Modeling an Inflammation‐Related Depressive Phenotype in Mice Using Bacille Calmette‐Guérin

Brian J. Platt1, Janet A. Clark1

1 Drexel University College of Medicine, Philadelphia, Pennsylvania
Publication Name:  Current Protocols in Neuroscience
Unit Number:  Unit 9.46
DOI:  10.1002/0471142301.ns0946s65
Online Posting Date:  October, 2013
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Abstract

The relationship between inflammation and neuropsychiatric symptoms is of interest to the scientific community for several reasons. A substantial subset of patients suffering from major depressive disorder also exhibit evidence of chronic inflammation including elevated levels of circulating pro‐inflammatory cytokines. Immune‐mediated inflammatory diseases and immunotherapy can result in depressive symptoms in some patients. Recent evidence suggests that the chronic inflammation may play a role in the pathophysiology of the depressive state, although the specific biological mechanisms are not clear. Herein we describe a model of an inflammation‐related depressive phenotype in mice using the tuberculosis vaccine, bacille Calmette‐Guérin, to induce chronic inflammation and a subsequent depressive phenotype which is assessed using the tail‐suspension test. The model provides an avenue to study not only the molecular and biochemical changes that may be associated with the development of the depressive phenotype, but also pharmacological manipulations of the phenotype. Curr. Protoc. Neurosci. 65:9.46.1‐9.46.10. © 2013 by John Wiley & Sons, Inc.

Keywords: inflammation; cytokines; depressive phenotype

     
 
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Table of Contents

  • Commentary
  • Literature Cited
  • Figures
  • Tables
     
 
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Materials

Basic Protocol 1:

  Materials
  • Male adult outbred CD‐1 mice (e.g., Harlan)
  • BCG live (intravesical), 81 mg/vial (TheraCys, Sanofi Pasteur; store protected from light at 2° to 8°C)
  • Normal saline: 0.9% sodium chloride (sterile, preservative‐free)
  • 70% ethanol
  • Clean standard size mouse cages containing fresh bedding
  • Balance with 0.1 g accuracy to weigh mice
  • 3‐ml sterile, disposable syringes with 25‐G needles attached
  • 1‐ml sterile, disposable tuberculin syringes with 25‐G needles attached
  • Cart for transporting mouse cages
  • Spray bottle
  • Seamless open field starter package for mouse (Med Associates) consisting of:
    • ENV‐510S, seamless open field arena for mouse
    • DIG‐729‐USB, USB high speed serial microcontroller
    • SG‐506, regulated power supply 120 V
    • ENV‐256, single channel IR source, detector, and controller (3)
    • ENV‐520, 48 channel IR controller for open field activity
    • SOF‐811, activity monitor
  • Additional test arena for mouse open field (Med Associates, cat. no. MED‐OFAS‐510)
  • Tail‐suspension starter package (Med Associates) consisting of:
    • PHM‐300, tail‐suspension test cubicle
    • MSUB‐PHM‐300‐01, tail‐suspension paddle
    • MSUB‐PHM‐300‐02, tail‐suspension catch
    • ENV‐505TS, tail‐suspension load cell and amplifier
    • SG‐6010, dual‐range constant current aversive stimulation module
    • DIG‐744, PCI data acquisition card
    • SOF‐821, tail‐suspension software
    • DIG‐735, tail‐suspension interface card
  • Tail‐suspension add‐on package and additional tail‐suspension catch (Med Associates, cat. nos. MED‐TSS‐300 and MSUB‐PHM‐300‐02)
  • Additional reagents and equipment for injection of mice ( appendix 4F), animal health assurance ( appendix 4C), animal identification ( appendix 4E), locomotor activity test (unit 8.1), and tail‐suspension test (unit 8.10)
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Figures

