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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

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 5

Chronic alcohol consumption impairs CIN-mediated suppression of glutamatergic transmission in DMS D1-MSNs.

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Chronic alcohol consumption impairs CIN-mediated suppression of glutamat...
(A) Sample image of a sagittal section from 9 ChAT-Cre Ai32 D1-tdT mice. Inset shows a green CIN with several red D1-MSNs (scale bar: 20 μm). DS, dorsal striatum; SNr, substantia nigra pars reticulata. (B) Schematic of the electrical and optical stimulation and selective recording of D1-MSNs. The stimulating electrodes were placed in the DMS close to the recording pipette. (C) Schematic of the electrical and light stimulation protocols. Electrical stimulation (top) was delivered every 20 seconds, 1 second after the delivery of a burst of 473-nm light (2 ms of 10 pulses at 15 Hz) (middle and bottom). (D) The amplitude of NMDAR-mediated EPSCs before light stimulation, during light stimulation, and during light stimulation in the presence of the muscarinic M4 antagonist PD 102807 (PD; 1 μM) showed that optogenetic excitation of DMS CINs caused an M4 receptor–dependent suppression of NMDAR activity in D1-MSNs; P < 0.01 by 1-way RM ANOVA, **P < 0.01 vs. the light group by Tukey’s post hoc test; n = 7 neurons from 4 male mice and 1 female mouse per group. (E) Chronic alcohol consumption abolished CIN-induced suppression of NMDAR-EPSCs; P > 0.05 by paired t test; n = 7 neurons from 4 male mice per group.

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

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