Differential regulation of alcohol consumption and reward by the transcriptional cofactor LMO4.
Differential regulation of alcohol consumption and reward by the transcriptional cofactor LMO4.
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转录辅因子LMO4对酒精消耗和奖赏的不同调控。
DOI：
10.1038/s41380-020-0706-8
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发表时间：
2021-06
影响因子：
11
通讯作者：
Messing RO
中科院分区：
文献类型：
--
作者：
Maiya R;Pomrenze MB;Tran T;Tiwari GR;Beckham A;Paul MT;Dayne Mayfield R;Messing RO
反复饮酒会导致基因表达发生变化，这被认为是从适度饮酒过渡到过度饮酒的基础。然而，这些变化如何被动员到导致酒精依赖的适应不良反应的机制还不是很清楚。一种机制可能涉及招募转录辅助调节因子，它们结合并调节几种转录因子的活性。我们的结果表明，转录调控因子LMO4就是这样一种候选调控因子。Lmo4基因缺陷小鼠(Lmo4gt/+)在24小时间歇性饮酒过程中显著增加了饮酒量，并表现出更强的酒精偏好。ShRNA介导的伏核(NAC)中LMO4的敲除增加了酒精的消耗，而杏仁基底外侧核(BLA)中的LMO4的敲除减少了酒精的消耗，并降低了对酒精的条件性位置偏好。为了确定这些不同表型背后的分子机制，我们对野生型和Lmo4gt/+小鼠的这两个大脑区域进行了无偏见的转录组谱分析。我们的结果显示，LMO4的转录靶点在两个大脑区域之间有很大的不同，这可能解释了LMO4基因敲除后观察到的不同表型。生物信息学分析表明，OPRK1和细胞外基质(ECM)相关基因是LMO4在BLA中的重要转录靶点。染色质免疫沉淀(ChIP)显示LMO4结合了OPRK1启动子元件。与这些结果一致的是，阻断ECM或在BLA中注入选择性kappa阿片受体(KOR)拮抗剂NorBNI可以减少酒精摄入量。因此，我们的结果表明，LMO4调节的转录网络调节BLA中的酒精消耗。
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 mobilized to 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 several 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-hour intermittent access procedure. shRNA-mediated knockdown of Lmo4 in the nucleus accumbens (NAc) enhanced alcohol consumption whereas knockdown in the basolateral amygdala (BLA) decreased alcohol consumption and reduced conditioned place preference to 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 (ChIP) revealed that LMO4 bound Oprk1 promoter elements. Consistent with these results, disruption of the ECM or infusion of NorBNI, a selective kappa opioid receptor (KOR) antagonist, in the BLA reduced alcohol consumption. Hence our results indicate that an LMO4-regulated transcriptional network regulates alcohol consumption in the BLA.
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酒精中毒的一二拳：中央杏仁核的作用/kappa-阿片受体。
影响因子：
10.6
作者：
Kissler, Jessica L.;Sirohi, Sunil;Reis, Daniel J.;Jansen, Heiko T.;Quock, Raymond M.;Smith, Daniel G.;Walker, Brendan M.
通讯作者：
Walker, Brendan M.
DOI：
10.1007/978-1-60761-058-8_17
发表时间：
2010-01-01
期刊：
MOUSE MODELS FOR DRUG DISCOVERY: METHODS AND PROTOCOLS
影响因子：
--
作者：
Lasek, Amy W.;Azouaou, Nourredine
通讯作者：
Azouaou, Nourredine
影响因子：
3.7
作者：
Lasek AW;Lim J;Kliethermes CL;Berger KH;Joslyn G;Brush G;Xue L;Robertson M;Moore MS;Vranizan K;Morris SW;Schuckit MA;White RL;Heberlein U
通讯作者：
Heberlein U
影响因子：
11.2
作者：
Hall AW;Battenhouse AM;Shivram H;Morris AR;Cowperthwaite MC;Shpak M;Iyer VR
通讯作者：
Iyer VR
影响因子：
3.1
作者：
Lim, Jana P.;Zou, Mimi E.;Janak, Patricia H.;Messing, Robert O.
通讯作者：
Messing, Robert O.