Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia, United States of America.
PLoS One. 2013 Nov 29;8(11):e82435. doi: 10.1371/journal.pone.0082435. eCollection 2013.
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.
在人类和动物模型中的研究表明，急性行为反应是长期饮酒行为风险的一个倾向因素。我们实验室之前的微阵列数据记录了基因表达谱对急性乙醇的反应存在与应变和脑区特异性的变化，这些变化可能是乙醇行为表型的潜在调节因子。非受体酪氨酸激酶 Fyn 以前在急性乙醇的镇静-催眠反应的机制中被牵涉。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分析。我们描述了对照和 Fyn 敲除小鼠伏隔核（NAC）、前额叶皮层（PFC）和腹侧中脑（VMB）中基础和急性乙醇诱导（3 g/kg）的基因表达模式。生物信息学分析确定了一组由急性乙醇在三个脑区不同调节的 Fyn 相关基因网络。特别是，我们的分析表明，NAC 和 PFC 中髓鞘相关基因表达的基础下调是 Fyn 敲除动物对乙醇镇静敏感性的一个潜在因素。对 BXD 重组近交系（RI）小鼠的计算机分析表明，Fyn 表达与先前发表的乙醇失去翻正反射（LORR）表型之间存在显著相关性。通过将 PFC 基因表达与多个基因组数据集的 Fyn 和 LORR 相关联，我们确定了与 LORR 相关的稳健的 Fyn 中心基因网络。我们的结果表明，Fyn 敲除小鼠的特定脑区存在多个系统范围的变化，而 PFC 中独特的 Fyn 依赖性表达网络可能是急性乙醇导致 LORR 的重要决定因素。这些结果增加了对 Fyn 激酶缺失动物急性乙醇行为敏感性的解释，并确定了影响乙醇 LORR 变异性的 Fyn 中心基因网络。这些网络也可能为治疗和预防酒精使用障碍的药物治疗提供信息。
