Skip to main content

Advertisement

SpringerLink
Log in

Animal models of depression: pros and cons

  • Review
  • Published:
Cell and Tissue Research Aims and scope Submit manuscript

Abstract

Animal models of depression are certainly needed but the question in the title has been raised owing to the controversies in the interpretation of the readout in a number of tests, to the perceived lack of progress in the development of novel treatments and to the expressed doubts in whether animal models can offer anything to make a true breakthrough in understanding the neurobiology of depression and producing novel drugs against depression. Herewith, it is argued that if anything is wrong with animal models, including those for depression, it is not about the principle of modelling complex human disorder in animals but in the way the tests are selected, conducted and interpreted. Further progress in the study of depression and in developing new treatments, will be supported by animal models of depression if these were more critically targeted to drug screening vs. studies of underlying neurobiology, clearly stratified to vulnerability and pathogenetic models, focused on well-defined endophenotypes and validated for each setting while bearing the existing limits to validation in mind. Animal models of depression need not to rely merely on behavioural readouts but increasingly incorporate neurobiological measures as the understanding of depression as human brain disorder advances. Further developments would be fostered by cross-fertilizinga translational approach that is bidirectional, research on humans making more use of neurobiological findings in animals.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Abramson L, Seligman MEP (1977) Modeling psychopathology in the laboratory: history and rationale. In: Maser J, Seligman MEP (eds) Psychopathology: experimental models. Freeman, San Francisco

    Google Scholar 

  • Airan RD, Meltzer LA, Roy M, Gong Y, Chen H, Deisseroth K (2007) High-speed imaging reveals neurophysiological links to behavior in an animal model of depression. Science 317:819–823

    Article  CAS  PubMed  Google Scholar 

  • Akil H, Gordon J, Hen R, Javitch J, Mayberg H, McEwen B, Meaney MJ, Nestler EJ (2018) Treatment resistant depression: a multi-scale, systems biology approach. Neurosci Biobehav Rev 84:272–288

    Article  PubMed  Google Scholar 

  • Andrus BM, Blizinsky K, Vedell PT, Shukla PK, Schaffer DJ, Radulovic J, Churchill GA, Redei EE (2012) Gene expression patterns in the hippocampus and amygdala of endogenous depression and chronic stress models. Mol Psychiatry 17:49–61

    Article  CAS  PubMed  Google Scholar 

  • Anisman H, Zacharko RM (1990) Multiple neurochemical and behavioral consequences of stressors: implications for depression. Pharmacol Ther 46:119–136

    Article  CAS  PubMed  Google Scholar 

  • Anisman H, Merali Z, Stead JDH (2008) Experiential and genetic contributions to depressive- and anxiety-like disorders: clinical and experimental studies. Neurosci Biobehav Rev 32:1185–1206

    Article  CAS  PubMed  Google Scholar 

  • Atzori M, Cuevas-Olguin R, Esquivel-Rendon E, Garcia-Oscos F, Salgado-Delgado RC, Saderi N, Miranda-Morales M, Trevino M, Pineda JC, Salgado H (2016) Locus ceruleus norepinephrine release: a central regulator of CNS spatio-temporal activation? Front Synaptic Neurosci 8:25

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bagot RC, Cates HM, Purushothaman I, Lorsch ZS, Walker DM, Wang J, Huang X, Schlüter OM, Maze I, Pena CJ, Heller EA, Issler O, Wang M, Song W, Stein JL, Liu X, Doyle MA, Scobie KN, Sun HS, Neve RL, Geschwind D, Dong Y, Shen L, Zhang B, Nestler EJ (2016) Circuit-wide transcriptional profiling reveals brain region-specific gene networks regulating depression susceptibility. Neuron 90:969–983

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bangasser DA, Wiesielis KR (2018) Sex differences in stress responses: a critical role for corticotropin-releasing factor. Hormones 17:5–13

    Article  PubMed  Google Scholar 

  • Belzung C (2014) Innovative drugs to treat depression: did animal models fail to be predictive or did clinical trials fail to detect effects? Neuropsychopharmacology 39:1041–1051

    Article  PubMed  PubMed Central  Google Scholar 

  • Berton O, McClung CA, DiLeone RJ, Krishnan V, Renthal W, Russo SJ, Graham D, Tsankova NM, Bolanos CA, Rios M, Monteggia LM, Self DW, Nestler EJ (2006) Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science 311:864–868

    Article  CAS  PubMed  Google Scholar 

  • Bogdanova OV, Kanekar S, D’Anci KE, Renshaw PF (2013) Factors influencing behavior in the forced swim test. Physiol Behav 118:227–239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Borrow AP, Bales NJ, Stover SA, Handa RJ (2018) Chronic variable stress induces sex-specific alterations in social behavior and neuropeptide expression in the mouse. Endocrinology 159:2803–2814

    Article  PubMed  PubMed Central  Google Scholar 

  • Burke NN, Coppinger J, Deaver DR, Roche M, Finn DP, Kelly J (2016) Sex differences and similarities in depressive- and anxiety-like behaviour in the Wistar-Kyoto rat. Physiol Behav 167:28–34

