Animal models of major depression and their clinical implications

Czéh, Boldizsár; Fuchs, Eberhard; Wiborg, Ove; Simon, Mária

doi:10.1016/j.pnpbp.2015.04.004

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

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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Sartorius, A., Mahlstedt, M. M., Vollmayr, B., Henn, F., & Ende, G. (2007) · NeuroReport · doi:10.1097/wnr.0b013e3282742153 · Cited by 85 · see citing works
The Ups and Downs of Modelling Mood Disorders in Rodents
Slattery, D. A., & Cryan, J. F. (2014) · ILAR Journal · doi:10.1093/ilar/ilu026 · Cited by 85 · see citing works
Alterations in the central nervous α2-adrenoceptor system under chronic psychosocial stress
Flügge, G. (1996) · Neuroscience · doi:10.1016/0306-4522(96)00292-8 · Cited by 85 · see citing works
Selective breeding for infant rat separation-induced ultrasonic vocalizations: Developmental precursors of passive and active coping styles
Brunelli, S. A., & Hofer, M. A. (2007) · Behavioural Brain Research · doi:10.1016/j.bbr.2007.04.014 · Cited by 80 · see citing works
Chronic psychosocial stress and antidepressant treatment in tree shrews: time-dependent behavioral and endocrine effects
Kramer, M., Hiemke, C., & Fuchs, E. (1999) · Neuroscience & Biobehavioral Reviews · doi:10.1016/s0149-7634(99)00027-5 · Cited by 78 · see citing works
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Spatial organization and territory of three shrews (Tupaia glis)
Kawamichi, T., & Kawamichi, M. (1979) · Animal Behaviour · doi:10.1016/0003-3472(79)90173-8 · Cited by 77 · see citing works
Evaluation of the face validity of reserpine administration as an animal model of depression–Parkinson's disease association
Skalisz, L. L. (2002) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/s0278-5846(01)00333-5 · Cited by 76 · see citing works
Behavioral and neurobiological characteristics of social stress versus depression in nonhuman primates
Shively, C. A., & Willard, S. L. (2011) · Experimental Neurology · doi:10.1016/j.expneurol.2011.09.026 · Cited by 74 · see citing works
Animal Models of Depressive Illness: The Importance of Chronic Drug Treatment
Mitchell, P. B., & Redfern, P. H. (2005) · Current Pharmaceutical Design · doi:10.2174/1381612053382250 · Cited by 73 · see citing works
Psychosocial conflict in the tree shrew: Effects on sympathoadrenal activity and blood pressure
Fuchs, E., Jöhren, O., & Flügge, G. (1993) · Psychoneuroendocrinology · doi:10.1016/0306-4530(93)90033-h · Cited by 72 · see citing works
Self-citation
Biomarkers of anhedonic-like behavior, antidepressant drug refraction, and stress resilience in a rat model of depression
Christensen, T. T., Bisgaard, C. F., & Wiborg, O. (2011) · Neuroscience · doi:10.1016/j.neuroscience.2011.08.024 · Cited by 72 · see citing works
Self-citation
Repeated positive fighting experience in male inbred mice
Kudryavtseva, N. N., Смагин, Д. А., Kovalenko, I. L., & Vishnivetskaya, G. B. (2014) · Nature Protocols · doi:10.1038/nprot.2014.156 · Cited by 70 · see citing works
Pituitary glucocorticoid receptor deletion reduces vulnerability to chronic stress
Wagner, K. V., Wang, X., Liebl, C., Scharf, S. H., Müller, M. B., & Schmidt, M. V. (2010) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2010.09.007 · Cited by 69 · see citing works
Isolation and Pharmacological Characterization of Two Functional Splice Variants of Corticotropin‐Releasing Factor Type 2 Receptor from Tupaia belangeri
Palchaudhuri, Hauger, Wille, Fuchs, & Dautzenberg (1999) · Journal of Neuroendocrinology · doi:10.1046/j.1365-2826.1999.00348.x · Cited by 67 · see citing works
Corticotropin‐releasing factor receptor type 1 from Tupaia belangeri
Palchaudhuri, M. R., Wille, S., Mevenkamp, G., Spiess, J., Fuchs, E., & Dautzenberg, F. M. (1998) · European Journal of Biochemistry · doi:10.1046/j.1432-1327.1998.2580078.x · Cited by 67 · see citing works
Self-citation
The Role of Corticotropin-Releasing Hormone in the Pathophysiology of Depression: Therapeutic Implications
Lloyd, R. B., & Nemeroff, C. B. (2011) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026611109060609 · Cited by 67 · see citing works
Modeling depression in adult female cynomolgus monkeys ( Macaca fascicularis )
Willard, S. L., & Shively, C. A. (2011) · American Journal of Primatology · doi:10.1002/ajp.21013 · Cited by 65 · see citing works
Anterior cingulate pyramidal neurons display altered dendritic branching in depressed suicides.
