Kisby Brent R, Farris Sean P, McManus Michelle M, Varodayan Florence P, Roberto Marisa, Harris R Adron, Ponomarev Igor
Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
Department of Neuroscience, University of Texas at Austin, Austin, TX 78715, USA.
Brain Sci. 2021 Aug 29;11(9):1149. doi: 10.3390/brainsci11091149.
Alcohol dependence is associated with adverse consequences of alcohol (ethanol) use and is evident in most severe cases of alcohol use disorder (AUD). The central nucleus of the amygdala (CeA) plays a critical role in the development of alcohol dependence and escalation of alcohol consumption in dependent subjects. Molecular mechanisms underlying the CeA-driven behavioral changes are not well understood. Here, we examined the effects of alcohol on global gene expression in the CeA using a chronic intermittent ethanol (CIE) vapor model in rats and RNA sequencing (RNA-Seq). The CIE procedure resulted in robust changes in CeA gene expression during intoxication, as the number of differentially expressed genes (DEGs) was significantly greater than those expected by chance. Over-representation analysis of cell types, functional groups and molecular pathways revealed biological categories potentially important for the development of alcohol dependence in our model. Genes specific for astrocytes, myelinating oligodendrocytes, and endothelial cells were over-represented in the DEG category, suggesting that these cell types were particularly affected by the CIE procedure. The majority of the over-represented functional groups and molecular pathways were directly related to the functions of glial and endothelial cells, including extracellular matrix (ECM) organization, myelination, and the regulation of innate immune response. A coordinated regulation of several ECM metalloproteinases (e.g., ; ), their substrates (e.g., multiple collagen genes and myelin basic protein; ), and a metalloproteinase inhibitor, , suggests a specific mechanism for ECM re-organization in response to chronic alcohol, which may modulate neuronal activity and result in behavioral changes, such as an escalation of alcohol drinking. Our results highlight the importance of glial and endothelial cells in the effects of chronic alcohol exposure on the CeA, and demonstrate further insight into the molecular mechanisms of alcohol dependence in rats. These molecular targets may be used in future studies to develop therapeutics to treat AUD.
酒精依赖与酒精（乙醇）使用的不良后果相关，在大多数严重酒精使用障碍（AUD）病例中很明显。杏仁核中央核（CeA）在酒精依赖的发展以及依赖个体酒精摄入量的增加中起关键作用。CeA驱动的行为变化背后的分子机制尚不清楚。在这里，我们使用大鼠慢性间歇性乙醇（CIE）蒸气模型和RNA测序（RNA-Seq）研究了酒精对CeA中全局基因表达的影响。CIE程序导致中毒期间CeA基因表达发生强烈变化，因为差异表达基因（DEG）的数量明显大于偶然预期的数量。对细胞类型、功能组和分子途径的过度表达分析揭示了在我们的模型中对酒精依赖发展可能重要的生物学类别。星形胶质细胞、有髓少突胶质细胞和内皮细胞特有的基因在DEG类别中过度表达，表明这些细胞类型特别受CIE程序影响。大多数过度表达的功能组和分子途径与神经胶质细胞和内皮细胞的功能直接相关，包括细胞外基质（ECM）组织、髓鞘形成和先天免疫反应的调节。几种ECM金属蛋白酶（例如；）、它们的底物（例如多种胶原蛋白基因和髓鞘碱性蛋白；）和一种金属蛋白酶抑制剂的协同调节表明，存在一种针对慢性酒精的ECM重组的特定机制，这可能调节神经元活动并导致行为变化，例如饮酒量增加。我们的结果突出了神经胶质细胞和内皮细胞在慢性酒精暴露对CeA影响中的重要性，并进一步深入了解了大鼠酒精依赖的分子机制。这些分子靶点可用于未来研究以开发治疗AUD的疗法。
