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Molecular Neurobiology

, Volume 56, Issue 12, pp 8524–8536 | Cite as

A Novel Animal Model for Studying Depression Featuring the Induction of the Unfolded Protein Response in Hippocampus

  • Matthew Timberlake II
  • Bhaskar Roy
  • Yogesh DwivediEmail author
Article

Abstract

Depression is the leading cause of disability worldwide with global distribution of 322 million people suffering from the disease. While much is understood about depression, the underlying pathophysiology is yet to be fully characterized. Recently, the unfolded protein response (UPR) has been shown to be involved in regulating key aspects like inflammation, cell death, and behavioral depression. The UPR is an evolutionarily conserved ancient response system that reacts to the stressful environmental impact on a cell; the net effect of stress to a cell is that the quality of protein folding is diminished. The UPR responds by repairing and removing misfolded proteins and, if necessary, initiates apoptosis. Here, we demonstrate that the UPR is not only involved in depression, but that its activation causes a depressive phenotype. The hippocampi of rats were directly infused with 500 ng of tunicamycin (TM), an agent that initiates the UPR by blocking N-terminal glycosylation. Three to 8 days post-surgery, the rats showed depressive behavior in escape latency, forced swim despair, sucrose preference anhedonia, and also physiological signs of depression like decreased weight. Further, these behavioral changes were associated with enhanced expression of key UPR genes and proteins in the hippocampus. We propose that this model will make an excellent tool for studying depression and for understanding pathways that are affected by the UPR which directly causes depressive behavior.

Keywords

Unfolded protein response Depression Tunicamycin Inflammation 

Notes

Acknowledgments

We would like to acknowledge Kevin Prall for technical help.

Sources of Funding

The research was partly supported by grants from National Institute of Mental Health (R01MH082802; 1R01MH101890; R01MH100616; 1R01MH107183) to Dr. Dwivedi.

Compliance with Ethical Standards

All the experiments were carried out according to the National Institutes of Health (NIH) guide for the care and use of laboratory animals and were approved by the Animal Care Committee (IACUC) of the University of Alabama at Birmingham.