Videos

Literature Cited

Literature Cited
  Bonaccorso, S., Marino, V., Puzella, A., Pasquini, M., Biondi, M., Artini, M., Almerighi, C., Verkerk, R., Meltzer, H., and Maes, M. 2002. Increased depressive ratings in patients with hepatitis C receiving interferon‐alpha‐based immunotherapy are related to interferon‐alpha‐induced changes in the serotonergic system. J. Clin. Psychopharmacol. 22:86‐90.
  Capuron, L., Neurauter, G., Musselman, D.L., Lawson, D.H., Nemeroff, C.B., Fuchs, D., and Miller, A.H. 2003. Interferon‐alpha‐induced changes in tryptophan metabolism. Relationship to depression and paroxetine treatment. Biol. Psychiatry 54:906‐914.
  Dowlati, Y., Herrmann, N., Swardfager, W., Liu, H., Sham, L., Reim, E.K., and Lanctôt, K.L. 2009. A meta‐analysis of cytokines in major depression. Biol. Psychiatry 67:446‐457.
  Frenois, F., Moreau, M., O'Connor, J., Lawson, M., Micon, C., Lestage, J., Kelley, K.W., Dantzer, R., and Castanon, N. 2007. Lipopolysaccharide induces delayed FosB/DeltaFosB immunostaining within the mouse extended amygdala, hippocampus and hypothalamus, that parallel the expression of depressive‐like behavior. Psychoneuroendocrinology 32:516‐531.
  Hiles, S.A., Baker, A.L., de Malmanche, T., and Attia, J. 2012. A meta‐analysis of differences in IL‐6 and IL‐10 between people with and without depression: Exploring the causes of heterogeneity. Brain Behav. Immun 26:1180‐1188.
  Howren, M.B., Lamkin, D.M., and Suls, J. 2009. Associations of depression with C‐reactive protein, IL‐1, and IL‐6: A meta‐analysis. Psychosom. Med. 71:171‐186.
  Liu, Y., Ho, R.C., and Mak, A. 2012. Interleukin (IL)‐6, tumour necrosis factor alpha (TNF‐alpha) and soluble interleukin‐2 receptors (sIL‐2R) are elevated in patients with major depressive disorder: A meta‐analysis and meta‐regression. J. Affect. Disord. 139:230‐239.
  Loftis, J.M. and Hauser, P. 2004. The phenomenology and treatment of interferon‐induced depression. J. Affect. Disord. 82:175‐190.
  Maes, M., Bosmans, E., De Jongh, R., Kenis, G., Vandoolaeghe, E., and Neels, H. 1997. Increased serum IL‐6 and IL‐1 receptor antagonist concentrations in major depression and treatment resistant depression. Cytokine 9:853‐858.
  Moreau, M., Andre, C., O'Connor, J.C., Dumich, S.A., Woods, J.A., Kelley, K.W., Dantzer, R., Lestage, J., and Castanon, N. 2008. Inoculation of Bacillus Calmette‐Guérin to mice induces an acute episode of sickness behavior followed by chronic depressive‐like behavior. Brain Behav. Immun. 22:1087‐1095.
  O'Connor, J.C., Lawson, M.A., Andre, C., Briley, E.M., Szegedi, S.S., Lestage, J., Castanon, N., Herkenham, M., Dantzer, R., and Kelley, K.W. 2009a. Induction of IDO by bacille Calmette‐Guérin is responsible for development of murine depressive‐like behavior. J. Immunol. 182:3202‐3212.
  O'Connor, J.C., Lawson, M.A., Andre, C., Moreau, M., Lestage, J., Castanon, N., Kelley, K.W., and Dantzer, R. 2009b. Lipopolysaccharide‐induced depressive‐like behavior is mediated by indoleamine 2,3‐dioxygenase activation in mice. Mol. Psychiatry 14:511‐522.
  Platt, B., Schulenberg, J., Klee, N., Nizami, M., and Clark, J.A. 2013. A depressive phenotype induced by Bacille Calmette Guérin in ‘susceptible’ animals: Sensitivity to antidepressants. Psychopharmacology 226:501‐513.
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