    Article  CAS  PubMed  Google Scholar 

  • Cabib S (1997) What is mild in mild stress? Psychopharmacology 134:344–346

    Article  CAS  PubMed  Google Scholar 

  • Carboni L, Nguyen T-P, Caberlotto L (2016) Systems biology integration of proteomic data in rodent models of depression reveals involvement of the immune response and glutamatergic signaling. Proteomics Clin Appl 10:1254–1263

    Article  CAS  PubMed  Google Scholar 

  • Carhart-Harris RL, Nutt DJ (2017) Serotonin and brain function: a tale of two receptors. J Psychopharmacol 31:1091–1120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Castrén E, Võikar V, Rantamäki T (2007) Role of neurotrophic factors in depression. Curr Opin Pharmacol 7:18–21

    Article  CAS  PubMed  Google Scholar 

  • Chesler EJ, Wilson SG, Lariviere WR, Rodriquez-Zas SL, Mogil JS (2002) Identification and ranking of genetic and laboratory environment factors influencing a behavioral trait, thermal nociception, via computational analysis of a large data archive. Neurosci Biobehav Rev 26:907–923

    Article  PubMed  Google Scholar 

  • Clemm von Hohenberg C, Weber-Fahr W, Lebhardt P, Ravi N, Braun U, Gass N, Becker R, Sack M, Cosa Linan A, Gerchen MF, Reinwald JR, Oettl LL, Meyer-Lindenberg A, Vollmayr B, Kelsch W, Sartorius A (2018) Lateral habenula perturbation reduces default-mode network connectivity in a rat model of depression. Transl Psychiatry 8:68

    Article  PubMed  PubMed Central  Google Scholar 

  • Commons KG, Cholanians AB, Babb JA, Ehlinger DG (2017) The rodent forced swim test measures stress-coping strategy, not depression-like behavior. ACS Chem Neurosci 8:955–960

    Article  CAS  PubMed  Google Scholar 

  • Cox DA, Gottschalk MG, Stelzhammer V, Wesseling H, Cooper JD, Bahn S (2016) Evaluation of molecular brain changes associated with environmental stress in rodent models compared to human major depression: a proteomic systems approach. World J Biol Psychiatry 25:1–12

    Google Scholar 

  • Cryan JF, Holmes A (2005) The ascent of mouse: advances in modeling human depression and anxiety. Nat Rev Drug Discov 4:775–790

    Article  CAS  PubMed  Google Scholar 

  • Cryan JF, Markou A, Lucki I (2002) Assessing antidepressant activity in rodents: recent developments and future needs. Trends Pharmacol Sci 23:238–245

    Article  CAS  PubMed  Google Scholar 

  • Csabai D, Seress L, Varga Z, Ábrahám H, Miseta A, Wiborg O, Czéh B (2017) Electron microscopic analysis of hippocampal axo-somatic synapses in a chronic stress model for depression. Hippocampus 27:17–27

    Article  CAS  PubMed  Google Scholar 

  • Czéh B, Fuchs E, Wiborg O, Simon M (2016) Animal models of major depression and their clinical implications. Prog Neuro-Psychopharmacol Biol Psychiatry 64:293–310

    Article  Google Scholar 

  • Dadomo H, Gioiosa L, Cigalotti J, Ceresini G, Parmigiani S, Palanza P (2018) What is stressful for females? Differential effects of unpredictable environmental or social stress in CD1 female mice. Horm Behav 98:22–32

    Article  PubMed  Google Scholar 

  • Dalla C, Pitychoutis PM, Kokras N, Papadopoulou-Daifoti Z (2010) Sex differences in animal models of depression. Basic Clin Pharmacol Toxicol 106:226–233

    Article  CAS  PubMed  Google Scholar 

  • Darcet F, Gardier AM, Gaillard R, David DJ, Guilloux J-P (2016) Cognitive dysfunction in major depressive disorder: a translational review in animal models of the disease. Pharmaceuticals 9:9

    Article  CAS  PubMed Central  Google Scholar 

  • De Kloet ER, Molendijk ML (2016) Coping with the forced swim stressor: towards understanding an adaptive mechanism. Neural Plast 2016:6503162

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • De Pablo JM, Parra A, Segovia S, Guillamon A (1989) Learned immobility explains the behavior of rats in the forced swimming test. Physiol Behav 46:229–237

    Article  PubMed  Google Scholar 

  • De Wit H, Epstein DH, Preston KL (2018) Does human language limit translatability of clinical and preclinical addiction research? Neuropsychopharmacology 43:1985–1988

    Article  PubMed  PubMed Central  Google Scholar 

  • Deakin JF, Harro J, Anderson IM (2011) NewMood: a productive European model of collaboration for translational research in depression. Eur Neuropsychopharmacol 21:1–2

    Article  CAS  PubMed  Google Scholar 

  • Deussing JM (2013) Targeted mutagenesis tools for modelling psychiatric disorders. Cell Tissue Res 354:9–25