Conflict of Interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Belmaker RH, Agam G (2008) Major depressive disorder. N Engl J Med 358(1):55–68.  https://doi.org/10.1056/NEJMra073096 CrossRefPubMedGoogle Scholar
  2. 2.
    Albert PR (2015) Why is depression more prevalent in women. J Psychiatry Neurosci 40(4):219–221CrossRefGoogle Scholar
  3. 3.
    Organization WH (2018) Depression.Google Scholar
  4. 4.
    Pompili M, Venturini P, Lamis DA, Giordano G, Serafini G, Belvederi Murri M, Amore M, Girardi P (2015) Suicide in stroke survivors: epidemiology and prevention. Drugs Aging 32(1):21–29.  https://doi.org/10.1007/s40266-014-0233-x CrossRefPubMedGoogle Scholar
  5. 5.
    Kaufman RJ (2002) Orchestrating the unfolded protein response in health and disease. J Clin Invest 110(10):1389–1398.  https://doi.org/10.1172/jci16886 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Ron D (2002) Translational control in the endoplasmic reticulum stress response. J Clin Invest 110(10):1383–1388.  https://doi.org/10.1172/jci16784 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Garg AD, Kaczmarek A, Krysko O, Vandenabeele P, Krysko DV, Agostinis aP (2012) ER stress-induced inflammation: does it aid or impede disease progression? Trends Mol Med 18(10):589–598CrossRefGoogle Scholar
  8. 8.
    Lee AH, Iwakoshi NN, Glimcher LH (2003) XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Mol Cell Biol 23(21):7448–7459CrossRefGoogle Scholar
  9. 9.
    Hotamisligil GS (2010) Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell 140(6):900–917.  https://doi.org/10.1016/j.cell.2010.02.034 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Yamazaki H, Hiramatsu N, Hayakawa K, Tagawa Y, Okamura M, Ogata R, Huang T, Nakajima S et al (2009) Activation of the Akt-NF-kappaB pathway by subtilase cytotoxin through the ATF6 branch of the unfolded protein response. J Immunol (Baltimore, Md : 1950) 183(2):1480–1487.  https://doi.org/10.4049/jimmunol.0900017 CrossRefGoogle Scholar
  11. 11.
    Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, Tuncman G, Gorgun C et al (2004) Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science (New York, NY) 306(5695):457–461.  https://doi.org/10.1126/science.1103160 CrossRefGoogle Scholar
  12. 12.
    Timberlake MI, Prall K, Roy B, Dwivedi Y (2018) Unfolded protein response and associated alterations in toll-like receptor expression and interaction in the hippocampus of restraint rats. Psychoneuroendocrinology 89:185–193.  https://doi.org/10.1016/j.psyneuen.2018.01.017 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Timberlake M II, Dwivedi Y (2018) Linking unfolded protein response to inflammation and depression: potential pathologic and therapeutic implications. Mol Psychiatry 24:987–994.  https://doi.org/10.1038/s41380-018-0241-z CrossRefGoogle Scholar
  14. 14.
    Hung Y-Y, Kang H-Y, Huang K-W, Huang T-L (2014) Association between toll-like receptors expression and major depressive disorder. Psychiatry Res 220:283–286CrossRefGoogle Scholar
  15. 15.
    Pandey GN, HS R XR, Dwivedi Y (2014) Toll-like receptors in the depressed and suicide brain. J Psychiatr Res 53:62–68CrossRefGoogle Scholar
  16. 16.
    Szegezdi E, Fitzgerald U, Samali A (2003) Caspase-12 and ER-stress-mediated apoptosis: the story so far. Ann NY Acad Sci:186–194 Google Scholar
  17. 17.
    Yamaguchi H, Wang HG (2004) CHOP is involved in endoplasmic reticulum stress-induced apoptosis by enhancing DR5 expression in human carcinoma cells. J Biol Chem 279(44):45495–45502.  https://doi.org/10.1074/jbc.M406933200
  18. 18.
    Endo M, Mori M, Akira S, Gotoh T (2006) C/EBP homologous protein (CHOP) is crucial for the induction of caspase-11 and the pathogenesis of lipopolysaccharide-induced inflammation. J Immunol (Baltimore, Md : 1950) 176(10):6245–6253CrossRefGoogle Scholar
