Nick Green, Hongyu Gao, Xiaona Chu, Qiuyue Yuan, Patrick C. McGuire, Dongbing Lai, Guanglong Jiang, Xiaoling Xuei, Jill L. Reiter, Julia Stevens, Greg T. Sutherland, Alison Goate, Zhiping P. Pang, Paul A. Slesinger, Ronald P. Hart, Jay A. Tischfield, Arpana Agrawal, Yue Wang, Zhana Duren, Howard J. Edenberg, Yunlong Liu
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.