Abstract:
Memory impairment is one of the main characteristics of postoperative cognitive dysfunction. It remains elusive how postoperative pathological changes of the brain link to the memory impairment. The clinical setting of perioperation was mimicked via partial hepatectomy under sevoflurane anaesthesia together with preoperative restraint stress (Hep-Sev-stress) in mice. Memory changes were assessed with fear conditioning. The medial prefrontal cortex (mPFC)-dorsal hippocampus connectivity was evaluated with injecting neurotracer 28 days before surgery. Astrocytic activation was limited via injecting AAV-GFAP-hM4Di-eGFP into the mPFC. Astrocytic and microglial phagocytosis of synapses were visualised with co-labelling hippocampal neuronal axon terminals with PSD-95 and S100β or Iba1. Neuroinflammation and oxidative stress status were also detected. Hep-Sev-stress impaired the memory consolidation (mean [standard error], 49.91 [2.55]% vs. 35.40 [3.97]% in the contextual memory, p = 0.007; 40.72 [2.78]% vs. 27.77 [2.22]% in cued memory, p = 0.002) and the cued memory retrieval (39.00 [3.08]% vs. 24.11 [2.06]%, p = 0.001) in mice when compared with these in the naïve controls. Hep-Sev-stress damaged the connectivity from the dorsal hippocampus to mPFC but not from the mPFC to the dorsal hippocampus and increased the astrocytic but not microglial phagocytosis of hippocampal neuronal axon terminals in the mPFC. The intervention also induced neuroinflammation and oxidative stress in the dorsal hippocampus and the mPFC in a regional-dependent manner. Limiting astrocyte activation in the mPFC alleviated memory consolidation impairment induced by Hep-Sev-stress. Postoperative memory consolidation was impaired due to astrocytic phagocytosis-induced connectivity injury from the dorsal hippocampus to the medial prefrontal cortex.
摘要:
记忆障碍是术后认知功能障碍的主要特征之一。大脑的术后病理变化如何与记忆障碍联系起来仍然难以捉摸。通过七氟醚麻醉下的部分肝切除术以及小鼠的术前约束应力(Hep-Sev-stress)来模拟围手术期的临床设置。通过恐惧条件评估记忆变化。手术前28天,通过注射神经示踪剂评估内侧前额叶皮质(mPFC)-背侧海马的连通性。通过将AAV-GFAP-hM4Di-eGFP注射到mPFC中来限制星形细胞活化。用PSD-95和S100β或Iba1共标记海马神经元轴突末端,可以观察到突触的星形细胞和小胶质细胞吞噬作用。还检测了神经炎症和氧化应激状态。Hep-Sev压力损害了记忆巩固(平均值[标准误差],49.91[2.55]%vs.在上下文记忆中35.40[3.97]%,p=0.007;40.72[2.78]%vs.提示内存中27.77[2.22]%,p=0.002)和提示记忆检索(39.00[3.08]%vs.24.11[2.06]%,与未处理的对照相比,小鼠中的p=0.001)。Hep-Sev应激破坏了从背侧海马到mPFC的连接,但没有破坏从mPFC到背侧海马的连接,并增加了mPFC中海马神经元轴突末端的星形细胞而不是小胶质细胞吞噬作用。干预还以区域依赖性方式诱导背侧海马和mPFC中的神经炎症和氧化应激。限制mPFC中的星形胶质细胞激活减轻了Hep-Sev应激引起的记忆巩固损害。由于星形细胞吞噬作用引起的从背侧海马到内侧前额叶皮层的连接损伤,术后记忆巩固受损。