  19. 19.
    Meares GP, Mines MA, Beurel E, Eom TY, Song L, Zmijewska AA, Jope RS (2011) Glycogen synthase kinase-3 regulates endoplasmic reticulum (ER) stress-induced CHOP expression in neuronal cells. Exp Cell Res 317(11):1621–1628.  https://doi.org/10.1016/j.yexcr.2011.02.012 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Zhang Y, Liu W, Zhou Y, Ma C, Li S, Cong B (2014) Endoplasmic reticulum stress is involved in restraint stress-induced hippocampal apoptosis and cognitive impairments in rats. Physiol Behav 131:41–48.  https://doi.org/10.1016/j.physbeh.2014.04.014 CrossRefPubMedGoogle Scholar
  21. 21.
    Timberlake M, II, , Dwivedi Y (2015) Altered expression of endoplasmic reticulum stress associated genes in Hippocampus of learned helpless rats: relevance to depression pathophysiology. Front Pharmacol 6:319. doi: https://doi.org/10.3389/fphar.2015.00319 CrossRefPubMedGoogle Scholar
  22. 22.
    Eilat E, Mendlovic S, Doron A, Zakuth V, Spirer Z (1999) Increased apoptosis in patients with major depression: a preliminary study. J Immunol 163(1):533–534PubMedGoogle Scholar
  23. 23.
    Fossati P, Radtchenko A, Boyer P (2004) Neuroplasticity: from MRI to depressive symptoms. Eur Neuropsychopharmacol 14(Suppl 5):S503–S510.  https://doi.org/10.1016/j.euroneuro.2004.09.001 CrossRefPubMedGoogle Scholar
  24. 24.
    Dwivedi Y (2009) Brain-derived neurotrophic factor: role in depression and suicide. Neuropsychiatr Dis Treat 5:433–449CrossRefGoogle Scholar
  25. 25.
    McKernan DP, TGD JFC (2009) “Killing the blues”: a role for cellular suicide (apoptosis) in depression and the antidepressant response? Prog Neurobiol 88(4):246–263CrossRefGoogle Scholar
  26. 26.
    Gold PW, Licinio J, Pavlatou MG (2013) Pathological parainflammation and endoplasmic reticulum stress in depression: potential translational targets through the CNS insulin, klotho and PPAR-gamma systems. Mol Psychiatry 18(2):154–165.  https://doi.org/10.1038/mp.2012.167 CrossRefPubMedGoogle Scholar
  27. 27.
    Yanxiao Xiang HY, Zhou J, Zhang Q, Hanley G, Caudle Y, LeSage G, Zhang X, Yin D (2015) The role of toll-like receptor 9 in chronic stress-induced apoptosis in macrophage. PLoS One 10(4):1–14Google Scholar
  28. 28.
    Harding HP, Zhang Y, Zeng H, Novoa I, Lu PD, Calfon M, Sadri N, Yun C et al (2003) An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell 11(3):619–633CrossRefGoogle Scholar
  29. 29.
    Fribley A, Zhang K, Kaufman RJ (2009) Regulation of apoptosis by the unfolded protein response. Methods Mol Biol (Clifton, NJ) 559:191–204.  https://doi.org/10.1007/978-1-60327-017-5_14 CrossRefGoogle Scholar
  30. 30.
    McCullough KD, Martindale JL, Klotz LO, Aw TY, Holbrook NJ (2001) Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state. Mol Cell Biol 21(4):1249–1259.  https://doi.org/10.1128/mcb.21.4.1249-1259.2001 CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    McEwen BS (2000) Effects of adverse experiences for brain structure and function. Biol Psychiatry 48(8):721–731CrossRefGoogle Scholar
  32. 32.
    Sala M, Perez J, Soloff P, Ucelli di Nemi S, Caverzasi E, Soares JC, Brambilla P (2004) Stress and hippocampal abnormalities in psychiatric disorders. Eur Neuropsychopharmacol 14(5):393–405.  https://doi.org/10.1016/j.euroneuro.2003.12.005 CrossRefPubMedGoogle Scholar
  33. 33.
    Frodl T, Schaub A, Banac S, Charypar M, Jager M, Kummler P, Bottlender R, Zetzsche T et al (2006) Reduced hippocampal volume correlates with executive dysfunctioning in major depression. J Psychiatry Neurosci 31(5):316–323PubMedPubMedCentralGoogle Scholar
  34. 34.
