Chronic alcohol drinking persistently suppresses thalamostriatal excitation of cholinergic neurons to impair cognitive flexibility
Tengfei Ma, … , Yubin Zhou, Jun Wang
Tengfei Ma, … , Yubin Zhou, Jun Wang
Published December 23, 2021
Citation Information: J Clin Invest. 2022;132(4):e154969. https://doi.org/10.1172/JCI154969.
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Research Article Neuroscience

Chronic alcohol drinking persistently suppresses thalamostriatal excitation of cholinergic neurons to impair cognitive flexibility

Abstract

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.

Authors

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

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Figure 3

Chronic alcohol consumption increases spontaneous, but not evoked, firing of DMS CINs.

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Chronic alcohol consumption increases spontaneous, but not evoked, firin...
ChAT-eGFP mice were trained to consume 20% alcohol for 8 weeks, and DMS slices were prepared 24 hours (1-d WD) and 21 days (21-d WD) after the last alcohol exposure. (A) Sample image from 13 mice showing green CINs in the striatum. D, dorsal; M, medial. (B) Sample traces of spontaneous CIN firing in the water and alcohol groups using the cell-attached recording. (C and D) Cumulative plots of the inter-event intervals (C) and the spontaneous firing rates of CINs (D) in the indicated groups; P < 0.01 by 1-way ANOVA, **P < 0.01 vs. water group by Tukey’s post hoc test; n = 49 neurons from 5 male and 2 female mice (Water), 31 neurons from 4 male and 2 female mice (Alcohol 1-d), and 36 neurons from 4 male mice (Alcohol 21-d). (E) Chronic alcohol did not change evoked CIN firing. Left and middle: Sample traces of membrane potentials generated in the indicated groups in response to a series of 500-ms current injections. Right: The input-output relationship between the injected current magnitude and the CIN firing frequency in water and alcohol groups; P > 0.05 by 2-way RM ANOVA; n = 16 neurons from 4 male mice (Water) and 13 neurons from 3 male mice (Alcohol).