Constant Darkness Induces IL-6-Dependent Depression-Like Behavior through the NF-κB Signaling Pathway
Constant Darkness Induces IL-6-Dependent Depression-Like Behavior through the NF-κB Signaling Pathway
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DOI：
10.1523/jneurosci.1537-11.2011
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发表时间：
2011-06-22
影响因子：
5.3
通讯作者：
Pollak, Daniela D.
中科院分区：
文献类型：
--
作者：
Monje, Francisco J.;Cabatic, Maureen;Pollak, Daniela D.
大量实验证据表明昼夜节律系统在情绪障碍中发挥着重要作用。此外，促炎细胞因子已被认为参与抑郁症的发病机制。然而，尚未描述决定这两个系统在抑郁症中功能相互作用的分子元件。在这里，我们研究在持续黑暗（DD）范式中长期剥夺光照是否会影响小鼠的抑郁样行为，并同时调节促炎细胞因子的水平。我们发现 DD 4 周后，小鼠表现出抑郁样行为，同时海马细胞增殖减少。这种时间生物学诱发的抑郁状态与海马血浆 IL-6（白细胞介素 6）和 IL-6 和 Il1-R1（白细胞介素 1 受体，I 型）蛋白水平升高相关，并且还改变海马时钟基因 per2 和 npas2 的蛋白水平。使用 NF-kappa B 通路的药理学阻断剂，我们提供了证据，证明 DD 对抑郁样行为、海马细胞增殖、脑和血浆 IL-6 表达水平改变以及时钟基因表达调节的影响是通过 NF-kappa B 信号传导介导的。此外，DD 小鼠海马组织中的 NF-κ B 活性增强。 IL-6（NF-κ B 的靶基因之一）缺失的小鼠能够抵抗 DD 诱导的抑郁样行为，这表明这种细胞因子在持续黑暗的小鼠抑郁模型中发挥着关键作用。我们在这里首先描述了在持续黑暗的抑郁症小鼠模型中桥接时间生物学和炎症过程的一些分子元件。
Substantial experimental evidence indicates a major role for the circadian system in mood disorders. Additionally, proinflammatory cytokines have been proposed to be involved in the pathogenesis of depression. However, the molecular elements determining the functional interplay between these two systems in depression have not been described as yet. Here we investigate whether long-term light deprivation in the constant darkness (DD) paradigm affects depression-like behavior in mice and concomitantly modulates the levels of proinflammatory cytokines. We find that after 4 weeks of DD, mice display depression-like behavior, which is paralleled by reduced hippocampal cell proliferation. This chronobiologically induced depressive state is associated with elevated levels of plasma IL-6 (interleukin-6) and IL-6 and Il1-R1 (interleukin 1 receptor, type I) protein levels in the hippocampus and also alters hippocampal protein levels of the clock genes per2 and npas2. Using pharmacological blockers of the NF-kappa B pathway, we provide evidence that the effects of DD on depression-like behavior, on hippocampal cell proliferation, on altered expressional levels of brain and plasma IL-6, and on the modulation of clock gene expression are mediated through NF-kappa B signaling. Moreover, NF-kappa B activity is enhanced in hippocampal tissue of DD mice. Mice with a deletion of IL-6, one of the target genes of NF-kappa B, are resistant to DD-induced depression-like behavior, which suggests a pivotal role for this cytokine in the constant darkness mouse model of depression. We here first describe some of the molecular elements bridging chronobiological and inflammatory processes in the constant darkness mouse model of depression.