Hercher, C., Canetti, L., Turecki, G., & Mechawar, N. (2010) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2009.08.011 · Cited by 64 · see citing works

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The Role of Microbiota-Gut-Brain Axis in Neuropsychiatric and Neurological Disorders
Socała, K., Doboszewska, U., Szopa, A., Serefko, A., Włodarczyk, M., Zielińska, A., Poleszak, E., Fichna, J., & Wlaź, P. (2021) · Pharmacological Research · doi:10.1016/j.phrs.2021.105840 · Cited by 857 · see citing works
Chronic unpredictable mild stress for modeling depression in rodents: Meta-analysis of model reliability
Antoniuk, 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
Brain-Derived Neurotrophic Factor, Depression, and Physical Activity: Making the Neuroplastic Connection
Phillips, C. (2017) · Neural Plasticity · doi:10.1155/2017/7260130 · Cited by 456 · see citing works
The Role of Early Growth Response 1 (EGR1) in Brain Plasticity and Neuropsychiatric Disorders
Duclot, F., & Kabbaj, M. (2017) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2017.00035 · Cited by 359 · see citing works
Immediate Early Genes, Memory and Psychiatric Disorders: Focus on c-Fos, Egr1 and Arc
Gallo, F. T., Katche, C., Morici, J. F., Medina, J. H., & Weisstaub, N. (2018) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2018.00079 · Cited by 339 · see citing works
“Animal models of depression have also shown a reduction in the volume of some regions of the prefrontal cortex and hippocampal formation (Hains et al., 2009; Czeh et al., 2016) with decreases in the length and complexity of dendrites and reduced number of dendritic spines.”
Background
Brain stimulation and brain lesions converge on common causal circuits in neuropsychiatric disease
Siddiqi, S. H., Schaper, F. L. W. V. J., Horn, A., Hsu, J., Padmanabhan, J. L., Brodtmann, A., Cash, R. F. H., Corbetta, M., Choi, K. S., Dougherty, D. D., et al. (2021) · Nature Human Behaviour · doi:10.1038/s41562-021-01161-1 · Cited by 296 · see citing works
Cortisol and major depressive disorder-translating findings from humans to animal models and Back
Nandam, L. S., Brazel, M., Zhou, M., & Jhaveri, D. J. (2020) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2019.00974 · Cited by 265 · see citing works
“To improve this, researchers have sought to develop models that maintain adequate face, predictive, etiological, and construct validity with MDD (3).”
