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. 2023 May 20;43(5):718-726.
doi: 10.12122/j.issn.1673-4254.2023.05.06.

[Activation of GABAergic neurons in the zona incerta accelerates anesthesia induction with sevoflurane and propofol without affecting anesthesia maintenance or awakening in mice]

[Article in Chinese]
F Cao  1   2 , Y Guo  1 , S Guo  1 , Z Zhou  1 , J Cao  1 , L Tong  1 , W Mi  1
Affiliations

[Activation of GABAergic neurons in the zona incerta accelerates anesthesia induction with sevoflurane and propofol without affecting anesthesia maintenance or awakening in mice]

[Article in Chinese]
F Cao et al. Nan Fang Yi Ke Da Xue Xue Bao. .

Abstract
in English, Chinese

Objective: To explore the regulatory effects of GABAergic neurons in the zona incerta (ZI) on sevoflurane and propofol anesthesia.

Methods: Forty-eight male C57BL/6J mice divided into 8 groups (n=6) were used in this study. In the study of sevoflurane anesthesia, chemogenetic experiment was performed in 2 groups of mice with injection of either adeno-associated virus carrying hM3Dq (hM3Dq group) or a virus carrying only mCherry (mCherry group). The optogenetic experiment was performed in another two groups of mice injected with an adeno-associated virus carrying ChR2 (ChR2 group) or GFP only (GFP group). The same experiments were also performed in mice for studying propofol anesthesia. Chemogenetics or optogenetics were used to induce the activation of GABAergic neurons in the ZI, and their regulatory effects on anesthesia induction and arousal with sevoflurane and propofol were observed; EEG monitoring was used to observe the changes in sevoflurane anesthesia maintenance after activation of the GABAergic neurons.

Results: In sevoflurane anesthesia, the induction time of anesthesia was significantly shorter in hM3Dq group than in mCherry group (P < 0.05), and also shorter in ChR2 group than in GFP group (P < 0.01), but no significant difference was found in the awakening time between the two groups in either chemogenetic or optogenetic tests. Similar results were observed in chemogenetic and optogenetic experiments with propofol (P < 0.05 or 0.01). Photogenetic activation of the GABAergic neurons in the ZI did not cause significant changes in EEG spectrum during sevoflurane anesthesia maintenance.

Conclusion: Activation of the GABAergic neurons in the ZI promotes anesthesia induction of sevoflurane and propofol but does not affect anesthesia maintenance or awakening.

目的: 探索未定带区（ZI）γ-氨基丁酸（GABA）能神经元对七氟醚和丙泊酚麻醉-觉醒的调控作用。

方法: 将48只雄性C57BL/6J小鼠分为8组（6只/组）。研究七氟醚麻醉时，化学遗传学实验分为hM3Dq组（注射携带hM3Dq的腺相关病毒）和mCherry组（注射仅携带mCherry的对照病毒）；光遗传学实验分为ChR2组（注射携带ChR2的腺相关病毒）和GFP组（注射仅携带GFP的对照病毒），注射剂量均为100 nL。研究丙泊酚麻醉时，化学遗传学实验分为hM3Dq组和mCherry组；光遗传学实验分为ChR2组和GFP组。上述各组处理方法同七氟醚。通过化学遗传学和光遗传学技术激活ZI区GABA能神经元，观察其对七氟醚和丙泊酚的麻醉诱导及觉醒的调节作用，通过脑电监测观察其在七氟醚麻醉维持中的作用。

结果: 在七氟醚麻醉中，与mCherry组比，hM3Dq组麻醉诱导时间显著缩短（P＜0.05），与GFP组比，ChR2组麻醉诱导时间显著缩短（P＜0.01），而两实验中麻醉觉醒时间差异均无统计学意义。在丙泊酚麻醉中，hM3Dq组比mCherry组麻醉诱导时间显著缩短（P＜0.05），ChR2组比GFP组麻醉诱导时间显著缩短（P＜0.01），而两实验中麻醉觉醒时间差异均无统计学意义。光遗传激活ZI区GABA能神经元没有改变七氟醚麻醉维持时的脑电频谱。

结论: ZI区GABA能神经元能够促进七氟醚和丙泊酚的麻醉诱导，而对麻醉维持及觉醒无调节作用。

Keywords: GABAergic neurons; gamma-aminobutyric acid; propofol; sevoflurane; zone incerta.

