4.7 Article

Aging exacerbates depressive-like behavior in mice in response to activation of the peripheral innate immune system

Journal

NEUROPSYCHOPHARMACOLOGY
Volume 33, Issue 10, Pages 2341-2351

Publisher

NATURE PUBLISHING GROUP
DOI: 10.1038/sj.npp.1301649

Keywords

aging; behavior; cytokines; lipopolysaccharide; serotonin; depression

Funding

  1. NIA NIH HHS [AG16710, R01 AG029573, R01 AG016710, AG029573] Funding Source: Medline
  2. NIMH NIH HHS [R03 MH076786, MH069148, MH071349, MH079829, MH076786, R01 MH071349-02, R01 MH079829, R01 MH071349, R01 MH069148, R01 MH079829-02] Funding Source: Medline

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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-hydroxyt-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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