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Aging Exacerbates Depressive-like Behavior in Mice in Response to Activation of the Peripheral Innate Immune System
Open accessAbstract
Exposure to peripheral infections may be permissive to cognitive and behavioral complications in the elderly. We have reported that peripheral stimulation of the innate immune system with lipopolysaccharide (LPS) causes an exaggerated neuroinflammatory response and prolonged sickness behavior in aged BALB/c mice. Because LPS also causes depressive behavior, the purpose of this study was to determine whether aging is associated with an exacerbated depressive-like response. We confirmed that LPS (0.33 mg/kg intraperitoneal) induced a protracted sickness response in aged mice with reductions in locomotor and feeding activities 24 and 48 h postinjection, when young adults had fully recovered. When submitted to the forced swim test 24 h post-LPS, both young adult and aged mice exhibited an increased duration of immobility. However, when submitted to either the forced swim test or the tail suspension test 72 h post-LPS, an increased duration of immobility was evident only in aged mice. This prolonged depressive-like behavior in aged LPS-treated mice was associated with a more pronounced induction of peripheral and brain indoleamine 2,3-dioxygenase and a markedly higher turnover rate of brain serotonin (as measured by the ratio of 5-hydroxy-indoleacetic acid over 5-hydroxy-tryptamine) compared to young adult mice at 24 post-LPS injection. These results provide the first evidence that age-associated reactivity of the brain cytokine system could play a pathophysiological role in the increased prevalence of depression observed in the elderly.
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“Although previous studies have identified elevated serum IL-6 and circulating leukocytes in stress disorders, this generally followed either depression diagnosis in humans (4, 25) or controlled stress exposure in rodents (26, 27).”
From Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress (2014) · cites this paper as [27]
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“This exaggerated expression of cytokines in the aged mice was associated with the prolonged sickness (Godbout et al, 2005) and depressive-like behavior (Godbout et al, 2008).”
From Microglia Priming with Aging and Stress (2017) · cites this paper as Godbout et al, 2008
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Citations
Cites
Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT Method
Livak, K. J., & Schmittgen, T. D. (2001) · Methods · doi:10.1006/meth.2001.1262 · Cited by 180,860
Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene
Caspi, A., Sugden, K., Moffitt, T. E., Taylor, A., Craig, I. W., Harrington, H., McClay, J., Mill, J., Martin, J., Braithwaite, A., et al. (2003) · Science · doi:10.1126/science.1083968 · Cited by 8,120
Cytokines sing the blues: inflammation and the pathogenesis of depression
Raison, C. L., Capuron, L., & Miller, A. H. (2006) · Trends in Immunology · doi:10.1016/j.it.2005.11.006 · Cited by 3,009
Stress-induced immune dysfunction: implications for health
Glaser, R., & Kiecolt-Glaser, J. K. (2005) · Nature Reviews Immunology · doi:10.1038/nri1571 · Cited by 2,190
Gene expression profile of aging and its retardation by caloric restriction
Lee, C.-K., Klopp, R. G., Weindruch, R., & Prolla, T. A. (1999) · Science · doi:10.1126/science.285.5432.1390 · Cited by 1,473
O'Connor, J. C., Lawson, M. A., André, C., Moreau, M., Lestage, J., Castanon, N., Kelley, K. W., & Dantzer, R. (2009) · Molecular Psychiatry · doi:10.1038/sj.mp.4002148 · Cited by 1,278
Self-citationChronic stress and age-related increases in the proinflammatory cytokine IL-6.
Kiecolt-Glaser, J. K., Preacher, K. J., MacCallum, R. C., Atkinson, C., Malarkey, W. B., & Glaser, R. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1531903100 · Cited by 1,267 · cited 1×
“…and depression is particularly relevant to an older population that has a high incidence of behavioral and cognitive complications concomitant with proinflammatory conditions (Dentino et al, 1999; Glaser et al, 2003; Kiecolt-Glaser et al, 2003; Mulsant and Ganguli, 1999; Penninx et al, 1999, 2003).”
