Department of Anesthesiology, University of Tennessee Medical Center, Knoxville, Tennessee.
Department of Psychology, University of Tennessee, Knoxville, Tennessee.
J Neurophysiol. 2020 Jun 1;123(6):2285-2296. doi: 10.1152/jn.00092.2020. Epub 2020 Apr 29.
This study quantified eight small-molecule neurotransmitters collected simultaneously from prefrontal cortex of C57BL/6J mice ( = 23) during wakefulness and during isoflurane anesthesia (1.3%). Using isoflurane anesthesia as an independent variable enabled evaluation of the hypothesis that isoflurane anesthesia differentially alters concentrations of multiple neurotransmitters and their interactions. Machine learning was applied to reveal higher order interactions among neurotransmitters. Using a between-subjects design, microdialysis was performed during wakefulness and during anesthesia. Concentrations (nM) of acetylcholine, adenosine, dopamine, GABA, glutamate, histamine, norepinephrine, and serotonin in the dialysis samples are reported (means ± SD). Relative to wakefulness, acetylcholine concentration was lower during isoflurane anesthesia (1.254 ± 1.118 vs. 0.401 ± 0.134, = 0.009), and concentrations of adenosine (29.456 ± 29.756 vs. 101.321 ± 38.603, < 0.001), dopamine (0.0578 ± 0.0384 vs. 0.113 ± 0.084, = 0.036), and norepinephrine (0.126 ± 0.080 vs. 0.219 ± 0.066, = 0.010) were higher during anesthesia. Isoflurane reconfigured neurotransmitter interactions in prefrontal cortex, and the state of isoflurane anesthesia was reliably predicted by prefrontal cortex concentrations of adenosine, norepinephrine, and acetylcholine. A novel finding to emerge from machine learning analyses is that neurotransmitter concentration profiles in mouse prefrontal cortex undergo functional reconfiguration during isoflurane anesthesia. Adenosine, norepinephrine, and acetylcholine showed high feature importance, supporting the interpretation that interactions among these three transmitters may play a key role in modulating levels of cortical and behavioral arousal. This study discovered that interactions between neurotransmitters in mouse prefrontal cortex were altered during isoflurane anesthesia relative to wakefulness. Machine learning further demonstrated that, relative to wakefulness, higher order interactions among neurotransmitters were disrupted during isoflurane administration. These findings extend to the neurochemical domain the concept that anesthetic-induced loss of wakefulness results from a disruption of neural network connectivity.
本研究同时定量了来自清醒状态和异氟烷麻醉（1.3%）下 C57BL/6J 小鼠前额皮质的 8 种小分子神经递质。使用异氟烷麻醉作为自变量，可评估异氟烷麻醉是否会改变多种神经递质的浓度及其相互作用。本研究采用机器学习方法揭示了神经递质之间的高阶相互作用。通过采用被试间设计，在清醒和麻醉状态下进行微透析。报告了透析样本中乙酰胆碱、腺苷、多巴胺、GABA、谷氨酸、组胺、去甲肾上腺素和 5-羟色胺的浓度（nM）（平均值±标准差）。与清醒状态相比，异氟烷麻醉时乙酰胆碱浓度降低（1.254±1.118 比 0.401±0.134， = 0.009），而腺苷（29.456±29.756 比 101.321±38.603， < 0.001）、多巴胺（0.0578±0.0384 比 0.113±0.084， = 0.036）和去甲肾上腺素（0.126±0.080 比 0.219±0.066， = 0.010）的浓度升高。异氟烷重新配置了前额皮质中的神经递质相互作用，并且前额皮质中腺苷、去甲肾上腺素和乙酰胆碱的浓度可可靠地预测异氟烷麻醉状态。从机器学习分析中出现的一个新发现是，在异氟烷麻醉期间，小鼠前额皮质中的神经递质浓度谱经历了功能重新配置。腺苷、去甲肾上腺素和乙酰胆碱的特征重要性较高，这支持了这样的解释，即这三种递质之间的相互作用可能在调节皮质和行为唤醒水平方面发挥关键作用。本研究发现，与清醒状态相比，异氟烷麻醉时小鼠前额皮质中的神经递质相互作用发生了改变。机器学习进一步表明，与清醒状态相比，异氟烷给药期间神经递质之间的高阶相互作用被破坏。这些发现将神经网络连接中断导致麻醉诱导的意识丧失的概念扩展到神经化学领域。
