Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, TX, USA.
Institute for Neuroscience, University of Texas at Austin, Austin, TX, USA.
Addict Biol. 2019 Jul;24(4):604-616. doi: 10.1111/adb.12625. Epub 2018 Apr 17.
Chronic alcohol consumption alters the levels of microRNAs and mRNAs in the brain, but the specific microRNAs and processes that target mRNAs to affect cellular function and behavior are not known. We examined the in vivo manipulation of previously identified alcohol-responsive microRNAs as potential targets to reduce alcohol consumption. Silencing of miR-411 by infusing antagomiR-411 into the prefrontal cortex of female C57BL/6J mice reduced alcohol consumption and preference, without altering total fluid consumption, saccharin consumption, or anxiety-related behaviors. AntagomiR-411 reduced alcohol consumption when given to mice exposed to a chronic alcohol drinking paradigm but did not affect the acquisition of consumption in mice without a history of alcohol exposure, suggesting that antagomiR-411 has a neuroadaptive, alcohol-dependent effect. AntagomiR-411 decreased the levels of miR-411, as well as the association of immunoprecipitated miR-411 with Argonaute2; and, it increased levels of Faah and Ppard mRNAs. Moreover, antagomiR-411 increased the neuronal expression of glutamate receptor AMPA-2 protein, a known alcohol target and a predicted target of miR-411. These results suggest that alcohol and miR-411 function in a homeostatic manner to regulate synaptic mRNA and protein, thus reversing alcohol-related neuroadaptations and reducing chronic alcohol consumption.
慢性酒精摄入会改变大脑中的 microRNAs 和 mRNAs 水平，但针对 mRNAs 的特定 microRNAs 和过程，以及它们如何影响细胞功能和行为尚不清楚。我们研究了先前鉴定的酒精反应性 microRNAs 的体内操作，作为减少酒精消耗的潜在靶点。通过将 antagomiR-411 注入雌性 C57BL/6J 小鼠的前额叶皮层来沉默 miR-411，可减少酒精消耗和偏好，而不改变总液体消耗、糖精消耗或与焦虑相关的行为。antagomiR-411 可减少暴露于慢性酒精摄入模型的小鼠的酒精消耗，但对没有酒精暴露史的小鼠的饮酒获取没有影响，这表明 antagomiR-411 具有神经适应性、酒精依赖性的作用。antagomiR-411 降低了 miR-411 的水平，以及免疫沉淀的 miR-411 与 Argonaute2 的关联；并且，它增加了 Faah 和 Ppard mRNAs 的水平。此外，antagomiR-411 增加了谷氨酸受体 AMPA-2 蛋白的神经元表达，该蛋白是已知的酒精靶点和 miR-411 的预测靶点。这些结果表明，酒精和 miR-411 以一种稳态的方式发挥作用，以调节突触 mRNA 和蛋白质，从而逆转与酒精相关的神经适应并减少慢性酒精消耗。