BackgroundCytokines and major depression
Schiepers, O. J. G., Wichers, M. C., & Maes, M. (2005) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2004.11.003 · Cited by 1,235
Gene-expression profile of the ageing brain in mice
Lee, C.-K., Weindruch, R., & Prolla, T. A. (2000) · Nature Genetics · doi:10.1038/77046 · Cited by 1,055
Systemic infections and inflammation affect chronic neurodegeneration
Perry, V. H., Cunningham, C., & Holmes, C. (2007) · Nature Reviews Immunology · doi:10.1038/nri2015 · Cited by 1,027
BDNF and 5-HT: a dynamic duo in age-related neuronal plasticity and neurodegenerative disorders
Mattson, M. P., Maudsley, S., & Martin, B. (2004) · Trends in Neurosciences · doi:10.1016/j.tins.2004.08.001 · Cited by 942
Godbout, J. P., Chen, J., Abraham, J., Richwine, A. F., Berg, B. M., Kelley, K. W., & Johnson, R. W. (2005) · The FASEB Journal · doi:10.1096/fj.05-3776fje · Cited by 813
Self-citationStress, depression, and anhedonia: caveats concerning animal models
Anisman, H., & Matheson, K. (2005) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2005.03.007 · Cited by 569
Millan, M. J. (2006) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2005.11.006 · Cited by 567
Penninx, B. W. J. H., Kritchevsky, S. B., Yaffe, K. S., Newman, A. B., Simonsick, E. M., Rubin, S. M., Ferrucci, L., Harris, T. B., & Pahor, M. (2003) · Biological Psychiatry · doi:10.1016/s0006-3223(02)01811-5 · Cited by 530
Minor and Major Depression and the Risk of Death in Older Persons
Penninx, B. W. J. H., Geerlings, S. W., Deeg, D. J. H., van Eijk, J. T. M., van Tilburg, W., & Beekman, A. T. F. (1999) · Archives of General Psychiatry · doi:10.1001/archpsyc.56.10.889 · Cited by 524
Guillemin, G. J., Smythe, G., Takikawa, O., & Brew, B. J. (2005) · Glia · doi:10.1002/glia.20090 · Cited by 497 · cited 2×
“This ubiquitous enzyme is expressed in many cell types including perivascular macrophages, astrocytes, and microglia of the CNS (Guillemin et al, 2005).”
BackgroundInterferon-alpha–induced changes in tryptophan metabolism
Capuron, L., Neurauter, G., Musselman, D. L., Lawson, D. H., Nemeroff, C. B., Fuchs, D., & Miller, A. H. (2003) · Biological Psychiatry · doi:10.1016/s0006-3223(03)00173-2 · Cited by 493
Capuron, L., Ravaud, A., Neveu, P. J., Miller, A. H., Maes, M., & Dantzer, R. (2002) · Molecular Psychiatry · doi:10.1038/sj.mp.4000995 · Cited by 473 · cited 2×
“…immune system (Barrientos et al, 2006; Godbout et al, 2005) and stimulation of the immune system can precipitate the occurrence of depression (Capuron et al, 2003, 2002; Glaser et al, 2003), we investigated whether aging was also associated with a higher sensitivity to the depressive-like…”
BackgroundSelf-citationOkuda, S., Nishiyama, N., Saitō, H., & Katsuki, H. (1998) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1998.70010299.x · Cited by 465
Cytokines as mediators of depression: what can we learn from animal studies?
