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浙江大学 Zhejiang University
教授 Professor
高志华,浙江大学教授,博士生导师,长期致力于神经内稳态(神经免疫与神经内分泌)调控在大脑中的生理病理作用与机制研究。近5年以通讯作者在领域内著名学术期刊,如Neuron, Nature Metabolism, Brain, Current Biology, Cell Reports, eLife, Journal of Clinical Investigation Insight, Cerebral Cortex (封面论文)发表论文20篇,研究成果被同行广泛引用和正面评述。
Zhihua GAO is a professor at Zhejiang University. She has focused on the role of neural homeostasis (neural-immune and neuroendocrine control) in the brain. She has published a number of papers in high-caliber journals, including Neuron, Nature Metabolism, Brain, Current Biology, Cell Reports, eLife, Journal of Clinical Investigation Insight, Cerebral Cortex.
报告题目:
小胶质细胞在麻醉中的作用
The role of microglia in anesthesia
报告摘要:
全身麻醉(General anesthesia, GA)诱导可逆的意识和痛觉丧失,被广泛应用于现代外科学手术及相关医学检查,极大地缓解了病患痛苦。已知全身麻醉药物主要通过作用于神经元上的相应受体,诱发脑内神经元的普遍地低活动状态,因此有关麻醉相关的机制研究一直以来都主要聚焦于神经元。小胶质细胞是脑内主要的免疫和稳态调控细胞,近期研究发现,在全身麻醉状态下,小胶质细胞呈现出更加活跃的状态,但他们是否参与麻醉调控不清。我们发现缺失了小胶质细胞的小鼠会提前从麻醉中苏醒,结合脑电记录和翻正反射等分析方法发现,小鼠缺失小胶质细胞后,对全身麻醉剂的敏感性降低,表现为麻醉深度的降低和提前苏醒。通过药理阻断和基因敲除手段发现小胶质细胞特异性表达的P2Y12受体是小胶质细胞调控麻醉的关键靶点,阻断或敲除P2Y12受体也会显著减轻小鼠对麻醉的敏感性,加速麻醉苏醒。该工作首次发现小胶质细胞是全身麻醉的重要参与者,丰富了小胶质细胞在非病理条件下的新功能,从新的视角揭示了全身麻醉的机制。
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 enhanced the dynamics of microglia, the primary brain immune cells, with increased processes motility and territory surveillance. However, whether microglia are actively involved in GA modulation remains unknown. Here, we report a previously unrecognized role for microglia in the regulation of multiple GA processes. We found that microglia ablation substantially reduced the duration, but not the induction, of loss of righting reflex (LORR) in mice, thereby promoting earlier emergence from GA in microglia-depleted mice. Microglia repopulation restored the regular anesthetic recovery, and chemogenetic activation of microglia further prolonged the duration of LORR. In addition, anesthesia-accompanying analgesia and hypothermia induced by different anesthetics were also attenuated after microglia depletion. Single-cell RNA sequencing analyses showed that anesthesia prominently affected the changes in the expression of chemotaxis and migration-related genes in microglia. By pharmacologically targeting different motility pathways, we found that blocking P2Y12 receptor (P2Y12R) reduced the duration of LORR in anesthesia. Moreover, P2Y12R-deficient mice also recapitulated the phenotypic changes observed in microglia-depleted mice, including decreased unconsciousness time and temperature drop during anesthesia, verifying the importance of microglial P2Y12R in anesthetic regulation. Our work provides the first evidence demonstrating the regulatory role of microglia in GA through P2Y12R-mediated signaling and expands the non-immune roles of microglia in the brain.
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高志华,浙江大学教授,博士生导师,长期致力于神经内稳态(神经免疫与神经内分泌)调控在大脑中的生理病理作用与机制研究。近5年以通讯作者在领域内著名学术期刊,如Neuron, Nature Metabolism, Brain, Current Biology, Cell Reports, eLife, Journal of Clinical Investigation Insight, Cerebral Cortex (封面论文)发表论文20篇,研究成果被同行广泛引用和正面评述。
Zhihua GAO is a professor at Zhejiang University. She has focused on the role of neural homeostasis (neural-immune and neuroendocrine control) in the brain. She has published a number of papers in high-caliber journals, including Neuron, Nature Metabolism, Brain, Current Biology, Cell Reports, eLife, Journal of Clinical Investigation Insight, Cerebral Cortex.
报告题目:
小胶质细胞在麻醉中的作用
The role of microglia in anesthesia
报告摘要:
全身麻醉(General anesthesia, GA)诱导可逆的意识和痛觉丧失,被广泛应用于现代外科学手术及相关医学检查,极大地缓解了病患痛苦。已知全身麻醉药物主要通过作用于神经元上的相应受体,诱发脑内神经元的普遍地低活动状态,因此有关麻醉相关的机制研究一直以来都主要聚焦于神经元。小胶质细胞是脑内主要的免疫和稳态调控细胞,近期研究发现,在全身麻醉状态下,小胶质细胞呈现出更加活跃的状态,但他们是否参与麻醉调控不清。我们发现缺失了小胶质细胞的小鼠会提前从麻醉中苏醒,结合脑电记录和翻正反射等分析方法发现,小鼠缺失小胶质细胞后,对全身麻醉剂的敏感性降低,表现为麻醉深度的降低和提前苏醒。通过药理阻断和基因敲除手段发现小胶质细胞特异性表达的P2Y12受体是小胶质细胞调控麻醉的关键靶点,阻断或敲除P2Y12受体也会显著减轻小鼠对麻醉的敏感性,加速麻醉苏醒。该工作首次发现小胶质细胞是全身麻醉的重要参与者,丰富了小胶质细胞在非病理条件下的新功能,从新的视角揭示了全身麻醉的机制。
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 enhanced the dynamics of microglia, the primary brain immune cells, with increased processes motility and territory surveillance. However, whether microglia are actively involved in GA modulation remains unknown. Here, we report a previously unrecognized role for microglia in the regulation of multiple GA processes. We found that microglia ablation substantially reduced the duration, but not the induction, of loss of righting reflex (LORR) in mice, thereby promoting earlier emergence from GA in microglia-depleted mice. Microglia repopulation restored the regular anesthetic recovery, and chemogenetic activation of microglia further prolonged the duration of LORR. In addition, anesthesia-accompanying analgesia and hypothermia induced by different anesthetics were also attenuated after microglia depletion. Single-cell RNA sequencing analyses showed that anesthesia prominently affected the changes in the expression of chemotaxis and migration-related genes in microglia. By pharmacologically targeting different motility pathways, we found that blocking P2Y12 receptor (P2Y12R) reduced the duration of LORR in anesthesia. Moreover, P2Y12R-deficient mice also recapitulated the phenotypic changes observed in microglia-depleted mice, including decreased unconsciousness time and temperature drop during anesthesia, verifying the importance of microglial P2Y12R in anesthetic regulation. Our work provides the first evidence demonstrating the regulatory role of microglia in GA through P2Y12R-mediated signaling and expands the non-immune roles of microglia in the brain.