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.
View: Text | PDF
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

×

Figure 6

Chronic alcohol intake compromises CIN-mediated short-term facilitation of glutamatergic transmission in DMS D2-MSNs.

Options: View larger image (or click on image) Download as PowerPoint
Chronic alcohol intake compromises CIN-mediated short-term facilitation ...
(A) Schematic of electrical and light stimulation and whole-cell recording of D2-MSNs in ChAT-Cre Ai32 D1-tdT mice. Putative D2-MSNs were identified by their absence of fluorescence. (B) Left: Sample traces showing that electrical stimulation led to 5 EPSPs in D2-MSNs before and after light-mediated excitation of CINs. Electrical stimulation 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). Right: Calculation of the relative amplitudes of 5 EPSPs detected short-term facilitation in water control mice after light-mediated excitation of CINs. EPSPs were normalized to the first one; #P < 0.05 by 2-way RM ANOVA; **P < 0.01 vs. the same pulse number in the pre-light group by Tukey’s post hoc test; ^P < 0.05, ^^^P < 0.001 vs. pulse number 1 within the post-light group by Tukey’s post hoc test; n = 9 neurons from 5 male mice and 1 female mouse per group. (C) Left: Sample traces showing the EPSPs before and after light stimulation of CINs in the alcohol group. Right: Calculation of the relative amplitudes of EPSPs in the alcohol group did not identify any change after light stimulation of CINs; P > 0.05, 2-way RM ANOVA; n = 12 neurons from 4 male mice per group.