Autophagy is crucial for cell survival, development, division, and homeostasis. The mammalian target of rapamycin (mTOR), which is the foremost negative controller of autophagy, plays a key role in many endogenous processes. The present study investigated whether rapamycin can ameliorate surgery-induced cognitive deficits by inhibiting mTOR and activating autophagy in the hippocampus. Both adult and aged C57BL/6J mice received an intraperitoneal injection of rapamycin (10 mg/kg/day) for 5 days per week for one and a half months. Mice were then subjected to partial hepatectomy under general anesthesia. Behavioral performance was assessed on postoperative days 3, 7, and 14. Hippocampal autophagy-related (Atg)-5, phosphorylated mTOR, and phosphorylated p70S6K were examined at each time point. Brain derived neurotrophic factor (BDNF), synaptophysin, and tau hyperphosphorylation (T396) in the hippocampus were also examined. Surgical trauma and anesthesia exacerbated spatial learning and memory impairment in aged mice on postoperative days 3 and 7. Following partial hepatectomy, the levels of phosphorylated mTOR, phosphorylated 70S6K, and phosphorylated tau were all increased in the hippocampus. A corresponding decline in BDNF and synaptophysin were observed. Rapamycin treatment restored autophagy function, attenuated phosphorylation of tau protein, and increased BDNF and synaptophysin expression in the hippocampus of surgical mice. Furthermore, surgery and anesthesia induced spatial learning and memory impairments were also reversed by rapamycin treatment. Autophagy impairments and mTOR hyperactivation were detected along with surgery-induced behavioral deficits. Inhibiting the mTOR signaling pathway with rapamycin successfully ameliorated surgery-related cognitive impairments by sustaining autophagic degradation, inhibiting tau hyperphosphorylation, and increasing synaptophysin and BDNF expression.

中文翻译：

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自噬功能障碍和mTOR过度激活涉及外科手术：老年C57BL / 6J小鼠诱发的行为缺陷。

自噬对于细胞存活，发育，分裂和体内平衡至关重要。雷帕霉素（mTOR）的哺乳动物靶标是自噬的最主要的负调控因子，在许多内源性过程中起着关键作用。本研究调查雷帕霉素是否可以通过抑制mTOR并激活海马中的自噬来改善手术引起的认知功能障碍。成年和成年C57BL / 6J小鼠都接受雷帕霉素（10 mg / kg /天）的腹膜内注射，每周5天，持续一个半月。然后在全身麻醉下对小鼠进行部分肝切除术。在术后第3、7和14天评估行为表现。在每个时间点检查海马自噬相关（Atg）-5，磷酸化mTOR和磷酸化p70S6K。脑源性神经营养因子（BDNF），突触素，还检查了海马中的tau和tau过度磷酸化（T396）。手术创伤和麻醉使衰老小鼠在术后第3天和第7天加剧了空间学习和记忆障碍。部分肝切除术后，海马中磷酸化的mTOR，70S6K磷酸化和tau磷酸化均升高。观察到BDNF和突触素的相应下降。雷帕霉素治疗可恢复自噬功能，减弱tau蛋白的磷酸化，并增加手术小鼠海马中的BDNF和突触素表达。此外，雷帕霉素治疗还可以逆转由手术和麻醉引起的空间学习和记忆障碍。自噬功能障碍和mTOR过度激活与手术引起的行为缺陷一起被检测到。