▎药明康德团队（文章来源：宋学军课题组）

关于意识的起源、消失和复苏一直是哲学家、心理学家、医生和科学家都很关心和困惑的问题。现代医学和科学提供了很多机会，包括麻醉病人和植物人等，让我们可以观察意识的存在、消失和恢复。但是，我们对意识生物学本质的认识依然非常有限。

19世纪40年代，全身麻醉药开始应用于临床外科手术，全麻药诱导产生的意识消失和恢复成为研究意识的理想生物学模型。全麻药是如何导致意识消失的？麻醉后，意识又是如何恢复的？

2024年3月14日，南方科技大学医学院宋学军教授带领团队受邀在神经科学著名期刊《神经科学趋势》（

Trends in Neurosciences）发表综述，系统总结了

迄今为止学界对麻醉和麻醉意识复苏的神经生物学机制的认识和理解。文章阐述了麻醉导致意识消失和麻醉意识复苏的神经生物学基础的研究成果，解析、归纳了有关科学研究的成果及其所能说明问题的边界，介绍了麻醉意识主动复苏的最新突破性进展，并提出进一步研究的方向和拟解决的关键问题。

关于麻醉机制，即全麻药是如何导致意识消失的，有三种理论假说：脂质学说（The lipid theory）、特异性蛋白质靶点学说（The specific protein targets theory）和神经网路学说（The neural circuit theory）。

脂质理论在早期研究中占主导地位，认为不同的麻醉药通过单一、共通的机制发挥作用，即通过溶解于细胞膜而引起麻醉。后来对于更多麻醉药的研究证明只有个别麻醉药是通过此机制发挥重要。20世纪80年代开始，分子药理学研究在阐述麻醉机制中研究取得了显著成果，特异性蛋白靶点理论随之诞生。该理论强调麻醉药通过作用于特定的蛋白质分子靶点，如中枢神经系统中的GABA

A受体、2PK离子通道以及NMDA受体等抑制神经元的活动而产生麻醉作用。不同麻醉药主要作用的蛋白质分子靶点不同。1993年开始，研究发现麻醉药的作用与其所作用的神经系统的解剖学位点关系密切，因而诞生了神经环路理论。实验证明不同麻醉药所作用的神经环路也有所不同。环路研究中的另一个重要发现是，麻醉作用与某些内源性促睡眠系统的激活，以及某些促清醒系统的抑制高度相关，引发了学界对于麻醉和睡眠相关性和不同点的关注。

总体而言，不同类型的全身麻醉药具有不同的作用机制，虽然导致意识消失的具体机制尚不明确，但是麻醉药导致意识消失均遵循一个基本原理，即药物分子通过与特异性蛋白靶点或膜介导的靶点相结合，干扰正常的神经元活动，破坏负责信号传导和意识感知/主观体验的神经环路的完整性和功能，从而诱导麻醉。三种假说从不同的角度和层面解释和阐述了麻醉机制，推动了全麻原理的研究进程。

但综述指出，这三种假说还不能形成一个可清楚完整阐明全麻原理的理论体系，更没有从本质上解释麻醉诱导意识消失现象的生物学基础。因此，

麻醉是如何导致意识消失的分子神经机制依然不清楚，需要继续深入研究。

图片来源：123RF

相较于麻醉药如何产生麻醉作用的研究和理解，

麻醉意识消失后大脑如何重新获得意识，是更令人费解的谜题。

学界长期公认的观点是意识的“被动恢复理论”（Purely passive recovery）, 即麻醉后意识恢复是一个基于麻醉药在脑内/体内代谢降解的过程，当麻醉药浓度在体内降低到一定水平之后，意识也就自然而然恢复了。这种假说认为麻醉意识恢复是麻醉药作用的逆向过程，所以，如果麻醉机制清楚了，麻醉意识恢复的机制也就清楚了。

然而，从麻醉状态中的觉醒，尽管与麻醉药从体内或脑内的清除紧密相关，但并不意味着意识会随着脑组织内麻醉药浓度的降低而自然复苏并完全恢复正常。近十几年来，研究发现麻醉深度和意识水平是可操控的，即麻醉条件下意识的深度是可以通过外界干预（如电刺激、光遗传、化学遗传等方法）脑内特定核团、神经元活动和神经环路及其所关联的神经递质系统（如谷氨酸、GABA、多巴胺、去甲肾上腺素、食欲素等递质系统）而调控，从而促进或者抑制麻醉，延迟或者加速麻醉意识恢复。

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麻醉意识恢复相关的神经环路和神经递质系统（图片来源：参考资料[1]；研究团队提供）

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麻醉意识恢复相关的神经核团（图片来源：参考资料[1]；研究团队提供）

麻醉意识的“被动恢复理论”着眼于麻醉药的药理作用，认为麻醉恢复等于麻醉诱导的逆向过程；麻醉意识的“可控性”则着眼于外力对大脑核团和神经环路的控制而改变麻醉意识状态。这两种情况都是外部力量对于大脑的作用和干预，却忽略了麻醉意识恢复的主体——大脑的内在驱动力与麻醉意识恢复的关系。

宋学军团队强调，

大脑在意识复苏过程中可能发挥非常重要甚至是决定性的“主动重启”作用。

2023年，宋学军团队首次揭示了麻醉意识复苏的大脑内在驱动机制，发现麻醉药导致意识消失状态下，丘脑腹后内侧核（VPM）钾氯共转运体（KCC2）的快速下调导致GABA

A受体介导的神经元去抑制效应，因此显著提高了局部神经网络的活性并启动神经环路的重建，驱动大脑走出意识消失的凶险境地。

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麻醉意识主动复苏的丘脑KCC2泛素化降解机制（图片来源：参考资料[1]；研究团队提供）

促进这一意识复苏过程的分子神经机制完全不同于麻醉停止后可以直观观察到的行为学水平的恢复，分子水平驱动意识复苏的努力在大脑被迫进入最底反应状态（minimum responsive state，MRS期）就已经开始，远早于可以观察到的行为恢复阶段，且复苏过程一直持续。该研究指出，意识复苏是一个独立于麻醉诱导的意识消失过程、受大脑内在驱动力控制的主动复苏过程；这个主动复苏过程不依赖于具体全麻药的药理学作用靶点，其本质不是麻醉诱导作用过程的逆向过程，而是遵循了完全不同的规律和分子机制。

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