Dunn, A. J., Swiergiel, A. H., & Beaurepaire, R. D. (2005) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2005.03.023 · Cited by 459
Frenois, F., Moreau, M., O’Connor, J., Lawson, M., Micon, C., Lestage, J., Kelley, K. W., Dantzer, R., & Castanon, N. (2007) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2007.03.005 · Cited by 438
Self-citationLira, A., Zhou, M., Castanon, N., Ansorge, M. S., Gordon, J. A., Francis, J. H., Bradley-Moore, M., Lira, J., Underwood, M. D., Arango, V., et al. (2003) · Biological Psychiatry · doi:10.1016/s0006-3223(03)00696-6 · Cited by 385
Self-citationAltered antigen expression of microglia in the aged rodent CNS
Perry, V. H., Matyszak, M. K., & Fearn, S. (1993) · Glia · doi:10.1002/glia.440070111 · Cited by 364
Stockmeier, C. A. (2003) · Journal of Psychiatric Research · doi:10.1016/s0022-3956(03)00050-5 · Cited by 357
Cerebrospinal Cytokine Levels in Patients with Acute Depression
Levine, J., Barak, Y., Chengappa, K. N. R., Rapoport, A., Rebey, M., & Barak, V. (1999) · Neuropsychobiology · doi:10.1159/000026615 · Cited by 354
Peripheral infection and aging interact to impair hippocampal memory consolidation
Barrientos, R. M., Higgins, E. A., Biedenkapp, J. C., Sprunger, D. B., Wright-Hardesty, K. J., Watkins, L. R., Rudy, J. W., & Maier, S. F. (2006) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2005.03.010 · Cited by 340
mRNA up-regulation of MHC II and pivotal pro-inflammatory genes in normal brain aging
Frank, M. G., Barrientos, R. M., Biedenkapp, J. C., Rudy, J. W., Watkins, L. R., & Maier, S. F. (2006) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2005.03.013 · Cited by 327
Increased interleukin-6 expression by microglia from brain of aged mice
Ye, S.-M., & Johnson, R. W. (1999) · Journal of Neuroimmunology · doi:10.1016/s0165-5728(98)00217-3 · Cited by 326
Self-citationAnisman, H., Ravindran, A. V., Griffiths, J., & Merali, Z. (1999) · Molecular Psychiatry · doi:10.1038/sj.mp.4000436 · Cited by 310
Interleukin‐6 Serum Levels in Depressed Patients before and after Treatment with Fluoxetine
Sluzewska, A., RYBAKOWSKI, J. K., Łaciak, M., Mackiewicz, A., Sobieska, M., & WIKTOROWICV, K. (1995) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1995.tb32372.x · Cited by 306
Dunn, A. J. (1992) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)11171-3 · Cited by 302
Animal Models of Depression: Utility for Transgenic Research
Porsolt, R. D. (2000) · Reviews in the Neurosciences · doi:10.1515/revneuro.2000.11.1.53 · Cited by 293
Increase in Interleukin-1β in Late-Life Depression
Thomas, A. J., Davis, S., Morris, C., Jackson, E., Harrison, R., & O’Brien, J. T. (2005) · American Journal of Psychiatry · doi:10.1176/appi.ajp.162.1.175 · Cited by 291
Wichers, M., & Maes, M. H. J. (2004) · Journal of Psychiatry and Neuroscience · doi:10.1139/jpn.0402 · Cited by 291
Dentino, A. N., Pieper, C. F., Rao, K. M. K., Currie, M. S., Harris, T., Blazer, D. G., & Cohen, H. J. (1999) · Journal of the American Geriatrics Society · doi:10.1111/j.1532-5415.1999.tb01894.x · Cited by 287
Cytokines and depression: The need for a new paradigm
Capuron, L., & Dantzer, R. (2003) · Brain Behavior and Immunity · doi:10.1016/s0889-1591(02)00078-8 · Cited by 282
Self-citationEpidemiology and diagnosis of depression in late life.
Mulsant, B. H., & Ganguli, M. (1999) · PubMed · Cited by 259
Glaser, R., Robles, T. F., Sheridan, J. F., Malarkey, W. B., & Kiecolt‐Glaser, J. K. (2003) · Archives of General Psychiatry · doi:10.1001/archpsyc.60.10.1009 · Cited by 242
IL-6 knockout mice exhibit resistance to stress-induced development of depression-like behaviors
Chourbaji, S., Urani, A., Inta, I., Sanchis-Segura, C., Brandwein, C., Zink, M., Schwaninger, M., & Gass, P. (2006) · Neurobiology of Disease · doi:10.1016/j.nbd.2006.05.001 · Cited by 241
Microglial Expression of MHC Class II Increases in Normal Aging of Nonhuman Primates
Sheffield, L. G., & Berman, N. E. J. (1998) · Neurobiology of Aging · doi:10.1016/s0197-4580(97)00168-1 · Cited by 234
Huang, Y., Henry, C. J., Dantzer, R., Johnson, R. W., & Godbout, J. P. (2007) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2007.04.012 · Cited by 226
Self-citationBehan, W. M. H., McDonald, M., Darlington, L. G., & Stone, T. W. (1999) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0702940 · Cited by 225
Low levels of circulating inflammatory cytokines—Do they affect human brain functions?