    Article  CAS  PubMed  Google Scholar 

  • Deussing JM, Jakovcevski M (2017) Histone modifications in major depressive disorder and related rodent models. Adv Exp Med Biol 978:169–183

    Article  CAS  PubMed  Google Scholar 

  • Drysdale AT, Grosenick L, Downar J, Dunlop K, Mansouri F, Meng Y, Fetcho RN, Zebley B, Oathes DJ, Etkin A, Schatzberg AF, Sudheimer K, Keller J, Mayberg HS, Gunning FM, Alexopoulos GS, Fox MD, Pascual-Leone A, Voss HU, Casey BJ, Dubin MJ, Liston C (2017) Resting-state connectivity biomarkers define neurophysiological subtypes of depression. Nat Med 23:28–38

    Article  CAS  PubMed  Google Scholar 

  • Duman RS, Aghajanian GK, Sanacora G, Krystal JH (2016) Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants. Nat Med 22:238–249

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Eliot L, Richardson SS (2016) Sex in context: limitations of animal studies for addressing human sex/gender neurobehavioral health disparities. J Neurosci 36:11823–11830

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Enginar N, Yamantürk-Celik P, Nurten A, Güney DB (2016) Learning and memory in the forced swimming test: effects of antidepressants having varying degrees of anticholinergic activity. Naunyn Schmiedeberg’s Arch Pharmacol 389:739–745

    Article  CAS  Google Scholar 

  • Fava M, Kendler KS (2000) Major depressive disorder. Neuron 28:335–341

    Article  CAS  PubMed  Google Scholar 

  • Gass P, Wotjak C (2013) Rodent models of psychiatric disorders—practical considerations. Cell Tissue Res 354:1–7

    Article  PubMed  Google Scholar 

  • Gass N, Becker R, Schwarz AJ, Weber-Fahr W, Clemm von Hohenberg C, Vollmayr B, Sartorius A (2016) Brain network reorganization differs in response to stress in rats genetically predisposed to depression and stress-resilient rats. Transl Psychiatry 6:e970

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Geyer MA, Markou A (1995) Animal models of psychiatric disorders. In: Bloom FE, Kupfer DJ (eds) Psychopharmacology: the fourth generation of progress. Raven, New York, pp 787–798

    Google Scholar 

  • Gottesman II, Gould TD (2003) The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry 160:636–645

    Article  PubMed  Google Scholar 

  • Grandjean J, Azzinari D, Seuwen A, Sigrist H, Seifritz E, Pryce CR, Rudin M (2016) Chronic psychosocial stress in mice leads to changes in brain functional connectivity and metabolite levels comparable to human depression. Neuroimage 142:544–552

    Article  CAS  PubMed  Google Scholar 

  • Häidkind R, Eller M, Kask A, Harro M, Rinken A, Oreland L, Harro J (2004) Increased behavioural activity of rats in forced swimming test after partial denervation of serotonergic system by parachloroamphetamine treatment. Neurochem Int 45:721–732

    Article  CAS  PubMed  Google Scholar 

  • Hammels C, Pishva E, De Vry J, van den Hove DL, Prickaerts J, van Winkel R, Selten JP, Lesch KP, Daskalakis NP, Steinbusch HW, van Os J, Kenis G, Rutten BP (2015) Defeat stress in rodents: from behavior to molecules. Neurosci Biobehav Rev 59:111–140

    Article  CAS  PubMed  Google Scholar 

  • Harro J (2002) Long-term partial 5-HT depletion: interference of anxiety and impulsivity? Psychopharmacology 164:433–434

    Article  CAS  PubMed  Google Scholar 

  • Harro J (2004) Animal models for better antidepressants: can pathogenetic models make a difference? PreClinica 2:402–407

    CAS  Google Scholar 

  • Harro J (2010) Inter-individual differences in neurobiology as vulnerability factors for disorders: implications to psychopharmacology. Pharmacol Ther 125:402–422

    Article  CAS  PubMed  Google Scholar 

  • Harro J (2013) Animal models of depression vulnerability. Curr Top Behav Neurosci 14:29–54

    Article  PubMed  Google Scholar 

  • Harro J (2018) Animals, anxiety, and anxiety disorders: how to measure anxiety in rodents and why. Behav Brain Res 352:81–93

    Article  PubMed  Google Scholar 

  • Harro J, Kiive E (2011) Droplets of black bile? Development of vulnerability and resilience to depression in young age. Psychoneuroendocrinology 36:380–392

    Article  PubMed  Google Scholar 

  • Harro J, Oreland L (2001) Depression as a spreading adjustment disorder of monoaminergic neurons: a case for primary implication of the locus coeruleus. Brain Res Rev 38:79–128

    Article  CAS  PubMed  Google Scholar 

  • Harro J, Oreland L (2016) The role of MAO in personality and drug use. Prog Neuro-Psychopharmacol Biol Psychiatry 69:101–111

    Article  CAS  Google Scholar 

  • Harro J, Pähkla R, Modiri A-R, Harro M, Kask A, Oreland L (1999) Dose-dependent effects of noradrenergic denervation by DSP-4 treatment on forced swimming and beta-adrenoceptor binding in the rat. J Neural Transm 106:619–629

