Fyn-dependent gene networks in acute ethanol sensitivity.
Fyn-dependent gene networks in acute ethanol sensitivity.
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DOI：
10.1371/journal.pone.0082435
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Miles MF
中科院分区：
文献类型：
--
作者：
Farris SP;Miles MF
在人类和动物模型中的研究证明，对酒精的急性行为反应是长期饮酒行为风险的诱因。来自我们实验室的先前的微阵列数据记录了急性乙醇对基因表达谱响应的品系和大脑区域特异性差异，这可能是乙醇行为表型的潜在调节因素。非受体酪氨酸激酶Fyn此前被认为与急性乙醇的镇静催眠反应有关。为了进一步了解Fyn如何调节乙醇行为，我们使用了全基因组表达谱。我们在对照组和Fyn基因敲除小鼠的伏隔核(NAC)、前额叶皮质(PFC)和腹侧中脑(VMB)研究了基础和急性乙醇诱发(3g/kg)的基因表达模式。生物信息学分析发现，在大脑的三个区域，一组与Fyn相关的基因网络受到急性乙醇的不同调控。特别是，我们的分析表明，NAC和PFC中髓鞘相关基因表达的协调基础减少是Fyn零动物对乙醇镇静敏感性的潜在因素。对BXD重组近交系(RI)小鼠进行的电子分析发现，Fyn的表达与先前发表的乙醇翻正反射丧失(Lorr)表型之间存在显著相关性。通过结合多个基因组数据集上与Fyn和LorR相关的PFC基因表达，我们识别了与LorR相关的以Fyn为中心的强大基因网络。因此，我们的结果表明，Fyn基因敲除小鼠的特定脑区存在多个系统范围的变化，PFC内不同的Fyn依赖的表达网络可能是急性乙醇引起的LOR的重要决定因素。这些结果增加了对Fyn激酶缺失动物急性酒精行为敏感性的解释，并确定了影响乙醇Lorr变异的Fyn中心基因网络。这样的网络还可能为未来治疗和预防酒精使用障碍的药物疗法的设计提供信息。
Studies in humans and animal models document that acute behavioral responses to ethanol are predisposing factor for the risk of long-term drinking behavior. Prior microarray data from our laboratory document strain- and brain region-specific variation in gene expression profile responses to acute ethanol that may be underlying regulators of ethanol behavioral phenotypes. The non-receptor tyrosine kinase Fyn has previously been mechanistically implicated in the sedative-hypnotic response to acute ethanol. To further understand how Fyn may modulate ethanol behaviors, we used whole-genome expression profiling. We characterized basal and acute ethanol-evoked (3 g/kg) gene expression patterns in nucleus accumbens (NAC), prefrontal cortex (PFC), and ventral midbrain (VMB) of control and Fyn knockout mice. Bioinformatics analysis identified a set of Fyn-related gene networks differently regulated by acute ethanol across the three brain regions. In particular, our analysis suggested a coordinate basal decrease in myelin-associated gene expression within NAC and PFC as an underlying factor in sensitivity of Fyn null animals to ethanol sedation. An in silico analysis across the BXD recombinant inbred (RI) strains of mice identified a significant correlation between Fyn expression and a previously published ethanol loss-of-righting-reflex (LORR) phenotype. By combining PFC gene expression correlates to Fyn and LORR across multiple genomic datasets, we identified robust Fyn-centric gene networks related to LORR. Our results thus suggest that multiple system-wide changes exist within specific brain regions of Fyn knockout mice, and that distinct Fyn-dependent expression networks within PFC may be important determinates of the LORR due to acute ethanol. These results add to the interpretation of acute ethanol behavioral sensitivity in Fyn kinase null animals, and identify Fyn-centric gene networks influencing variance in ethanol LORR. Such networks may also inform future design of pharmacotherapies for the treatment and prevention of alcohol use disorders.
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DOI：
10.1111/j.1530-0277.2006.00296.x
发表时间：
2007-02-01
影响因子：
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作者：
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