Pollmächer, T., Haack, M., Schuld, A., Reichenberg, A., & Yirmiya, R. (2002) · Brain, Behavior, and Immunity · doi:10.1016/s0889-1591(02)00004-1 · Cited by 202
Capuron, L., Ravaud, A., Gualde, N., Bosmans, E., Dantzer, R., Maes, M., & Neveu, P. J. (2001) · Psychoneuroendocrinology · doi:10.1016/s0306-4530(01)00030-0 · Cited by 201
Immune activation and degradation of tryptophan in coronary heart disease
Wirleitner, B., Rudzite, V., Neurauter, G., Murr, C., Kalnins, U., Ērglis, A., Trušinskis, K., & Fuchs, D. (2003) · European Journal of Clinical Investigation · doi:10.1046/j.1365-2362.2003.01186.x · Cited by 190
A mechanism for increased quinolinic acid formation following acute systemic immune stimulation
Saito, K., Crowley, J. S., Markey, S. P., & Heyes, M. P. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)82284-0 · Cited by 186
Lestage, J., Verrier, D., Palin, K., & Dantzer, R. (2002) · Brain, Behavior, and Immunity · doi:10.1016/s0889-1591(02)00014-4 · Cited by 170
Self-citationEffects of interleukin-1 and endotoxin in the forced swim and tail suspension tests in mice
DUNN, A., & Swiergiel, A. H. (2005) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2005.04.019 · Cited by 169
Activation of microglia in the brains of humans with heart disease and hypercholesterolemic rabbits
Streit, W. J., & Sparks, D. L. (1997) · Journal of Molecular Medicine · doi:10.1007/s001090050097 · Cited by 167
Mouse interleukin-6 stimulates the HPA axis and increases brain tryptophan and serotonin metabolism
Wang, J., & Dunn, A. J. (1998) · Neurochemistry International · doi:10.1016/s0197-0186(98)00016-3 · Cited by 144
Synthesis and release of neurotoxic kynurenine metabolites by human monocyte-derived macrophages
Chiarugi, A., Calvani, M., Meli, E., Traggiai, E., & Moroni, F. (2001) · Journal of Neuroimmunology · doi:10.1016/s0165-5728(01)00418-0 · Cited by 125
Age and Neuroinflammation: A Lifetime of Psychoneuroimmune Consequences
Godbout, J. P., & Johnson, R. W. (2006) · Neurologic Clinics · doi:10.1016/j.ncl.2006.03.010 · Cited by 123
Self-citationSaito, K., Nowak, T. S., Suyama, K., Quearry, B. J., Saito, M., Crowley, J. S., Markey, S. P., & Heyes, M. P. (1993) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1993.tb07443.x · Cited by 116
Maes, M. H. J., Bonaccorso, S., Marino, V., Puzella, A., Pasquini, M., Biondi, M., Artini, M., Almerighi, C., & Meltzer, H. Y. (2001) · Molecular Psychiatry · doi:10.1038/sj.mp.4000872 · Cited by 108
Godbout, J., Berg, B. M., Kelley, K. W., & Johnson, R. W. (2004) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2003.12.017 · Cited by 107
Self-citationMoreau, M. M., Lestage, J., Verrier, D., Mormède, C., Kelley, K. W., Dantzer, R., & Castanon, N. (2005) · The Journal of Infectious Diseases · doi:10.1086/431603 · Cited by 104
Self-citationSerotonergic gene expression and depression: implications for developing novel antidepressants
Lesch, K. P. (2001) · Journal of Affective Disorders · doi:10.1016/s0165-0327(00)00351-7 · Cited by 93
Role of IL-1 in Poststroke Depressive-like Behavior in Mice
Craft, T. K. S., & DeVries, A. C. (2006) · Biological Psychiatry · doi:10.1016/j.biopsych.2006.03.011 · Cited by 87
α-Tocopherol attenuates lipopolysaccharide-induced sickness behavior in mice
Berg, B. M., Godbout, J. P., Kelley, K. W., & Johnson, R. W. (2003) · Brain Behavior and Immunity · doi:10.1016/s0889-1591(03)00113-2 · Cited by 83
