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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 Article has an altmetric score of 20

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

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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 7

Optogenetic stimulation of PfN-to-CIN synapses in the DMS rescues the alcohol-induced impairment of reversal learning.

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Optogenetic stimulation of PfN-to-CIN synapses in the DMS rescues the al...
(A) Schematic of viral injection and optical fiber implantation. ChAT-Cre rats were bilaterally infused with AAV-FLEX-Chrimson-tdT and AAV-Chronos-GFP into the DMS and PfN, respectively. Optical fibers were bilaterally implanted into the DMS. Rats were then trained using the same schedule as in Figure 1. (B) Optical stimulation protocol used during the reversal learning. Rats pressed the lever to receive a reward and light stimulation, which was time-locked to the reward delivery. Light stimulation contained 5 repeats of dual light stimulus within a 5-second reward delivery period. Each repeat consisted of optogenetic high-frequency stimulation (oHFS; 473 nm, 10 pulses, 50 Hz) and optogenetic postsynaptic depolarization (oPSD; 590 nm, 200 ms). (C) The initial acquisition learning curve. (D) Outcome-specific devaluation testing showed that rats pressed the DeV lever significantly fewer times than the Val lever; **P < 0.01 by paired t test. (E) There was no significant difference in lever pressing between the 2 groups during the reversed contingency training sessions; P > 0.05 by 2-way RM ANOVA. (F) Outcome-specific devaluation after reversed action-outcome contingency learning showed that the sham group still interacted more with the DeV lever (which was the Val lever during initial learning), while the group that received light stimulation showed successful devaluation after the reversed action-outcome contingency; NS, P > 0.05, and *P < 0.05 by paired t test. (G) The devaluation index was significantly higher in the opto group than in the sham group; *P < 0.05 by unpaired t test; n = 14 male and 5 female rats for C and D; n = 6 male and 3 female rats (Alcohol-sham) and 8 male and 2 female rats (Alcohol-opto) for E–G.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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