Cited by 375Treatment of Major DepressionNeurotransmitter Receptor Influence on BehaviorStress Responses and Cortisol

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Animal models of major depression and their clinical implications

Czéh, Boldizsár, Fuchs, Eberhard, Wiborg, Ove, Simon, Mária·2016·Progress in Neuro-Psychopharmacology and Biological Psychiatry

DOI 10.1016/j.pnpbp.2015.04.004

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Abstract

Major depressive disorder is a common, complex, and potentially life-threatening mental disorder that imposes a severe social and economic burden worldwide. Over the years, numerous animal models have been established to elucidate pathophysiology that underlies depression and to test novel antidepressant treatment strategies. Despite these substantial efforts, the animal models available currently are of limited utility for these purposes, probably because none of the models mimics this complex disorder fully. It is presumable that psychiatric illnesses, such as affective disorders, are related to the complexity of the human brain. Here, we summarize the animal models that are used most commonly for depression, and discuss their advantages and limitations. We discuss genetic models, including the recently developed optogenetic tools and the stress models, such as the social stress, chronic mild stress, learned helplessness, and early-life stress paradigms. Moreover, we summarize briefly the olfactory bulbectomy model, as well as models that are based on pharmacological manipulations and disruption of the circadian rhythm. Finally, we highlight common misinterpretations and often-neglected important issues in this field.

