Shared and divergent transcriptomic regulation in nucleus accumbens D1 and D2 medium spiny neurons by cocaine and morphine.
Shared and divergent transcriptomic regulation in nucleus accumbens D1 and D2 medium spiny neurons by cocaine and morphine.
复制标题
可卡因和吗啡对伏隔核 D1 和 D2 中棘神经元的共享和不同的转录组调节。
DOI：
10.1101/2023.09.19.558477
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Nestler,EricJ
中科院分区：
文献类型：
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作者：
Browne,CalebJ;Mews,Philipp;Zhou,Xianxiao;Holt,LeanneM;Estill,Molly;Futamura,Rita;Schaefer,Anne;Kenny,PaulJ;Hurd,YasminL;Shen,Li;Zhang,Bin;Nestler,EricJ
物质使用障碍（SUD）引起广泛的分子失调，在脑桥核（NAc），大脑区域的关键协调动机和奖励。这些分子变化被认为支持持久的神经和行为障碍，促进成瘾中的药物寻求。然而，不同的药物类别对神经回路、细胞类型、生理学和基因表达产生独特的影响，尽管SUD的药理学重叠。为了更好地了解共同和不同的分子机制，SUD病理，我们的目标是调查细胞类型特异性重组的NAc转录景观后，精神兴奋剂或阿片类药物暴露。我们结合荧光激活细胞核分选和RNA测序来分析NAc D1和D2中棘神经元（MSN）在可卡因和吗啡暴露范例中的分布，包括初始暴露、重复暴露后的长期戒断和戒断后的再暴露。我们的分析表明，D1 MSNs在暴露期间显示出许多跨药物类别的会聚转录反应，而D2 MSNs主要表现出可卡因和吗啡之间的发散反应，吗啡在这种细胞类型中引起更多的适应。利用多尺度嵌入式基因共表达网络分析（MEGENA），我们发现了可卡因和吗啡之间共享的生物功能的转录调控网络。我们观察到D1 MSN中药物类别之间重叠基因网络的主要整合参与，但关键D2网络的调控相反，突出了MSN中潜在的治疗基因网络靶标。这些研究建立了一个具有里程碑意义的，细胞类型特异性的转录调控图谱诱导可卡因和吗啡，可以作为未来的研究对SUD的机制理解的基础。我们的研究结果以及利用该数据集的未来工作将为开发有针对性的治疗干预措施铺平道路，解决对可卡因使用障碍更有效治疗的迫切需求，并加强阿片类药物使用障碍的现有策略。
Substance use disorders (SUDs) induce widespread molecular dysregulation in the nucleus accumbens (NAc), a brain region pivotal for coordinating motivation and reward. These molecular changes are thought to support lasting neural and behavioral disturbances that promote drug-seeking in addiction. However, different drug classes exert unique influences on neural circuits, cell types, physiology, and gene expression despite the overlapping symptomatology of SUDs. To better understand common and divergent molecular mechanisms governing SUD pathology, our goal was to survey cell-type-specific restructuring of the NAc transcriptional landscape in after psychostimulant or opioid exposure. We combined fluorescence-activated nuclei sorting and RNA sequencing to profile NAc D1 and D2 medium spiny neurons (MSNs) across cocaine and morphine exposure paradigms, including initial exposure, prolonged withdrawal after repeated exposure, and re-exposure post-withdrawal. Our analyses reveal that D1 MSNs display many convergent transcriptional responses across drug classes during exposure, whereas D2 MSNs manifest mostly divergent responses between cocaine and morphine, with morphine causing more adaptations in this cell type. Utilizing multiscale embedded gene co-expression network analysis (MEGENA), we discerned transcriptional regulatory networks subserving biological functions shared between cocaine and morphine. We observed largely integrative engagement of overlapping gene networks across drug classes in D1 MSNs, but opposite regulation of key D2 networks, highlighting potential therapeutic gene network targets within MSNs. These studies establish a landmark, cell-type-specific atlas of transcriptional regulation induced by cocaine and by morphine that can serve as a foundation for future studies towards mechanistic understanding of SUDs. Our findings, and future work leveraging this dataset, will pave the way for the development of targeted therapeutic interventions, addressing the urgent need for more effective treatments for cocaine use disorder and enhancing the existing strategies for opioid use disorder.