Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Genetics and Genomic Sciences and Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Sci Adv. 2023 Jun 9;9(23):eadg8558. doi: 10.1126/sciadv.adg8558.
Opioid use disorder (OUD) looms as one of the most severe medical crises facing society. More effective therapeutics will require a deeper understanding of molecular changes supporting drug-taking and relapse. Here, we develop a brain reward circuit-wide atlas of opioid-induced transcriptional regulation by combining RNA sequencing (RNA-seq) and heroin self-administration in male mice modeling multiple OUD-relevant conditions: acute heroin exposure, chronic heroin intake, context-induced drug-seeking following abstinence, and relapse. Bioinformatics analysis of this rich dataset identified numerous patterns of transcriptional regulation, with both region-specific and pan-circuit biological domains affected by heroin. Integration of RNA-seq data with OUD-relevant behavioral outcomes uncovered region-specific molecular changes and biological processes that predispose to OUD vulnerability. Comparisons with human OUD RNA-seq and genome-wide association study data revealed convergent molecular abnormalities and gene candidates with high therapeutic potential. These studies outline molecular reprogramming underlying OUD and provide a foundational resource for future investigations into mechanisms and treatment strategies.
阿片类药物使用障碍 (OUD) 是社会面临的最严重的医学危机之一。更有效的治疗方法需要更深入地了解支持吸毒和复发的分子变化。在这里，我们通过结合 RNA 测序 (RNA-seq) 和雄性小鼠中模拟多种与 OUD 相关条件的海洛因自我给药，开发了一个大脑奖励回路的阿片类药物诱导转录调控图谱：急性海洛因暴露、慢性海洛因摄入、戒断后环境诱导的觅药和复发。对这个丰富数据集的生物信息学分析确定了许多转录调控模式，海洛因影响了区域特异性和全回路生物域。将 RNA-seq 数据与与 OUD 相关的行为结果进行整合，揭示了易患 OUD 的区域特异性分子变化和生物学过程。与人类 OUD RNA-seq 和全基因组关联研究数据的比较揭示了趋同的分子异常和具有高治疗潜力的候选基因。这些研究概述了 OUD 的分子重编程，并为未来对机制和治疗策略的研究提供了基础资源。
