alcohol.2022.02.001 · Cited by 35 · see citing works
The Eph receptor A4 plays a role in demyelination and depression-related behavior
Li, Y., Su, P., Chen, Y., Nie, J., Yuan, T., Wong, A. H. C., & Liu, F. (2022) · DOAJ (DOAJ: Directory of Open Access Journals) · Cited by 36 · see citing works
The Wistar Kyoto Rat: A Model of Depression Traits
Redei, E. E., Udell, M. E., Woods, L. C. S., & Chen, H. (2022) · Current Neuropharmacology · doi:10.2174/1570159x21666221129120902 · Cited by 35 · see citing works
“The SPT relies on the long-term preference for sugar solutions and suggests a decreased preference for sucrose is related to anhedonia [11].”
BackgroundT helper cells in depression: central role of Th17 cells
Ghosh, R., Mitra, P., Kumar, P. V. S. N. K., Goyal, T., & Sharma, P. (2021) · Critical Reviews in Clinical Laboratory Sciences · doi:10.1080/10408363.2021.1965535 · Cited by 35 · see citing works
“[145] in the subsequent year using a three-week-long CUMS model in male BALB/c mice, one of the most widely validated animal models of depression [147].”
MethodSucrose intake and preference by Wistar Han rats are not influenced by sex or food/water deprivation
Fonseca‐Rodrigues, D., Gonçalves, J., Laranjeira, I. M., Almeida, A., & Pinto‐Ribeiro, F. (2022) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2022.173387 · Cited by 35 · see citing works
Barone, P. R. (2019) · Behavioural Pharmacology · doi:10.1097/fbp.0000000000000477 · Cited by 33 · see citing works
Depoortère, R., Papp, M., Gruca, P., Łasoń, M., Niemczyk, M., Varney, M. A., & Newman‐Tancredi, A. (2019) · Journal of Psychopharmacology · doi:10.1177/0269881119860666 · Cited by 33 · see citing works
“One model that may possess all three dimensions of validity (construct, face and predictive) is the CMS, which is considered to have high translational potential (Antoniuk et al., 2019; Willner, 2017a; Willner, 2017b).”
BackgroundKhayum, M. A., Moraga‐Amaro, R., Buwalda, B., Koole, M. J. B., den Boer, J. A., Dierckx, R., Doorduin, J., & de Vries, E. F. J. (2020) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2020.104610 · Cited by 32 · see citing works
“Third, the high variability and contradictory results amongst the different studies could be explained by the type of stressors the duration of exposure to CMS, as CMS protocols lasting between 2 and 8 weeks have been used (Willner, 2017a, 2017b).”
Shoji, H., & Miyakawa, T. (2019) · Molecular Brain · doi:10.1186/s13041-019-0490-z · Cited by 30 · see citing works
Chang, M., Zhang, L., Dai, H., & Sun, L. (2021) · Brain and Behavior · doi:10.1002/brb3.2300 · Cited by 30 · see citing works
“Chronic mild stress was induced in rats according to a previously described procedure with slight modifications (Willner, 2016).”
MethodLiang, W., Liu, Y., Zhou, K., Jian, P., Zhang, Q., Chang, Z., Wu, L., Hong-sheng, C., & Zhang, L. (2021) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2021.114655 · Cited by 28 · see citing works
Yang, F., Bi, Y., & Chen, H. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.635762 · Cited by 27 · see citing works
“Unpredictable chronic stresses have been reported as a promising method to cause a series of depressive behaviors in rodents (Farooq et al., 2012; Nollet et al., 2013; Willner 2017).”
BackgroundLiu, C., Yuan, D., Zhang, C., Tao, Y., Meng, Y., Jin, M., Wu, S., Wang, B., & Wei, L. (2022) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2022/7558825 · Cited by 27 · see citing works
“Reduced sucrose consumption is regarded as a key indicator in animals [16].”
