IL-1β is an essential mediator of the antineurogenic and anhedonic effects of stress

Abstract

Stress decreases neurogenesis in the adult hippocampus, and blockade of this effect is required for the actions of antidepressants in behavioral models of depression. However, the mechanisms underlying these effects of stress have not been identified. Here, we demonstrate an essential role for the proinflammatory cytokine IL-1␤. Administration of IL-1␤ or acute stress suppressed hippocampal cell proliferation. Blockade of the IL-1␤ receptor, IL-1RI, by using either an inhibitor or IL-1RI null mice blocks the antineurogenic effect of stress and blocks the anhedonic behavior caused by chronic stress exposure. In vivo and in vitro studies demonstrate that hippocampal neural progenitor cells express IL-1RI and that activation of this receptor decreases cell proliferation via the nuclear factor-B signaling pathway. These findings demonstrate that IL-1␤ is a critical mediator of the antineurogenic and depressive-like behavior caused by acute and chronic stress.cytokine ͉ depression ͉ neurogenesis T he profound consequences of stress exposure, defined as disturbances of physiological homeostasis, include a detrimental impact on certain aspects of brain function (1, 2). In particular, uncontrollable stress is a major contributing factor for neuropsychiatric disorders such as major depression and posttraumatic stress disorders (3, 4). Alterations at the cellular level in the hippocampus have been linked to the pathophysiology of stress-related mood disorders (5-7). Many studies demonstrate that stressful experiences suppress hippocampal neurogenesis, which could contribute to the hippocampal atrophy observed in depressed patients (8-10). In contrast, antidepressant treatment increases hippocampal neurogenesis, blocks the antineurogenic effects of stress (11,12), and reduces or even reverses hippocampal atrophy (9, 11). Recent studies demonstrate that new hippocampal neurons are required for the actions of antidepressants in behavioral models of depression and anxiety (13, 14) with some exceptions (15,16).Despite this progress, the mechanisms underlying the antineurogenic and behavioral actions of stress remain ill defined. One possibility is that excessive proinflammatory cytokines, particularly IL-1␤, contribute to the actions of stress. Animal studies demonstrate that exposure to stress increases IL-1␤ in several brain areas, including the hippocampus (17-20), and central administration of IL-1␤ produces several stress-like effects, including activation of the hypothalamic-pituitary-adrenal (HPA) axis (17, 21), inhibition of hippocampal long-term potentiation (22), down-regulation of hippocampal brain-derived neurotrophic factor (23), and impaired hippocampal-dependent contextual fear conditioning (24). In contrast, blockade of the receptor, IL-1RI that mediates the actions of IL-1␤ (25) inhibits these stress-like effects (23, 24) and blocks the antiproliferative effects of INF-␣ in the hippocampus (26).Based on this evidence, the current study was undertaken to test the hypothesis that the antineurogenic and depressiv...

Effects of Inhibitor of κB Kinase Activity in the Nucleus Accumbens on Emotional Behavior

“…IkK activity in the hippocampus has also been found to affect histone acteylation, and this action was shown to be a critical regulator of reconsolidation of conditioned fear memories (Lubin and Sweatt, 2007). Interestingly, activation of NFkB in the hippocampus by IL-1b has been shown to inhibit neurogenesis and is important in the pro-depressant effects of chronic unpredictable stress (Koo and Duman, 2008;Koo et al, 2010). Complementary to our findings, Koo et al (2010) found that inhibition of NFkB in hippocampus blocked the anhedonic effects of CUS as measured by sucrose consumption.…”

Brain-Derived Neurotrophic Factor Serum Levels and Genotype: Association with Depression during Interferon-α Treatment

“…Therefore, in addition to IFN-a's effects on serotonin , dopamine (Felger et al, 2007), glutamate (Raison et al, 2010b), and the hypothalamic-pituitary-adrenal axis (Raison et al, 2010a), a decrease in BDNF may ultimately be the reason for the development of depression during IFN-a treatment. Related to this, social isolation decreases central BDNF, an effect which is likely mediated by the inflammatory cytokine IL1b (Barrientos et al, 2003;Ben Menachem-Zidon et al, 2008;Koo and Duman, 2008). IFN-a also appears to decrease cell proliferation in the hippocampus via increased IL-1b (Kaneko et al, 2006).…”

Distinctive effects of eicosapentaenoic and docosahexaenoic acids in regulating neural stem cell fate are mediated via endocannabinoid signalling pathways

“…Several studies indicate that IL-1β is antineurogenic (Koo and Duman, 2008;Ryan et al, 2013) by activation of the tumor suppressor p53 (Guadagno et al, 2015) or via adrenocortical activation (Goshen et al, 2008). Other findings suggest a proneurogenic effect of IL-1β (de la Mano et al, 2007;Xue et al, 2015).…”