Skip to main content
SpringerLink
Log in

Animal Models of Stress Vulnerability and Resilience in Translational Research

  • GENETIC DISORDERS (JF CUBELLS AND EB BINDER, SECTION EDITORS)
  • Published:
Current Psychiatry Reports Aims and scope Submit manuscript

Abstract

Stress has been identified as a key risk factor for a multitude of human pathologies. However, stress by itself is often not sufficient to induce a disease, as a large contribution comes from an individual’s genetic background. Therefore, many stress models have been created to investigate this so-called gene–environment interaction for different diseases. Recently, evidence has been accumulating to indicate that not only the exposure to stress, but also the vulnerability to such an exposure can have a significant impact on the development of disease. Herein we review recent animal models of stress vulnerability and resilience, with special attention devoted to the readout parameters and the potential for translatability of the results.

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

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as:• Of importance

  1. • Joels M, Baram TZ. The neuro-symphony of stress. Nat Rev Neurosci. 2009;10:459–66. This excellent review illustrates the complexity of the stress response.

    PubMed  CAS  Google Scholar 

  2. Dayas CV, Buller KM, Crane JW, et al. Stressor categorization: acute physical and psychological stressors elicit distinctive recruitment patterns in the amygdala and in medullary noradrenergic cell groups. Eur J Neurosci. 2001;14:1143–52.

    Article  PubMed  CAS  Google Scholar 

  3. Pacak K, Palkovits Ms. Stressor specificity of central neuroendocrine responses: implications for stress-related disorders. Endocr Rev. 2001;22:502–48.

    Article  PubMed  CAS  Google Scholar 

  4. Koolhaas JM, Bartolomucci A, Buwalda B, et al. Stress revisited: a critical evaluation of the stress concept. Neurosci Biobehav Rev. 2011;35:1291–301.

    Article  PubMed  CAS  Google Scholar 

  5. McEwen BS. Physiology and neurobiology of stress and adaptation: central role of the brain. Physiol Rev. 2007;87:873–904.

    Article  PubMed  Google Scholar 

  6. McEwen BS. Stress, Adaptation, and disease: allostasis and allostatic load. Ann N Y Acad Sci. 1998;840:33–44.

    Article  PubMed  CAS  Google Scholar 

  7. Rosengren A, Hawken S, Ounpuu S, et al. Association of psychosocial risk factors with risk of acute myocardial infarction in 11119 cases and 13648 controls from 52 countries (the INTERHEART study): case-control study. The Lancet. 2004;364:953–62.

    Article  Google Scholar 

  8. Abraham NG, Brunner EJ, Eriksson JW, Robertson RP. Metabolic syndrome: psychosocial, neuroendocrine, and classical risk factors in type 2 diabetes. Ann N Y Acad Sci. 2007;1113:256–75.

    Article  PubMed  CAS  Google Scholar 

  9. Charney DS, Manji HK. Life stress, genes, and depression: multiple pathways lead to increased risk and new opportunities for intervention. Sci STKE. 2004;2004:re5.

    Article  PubMed  Google Scholar 

  10. de Kloet ER, Joels M, Holsboer F. Stress and the brain: from adaption to disease. Nat Rev Neurosci. 2005;6:463–75.

    Article  PubMed  Google Scholar 

  11. Kendler KS. Genetic epidemiology in psychiatry: taking both genes and environment seriously. Arch Gen Psychiatry. 1995;52:895–9.

    Article  PubMed  CAS  Google Scholar 

  12. Cichon S, Craddock N, Daly M, et al. Genomewide association studies: history, rationale, and prospects for psychiatric disorders. Am J Psychiatry. 2009;166:540–56.

    Article  PubMed  Google Scholar 

  13. Binder EB, Bradley RG, Liu W, et al. Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults. JAMA. 2008;299:1291–305.

    Article  PubMed  CAS  Google Scholar 

  14. Kohli MA, Salyakina D, Pfennig A, et al. Association of genetic variants in the neurotrophic receptor-encoding gene NTRK2 and a lifetime history of suicide attempts in depressed patients. Arch Gen Psychiatry. 2010;67:348–59.

