Tong Kun, Song Yu-Tong, Jing Si-Qi, You Yue, Wang Shi-Jie, Wu Tong, Xu Han, Zhang Jing-Wei, Liu Le, Hao Jing-Ru, Sun Nan, Cao Jun-Li, Gao Can
NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application, Xuzhou Medical University, Xuzhou, Jiangsu, China; Department of Anesthesia, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application, Xuzhou Medical University, Xuzhou, Jiangsu, China.
Br J Anaesth. 2025 Jan;134(1):111-123. doi: 10.1016/j.bja.2024.08.043. Epub 2024 Nov 26.
Surgery can induce severe neuroinflammation and negative emotional symptoms, such as anxiety-like behaviour. We studied whether reactive astrocytes in the zona incerta (ZI) mediate surgery-induced anxiety in mice.
Laparotomy under isoflurane 1.5 vol% was used as a model in adult mice. The role of the ZI in surgery-induced anxiety was evaluated by behavioural tests, optical fibre recordings of neuronal activity, in vivo electrophysiological recordings, chemogenetics, and optogenetics.
Operative mice showed increased anxiety-like behaviour. Immunostaining and optical calcium recording revealed that astrocytes were abnormally activated in the ZI. Pharmacologic (F=5.837, P=0.044) or genetic manipulation (open field test: t=3.66, P=0.007; elevated plus maze [EPM]: t=2.70, P=0.022) of astrocyte activation in the ZI relieved anxiety-like behaviour in surgery-treated mice. Compared with the sham group, the surgery group showed increased extrasynaptic GABA concentrations and decreased GABA transporter-3 (GAT-3) expression, and inactivation of GABAergic neurones in the ZI. Upregulating GAT-3 in ZI astrocytes (OFT: t=2.91, P=0.014; EPM: t=3.55, P=0.006) or activating the GABAergic projection from ZI to the median raphe nucleus (ZI→median raphe nucleus) (EPM: entries: F=3.45, P=0.027; time: F=4.07, P=0.043) ameliorated surgery-induced anxiety.
Reactive astrocytes in the zona incerta mediate surgery-induced anxiety, possibly by regulating GAT-3-mediated GABA homeostasis and inactivating ZI→median raphe nucleus projections in mice.
手术可引发严重的神经炎症及负面情绪症状，如焦虑样行为。我们研究了未定带（ZI）中的反应性星形胶质细胞是否介导小鼠手术诱导的焦虑。
以1.5体积%异氟烷进行剖腹手术作为成年小鼠的模型。通过行为测试、神经元活动的光纤记录、体内电生理记录、化学遗传学和光遗传学评估ZI在手术诱导焦虑中的作用。
手术小鼠表现出焦虑样行为增加。免疫染色和光学钙记录显示，ZI中的星形胶质细胞被异常激活。对ZI中星形胶质细胞激活进行药理学（F = 5.837，P = 0.044）或基因操作（旷场试验：t = 3.66，P = 0.007；高架十字迷宫[EPM]：t = 2.70，P = 0.022）可减轻手术治疗小鼠的焦虑样行为。与假手术组相比，手术组突触外GABA浓度增加，GABA转运体-3（GAT-3）表达降低，且ZI中GABA能神经元失活。上调ZI星形胶质细胞中的GAT-3（旷场试验：t = 2.91，P = 0.014；EPM：t = 3.55，P = 0.006）或激活从ZI到中缝正中核的GABA能投射（ZI→中缝正中核）（EPM：进入次数：F = 3.45，P = 0.027；时间：F = 4.07，P = 0.043）可改善手术诱导的焦虑。
未定带中的反应性星形胶质细胞可能通过调节GAT-3介导的GABA稳态以及使小鼠中ZI→中缝正中核投射失活来介导手术诱导的焦虑。