    Article  CAS  PubMed  Google Scholar 

  • Harro J, Tõnissaar M, Eller M, Kask A, Oreland L (2001) Chronic variable stress and partial 5-HT denervation by parachloroamphetamine treatment in rat: effects on behavior and monoamine neurochemistry. Brain Res 899:227–239

    Article  CAS  PubMed  Google Scholar 

  • Harro J, Kanarik M, Matrov D, Panksepp J (2011) Mapping patterns of depression-related brain regions with cytochrome oxidase histochemistry: relevance of animal affective systems to human disorders, with a focus on resilience to adverse events. Neurosci Biobehav Rev 35:1876–1889

    Article  CAS  PubMed  Google Scholar 

  • Harro J, Kanarik M, Kaart T, Matrov D, Kõiv K, Mällo T, Del Rio J, Tordera RM, Ramirez MJ (2014) Revealing the cerebral regions and networks mediating vulnerability to depression: oxidative metabolism mapping of rat brain. Behav Brain Res 267:83–94

    Article  CAS  PubMed  Google Scholar 

  • Hendrie CA, Pickles AR (2009) Depression as an evolutionary adaptation: implications for the development of preclinical models. Med Hypotheses 72:342–347

    Article  CAS  PubMed  Google Scholar 

  • Hendriksen H, Korte SM, Olivier B, Oosting RS (2015) The olfactory bulbectomy model in mice and rat: one story or two tails? Eur J Pharmacol 753:105–113

    Article  CAS  PubMed  Google Scholar 

  • Hodes GE, Pfau ML, Purushothaman I, Ahn HF, Golden SA, Christoffel DJ, Magida J, Brancato A, Takahashi A, Flanigan ME, Ménard C, Aleyasin H, Koo JW, Lorsch ZS, Feng J, Meshmati M, Wang M, Turecki G, Neve R, Zhang B, Shen L, Nestler EJ, Russo SJ (2015) Sex differences in nucleus accumbens transcriptome profiles associated with susceptibility versus resilience to subchronic variable stress. J Neurosci 35:16362–16376

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hoyle D, Juhasz G, Aso E, Chase D, del Rio J, Fabre V, Hamon M, Lanfumey L, Lesch KP, Maldonado R, Serra MA, Sharp T, Tordera R, Toro C, Deakin JFW (2011) Shared changes in gene expression in frontal cortex of four genetically modified mouse models of depression. Eur Neuropsychopharmacol 21:3–10

    Article  CAS  PubMed  Google Scholar 

  • Hyman SE (2014) Revitalizing psychiatric therapeutics. Neuropsychopharmacology 39:220–229

    Article  CAS  PubMed  Google Scholar 

  • Jaako-Movits K, Zharkovsky A (2005) Impaired fear memory and decreased hippocampal neurogenesis following olfactory bulbectomy in rats. Eur J Neurosci 22:2871–2878

    Article  PubMed  Google Scholar 

  • Kaiser RH, Andrews-Hanna JR, Wager TD, Pizzagalli DA (2015) Large-scale network dysfunction in major depressive disorder: a meta-analysis of resting-state functional connectivity. JAMA Psychiatry 72:603–611

    Article  PubMed  PubMed Central  Google Scholar 

  • Kanarik M, Harro J (2018) Sociability trait and regional cerebral oxidative metabolism in rats: predominantly nonlinear relations. Behav Brain Res 337:186–192

    Article  CAS  PubMed  Google Scholar 

  • Kanarik M, Alttoa A, Matrov D, Kõiv K, Sharp T, Panksepp J, Harro J (2011) Brain responses to chronic social defeat stress: effects on regional oxidative metabolism as a function of a hedonic trait, and gene expression susceptible and resilient rats. Eur Neuropsychopharmacol 21:92–107

    Article  CAS  PubMed  Google Scholar 

  • Kara NZ, Stukalin Y, Einat H (2018) Revisiting the validity of the mouse forced swim test: systematic review and meta-analysis of the effects of prototypic antidepressants. Neurosci Biobehav Rev 84:1–11

    Article  CAS  PubMed  Google Scholar 

  • Kas MJ, Krishnan V, Gould TD, Collier DA, Olivier B, Lesch KP, Domenici E, Fuchs E, Gross C, Castrén E (2011) Advances in multidisciplinary and cross-species approaches to examine the neurobiology of psychiatric disorders. Eur Neuropsychopharmacol 21:532–544

    Article  CAS  PubMed  Google Scholar 

  • Katz RJ (1982) Animal model of depression: pharmacological sensitivity of a hedonic deficit. Pharmacol Biochem Behav 16:965–968

    Article  CAS  PubMed  Google Scholar 

  • Katz RJ, Roth KA, Carroll BJ (1981) Acute and chronic stress effects on open field activity in the rat: implications for a model of depression. Neurosci Biobehav Rev 5:247–251

    Article  CAS  PubMed  Google Scholar 

  • Keeler JF, Robbins TW (2011) Translating cognition from animals to humans. Biochem Pharmacol 81:1356–1366