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Figures

图 1
图 1
脑电监测方法示意图 Schematic diagram of the timeline of EEG monitoring in mice with optogenetic activation of the GABAergic neurons of ZI receiving 1.5% sevoflurane anesthesia
图 2
图 2
研究七氟醚麻醉时，化学遗传学方法示意图 Schematic diagram of chemogenetic methods for studying sevoflurane anesthesia. A: Virus injection in the ZI. B: Righting reflex detection in the anesthesia barrel (upper) and detection of anesthesia induction and emergence time through chemogenetic activation of the ZI in 2.0% sevoflurane anesthesia (lower).
图 3
图 3
研究丙泊酚麻醉时，化学遗传学方法示意图 Schematic diagram of chemogenetic methods for studying propofol anesthesia. A: Virus injection in the ZI. B: Righting reflex detection in the anesthesia barrel (upper) and detection of anesthesia induction and emergence time through chemogenetic activation of the ZI in 2.0% propofol ip anesthesia (lower).
图 4
图 4
研究七氟醚麻醉时，光遗传学方法示意图 Schematic diagram of optogenetic experiment for studying sevoflurane anesthesia. A: Virus injection in the ZI. B: Righting reflex detection in the anesthesia barrel (upper) and detection of anesthesia induction and emergence time through optogenetic activation the GABAergic neurons of ZI in 2.0% sevoflurane anesthesia (lower).
图 5
图 5
研究丙泊酚麻醉时，光遗传学方法示意图 Schematic diagram of optogenetic experiment for studying propofol anesthesia. A: Virus injection in the ZI. B: Righting reflex detection in the anesthesia barrel (upper) and detection of anesthesia induction and emergence time through optogenetic activation of the ZI in 2.0% propofol ip anesthesia (lower).
图 6
图 6
通过化学遗传学方法激活ZI区GABA能神经元促进七氟醚麻醉诱导 Chemogenetic activation of ZI GABAergic neurons accelerates sevoflurane anesthesia induction. A: Left, Co-labelled immunofluorescence of virus autofluorescence (mCherry, red) and c-fos (green); right, the propotion of GABAergic neurons co-expressing c-fos/mCherry in the hM3Dq group is significantly higher. ****P < 0.0001 vs CON group. B: Expression of chemogenetic virus (mCherry, red) in the GABAergic neurons (green). C: Left, anesthesia induction time is shorter in the hM3Dq group. *P < 0.05 vs mCherry group; right, anesthesia emergence time is not significantly different between the two groups.
图 7
图 7
通过光遗传学方法激活ZI区GABA能神经元促进七氟醚麻醉诱导 Optogenetic activation of ZI GABAergic neurons accelerates sevoflurane anesthesia induction. A: Left, co-labelled immunofluorescence of virus autofluorescence (GFP, green) and c-fos (red) right, the propotion of GABAergic neurons co-expressing c-fos/GFP in the CHR2 group is significantly higher. ***P < 0.001 vs CON group. B: Expression of optogenetic virus (GFP, green) in the GABAergic neurons (red). C: Left, anesthesia induction time is shorter in CHR2 group. **P < 0.01 vs GFP group; right, anesthesia emergence time show no significant difference between the two groups.
图 8
图 8
光遗传激活ZI区GABA能神经元对七氟醚麻醉维持没有显著影响 Optogenetic activation of the ZI GABAergic neurons has no significant effect on sevoflurane anesthesia maintenance. A: The percentages of power in all bands show no significant changes in either GFP group or CHR2 group. B: Representative EEG spectra for GPF group and CHR2 group.
图 9
图 9
通过化学遗传学方法激活ZI区GABA能神经元促进丙泊酚麻醉诱导 Chemogenetic activation of ZI GABAergic neurons accelerates propofol anesthesia induction. Left, anesthesia induction time is shorter inhM3Dq group. *P < 0.05 vs mCherry group; right, anesthesia emergence time shows no significant difference between the two groups.
图 10
图 10
通过光遗传学方法激活ZI区GABA能神经元促进丙泊酚麻醉诱导 Optical activation of ZI GABAergic neurons accelerates propofol anesthesia induction. Left: Anesthesia induction time is shorter in CHR2 group. **P < 0.01 vs GFP group; Right: Anesthesia emergence time shows no significant difference between the two groups.
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