Department of Neuroscience, The University of Texas at Austin, Austin, TX, 78712, USA.
Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, TX, 78712, USA.
Mol Psychiatry. 2021 Jun;26(6):2175-2186. doi: 10.1038/s41380-020-0706-8. Epub 2020 Mar 6.
Repeated alcohol exposure leads to changes in gene expression that are thought to underlie the transition from moderate to excessive drinking. However, the mechanisms by which these changes are integrated into a maladaptive response that leads to alcohol dependence are not well understood. One mechanism could involve the recruitment of transcriptional co-regulators that bind and modulate the activity of transcription factors. Our results indicate that the transcriptional regulator LMO4 is one such candidate regulator. Lmo4-deficient mice (Lmo4gt/+) consumed significantly more and showed enhanced preference for alcohol in a 24 h intermittent access drinking procedure. shRNA-mediated knockdown of Lmo4 in the nucleus accumbens enhanced alcohol consumption, whereas knockdown in the basolateral amygdala (BLA) decreased alcohol consumption and reduced conditioned place preference for alcohol. To ascertain the molecular mechanisms that underlie these contrasting phenotypes, we carried out unbiased transcriptome profiling of these two brain regions in wild type and Lmo4gt/+ mice. Our results revealed that the transcriptional targets of LMO4 are vastly different between the two brain regions, which may explain the divergent phenotypes observed upon Lmo4 knockdown. Bioinformatic analyses revealed that Oprk1 and genes related to the extracellular matrix (ECM) are important transcriptional targets of LMO4 in the BLA. Chromatin immunoprecipitation revealed that LMO4 bound Oprk1 promoter elements. Consistent with these results, disruption of the ECM or infusion of norbinaltorphimine, a selective kappa opioid receptor antagonist, in the BLA reduced alcohol consumption. Hence our results indicate that an LMO4-regulated transcriptional network regulates alcohol consumption in the BLA.
反复饮酒会导致基因表达的改变，这些改变被认为是从适度饮酒向过度饮酒转变的基础。然而，这些变化如何整合到导致酒精依赖的适应不良反应中尚不清楚。一种机制可能涉及募集转录共调节剂，这些调节剂结合并调节转录因子的活性。我们的研究结果表明，转录调节因子 LMO4 就是这样一个候选调节因子。Lmo4 缺陷型小鼠（Lmo4gt/+）在 24 小时间歇性酒精摄入实验中消耗了更多的酒精，并表现出对酒精的偏好增强。在伏隔核中用 shRNA 敲低 Lmo4 会增强酒精消耗，而在基底外侧杏仁核（BLA）中敲低 Lmo4 会减少酒精消耗并降低酒精的条件性位置偏好。为了确定这些相反表型的潜在分子机制，我们对野生型和 Lmo4gt/+ 小鼠的这两个脑区进行了无偏转录组谱分析。我们的结果表明，LMO4 的转录靶标在两个脑区之间有很大的不同，这可能解释了在 Lmo4 敲低时观察到的不同表型。生物信息学分析表明，Oprk1 和与细胞外基质（ECM）相关的基因是 LMO4 在 BLA 中的重要转录靶标。染色质免疫沉淀显示 LMO4 结合 Oprk1 启动子元件。与这些结果一致，破坏 ECM 或在 BLA 中注入选择性κ阿片受体拮抗剂诺布纳他林可减少酒精消耗。因此，我们的结果表明，LMO4 调节的转录网络调节了 BLA 中的酒精消耗。