    Article  CAS  PubMed  Google Scholar 

  • Kelly JP, Wrynn AS, Leonard BE (1997) The olfactory bulbectomized rat as a model of depression: an update. Pharmacol Ther 74:299–316

    Article  CAS  PubMed  Google Scholar 

  • Kendler KS, Gatz M, Gardner CO, Pedersen NL (2006) Personality and major depression. A Swedish longitudinal, population-based twin study. Arch Gen Psychiatry 63:1113–1120

    Article  PubMed  Google Scholar 

  • Khan AR, Kroenke CD, Wiborg O, Chuhutin A, Nyengaard JR, Hansen B, Jespersen SN (2018) Differential microstructural alterations in rat cerebral cortex in a model of chronic mild stress depression. PLoS One 13:e0192329

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim Y, Perova Z, Mirrione MM, Pradham K, Henn FA, Shea S, Osten P, Li B (2016) Whole-brain mapping of neuronal activity in the learned helplessness model of depression. Front Neural Circuits 10:3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Knowland D, Lim BK (2018) Circuit-based frameworks of depressive behaviors: the role of reward circuitry and beyond. Pharmacol Biochem Behav in press

  • Kokras N, Antoniou K, Mikail HG, Kafetzopoulos V, Papadopoulou-Daifoti Z, Dalla C (2015) Forced swim test: what about females? Neuropharmacology 99:408–421

    Article  CAS  PubMed  Google Scholar 

  • Labonté B, Engmann O, Purushothaman I, Menard C, Wang J, Tan C, Scarpa JR, Moy G, Loh YHE, Cahill M, Lorsch ZS, Hamilton PJ, Calipari ES, Hodes GE, Issler O, Kronman H, Pfau M, Obradovic ALJ, Dong Y, Neve RL, Russo S, Kasarskis A, Tamminga C, Mechawar N, Turecki G, Zhang B, Shen L, Nestler EJ (2017) Sex-specific transcriptional signatures in human depression. Nat Med 23:1102–1111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu J, Scira J, Donaldson S, Kajiji N, Dash GH, Donaldson ST (2018) Sex and trait anxiety differences in psychological stress are modified by environment. Neuroscience 383:178–190

    Article  CAS  PubMed  Google Scholar 

  • Malki K, Keers R, Tosto MG, Lourdusamy A, Carboni L, Domenici E, Uher R, McGuffin P, Schalkwyk LC (2014) The endogenous and reactive depression subtypes revisited: integrative animal and human studies implicate multiple distinct molecular mechanisms underlying major depressive disorder. BMC Med 12:73

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Malki K, Tosto MG, Mourino-Talín H, Rodríguez-Lorenzo S, Pain O, Jumhaboy I, Liu T, Parpas P, Newman S, Malykh A, Carboni L, Uher R, McGuffin P, Schalkwyk LC, Bryson K, Herbster M (2017) Highly polygenic architecture of antidepressant treatment response: comparative analysis of SSRI and NRI treatment in an animal model of depression. Am J Med Genet B Neuropsychiatr Genet 174:235–250

    Article  CAS  PubMed  Google Scholar 

  • Mällo T, Matrov D, Kõiv K, Harro J (2009) Effect of chronic stress on behavior and cerebral oxidative metabolism in rats with high or low positive affect. Neuroscience 164:963–974

    Article  CAS  PubMed  Google Scholar 

  • Marks HE, Remley NR, Seago JD, Hastings DW (1971) Effects of bilateral lesions of the olfactory bulbs of rats on measures of learning and motivation. Physiol Behav 7:1–6

    Article  CAS  PubMed  Google Scholar 

  • Mason JW (1975) A historical view of stress fields. J Hum Stress 1:6–12

    Article  CAS  Google Scholar 

  • Matrov D, Vonk A, Herm L, Rinken A, Harro J (2011) Activating effects of chronic variable stress in rats with different exploratory activity: association with dopamine D1 receptor function in nucleus accumbens. Neuropsychobiology 64:110–122

    Article  CAS  PubMed  Google Scholar 

  • Matrov D, Kõiv K, Kanarik M, Peet K, Raudkivi K, Harro J (2016) Middle-range exploratory activity in adult rats suggest higher resilience to chronic social defeat. Acta Neuropsychiatr 28:125–140

    Article  PubMed  Google Scholar 

  • Matrov D, Kaart T, Lanfumey L, Maldonado R, Sharp T, Tordera RM, Kelly PA, Deakin B, Harro J (2018) Cerebral oxidative metabolism mapping in four genetic models of anxiety and mood disorders. Behav Brain Res 356:435–443. https://doi.org/10.1016/j.bbr.2018.05.031

    Article  CAS  PubMed  Google Scholar 

  • McCoy CR, Golf SR, Melendez-Ferro M, Perez-Costas E, Glover ME, Jackson NL, Stringfellow SA, Pugh PC, Fant AD, Clinton SM (2016) Altered metabolic activity in the developing barin of rats predisposed to high versus low depression-like behavior. Neuroscience 324:469–484

