Nicotine-induced transcriptional changes and mitochondrial dysfunction in the ventral tegmental area revealed by single-nucleus transcriptomics.

IF 6.6 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Lei Fan, Boxin Liu, Ru Yao, Xia Gao, Hongjuan Wang, Sanjie Jiang, Xiaomin Zheng, Huan Chen, Hongwei Hou, Yong Liu, Qingyuan Hu
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引用次数: 0

Abstract

Nicotine is widely recognized as the primary contributor to tobacco dependence. Previous studies have indicated that molecular and behavioral responses to nicotine are primarily mediated by ventral tegmental area (VTA) neurons, and accumulating evidence suggests that glia play prominent roles in nicotine addiction. However, VTA neurons and glia have yet to be characterized at the transcriptional level during the progression of nicotine self-administration. Here, a male mouse model of nicotine self-administration was established and the timing of three critical phases (pre-addiction, addicting, and post-addiction phase) was characterized. Single-nucleus RNA sequencing (snRNA-seq) in the VTA at each phase was performed to comprehensively classify specific cell subtypes. Adaptive changes occurred during the addicting and post-addiction phases, with the addicting phase displaying highly dynamic neuroplasticity that profoundly impacted the transcription in each cell subtype. Furthermore, significant transcriptional changes in energy metabolism-related genes were observed, accompanied by notable structural alterations in neuronal mitochondria during the progression of nicotine self-administration. The results provide insights into mechanisms underlying the progression of nicotine addiction, serving as important resource for identifying potential molecular targets for nicotine cessation.

单核转录组学揭示尼古丁诱导的腹侧被盖区转录变化和线粒体功能障碍
尼古丁是公认的导致烟草依赖的主要因素。以往的研究表明,尼古丁的分子和行为反应主要由腹侧被盖区(VTA)神经元介导,而且越来越多的证据表明,神经胶质细胞在尼古丁成瘾中发挥着重要作用。然而,在尼古丁自我给药的进展过程中,VTA神经元和神经胶质细胞尚未在转录水平上得到表征。在此,研究人员建立了尼古丁自我成瘾雄性小鼠模型,并对三个关键阶段(成瘾前、成瘾中和成瘾后)的时间进行了表征。在每个阶段都对VTA进行了单核RNA测序(snRNA-seq),以全面划分特定的细胞亚型。在成瘾阶段和成瘾后阶段都发生了适应性变化,成瘾阶段表现出高度动态的神经可塑性,对每种细胞亚型的转录都产生了深刻影响。此外,在尼古丁自我给药过程中,能量代谢相关基因的转录发生了重大变化,同时神经元线粒体的结构也发生了明显改变。研究结果为了解尼古丁成瘾的进展机制提供了见解,是确定尼古丁戒断潜在分子靶点的重要资源。
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来源期刊
Journal of Genetics and Genomics
Journal of Genetics and Genomics 生物-生化与分子生物学
CiteScore
8.20
自引率
3.40%
发文量
4756
审稿时长
14 days
期刊介绍: The Journal of Genetics and Genomics (JGG, formerly known as Acta Genetica Sinica ) is an international journal publishing peer-reviewed articles of novel and significant discoveries in the fields of genetics and genomics. Topics of particular interest include but are not limited to molecular genetics, developmental genetics, cytogenetics, epigenetics, medical genetics, population and evolutionary genetics, genomics and functional genomics as well as bioinformatics and computational biology.
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