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Background
Behavior and oxidative stress parameters in rats subjected to the animal's models induced by chronic mild stress and 6-hydroxydopamine
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Xanthoceraside administration produces significant antidepressant effects in mice through activation of the hippocampal BDNF signaling pathway
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Awakening the dormant: Role of axonal guidance cues in stress-induced reorganization of the adult prefrontal cortex leading to depression-like behavior
Mahmud, A., Avramescu, R. G., Niu, Z., & Flores, C. (2023) · Frontiers in Neural Circuits · doi:10.3389/fncir.2023.1113023 · Cited by 20
“The effect of stress on anhedonia, learned helplessness, social avoidance, appetite and body weight, sleep and circadian rhythms, self-care/grooming, among several other measures, are assessed to determine the impact of stress on depression-like behavioral states (Nestler and Hyman, 2010; Krishnan and Nestler, 2011; C…”
Background
Antidepressant effects of novel positive allosteric modulators of Trk-receptor mediated signaling – a potential therapeutic concept?
Madjid, N., Lidell, V., Nordvall, G., Lindskog, M., Ögren, S. O., Forsell, P. K. A. L., & Sandin, J. (2023) · Psychopharmacology · doi:10.1007/s00213-023-06410-x · Cited by 19
“However, more recent data rather suggest that imbalances in the levels of biogenic amines, such as dopamine (DA) and serotonin (5-HT), are involved in the etiology of psychiatric disorders like schizophrenia and depression (Sánchez et al. 2010; Sghendo and Mifsud 2012; Czéh et al. 2016).”
Background
Glatiramer acetate attenuates depressive/anxiety-like behaviors and cognitive deficits induced by post-weaning social isolation in male mice
Salihu, S. A., Ghafari, H., Ahmadimanesh, M., Gortany, N. K., Shafaroodi, H., & Ghazi‐Khansari, M. (2021) · Psychopharmacology · doi:10.1007/s00213-021-05836-5 · Cited by 19
“Also, it is ambiguous if these two tests can measure the antidepressant activity of a novel compound with a completely different acting mechanism compared to tricyclic antidepressants, SSRIs or SNRIs (Czéh et al. 2016).”
Background
OBscure but not OBsolete: Perturbations of the frontal cortex in common between rodent olfactory bulbectomy model and major depression
Rajkumar, R., & Dawe, G. S. (2018) · Journal of Chemical Neuroanatomy · doi:10.1016/j.jchemneu.2018.04.001 · Cited by 20
Brain region–specific roles of brain-derived neurotrophic factor in social stress–induced depressive-like behavior
Han, M., Zeng, D., Tan, W., Chen, X.-X., Bai, S.-Y., Wu, Q., Chen, Y., Wei, Z., Mei, Y., & Zeng, Y. (2024) · Neural Regeneration Research · doi:10.4103/nrr.nrr-d-23-01419 · Cited by 21
“The stress hypothesis of emotional disorders has stimulated the development of several animal models for studying the pathogenesis and treatment of depression (Gold et al., 2015; Czeh et al., 2016).”
Method
Age-Dependent FOSB/ΔFOSB Response to Acute and Chronic Stress in the Extended Amygdala, Hypothalamic Paraventricular, Habenular, Centrally-Projecting Edinger-Westphal, and Dorsal Raphe Nuclei in Male Rats
Kovács, L. Á., Füredi, N., Ujvari, B., Golgol, A., & Gaszner, B. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.862098 · Cited by 22
Stress-induced myelin damage in the hippocampal formation in a rat model of depression
Huang, C., Xiao, Q., Zhang, L., Gao, Y., Ma, J., Liang, X., Tang, J., Wang, S., Luo, Y., Chao, F., et al. (2022) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2022.09.025 · Cited by 18
Evolutionarily conserved gene expression patterns for affective disorders revealed using cross-species brain transcriptomic analyses in humans, rats and zebrafish
Demin, K. A., Krotova, N. A., Ilyin, N. P., Galstyan, D. S., Kolesnikova, T. O., Strekalova, T. V., de Abreu, M. S., Petersen, E. V., Zabegalov, K. N., & Kalueff, A. V. (2022) · Scientific Reports · doi:10.1038/s41598-022-22688-x · Cited by 19
Alpha‐Asarone modulates kynurenine disposal in muscle and mediates resilience to stress‐induced depression via PGC ‐1α induction
Yan, A. L., Liu, C., Xu, S. L., Qian, Y., Song, P., Wei, M., & Liu, B. (2022) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.14030 · Cited by 17
Breakdown of the blood-brain barrier in depressed mice induced by chronic unpredictable mild stress
Shi, W., Zhang, S., Yao, K., Meng, Q., Lu, Y., Ren, Y., Li, L., & Zhao, J. (2024) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2024.10.004 · Cited by 20
The level of the zinc homeostasis regulating proteins in the brain of rats subjected to olfactory bulbectomy model of depression
Rafało-Ulińska, A., Zadrożna, M., Nowak, B., Kotarska, K., Wiatrowska, K., Pochwat, B., Sowa-Kućma, M., Misztak, P., Nowak, G., & Szewczyk, B. (2016) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2016.08.009 · Cited by 18
“One of the most widely used animal models of depression is the olfactory bulbectomy model (OB), characterized by both face and predictive validity (Czeh et al., 2016).”
Method
BDNF+/− rats exhibit depressive phenotype and altered expression of genes relevant in mood disorders
Martis, L., Wiborg, O., Holmes, M. C., & Harris, A. P. (2018) · Genes Brain & Behavior · doi:10.1111/gbb.12546 · Cited by 20
Self-citation
