Department of Anesthesiology and Critical Care, University of Pennsylvania, Perelman School of Medicine, 3620 Hamilton Walk, 334 John Morgan Building, Philadelphia, PA 19104, USA; Mahoney Institute for Neurosciences, University of Pennsylvania, Philadelphia, PA 19104, USA; Circadian and Sleep Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
Department of Anesthesiology and Critical Care, University of Pennsylvania, Perelman School of Medicine, 3620 Hamilton Walk, 334 John Morgan Building, Philadelphia, PA 19104, USA; Circadian and Sleep Institute, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA.
Curr Biol. 2021 Jan 25;31(2):394-405.e4. doi: 10.1016/j.cub.2020.10.050. Epub 2020 Nov 13.
Endogenous sleep and general anesthesia are distinct states that share similar traits. Of particular interest to neuroscience is the loss of consciousness that accompanies both states. Multiple lines of evidence demonstrate that general anesthetics can co-opt the neural circuits regulating arousal to produce unconsciousness. However, controversy remains as to whether the neural circuits and, more specifically, the same neurons shaping sleep and wakefulness actually do influence the anesthetic state in vivo. Hypothalamic preoptic area (POA) neurons are intimately involved in modulating spontaneous and anesthetic-induced changes in arousal. Nevertheless, recent work suggests that POA GABAergic or glutamatergic neurons capable of regulating endogenous sleep fail to influence the onset or dissipation of anesthesia. We hypothesized that the POA's broad neuronal diversity could mask convergent roles of a subset of neurons in regulating both arousal and anesthesia. Contrary to a previously published report, we show that chemogenetic activation of POA Tac1 neurons obliterates both non-rapid eye movement (NREM) and rapid eye movement (REM) sleep, strongly consolidating the waking state for hours, even during a period of elevated sleep drive. Moreover, chemogenetic activation of Tac1 POA neurons stabilizes the wake state against both isoflurane- and sevoflurane-induced unconsciousness. Tac1-activated mice display a partial resistance to entering isoflurane anesthesia and a more pronounced ability to exit both isoflurane- and sevoflurane-induced unconscious states. We conclude that POA Tac1 neurons can potently reinforce arousal both against endogenous and drug-induced unconscious states. POA Tac1 neurons thus add causal support for the involvement of arousal-regulating systems in the state of general anesthesia.
内源性睡眠和全身麻醉是两种不同的状态，它们具有相似的特征。特别引起神经科学关注的是这两种状态都伴随着意识丧失。有多项证据表明，全身麻醉剂可以利用调节觉醒的神经回路来产生无意识。然而，关于调节觉醒的神经回路，更具体地说，是否正是塑造睡眠和觉醒的相同神经元实际上会影响体内麻醉状态，仍存在争议。下丘脑视前区（POA）神经元密切参与调节自发和麻醉诱导的觉醒变化。然而，最近的工作表明，能够调节内源性睡眠的 POA GABA 能或谷氨酸能神经元未能影响麻醉的开始或消散。我们假设，POA 的广泛神经元多样性可能掩盖了一组神经元在调节觉醒和麻醉方面的趋同作用。与之前发表的一份报告相反，我们表明，POA Tac1 神经元的化学遗传激活消除了非快速眼动（NREM）和快速眼动（REM）睡眠，强烈地巩固了清醒状态数小时，即使在睡眠驱动力增加的时期也是如此。此外，化学遗传激活 Tac1 POA 神经元稳定了清醒状态，使其能够抵抗异氟烷和七氟烷诱导的无意识。 Tac1 激活的小鼠对进入异氟烷麻醉具有部分抗性，并对异氟烷和七氟烷诱导的无意识状态具有更明显的退出能力。我们得出结论，POA Tac1 神经元可以有效地增强对内源性和药物诱导的无意识状态的觉醒。因此，POA Tac1 神经元为参与全身麻醉状态的觉醒调节系统提供了因果支持。
