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

BACKGROUND

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.

METHODS

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.

RESULTS

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.

CONCLUSIONS

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.