Department of Physiology and Pharmacology, Des Moines University, Des Moines, IA, 50312, USA.
Department of Physiology and Pharmacology, Des Moines University, Des Moines, IA, 50312, USA; Department of Molecular Pharmacology and Therapeutics, Columbia University, New York, NY, 10032, USA.
Eur J Pharmacol. 2024 Feb 5;964:176273. doi: 10.1016/j.ejphar.2023.176273. Epub 2023 Dec 21.
Altered mood and psychiatric disorders are commonly associated with chronic pain conditions; however, brain mechanisms linking pain and comorbid clinical depression are still largely unknown. In this study, we aimed to identify whether key genes/cellular mechanisms underlie susceptibility/resiliency to development of depressive-like behaviors during chronic pain state. Genome-wide RNA-seq analysis was used to examine the transcriptomic profile of the hippocampus, a limbic brain region that regulates mood and stress responses, from male rats exposed to chronic inflammatory pain. Pain-exposed animals were separated into either 'resilient' or 'susceptible' to development of enhanced behavioral emotionality based on behavioral testing. RNA-seq bioinformatic analysis, followed by validation using qPCR, revealed dysregulation of hippocampal genes involved in neuroinflammation, cell cycle/neurogenesis and blood-brain barrier integrity. Specifically, ADAM Metallopeptidase Domain 8 (Adam8) and Aurora Kinase B (Aurkb), genes with functional roles in activation of the NLRP3 inflammasome and microgliosis, respectively, were significantly upregulated in the hippocampus of 'susceptible' animals expressing increased behavioral emotionality. In addition, genes associated with blood-brain barrier integrity, such as the Claudin 4 (Cldn4), a tight junction protein and a known marker of astrocyte activation, were also significantly dysregulated between 'resilient' or 'susceptible' pain groups. Furthermore, differentially expressed genes (DEGs) were further characterized in rodents stress models to determine whether their hippocampal dysregulation is driven by common stress responses vs. affective pain processing. Altogether these results continue to strengthen the connection between dysregulation of hippocampal genes involved in neuroinflammatory and neurodegenerative processes with increased behavioral emotionality often expressed in chronic pain state.
改变的情绪和精神障碍通常与慢性疼痛状况有关;然而，将疼痛与共病临床抑郁症联系起来的大脑机制在很大程度上仍然未知。在这项研究中，我们旨在确定关键基因/细胞机制是否在慢性疼痛状态下易患抑郁样行为的发展中起作用。使用全基因组 RNA-seq 分析来检查海马体的转录组谱，海马体是调节情绪和应激反应的边缘大脑区域，来自暴露于慢性炎症性疼痛的雄性大鼠。根据行为测试，将疼痛暴露的动物分为对增强的行为情感发展具有“弹性”或“易感性”的动物。RNA-seq 生物信息学分析，随后使用 qPCR 进行验证，揭示了海马体中参与神经炎症、细胞周期/神经发生和血脑屏障完整性的基因失调。具体而言，ADAM 金属肽酶结构域 8 (Adam8)和极光激酶 B (Aurkb)，分别在 NLRP3 炎症小体和小胶质细胞激活中具有功能作用的基因，在表现出增加的行为情感的“易感”动物的海马体中显著上调。此外，与血脑屏障完整性相关的基因，如紧密连接蛋白 Claudin 4 (Cldn4)和已知的星形胶质细胞激活标志物，在“弹性”或“易感”疼痛组之间也存在明显失调。此外，进一步在啮齿动物应激模型中对差异表达基因 (DEGs) 进行了特征描述，以确定其海马体失调是由共同的应激反应还是情感性疼痛处理驱动的。总之，这些结果继续加强了参与神经炎症和神经退行性过程的海马体基因失调与慢性疼痛状态下经常表达的行为情感增强之间的联系。
