Integrated Single-Cell Multiomic Profiling of Caudate Nucleus Suggests Key Mechanisms in Alcohol Use Disorder

Alcohol use disorder (AUD) is likely associated with complex transcriptional alterations in addiction-relevant brain regions. We characterize AUD-associated differences in cell type-specific gene expression and chromatin accessibility in the caudate nucleus by conducting a single-nucleus RNA-seq assay and a single-nucleus RNA-seq + ATAC-seq (multiome) assay on caudate tissue from 143 human postmortem brains (74 with AUD). We identified 17 cell types. AUD was associated with a higher proportion of microglia in an activated state and more astrocytes in a reactive state. There was widespread evidence for differentially expressed genes across cell types with the most identified in oligodendrocytes and astrocytes, including genes involved in immune response and synaptic regulation, many of which appeared to be regulated in part by JUND and OLIG2. Microglia-astrocyte communication via interleukin-1 beta, and microglia-astrocyte-oligodendrocyte interaction via transforming growth factor beta 1 were increased in individuals with AUD. Expression quantitative trait loci analysis revealed potential driver genes of AUD, including ADAL, that may protect against AUD in medium spiny neurons and interneurons. This work provides a thorough profile of the effects of AUD in the human brain and identifies several promising genes for further study.

酒精使用障碍（Alcohol use disorder, AUD）极可能与成瘾相关脑区内复杂的转录组改变存在关联。本研究通过对143例人类死后尾状核（caudate nucleus）脑组织（其中74例来自酒精使用障碍患者）开展单细胞核RNA测序（single-nucleus RNA-seq）以及单细胞核RNA-seq+ATAC-seq（多组学测序，multiome）实验，解析了尾状核内细胞类型特异性基因表达与染色质可及性的AUD相关差异。本研究共鉴定出17种细胞类型。酒精使用障碍与激活态小胶质细胞（microglia）比例升高以及反应性星形胶质细胞（astrocytes）数量增加存在关联。跨细胞类型的差异表达基因广泛存在，其中在少突胶质细胞（oligodendrocytes）与星形胶质细胞中鉴定出的差异基因数量最多，这些基因涉及免疫应答与突触调控，其中多数似乎部分受JUND与OLIG2调控。酒精使用障碍患者体内，经白细胞介素-1β（interleukin-1 beta）介导的小胶质细胞-星形胶质细胞通信，以及经转化生长因子β1（transforming growth factor beta 1）介导的小胶质细胞-星形胶质细胞-少突胶质细胞相互作用均显著增强。表达数量性状基因座（expression quantitative trait loci, eQTL）分析揭示了若干酒精使用障碍的潜在驱动基因，其中ADAL可在中型多棘神经元（medium spiny neurons）与中间神经元（interneurons）中发挥抗酒精使用障碍的保护作用。本研究全面描绘了酒精使用障碍对人类大脑的影响，并鉴定出若干具有进一步研究价值的候选基因。