    Article  PubMed  CAS  Google Scholar 

  15. Green EK, Grozeva D, Jones I, et al. The bipolar disorder risk allele at CACNA1C also confers risk of recurrent major depression and of schizophrenia. Mol Psychiatry. 2010;15:1016–22.

    Article  PubMed  CAS  Google Scholar 

  16. McMahon FJ, Akula N, Schulze TG, et al. Meta-analysis of genome-wide association data identifies a risk locus for major mood disorders on 3p21.1. Nat Genet. 2010;42:128–31.

    Article  PubMed  CAS  Google Scholar 

  17. Demirkan A, Penninx BWJH, Hek K, et al. Genetic risk profiles for depression and anxiety in adult and elderly cohorts. Mol Psychiatry. 2011;16:773–83.

    Article  PubMed  CAS  Google Scholar 

  18. • Ising M, Lucae S, Binder EB, et al. A genomewide association study points to multiple loci that predict antidepressant drug treatment outcome in depression. Arch Gen Psychiatry. 2009;66:966–75. This study nicely showed that multiple, not single genes are involved in depression-related characteristics.

    Article  PubMed  CAS  Google Scholar 

  19. Nederhoff E, Schmidt MV. Mismatch or cumulative stress: towards an integrated hypothesis of programming effects. Physiol Behav. 2012; doi:10.1016/j.physbeh.2011.12.008.

  20. Schmidt MV. Animal models for depression and the mismatch hypothesis of disease. Psychoneuroendocrinology. 2011;36:330–8.

    Article  PubMed  Google Scholar 

  21. Veenema AH, Reber SO, Selch S, et al. Early life stress enhances the vulnerability to chronic psychosocial stress and experimental colitis in adult mice. Endocrinology. 2008;149:2727–36.

    Article  PubMed  CAS  Google Scholar 

  22. Uchida S, Hara K, Kobayashi A, et al. Early life stress enhances behavioral vulnerability to stress through the activation of REST4-mediated gene transcription in the medial prefrontal cortex of rodents. The Journal of Neuroscience. 2010;30:15007–18.

    Article  PubMed  CAS  Google Scholar 

  23. Bilbo SD, Yirmiya R, Amat J, et al. Bacterial infection early in life protects against stressor-induced depressive-like symptoms in adult rats. Psychoneuroendocrinology. 2008;33:261–9.

    Article  PubMed  Google Scholar 

  24. Champagne DL, Bagot RC, van Hasselt F, et al. Maternal care and hippocampal plasticity: evidence for experience-dependent structural plasticity, altered synaptic functioning, and differential responsiveness to glucocorticoids and stress. Int J Neurosci. 2008;28:6037–45.

    Article  CAS  Google Scholar 

  25. Schmidt MV, Scharf SH, Sterlemann V, et al. High susceptibility to chronic social stress is associated with a depression-like phenotype. Psychoneuroendocrinology. 2010;35:635–43.

    Article  PubMed  CAS  Google Scholar 

  26. Stedenfeld KA, Clinton SM, Kerman IA, et al. Novelty-seeking behavior predicts vulnerability in a rodent model of depression. Physiol Behav. 2011;103:210–6.

    Article  PubMed  CAS  Google Scholar 

  27. Pryce CR, Seifritz E. A translational research framework for enhanced validity of mouse models of psychopathological states in depression. Psychoneuroendocrinology. 2011;36:308–29.

    Article  PubMed  Google Scholar 

  28. Porsolt RD, Le Pichon M, Jalfre M. Depression: a new animal model sensitive to antidepressant treatments. Nature. 1977;266:730–2.

    Article  PubMed  CAS  Google Scholar 

  29. Pollak DD, Rey CE, Monje FJ. Rodent models in depression research: classical strategies and new directions. Ann Med. 2010;42:252–64.

    Article  PubMed  Google Scholar 

  30. Bächli H, Steiner MA, Habersetzer U, Wotjak CT. Increased water temperature renders single-housed C57BL/6 J mice susceptible to antidepressant treatment in the forced swim test. Behav Brain Res. 2008;187:67–71.