Background
From Serotonin to Neuroplasticity: Evolvement of Theories for Major Depressive Disorder
Liu, B., Liu, J., Wang, M., Zhang, Y., & Li, L. (2017) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2017.00305 · Cited by 249 · 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
“Although it is currently unclear whether investigators will manage to identify the biological mechanism of depression based on the manifestations observed in animals, models of depression can still describe similar molecular alterations and pathogeneses to a great extent by utilizing appropriate criteria and methods […”
Background
The molecular and cellular mechanisms of depression: a focus on reward circuitry
Fox, M. E., & Lobo, M. K. (2019) · Molecular Psychiatry · doi:10.1038/s41380-019-0415-3 · Cited by 232 · see citing works
Effects of Withania somnifera (Ashwagandha) on Stress and the Stress- Related Neuropsychiatric Disorders Anxiety, Depression, and Insomnia
Speers, A. B., Cabey, K., Soumyanath, A., & Wright, K. M. (2021) · Current Neuropharmacology · doi:10.2174/1570159x19666210712151556 · Cited by 242 · see citing works
“The LHT involves dividing study animals into three groups with differing exposure to electrical shocks [115, 116].”
Background
Chronic Stress Induces Activity, Synaptic, and Transcriptional Remodeling of the Lateral Habenula Associated with Deficits in Motivated Behaviors
Cerniauskas, I., Winterer, J., de Jong, J. W., Lukacsovich, D., Yang, H., Khan, F., Peck, J. R., Obayashi, S. K., Lilascharoen, V., Lim, B. K., et al. (2019) · Neuron · doi:10.1016/j.neuron.2019.09.005 · Cited by 187 · see citing works
“This has led to the development of several animal models of depression that have been extensively used in basic research over the last few decades (Czéh et al., 2016; Nestler and Hyman, 2010; Willner, 2017).”
Method
Bidirectional relationship between sleep and depression
Yasugaki, S., Okamura, H., Kaneko, A., & Hayashi, Y. (2023) · Neuroscience Research · doi:10.1016/j.neures.2023.04.006 · Cited by 216 · see citing works
Understanding stress: Insights from rodent models
Atrooz, F., Alkadhi, K. A., & Salim, S. (2021) · Current Research in Neurobiology · doi:10.1016/j.crneur.2021.100013 · Cited by 201 · see citing works
Animal Models of Depression: What Can They Teach Us about the Human Disease?
Becker, M., Pinhasov, A., & Ornoy, A. (2021) · Diagnostics · doi:10.3390/diagnostics11010123 · Cited by 185 · see citing works
“It is therefore believed that depression results from the interaction of genetic and environmental factors [3,16].”
Background
Lipopolysaccharide-induced depression-like model in mice: meta-analysis and systematic evaluation
Yin, R., Zhang, K., Li, Y., Tang, Z., Zheng, R., Ma, Y., Chen, Z., Lei, N., Xiong, L., Guo, P., et al. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1181973 · Cited by 160 · see citing works
Depression as a risk factor for Alzheimer’s disease: Genes, steroids, cytokines and neurogenesis – What do we need to know?
Herbert, J., & Lucassen, P. J. (2016) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2015.12.001 · Cited by 150 · see citing works
“The problem is even more serious in MDD (Czeh et al., 2015).”
Background
Updated review of research on the gut microbiota and their relation to depression in animals and human beings
Yang, Z., Li, J., Gui, X., Shi, X., Bao, Z., Han, H., & Li, M. D. (2020) · Molecular Psychiatry · doi:10.1038/s41380-020-0729-1 · Cited by 138 · see citing works
“animals with various models of depression, including CSDS, unpredictable chronic mild stress, MS, and learned helplessness (LH) [65, 66].”
Background
Animal models in psychiatric research: The RDoC system as a new framework for endophenotype-oriented translational neuroscience
Anderzhanova, E. A., Kirmeier, T., & Wotjak, C. T. (2017) · Neurobiology of Stress · doi:10.1016/j.ynstr.2017.03.003 · Cited by 128 · see citing works
Altered gut metabolome contributes to depression-like behaviors in rats exposed to chronic unpredictable mild stress
Li, J., Xueyang, J., Cui, W., Wu, C., & Xue-mei, Q. (2019) · Translational Psychiatry · doi:10.1038/s41398-019-0391-z · Cited by 129 · see citing works
Long-Term Stress Disrupts the Structural and Functional Integrity of GABAergic Neuronal Networks in the Medial Prefrontal Cortex of Rats
Czéh, 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
“We tested this hypothesis in an animal model which involved long-term stress exposure since chronicstress models are useful to investigate study the neurobiology of depressive disorders (Willner, 1997; Wiborg, 2013; Czéh et al., 2016).”
