Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
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 Article has an altmetric score of 20

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

  • Text
  • PDF
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 4

Chronic alcohol consumption shortens pause response of DMS CINs.

Options: View larger image (or click on image) Download as PowerPoint
Chronic alcohol consumption shortens pause response of DMS CINs.
ChAT-Cr...
ChAT-Cre Ai32 mice were trained to consume 20% alcohol for at least 8 weeks. Then DMS slices were prepared 24 hours after last alcohol exposure, and optically evoked burst-pause responses of CINs were measured. (A) Sample traces of burst-pause responses of a CIN from the water (top) and alcohol (bottom) groups using the cell-attached recording. ISI, interspike interval. (B) The pause durations in the indicated groups; *P < 0.05 by unpaired t test; n = 26 neurons from 3 male and 2 female mice (Water) and 16 neurons from 3 male mice and 1 female mouse (Alcohol). The pause duration is defined by the first ISI right after optical stimulation divided by baseline average ISI before the optical stimulation. (C) Sample traces of burst-pause responses of a CIN from the water (top) and alcohol (bottom) groups using whole-cell recording. (D) The pause durations in the indicated groups; *P < 0.05 by unpaired t test; n = 22 neurons from 3 male and 2 female mice (Water) and 11 neurons from 3 male mice (Alcohol).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Picked up by 1 news outlets
Blogged by 1
Posted by 8 X users
26 readers on Mendeley
See more details