    Article  PubMed  Google Scholar 

  31. West AP. Neurobehavioral studies of forced swimming: the role of learning and memory in the forced swim test. Prog Neuropsychopharmacol Biol Psychiatry. 1990;14:863–77.

    Article  PubMed  CAS  Google Scholar 

  32. Sun P, Wang F, Wang L, et al. Increase in cortical pyramidal cell excitability accompanies depression-like behavior in mice: a transcranial magnetic stimulation study. J Neurosci. 2011;31:16464–72.

    Article  PubMed  CAS  Google Scholar 

  33. Lesch KP. When the serotonin transporter gene meets adversity: the contribution of animal models to understanding epigenetic mechanisms in affective disorders and resilience. In: Hagan JJ, editor. Molecular and functional models in neuropsychiatry. Berlin Heidelberg: Springer; 2011. p. 251–80.

    Chapter  Google Scholar 

  34. Wagner KV, Wang XD, Liebl C, et al. Pituitary glucocorticoid receptor deletion reduces vulnerability to chronic stress. Psychoneuroendocrinology. 2011;36:579–87.

    Article  PubMed  CAS  Google Scholar 

  35. Hartmann J, Wagner KV, Liebl C, et al. The involvement of FK506-binding protein 51 (FKBP5) in the behavioral and neuroendocrine effects of chronic social defeat stress. Neuropharmacology. 2012;62:332–9.

    Article  PubMed  CAS  Google Scholar 

  36. O’Leary III JC, Dharia S, Blair LJ, et al. A new anti-depressive strategy for the elderly: ablation of FKBP5/FKBP51. PLoS One. 2011;6:e24840.

    Article  PubMed  Google Scholar 

  37. Sanacora G, Treccani G, Popoli M. Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders. Neuropharmacology. 2012;62:63–77.

    Article  PubMed  CAS  Google Scholar 

  38. Garcia-Garcia AL, Elizalde N, Matrov D, et al. Increased vulnerability to depressive-like behavior of mice with decreased expression of VGLUT1. Biol Psychiatry. 2009;66:275–82.

    Article  PubMed  CAS  Google Scholar 

  39. Bisaz R, Sandi C. Vulnerability of conditional NCAM-deficient mice to develop stress-induced behavioral alterations. Stress. 2012; doi:10.3109/10253890.2011.608226.

  40. • Refojo D, Schweizer M, Kuehne C, et al. Glutamatergic and dopaminergic neurons mediate anxiogenic and anxiolytic effects of CRHR1. Science. 2011;333:1903–7. Using state-of-the-art genetic approaches, this paper demonstrated that single genes can have very different functions in different brain regions or cell types.

    Article  PubMed  CAS  Google Scholar 

  41. Lupien SJ, McEwen BS, Gunnar MR, Heim C. Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nat Rev Neurosci. 2009;10:434–45.

    Article  PubMed  CAS  Google Scholar 

  42. Andersson K, Winer L, Mork H, et al. Tamoxifen administration routes and dosage for inducible Cre-mediated gene disruption in mouse hearts. Transgenic Res. 2010;19:715–25.

    Article  PubMed  CAS  Google Scholar 

  43. Bergström A, Jayatissa MN, Mork A, Wiborg O. Stress sensitivity and resilience in the chronic mild stress rat model of depression; an in situ hybridization study. Brain Res. 2008;1196:41–52.

    Article  PubMed  Google Scholar 

  44. Bergström A, Jayatissa M, Thykjaer T, Wiborg O. Molecular pathways associated with stress resilience and drug resistance in the chronic mild stress rat model of depression—a gene expression study. J Mol Neurosci. 2007;33:201–15.

    Article  PubMed  Google Scholar 

  45. Christensen T, Bisgaard CF, Wiborg O. Biomarkers of anhedonic-like behavior, antidepressant drug refraction, and stress resilience in a rat model of depression. Neuroscience. 2011;196:66–79.

    Article  PubMed  CAS  Google Scholar 

  46. Palacios R, Campo A, Henningsen K, et al. Magnetic resonance imaging and spectroscopy reveal differential hippocampal changes in anhedonic and resilient subtypes of the chronic mild stress rat model. Biol Psychiatry. 2011;70:449–57.

