BACKGROUND Brain homeostasis imbalance, characterized by cognitive dysfunction and delirium, frequently occurs in the elderly after surgery. Investigating why this complication only affects part of patients undergoing the same surgery, and anesthesia remains intriguing. This study tested the role of preoperative blood-brain barrier (BBB) integrity in the occurrence of postoperative brain homeostasis imbalance using mice with conditional BBB damage. METHODS Preoperative BBB breakdown was induced in End-SCL-Cre-ctnnb1fl//fl (iCKO) mice by administering tamoxifen (intraperitoneal [i.p.]). This breakdown was assessed using Evans Blue (EB) leakage and immunoglobulin G (IgG) staining. Postoperative brain homeostasis imbalance was evaluated through the Novel Object Recognition test, the Barnes Maze, and neuroinflammation tests. Synapse loss was detected by colabeling synaptophysin and PSD-95, followed by Western blotting. The role of astrocytes in this pathogenesis was evaluated by comparing cognitive behaviors, hippocampal gene expression, and astrocytic phagocytosis of synaptophysin in iCKO mice with and without genetic inhibition of perioperative astrocyte activity. RESULTS Tamoxifen treatment (30 mg/kg/d) induced BBB breakdown of iCKO mice in a time-dependent manner (analysis of variance [ANOVA] for time, P = .0006), but not in their littermate control mice (nCKO, P > .999). A 3-day tamoxifen treatment induced slight BBB breakdown (EB leakage: 95% confidence interval [CI], 13.9-204.8, P = .013; IgG level: 95% CI, 12.6-51.4: P = .001), but did not cause significant cognitive impairment in the Novel Object Recognition test in iCKO mice (95% CI, -7.99 to 6.12; P > .999). Anesthesia and surgery-induced significant cognitive impairment (all P < .0001 for the Novel Object Recognition test, Barnes Maze test), neuroinflammation, and synaptic loss in iCKO mice with 3-day tamoxifen treatment, but not in nCKO mice with the same treatment. Inhibiting astrocyte activity alleviated the impact of anesthesia and surgery on cognitive function (all P < .0001 for the Novel Object Recognition test, Barnes Maze test), gene expression, and synapse pruning in iCKO mice with 3-day tamoxifen treatment. CONCLUSIONS Preoperative BBB integrity influences the impact of anesthesia and surgery on the brain, with astrocytes modulating this effect. These findings partly explain the heterogeneity in the occurrence of postoperative brain homeostasis imbalance.

中文翻译：

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术前血脑屏障完整性对麻醉和手术对小鼠大脑影响的影响。


背景 以认知功能障碍和谵妄为特征的大脑稳态失衡经常发生在手术后的老年人中。调查为什么这种并发症只影响接受相同手术的部分患者，而麻醉仍然很有趣。本研究使用条件性 BBB 损伤的小鼠测试了术前血脑屏障 （BBB） 完整性在术后脑稳态失衡发生中的作用。方法 通过给予他莫昔芬 （腹膜内 [i.p.]） 诱导 End-SCL-Cre-ctnnb1fl//fl （iCKO） 小鼠术前 BBB 崩溃。使用 Evans Blue （EB） 渗漏和免疫球蛋白 G （IgG） 染色评估这种分解。通过新物体识别测试、Barnes Maze 和神经炎症测试评估术后脑稳态失衡。通过共标记突触素和 PSD-95 检测突触丢失，然后进行 Western blotting。通过比较有和没有围手术期星形胶质细胞活性遗传抑制的 iCKO 小鼠的认知行为、海马基因表达和突触素的星形胶质细胞吞噬作用，评估星形胶质细胞在这种发病机制中的作用。结果 他莫昔芬治疗 （30 mg/kg/d） 以时间依赖性方式诱导 iCKO 小鼠的 BBB 分解 （时间方差分析 [ANOVA]，P = .0006），但在同窝对照小鼠中未诱导 （nCKO，P > .999）。3 天他莫昔芬治疗诱导轻微的 BBB 崩溃（EB 泄漏：95% 置信区间 [CI]，13.9-204.8，P = .013;IgG 水平：95% CI，12.6-51.4：P = .001），但在 iCKO 小鼠的新物体识别测试中没有引起明显的认知障碍（95% CI，-7.99 至 6.12;P > .999）.麻醉和手术诱导的显著认知障碍 （均 P < .0001 用于新型物体识别测试、Barnes Maze 测试）、神经炎症和突触丢失，用于他莫昔芬治疗 3 天的 iCKO 小鼠，但在接受相同治疗的 nCKO 小鼠中则没有。抑制星形胶质细胞活性减轻了麻醉和手术对认知功能的影响 （新物体识别测试、Barnes Maze 测试均 P < .0001）、基因表达和他莫昔芬治疗 3 天的 iCKO 小鼠的突触修剪。结论术前 BBB 完整性影响麻醉和手术对大脑的影响，星形胶质细胞调节这种影响。这些发现部分解释了术后脑稳态失衡发生的异质性。