Transcriptional Alterations in Dorsolateral Prefrontal Cortex and Nucleus Accumbens Implicate Neuroinflammation and Synaptic Remodeling in Opioid Use Disorder.
Transcriptional Alterations in Dorsolateral Prefrontal Cortex and Nucleus Accumbens Implicate Neuroinflammation and Synaptic Remodeling in Opioid Use Disorder.
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DOI：
10.1016/j.biopsych.2021.06.007
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发表时间：
2021-10-15
影响因子：
10.6
通讯作者：
Logan RW
中科院分区：
文献类型：
--
作者：
Seney ML;Kim SM;Glausier JR;Hildebrand MA;Xue X;Zong W;Wang J;Shelton MA;Phan BN;Srinivasan C;Pfenning AR;Tseng GC;Lewis DA;Freyberg Z;Logan RW
阿片类药物使用障碍（OUD）的患病率急剧增加，伴随着过量死亡的激增。虽然阿片类药物依赖已在临床前模型中得到广泛研究，但对长期使用阿片类药物和被诊断患有OUD的人大脑中发生的生物学改变的理解仍然有限。为了解决这一限制，在OUD受试者死后大脑的背外侧前额叶皮层（DLPFC）和背外侧前额叶核（NAc）（与OUD密切相关的区域）上进行RNA测序（RNA-seq）。我们对来自未受影响的对照受试者（n=20）和诊断为OUD的受试者（n = 20）的DLPFC和NAc进行了RNA-seq。我们的转录组学分析确定了差异表达（DE）的转录本，并使用秩-秩超几何排序（RRHO）研究了大脑区域之间的转录一致性。加权基因共表达分析（WGCNA）也确定了OUD特异性模块和基因网络。利用连锁不平衡评分（LDSC）对DE转录本和GWAS数据集进行整合分析，评估精神病相关表型的遗传易感性。RRHO分析显示，在OUD中DLPFC和NAc之间的转录物存在广泛的重叠，主要与突触重塑和神经炎症有关。鉴定的转录本富含控制促炎性丝氨酸介导的因子、硫酸软骨素和细胞外基质信号传导。细胞类型去卷积暗示了小胶质细胞作为阿片类药物诱导的神经可塑性的潜在驱动因素的作用。LDSC分析提示OUD受试者的危险行为、注意缺陷多动障碍和抑郁具有遗传倾向。总的来说，我们的研究结果表明大脑免疫系统与人类大脑中的阿片类药物依赖之间存在联系。
Prevalence rates of opioid use disorder (OUD) have increased dramatically, accompanied by a surge of overdose deaths. While opioid dependence has been extensively studied in preclinical models, an understanding of the biological alterations that occur in the brains of people who chronically use opioids and who are diagnosed with OUD remains limited. To address this limitation, RNA-sequencing (RNA-seq) was conducted on the dorsolateral prefrontal cortex (DLPFC) and nucleus accumbens (NAc), regions heavily implicated in OUD, from postmortem brains in subjects with OUD. We performed RNA-seq on the DLPFC and NAc from unaffected comparison subjects (n=20) and subjects diagnosed with OUD (n=20). Our transcriptomic analyses identified differentially expressed (DE) transcripts and investigated the transcriptional coherence between brain regions using rank-rank hypergeometric ordering (RRHO). Weighted gene co-expression analyses (WGCNA) also identified OUD-specific modules and gene networks. Integrative analyses between DE transcripts and GWAS datasets using linkage disequilibrium score (LDSC) assessed the genetic liability psychiatric-related phenotypes. RRHO analyses revealed extensive overlap in transcripts between DLPFC and NAc in OUD, primarily relating to synaptic remodeling and neuroinflammation. Identified transcripts were enriched for factors that control pro-inflammatory cytokine-mediated, chondroitin sulfate, and extracellular matrix signaling. Cell-type deconvolution implicated a role for microglia as a potential driver for opioid-induced neuroplasticity. LDSC analysis suggested genetic liabilities for risky behavior, attention deficit hyperactivity disorder, and depression in subjects with OUD. Overall, our findings suggest connections between the brain’s immune system and opioid dependence in the human brain.
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影响因子：
30.8
作者：
Bulik-Sullivan, Brendan K.;Loh, Po-Ru;Finucane, Hilary K.;Ripke, Stephan;Yang, Jian;Patterson, Nick;Daly, Mark J.;Price, Alkes L.;Neale, Benjamin M.
通讯作者：
Neale, Benjamin M.
影响因子：
15.9
作者：
Baldo BA
通讯作者：
Baldo BA
影响因子：
4.6
作者：
Cahill KM;Huo Z;Tseng GC;Logan RW;Seney ML
通讯作者：
Seney ML
影响因子：
3.4
作者：
Bora, Emre;Yuecel, Murat;Lubman, Dan I.
通讯作者：
Lubman, Dan I.
影响因子：
7.6
作者：
de Guglielmo, Giordano;Melis, Miriam;Ciccocioppo, Roberto
通讯作者：
Ciccocioppo, Roberto