Drug reinforcement impairs cognitive flexibility by inhibiting striatal cholinergic neurons
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...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-06-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-39623-x |
| _version_ | 1797789696823132160 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Himanshu Gangal |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-13T01:54:21Z |
| format | Article |
| id | doaj.art-52013e0521bf48aa8a5e2ea1854d1681 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-13T01:54:21Z |
| publishDate | 2023-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-52013e0521bf48aa8a5e2ea1854d16812023-07-02T11:19:37ZengNature PortfolioNature Communications2041-17232023-06-0114111510.1038/s41467-023-39623-xDrug reinforcement impairs cognitive flexibility by inhibiting striatal cholinergic neuronsHimanshu Gangal0Xueyi Xie1Zhenbo Huang2Yifeng Cheng3Xuehua Wang4Jiayi Lu5Xiaowen Zhuang6Amanda Essoh7Yufei Huang8Ruifeng Chen9Laura N. Smith10Rachel J. Smith11Jun Wang12Department of Neuroscience and Experimental Therapeutics, School of Medicine, Texas A&M University Health Science CenterDepartment of Neuroscience and Experimental Therapeutics, School of Medicine, Texas A&M University Health Science CenterDepartment of Neuroscience and Experimental Therapeutics, School of Medicine, Texas A&M University Health Science CenterDepartment of Neuroscience and Experimental Therapeutics, School of Medicine, Texas A&M University Health Science CenterDepartment of Neuroscience and Experimental Therapeutics, School of Medicine, Texas A&M University Health Science CenterDepartment of Neuroscience and Experimental Therapeutics, School of Medicine, Texas A&M University Health Science CenterDepartment of Neuroscience and Experimental Therapeutics, School of Medicine, Texas A&M University Health Science CenterDepartment of Neuroscience and Experimental Therapeutics, School of Medicine, Texas A&M University Health Science CenterDepartment of Neuroscience and Experimental Therapeutics, School of Medicine, Texas A&M University Health Science CenterDepartment of Neuroscience and Experimental Therapeutics, School of Medicine, Texas A&M University Health Science CenterDepartment of Neuroscience and Experimental Therapeutics, School of Medicine, Texas A&M University Health Science CenterInstitute for Neuroscience, Texas A&M UniversityDepartment of Neuroscience and Experimental Therapeutics, School of Medicine, Texas A&M University Health Science CenterAbstract 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.https://doi.org/10.1038/s41467-023-39623-x |
| spellingShingle | 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 Drug reinforcement impairs cognitive flexibility by inhibiting striatal cholinergic neurons Nature Communications |
| title | Drug reinforcement impairs cognitive flexibility by inhibiting striatal cholinergic neurons |
| title_full | Drug reinforcement impairs cognitive flexibility by inhibiting striatal cholinergic neurons |
| title_fullStr | Drug reinforcement impairs cognitive flexibility by inhibiting striatal cholinergic neurons |
| title_full_unstemmed | Drug reinforcement impairs cognitive flexibility by inhibiting striatal cholinergic neurons |
| title_short | Drug reinforcement impairs cognitive flexibility by inhibiting striatal cholinergic neurons |
| title_sort | drug reinforcement impairs cognitive flexibility by inhibiting striatal cholinergic neurons |
| url | https://doi.org/10.1038/s41467-023-39623-x |
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