Cross-Species Co-analysis of Prefrontal Cortex Chronic Ethanol Transcriptome Responses in Mice and Monkeys
Cross-Species Co-analysis of Prefrontal Cortex Chronic Ethanol Transcriptome Responses in Mice and Monkeys
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DOI：
10.3389/fnmol.2019.00197
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发表时间：
2019-08-13
影响因子：
4.8
通讯作者：
Miles, Michael F.
中科院分区：
文献类型：
--
作者：
Bogenpoh, James W.;Smith, Maren L.;Miles, Michael F.
尽管最近广泛的基因组和遗传研究的行为反应，乙醇，相对较少的新的治疗酒精使用障碍的治疗目标已被验证。在这里，我们描述了一个跨物种的基因组方法，重点是识别与慢性乙醇消费相关的基因网络。为了确定与人类酒精使用障碍高度相关的慢性乙醇消耗表型的大脑机制，并阐明未来潜在的治疗靶点，我们在慢性开放获取乙醇消耗的非人灵长类动物模型中进行了基因组研究。在多个动物队列中对来自恒河猴的前扣带回和膝下皮质中的RNA表达进行微阵列分析。基因网络与乙醇消费或显示富集乙醇调节基因的确定，因为是主要的乙醇相关的枢纽基因在这些网络。随后的共识模块分析用于共同分析猴数据与C57BU6J小鼠慢性间歇性乙醇蒸汽暴露和消耗模型的表达数据。在灵长类动物和啮齿类动物之间保守的乙醇相关基因网络富集了参与离散生物学功能的基因，包括髓鞘形成、突触传递、染色质修饰、高尔基体功能、翻译、细胞呼吸和RNA加工。特别是髓鞘相关的网络，表现出强烈的相关性与乙醇消费行为，并显示显着的网络重组之间的控制和乙醇饮用动物。进一步的生物信息学分析显示，这些网络也显示出与其他乙醇调节基因集的高度显著重叠。总之，这些研究提供了强大的灵长类动物和啮齿类动物的跨物种验证与慢性乙醇消费相关的基因网络。我们的研究结果也为酒精使用障碍的未来治疗干预提供了潜在的新焦点。
Despite recent extensive genomic and genetic studies on behavioral responses to ethanol, relatively few new therapeutic targets for the treatment of alcohol use disorder have been validated. Here, we describe a cross-species genomic approach focused on identifying gene networks associated with chronic ethanol consumption. To identify brain mechanisms underlying a chronic ethanol consumption phenotype highly relevant to human alcohol use disorder, and to elucidate potential future therapeutic targets, we conducted a genomic study in a non-human primate model of chronic open-access ethanol consumption. Microarray analysis of RNA expression in anterior cingulate and subgenual cortices from rhesus macaques was performed across multiple cohorts of animals. Gene networks correlating with ethanol consumption or showing enrichment for ethanol-regulated genes were identified, as were major ethanol-related hub genes within these networks. A subsequent consensus module analysis was used to co-analyze monkey data with expression data from a chronic intermittent ethanol vapor-exposure and consumption model in C57BU6J mice. Ethanol-related gene networks conserved between primates and rodents were enriched for genes involved in discrete biological functions, including; myelination, synaptic transmission, chromatin modification, Golgi apparatus function, translation, cellular respiration, and RNA processing. The myelin-related network, in particular, showed strong correlations with ethanol consumption behavior and displayed marked network reorganization between control and ethanol-drinking animals. Further bioinformatics analysis revealed that these networks also showed highly significant overlap with other ethanol-regulated gene sets. Altogether, these studies provide robust primate and rodent cross-species validation of gene networks associated with chronic ethanol consumption. Our results also suggest potential novel focal points for future therapeutic interventions in alcohol use disorder.