    Article  CAS  PubMed  Google Scholar 

  • McIntosh AL, Gormley S, Tozzi L, Frodl T, Harkin A (2017) Recent advances in translational magnetic resonance imaging in animal models of stress and depression. Front Cell Neurosci 11:150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McKinney WT Jr, Bunney WE Jr (1969) Animal models of depression. I: review of evidence: implications for research. Arch Gen Psychiatry 21:240–248

    Article  PubMed  Google Scholar 

  • Medel-Matus J-S, Shin D, Sankar R, Mazarati A (2017) Inherent vulnerabilities in monoaminergic patways predict the emergence of depressiove impairments in an animal model of chronic epilepsy. Epilepsia 58:e116–e121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Molendijk ML, de Kloet ER (2015) Immobility in the forced swim test is adaptive and does not reflect depression. Psychoneuroendocrinology 62:389–391

    Article  PubMed  Google Scholar 

  • Molteni R, Macchi F, Riva MA (2013) Gene expression profiling as functional readout of rodent models for psychiatric disorders. Cell Tissue Res 354:51–60

    Article  CAS  PubMed  Google Scholar 

  • Morales-Medina JC, Ianniti T, Freeman A, Caldwell HK (2017) The olfactory bulbectomized rat as a model of depression: the hippocampal pathway. Behav Brain Res 317:562–575

    Article  CAS  PubMed  Google Scholar 

  • Mul JD, Zheng J, Goodyear LJ (2016) Validity assessment of 5 day repeated forced-swim stress to model human depression in young-adult C57BL/6J and BALB/cJ mice. eNeuro 3(6):ENEURO.0201-16.2016

    Article  PubMed  PubMed Central  Google Scholar 

  • Mulders PC, van Eijndhoven PF, Schene AH, Beckmann CF, Tendolkar I (2015) Resting-state functional connectivity in major depressive disorder: a review. Neurosci Biobehav Rev 56:330–344

    Article  PubMed  Google Scholar 

  • Muscat R, Willner P (1992) Suppression of sucrose drinking by chronic mild unpredictable stress: a methodological analysis. Neurosci Biobehav Rev 16:507–517

    Article  CAS  PubMed  Google Scholar 

  • Nishimura H, Tsuda A, Oguchi M, Ida Y, Tanaka M (1988) Is immobility of rats in the forced swim test “behavioral despair”? Physiol Behav 42:93–95

    Article  CAS  PubMed  Google Scholar 

  • Nutt DJ (2008) Relationship of neurotransmitters to the symptoms of major depressive disorder. J Clin Psychiatry 69E1:4–7

    Google Scholar 

  • O’Leary OF, Cryan JF (2013) Towards translational rodent models of depression. Cell Tissue Res 354:141–153

    Article  CAS  PubMed  Google Scholar 

  • O’Neil MF, Moore NA (2003) Animal models of depression: are there any? Hum Psychopharmacol Clin Exp 18:239–254

    Article  Google Scholar 

  • Oosterhof CA, El Mansari M, Merali Z, Blier P (2016) Altered monoamine system activities after prenatal and adult stress: a role for stress resilience? Brain Res 1642:409–418

    Article  CAS  PubMed  Google Scholar 

  • Pajer K, Andrus BM, Gardner W, Lourie A, Strange B, Campo J, Bridge J, Blizinsky K, Dennis K, Vedell P, Churchill GA, Redei EE (2012) Discovery of blood transcriptomic markers for depression in animal models and pilot validation in subjects with early-onset major depression. Transl Psychiatry 2:e101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Panksepp J (1998) Affective neuroscience: the foundations of human and animal emotions. Oxford University Press

  • Panksepp J (2017) The psycho-neurology of cross-species affective/social neuroscience: understanding animal affective states as a guide to development of novel psychiatric treatments. Curr Top Behav Neurosci 30:109–125

    Article  PubMed  Google Scholar 

  • Platt JE, Stone EA (1982) Chronic restraint elicits a positive antidepressant response on the forced swim test. Eur J Pharmacol 82:179–181

    Article  CAS  PubMed  Google Scholar 

  • Porsolt RD, Le Pichom M, Jalfre M (1977) Depression: a new animal model sensitive to antidepressant treatments. Nature 266:730–732

    Article  CAS  PubMed  Google Scholar 

  • Porsolt RD, Anton G, Blavet N, Jalfre M (1978) Behavioural despair in rats: a new model sensitive to antidepressant treatments. Eur J Pharmacol 47:379–391

    Article  CAS  PubMed  Google Scholar 

  • Rajkumar R, Dawe GS (2018) Obscure but not obsolete: perturbations of the frontal cortex in common between rodent olfactory bulbectomy model and major depression. J Chem Neuroanat 91:63–100

    Article  PubMed  Google Scholar 

  • Redish AD, Kummerfeld E, Morries RL, Love AC (2018) Reproducibility failures are essential to scientific inquiry. Proc Natl Acad Sci U S A 115:5042–5046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rincón-Cortés M, Grace AA (2017) Sex-dependent effects of stress on immobility behavior and VTA dopamine neuron activity: modulation by ketamine. Int J Neuropsychopharmacol 20:823–832

