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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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 2

Chronic alcohol consumption reduces thalamostriatal glutamatergic inputs onto DMS CINs.

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Chronic alcohol consumption reduces thalamostriatal glutamatergic inputs...
(A) Schematic of light stimulation of ChR2-expressing thalamic inputs and whole-cell recording of CINs. (B) Chronic alcohol consumption suppressed thalamostriatal inputs onto CINs in DMS slices prepared 24 hours after the last alcohol exposure (1-day withdrawal [WD]); #P < 0.05; *P < 0.05, ***P < 0.001; n = 11 neurons from 4 male mice (Water) and 13 neurons from 3 male mice (Alcohol). (C) Chronic alcohol consumption did not alter the glutamate release probability indicated by paired-pulse measurement; NS, P > 0.05; n = 10 neurons from 3 male mice (Water) and 11 neurons from 3 male mice (Alcohol). (D) Schematic showing viral infusions. We infused helper viruses (AAV-DIO-TVA-mCherry and AAV-DIO-RG) into the DMS of ChAT-Cre D1-tdT mice (Inj. 1) and rabies-GFP into the same site 2 weeks later (Inj. 2). (E) Sample coronal images from 4 mice showing that rabies-GFP–labeled PfN neurons projected to DMS CINs. fr, fasciculus retroflexus. (F) Sample images of tdT fluorescence in the PfN (injection site) and striatum from 8 mice. (G) Sample image from 8 mice showing a GFP-expressing recorded (Rec.) CIN and tdT-positive fiber. (H) Input-output curves of oEPSC amplitudes in CINs measured 21 days after the last alcohol exposure (21-d WD) from mice injected with AAV-Chrimson-tdT in the PfN; ##P < 0.01; *P < 0.05, **P < 0.01, ***P < 0.001; n = 15 neurons from 2 male and 2 female mice (Water) and 14 neurons from 4 female mice (Alcohol). (I) Paired-pulse ratios in mice injected with AAV-Chrimson-tdT; NS, P > 0.05; n = 27 neurons from 2 male and 3 female mice (Water) and 32 neurons from 1 male and 4 female mice (Alcohol). Two-way RM ANOVA followed by post hoc test (B and H); unpaired t test (C and I).