Kerns Robnet T, Ravindranathan Ajay, Hassan Sajida, Cage Mary P, York Tim, Sikela James M, Williams Robert W, Miles Michael F
Department of Pharmacology/Toxicology and the Center for Study of Biological Complexity, Virginia Commonwealth University, Richmond, Virginia 23298, USA.
J Neurosci. 2005 Mar 2;25(9):2255-66. doi: 10.1523/JNEUROSCI.4372-04.2005.
Activation of the mesolimbic dopamine reward pathway by acute ethanol produces reinforcement and changes in gene expression that appear to be crucial to the molecular basis for adaptive behaviors and addiction. The inbred mouse strains DBA/2J and C57BL/6J exhibit contrasting acute behavioral responses to ethanol. We used oligonucleotide microarrays and bioinformatics methods to characterize patterns of gene expression in three brain regions of the mesolimbic reward pathway of these strains. Expression profiling included examination of both differences in gene expression 4 h after saline injection or acute ethanol (2 g/kg). Using a rigorous stepwise method for microarray analysis, we identified 788 genes differentially expressed in control DBA/2J versus C57BL/6J mice and 307 ethanol-regulated genes in the nucleus accumbens, prefrontal cortex, and ventral tegmental area. There were strikingly divergent patterns of ethanol-responsive gene expression in the two strains. Ethanol-responsive genes also showed clustering at discrete chromosomal regions, suggesting local chromatin effects in regulation. Ethanol-regulated genes were generally related to neuroplasticity, but regulation of discrete functional groups and pathways was brain region specific: glucocorticoid signaling, neurogenesis, and myelination in the prefrontal cortex; neuropeptide signaling and developmental genes, including factor Bdnf, in the nucleus accumbens; and retinoic acid signaling in the ventral tegmental area. Bioinformatics analysis identified several potential candidate genes for quantitative trait loci linked to ethanol behaviors, further supporting a role for expression profiling in identifying genes for complex traits. Brain region-specific changes in signaling and neuronal plasticity may be critical components in development of lasting ethanol behavioral phenotypes such as dependence, sensitization, and craving.
急性乙醇激活中脑边缘多巴胺奖赏通路会产生强化作用以及基因表达变化，这些变化似乎对适应性行为和成瘾的分子基础至关重要。近交系小鼠品系DBA/2J和C57BL/6J对乙醇表现出截然不同的急性行为反应。我们使用寡核苷酸微阵列和生物信息学方法来表征这些品系中脑边缘奖赏通路三个脑区的基因表达模式。表达谱分析包括检查注射生理盐水或急性乙醇（2 g/kg）后4小时基因表达的差异。使用严格的逐步微阵列分析方法，我们在对照DBA/2J与C57BL/6J小鼠中鉴定出788个差异表达基因，以及伏隔核、前额叶皮质和腹侧被盖区中的307个乙醇调节基因。这两个品系中乙醇反应性基因表达模式存在显著差异。乙醇反应性基因在离散的染色体区域也表现出聚类，表明在调控中存在局部染色质效应。乙醇调节基因通常与神经可塑性相关，但离散功能组和通路的调节具有脑区特异性：前额叶皮质中的糖皮质激素信号传导、神经发生和髓鞘形成；伏隔核中的神经肽信号传导和发育基因，包括脑源性神经营养因子（Bdnf）；以及腹侧被盖区中的视黄酸信号传导。生物信息学分析确定了几个与乙醇行为相关的数量性状位点的潜在候选基因，进一步支持了表达谱分析在识别复杂性状基因中的作用。信号传导和神经元可塑性的脑区特异性变化可能是持久乙醇行为表型（如依赖、敏化和渴望）发展的关键组成部分。