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ritchie SJ, Cox SR, Shen X, Lombardo MV, Reus LM, Alloza C, Harris MA, Alderson HL, Hunter S, Neilson E, Liewald DCM, Auyeung B, Whalley HC, Lawrie SM, Gale CR, Bastin ME, McIntosh AM, Deary IJ (2018) Sex differences in the adult human brain: evidence from 5216 UK biobank participants. Cereb Cortex 28:2959–2975

    Article  PubMed  PubMed Central  Google Scholar 

  • Robinson ESJ (2018) Translational new approaches for investigating mood disorders in rodents and what they may reveal about the underlying neurobiology of major depressive disorder. Philos Trans R Soc Lond Ser B Biol Sci 373(1742). https://doi.org/10.1098/rstb.2017.0036

  • Rummel J, Voget M, Hadar R, Ewing S, Sohr R, Klein J, Sartorius A, Heinz A, Mathé AA, Vollmayr B, Winter C (2016) Testing different paradigms to optimize antidepressant deep brain stimulation in different rat models of depression. J Psychiatr Res 81:36–45

    Article  PubMed  Google Scholar 

  • Sakata JT, Crews D, Gonzalez-Lima F (2005) Behavioral correlates of differences in neural metabolic capacity. Brain Res Rev 48:1–15

    Article  PubMed  Google Scholar 

  • Salamone JD, Correa M, Yang JH, Rotolo R, Presby R (2018) Dopamine, effort-based choice, and behavioral economics: basic and translational research. Front Behav Neurosci 12:52

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sanchez C, El Khoury A, Hassan M, Wegener G, Mathé AA (2018) Sex-dependent behavior, neuropeptide profile and antidepressant response in rat model of depression. Behav Brain Res in press

  • Sapolsky RM (2016) Psychiatric distress in animals versus animal models of psychiatric distress. Nat Neurosci 19:1387–1389

    Article  CAS  PubMed  Google Scholar 

  • Seney ML, Huo Z, Cahill K, French L, Puralewski R, Zhang J, Logan RW, Tseng G, Lewis DA, Sibille E (2018) Opposite molecular signatures of depression in men and women. Biol Psychiatry 84:18–27

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shansky RM (2018) Sex differences in behavioral strategies: avoiding interpretational pitfalls. Curr Opin Neurobiol 49:95–98

    Article  CAS  PubMed  Google Scholar 

  • Sild M, Ruthazer ES, Booij L (2017) Major depressive disorder and anxiety disorders from the glial perspective: etiological mechanisms, intervention and monitoring. Neurosci Biobehav Rev 83:474–488

    Article  PubMed  Google Scholar 

  • Slattery DA, Cryan JF (2014) The ups and downs of modelling mood disorders in rodents. ILAR J 55:297–309

    Article  CAS  PubMed  Google Scholar 

  • Slattery DA, Cryan JF (2017) Modelling depression in animals: at the interface of reward and stress pathways. Psychopharmacology 234:1451–1465

    Article  CAS  PubMed  Google Scholar 

  • Slattery DA, Hudson AL, Nutt DJ (2004) Invited review: the evolution of antidepressant mechanisms. Fundam Clin Pharmacol 18:1–21

    Article  CAS  PubMed  Google Scholar 

  • Söderlund J, Lindskog M (2018) Relevance of rodent models of depression in clinical practice: can we overcome the obstacles in translational neuropsychiatry? Int J Neuropsychopharmacol 21:668–676

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stanford SC (2017) Confusing preclinical (predictive) drug screens with animal ‘models’ of psychiatric disorders, or ‘disorder-like’ behavior, is undermining confidence in behavioural neuroscience. J Psychopharmacol 31:641–643

    Article  CAS  PubMed  Google Scholar 

  • Steinman MQ, Trainor BC (2017) Sex differences in the effects of social defeat on brain and behavior in the California mouse: insights from a monogamous rodent. Semin Cell Dev Biol 61:92–98

    Article  PubMed  Google Scholar 

  • Sun H, Kennedy PJ, Nestler EJ (2013) Epigenetics of the depressed brain: role of histone acetylation and methylation. Neuropsychopharmacology 38:124–137

    Article  CAS  PubMed  Google Scholar 

  • Theilmann W, Kleimann A, Rhein M, Bleich S, Frieling H, Löscher W, Brandt C (2016) Behavioral differences of male Wistar rats from different vendors in vulnerability and resilience to chronic mild stress are reflected in epigenetic regulation and expression of p11. Brain Res 1642:505–515

    Article  CAS  PubMed  Google Scholar 

  • Tõnissaar M, Mällo T, Eller M, Häidkind R, Kõiv K, Harro J (2008) Rat behavior after chronic variable stress and partial lesioning of 5-HT-ergic neurotransmission: effects of citalopram. Prog Neuro-Psychopharmacol Biol Psychiatry 32:164–177

    Article  CAS  Google Scholar 

  • Tye KM, Mirzabekov JJ, Warden MR, Ferenczi EA, Tsai H-C, Finkelstein J, Kim S-Y, Adhikari A, Thompson KR, Andalman AS, Gunaydin LA, Witten IB, Deisseroth K (2013) Dopamine neurons modulate neural encoding and expression of depression-related behaviour. Nature 493:537–541