BackgroundSelf-citation
Brexanolone, a neurosteroid antidepressant, vindicates the GABAergic deficit hypothesis of depression and may foster resilience
Lüscher, B., & Möhler, H. (2019) · F1000Research · doi:10.12688/f1000research.18758.1 · Cited by 105 · see citing works
Role of Mesolimbic Brain-Derived Neurotrophic Factor in Depression
Koo, J. W., Chaudhury, D., Han, M.-H., & Nestler, E. J. (2019) · Biological Psychiatry · doi:10.1016/j.biopsych.2019.05.020 · Cited by 112 · see citing works
The Evidence for Altered BDNF Expression in the Brain of Rats Reared or Housed in Social Isolation: A Systematic Review
Murínová, J., Hlaváčová, N., Chmelová, M., & Riečanský, I. (2017) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2017.00101 · Cited by 110 · see citing works
“The consequences of isolation are more severe in rats compared with other rodent species (Einon et al., 1981) and it has been argued that social isolation of rats has a good etiological validity to model human mental illness (Powell, 2010; Czéh et al., 2016).”
Background
Anti-depression effects of ketogenic diet are mediated via the restoration of microglial activation and neuronal excitability in the lateral habenula
Guan, Y., Huang, G., Xu, M.-D., Gao, F., Lin, S., Huang, J., Wang, J., Li, Y., Wu, C.-H., Yao, S., et al. (2020) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2020.05.032 · Cited by 112 · see citing works
Modelling depression in animals: at the interface of reward and stress pathways
Slattery, D. A., & Cryan, J. F. (2017) · Psychopharmacology · doi:10.1007/s00213-017-4552-6 · Cited by 110 · see citing works
Confronting Racism in All Forms of Pain Research: Reframing Study Designs
Letzen, J. E., Mathur, V. A., Janevic, M. R., Burton, M. D., Hood, A., Moraís, C. A., Booker, S. Q., Campbell, C. M., Aroke, E. N., Goodin, B. R., et al. (2022) · Journal of Pain · doi:10.1016/j.jpain.2022.01.010 · Cited by 111 · see citing works
Novel drug developmental strategies for treatment‐resistant depression
Borbély, É., Simon, M., Fuchs, E., Wiborg, O., Czéh, B., & Helyes, Z. (2021) · British Journal of Pharmacology · doi:10.1111/bph.15753 · Cited by 111 · see citing works
“Its effect in MDD patients has not been published (Wilkinson & Sanacora, 2019) and has not yet been investigated in TRD (Table 1).”
BackgroundInfluentialSelf-citation
Animal models of depression: pros and cons
Harro, J. (2018) · Cell and Tissue Research · doi:10.1007/s00441-018-2973-0 · Cited by 104 · see citing works
Oxidative Stress Implications in the Affective Disorders: Main Biomarkers, Animal Models Relevance, Genetic Perspectives, and Antioxidant Approaches
Balmus, I. M., Ciobica, A., Antioch, I., Dobrin, R., & Timofte, D. (2016) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2016/3975101 · Cited by 103 · see citing works
“For this reason, they must be comparable to the human dysfunction in the aspects of symptomatology (face validity), treatment manners (predictive validity), similar causative neurobiological factors (construct validity), and common etiology (etiological validity) [59].”
