• Br J Anaesth · Nov 2024

    Reactive astrocytes mediate postoperative surgery-induced anxiety through modulation of GABAergic signalling in the zona incerta of mice.

    • Kun Tong, Yu-Tong Song, Si-Qi Jing, Yue You, Shi-Jie Wang, Tong Wu, Han Xu, Jing-Wei Zhang, Le Liu, Jing-Ru Hao, Nan Sun, Jun-Li Cao, and Can Gao.
    • 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.
    • Br J Anaesth. 2024 Nov 25.

    BackgroundSurgery 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.MethodsLaparotomy 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.ResultsOperative mice showed increased anxiety-like behaviour. Immunostaining and optical calcium recording revealed that astrocytes were abnormally activated in the ZI. Pharmacologic (F3, 15=5.837, P=0.044) or genetic manipulation (open field test: t7.41=3.66, P=0.007; elevated plus maze [EPM]: t10=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: t10.83=2.91, P=0.014; EPM: t9.15=3.55, P=0.006) or activating the GABAergic projection from ZI to the median raphe nucleus (ZIGABA→median raphe nucleus) (EPM: entries: F1, 24=3.45, P=0.027; time: F1, 25=4.07, P=0.043) ameliorated surgery-induced anxiety.ConclusionsReactive astrocytes in the zona incerta mediate surgery-induced anxiety, possibly by regulating GAT-3-mediated GABA homeostasis and inactivating ZIGABA→median raphe nucleus projections in mice.Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.

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