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Drug reinforcement impairs cognitive flexibility by inhibiting striatal cholinergic neurons

Author

Listed:
  • Himanshu Gangal

    (Texas A&M University Health Science Center
    Texas A&M University)

  • Xueyi Xie

    (Texas A&M University Health Science Center)

  • Zhenbo Huang

    (Texas A&M University Health Science Center)

  • Yifeng Cheng

    (Texas A&M University Health Science Center)

  • Xuehua Wang

    (Texas A&M University Health Science Center)

  • Jiayi Lu

    (Texas A&M University Health Science Center)

  • Xiaowen Zhuang

    (Texas A&M University Health Science Center)

  • Amanda Essoh

    (Texas A&M University Health Science Center)

  • Yufei Huang

    (Texas A&M University Health Science Center
    Texas A&M University)

  • Ruifeng Chen

    (Texas A&M University Health Science Center
    Texas A&M University)

  • Laura N. Smith

    (Texas A&M University Health Science Center
    Texas A&M University)

  • Rachel J. Smith

    (Texas A&M University
    Texas A&M University)

  • Jun Wang

    (Texas A&M University Health Science Center
    Texas A&M University
    Texas A&M University)

Abstract

Addictive substance use impairs cognitive flexibility, with unclear underlying mechanisms. The reinforcement of substance use is mediated by the striatal direct-pathway medium spiny neurons (dMSNs) that project to the substantia nigra pars reticulata (SNr). Cognitive flexibility is mediated by striatal cholinergic interneurons (CINs), which receive extensive striatal inhibition. Here, we hypothesized that increased dMSN activity induced by substance use inhibits CINs, reducing cognitive flexibility. We found that cocaine administration in rodents caused long-lasting potentiation of local inhibitory dMSN-to-CIN transmission and decreased CIN firing in the dorsomedial striatum (DMS), a brain region critical for cognitive flexibility. Moreover, chemogenetic and time-locked optogenetic inhibition of DMS CINs suppressed flexibility of goal-directed behavior in instrumental reversal learning tasks. Notably, rabies-mediated tracing and physiological studies showed that SNr-projecting dMSNs, which mediate reinforcement, sent axonal collaterals to inhibit DMS CINs, which mediate flexibility. Our findings demonstrate that the local inhibitory dMSN-to-CIN circuit mediates the reinforcement-induced deficits in cognitive flexibility.

Suggested Citation

  • Himanshu Gangal & Xueyi Xie & Zhenbo Huang & Yifeng Cheng & Xuehua Wang & Jiayi Lu & Xiaowen Zhuang & Amanda Essoh & Yufei Huang & Ruifeng Chen & Laura N. Smith & Rachel J. Smith & Jun Wang, 2023. "Drug reinforcement impairs cognitive flexibility by inhibiting striatal cholinergic neurons," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39623-x
    DOI: 10.1038/s41467-023-39623-x
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    References listed on IDEAS

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