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...

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Bibliographic Details
Published in:	The Journal of clinical investigation Vol. 132; no. 4; pp. 1 - 14
Main Authors:	Ma, Tengfei, Huang, Zhenbo, Xie, Xueyi, Cheng, Yifeng, Zhuang, Xiaowen, Childs, Matthew J, Gangal, Himanshu, Wang, Xuehua, Smith, Laura N, Smith, Rachel J, Zhou, Yubin, Wang, Jun
Format:	Journal Article
Language:	English
Published:	United States American Society for Clinical Investigation 15-02-2022
Subjects:	Alcohol Drinking - metabolism Alcohol Drinking - physiopathology Alcohol use Alcoholism Alcoholism - metabolism Alcoholism - physiopathology Animals Biomedical research Brain research Cholinergic mechanisms Cholinergic Neurons - metabolism Chronic Disease Cognition Cognition disorders Cognitive ability Complications and side effects Corpus Striatum - metabolism Corpus Striatum - physiopathology Decision making Dopamine Dopamine D1 receptors Dopamine D2 receptors Drinking behavior Flexibility Glutamatergic transmission Health aspects Interneurons Long-term potentiation Mice Mice, Transgenic Neostriatum Neural circuitry Neurons Neuroscience Reversal learning Risk factors Spiny neurons Sucrose Thalamus Transgenic animals Withdrawal United States Neuroscience Psychiatric diseases Behavior Addiction
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Authorship note: TM and ZH contributed equally to this work.
ISSN:	1558-8238 0021-9738 1558-8238
DOI:	10.1172/JCI154969