    Nevell L, Zhang K, Aiello AE, Koenen K, Galea S, Soliven R, Zhang C, Wildman DE et al (2014) Elevated systemic expression of ER stress related genes is associated with stress-related mental disorders in the Detroit neighborhood health study. Psychoneuroendocrinology 43:62–70.  https://doi.org/10.1016/j.psyneuen.2014.01.013 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Mao QQ, Huang Z, Ip SP, Xian YF, Che CT (2012) Peony glycosides reverse the effects of corticosterone on behavior and brain BDNF expression in rats. Behav Brain Res 227(1):305–309.  https://doi.org/10.1016/j.bbr.2011.11.016 CrossRefPubMedGoogle Scholar
  36. 36.
    Pellow S, Chopin P, File SE, Briley M (1985) Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods 14(3):149–167CrossRefGoogle Scholar
  37. 37.
    Dwivedi Y, Mondal AC, Shukla PK, Rizavi HS, Lyons J (2004) Altered protein kinase a in brain of learned helpless rats: effects of acute and repeated stress. Biol Psychiatry 56(1):30–40.  https://doi.org/10.1016/j.biopsych.2004.03.018 CrossRefPubMedGoogle Scholar
  38. 38.
    O'Donovan S, Kennedy M, Guinan B, O'Mara S, McLoughlin DM (2012) A comparison of brief pulse and ultrabrief pulse electroconvulsive stimulation on rodent brain and behaviour. Prog Neuro-Psychopharmacol Biol Psychiatry 37(1):147–152.  https://doi.org/10.1016/j.pnpbp.2011.12.012 CrossRefGoogle Scholar
  39. 39.
    Hatcher JP, Jones DN, Rogers DC, Hatcher PD, Reavill C, Hagan JJ, Hunter AJ (2001) Development of SHIRPA to characterise the phenotype of gene-targeted mice. Behav Brain Res 125(1–2):43–47CrossRefGoogle Scholar
  40. 40.
    Rogers DC, Fisher EMC, Brown SDM, Peters J, Hunter AJ, Martin JE (1997) Behavioral and functional analysis of mouse phenotype: SHIRPA, a proposed protocol for comprehensive phenotype assessment. Mamm Genome 8(10):711–713.  https://doi.org/10.1007/s003359900551 CrossRefPubMedGoogle Scholar
  41. 41.
    Porsolt RD, Bertin A, Jalfre M (1977) Behavioral despair in mice: a primary screening test for antidepressants. Arch Int Pharmacodyn Ther 229(2):327–336PubMedGoogle Scholar
  42. 42.
    Wang Q, Timberlake M II, Prall K, Dwivedi Y (2017) The recent progress in animal models of depression. Prog Neuro-Psychopharmacol Biol Psychiatry 77:99–109.  https://doi.org/10.1016/j.pnpbp.2017.04.008 CrossRefGoogle Scholar
  43. 43.
    Klein DF (1974) Endogenomorphic depression. A conceptual and terminological revision. Arch Gen Psychiatry 31(4):447–454CrossRefGoogle Scholar
  44. 44.
    Lucassen PJ, Heine VM, Muller MB, van der Beek EM, Wiegant VM, De Kloet ER, Joels M, Fuchs E et al (2006) Stress, depression and hippocampal apoptosis. CNS Neurol Disord Drug Targets 5(5):531–546CrossRefGoogle Scholar
  45. 45.
    Lucassen PJ, Muller MB, Holsboer F, Bauer J, Holtrop A, Wouda J, Hoogendijk WJ, De Kloet ER et al (2001) Hippocampal apoptosis in major depression is a minor event and absent from subareas at risk for glucocorticoid overexposure. Am J Pathol 158(2):453–468.  https://doi.org/10.1016/S0002-9440(10)63988-0 CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Woo HI, Lim SW, Myung W, Kim DK, Lee SY (2018) Differentially expressed genes related to major depressive disorder and antidepressant response: genome-wide gene expression analysis. Exp Mol Med 50(8):92.  https://doi.org/10.1038/s12276-018-0123-0 CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Hemmi H, Kaisho T, Takeda K, Akira S (2003) The roles of toll-like receptor 9, MyD88, and DNA-dependent protein kinase catalytic subunit in the effects of two distinct CpG DNAs on dendritic cell subsets. J Immunol 170(6):3059–3064CrossRefGoogle Scholar
  48. 48.