BackgroundLiu, Y.-W., Ong, J. S., Gan, C., Khoo, B. Y., Yahaya, S., Choi, S. B., Low, W. Y., Tsai, Y.-C., & Liong, M. T. (2019) · Journal of Functional Foods · doi:10.1016/j.jff.2019.05.043 · Cited by 26 · see citing works
Lamanna, J., Isotti, F., Ferro, M., Spadini, S., Racchetti, G., Musazzi, L., & Malgaroli, A. (2022) · Scientific Reports · doi:10.1038/s41598-022-14694-w · Cited by 26 · see citing works
“1b) and a parallel decrease in moderate (rANOVA: Time F(4,44) = 5.”
BackgroundMethodT cell-mediated skin-brain axis: Bridging the gap between psoriasis and psychiatric comorbidities
Yang, J., Zhang, S., Wu, Q., Chen, P., Dai, Y., Long, J., Wu, Y., & Lin, Y. (2024) · Journal of Autoimmunity · doi:10.1016/j.jaut.2024.103176 · Cited by 25 · see citing works
Papp, M., Gruca, P., Łasoń, M., Niemczyk, M., & Willner, P. (2019) · Journal of Psychopharmacology · doi:10.1177/0269881119827889 · Cited by 25 · see citing works
“Email: nfpapp@cyfronet.pl The most extensively validated animal model of depression is the chronic mild stress (CMS) model (Willner, 1997, 2017), in which rats or mice are subjected over several weeks to a constant bombardment of varying mild stressors, resulting in a wide range of behavioural and…”
BackgroundSelf-citationWang, Q., Bi, H., Huang, H., Wang, Y., Gong, L., Qi, N., Li, D., Jin, X., Xu, T., & Shi, B. (2022) · Neuropsychobiology · doi:10.1159/000521185 · Cited by 25 · see citing works
Lee, J., Kim, W., Jeon, Y.-J., Lee, S.-B., Lee, D., & Son, C. (2019) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.00683 · Cited by 25 · see citing works
Can animals develop depression? An overview and assessment of ‘depression-like’ states
MacLellan, A., Fureix, C., Polanco, A., & Mason, G. J. (2021) · Behaviour · doi:10.1163/1568539x-bja10132 · Cited by 23 · see citing works
Jaggar, M., Weisstaub, N., Gingrich, J. A., & Vaidya, V. A. (2017) · Neurobiology of Stress · doi:10.1016/j.ynstr.2017.06.001 · Cited by 23 · see citing works
The Comparison of a New Ultrasound-Induced Depression Model to the Chronic Mild Stress Paradigm
Zorkina, Y., Zubkov, E. A., Morozova, A. Y., Ushakova, V. M., & Chekhonin, V. P. (2019) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2019.00146 · Cited by 23 · see citing works
Baugher, B. J., Buckhaults, K., Case, J. M., Sullivan, A., Huq, S. N., & Sachs, B. D. (2022) · Behavioural Brain Research · doi:10.1016/j.bbr.2022.113811 · Cited by 22 · see citing works
Feng, X., Yang, F., & Chung, C. Y. (2020) · Brain Research · doi:10.1016/j.brainres.2020.146846 · Cited by 22 · see citing works
Wang, H., Li, F., Zheng, X., Meng, L., Chen, M., Hui, Y., Li, Y., Xie, K., Zhang, J., & Guo, G. (2022) · Translational Psychiatry · doi:10.1038/s41398-022-02151-1 · Cited by 21 · see citing works
“The CUMS procedure was adopted from the previous studies [32, 33].”
MethodPapp, M., Gruca, P., Łasoń, M., Litwa, E., Solecki, W., & Willner, P. (2020) · Journal of Psychopharmacology · doi:10.1177/0269881120967857 · Cited by 21 · see citing works
“The chronic mild stress (CMS) procedure is the most widely used animal model of depression (Antoniuk et al., 2019; Willner, 2017).”
