Distinctive recruitment of endogenous sleep-promoting neurons by volatile anesthetics and a nonimmobilizer.
Distinctive recruitment of endogenous sleep-promoting neurons by volatile anesthetics and a nonimmobilizer.
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DOI：
10.1097/aln.0000000000000383
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发表时间：
2014-11
期刊：
影响因子：
8.8
通讯作者：
Kelz MB
中科院分区：
文献类型：
--
作者：
Han B;McCarren HS;O'Neill D;Kelz MB
大量研究表明，麻醉引起的意识丧失伴随着下丘脑睡眠促进神经元的激活，这通过突触前和突触后机制发生。然而，药物暴露、神经元激活和催眠发作之间的相关性仍不完全清楚。此外，麻醉剂激活腹外侧视前核 (VLPO) 和正中视前核 (MnPO) 内源性 GABA 能睡眠促进神经元群的程度仍不清楚。让小鼠接触氧气、催眠剂量的异氟烷或氟烷，或 1,2-二氯六氟环丁烷 (F6)（一种非固定剂）。从未接受麻醉的小鼠制备的下丘脑脑切片也暴露于氧气、挥发性麻醉剂或 F6 离体条件下，无论是否存在河鲀毒素。采用双标记免疫组织化学来量化 VLPO 和 MnPO 中 GABA 能神经元亚群中 c-Fos 免疫反应性细胞核的数量，以检验挥发性麻醉剂（而非非固定剂）激活两个细胞核中促睡眠神经元的假设。体内暴露于异氟烷和氟烷使 VLPO 中活跃的、表达 c-Fos 的 GABA 能神经元的比例增加了一倍，而 F6 未能影响 VLPO c-Fos 的表达。在河豚毒素存在和不存在的情况下，异氟烷剂量依赖性地增加离体 GABA 能神经元中的 c-Fos 表达，而 F6 未能改变表达。在 MnPO 的 GABA 能神经元中，异氟烷和 F6 会增加 c-Fos 表达，但接触氟烷则不会增加。麻醉性无意识并不伴随着所有假定的促进睡眠的神经元的整体激活。然而，在 VLPO 催眠剂量内，挥发性麻醉剂而非非固定剂会激活假定的促进睡眠的神经元，与催眠状态的出现相关。
Numerous studies demonstrate that anesthetic-induced unconsciousness is accompanied by activation of hypothalamic sleep-promoting neurons, which occurs through both pre- and postsynaptic mechanisms. However, the correlation between drug exposure, neuronal activation, and onset of hypnosis remains incompletely understood. Moreover, the degree to which anesthetics activate both endogenous populations of GABAergic sleep-promoting neurons within the ventrolateral preoptic (VLPO) and median preoptic (MnPO) nuclei remains unknown. Mice were exposed to oxygen, hypnotic doses of isoflurane or halothane, or 1,2-dicholorhexafluorocyclobutane (F6), a nonimmobilizer. Hypothalamic brain slices prepared from anesthetic-naïve mice were also exposed to oxygen, volatile anesthetics, or F6 ex vivo, both in the presence and absence of tetrodotoxin. Double-label immunohistochemistry was performed to quantify the number of c-Fos-immunoreactive nuclei in the GABAergic subpopulation of neurons in the VLPO and the MnPO to test the hypothesis that volatile anesthetics, but not non-immobilizers, activate sleep-promoting neurons in both nuclei. In vivo exposure to isoflurane and halothane doubled the fraction of active, c-Fos-expressing GABAergic neurons in the VLPO, while F6 failed to affect VLPO c-Fos expression. Both in the presence and absence of tetrodotoxin, isoflurane dose-dependently increased c-Fos expression in GABAergic neurons ex vivo, while F6 failed to alter expression. In GABAergic neurons of the MnPO, c-Fos expression increased with isoflurane and F6, but not with halothane exposure. Anesthetic unconsciousness is not accompanied by global activation of all putative sleep-promoting neurons. However, within the VLPO hypnotic doses of volatile anesthetics, but not non-immobilizers, activate putative sleep-promoting neurons, correlating with the appearance of the hypnotic state.