Dehydrocorydaline induced antidepressant-like effect in a chronic unpredictable mild stress mouse model via inhibiting uptake-2 monoamine transporters
Jin, L., Zhou, S., Zhu, S., Lei, S., Du, W., Jiang, H., Zeng, S., & Zhou, H. (2019) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2019.172725 · Cited by 18
Selective activation of D1 dopamine receptors exerts antidepressant-like activity in rats
Désormeaux, C., Demars, F., Davenas, E., Jay, T. M., & Lavergne, F. (2020) · Journal of Psychopharmacology · doi:10.1177/0269881120959613 · Cited by 20
“of the amount of time animals stay immobile in the FST have been reported (Czéh et al., 2016; Scheggi et al., 2018).”
Background
Effects of repeated drug administration on behaviors in normal mice and fluoxetine efficacy in chronic unpredictable mild stress mice
Li, Q., Zhao, B., Li, W., He, Y., Tang, X., Zhang, T., Zhong, Z., Pan, Q., & Zhang, Y. (2022) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2022.05.041 · Cited by 17
Anti-depression effectiveness of essential oil from the fruits of Zanthoxylum bungeanum maxim. on chronic unpredictable mild stress-induced depression behavior in mice
Tang, D., Liang, Q., Zhang, M., Li, M., Zhang, Q., Zhang, S., Ai, L., & Wu, C. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.999962 · Cited by 17
“The despair Behavior model could preliminarily evaluate the antidepressant activity of drugs (Czéh et al., 2016).”
Method
Icariin prevents depression-like behaviors in chronic unpredictable mild stress-induced rats through Bax/cytoplasm C/caspase-3 axis to alleviate neuronal apoptosis
Wu, X., Zhang, X., Sun, L., Lu, X., & Shen, C. (2023) · Cellular and Molecular Biology · doi:10.14715/cmb/2023.69.7.32 · Cited by 17
The bidirectional relationship of depression and disturbances in B cell homeostasis: Double trouble
Wu, S., Yin, Y., & Du, L. (2024) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2024.110993 · Cited by 17
Reserpine-induced depression is associated in female, but not in male, adolescent rats with heightened, fluoxetine-sensitive, ethanol consumption
Ruiz, P., Calliari, A. J., & Pautassi, R. M. (2018) · Behavioural Brain Research · doi:10.1016/j.bbr.2018.04.011 · Cited by 17
Early Attachment Disruption, Inflammation, and Vulnerability for Depression in Rodent and Primate Models
Hennessy, M. B., Schiml, P. A., Berberich, K., Beasley, N. L., & Deak, T. (2019) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2018.00314 · Cited by 17
Combination of electroconvulsive stimulation with ketamine or escitalopram protects the brain against inflammation and oxidative stress induced by maternal deprivation and is critical for associated behaviors in male and female rats
Abelaira, H. M., Rosa, T., de Moura, A. B., Andrade, N. M., Martinello, N. S., Maciel, L. R., Botelho, M. E. M., Borba, L. A., Chede, B. C., Arent, C. O., et al. (2022) · Molecular Neurobiology · doi:10.1007/s12035-021-02718-x · Cited by 17
Prelimbic medial prefrontal cortex disruption during adolescence increases susceptibility to helpless behavior in adult rats
Uliana, D. L., Gomes, F. V., & Grace, A. A. (2020) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2020.04.004 · Cited by 19
“Several animal models based on stressful situations are used to study depression, such as chronic mild stress (CMS), social defeat, and learned helplessness (LH) (Czéh et al., 2016; Muir et al., 2018).”
Background
Metabolite signature associated with stress susceptibility in socially defeated mice
Prabhu, V. V., Nguyen, T. B., Cui, Y., Oh, Y.-E., Piao, Y. H., Baek, H., Kim, J.-Y., Shin, K., Kim, J. H., Lee, K., et al. (2018) · Brain Research · doi:10.1016/j.brainres.2018.12.020 · Cited by 16
Gene expression signature of antidepressant treatment response/non-response in Flinders Sensitive Line rats subjected to maternal separation
Marchetti, L., Lauria, M., Caberlotto, L., Musazzi, L., Popoli, M., Mathé, A. A., Domenici, E., & Carboni, L. (2019) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2019.11.004 · Cited by 17
Behavioral Effect of Terahertz Waves in C57BL/6 Mice
Miao, Q., Liu, R., Li, B., Wang, S., Fan, R., Zhao, X., & Xu, D. (2022) · Biosensors · doi:10.3390/bios12020079 · Cited by 16
“At present, several mouse disease models, such as depression [24,25], Alzheimer’s disease [26], autism [27], and schizophrenia [28], have been established.”
Background
Stress-Induced Microstructural Alterations Correlate With the Cognitive Performance of Rats: A Longitudinal in vivo Diffusion Tensor Imaging Study
Nagy, S. A., Vranesics, A., Varga, Z., Csabai, D., Bruszt, N., Bali, Z. K., Perlaki, G., Hernádi, I., Berente, Z., Miseta, A., et al. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.00474 · Cited by 15
“Chronic stress models are typically regarded as valid models for major depressive disorder (MDD) (see, e.g., Willner, 1997; Czéh et al., 2016), and the translational value of neuroimaging has been well-demonstrated in earlier studies using chronic psychosocial stress protocols, which had led to alterations in brain vo…”
InfluentialSelf-citation
Adult Neurogenesis, Chronic Stress and Depression
Lucassen, P. J., Oomen, C. A., Schouten, M., Encinas, J. M., & Fitzsimons, C. P. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-801977-1.00008-8 · Cited by 15
