Department of Anesthesiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Department of Anesthesiology, Peking University Third Hospital, Beijing, China.
PeerJ. 2024 Aug 9;12:e17775. doi: 10.7717/peerj.17775. eCollection 2024.
Perioperative neurocognitive disorders (PND) refer to neurocognitive abnormalities during perioperative period, which are a great challenge for elderly patients and associated with increased morbidity and mortality. Our studies showed that long non-coding RNAs (lncRNAs) regulate mitochondrial function and aging-related pathologies in the aged hippocampus after anesthesia, and lncRNAs are associated with multiple neurodegenerations. However, the regulatory role of lncRNAs in PND-related pathological processes remains unclear.
A total of 18-month mice were assigned to control and surgery (PND) groups, mice in PND group received sevoflurane anesthesia and laparotomy. Cognitive function was assessed with fear conditioning test. Hippocampal RNAs were isolated for sequencing, lncRNA and microRNA libraries were constructed, mRNAs were identified, Gene Ontology (GO) analysis were performed, and lncRNA-microRNA-mRNA networks were established. qPCR was performed for gene expression verification.
A total of 312 differentially expressed (DE) lncRNAs, 340 DE-Transcripts of Uncertain Coding Potential (TUCPs), and 2,003 DEmRNAs were identified in the hippocampus between groups. The lncRNA-microRNA-mRNA competing endogenous RNA (ceRNA) network was constructed with 29 DElncRNAs, 90 microRNAs, 493 DEmRNAs, 148 lncRNA-microRNA interaction pairs, 794 microRNA-mRNA interaction pairs, and 110 lncRNA-mRNA co-expression pairs. 795 GO terms were obtained. Based on the frequencies of involved pathological processes, BP terms were divided into eight categories: neurological system alternation, neuronal development, metabolism alternation, immunity and neuroinflammation, apoptosis and autophagy, cellular communication, molecular modification, and behavior changes. LncRNA-microRNA-mRNA ceRNA networks in these pathological categories were constructed, and involved pathways and targeted genes were revealed. The top relevant lncRNAs in these ceRNA networks included RP23-65G6.4, RP24-396L14.1, RP23-251I16.2, XLOC_113622, RP24-496E14.1, ., and the top relevant mRNAs in these ceRNA networks included Dlg4 (synaptic function), Avp (lipophagy), Islr2 (synaptic function), Hcrt (regulation of awake behavior), Tnc (neurotransmitter uptake).
In summary, we have constructed the lncRNA-associated ceRNA network during PND development in mice, explored the role of lncRNAs in multiple pathological processes in the mouse hippocampus, and provided insights into the potential mechanisms and therapeutic gene targets for PND.
围手术期神经认知障碍（PND）是指围手术期期间的神经认知异常，这对老年患者是一个巨大的挑战，并与发病率和死亡率的增加有关。我们的研究表明，长链非编码 RNA（lncRNA）在麻醉后调节衰老海马体中的线粒体功能和与衰老相关的病理学，并且 lncRNA 与多种神经退行性疾病有关。然而，lncRNA 在与 PND 相关的病理过程中的调节作用仍不清楚。
将 18 个月大的小鼠分为对照组和手术组（PND 组），PND 组小鼠接受七氟醚麻醉和剖腹手术。使用恐惧条件反射测试评估认知功能。分离海马 RNA 进行测序，构建 lncRNA 和 microRNA 文库，鉴定 mRNAs，进行基因本体论（GO）分析，并建立 lncRNA-microRNA-mRNA 网络。进行 qPCR 以验证基因表达。
在两组之间的海马体中总共鉴定出 312 个差异表达（DE）lncRNA、340 个不确定编码潜能的转录物（TUCP）DE 和 2003 个 DEmRNA。构建了 lncRNA-microRNA-mRNA 竞争内源性 RNA（ceRNA）网络，其中包含 29 个 DElncRNA、90 个 microRNA、493 个 DEmRNA、148 个 lncRNA-microRNA 相互作用对、794 个 microRNA-mRNA 相互作用对和 110 个 lncRNA-mRNA 共表达对。获得了 795 个 GO 术语。基于涉及的病理过程的频率，BP 术语分为八个类别：神经系统改变、神经元发育、代谢改变、免疫和神经炎症、细胞凋亡和自噬、细胞通讯、分子修饰和行为改变。构建了这些病理类别中的 lncRNA-microRNA-mRNA ceRNA 网络，并揭示了涉及的途径和靶向基因。这些 ceRNA 网络中的 top 相关 lncRNA 包括 RP23-65G6.4、RP24-396L14.1、RP23-251I16.2、XLOC_113622、RP24-496E14.1、……，这些 ceRNA 网络中的 top 相关 mRNAs 包括 Dlg4（突触功能）、Avp（脂噬）、Islr2（突触功能）、Hcrt（觉醒行为调节）、Tnc（神经递质摄取）。
总之，我们构建了围手术期神经认知障碍发展过程中 lncRNA 相关的 ceRNA 网络，探索了 lncRNA 在小鼠海马体中多种病理过程中的作用，为围手术期神经认知障碍的潜在机制和治疗基因靶点提供了新的见解。