    Article  Google Scholar 

  47. • Schmidt MV, Trümbach D, Weber P, et al. Individual stress vulnerability is predicted by short-term memory and AMPA receptor subunit ratio in the hippocampus. J Neurosci. 2010;30:16949–58. This paper identified a genetic polymorphism in the AMPA subunit GluR1 gene that is causally linked to differences in stress vulnerability.

    Article  PubMed  CAS  Google Scholar 

  48. Vialou V, Maze I, Renthal W, et al. Serum response factor promotes resilience to chronic social stress through the induction of [delta]öFosB. J Neurosci. 2010;30:14585–92.

    Article  PubMed  CAS  Google Scholar 

  49. • Vialou V, Robison AJ, LaPlant QC, et al. [Delta]FosB in brain reward circuits mediates resilience to stress and antidepressant responses. Nat Neurosci. 2010;13:745–52. This study nicely demonstrated the use of multiple techniques and approaches to achieve robust results.

    Article  PubMed  CAS  Google Scholar 

  50. Berton O, McClung CA, DiLeone RJ, et al. Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science. 2006;311:864–8.

    Article  PubMed  CAS  Google Scholar 

  51. Krishnan V, Han MH, Mazei-Robison M, et al. AKT Signaling within the ventral tegmental area regulates cellular and behavioral responses to stressful stimuli. Biol Psychiatr. 2008;64:691–700.

    Article  CAS  Google Scholar 

  52. Krishnan V, Han MH, Graham DL, et al. Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell. 2007;131:391–404.

    Article  PubMed  CAS  Google Scholar 

  53. Cao JL, Covington HE, Friedman AK, et al. Mesolimbic dopamine neurons in the brain reward circuit mediate susceptibility to social defeat and antidepressant action. J Neurosci. 2010;30:16453–8.

    Article  PubMed  CAS  Google Scholar 

  54. Touma C, Bunck M, Glasl L, et al. Mice selected for high versus low stress reactivity: a new animal model for affective disorders. Psychoneuroendocrinology. 2008;33:839–62.

    Article  PubMed  CAS  Google Scholar 

  55. Fenzl T, Touma C, Romanowski C, et al. Sleep disturbances in highly stress reactive mice: modeling endophenotypes of major depression. BMC Neuroscience. 2011;12:29.

    Article  PubMed  Google Scholar 

  56. Knapman A, Heinzmann JM, Holsboer F, et al. Modeling psychotic and cognitive symptoms of affective disorders: disrupted latent inhibition and reversal learning deficits in highly stress reactive mice. Neurobiol Learn Mem. 2010;94:145–52.

    Article  PubMed  CAS  Google Scholar 

  57. Knapman A, Heinzmann JM, Hellweg R, et al. Increased stress reactivity is associated with cognitive deficits and decreased hippocampal brain-derived neurotrophic factor in a mouse model of affective disorders. J Psychiatr Res. 2010;44:566–75.

    Article  PubMed  CAS  Google Scholar 

  58. Bunck M, Czibere L, Horvath C, et al. A hypomorphic vasopressin allele prevents anxiety-related behavior. PLoS One. 2009;4:e5129.

    Article  PubMed  Google Scholar 

Download references

Disclosure

No potential conflicts of interest relevant to this article were reported.

Author information

Authors and Affiliations

  1. Max Planck Institute of Psychiatry, Kraepelinstr. 2, 80804, Munich, Germany

    Sebastian H. Scharf

  2. Max Planck Institute of Psychiatry, Research Group Neurobiology of Stress, Kraepelinstr. 2-10, 80804, Munich, Germany

    Mathias V. Schmidt

Authors
  1. Sebastian H. Scharf
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mathias V. Schmidt
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mathias V. Schmidt.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Scharf, S.H., Schmidt, M.V. Animal Models of Stress Vulnerability and Resilience in Translational Research. Curr Psychiatry Rep 14, 159–165 (2012). https://doi.org/10.1007/s11920-012-0256-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11920-012-0256-0

Keywords

Search

Navigation