Integrated single-cell multiomic profiling of caudate nucleus suggests key mechanisms in alcohol use disorder

Nicholas C. Green, Hongyu Gao, Xiaona Chu, Qiuyue Yuan, Patrick McGuire, Dongbing Lai, Guanglong Jiang, Xiaoling Xuei, Jill L. Reiter, Julia Stevens, Greg T. Sutherland, Alison M. Goate, Zhiping P. Pang, Paul A. Slesinger, Ronald P. Hart, Jay A. Tischfield, Arpana Agrawal, Yue Wang, Zhana Duren, Howard J. Edenberg () and Yunlong Liu ()
Additional contact information
Nicholas C. Green: Indiana University School of Medicine
Hongyu Gao: Indiana University School of Medicine
Xiaona Chu: Indiana University School of Medicine
Qiuyue Yuan: Southern University of Science and Technology
Patrick McGuire: Indiana University School of Medicine
Dongbing Lai: Indiana University School of Medicine
Guanglong Jiang: Indiana University School of Medicine
Xiaoling Xuei: Indiana University School of Medicine
Jill L. Reiter: Indiana University School of Medicine
Julia Stevens: The University of Sydney
Greg T. Sutherland: The University of Sydney
Alison M. Goate: Icahn School of Medicine at Mount Sinai
Zhiping P. Pang: Rutgers University
Paul A. Slesinger: Icahn School of Medicine at Mount Sinai
Ronald P. Hart: Rutgers University
Jay A. Tischfield: Rutgers University
Arpana Agrawal: Washington University in St. Louis School of Medicine
Yue Wang: Indiana University School of Medicine
Zhana Duren: Indiana University School of Medicine
Howard J. Edenberg: Indiana University School of Medicine
Yunlong Liu: Indiana University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract Alcohol use disorder (AUD) induces complex transcriptional and regulatory changes across multiple brain regions including the caudate nucleus, which remains understudied. Using paired single-nucleus RNA-seq and ATAC-seq on caudate samples from 143 human postmortem brains, including 74 with AUD, we identified 17 distinct cell types. A significant portion of the alcohol-related differences in gene expression were accompanied by a corresponding difference in chromatin accessibility within the gene. We observed transcriptional differences in medium spiny neurons that impact RNA metabolism and immune response pathways. A small cluster of D1/D2 hybrid neurons showed AUD-induced differences distinct from the D1 and D2 types, suggesting a unique role in AUD. Those with AUD had a higher proportion of microglia in an inflammatory state; astrocytes entered a reactive state partially regulated by JUND. Oligodendrocyte dysregulation was driven in part by OLIG2 activity and increased TGF-β1 signaling from microglia and astrocytes. We also observed increased microglia-astrocyte communication via the IL-1β pathway. These findings provide valuable insights into the genetic and cellular mechanisms in the caudate related to AUD. They also demonstrate the broader utility of large-scale multiomic studies in uncovering complex gene regulation across diverse cell types, which has implications beyond the substance use field.

Date: 2025
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DOI: 10.1038/s41467-025-64136-0

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