Background
Reduced Synapse and Axon Numbers in the Prefrontal Cortex of Rats Subjected to a Chronic Stress Model for Depression
Csabai, D., Wiborg, O., & Czéh, B. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00024 · Cited by 100 · see citing works
“Animal models based on chronic-stress paradigms are valuable tools to investigate the neurobiology of depressive disorders (Czéh et al., 2016).”
BackgroundSelf-citation
Chronic unpredictable mild stress-induced behavioral changes are coupled with dopaminergic hyperfunction and serotonergic hypofunction in mouse models of depression
Lu, Q., Mouri, A., Yang, Y., Kunisawa, K., Teshigawara, T., Hirakawa, M., Mori, Y., Yamamoto, Y., Libo, Z., Nabeshima, T., et al. (2019) · Behavioural Brain Research · doi:10.1016/j.bbr.2019.112053 · Cited by 94 · see citing works
Optimization of food deprivation and sucrose preference test in SD rat model undergoing chronic unpredictable mild stress
He, L., Zeng, L., Tian, N., Li, Y., He, T., Tan, D., Zhang, Q., & Tan, Y. (2020) · Animal Models and Experimental Medicine · doi:10.1002/ame2.12107 · Cited by 92 · see citing works
Chronic psychosocial stressors in adulthood: Studies in mice, rats and tree shrews
Pryce, C. R., & Fuchs, E. (2016) · Neurobiology of Stress · doi:10.1016/j.ynstr.2016.10.001 · Cited by 91 · see citing works
Self-citation
Defining Valid Chronic Stress Models for Depression With Female Rodents
Lopez, J., & Bagot, R. C. (2021) · Biological Psychiatry · doi:10.1016/j.biopsych.2021.03.010 · Cited by 86 · see citing works
DARK Classics in Chemical Neuroscience: Atropine, Scopolamine, and Other Anticholinergic Deliriant Hallucinogens
Lakstygal, A. M., Kolesnikova, T. O., Khatsko, S. L., Zabegalov, K. N., Volgin, A. D., Demin, K. A., Shevyrin, V. A., Wappler-Guzzetta, E. A., & Kalueff, A. V. (2018) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.8b00615 · Cited by 89 · see citing works
Validity of chronic restraint stress for modeling anhedonic-like behavior in rodents: a systematic review and meta-analysis
Ye, M., Xu, Y., & Yuan, X. (2022) · Journal of International Medical Research · doi:10.1177/03000605221075816 · Cited by 87 · see citing works
Isoflurane produces antidepressant effects and induces TrkB signaling in rodents
Antila, H., Ryazantseva, M., Popova, D., Sipilä, P., Guirado, R., Kohtala, S., Yalcin, I., Lindholm, J., Vesa, L., Sato, V., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-08166-9 · Cited by 84 · see citing works
The role of serotonergic, adrenergic and dopaminergic receptors in antidepressant-like effect
Pytka, K., Podkowa, K., Rapacz, A., Podkowa, A., Żmudzka, E., Olczyk, A., Sapa, J., & Filipek, B. (2015) · Pharmacological Reports · doi:10.1016/j.pharep.2015.08.007 · Cited by 84 · see citing works
Ethological Evaluation of the Effects of Social Defeat Stress in Mice: Beyond the Social Interaction Ratio
Henriques-Alves, A. M., & Queiroz, C. M. (2016) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2015.00364 · Cited by 77 · see citing works
“This has prompted the general idea that chronic social defeat stress in mice is a suitable animal model to study stressrelated psychiatric disorders, such as anxiety and depression (Bartolomucci et al., 2009; Nestler and Hyman, 2010; Hollis and Kabbaj, 2014; Czéh et al., 2016).”
Background
Liver Soluble Epoxide Hydrolase Regulates Behavioral and Cellular Effects of Chronic Stress
Qin, X.-H., Wu, Z., Dong, J.-H., Zeng, Y.-N., Xiong, W.-C., Liu, C., Wang, M.-Y., Zhu, M.-Z., Chen, W.-J., Zhang, Y., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.11.006 · Cited by 80 · see citing works
MicroRNA-dependent control of neuroplasticity in affective disorders
Martins, H. C., & Schratt, G. M. (2021) · Translational Psychiatry · doi:10.1038/s41398-021-01379-7 · Cited by 73 · see citing works
How Oxidative Stress Induces Depression?