Ocimum basilicum (Basil) Modulates Apoptosis and Neurogenesis in Olfactory Pulp of Mice Exposed to Chronic Unpredictable Mild Stress
Ayuob, N. N., Balgoon, M. J., Ali, S. S., Alnoury, I. S., Almohaimeed, H. M., & AbdElfattah, A. A. (2020) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2020.569711 · Cited by 15
“This model is characterized by the occurrence of long-lasting neurodegenerative changes including behavioral, neurochemical, and neuroendocrinal changes that mimic those observed in depressed patients (5).”
Background
Antidepressant-Like Effects of Chronic Guanosine in the Olfactory Bulbectomy Mouse Model
Almeida, R. F., Nonose, Y., Ganzella, M., Loureiro, S. O., da Rocha, A. S., Machado, D. G., Bellaver, B., Fontella, F. U., Leffa, D. T., Pettenuzzo, L. F., et al. (2021) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.701408 · Cited by 15
Negative expectations and vulnerability to stressors in animals
Lecorps, B., Weary, D. M., & von Keyserlingk, M. A. G. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.08.025 · Cited by 16
sst-receptor gene deletion exacerbates chronic stress-induced deficits: Consequences for emotional and cognitive ageing
Prevot, T. D., Viollet, C., Epelbaum, J., Dominguez, G., Béracochéa, D., & Guillou, J. (2018) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2018.01.022 · Cited by 15
“Both sst2 gene deletion and UCMS exposure increased immobility in the FST and TST indicating a depressive-like emotional state as previously described (Czeh et al., 2016; Czeh et al., 2015; Prevot et al., 2017).”
Regional alterations of cerebral [18F]FDG metabolism in the chronic unpredictable mild stress- and the repeated corticosterone depression model in rats
Laeken, N. V., Pauwelyn, G., Dockx, R., Descamps, B., Brans, B. T., Peremans, K. Y., Baeken, C., Goethals, I., Vanhove, C., & Vos, F. D. (2018) · Journal of Neural Transmission · doi:10.1007/s00702-018-1899-8 · Cited by 18
Nucleus reuniens inactivation reverses stress-induced hypodopaminergic state and altered hippocampal-accumbens synaptic plasticity
Uliana, D. L., Gomes, F. V., & Grace, A. A. (2022) · Neuropsychopharmacology · doi:10.1038/s41386-022-01333-1 · Cited by 14
“Models such as chronic mild stress and repeated chronic stressors induce amotivational states which can be reflected by increased immobility time in the FST [19, 20, 51].”
Background
In search of sex-related mediators of affective illness
Sikes-Keilp, C., & Rubinow, D. R. (2021) · Biology of Sex Differences · doi:10.1186/s13293-021-00400-4 · Cited by 13
Sex Differences in Anxiety and Depression: What Can (and Cannot) Preclinical Studies Tell Us?
Mir, F. R., & Rivarola, M. A. (2022) · Sexes · doi:10.3390/sexes3010012 · Cited by 14
BDNF Alterations in Brain Areas and the Neurocircuitry Involved in the Antidepressant Effects of Ketamine in Animal Models, Suggest the Existence of a Primary Circuit of Depression
Carboni, E., & Carta, A. R. (2022) · Journal of Integrative Neuroscience · doi:10.31083/j.jin2105144 · Cited by 16
Fluoxetine treatment supports predictive validity of the three hit model of depression in male PACAP heterozygous mice and underpins the impact of early life adversity on therapeutic efficacy
Gaszner, T., Farkas, J. I., Kun, D., Ujvari, B., Berta, G., CSERNUS, V. J., Füredi, N., Kovács, L. Á., Hashimoto, H., Reglődi, D., et al. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.995900 · Cited by 14
The olfactory bulbectomized rat model is not an appropriate model for studying depression based on morphological/stereological studies of the hippocampus
Yurttaş, C., Schmitz, C., Turgut, M., Strekalova, T. V., & Steinbusch, H. W. M. (2017) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2017.07.010 · Cited by 14
“…like increased muricidal behavior and hyperactivity in open fields under bright light, which were reversed by chronic, but not acute, treatment with classic antidepressants (Klein and Brown, 1969; Thorne et al., 1973; Jancsár and Leonard, 1983; van Riezen and Leonard, 1990; Czéh et al., 2015).”
Background
The effect of rat strain and stress exposure on performance in touchscreen tasks
Martis, L., Krog, S., Tran, T. P., Bouzinova, E. V., Christiansen, S. L., Møller, A., Holmes, M. C., & Wiborg, O. (2017) · Physiology & Behavior · doi:10.1016/j.physbeh.2017.11.010 · Cited by 17
Self-citation
Enhancing HIF-1α–P2X2 signaling in dorsal raphe serotonergic neurons promotes psychological resilience
Zhang, Y., Pan, Y., Zheng, W.-Y., Li, H.-Y., Zhu, M., yang, W.-J. O., Qian, Y., Turecki, G., Mechawar, N., & Zhu, X. (2023) · Redox Biology · doi:10.1016/j.redox.2023.103005 · Cited by 13
“To further characterize IHHT promoting psychological resilience, we generated a mouse model of depression using a well-established chronic mild stress (CMS) paradigm [24].”
Method
Potential Role of Bmal1 in Lipopolysaccharide-Induced Depression-Like Behavior and its Associated "Inflammatory Storm"
Xu, D., Hou, Z., Xu, Y., Liang, J., Gao, Y.-J., Zhang, C., Guo, F., Huang, D., Ge, J., & Xia, Q. (2024) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-024-10103-3 · Cited by 13
“Decreased BDNF abundance and imbalanced synaptic plasticity associated proteins have been demonstrated in the brain animal models of depression, induced by stress (Muller et al. 2011), LPS (Zhang et al. 2016), and other stimulators (Czeh et al. 2016).”

