Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania.
Biol Psychiatry. 2018 Dec 15;84(12):867-880. doi: 10.1016/j.biopsych.2018.04.009. Epub 2018 Apr 25.
Global changes in gene expression underlying circuit and behavioral dysregulation associated with cocaine addiction remain incompletely understood. Here, we show how a history of cocaine self-administration (SA) reprograms transcriptome-wide responses throughout the brain's reward circuitry at baseline and in response to context and/or cocaine re-exposure after prolonged withdrawal (WD).
We assigned male mice to one of six groups: saline/cocaine SA + 24-hour WD or saline/cocaine SA + 30-day WD + an acute saline/cocaine challenge within the previous drug-paired context. RNA sequencing was conducted on six interconnected brain reward regions. Using pattern analysis of gene expression and factor analysis of behavior, we identified genes that are strongly associated with addiction-related behaviors and uniquely altered by a history of cocaine SA. We then identified potential upstream regulators of these genes.
We focused on three patterns of gene expression that reflect responses to 1) acute cocaine, 2) context re-exposure, and 3) drug + context re-exposure. These patterns revealed region-specific regulation of gene expression. Further analysis revealed that each of these gene expression patterns correlated with an addiction index-a composite score of several addiction-like behaviors during cocaine SA-in a region-specific manner. Cyclic adenosine monophosphate response element binding protein and nuclear receptor families were identified as key upstream regulators of genes associated with such behaviors.
This comprehensive picture of transcriptome-wide regulation in the brain's reward circuitry by cocaine SA and prolonged WD provides new insight into the molecular basis of cocaine addiction, which will guide future studies of the key molecular pathways involved.
可卡因成瘾相关的回路和行为失调的基因表达的全球变化仍然不完全清楚。在这里，我们展示了可卡因自我给药（SA）的历史如何在基线以及在长时间戒断（WD）后重新暴露于环境和/或可卡因后，重塑大脑奖励回路中全转录组反应。
我们将雄性小鼠分为六组之一：盐水/可卡因 SA + 24 小时 WD 或盐水/可卡因 SA + 30 天 WD + 在以前药物配对环境内的急性盐水/可卡因挑战。对六个相互连接的大脑奖励区域进行 RNA 测序。使用基因表达模式分析和行为因子分析，我们确定了与成瘾相关行为强烈相关且因可卡因 SA 历史而独特改变的基因。然后，我们确定了这些基因的潜在上游调节剂。
我们专注于反映对 1）急性可卡因、2）环境重新暴露和 3）药物+环境重新暴露的三种基因表达模式。这些模式揭示了区域特异性的基因表达调控。进一步分析表明，这些基因表达模式中的每一种都以区域特异性的方式与成瘾指数（可卡因 SA 期间几种成瘾样行为的综合得分）相关。环磷酸腺苷反应元件结合蛋白和核受体家族被确定为与这些行为相关的基因的关键上游调节剂。
可卡因 SA 和长时间 WD 对大脑奖励回路全转录组调节的这种全面描述为可卡因成瘾的分子基础提供了新的见解，并将指导涉及的关键分子途径的未来研究。
