Mechanisms by which sevoflurane affects cognitive function in aged marmosets and mice: up-regulation of FKBP5 expression in brain microglia

Zhang, Lei1,2,*,#; Zhu, Jiao1,#; Miao, Zhengjie1; Mao, Haoli1; Jiang, Hong1,*

Author Information

1Department of Anesthesiology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

2Department of Anesthesiology, Shandong Provincial Key Medical and Health Laboratory of Anesthesia and Brain Function (The Affiliated Hospital of Qingdao University), The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China

*Correspondence to: Lei Zhang, MD, PhD, weiymzhl@126.com; Hong Jiang, MD, PhD, jianghongjiuyuan@163.com.

#Both authors contributed equally to this work.Funding:This study was supported by the National Natural Science Foundation of China (Nos. 82471280, 82171173); the Science and Technology Commission of Shanghai Municipality (STCSM) (Nos. 22ZR1437200, 22YF1422500); and the Cross disciplinary Research Fund of Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine (Nos. JYLJ202304 and JYLJ202221).

Abstract

Inhalation anesthetics may trigger the hypothalamic–pituitary–adrenal axis. FK-506 binding protein (FKBP5) is a critical regulator of the hypothalamic–pituitary–adrenal axis and has been implicated in postoperative cognitive dysfunction. However, how inhalation anesthetics affect the expression and function of FKBP5 in the brain is unclear. We employed single-nucleus RNA sequencing to delineate the hippocampal transcriptomic profiles of the brains of aged marmosets and mice after sevoflurane anesthesia. The results of single-nucleus RNA sequencing revealed that long-term exposure (6 hours) to sevoflurane significantly increased FKBP5 expression in the hippocampus of aged marmosets and mice, especially in microglia. Western blot assay also verified the above results. The Barnes maze test showed that, compared with heterozygous control mice, microglia-specific FKBP5 conditional knockout mice exhibited improved neurocognitive function after sevoflurane/surgery. Transcriptome sequencing analysis was performed on the brains of microglia-specific FKBP5 conditional knockout mice and heterozygous mice after sevoflurane/surgery and further revealed that FKBP5 was related mainly to inflammatory signaling pathways. Therefore, these findings indicate that long-term exposure to sevoflurane increases FKBP5 expression in the hippocampus of aged marmosets and mice, which thereby affects inflammatory signaling pathways and leads to postoperative cognitive dysfunction.

摘要

吸入性麻醉药可能触发下丘脑-垂体-肾上腺轴。FK-506结合蛋白5（FKBP5）是下丘脑-垂体-肾上腺轴的关键调节因子，并与术后认知功能障碍有关。然而，吸入性麻醉药如何影响大脑中FKBP5的表达和功能尚不清楚。我们采用单细胞核RNA测序技术，描绘了老年狨猴和小鼠在七氟烷麻醉后海马体的转录组图谱。单细胞核RNA测序结果显示，长时间（6小时）暴露于七氟烷会显著增加老年狨猴和小鼠海马体中FKBP5的表达，尤其是在小胶质细胞中。蛋白质印迹分析也验证了上述结果。巴恩斯迷宫测试表明，与杂合子对照小鼠相比，小胶质细胞特异性FKBP5条件性敲除小鼠在七氟烷/手术后表现出神经认知功能改善。对七氟烷/手术后的小胶质细胞特异性FKBP5条件性敲除小鼠和杂合子小鼠的大脑进行转录组测序分析，进一步揭示FKBP5主要与炎症信号通路相关。因此，这些研究结果表明，长时间暴露于七氟烷会增加老年狨猴和小鼠海马体中FKBP5的表达，从而影响炎症信号通路并导致术后认知功能障碍。