    Lund J, Sato A, Akira S, Medzhitov R, Iwasaki A (2003) Toll-like receptor 9–mediated recognition of herpes simplex Virus-2 by plasmacytoid dendritic cells. J Exp Med 198(3):513–520CrossRefGoogle Scholar
  49. 49.
    Kai Zacharowski PAZ, Koch A, Baban A, Tran N, Berkels R, Papewalis C, Schulze-Osthoff K, Knuefermann P et al (2006) Toll-like receptor 4 plays a crucial role in the immune–adrenal response to systemic inflammatory response syndrome. PNAS 103(16):6392–6397CrossRefGoogle Scholar
  50. 50.
    Sher GTA (2007) Cooperation of toll-like receptor signals in innate immune defence. Nat Rev Immunol 7:179–190CrossRefGoogle Scholar
  51. 51.
    Yang Y, Liu B, Dai J, Srivastava PK, Zammit DJ, Lefrancois L, Li Z (2007) Heat shock protein gp96 is a master chaperone for toll-like receptors and is important in the innate function of macrophages. Immunity 26(2):215–226.  https://doi.org/10.1016/j.immuni.2006.12.005 CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Ungaro RFM, Hsu D, Hernandez Y, Breglio K, Chen A, Xu R, Sotolongo J, Espana C et al (2009) A novel toll-like receptor 4 antagonist antibody ameliorates inflammation but impairs mucosal healing in murine colitis. Am J Physiol Gastrointest Liver Physiol 296:1167–1179CrossRefGoogle Scholar
  53. 53.
    Kawasaki T, Kawai T (2014) Toll-like receptor signaling pathway. Front Immunol 5(461):1–8Google Scholar
  54. 54.
    Ming-Kung Wu T-LH, Huang K-W, Huang Y-L, Hung Y-Y (2015) Association between toll-like receptor 4 expression and symptoms of major depressive disorder. Neuropsychiatr Dis Treat 11:1853–1857PubMedPubMedCentralGoogle Scholar
  55. 55.
    Charles L, Raison LC, Miller AH (2006) Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol 27(1):24–31CrossRefGoogle Scholar
  56. 56.
    AH M, V M CLR (2009) Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry 65(9):732–741CrossRefGoogle Scholar
  57. 57.
    Lotrich F (2012) Inflammatory cytokines, growth factors, and depression. Curr Pharm Des 18(36):5920–5935CrossRefGoogle Scholar
  58. 58.
    Felger JC, Lotrich FE (2013) Inflammatory cytokines in depression: neurobiological mechanisms and therapeutic implications. Neuroscience 246:199–229.  https://doi.org/10.1016/j.neuroscience.2013.04.060 CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Joep Grootjans AK, Kaufman RJ, Blumberg RS (2016) The unfolded protein response in immunity and inflammation. Nat Rev Immunol 16:469–484CrossRefGoogle Scholar
  60. 60.
    Raison AHMCL (2016) The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol 16:22–34CrossRefGoogle Scholar
  61. 61.
    Setiawan E, Attwells S, Wilson AA, Mizrahi R, Rusjan PM, Miler L, Xu C, Sharma S et al (2018) Association of translocator protein total distribution volume with duration of untreated major depressive disorder: a cross-sectional study. Lancet Psychiatry 5(4):339–347.  https://doi.org/10.1016/s2215-0366(18)30048-8 CrossRefPubMedGoogle Scholar
  62. 62.
    Kaneko M, Niinuma Y, Nomura Y (2003) Activation signal of nuclear factor-kappa B in response to endoplasmic reticulum stress is transduced via IRE1 and tumor necrosis factor receptor-associated factor 2. Biol Pharm Bull 26(7):931–935CrossRefGoogle Scholar
  63. 63.
    Kim SY, Hwang JS, Han IO (2013) Tunicamycin inhibits Toll-like receptor-activated inflammation in RAW264.7 cells by suppression of NF-kappaB and c-Jun activity via a mechanism that is independent of ER-stress and N-glycosylation. Eur J Pharmacol 721(1–3):294–300.  https://doi.org/10.1016/j.ejphar.2013.09.022 CrossRefPubMedGoogle Scholar

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Authors and Affiliations

  1. 1.Department of Psychiatry and Behavioral Neurobiology, SC711 Sparks CenterUniversity of Alabama at BirminghamBirminghamUSA

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