Brain interleukin-1 mediates chronic stress-induced depression in mice via adrenocortical activation and hippocampal neurogenesis suppression

I. Goshen, T. Kreisel, O. Ben-Menachem-Zidon, T. Licht, J. Weidenfeld, T. Ben-Hur, R. Yirmiya*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

606 Scopus citations


Several lines of evidence implicate the pro-inflammatory cytokine interleukin-1 (IL-1) in the etiology and pathophysiology of major depression. To explore the role of IL-1 in chronic stress-induced depression and some of its underlying biological mechanisms, we used the chronic mild stress (CMS) model of depression. Mice subjected to CMS for 5 weeks exhibited depressive-like symptoms, including decreased sucrose preference, reduced social exploration and adrenocortical activation, concomitantly with increased IL-1β levels in the hippocampus. In contrast, mice with deletion of the IL-1 receptor type I (IL-1rKO) or mice with transgenic, brain-restricted overexpression of IL-1 receptor antagonist did not display CMS-induced behavioral or neuroendocrine changes. Similarly, whereas in wild-type (WT) mice CMS significantly reduced hippocampal neurogenesis, measured by incorporation of bromodeoxyuridine (BrdU) and by doublecortin immunohistochemistry, no such decrease was observed IL-1rKO mice. The blunting of the adrenocortical activation in IL-1rKO mice may play a causal role in their resistance to depression, because removal of endogenous glucocorticoids by adrenalectomy also abolished the depressive-like effects of CMS, whereas chronic administration of corticosterone for 4 weeks produced depressive symptoms and reduced neurogenesis in both WT and IL-1rKO mice. The effects of CMS on both behavioral depression and neurogenesis could be mimicked by exogenous subcutaneous administration of IL-1β via osmotic minipumps for 4 weeks. These findings indicate that elevation in brain IL-1 levels, which characterizes many medical conditions, is both necessary and sufficient for producing the high incidence of depression found in these conditions. Thus, procedures aimed at reducing brain IL-1 levels may have potent antidepressive actions.

Original languageAmerican English
Pages (from-to)717-728
Number of pages12
JournalMolecular Psychiatry
Issue number7
StatePublished - Jul 2008

Bibliographical note

Funding Information:
We thank Professor K Iverfeldt for the IL-1raTG mice. This study was supported by a grant from the Israel Science Foundation (to RY). RY is a member of the Eric Roland Center for Neurodegenerative Diseases at the Hebrew University of Jerusalem.


  • Adrenalectomy
  • Chronic mild stress (CMS)
  • Hippocampus
  • Hypothalamus-pituitary-adrenal (HPA) axis
  • Major depression
  • Pro-inflammatory cytokines


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