Drug reinforcement impairs cognitive flexibility by inhibiting striatal cholinergic neurons

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 and Jun Wang ()
Additional contact information
Himanshu Gangal: Texas A&M University Health Science Center
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
Ruifeng Chen: Texas A&M University Health Science Center
Laura N. Smith: Texas A&M University Health Science Center
Rachel J. Smith: Texas A&M University
Jun Wang: Texas A&M University Health Science Center

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-39623-x

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