Baker Jessica A, Li Jingxin, Zhou Diana, Yang Ming, Cook Melloni N, Jones Byron C, Mulligan Megan K, Hamre Kristin M, Lu Lu
Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN, 38163, USA.
Department of Biological Sciences, Vanderbilt University, Nashville, TN, 37235, USA.
Alcohol. 2017 Feb;58:139-151. doi: 10.1016/j.alcohol.2016.08.008. Epub 2016 Dec 16.
Alcohol abuse is a complex disorder, which is confounded by other factors, including stress. In the present study, we examined gene expression in the hippocampus of BXD recombinant inbred mice after exposure to ethanol (NOE), stress (RSS), and the combination of both (RSE). Mice were given an intraperitoneal (i.p.) injection of 1.8 g/kg ethanol or saline, and subsets of both groups were exposed to acute restraint stress for 15 min or controls. Gene expression in the hippocampus was examined using microarray analysis. Genes that were significantly (p < 0.05, q < 0.1) differentially expressed were further evaluated. Bioinformatic analyses were predominantly performed using tools available at GeneNetwork.org, and included gene ontology, presence of cis-regulation or polymorphisms, phenotype correlations, and principal component analyses. Comparisons of differential gene expression between groups showed little overlap. Gene Ontology demonstrated distinct biological processes in each group with the combined exposure (RSE) being unique from either the ethanol (NOE) or stress (RSS) group, suggesting that the interaction between these variables is mediated through diverse molecular pathways. This supports the hypothesis that exposure to stress alters ethanol-induced gene expression changes and that exposure to alcohol alters stress-induced gene expression changes. Behavior was profiled in all groups following treatment, and many of the differentially expressed genes are correlated with behavioral variation within experimental groups. Interestingly, in each group several genes were correlated with the same phenotype, suggesting that these genes are the potential origins of significant genetic networks. The distinct sets of differentially expressed genes within each group provide the basis for identifying molecular networks that may aid in understanding the complex interactions between stress and ethanol, and potentially provide relevant therapeutic targets. Using Ptp4a1, a candidate gene underlying the quantitative trait locus for several of these phenotypes, and network analyses, we show that a large group of differentially expressed genes in the NOE group are highly interrelated, some of which have previously been linked to alcohol addiction or alcohol-related phenotypes.
酒精滥用是一种复杂的疾病，它受到包括压力在内的其他因素的干扰。在本研究中，我们检测了BXD重组近交系小鼠在暴露于乙醇（NOE）、压力（RSS）以及二者联合作用（RSE）后海马体中的基因表达情况。给小鼠腹腔注射1.8 g/kg乙醇或生理盐水，两组中的部分小鼠暴露于急性束缚应激15分钟或作为对照。使用微阵列分析检测海马体中的基因表达。对显著差异表达（p < 0.05，q < 0.1）的基因进行进一步评估。生物信息学分析主要使用GeneNetwork.org上可用的工具，包括基因本体论、顺式调控或多态性的存在、表型相关性以及主成分分析。组间差异基因表达的比较显示几乎没有重叠。基因本体论表明每组都有独特的生物学过程，联合暴露组（RSE）与乙醇组（NOE）或应激组（RSS）均不同，这表明这些变量之间的相互作用是通过多种分子途径介导的。这支持了以下假设：暴露于压力会改变乙醇诱导的基因表达变化，而暴露于酒精会改变压力诱导的基因表达变化。在处理后的所有组中对行为进行了分析，许多差异表达基因与实验组内的行为变化相关。有趣的是，在每组中几个基因与相同的表型相关，这表明这些基因是重要遗传网络的潜在起源。每组中不同的差异表达基因集为识别分子网络提供了基础，这些分子网络可能有助于理解压力与乙醇之间的复杂相互作用，并有可能提供相关的治疗靶点。使用Ptp4a1（这些表型中几个数量性状位点的候选基因）和网络分析，我们表明NOE组中一大组差异表达基因高度相关，其中一些基因先前已与酒精成瘾或酒精相关表型相关联。
