From the Department of Anesthesiology, Eye & ENT Hospital, Fudan University, Shanghai, China.
Department of Pharmacology, School of Basic Medical Sciences, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai, China.
Anesth Analg. 2023 Jul 1;137(1):87-97. doi: 10.1213/ANE.0000000000006436. Epub 2023 Jun 16.
Emerging evidence has uncovered a vital role of nucleus accumbens (NAc) neurons that express the dopamine D1 receptor (D1R) and its upstream neural circuit in general anesthesia (GA) regulation. However, the underlying downstream neural basis of the modulation of GA emergence by NAc D1R neurons remains unknown. In the present study, we explored the downstream neural mechanism of NAc D1R neurons in the modulation of emergence from sevoflurane GA.
We traced the axonal projections of NAc D1R neurons using a cell type-specific anterograde tracing method and immunohistochemical techniques in D1R-Cre mice. Optogenetic stimulations combined with electroencephalogram/electromyogram recordings and behavioral tests were used to determine the effects of optogenetic activation of the axonal terminals of NAc D1R neurons on sevoflurane emergence during sevoflurane-induced continuous, steady-state general anesthesia (CSSGA) or burst-suppression oscillations.
Labeled efferent fibers of NAc D1R neurons were highly distributed in the ventral pallidum (VP), lateral hypothalamus (LH), and substantia nigra pars compacta. Optogenetic activation of the NAc D1R -VP circuit during CSSGA with sevoflurane induced cortical activation (mean ± standard deviation [SD]; delta power: prestimulation versus during stimulation, 48.7% ± 5.7% vs 35.1% ± 3.3%, P < .0001; beta power: 7.1% ± 2.7% vs 14.2% ± 3.3%, P = .0264) and behavioral emergence, and restored the righting reflex in 66.7% of ChR2 mice. Optogenetic stimulation of the NAc D1R -LH circuit also produced cortical activation (delta power: prestimulation versus during stimulation, 45.0% ± 6.5% vs 36.1% ± 4.6%, P = .0016) and behavioral emergence, and restored the righting reflex in 100% of the ChR2 mice during CSSGA with sevoflurane. Under a sevoflurane-induced burst-suppression state, NAc D1R -VP/LH circuit activation produced evidence of cortical activation (burst-suppression ratio [BSR]: NAc D1R -VP circuit, prestimulation versus during stimulation, 42.4% ± 4.0% vs 26.3% ± 6.0%, P = .0120; prestimulation versus poststimulation, 42.4% ± 4.0% vs 5.9% ± 5.6%, P = .0002; BSR: NAc D1R -LH circuit, prestimulation versus during stimulation, 33.3% ± 13.4% vs 5.1% ± 4.9%, P = .0177; prestimulation vs poststimulation, 33.3% ± 13.4% vs 3.2% ± 4.0%, P = .0105) and behavioral emergence.
Both NAc D1R -VP and NAc D1R -LH circuits are sufficient to promote reanimation from sevoflurane GA by simultaneously inducing cortical and behavioral emergence.
越来越多的证据揭示了伏隔核（NAc）中表达多巴胺 D1 受体（D1R）及其上游神经回路在全身麻醉（GA）调节中的重要作用。然而，NAc D1R 神经元对 GA 苏醒的调节的下游神经基础尚不清楚。在本研究中，我们探讨了 NAc D1R 神经元在七氟醚 GA 苏醒中的调节的下游神经机制。
我们使用细胞类型特异性顺行示踪方法和免疫组织化学技术在 D1R-Cre 小鼠中追踪 NAc D1R 神经元的轴突投射。光遗传学刺激结合脑电图/肌电图记录和行为测试，用于确定 NAc D1R 神经元轴突末梢的光遗传学激活对七氟醚诱导的连续、稳态全身麻醉（CSSGA）或爆发抑制振荡期间七氟醚苏醒的影响。
标记的 NAc D1R 神经元的传出纤维在腹侧苍白球（VP）、外侧下丘脑（LH）和黑质致密部中高度分布。在 CSSGA 期间，NAc D1R-VP 回路的光遗传学激活伴随着七氟醚诱导的皮质激活（均值±标准差[SD]；δ功率：刺激前与刺激期间，48.7%±5.7%比 35.1%±3.3%，P<0.0001；β功率：7.1%±2.7%比 14.2%±3.3%，P=0.0264）和行为苏醒，并使 ChR2 小鼠中 66.7%的翻正反射恢复。NAc D1R-LH 回路的光遗传学刺激也产生了皮质激活（δ功率：刺激前与刺激期间，45.0%±6.5%比 36.1%±4.6%，P=0.0016）和行为苏醒，并使 100%的 ChR2 小鼠在 CSSGA 期间恢复翻正反射。在七氟醚诱导的爆发抑制状态下，NAc D1R-VP/LH 回路的激活产生了皮质激活的证据（爆发抑制比[BSR]：NAc D1R-VP 回路，刺激前与刺激期间，42.4%±4.0%比 26.3%±6.0%，P=0.0120；刺激前与刺激后，42.4%±4.0%比 5.9%±5.6%，P=0.0002；BSR：NAc D1R-LH 回路，刺激前与刺激期间，33.3%±13.4%比 5.1%±4.9%，P=0.0177；刺激前与刺激后，33.3%±13.4%比 3.2%±4.0%，P=0.0105）和行为苏醒。
NAc D1R-VP 和 NAc D1R-LH 回路都足以通过同时诱导皮质和行为苏醒来促进从七氟醚 GA 中苏醒。
