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Volume 51 Issue 11
Nov.  2024
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Article Navigation >  Journal of Genetics and Genomics  > 2024  >  51(11): 1237-1251

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

doi: 10.1016/j.jgg.2024.08.009
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    a. Anhui Institute of Optics and Fine Mechanics, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui 230000, China;

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    b. University of Science and Technology of China, Hefei, Anhui 230000, China;

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    c. Beijing Life Science Academy, Beijing 100000, China;

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    d. Key Laboratory of Tobacco Biological Effects and Biosynthesis, Beijing 100000, China;

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    e. China National Tobacco Quality Supervision & Test Center, Zhengzhou, Henan 450000, China;

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    f. Key Laboratory of Tobacco Biological Effects, Zhengzhou, Henan 450000, China;

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    g. BGI Genomics, BGI-Shenzhen, Guangdong 518018, China

Funds:

This work was supported by the Major Project of Tobacco Biological Effects (552022AK0070, 110202102014).

  • Received Date: 2024-06-03
  • Accepted Date: 2024-08-26
  • Rev Recd Date: 2024-08-22
    • Available Online: 2025-06-06
  • Publish Date: 2024-09-05
    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 is established and the timing of three critical phases (pre-addiction, addicting, and post-addiction phase) is characterized. Single-nucleus RNA sequencing in the VTA at each phase is 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 impacts the transcription in each cell subtype. Furthermore, significant transcriptional changes in energy metabolism-related genes are 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 an important resource for identifying potential molecular targets for nicotine cessation.
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