Chronic alcohol exposure results in widespread dysregulation of gene expression that contributes to the pathogenesis of Alcohol Use Disorder (AUD). Long noncoding RNAs are key regulators of the transcriptome that we hypothesize coordinate alcohol‐induced transcriptome dysregulation and contribute to AUD. Based on RNA‐Sequencing data of human prefrontal cortex, basolateral amygdala and nucleus accumbens of AUD versus non‐AUD brain, the human LINC01265 and its predicted murine homolog Gm41261 (i.e., TX2) were selected for functional interrogation. We tested the hypothesis that TX2 contributes to ethanol drinking and behavioral responses to ethanol. CRISPR/Cas9 mutagenesis was used to create a TX2 mutant mouse line in which 306 base‐pairs were deleted from the locus. RNA analysis revealed that an abnormal TX2 transcript was produced at an unchanged level in mutant animals. Behaviorally, mutant mice had reduced ethanol, gaboxadol and zolpidem‐induced loss of the righting response and reduced tolerance to ethanol in both sexes. In addition, a male‐specific reduction in two‐bottle choice every‐other‐day ethanol drinking was observed. Male TX2 mutants exhibited evidence of enhanced GABA release and altered GABAA receptor subunit composition in neurons of the nucleus accumbens shell. In C57BL6/J mice, TX2 within the cortex was cytoplasmic and largely present in Rbfox3+ neurons and IBA1+ microglia, but not in Olig2+ oligodendrocytes or in the majority of GFAP+ astrocytes. These data support the hypothesis that TX2 mutagenesis and dysregulation impacts ethanol drinking behavior and ethanol‐induced behavioral responses in mice, likely through alterations in the GABAergic system.

中文翻译：

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新型乙醇反应性lncRNAGm41261突变影响小鼠乙醇相关行为反应

长期接触酒精会导致基因表达广泛失调，从而导致酒精使用障碍 (AUD) 的发病机制。长非编码 RNA 是转录组的关键调节因子，我们假设其协调酒精诱导的转录组失调并导致 AUD。根据 AUD 与非 AUD 大脑的人类前额皮质、基底外侧杏仁核和伏核的 RNA 测序数据，人类LINC01265及其预测的鼠同源物GM41261（即TX2）被选择用于功能询问。我们测试了 TX2 有助于乙醇饮用和对乙醇的行为反应的假设。使用 CRISPR/Cas9 诱变创建了 TX2 突变小鼠品系，其中 306 个碱基对从基因座中删除。RNA 分析显示，突变动物中产生的异常 TX2 转录物水平未发生变化。在行为上，突变小鼠的乙醇、加波沙朵和唑吡坦引起的翻正反应丧失减少，并且对乙醇的耐受性降低。此外，还观察到男性每隔一天选择两瓶乙醇的次数有所减少。雄性 TX2 突变体表现出 GABA 释放增强和 GABA 改变的证据A伏隔核壳神经元中受体亚基的组成。在 C57BL6/J 小鼠中，皮质内的 TX2 位于细胞质中，主要存在于RBFOX3+ 神经元和 IBA1+ 小胶质细胞，但不在寡核苷酸2+ 少突胶质细胞或大多数 GFAP+ 星形胶质细胞。这些数据支持这样的假设：TX2 突变和失调可能通过 GABA 能系统的改变影响小鼠的乙醇饮用行为和乙醇诱导的行为反应。