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
- Yunlong Liu
2025-10-13
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.