Department of Pharmacology, Health Science Center, Ningbo University, 818 Fenghua Rd, Ningbo, Zhejiang 315211, China.
Department of Pharmacology, Health Science Center, Ningbo University, 818 Fenghua Rd, Ningbo, Zhejiang 315211, China; Faculty of Electrical Engineering and Computer Science, Ningbo University, 818 Fenghua Rd, Ningbo, Zhejiang 315211, China.
Neurosci Lett. 2024 Oct 15;841:137953. doi: 10.1016/j.neulet.2024.137953. Epub 2024 Aug 28.
The behavioral sensitization, characterized by escalated behavioral responses triggered by recurrent exposure to psychostimulants, involves neurobiological mechanisms that are brain-region and cell-type specific. Enduring neuroadaptive changes have been observed in response to methamphetamine (METH) within the orbitofrontal cortex (OFC), the cell-type specific transcriptional alterations in response to METH sensitization remain understudied. In this study, we utilized Single-nucleus RNA-sequencing (snRNA-seq) to profile the gene expression changes in the OFC of a rat METH sensitization model. The analyses of differentially expressed genes (DEGs) unveiled cell-type specific transcriptional reactions associated with METH sensitization, with the most significant alterations documented in microglial cells. Bioinformatic investigations revealed that distinct functional and signaling pathways enriched in microglia-specific DEGs majorly involved in macroautophagy processes and the activation of N-methyl-D-aspartate ionotropic glutamate receptors (NMDAR). To validate the translational relevance of our findings, we analyzed our snRNA-seq data in conjunction with a transcriptomic study of individuals with opioid use disorder (OUD) and a large-scale Genome-Wide Association Studies (GWAS) from multiple externalizing phenotypes related to drug addiction. The validation analysis confirmed the consistent expression changes of key microglial DEGs in human METH addiction. Moreover, the integration with GWAS data revealed associations between addiction risk genes and the DEGs observed in specific cell types, particularly microglia and excitatory neurons. Our study highlights the importance of cell-type specific transcriptional alterations in the OFC in the context of METH sensitization and their potential translational relevance to human drug addiction.
行为敏化，表现为反复暴露于精神兴奋剂后行为反应加剧，涉及到特定脑区和细胞类型的神经生物学机制。在眶额皮质（OFC）中，已经观察到对甲基苯丙胺（METH）的持久神经适应性变化，而对 METH 敏化的细胞类型特异性转录改变仍研究不足。在这项研究中，我们利用单细胞 RNA 测序（snRNA-seq）来描绘 METH 敏化大鼠模型 OFC 的基因表达变化。差异表达基因（DEGs）的分析揭示了与 METH 敏化相关的特定细胞类型特异性转录反应，其中在小胶质细胞中记录到最显著的改变。生物信息学研究表明，在小胶质细胞特异性 DEGs 中富集的不同功能和信号通路主要涉及巨自噬过程和 N-甲基-D-天冬氨酸离子型谷氨酸受体（NMDAR）的激活。为了验证我们发现的转化相关性，我们结合了一项关于阿片类药物使用障碍（OUD）个体的转录组学研究以及来自多个与药物成瘾相关的外在表型的大规模全基因组关联研究（GWAS），分析了我们的 snRNA-seq 数据。验证分析证实了关键小胶质细胞 DEGs 在人类 METH 成瘾中的一致表达变化。此外，与 GWAS 数据的整合揭示了成瘾风险基因与特定细胞类型（特别是小胶质细胞和兴奋性神经元）中观察到的 DEGs 之间的关联。我们的研究强调了 OFC 中特定细胞类型的转录改变在 METH 敏化中的重要性及其对人类药物成瘾的潜在转化相关性。
