Hao Shiyu, Zhang Qidi, Zhang Xianzheng, Feng Zunsai, Wu Jiangnan, Xu Ziqing, Li Jingjing, Wang Gongming
Department of Anesthesiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
Department of Anesthesiology, Central Hospital Affiliated to Shandong First Medical University, Jinan, China.
J Mol Neurosci. 2025 Aug 2;75(3):97. doi: 10.1007/s12031-025-02380-1.
Perioperative neurocognitive disorder (PND) is a prevalent postoperative complication of the central nervous system (CNS) in elderly patients. Advanced age is an independent risk factor for developing PND. Microglia are essential immune cells in the CNS and play a critical role in neuroinflammation. The activation of microglia is closely linked to PND, although the precise mechanism remains unclear. Gamma oscillations (30-100 Hz) are associated with higher cognitive functions, including attention. The aim of this study was to investigate the mechanism by which microglial activation in PND disrupts gamma oscillations. The study utilized 18-month-old male C57BL/6 J mice and established a PND model through exploratory laparotomy. The results of both Contextual Fear Conditioning (CFC) and Morris Water Maze (MWM) experiments demonstrated that exploratory laparotomy could lead to hippocampus-dependent neurocognitive dysfunction in aged mice. We observed that exploratory laparotomy induced the transformation of microglia in the hippocampus of aged mice into an activated phenotype characterized by enlarged cell bodies and shortened processes. This transformation was accompanied by a significant increase in the expression levels of pro-inflammatory factors in hippocampal tissue, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6). Specific depletion of microglia in aged mice, achieved by drinking water supplemented with the colony-stimulating factor 1 receptor (CSF1R)/c-Kit kinase inhibitor PLX3397 for seven consecutive days, resulted in a reduction of postoperative hippocampal neuroinflammation and a significant improvement in cognitive dysfunction. Similarly, perioperative inhibition of microglial activation with minocycline resulted in cognitive improvement. Additionally, we found that the expression levels of hippocampal parvalbumin (PV) and glutamate decarboxylase 67 (GAD67) were significantly reduced following exploratory laparotomy, which was accompanied by disturbed gamma oscillations. Depletion of microglia restored the expression levels of PV and GAD67 and significantly improved the disturbances in gamma oscillations. These findings suggest that the activation of hippocampal microglia and the associated neuroinflammatory response following surgery play a crucial role in PND. The underlying mechanism may be related to disturbed gamma oscillations and a reduction in the inhibitory function of PV interneurons.
围手术期神经认知障碍（PND）是老年患者中枢神经系统（CNS）常见的术后并发症。高龄是发生PND的独立危险因素。小胶质细胞是中枢神经系统中的重要免疫细胞，在神经炎症中起关键作用。小胶质细胞的激活与PND密切相关，尽管确切机制尚不清楚。γ振荡（30 - 100Hz）与包括注意力在内的更高认知功能相关。本研究的目的是探讨PND中小胶质细胞激活破坏γ振荡的机制。该研究使用18月龄雄性C57BL/6J小鼠，通过剖腹探查建立PND模型。情境恐惧条件反射（CFC）和莫里斯水迷宫（MWM）实验结果均表明，剖腹探查可导致老年小鼠出现海马依赖性神经认知功能障碍。我们观察到，剖腹探查诱导老年小鼠海马中的小胶质细胞转变为活化表型，其特征为细胞体增大和突起缩短。这种转变伴随着海马组织中促炎因子表达水平的显著增加，包括肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）和白细胞介素-6（IL-6）。通过连续七天饮用补充集落刺激因子1受体（CSF1R）/c-Kit激酶抑制剂PLX3397的水，特异性清除老年小鼠中的小胶质细胞，导致术后海马神经炎症减轻，认知功能障碍显著改善。同样，围手术期用米诺环素抑制小胶质细胞激活可改善认知功能。此外，我们发现剖腹探查后海马小白蛋白（PV）和谷氨酸脱羧酶67（GAD67）的表达水平显著降低，同时伴有γ振荡紊乱。小胶质细胞的清除恢复了PV和GAD67的表达水平，并显著改善了γ振荡紊乱。这些发现表明，手术后海马小胶质细胞的激活及相关神经炎症反应在PND中起关键作用。潜在机制可能与γ振荡紊乱和PV中间神经元抑制功能降低有关。