BackgroundMethodSelf-citationEcological validity of social defeat stressors in mouse models of vulnerability and resilience
Lyons, D. M., Ayash, S., Schatzberg, A. F., & Müller, M. B. (2023) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2023.105032 · Cited by 20 · see citing works
Montgomery, K. R., Bridi, M. S., Folts, L. M., Marx-Rattner, R., Zierden, H. C., Wulff, A. B., Kodjo, E., Thompson, S. M., & Bale, T. L. (2023) · Neuropsychopharmacology · doi:10.1038/s41386-023-01739-5 · Cited by 20 · see citing works
Głuch‐Lutwin, M., Sałaciak, K., Gawalska, A., Jamrozik, M., Śniecikowska, J., Newman‐Tancredi, A., Kołaczkowski, M., & Pytka, K. (2021) · Psychopharmacology · doi:10.1007/s00213-021-05849-0 · Cited by 20 · see citing works
“This model is considered among the best animal models of depression, reproducing not only behavioral (anhedonia) but also neurobiological aspects of the human pathology and also exhibiting a high degree of validity and translational potential (Willner 2017).”
MethodAnimal models of postpartum depression revisited
Mir, F. R., Pollano, A., & Rivarola, M. A. (2021) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2021.105590 · Cited by 20 · see citing works
de Sousa, C. N. S., Medeiros, I. D. S., Vasconcelos, G. S., de Aquino, G. Â., Filho, F. M. S. C., Cysne, J. C. D. A., Macêdo, D. S., & Vasconcelos, S. M. M. (2022) · Psychopharmacology · doi:10.1007/s00213-021-05994-6 · Cited by 20 · see citing works
“Depression is a stress-related disorder, and in this regard, the chronic unpredictable stress (CUS) model is considered a robust model since it simulates the condition of daily exposure to moderate and variable stressors (Willner 1997, 2005, 2017a).”
BackgroundMethodErkizia-Santamaría, I., Horrillo, I., Martínez-Álvarez, N., Pérez-Martínez, D., Rivero, G., Erdozain, A. M., Meana, J. J., & Ortega, J. E. (2025) · Translational Psychiatry · doi:10.1038/s41398-025-03421-4 · Cited by 22 · see citing works
“A combination of stressors was designed to reach an equilibrium of stress intensity every day of the protocol, according to a severity point system (1: mild, 2: moderate, 3: high) [41].”
Takaba, R., Ibi, D., Watanabe, K., Hayakawa, K., Nakasai, G., & Hiramatsu, M. (2022) · Physiology & Behavior · doi:10.1016/j.physbeh.2022.113971 · Cited by 18 · see citing works
MicroRNA‐451a is a candidate biomarker and therapeutic target for major depressive disorder
Hu, P., Cao, Q., Hu, F., Liu, Y., Chen, Y., Xu, J., Feng, W., Sun, H., Ding, H., Wang, C., et al. (2024) · General Psychiatry · doi:10.1136/gpsych-2023-101291 · Cited by 19 · see citing works
Lei, Y., Wang, D., Bai, Y., Nougaisse, J., Weintraub, N. L., Guo, M., & Lu, X. (2022) · Molecular Psychiatry · doi:10.1038/s41380-022-01778-2 · Cited by 18 · see citing works
Dandi, Ε., Spandou, E., Dalla, C., & Tata, D. Α. (2023) · European Journal of Neuroscience · doi:10.1111/ejn.16089 · Cited by 18 · see citing works
“The CUMS is a valid, reliable and effective animal model of stress to cause anxiety and depression-like behavior (Willner, 2017).”
MethodInfluentialÜnal, G. Ö., Demirdaş, A., Nazıroğlu, M., & Övey, İ. S. (2022) · Behavioural Brain Research · doi:10.1016/j.bbr.2022.114033 · Cited by 17 · see citing works
Attenuation of stress-induced weight loss with a ketogenic diet
Sahagún, E., Ward, L. M., & Kinzig, K. P. (2019) · Physiology & Behavior · doi:10.1016/j.physbeh.2019.112654 · Cited by 17 · see citing works
Brain matrix metalloproteinase-9 activity is altered in the corticosterone mouse model of depression
Breviario, S., Senserrich, J., Florensa-Zanuy, E., Garro-Martínez, E., Díaz, Á., Castro, E., Pazos, Á., & Pilar-Cuéllar, F. (2022) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2022.110624 · Cited by 16 · see citing works
“These behavioural outcomes are in line with the results reported by other authors in CORT (Murray et al., 2008; David et al., 2009), and several models of chronic stress (reviewed in Willner, 2016).”
