Chronic alcohol drinking persistently suppresses thalamostriatal excitation of cholinergic neurons to impair cognitive flexibility
Exposure to addictive substances impairs flexible decision making. Cognitive flexibility is mediated by striatal cholinergic interneurons (CINs). However, how chronic alcohol drinking alters cognitive flexibility through CINs remains unclear. Here, we report that chronic alcohol consumption and with...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical Investigation
2022-02-01
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| Series: | The Journal of Clinical Investigation |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/JCI154969 |
| _version_ | 1828807935342411776 |
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| author | Tengfei Ma Zhenbo Huang Xueyi Xie Yifeng Cheng Xiaowen Zhuang Matthew J. Childs Himanshu Gangal Xuehua Wang Laura N. Smith Rachel J. Smith Yubin Zhou Jun Wang |
| author_facet | Tengfei Ma Zhenbo Huang Xueyi Xie Yifeng Cheng Xiaowen Zhuang Matthew J. Childs Himanshu Gangal Xuehua Wang Laura N. Smith Rachel J. Smith Yubin Zhou Jun Wang |
| author_sort | Tengfei Ma |
| collection | DOAJ |
| description | Exposure to addictive substances impairs flexible decision making. Cognitive flexibility is mediated by striatal cholinergic interneurons (CINs). However, how chronic alcohol drinking alters cognitive flexibility through CINs remains unclear. Here, we report that chronic alcohol consumption and withdrawal impaired reversal of instrumental learning. Chronic alcohol consumption and withdrawal also caused a long-lasting (21 days) reduction of excitatory thalamic inputs onto CINs and reduced pause responses of CINs in the dorsomedial striatum (DMS). CINs are known to inhibit glutamatergic transmission in dopamine D1 receptor–expressing medium spiny neurons (D1-MSNs) but facilitate this transmission in D2-MSNs, which may contribute to flexible behavior. We discovered that chronic alcohol drinking impaired CIN-mediated inhibition in D1-MSNs and facilitation in D2-MSNs. Importantly, in vivo optogenetic induction of long-term potentiation of thalamostriatal transmission in DMS CINs rescued alcohol-induced reversal learning deficits. These results demonstrate that chronic alcohol drinking reduces thalamic excitation of DMS CINs, compromising their regulation of glutamatergic transmission in MSNs, which may contribute to alcohol-induced impairment of cognitive flexibility. These findings provide a neural mechanism underlying inflexible drinking in alcohol use disorder. |
| first_indexed | 2024-12-12T08:33:20Z |
| format | Article |
| id | doaj.art-6bb74d02ba08469f9c76bc0043eb7d55 |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-12-12T08:33:20Z |
| publishDate | 2022-02-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-6bb74d02ba08469f9c76bc0043eb7d552022-12-22T00:31:02ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382022-02-011324Chronic alcohol drinking persistently suppresses thalamostriatal excitation of cholinergic neurons to impair cognitive flexibilityTengfei MaZhenbo HuangXueyi XieYifeng ChengXiaowen ZhuangMatthew J. ChildsHimanshu GangalXuehua WangLaura N. SmithRachel J. SmithYubin ZhouJun WangExposure to addictive substances impairs flexible decision making. Cognitive flexibility is mediated by striatal cholinergic interneurons (CINs). However, how chronic alcohol drinking alters cognitive flexibility through CINs remains unclear. Here, we report that chronic alcohol consumption and withdrawal impaired reversal of instrumental learning. Chronic alcohol consumption and withdrawal also caused a long-lasting (21 days) reduction of excitatory thalamic inputs onto CINs and reduced pause responses of CINs in the dorsomedial striatum (DMS). CINs are known to inhibit glutamatergic transmission in dopamine D1 receptor–expressing medium spiny neurons (D1-MSNs) but facilitate this transmission in D2-MSNs, which may contribute to flexible behavior. We discovered that chronic alcohol drinking impaired CIN-mediated inhibition in D1-MSNs and facilitation in D2-MSNs. Importantly, in vivo optogenetic induction of long-term potentiation of thalamostriatal transmission in DMS CINs rescued alcohol-induced reversal learning deficits. These results demonstrate that chronic alcohol drinking reduces thalamic excitation of DMS CINs, compromising their regulation of glutamatergic transmission in MSNs, which may contribute to alcohol-induced impairment of cognitive flexibility. These findings provide a neural mechanism underlying inflexible drinking in alcohol use disorder.https://doi.org/10.1172/JCI154969Neuroscience |
| spellingShingle | Tengfei Ma Zhenbo Huang Xueyi Xie Yifeng Cheng Xiaowen Zhuang Matthew J. Childs Himanshu Gangal Xuehua Wang Laura N. Smith Rachel J. Smith Yubin Zhou Jun Wang Chronic alcohol drinking persistently suppresses thalamostriatal excitation of cholinergic neurons to impair cognitive flexibility The Journal of Clinical Investigation Neuroscience |
| title | Chronic alcohol drinking persistently suppresses thalamostriatal excitation of cholinergic neurons to impair cognitive flexibility |
| title_full | Chronic alcohol drinking persistently suppresses thalamostriatal excitation of cholinergic neurons to impair cognitive flexibility |
| title_fullStr | Chronic alcohol drinking persistently suppresses thalamostriatal excitation of cholinergic neurons to impair cognitive flexibility |
| title_full_unstemmed | Chronic alcohol drinking persistently suppresses thalamostriatal excitation of cholinergic neurons to impair cognitive flexibility |
| title_short | Chronic alcohol drinking persistently suppresses thalamostriatal excitation of cholinergic neurons to impair cognitive flexibility |
| title_sort | chronic alcohol drinking persistently suppresses thalamostriatal excitation of cholinergic neurons to impair cognitive flexibility |
| topic | Neuroscience |
| url | https://doi.org/10.1172/JCI154969 |
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