Binge Ethanol Drinking Produces Sexually Divergent and Distinct Changes in Nucleus Accumbens Signaling Cascades and Pathways in Adult C57BL/6J Mice.
Binge Ethanol Drinking Produces Sexually Divergent and Distinct Changes in Nucleus Accumbens Signaling Cascades and Pathways in Adult C57BL/6J Mice.
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DOI：
10.3389/fgene.2018.00325
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发表时间：
2018
影响因子：
3.7
通讯作者：
Guizzetti M
中科院分区：
文献类型：
--
作者：
Finn DA;Hashimoto JG;Cozzoli DK;Helms ML;Nipper MA;Kaufman MN;Wiren KM;Guizzetti M
我们之前已经确定，反复狂饮乙醇在成年C57BL/6J小鼠伏隔核（NAc） 1组代谢性谷氨酸受体下游信号的调节中产生了性别差异。本研究的目的是表征成年雄性和雌性C57BL/6J小鼠在7次酗酒后NAc中RNA表达的差异，与对照组相比。这种狂饮过程产生了高摄入量（平均2.2 g/kg/30分钟）和血液乙醇浓度（平均1.3 mg/ml）。在第7次暴食后24 h，对小鼠实施安乐死，并对NAc组织进行集中qPCR阵列分析，量化384个基因在定制小鼠情绪障碍阵列中的表达水平，重点是谷氨酸能信号（3个阵列/组）。我们发现，在7次酒精狂欢后，雄性小鼠的50个基因和雌性小鼠的70个基因发生了显著调节。值得注意的是，14个基因在男性和女性中都受到调节，代表了酗酒的共同目标。然而，这14个基因中有10个基因的表达具有强烈的二态性（例如，对Crhr2、Fos、Nos1和Star等基因的调控相反），14个基因中只有4个基因的调控方向相同（Drd5、Grm4、Ranbp9和Reln）。有趣的是，在雄性和雌性小鼠中，狂饮酒精对每种性别的前30个受调节基因有显著差异，NAc中这种不同的神经适应性反应可能导致不同性别之间不同生物途径的失调。利用独创性途径分析来表征表达差异，以确定典型途径、上游调节因子和重要的生物学功能。表达差异表明雌性小鼠狂欢饮酒会改变激素信号和免疫功能，而雄性小鼠狂欢饮酒的主要目标是神经递质代谢。因此，这些结果表明，反复狂饮酒精的转录反应受到性别的强烈影响，并强调了在开发治疗酒精使用障碍的潜在药物治疗靶点时考虑性别的重要性。
We previously determined that repeated binge ethanol drinking produced sex differences in the regulation of signaling downstream of Group 1 metabotropic glutamate receptors in the nucleus accumbens (NAc) of adult C57BL/6J mice. The purpose of the present study was to characterize RNA expression differences in the NAc of adult male and female C57BL/6J mice following 7 binge ethanol drinking sessions, when compared with controls consuming water. This binge drinking procedure produced high intakes (average >2.2 g/kg/30 min) and blood ethanol concentrations (average >1.3 mg/ml). Mice were euthanized at 24 h after the 7th binge session, and focused qPCR array analysis was employed on NAc tissue to quantify expression levels of 384 genes in a customized Mouse Mood Disorder array, with a focus on glutamatergic signaling (3 arrays/group). We identified significant regulation of 50 genes in male mice and 70 genes in female mice after 7 ethanol binges. Notably, 14 genes were regulated in both males and females, representing common targets to binge ethanol drinking. However, expression of 10 of these 14 genes was strongly dimorphic (e.g., opposite regulation for genes such as Crhr2, Fos, Nos1, and Star), and only 4 of the 14 genes were regulated in the same direction (Drd5, Grm4, Ranbp9, and Reln). Interestingly, the top 30 regulated genes by binge ethanol drinking for each sex differed markedly in the male and female mice, and this divergent neuroadaptive response in the NAc could result in dysregulation of distinct biological pathways between the sexes. Characterization of the expression differences with Ingenuity Pathway Analysis was used to identify Canonical Pathways, Upstream Regulators, and significant Biological Functions. Expression differences suggested that hormone signaling and immune function were altered by binge drinking in female mice, whereas neurotransmitter metabolism was a central target of binge ethanol drinking in male mice. Thus, these results indicate that the transcriptional response to repeated binge ethanol drinking was strongly influenced by sex, and they emphasize the importance of considering sex in the development of potential pharmacotherapeutic targets for the treatment of alcohol use disorder.
影响因子：
4.1
作者：
Wiren, Kristine M.;Semirale, Anthony A.;Hashimoto, Joel G.;Zhang, Xiao-Wei
通讯作者：
Zhang, Xiao-Wei