Aging Exacerbates Depressive-like Behavior in Mice in Response to Activation of the Peripheral Innate Immune System
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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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Previous studies have identified elevated serum IL-6 and circulating leukocytes in stress disorders, but this generally followed either depression diagnosis in humans or controlled stress exposure in rodents.
“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]
The Experimental Protocols describe a controlled LPS immune challenge in mice, and “Plasma IL-6 is Elevated in Aged Mice 24 h After Peripheral LPS” reports higher plasma IL-6 after that challenge. The cited paper does not report circulating leukocyte counts or a controlled stress-exposure experiment; its intervention was immune activation, not a stress paradigm. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe exaggerated expression of cytokines in the aged mice was associated with prolonged sickness and depressive-like behavior.
“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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- 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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