Endocannabinoid signaling in hypothalamic circuits regulates arousal from general anesthesia in mice
Endocannabinoid signaling in hypothalamic circuits regulates arousal from general anesthesia in mice
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下丘脑回路中的内源性大麻素信号传导调节麦克风全身麻醉的唤醒。
DOI：
10.1172/jci91038
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发表时间：
2017-06-01
影响因子：
15.9
通讯作者：
Zhang, Xia
中科院分区：
文献类型：
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作者：
Zhong, Haixing;Tong, Li;Zhang, Xia
意识可以由两个主要属性来定义：对环境和自我的意识，以及反映意识水平的唤醒。全身麻醉后唤醒的恢复为探索控制意识的神经机制提供了一种实验工具。在这里，我们已经确定，全身或脑内注射大麻素CB 1受体（CB 1 R）拮抗剂AM 281到下丘脑背内侧核（DMH）-而不是相邻的穹窿周围区（Pef）或下丘脑腹外侧视前核（VLPO）-加速唤醒小鼠从全身麻醉恢复。麻醉剂选择性激活DMH能突触而非GABA能突触的内源性大麻素（eCB）信号传导，导致抑制DMH能-Pef和GABA能DMH-VLPO投射。从广泛的大脑皮层或前额叶皮层（PFC）的海马神经元，包括那些支配DMH的CB 1 R的删除，模仿唤醒加速AM 281的影响。与此相反，脑GABA能神经元或下丘脑多巴胺能神经元的CB 1 R缺失不影响麻醉恢复时间。PFC-DMH、DMH-VLPO或DMH-Pef投射的失活阻断了AM 281加速的唤醒，而这些投射的激活则模仿了AM 281的作用。我们认为，减少eCB信号在PFC-DMH的投射神经末梢加速唤醒全身麻醉通过增强兴奋性DMH-Pef的投影，抑制DMH-VLPO投影，或两者兼而有之。
Consciousness can be defined by two major attributes: awareness of environment and self, and arousal, which reflects the level of awareness. The return of arousal after general anesthesia presents an experimental tool for probing the neural mechanisms that control consciousness. Here we have identified that systemic or intracerebral injection of the cannabinoid CB1 receptor (CB1R) antagonist AM281 into the dorsomedial nucleus of the hypothalamus (DMH) - but not the adjacent perifornical area (Pef) or the ventrolateral preoptic nucleus of the hypothalamus (VLPO) - accelerates arousal in mice recovering from general anesthesia. Anesthetics selectively activated endocannabinoid (eCB) signaling at DMH glutamatergic but not GABAergic synapses, leading to suppression of both glutamatergic DMH-Pef and GABAergic DMH-VLPO projections. Deletion of CB1R from widespread cerebral cortical or prefrontal cortical (PFC) glutamatergic neurons, including those innervating the DMH, mimicked the arousal-accelerating effects of AM281. In contrast, CB1R deletion from brain GABAergic neurons or hypothalamic glutamatergic neurons did not affect recovery time from anesthesia. Inactivation of PFC-DMH, DMH-VLPO, or DMH-Pef projections blocked AM281-accelerated arousal, whereas activation of these projections mimicked the effects of AM281. We propose that decreased eCB signaling at glutamatergic terminals of the PFC-DMH projection accelerates arousal from general anesthesia through enhancement of the excitatory DMH-Pef projection, the inhibitory DMH-VLPO projection, or both.