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Abstract：
BACKGROUND: Depression is a common psychiatric disorder in diabetic patients. Depressive mood associated with obesity/metabolic disorders is related to the inflammatory response caused by long-term consumption of high-fat diets, but its molecular mechanism is unclear. In this study, we investigated whether the antidepressant effect of transcutaneous auricular vagus nerve stimulation (taVNS) in high-fat diet rats works through the P2X7R/NLRP3/IL-1β pathway.
METHODS: We first used 16S rRNA gene sequencing analysis and LC-MS metabolomics assays in Zucker diabetic fatty (ZDF) rats with long-term high-fat diet (Purina #5008) induced significant depression-like behaviors. Next, the forced swimming test (FST) and open field test (OFT) were measured to evaluate the antidepressive effect of taVNS. Immunofluorescence and western blotting (WB) were used to measure the microglia state and the expression of P2X7R, NLRP3, and IL-1β in PFC.
RESULTS: Purina#5008 diet induced significant depression-like behaviors in ZDF rats and was closely related to purine and inflammatory metabolites. Consecutive taVNS increased plasma insulin concentration, reduced glycated hemoglobin and glucagon content in ZDF rats, significantly improved the depressive-like phenotype in ZDF rats through reducing the microglia activity, and increased the expression of P2X7R, NLRP3, and IL-1β in the prefrontal cortex (PFC).
CONCLUSIONS: The P2X7R/NLRP3/IL-1β signaling pathway may play an important role in the antidepressant-like behavior of taVNS, which provides a promising mechanism for taVNS clinical treatment of diabetes combined with depression.
METHODS: We first used 16S rRNA gene sequencing analysis and LC-MS metabolomics assays in Zucker diabetic fatty (ZDF) rats with long-term high-fat diet (Purina #5008) induced significant depression-like behaviors. Next, the forced swimming test (FST) and open field test (OFT) were measured to evaluate the antidepressive effect of taVNS. Immunofluorescence and western blotting (WB) were used to measure the microglia state and the expression of P2X7R, NLRP3, and IL-1β in PFC.
RESULTS: Purina#5008 diet induced significant depression-like behaviors in ZDF rats and was closely related to purine and inflammatory metabolites. Consecutive taVNS increased plasma insulin concentration, reduced glycated hemoglobin and glucagon content in ZDF rats, significantly improved the depressive-like phenotype in ZDF rats through reducing the microglia activity, and increased the expression of P2X7R, NLRP3, and IL-1β in the prefrontal cortex (PFC).
CONCLUSIONS: The P2X7R/NLRP3/IL-1β signaling pathway may play an important role in the antidepressant-like behavior of taVNS, which provides a promising mechanism for taVNS clinical treatment of diabetes combined with depression.
摘要：
背景：抑郁症是糖尿病患者常见的精神疾病。与肥胖/代谢紊乱相关的抑郁情绪与长期食用高脂肪饮食引起的炎症反应有关，但其分子机制尚不清楚。在这项研究中,我们研究了经皮耳迷走神经刺激（taVNS）对高脂饮食大鼠的抗抑郁作用是否通过P2X7R/NLRP3/IL-1β途径起作用。
方法：我们首先对长期高脂饮食（Purina#5008）的Zucker糖尿病脂肪（ZDF）大鼠进行16SrRNA基因测序分析和LC-MS代谢组学测定，诱导了明显的抑郁样行为。接下来,测量强迫游泳试验（FST）和野外试验（OFT）以评估taVNS的抗抑郁作用。免疫荧光和免疫印迹(WB)检测小胶质细胞状态和P2X7R的表达,PFC中的NLRP3和IL-1β。
结果：Purina#5008饮食在ZDF大鼠中引起明显的抑郁样行为，并且与嘌呤和炎症代谢产物密切相关。连续的taVNS增加血浆胰岛素浓度，降低ZDF大鼠的糖化血红蛋白和胰高血糖素含量，通过降低小胶质细胞活性，显著改善ZDF大鼠的抑郁样表型，并增加P2X7R的表达，前额叶皮质(PFC)中的NLRP3和IL-1β。
结论：P2X7R/NLRP3/IL-1β信号通路可能在taVNS的抗抑郁样行为中起重要作用，为taVNS临床治疗糖尿病合并抑郁症提供了有前景的机制。
方法：我们首先对长期高脂饮食（Purina#5008）的Zucker糖尿病脂肪（ZDF）大鼠进行16SrRNA基因测序分析和LC-MS代谢组学测定，诱导了明显的抑郁样行为。接下来,测量强迫游泳试验（FST）和野外试验（OFT）以评估taVNS的抗抑郁作用。免疫荧光和免疫印迹(WB)检测小胶质细胞状态和P2X7R的表达,PFC中的NLRP3和IL-1β。
结果：Purina#5008饮食在ZDF大鼠中引起明显的抑郁样行为，并且与嘌呤和炎症代谢产物密切相关。连续的taVNS增加血浆胰岛素浓度，降低ZDF大鼠的糖化血红蛋白和胰高血糖素含量，通过降低小胶质细胞活性，显著改善ZDF大鼠的抑郁样表型，并增加P2X7R的表达，前额叶皮质(PFC)中的NLRP3和IL-1β。
结论：P2X7R/NLRP3/IL-1β信号通路可能在taVNS的抗抑郁样行为中起重要作用，为taVNS临床治疗糖尿病合并抑郁症提供了有前景的机制。
