Wildermuth Erin, Patton Michael S, Cortes-Gutierrez Marcia, Jinwala Zeal, Grissom Benjamin H, Campbell Rianne R, Kranzler Henry R, Lobo Mary Kay, Ament Seth A, Mathur Brian N
Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, USA.
Medical Scientist Training Program, University of Maryland School of Medicine, Baltimore, MD, USA.
Mol Psychiatry. 2025 Apr 16. doi: 10.1038/s41380-025-03014-z.
Alcohol use disorder (AUD) is characterized by compulsive drinking, which is thought to be mediated by effects of chronic intermittent ethanol exposure on the dorsal striatum, the input nucleus of the basal ganglia. Despite significant efforts to understand the impact of ethanol on the dorsal striatum, the rich diversity of striatal cell types and multitude of ethanol targets expressed by them necessitates an unbiased, discovery-based approach. In this study, we used single-nuclei RNA-sequencing (snRNA-seq; n = 86,715 cells) to examine the impact of chronic intermittent ethanol exposure on the dorsal striatum in C57BL/6 male and female mice. We detected 462 differentially expressed genes at FDR < 0.05, the majority of which were mapped to spiny projection neurons (SPNs), the most prominent cell type in the striatum. Gene co-expression network analysis and functional annotation of differentially expressed genes revealed down-regulation of postsynaptic intracellular signaling cascades in SPNs. Inflammation-related genes were down-regulated across many neuronal and non-neuronal cell types. Gene set enrichment analyses also pointed to altered states of rare cell types, including the induction of angiogenesis-related genes in vascular cells. A gene module down-regulated specifically in canonical SPNs was enriched for calcium-signaling genes and components of glutamatergic synapses, as well as for genes associated with genetic risk for AUD. Genetic perturbations of six of this module's hub genes - Foxp1, Bcl11b, Pde10a, Rarb, Rgs9, and Itgr1 - had causal effects on its expression in the mouse striatum and/or on the broader set of differentially expressed genes in alcohol-exposed mice. These data provide important clues as to the impact of ethanol on striatal biology and provide a key resource for future investigation.
酒精使用障碍（AUD）的特征是强迫性饮酒，据认为这是由慢性间歇性乙醇暴露对背侧纹状体（基底神经节的输入核）的影响介导的。尽管人们为了解乙醇对背侧纹状体的影响付出了巨大努力，但纹状体细胞类型的丰富多样性以及它们所表达的众多乙醇靶点，使得有必要采用一种无偏见的、基于发现的方法。在本研究中，我们使用单核RNA测序（snRNA-seq；n = 86,715个细胞）来研究慢性间歇性乙醇暴露对C57BL/6雄性和雌性小鼠背侧纹状体的影响。我们在错误发现率（FDR）< 0.05时检测到462个差异表达基因，其中大多数映射到棘状投射神经元（SPN），这是纹状体中最突出的细胞类型。差异表达基因的基因共表达网络分析和功能注释显示，SPN中突触后细胞内信号级联反应下调。许多神经元和非神经元细胞类型中的炎症相关基因均下调。基因集富集分析还指出了稀有细胞类型的状态改变，包括血管细胞中血管生成相关基因的诱导。在典型SPN中特异性下调的一个基因模块富含钙信号基因和谷氨酸能突触的成分，以及与AUD遗传风险相关的基因。该模块的六个枢纽基因——Foxp1、Bcl11b、Pde10a、Rarb、Rgs9和Itgr1——的基因扰动对其在小鼠纹状体中的表达和/或对酒精暴露小鼠中更广泛的差异表达基因集有因果影响。这些数据为乙醇对纹状体生物学的影响提供了重要线索，并为未来的研究提供了关键资源。
