GABAergic inhibition of histaminergic neurons regulates active waking but not the sleep-wake switch or propofol-induced loss of consciousness.
GABAergic inhibition of histaminergic neurons regulates active waking but not the sleep-wake switch or propofol-induced loss of consciousness.
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DOI：
10.1523/jneurosci.2931-12.2012
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发表时间：
2012-09-19
期刊：
影响因子：
--
通讯作者：
Wisden W
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文献类型：
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作者：
Zecharia AY;Yu X;Götz T;Ye Z;Carr DR;Wulff P;Bettler B;Vyssotski AL;Brickley SG;Franks NP;Wisden W
下丘脑结节乳头核（TMN）中组胺能神经元的活动与动物的行为状态相关，并维持唤醒。我们研究了GABA能输入组胺能神经元如何调节这种行为。一个突出的假说，即“触发器”模型，预测增加和持续的GABA能驱动这些细胞促进睡眠。类似地，由于组胺能神经元在唤醒回路中的关键枢纽样位置，也有人提出，麻醉剂如丙泊酚通过主要作用于组胺能神经元来诱导意识丧失。我们测试了这两个假设在小鼠中遗传去除亲离子型GABAA或亲代谢型GABAB受体从组氨酸脱羧酶表达神经元。在细胞水平上，缺乏突触GABAA受体的组胺能神经元明显更易兴奋，对麻醉剂丙泊酚不敏感。在行为水平上，记录了24 h内未栓系小鼠的EEG曲线。令人惊讶的是，GABA能传递到组胺能神经元在调节自然睡眠-觉醒周期方面没有作用，在GABAA受体的情况下，对丙泊酚诱导的翻正反射丧失没有作用。后一个发现使得组胺能TMN不太可能在麻醉中起中心作用。组胺能神经元上的GABAB受体对所有检查的行为均无影响。然而，GABAA受体对组胺能细胞的突触抑制是适应新环境所必需的。
The activity of histaminergic neurons in the tuberomammillary nucleus (TMN) of the hypothalamus correlates with an animal’s behavioral state and maintains arousal. We examined how GABAergic inputs onto histaminergic neurons regulate this behavior. A prominent hypothesis, the “flip-flop” model, predicts that increased and sustained GABAergic drive onto these cells promotes sleep. Similarly, because of the histaminergic neurons’ key hub-like place in the arousal circuitry, it has also been suggested that anesthetics such as propofol induce loss of consciousness by acting primarily at histaminergic neurons. We tested both these hypotheses in mice by genetically removing ionotropic GABAA or metabotropic GABAB receptors from histidine decarboxylase-expressing neurons. At the cellular level, histaminergic neurons deficient in synaptic GABAA receptors were significantly more excitable and were insensitive to the anesthetic propofol. At the behavioral level, EEG profiles were recorded in nontethered mice over 24 h. Surprisingly, GABAergic transmission onto histaminergic neurons had no effect in regulating the natural sleep–wake cycle and, in the case of GABAA receptors, for propofol-induced loss of righting reflex. The latter finding makes it unlikely that the histaminergic TMN has a central role in anesthesia. GABAB receptors on histaminergic neurons were dispensable for all behaviors examined. Synaptic inhibition of histaminergic cells by GABAA receptors, however, was essential for habituation to a novel environment.