Browne Caleb J, Futamura Rita, Minier-Toribio Angélica, Hicks Emily M, Ramakrishnan Aarthi, Martínez-Rivera Freddyson, Estill Molly, Godino Arthur, Parise Eric M, Torres-Berrío Angélica, Cunningham Ashley M, Hamilton Peter J, Walker Deena M, Huckins Laura M, Hurd Yasmin L, Shen Li, Nestler Eric J
Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
Dept. of Genetics and Genomic Sciences and Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai.
bioRxiv. 2023 Jan 12:2023.01.11.523688. doi: 10.1101/2023.01.11.523688.
Opioid use disorder (OUD) looms as one of the most severe medical crises currently facing society. More effective therapeutics for OUD requires in-depth understanding of molecular changes supporting drug-taking and relapse. Recent efforts have helped advance these aims, but studies have been limited in number and scope. Here, we develop a brain reward circuit-wide atlas of opioid-induced transcriptional regulation by combining RNA sequencing (RNAseq) and heroin self-administration in male mice modeling multiple OUD-relevant conditions: acute heroin exposure, chronic heroin intake, context-induced drug-seeking following prolonged abstinence, and heroin-primed drug-seeking (i.e., "relapse"). Bioinformatics analysis of this rich dataset identified numerous patterns of molecular changes, transcriptional regulation, brain-region-specific involvement in various aspects of OUD, and both region-specific and pan-circuit biological domains affected by heroin. Integrating RNAseq data with behavioral outcomes using factor analysis to generate an "addiction index" uncovered novel roles for particular brain regions in promoting addiction-relevant behavior, and implicated multi-regional changes in affected genes and biological processes. Comparisons with RNAseq and genome-wide association studies from humans with OUD reveal convergent molecular regulation that are implicated in drug-taking and relapse, and point to novel gene candidates with high therapeutic potential for OUD. These results outline broad molecular reprogramming that may directly promote the development and maintenance of OUD, and provide a foundational resource to the field for future research into OUD mechanisms and treatment strategies.
阿片类药物使用障碍（OUD）俨然成为当前社会面临的最严重的医学危机之一。要找到更有效的OUD治疗方法，需要深入了解支持药物使用和复发的分子变化。近期的研究努力推动了这些目标的实现，但研究数量和范围有限。在此，我们通过结合RNA测序（RNAseq）和海洛因自我给药，在模拟多种与OUD相关情况的雄性小鼠中构建了一个全脑奖赏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、长期禁欲后的情境诱导觅药行为以及海洛因激发的觅药行为（即“复发”）。对这个丰富数据集的生物信息学分析确定了分子变化、转录调控、脑区在OUD各个方面的特异性参与以及受海洛因影响的区域特异性和全回路生物学领域的多种模式。使用因子分析将RNAseq数据与行为结果相结合以生成“成瘾指数”，揭示了特定脑区在促进成瘾相关行为中的新作用，并暗示了受影响基因和生物学过程的多区域变化。与患有OUD的人类的RNAseq和全基因组关联研究进行比较，揭示了与药物使用和复发相关的趋同分子调控，并指出了具有高OUD治疗潜力的新基因候选物。这些结果概述了可能直接促进OUD发展和维持的广泛分子重编程，并为该领域未来对OUD机制和治疗策略的研究提供了基础资源。