    Article  CAS  PubMed  Google Scholar 

  • van Dijken HH, Mos J, van der Heyden JA, Tilders FJ (1992) Characterization of stress-induced long-term behavioural changes in rats: evidence in favor of anxiety. Physiol Behav 52:945–951

    Article  PubMed  Google Scholar 

  • van Riezen H, Schnieden H, Wren A (1977) Olfactory bulb ablation in the rat: behavioural changes and their reversal by antidepressant drugs. Br J Pharmacol 60:521–528

    Article  PubMed  PubMed Central  Google Scholar 

  • Vollmayr B, Gass P (2013) Learned helplessness: unique features and translational value of a cognitive depression model. Cell Tissue Res 354:171–178

    Article  PubMed  Google Scholar 

  • Wang Q, Jie W, Liu J-H, Yang J-M, Gao T-M (2017a) An astroglial basis of major depressive disorder? An overview. Glia 65:1227–1250

    Article  PubMed  Google Scholar 

  • Wang Q, Timberlake MA II, Prall K, Dwiwedi Y (2017b) The recent progress in animal models of depression. Prog Neuro-Psychopharmacol Biol Pschiatry 77:99–109

    Article  Google Scholar 

  • Weiss JM, Kilts CD (1998) Animal models of depression and schizophrenia. In: Schatzberg AF, Nemeroff CB (eds) Textbook of psychopharmacology, 2nd edn. American Psychiatric Press, Washington, DC

    Google Scholar 

  • WHO Report by the secretariat (2011) Global burden of mental disorders and the need for a comprehensive, coordinated response from health and social sectors at the country level. Executive board EB 130/9 (130th session, Provisional agenda item 6.2)

  • Wiborg O (2013) Chronic mild stress for modeling anhedonia. Cell Tissue Res 354:155–169

    Article  PubMed  Google Scholar 

  • Wierenga LM, Sexton JA, Laake P, Giedd JN, Tamnes CK (2018) A key characteristic of sex differences in the developing brain: greater variability in brain structure of boys than girls. Cereb Cortex 28:2741–2751

    Article  PubMed  Google Scholar 

  • Williams M (2011) Productivity shortfalls in drug discovery: contributions from the preclinical sciences? J Pharmacol Exp Ther 336:3–8

    Article  CAS  PubMed  Google Scholar 

  • Willner P (1984) The validity of animal models of depression. Psychopharmacology 83:1–16

    Article  CAS  PubMed  Google Scholar 

  • Willner P (2017) The chronic mild stress (CMS) model of depression: history, evaluation and usage. Neurobiol Stress 6:78–93

    Article  PubMed  Google Scholar 

  • Willner P, Belzung C (2015) Treatment-resistant depression: are animal models of depression fit for purpose? Psychopharmacology 232:3473–3495

    Article  CAS  PubMed  Google Scholar 

  • Willner P, Mitchell PJ (2002) The validity of animal models of predisposition to depression. Behav Pharmacol 13:169–188

    Article  CAS  PubMed  Google Scholar 

  • Wittchen HU, Jacobi F, Rehm J, Gustavsson A, Svensson M, Jönsson B, Olesen J, Allgulander C, Alonso J, Faravelli C, Fratiglioni L, Jennum P, Lieb R, Maercker A, van Os J, Preisig M, Salvador -Carulla L, Simon R, Steinhausen H-C (2011) The size and burden of mental disorders and other disorders of the brain in Europe 2010. Eur Neuropsychopharmacol 21:655–679

    Article  CAS  PubMed  Google Scholar 

  • Wurtman RJ, Wurtman JJ (1995) Brain serotonin, carbohydrate-craving, obesity and depression. Obes Res 4:477S–480S

    Article  Google Scholar 

  • Yin X, Guven N, Dietis N (2016) Stress-based animal models of depression: do we actually know what we are doing? Brain Res 1652:30–42

    Article  CAS  PubMed  Google Scholar 

  • Yuan H, Mischoulon D, Fava M, Otto MW (2018) Circulating microRNAs as biomarkers for depression: many candidates, few finalists. J Affect Disord 233:68–78

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Relevant research by the author was supported by the Estonian Ministry of Education and Research project IUT20-40, the Hope for Depression Research Foundation, Institute for the Study of Affective Neuroscience and the EU Framework 6 Integrated Project NEWMOOD (LSHM-CT-2004-503474).

Author information

Authors and Affiliations

  1. Division of Neuropsychopharmacology, Department of Psychology, Estonian Centre of Behavioural and Health Sciences, University of Tartu, Ravila 14A Chemicum, 50411, Tartu, Estonia

    Jaanus Harro

Authors
  1. Jaanus Harro
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jaanus Harro.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Harro, J. Animal models of depression: pros and cons. Cell Tissue Res 377, 5–20 (2019). https://doi.org/10.1007/s00441-018-2973-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00441-018-2973-0

Keywords

Search

Navigation