Wei Julong, Lambert Tova Y, Valada Aditi, Patel Nikhil, Walker Kellie, Lenders Jayna, Schmidt Carl J, Iskhakova Marina, Alazizi Adnan, Mair-Meijers Henriette, Mash Deborah C, Luca Francesca, Pique-Regi Roger, Bannon Michael J, Akbarian Schahram
Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201.
Department of Psychiatry, Department of Neuroscience and Department of Genetics and Genomic Sciences, Friedman Brain Institute Icahn School of Medicine at Mount Sinai, New York, NY 10029.
bioRxiv. 2023 Mar 9:2023.03.07.531400. doi: 10.1101/2023.03.07.531400.
Dynamic interactions of neurons and glia in the ventral midbrain (VM) mediate reward and addiction behavior. We studied gene expression in 212,713 VM single nuclei from 95 human opioid overdose cases and drug-free controls. Chronic exposure to opioids left numerical proportions of VM glial and neuronal subtypes unaltered, while broadly affecting glial transcriptomes, involving 9.5 - 6.2% of expressed genes within microglia, oligodendrocytes, and astrocytes, with prominent activation of the immune response including interferon, NFkB signaling, and cell motility pathways, sharply contrasting with down-regulated expression of synaptic signaling and plasticity genes in VM non-dopaminergic neurons. VM transcriptomic reprogramming in the context of opioid exposure and overdose included 325 genes with genetic variation linked to substance use traits in the broader population, thereby pointing to heritable risk architectures in the genomic organization of the brain's reward circuitry.
中脑腹侧（VM）中神经元与神经胶质细胞的动态相互作用介导奖赏和成瘾行为。我们研究了来自95例人类阿片类药物过量病例和无药物对照组的212,713个VM单细胞核中的基因表达。长期接触阿片类药物并未改变VM神经胶质细胞和神经元亚型的数量比例，但广泛影响神经胶质细胞转录组，涉及小胶质细胞、少突胶质细胞和星形胶质细胞中9.5%-6.2%的表达基因，免疫反应显著激活，包括干扰素、NFkB信号传导和细胞运动途径，这与VM非多巴胺能神经元中突触信号传导和可塑性基因的表达下调形成鲜明对比。在阿片类药物暴露和过量的情况下，VM转录组重编程包括325个基因，其基因变异与更广泛人群中的物质使用特征相关，从而指出大脑奖赏回路基因组组织中的遗传风险结构。