Berrío, J. P., & Kalliokoski, O. (2023) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2023.109910 · Cited by 15 · see citing works
Belo-Silva, A. E., Silva, N. K. D. G. T., Marianno, P., Costa, G. D. A., da Rovare, V. P., Bailey, A., Munhoz, C. D., Novaes, L. S., & Camarini, R. (2024) · Hormones and Behavior · doi:10.1016/j.yhbeh.2024.105538 · Cited by 15 · see citing works
Papp, M., Gruca, P., Litwa, E., Łasoń, M., Newman‐Tancredi, A., & Depoortère, R. (2024) · Journal of Psychopharmacology · doi:10.1177/02698811241254832 · Cited by 15 · see citing works
“Using the rat chronic mild stress (CMS) model of depression (Antoniuk et al., 2018; Willner, 2017a, 2017b), we previously investigated, in male Wistar rats, the activity of systemic (i.p.) NLX-204 and NLX-101.”
Deciphering the Metabolome under Stress: Insights from Rodent Models
Papageorgiou, M. P., Theodoridou, D., Nußbaumer, M., Syrrou, M., & Filiou, M. D. (2023) · Current Neuropharmacology · doi:10.2174/1570159x21666230713094843 · Cited by 14 · see citing works
“Furthermore, this phenotype is subject to reversal by a wide range of anti-depressant drugs [21].”
BackgroundCosta‐Ferro, Z. S. M., do Prado‐Lima, P. A. S., Onsten, G. A., de Oliveira, G. N., Brito, G. C., Ghilardi, I. M., dos Santos, P. G., Bertinatto, R. J., da Silva, D. V., Salamoni, S. D., et al. (2021) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2021.110455 · Cited by 13 · see citing works
Systematic review and meta-analysis of 10 years of unpredictable chronic stress in zebrafish
Gallas‐Lopes, M., Bastos, L. M., Benvenutti, R., Panzenhagen, A. C., Piato, Â., & Herrmann, A. P. (2023) · Lab Animal · doi:10.1038/s41684-023-01239-5 · Cited by 14 · see citing works
Tekşen, Y., Gündüz, M. K., Berikten, D., Özatik, F. Y., & Aydın, H. E. (2024) · Metabolic Brain Disease · doi:10.1007/s11011-024-01416-6 · Cited by 13 · see citing works
“Today, the CUMS is a validated and widely used animal model for depression and anxi - ety studies, and is an important tool for the investigating of the therapeutic potential of molecules for the treatment of depression (Willner 2016).”
Bansal, Y., Fee, C., Misquitta, K. A., Codeluppi-Arrowsmith, S. A., Sibille, E. L., Berman, R., Coric, V., Sanacora, G., & Banasr, M. (2023) · Complex Psychiatry · doi:10.1159/000529534 · Cited by 12 · see citing works
Papp, M., Gruca, P., Łasoń, M., Litwa, E., Newman‐Tancredi, A., & Depoortère, R. (2023) · Psychopharmacology · doi:10.1007/s00213-023-06389-5 · Cited by 13 · see citing works
“…the effects of the three compounds in the novel object recognition (NOR) and the elevated plus maze (EPM), two pre-clinical models of working memory and anxiety, respectively (Ennaceur and Delacour 1988; Pellow et al. 1985), traits that are also affected in depressed patients (Willner 2017a).”
BackgroundFaron‐Górecka, A., Kuśmider, M., Solich, J., Kolasa, M., Pabian, P., Gruca, P., Romańska, I., Żurawek, D., Szlachta, M., Papp, M., et al. (2018) · Psychopharmacology · doi:10.1007/s00213-018-4912-x · Cited by 14 · see citing works
“This result highlights an advantage of this animal model of depression (for review: Willner 2016), which is the expression of a treatment-resistant model of depression, as is frequently encountered in patients in the clinic.”
Keenan, R. J., Chan, J., Donnelly, P. S., Barnham, K. J., & Jacobson, L. H. (2018) · Neurobiology of Stress · doi:10.1016/j.ynstr.2018.09.008 · Cited by 13 · see citing works
“In Willner's 2017 investigation few, if any, differences were identified between laboratories that reliably reproduced the CMS model versus those which did not.”
MethodResultInfluential
- 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 · 2016: 2
- 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
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