Ji, N., Lei, M., Chen, Y., Tian, S., Li, C., & Zhang, B. (2023) · ASN NEURO · doi:10.1177/17590914231181037 · Cited by 82 · see citing works
“To uncover the intricate disease pathogenesis, several animal models (especially in rodents) have been established, through acute and chronic stress exposures, olfactory bulbectomy, drug administration (e.g., LPS and corticosterone), genetic manipulation, etc. (Czéh et al., 2016; Zhang, 2017).”
Background
Clock-Enhancing Small Molecules and Potential Applications in Chronic Diseases and Aging
Gloston, G. F., Yoo, S. H., & Chen, Z. (2017) · Frontiers in Neurology · doi:10.3389/fneur.2017.00100 · Cited by 73 · see citing works
“OBX mice share clinical features with both human neurodegenerative diseases and major depression (174).”
Background
Correction: Altered gut metabolome contributes to depression-like behaviors in rats exposed to chronic unpredictable mild stress
Li, J., Xueyang, J., Cui, W., Wu, C., & Xue-mei, Q. (2019) · Translational Psychiatry · doi:10.1038/s41398-019-0645-9 · Cited by 72 · see citing works
Encore: Behavioural animal models of stress, depression and mood disorders
Petković, A., & Chaudhury, D. (2022) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2022.931964 · Cited by 70 · see citing works
“However, distinct disorders can have similar primary symptoms, which makes experimental conclusions in the animal context uncertain at best, even in the case of translatable core symptoms (Matthews et al., 2005; Czéh et al., 2016; Anderzhanova et al., 2017).”
BackgroundInfluential
The heartbreak of depression: ‘Psycho-cardiac’ coupling in myocardial infarction
Headrick, J. P., Peart, J. N., Budiono, B. P., Shum, D., Neumann, D. L., & Stapelberg, N. J. C. (2017) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2017.03.007 · Cited by 69 · see citing works
“AC C EP TE D M AN U SC R IP T been reviewed in detail previously [211,223-225], they are addressed here in brief.”
Background
Depression and substance use disorders: Clinical comorbidity and shared neurobiology
Calarco, C. A., & Lobo, M. K. (2020) · International review of neurobiology · doi:10.1016/bs.irn.2020.09.004 · Cited by 69 · see citing works
Asymmetric total synthesis and antidepressant activity of (−)-sila-mesembranol bearing a silicon stereocenter
Luo, G., Chen, L., Li, Y., Fan, Y., Wang, D., Yang, Y., Gao, L., Jiang, R., & Song, Z. (2021) · Organic Chemistry Frontiers · doi:10.1039/d1qo00682g · Cited by 65 · see citing works
Relaxin’ the brain: a case for targeting the nucleus incertus network and relaxin‐3/RXFP3 system in neuropsychiatric disorders
Kumar, J. R., Rajkumar, R., Jayakody, T., Marwari, S., Hóng, J., Ma, S., Gundlach, A. L., Lai, M. K. P., & Dawe, G. S. (2016) · British Journal of Pharmacology · doi:10.1111/bph.13564 · Cited by 62 · see citing works
“The chronic mild stress (CMS) model of depression, which is preferred for rats but has also been used in mice, is extensively validated and produces enduring changes in behaviour, neurotransmitter and hormonal concentrations and the immune system (Overstreet, 2012; Abelaira et al., 2013; Czeh et al., 2016).”
