Peripheral interleukin-6-associated microglial QUIN elevation in basolateral amygdala contributed to cognitive dysfunction in a mouse model of postoperative delirium.
Peripheral interleukin-6-associated microglial QUIN elevation in basolateral amygdala contributed to cognitive dysfunction in a mouse model of postoperative delirium.
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基底外侧杏仁核外周白细胞介素 6 相关小胶质细胞 QUIN 升高导致术后谵妄小鼠模型认知功能障碍
DOI：
10.3389/fmed.2022.998397
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发表时间：
2022
影响因子：
3.9
通讯作者：
中科院分区：
文献类型：
--
作者：
由于缺乏病理生理学相似的动物模型来深入了解发病机制，因此开发有效的术后谵妄方法受到阻碍。因此，本研究旨在建立一种谵妄样小鼠模型，并探讨其潜在机制。在成年雄性C57 BL/6小鼠中进行3个循环的10分钟钳夹，然后5分钟重新打开上级肠系膜动脉（SMA），以诱导谵妄样表型。采用基于旷场、Y迷宫和埋藏食物试验结果计算的复合Z评分来评估小鼠的谵妄表型。通过免疫荧光染色和综合形态学分析监测小胶质细胞的活性。应用米诺环素（MINO）、IL-6抗体或IL-6中和抗体全身给药来操纵小胶质细胞。采用RT-PCR和高效液相色谱/质谱法分别检测吲哚胺2，3-双加氧酶-1（IDO-1）和喹啉酸（QUIN）的表达。采用荧光激活细胞分选法测定细胞因子。反复缺血/再灌注（I/R）手术后24 h，小鼠出现明显的焦虑（P < 0.05），工作记忆和定向能力下降（P < 0.05）。表明脑功能总体障碍的复合Z评分在I/R手术后24小时内波动（P < 0.001）。免疫荧光染色显示，基底外侧杏仁核（BLA）中的小胶质细胞百分比（P < 0.05）在I/R手术后重新激活，并与Y迷宫停留时间呈负相关（R =-0.759，P = 0.035）。MINO抑制小胶质细胞的活性可减少QUIN的产生（P < 0.01），从而改善认知功能障碍（P < 0.05）。外周血IL-6可能引起BLA中IL-6水平升高。全身给予IL-6抗体抑制了BLA中I/R诱导的IL-6升高（P <0.05）、小胶质细胞再活化（P < 0.05）、IDO-1表达（P < 0.01）和神经活性代谢物QUIN产生（P <0.05），导致认知缺陷恢复（P < 0.05）。注射IL-6则产生相反的作用。重复肠道I/R手术诱导的小鼠模型是一种简单且可重复的术后谵妄模型。BLA中外周IL-6相关小胶质细胞QUIN升高导致术后谵妄模型中的认知功能障碍。
Developing effective approaches for postoperative delirium has been hampered due to the lack of a pathophysiologically similar animal model to offer insights into the pathogenesis. The study, therefore, aimed to develop a delirium-like mouse model and explore the underlying mechanism. The three cycles of 10-min clamp following 5-min reopening of the superior mesenteric artery (SMA) were performed in adult male C57BL/6 mice to induce a delirium-like phenotype. Composite Z score calculated based on the results of Open Field, Y Maze and Buried Food Tests was employed to assess the delirium phenotype in mice. Microglia activities were monitored by immunofluorescence staining and comprehensive morphological analysis. Systemic administration of minocycline (MINO), IL-6 antibody or IL-6 neutralizing antibody, was applied to manipulate microglia. The expressions of Indoleamine 2,3-dioxygenase-1 (IDO-1) and quinolinic acid (QUIN) were examined by RT-PCR and High-Performance Liquid Chromatography/Mass Spectrometry, respectively. Cytokines were measured using fluorescence activated cell sorting method. The repeated ischemia/reperfusion (I/R) surgery caused significant anxiety (P < 0.05) and cognition decline in working memory and orientation (P < 0.05) in mice at postoperative 24 h. The composite Z score, indicating an overall disturbance of brain function, fluctuated over 24 h after I/R surgery (P < 0.001). Immunofluorescent staining showed that the percentage of microglia in the basolateral amygdala (BLA) (P < 0.05) was reactivated after I/R surgery and was negatively correlated with dwell time at Y maze (R = −0.759, P = 0.035). Inhibiting microglia activities by MINO reduced QUIN productions (P < 0.01) that improved cognitive deficits (P < 0.05). The peripheral IL-6 might cause IL-6 elevation in the BLA. Systemic administration of IL-6 antibodies suppressed I/R-induced IL-6 elevations (P < 0.05), microglial reactivations (P < 0.05), IDO-1 expressions (P < 0.01), and neuroactive metabolite QUIN productions (P < 0.05) in the BLA, resulting in a recovery of cognitive deficits (P < 0.05). Injection of IL-6 exerted opposite effects. The repeated intestinal I/R surgery-induced mouse model is a simple and reproducible one of postoperative delirium. Peripheral IL-6-associated microglial QUIN elevations in the BLA contributed to cognitive dysfunction in the model of postoperative delirium.
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影响因子：
39.2
作者：
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Kreutzberg, GW
影响因子：
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通讯作者：
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