Genetic and anatomical basis of the barrier separating wakefulness and anesthetic-induced unresponsiveness.
Genetic and anatomical basis of the barrier separating wakefulness and anesthetic-induced unresponsiveness.
复制标题
DOI：
10.1371/journal.pgen.1003605
复制
发表时间：
2013
期刊：
影响因子：
4.5
通讯作者：
Kelz MB
中科院分区：
文献类型：
--
作者：
Joiner WJ;Friedman EB;Hung HT;Koh K;Sowcik M;Sehgal A;Kelz MB
一个强大的神经开关调节着清醒和自然睡眠之间的波动，以及清醒和麻醉诱导的无反应之间的波动。我们之前提供了实验证据，证明在这些唤醒状态之间存在行为障碍，我们称之为神经惰性。在这里，我们表明神经惯性是由有助于睡眠稳态的过程控制的，并且需要四个参与电兴奋性的基因：Sh、sss、na和unc 79。尽管这些基因的功能缺失突变可以增加或降低对麻醉诱导的敏感性，但令人惊讶的是，它们都使神经惰性崩溃。这些影响是遗传选择性的：神经惰性不会受到睡眠/觉醒周期所需的所有基因的功能缺失突变的干扰。这些效应在解剖学上也是有选择性的：sss作用于不同的神经元，影响神经惰性下的唤醒促进和唤醒抑制过程。支持麻醉和睡眠共享一些，但不是全部，遗传和解剖觉醒调节途径的想法，我们证明，增加稳态睡眠驱动器扩大神经惯性屏障。我们认为，选择性有助于睡眠稳态和神经惯性的过程可能会受损的病理生理条件，如昏迷和持续植物人状态。全世界每年进行2.34亿次外科手术，使全身麻醉剂成为人类最常用的药物之一。然而，值得注意的是，我们仍然不了解全身麻醉剂使患者失去知觉的机制，或者在麻醉后重新建立意识的过程。我们先前表明，大脑通过在两个方向上对这种转换产生障碍来抵抗清醒和麻醉状态之间的转换。我们还表明，这种障碍的存在是保守的无脊椎动物哺乳动物。在我们目前的工作中，我们使用遗传的易处理性和简化的果蝇的神经系统，表明需要四个基因来维持这一障碍。我们还表明，在哺乳动物中，调节自然睡眠和全身麻醉的途径之间存在重叠。我们认为，这些共享的通路中的一些在昏迷和持续植物人状态等条件下受损，其中过渡到清醒状态的障碍似乎是无法克服的。
A robust, bistable switch regulates the fluctuations between wakefulness and natural sleep as well as those between wakefulness and anesthetic-induced unresponsiveness. We previously provided experimental evidence for the existence of a behavioral barrier to transitions between these states of arousal, which we call neural inertia. Here we show that neural inertia is controlled by processes that contribute to sleep homeostasis and requires four genes involved in electrical excitability: Sh, sss, na and unc79. Although loss of function mutations in these genes can increase or decrease sensitivity to anesthesia induction, surprisingly, they all collapse neural inertia. These effects are genetically selective: neural inertia is not perturbed by loss-of-function mutations in all genes required for the sleep/wake cycle. These effects are also anatomically selective: sss acts in different neurons to influence arousal-promoting and arousal-suppressing processes underlying neural inertia. Supporting the idea that anesthesia and sleep share some, but not all, genetic and anatomical arousal-regulating pathways, we demonstrate that increasing homeostatic sleep drive widens the neural inertial barrier. We propose that processes selectively contributing to sleep homeostasis and neural inertia may be impaired in pathophysiological conditions such as coma and persistent vegetative states. An annual 234 million surgical procedures are performed worldwide, making general anesthetics among the most common drugs administered to humans. Remarkably, however, we still do not understand the mechanisms by which general anesthetics render patients unconscious or the processes that re-establish consciousness upon emergence from anesthesia. We previously showed that the brain resists transitions between the wakeful and anesthesia states by generating a barrier to such transitions in both directions. We also showed that the existence of this barrier is conserved from invertebrates to mammals. In our present work, we use the genetic tractability and the simplified nervous system of the fruit fly Drosophila melanogaster to show that four genes are required to maintain this barrier. We also show that, as in mammals, there is overlap between pathways regulating natural sleep and general anesthesia. We propose that some of these shared pathways are impaired in conditions such as coma and persistent vegetative states, in which the barrier to transitioning to the waking state appears to be insurmountable.
登录
查看更多内容
影响因子：
3.5
作者：
Hendricks, JC;Lu, SM;Sehgal, A
通讯作者：
Sehgal, A
影响因子：
2.5
作者：
Lu, Jun;Nelson, Laura E.;Saper, Clifford B.
通讯作者：
Saper, Clifford B.
影响因子：
64.5
作者：
Laslo, Peter;Spooner, Chauncey J.;Singh, Harinder
通讯作者：
Singh, Harinder
影响因子：
9.2
作者：
Humphrey, John A.;Hamming, Kevin S.;Nash, Howard A.
通讯作者：
Nash, Howard A.
影响因子：
5.3
作者：
Kume, K;Kume, S;Jackson, FR
通讯作者：
Jackson, FR