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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 Because failures to replicate frequently remain unpublished, a survey methodology was used.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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Citations
Cites
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“…a more intense social stressor, repeated exposure to social defeat does elicit a sustained decrease in rewarded behaviour in rats (Willner et al., 1995; von Frietag et al., 2000; Rygula et al., 2005; Miczek et al., 2011) and mice (Krishnan et al., 2007; Yu et al., 2011; Zhang et al., 2015).”
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Self-citationBelieve it or not: how much can we rely on published data on potential drug targets?
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Self-citationChronic mild stress-induced anhedonia: A realistic animal model of depression
Willner, P., Muscat, R., & Papp, M. (1992) · Neuroscience & Biobehavioral Reviews · doi:10.1016/s0149-7634(05)80194-0 · Cited by 1,160 · cited 2×
“%) said that their procedure was based on the original CMS publications (Willner et al., 1987, 1992), with others citing more recent studies from other labs.”
BackgroundMethodSelf-citation
Cited by
Sorted by citations
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
“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
“…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 392
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 257
“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 220
“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
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 184
Chronic mild stress paradigm as a rat model of depression: facts, artifacts, and future perspectives
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“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 133
Markov, D. D. (2022) · Brain Sciences · doi:10.3390/brainsci12101287 · Cited by 134
“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 109
“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 102
Gáll, Z., Farkas, S., Albert, Á., Ferencz, E., Vancea, S., Urkon, M., & Kolcsár, M. (2020) · Biomolecules · doi:10.3390/biom10050801 · Cited by 99
“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
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
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
Brimson, J. M., Brimson, S., Prasanth, M. I., Thitilertdecha, P., Malar, D. S., & Tencomnao, T. (2021) · Scientific Reports · doi:10.1038/s41598-020-80045-2 · Cited by 96
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 96
“…(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 101
“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 93
“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 77
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 74
“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
“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 67
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 60
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 56
“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 54
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
“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
“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 56
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 51
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) · Journal of Clinical Investigation · doi:10.1172/jci152187 · Cited by 52
“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 54
“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 60
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 50
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 50
“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 47
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 48
Rojas‐Carvajal, M., Sequeira‐Cordero, A., & Brenes, J. C. (2021) · European Journal of Neuroscience · doi:10.1111/ejn.15160 · Cited by 51
“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 46
Berrio, J. P., Hestehave, S., & Kalliokoski, O. (2024) · Translational Psychiatry · doi:10.1038/s41398-024-02742-0 · Cited by 49
“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 43
“…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
“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 42
“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
“(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 41
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
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 41
“…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 40
“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 38
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
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 37
“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 37
“[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 37
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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 35
“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
“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
Chang, M., Zhang, L., Dai, H., & Sun, L. (2021) · Brain and Behavior · doi:10.1002/brb3.2300 · Cited by 30
“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 27
Yang, F., Bi, Y., & Chen, H. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.635762 · Cited by 27
“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
“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 27
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
“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
Papp, M., Gruca, P., Łasoń, M., Niemczyk, M., & Willner, P. (2019) · Journal of Psychopharmacology · doi:10.1177/0269881119827889 · Cited by 30
“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
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 26
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 27
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
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
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
Feng, X., Yang, F., & Chung, C. Y. (2020) · Brain Research · doi:10.1016/j.brainres.2020.146846 · Cited by 22
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
“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 23
“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
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
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
“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 21
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
“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 23
“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
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 22
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 20
Dandi, Ε., Spandou, E., Dalla, C., & Tata, D. Α. (2023) · European Journal of Neuroscience · doi:10.1111/ejn.16089 · Cited by 22
“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
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
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
“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
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
Papp, M., Gruca, P., Litwa, E., Łasoń, M., Newman‐Tancredi, A., & Depoortère, R. (2024) · Journal of Psychopharmacology · doi:10.1177/02698811241254832 · Cited by 15
“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 15
“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
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 15
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
“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
Papp, M., Gruca, P., Łasoń, M., Litwa, E., Newman‐Tancredi, A., & Depoortère, R. (2023) · Psychopharmacology · doi:10.1007/s00213-023-06389-5 · Cited by 16
“…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
“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
“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
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
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