Cargando…
Drug reinforcement impairs cognitive flexibility by inhibiting striatal cholinergic neurons
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 stria...
Autores principales: | , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10313783/ https://www.ncbi.nlm.nih.gov/pubmed/37391566 http://dx.doi.org/10.1038/s41467-023-39623-x |
_version_ | 1785067184115941376 |
---|---|
author | Gangal, Himanshu Xie, Xueyi Huang, Zhenbo Cheng, Yifeng Wang, Xuehua Lu, Jiayi Zhuang, Xiaowen Essoh, Amanda Huang, Yufei Chen, Ruifeng Smith, Laura N. Smith, Rachel J. Wang, Jun |
author_facet | Gangal, Himanshu Xie, Xueyi Huang, Zhenbo Cheng, Yifeng Wang, Xuehua Lu, Jiayi Zhuang, Xiaowen Essoh, Amanda Huang, Yufei Chen, Ruifeng Smith, Laura N. Smith, Rachel J. Wang, Jun |
author_sort | Gangal, Himanshu |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-10313783 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-103137832023-07-02 Drug reinforcement impairs cognitive flexibility by inhibiting striatal cholinergic neurons Gangal, Himanshu Xie, Xueyi Huang, Zhenbo Cheng, Yifeng Wang, Xuehua Lu, Jiayi Zhuang, Xiaowen Essoh, Amanda Huang, Yufei Chen, Ruifeng Smith, Laura N. Smith, Rachel J. Wang, Jun Nat Commun Article 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. Nature Publishing Group UK 2023-06-30 /pmc/articles/PMC10313783/ /pubmed/37391566 http://dx.doi.org/10.1038/s41467-023-39623-x Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Gangal, Himanshu Xie, Xueyi Huang, Zhenbo Cheng, Yifeng Wang, Xuehua Lu, Jiayi Zhuang, Xiaowen Essoh, Amanda Huang, Yufei Chen, Ruifeng Smith, Laura N. Smith, Rachel J. Wang, Jun Drug reinforcement impairs cognitive flexibility by inhibiting striatal cholinergic neurons |
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 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10313783/ https://www.ncbi.nlm.nih.gov/pubmed/37391566 http://dx.doi.org/10.1038/s41467-023-39623-x |
work_keys_str_mv | AT gangalhimanshu drugreinforcementimpairscognitiveflexibilitybyinhibitingstriatalcholinergicneurons AT xiexueyi drugreinforcementimpairscognitiveflexibilitybyinhibitingstriatalcholinergicneurons AT huangzhenbo drugreinforcementimpairscognitiveflexibilitybyinhibitingstriatalcholinergicneurons AT chengyifeng drugreinforcementimpairscognitiveflexibilitybyinhibitingstriatalcholinergicneurons AT wangxuehua drugreinforcementimpairscognitiveflexibilitybyinhibitingstriatalcholinergicneurons AT lujiayi drugreinforcementimpairscognitiveflexibilitybyinhibitingstriatalcholinergicneurons AT zhuangxiaowen drugreinforcementimpairscognitiveflexibilitybyinhibitingstriatalcholinergicneurons AT essohamanda drugreinforcementimpairscognitiveflexibilitybyinhibitingstriatalcholinergicneurons AT huangyufei drugreinforcementimpairscognitiveflexibilitybyinhibitingstriatalcholinergicneurons AT chenruifeng drugreinforcementimpairscognitiveflexibilitybyinhibitingstriatalcholinergicneurons AT smithlauran drugreinforcementimpairscognitiveflexibilitybyinhibitingstriatalcholinergicneurons AT smithrachelj drugreinforcementimpairscognitiveflexibilitybyinhibitingstriatalcholinergicneurons AT wangjun drugreinforcementimpairscognitiveflexibilitybyinhibitingstriatalcholinergicneurons |