Brain interleukin-1 mediates chronic stress-induced depression in mice via adrenocortical activation and hippocampal neurogenesis suppression
Brain interleukin-1 mediates chronic stress-induced depression in mice via adrenocortical activation and hippocampal neurogenesis suppression
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DOI：
10.1038/sj.mp.4002055
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发表时间：
2008-07-01
影响因子：
11
通讯作者：
Yirmiya, R.
中科院分区：
文献类型：
--
作者：
Goshen, I.;Kreisel, T.;Yirmiya, R.
一些证据表明，促炎细胞因子白细胞介素-1 （IL-1）参与了重度抑郁症的病因学和病理生理。为了探讨IL-1在慢性应激性抑郁症中的作用及其潜在的生物学机制，我们采用慢性轻度应激（CMS）抑郁症模型。接受CMS治疗5周的小鼠表现出抑郁样症状，包括蔗糖偏好降低、社交探索减少和肾上腺皮质激活减少，同时海马中IL-1 β水平升高。相比之下，IL-1受体I型（IL-1rKO）缺失的小鼠或IL-1受体拮抗剂转基因、脑限制性过表达的小鼠没有表现出cms诱导的行为或神经内分泌变化。同样，在野生型（WT）小鼠中，通过掺入溴脱氧尿苷（BrdU）和双皮质素免疫组织化学测量，CMS显著减少了海马神经发生，而IL-1rKO小鼠没有观察到这种减少。IL-1rKO小鼠肾上腺皮质激活的钝化可能在其抗抑郁中发挥了因果作用，因为通过肾上腺切除术去除内源性糖皮质激素也消除了CMS的抑郁样作用，而在WT和IL-1rKO小鼠中，慢性给予皮质酮4周会产生抑郁症状并减少神经发生。通过渗透微型泵外源性皮下注射IL-1 β 4周，可以模拟CMS对行为抑郁和神经发生的影响。这些发现表明，大脑IL-1水平的升高，是许多疾病的特征，是产生这些疾病中发现的高发生率抑郁症的必要和充分条件。因此，旨在降低脑IL-1水平的程序可能具有有效的抗抑郁作用。
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.