Department of Neurobiology and Department of Neurology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Liangzhu Laboratory, Zhejiang University Medical Center, MOE Frontier Science Center for Brain Science and Brain-Machine Integration, State Key Laboratory of Brain-Machine Intelligence, Zhejiang University, 1369 West Wenyi Road, Hangzhou 311121, China; NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University, Hangzhou 310058, China.
Spine Lab, Department of Orthopedic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
Curr Biol. 2023 Jun 5;33(11):2187-2200.e6. doi: 10.1016/j.cub.2023.04.047. Epub 2023 May 10.
General anesthesia (GA) is an unconscious state produced by anesthetic drugs, which act on neurons to cause overall suppression of neuronal activity in the brain. Recent studies have revealed that GA also substantially enhances the dynamics of microglia, the primary brain immune cells, with increased process motility and territory surveillance. However, whether microglia are actively involved in GA modulation remains unknown. Here, we report a previously unrecognized role for microglia engaging in multiple GA processes. We found that microglial ablation reduced the sensitivity of mice to anesthetics and substantially shortened duration of loss of righting reflex (LORR) or unconsciousness induced by multiple anesthetics, thereby promoting earlier emergence from GA. Microglial repopulation restored the regular anesthetic recovery, and chemogenetic activation of microglia prolonged the duration of LORR. In addition, anesthesia-accompanying analgesia and hypothermia were also attenuated after microglial depletion. Single-cell RNA sequencing analyses showed that anesthesia prominently affected the transcriptional levels of chemotaxis and migration-related genes in microglia. By pharmacologically targeting different microglial motility pathways, we found that blocking P2Y receptor (P2YR) reduced the duration of LORR of mice. Moreover, genetic ablation of P2YR in microglia also promoted quicker recovery in mice from anesthesia, verifying the importance of microglial P2YR in anesthetic regulation. Our work presents the first evidence that microglia actively participate in multiple processes of GA through P2YR-mediated signaling and expands the non-immune roles of microglia in the brain.
全身麻醉（GA）是一种由麻醉药物产生的无意识状态，这些药物作用于神经元，导致大脑中神经元活动的全面抑制。最近的研究表明，GA 还显著增强了小胶质细胞的动力学，小胶质细胞是大脑的主要免疫细胞，其突起运动和领地监视能力增强。然而，小胶质细胞是否主动参与 GA 调节仍不清楚。在这里，我们报告了小胶质细胞参与多种 GA 过程的一个先前未被认识的作用。我们发现，小胶质细胞消融降低了小鼠对麻醉剂的敏感性，并大大缩短了多种麻醉剂诱导的翻正反射（LORR）丧失或失去知觉的持续时间，从而促进了 GA 的更早出现。小胶质细胞再定植恢复了正常的麻醉恢复，小胶质细胞的化学遗传激活延长了 LORR 的持续时间。此外，小胶质细胞耗竭后，麻醉伴随的镇痛和体温过低也减弱了。单细胞 RNA 测序分析表明，麻醉显著影响了小胶质细胞中趋化和迁移相关基因的转录水平。通过药理学靶向不同的小胶质细胞运动途径，我们发现阻断 P2Y 受体（P2YR）减少了小鼠的 LORR 持续时间。此外，小胶质细胞中 P2YR 的基因缺失也促进了小鼠从麻醉中更快恢复，验证了小胶质细胞 P2YR 在麻醉调节中的重要性。我们的工作首次提供了证据，表明小胶质细胞通过 P2YR 介导的信号主动参与 GA 的多个过程，并扩展了小胶质细胞在大脑中的非免疫作用。