Self-citationHeyes, M. P., Saito, K., Chen, C. Y., Proescholdt, M. G., Nowak, T. S., Li, J., Beagles, K. E., Proescholdt, M. A., Zito, M. A., Kawai, K., et al. (1997) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1997.69041519.x · Cited by 82
Wang, J., & Dunn, A. J. (1999) · Brain Research · doi:10.1016/s0006-8993(98)01091-9 · Cited by 81
Zhang, J., Terreni, L., Simoni, M. G. D., & Dunn, A. J. (2001) · Neurochemistry International · doi:10.1016/s0197-0186(00)00099-1 · Cited by 67
Richwine, A. F., Godbout, J. P., Berg, B. M., Chen, J., Escobar, J., MILLARD, D. K., & Johnson, R. W. (2005) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2004.12.005 · Cited by 56
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Self-citationNeuroinflammation: The Devil Is in the Details
DiSabato, D. J., Quan, N., & Godbout, J. P. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13607 · Cited by 1,640
Self-citationRegulation of learning and memory by meningeal immunity: a key role for IL-4
Derecki, N. C., Cardani, A. N., Yang, C. H., Quinnies, K. M., Crihfield, A., Lynch, K. R., & Kipnis, J. (2010) · Journal of Experimental Medicine · doi:10.1084/jem.20091419 · Cited by 800
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Norden, D. M., & Godbout, J. P. (2013) · Neuropathology and Applied Neurobiology · doi:10.1111/j.1365-2990.2012.01306.x · Cited by 792
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Cunningham, C. (2013) · Glia · doi:10.1002/glia.22350 · Cited by 769
Metadata
- Authors
- Godbout, J. P., Moreau, M., Lestage, J., Chen, J., Sparkman, N. L., Connor, J. O., Castanon, N., Kelley, K. W., Dantzer, R., & Johnson, R. W.
- Affiliations
- Institute for Behavioral Medicine (US)
- Centre National de la Recherche Scientifique (FR)
- University of Illinois Urbana-Champaign (US)
- Corresponding author
- Johnson, Rodney W
- Venue
- Neuropsychopharmacology
- Published
- 2007-12-12
- Volume
- 33
- Issue
- 10
- Pages
- 2341-2351
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC2907915
- OpenAlex
- W2001809220
- Cited by
- 299
- References
- 64
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 6 · 2023: 7 · 2022: 18 · 2021: 23 · 2020: 12 · 2019: 10 · 2018: 21 · 2017: 13 · 2016: 25 · 2015: 21 · 2014: 17 · 2013: 28 · 2012: 25
- FWCI
- 5.52
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion)
- Funders
- American Federation for Aging Research
- National Institutes of Health
- National Institute on Aging (AG029573, AG 16710, R01AG016710, R01AG029573)
- National Institute of Mental Health (MH071349, MH-079829, R01MH079829, MH 069148, R01MH071349, MH076786, R01MH069148, R03MH076786)
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- aging, depression-like behavior, lipopolysaccharide, sickness behavior, neuroinflammation, indoleamine 2,3-dioxygenase, serotonin turnover, 5-hydroxyindoleacetic acid, brain cytokines, geriatric depression, forced swim test, tail suspension test
- MeSH terms
- Aging, Animals, Behavior, Animal, Brain, Brain Chemistry, Depressive Disorder, Disease Models, Animal, Immunity, Innate, Infections, Inflammation, Lipopolysaccharides, Male, Mice, Inbred BALB C, Motor Activity, Serotonin, Down-Regulation, Cytokines, Inflammation Mediators, Indoleamine-Pyrrole 2,3,-Dioxygenase, Mice, Illness Behavior
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