From the, Department of Behavioral Neuroscience, VA Portland Health Care System, Oregon Health & Science University, Portland, Oregon.
Alcohol Clin Exp Res. 2020 Apr;44(4):820-830. doi: 10.1111/acer.14312. Epub 2020 Mar 16.
Genetic factors significantly affect alcohol consumption and vulnerability to withdrawal. Furthermore, some genetic models showing predisposition to severe withdrawal are also predisposed to low ethanol (EtOH) consumption and vice versa, even when tested independently in naïve animals.
Beginning with a C57BL/6J × DBA/2J F2 intercross founder population, animals were simultaneously selectively bred for both high alcohol consumption and low acute withdrawal (SOT line), or vice versa (NOT line). Using randomly chosen fourth selected generation (S4) mice (N = 18-22/sex/line), RNA-Seq was employed to assess genome-wide gene expression in ventral striatum. The MegaMUGA array was used to detect genome-wide genotypic differences. Differential gene expression and the weighted gene co-expression network analysis were implemented as described elsewhere (Genes Brain Behav 16, 2017, 462).
The new selection of the SOT and NOT lines was similar to that reported previously (Alcohol Clin Exp Res 38, 2014, 2915). One thousand eight hundred and sixteen transcripts were detected as differentially expressed between the lines. For genes more highly expressed in the SOT line, there was enrichment in genes associated with cell adhesion, synapse organization, and postsynaptic membrane. The genes with a cell adhesion annotation included 23 protocadherins, Mpdz and Dlg2. Genes with a postsynaptic membrane annotation included Gabrb3, Gphn, Grid1, Grin2b, Grin2c, and Grm3. The genes more highly expressed in the NOT line were enriched in a network module (red) with annotations associated with mitochondrial function. Several of these genes were module hub nodes, and these included Nedd8, Guk1, Elof1, Ndufa8, and Atp6v1f.
Marked effects of selection on gene expression were detected. The NOT line was characterized by higher expression of hub nodes associated with mitochondrial function. Genes more highly expressed in the SOT aligned with previous findings, for example, Colville and colleagues (Genes Brain Behav 16, 2017, 462) that both high EtOH preference and consumption are associated with effects on cell adhesion and glutamate synaptic plasticity.
遗传因素对饮酒量和戒断易感性有显著影响。此外，一些显示易患严重戒断的遗传模型也易患低乙醇（EtOH）消耗，反之亦然，即使在未经处理的动物中独立测试也是如此。
从 C57BL/6J×DBA/2J F2 杂交创始人群开始，动物同时被选择性繁殖为高酒精消耗和低急性戒断（SOT 线），或反之亦然（NOT 线）。使用随机选择的第四代（S4）小鼠（N=18-22/性别/线），使用 RNA-Seq 评估腹侧纹状体的全基因组基因表达。使用 MegaMUGA 阵列检测全基因组基因型差异。如前所述（Genes Brain Behav 16, 2017, 462），实施差异基因表达和加权基因共表达网络分析。
SOT 和 NOT 线的新选择与之前报道的相似（Alcohol Clin Exp Res 38, 2014, 2915）。1816 个转录本被检测为线间差异表达。对于在 SOT 线中表达更高的基因，与细胞粘附、突触组织和突触后膜相关的基因富集。具有细胞粘附注释的基因包括 23 个原钙粘蛋白、Mpdz 和Dlg2。具有突触后膜注释的基因包括 Gabrb3、Gphn、Grid1、Grin2b、Grin2c 和 Grm3。在 NOT 线中表达更高的基因富集在一个具有与线粒体功能相关注释的网络模块（红色）中。这些基因中的几个是模块枢纽节点，包括 Nedd8、Guk1、Elof1、Ndufa8 和 Atp6v1f。
检测到选择对基因表达的显著影响。NOT 线的特征是与线粒体功能相关的枢纽节点表达更高。在 SOT 中表达更高的基因与 Colville 及其同事的先前发现一致（Genes Brain Behav 16, 2017, 462），即高 EtOH 偏好和消耗都与细胞粘附和谷氨酸突触可塑性的影响有关。
