Effects of Repeated Alcohol Abstinence on Within-Subject Prefrontal Cortical Gene Expression in Rhesus Macaques

This study focuses on the intersection of brain gene expression and the behavioral effects of repeated abstinence in a non-human primate (NHP) model of chronic ethanol consumption. We have previously published on the effects of how chronic consumption affects brain gene expression without abstinence. This study complements our prior publications. Our results illustrate that repeated abstinence increases ethanol consumption across all drinking phenotypes, from light to binge to heavy to very heavy drinking. Our biopsy/necropsy within subject design, was used to collect area 46 gene expression data (RNA-Seq). For the individuals that converted from heavy to very heavy drinking, post-abstinence within-subject gene expression changes were associated with highly significant ontologies that included immune response (FDR < 9 x 10-7), plasma membrane changes (FDR < 1 x 10-7) and the negative regulation of MAP kinase activity (FDR < 3 x 10-5). The genes associated with these ontologies suggest new targets for treating severe escalated drinking following repeated alcohol abstinence attempts.

本研究聚焦于慢性乙醇摄入非人灵长类（NHP）模型中，大脑基因表达与反复戒断行为效应之间的关联。我们此前已发表过关于无戒断状态下慢性乙醇摄入对大脑基因表达影响的相关成果，本研究是对前述研究的补充与完善。本研究结果显示，反复戒断可提升所有饮酒表型个体的乙醇摄入量，覆盖轻度饮酒、暴饮、重度饮酒及极重度饮酒群体。我们采用受试者内活检/尸检设计，收集了大脑46区的基因表达数据（RNA测序（RNA-Seq））。对于从重度饮酒转向极重度饮酒的个体而言，戒断后受试者内的基因表达变化与多个高度显著的基因本体（Gene Ontology，GO）条目显著相关，包括免疫应答（错误发现率（False Discovery Rate，FDR）< 9×10^-7）、质膜改变（FDR < 1×10^-7）以及丝裂原活化蛋白激酶（Mitogen-Activated Protein Kinase，MAPK）活性负调控（FDR < 3×10^-5）。与这些基因本体条目相关的基因，为反复戒酒尝试后出现严重饮酒量升级的人群提供了全新的治疗靶点。