Brain interleukin-1 mediates chronic stress-induced depression in mice via adrenocortical activation and hippocampal neurogenesis suppression.
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-1 beta 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-1 beta 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.
Goshen
I
I
Department of Psychology, The Hebrew University, Jerusalem, Israel.
Kreisel
T
T
Ben-Menachem-Zidon
O
O
Licht
T
T
Weidenfeld
J
J
Ben-Hur
T
T
Yirmiya
R
R
D000302:Adrenal Cortex / Q000503:physiopathology; D000818:Animals; D001921:Brain / Q000503:physiopathology*; D001973:Bromodeoxyuridine; D002908:Chronic Disease; D003863:Depression / Q000503:physiopathology* / Q000517:prevention & control; D004797:Enzyme-Linked Immunosorbent Assay; D006624:Hippocampus / Q000503:physiopathology*; D007375:Interleukin-1 / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017472:Receptors, Interleukin-1 / Q000172:deficiency* / Q000235:genetics; D013315:Stress, Psychological / Q000523:psychology*
D007375:Interleukin-1; D017472:Receptors, Interleukin-1; D001973:Bromodeoxyuridine