Neurobiological consequences of juvenile stress: A GABAergic perspective on risk and resilience
Albrecht, A., Müller, I., Ardi, Z., Çalışkan, G., Gruber, D., Ivens, S., Segal, M., Behr, J., Heinemann, U., Stork, O., et al. (2017) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2017.01.005 · Cited by 63 · see citing works
SIRT2 inhibition modulate glutamate and serotonin systems in the prefrontal cortex and induces antidepressant-like action
Erburu, M. M., Muñoz-Cobo, I., Diaz-Perdigón, T., Mellini, P., Suzuki, T., Puerta, E., & Tordera, R. M. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2017.01.033 · Cited by 64 · see citing works
Stress-Induced Morphological, Cellular and Molecular Changes in the Brain—Lessons Learned from the Chronic Mild Stress Model of Depression
Khan, A. R., Geiger, L., Wiborg, O., & Czéh, B. (2020) · Cells · doi:10.3390/cells9041026 · Cited by 62 · see citing works
“Most importantly the CMS model, like a few related rodent models based on stress exposure, such as social defeat and learned helplessness models [13,19,20], all mimic one of the core symptoms in depression; anhedonia, which is a decreased interest in activities that used to be pleasurable in the premorbid state.”
BackgroundSelf-citation
Elevation of synaptic protein is associated with the antidepressant-like effects of ferulic acid in a chronic model of depression
Liu, Y., Hu, C., Shen, J.-D., Wu, S., Li, Y., & Yi, L. (2016) · Physiology & Behavior · doi:10.1016/j.physbeh.2016.12.003 · Cited by 61 · see citing works
The Netrin-1/DCC Guidance Cue Pathway as a Molecular Target in Depression: Translational Evidence
Torres‐Berrío, A., Hernández, G., Nestler, E. J., & Flores, C. (2020) · Biological Psychiatry · doi:10.1016/j.biopsych.2020.04.025 · Cited by 64 · see citing works
“At the completion of the paradigms, animals are assessed in a battery of behavioral tests that measure phenotypic traits such as reward sensitivity, social interaction, sucrose preference, and time spent grooming (for an extensive review, see(81,82,85)).”
Background
Chronic unpredictable stress negatively regulates hippocampal neurogenesis and promote anxious depression-like behavior via upregulating apoptosis and inflammatory signals in adult rats
Parul, P., Mishra, A., Singh, S., Singh, S., Tiwari, V., Chaturvedi, S., Wahajuddin, M., Palit, G., & Shukla, S. (2021) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2021.04.017 · Cited by 62 · see citing works
Regulatory effect of lithium on hippocampal blood‐brain barrier integrity in a rat model of depressive‐like behavior
Taler, M., Aronovich, R., Hornfeld, S. H., Dar, S., Sasson, E., Weizman, A., & Hochman, E. (2020) · Bipolar Disorders · doi:10.1111/bdi.12962 · Cited by 63 · see citing works
A Microbial-Based Approach to Mental Health: The Potential of Probiotics in the Treatment of Depression
Johnson, D., Letchumanan, V., Thum, C. C., Thurairajasingam, S., & Lee, L. (2023) · Nutrients · doi:10.3390/nu15061382 · Cited by 65 · see citing works
Alterations and adaptation of ventral tegmental area dopaminergic neurons in animal models of depression
Kaufling, J. (2019) · Cell and Tissue Research · doi:10.1007/s00441-019-03007-9 · Cited by 60 · see citing works
Reinstating olfactory bulb-derived limbic gamma oscillations alleviates depression-like behavioral deficits in rodents
Li, Q., Takeuchi, Y., Wang, J., Gellért, L., Barcsai, L., Pedraza, L. K., Nagy, A. J., Kozák, G., Nakai, S., Kato, S., et al. (2023) · Neuron · doi:10.1016/j.neuron.2023.04.013 · Cited by 61 · see citing works
Human amygdala engagement moderated by early life stress exposure is a biobehavioral target for predicting recovery on antidepressants
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Astroglial Connexin43 as a Potential Target for a Mood Stabiliser
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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 · 2015: 3
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 › 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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