Authors: Czéh, B., Fuchs, E., Wiborg, O., & Simon, M.
Affiliations: Aarhus University (DK)
German Primate Center (DE)
University of Pecs (HU)
Corresponding author: Czéh, Boldizsár
ORCID: Czéh, Boldizsár
Wiborg, Ove
Simon, Mária
Venue: Progress in Neuro-Psychopharmacology and Biological Psychiatry
Publisher: Elsevier BV
Published: 2016-01
Volume: 64
Pages: 293-310
ISSN: 0278-5846 (ISSN-L)
DOI: 10.1016/j.pnpbp.2015.04.004
OpenAlex: W1978343268
Semantic Scholar: 0da6df41578259009c908495102e570eae27700e
Cited by: 375
References: 233
Citations by year: 2026: 9 · 2025: 41 · 2024: 19 · 2023: 43 · 2022: 47 · 2021: 48 · 2020: 46 · 2019: 34 · 2018: 30 · 2017: 31 · 2016: 22
FWCI: 20.50
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Progress in Neuro-Psychopharmacology and Biological Psychiatry (publishedVersion)
PubMed (publishedVersion)
GRO (submittedVersion)
Funders: Hungarian Brain Research Program “B” (KTIA_NAP_13-2014-0019)
Lundbeck Foundation (R83-A7631)
Topics: Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Keywords: major depressive disorder, animal models of depression, optogenetics, social stress, chronic mild stress, learned helplessness, early life stress, olfactory bulbectomy, circadian rhythm disruption, depression pathophysiology
MeSH terms: Animals, Brain, Depressive Disorder, Disease Models, Animal, Humans

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Animal models of major depression and their clinical implications

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