小胶质细胞控制酒精依赖小鼠饮酒行为的加剧：基因组和突触驱动因素。
Microglia Control Escalation of Drinking in Alcohol-Dependent Mice: Genomic and Synaptic Drivers.
机构信息
Waggoner Center for Alcoholism and Addiction Research, University of Texas at Austin, Austin, Texas; Institute for Neuroscience, University of Texas at Austin, Austin, Texas.
Departments of Molecular Medicine and Neuroscience, The Scripps Research Institute, La Jolla, California.
出版信息
Biol Psychiatry. 2020 Dec 15;88(12):910-921. doi: 10.1016/j.biopsych.2020.05.011. Epub 2020 May 19.
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 GABA 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.
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的激活是否导致了从饮酒到酒精使用障碍的转变，或者是否是酒精摄入的结果。
方法
我们使用集落刺激因子 1 受体抑制剂（PLX5622）来耗尽小胶质细胞，并采用慢性间歇性乙醇蒸气双瓶选择饮用程序，在酒精依赖的小鼠模型中研究了小胶质细胞的作用。此外，我们还在戒断期间检查了类似焦虑的行为。然后，我们分析了中央杏仁核（CeA）中的突触神经适应和来自用于行为研究的相同动物的内侧前额叶皮质和 CeA 中的基因表达变化。
结果
PLX5622 可预防自愿饮酒量的增加，并减少与酒精依赖相关的类似焦虑的行为。PLX5622 还逆转了内侧前额叶皮质和 CeA 中与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 GABA 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诱导的神经元功能变化的假说。
结论
我们的多方面方法是首次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，这表明小胶质细胞也可能是酒精使用障碍发展和进展的关键。
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