BACKGROUND Microglia, the primary immune cells of the brain, are implicated in alcohol use disorder. However, it is not known if microglial activation contributes to the transition from alcohol use to alcohol use disorder or is a consequence of alcohol intake. METHODS We investigated the role of microglia in a mouse model of alcohol dependence using a colony stimulating factor 1 receptor inhibitor (PLX5622) to deplete microglia and a chronic intermittent ethanol vapor two-bottle choice drinking procedure. Additionally, we examined anxiety-like behavior during withdrawal. We then analyzed synaptic neuroadaptations in the central nucleus of the amygdala (CeA) and gene expression changes in the medial prefrontal cortex and CeA from the same animals used for behavioral studies. RESULTS PLX5622 prevented escalations in voluntary alcohol intake and decreased anxiety-like behavior associated with alcohol dependence. PLX5622 also reversed expression changes in inflammatory-related genes and glutamatergic and GABAergic (gamma-aminobutyric acidergic) genes in the medial prefrontal cortex and CeA. At the cellular level in these animals, microglia depletion reduced inhibitory GABAA and excitatory glutamate receptor-mediated synaptic transmission in the CeA, supporting the hypothesis that microglia regulate dependence-induced changes in neuronal function. CONCLUSIONS Our multifaceted approach is the first to link microglia to the molecular, cellular, and behavioral changes associated with the development of alcohol dependence, suggesting that microglia may also be critical for the development and progression of alcohol use disorder.

中文翻译：

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酒精依赖小鼠饮酒的小胶质细胞控制升级：基因组和突触驱动因素

背景小胶质细胞是大脑的主要免疫细胞，与酒精使用障碍有关。然而，尚不清楚小胶质细胞激活是否有助于从酒精使用到酒精使用障碍的转变，或者是酒精摄入的结果。方法我们使用集落刺激因子 1 受体抑制剂 (PLX5622) 来消耗小胶质细胞和慢性间歇性乙醇蒸汽两瓶选择饮酒程序，研究了小胶质细胞在酒精依赖小鼠模型中的作用。此外，我们检查了戒断期间的焦虑样行为。然后，我们分析了杏仁核中央核 (CeA) 中的突触神经适应以及内侧前额叶皮层和来自用于行为研究的相同动物的 CeA 中的基因表达变化。结果 PLX5622 阻止了自愿饮酒的增加，并减少了与酒精依赖相关的焦虑样行为。PLX5622 还逆转了内侧前额叶皮层和 CeA 中炎症相关基因以及谷氨酸能和 GABA 能（γ-氨基丁酸能）基因的表达变化。在这些动物的细胞水平上，小胶质细胞耗竭减少了 CeA 中抑制性 GABAA 和兴奋性谷氨酸受体介导的突触传递，支持了小胶质细胞调节依赖引起的神经元功能变化的假设。结论我们的多方面方法是第一个将小胶质细胞与与酒精依赖发展相关的分子、细胞和行为变化联系起来的方法，