Department of Cell Pathology, Príncipe Felipe Research Center, Avda. Autopista del Saler 16, 46012 Valencia, Spain.
Brain Behav Immun. 2011 Jun;25 Suppl 1:S80-91. doi: 10.1016/j.bbi.2011.02.012. Epub 2011 Feb 23.
Toll-like receptors (TLRs) play an important role in the innate immune response, and emerging evidence indicates their role in brain injury and neurodegeneration. Our recent results have demonstrated that ethanol is capable of activating glial TLR4 receptors and that the elimination of these receptors in mice protects against ethanol-induced glial activation, induction of inflammatory mediators and apoptosis. This study was designed to assess whether ethanol-induced inflammatory damage causes behavioral and cognitive consequences, and if behavioral alterations are dependent of TLR4 functions. Here we show in mice drinking alcohol for 5months, followed by a 15-day withdrawal period, that activation of the astroglial and microglial cells in frontal cortex and striatum is maintained and that these events are associated with cognitive and anxiety-related behavioral impairments in wild-type (WT) mice, as demonstrated by testing the animals with object memory recognition, conditioned taste aversion and dark and light box anxiety tasks. Mice lacking TLR4 receptors are protected against ethanol-induced inflammatory damage, and behavioral associated effects. We further assess the possibility of the epigenetic modifications participating in short- or long-term behavioral effects associated with neuroinflammatory damage. We show that chronic alcohol treatment decreases H4 histone acetylation and histone acetyltransferases activity in frontal cortex, striatum and hippocampus of WT mice. Alterations in chromatin structure were not observed in TLR4(-/-) mice. These results provide the first evidence of the role that TLR4 functions play in the behavioral consequences of alcohol-induced inflammatory damage and suggest that the epigenetic modifications mediated by TLR4 could contribute to short- or long-term alcohol-induced behavioral or cognitive dysfunctions.
Toll 样受体 (TLRs) 在先天免疫反应中发挥重要作用，新出现的证据表明它们在脑损伤和神经退行性变中发挥作用。我们最近的研究结果表明，乙醇能够激活神经胶质 TLR4 受体，而在小鼠中消除这些受体可防止乙醇诱导的神经胶质激活、炎症介质诱导和细胞凋亡。本研究旨在评估乙醇诱导的炎症损伤是否会导致行为和认知后果，以及行为改变是否依赖于 TLR4 功能。在这里，我们在饮酒 5 个月后，接着进行 15 天戒断期的小鼠中显示，在前额皮质和纹状体中的星形胶质细胞和小胶质细胞的激活被维持，并且这些事件与野生型 (WT) 小鼠的认知和焦虑相关的行为障碍相关，这通过测试动物的物体记忆识别、条件性味觉厌恶和黑暗和明亮箱焦虑任务来证明。缺乏 TLR4 受体的小鼠可防止乙醇诱导的炎症损伤和与行为相关的影响。我们进一步评估了表观遗传修饰参与与神经炎症损伤相关的短期或长期行为效应的可能性。我们表明，慢性酒精处理降低了 WT 小鼠前额皮质、纹状体和海马中的 H4 组蛋白乙酰化和组蛋白乙酰转移酶活性。在 TLR4(-/-) 小鼠中未观察到染色质结构的改变。这些结果首次提供了 TLR4 功能在酒精诱导的炎症损伤所致行为后果中的作用的证据，并表明 TLR4 介导的表观遗传修饰可能导致短期或长期酒精引起的行为或认知功能障碍。
