Basal Forebrain Cholinergic Neurons Primarily Contribute to Inhibition of Electroencephalogram Delta Activity; Rather Than Inducing Behavioral Wakefulness in Mice
Basal Forebrain Cholinergic Neurons Primarily Contribute to Inhibition of Electroencephalogram Delta Activity; Rather Than Inducing Behavioral Wakefulness in Mice
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基底前脑胆碱能神经元主要有助于抑制脑电图 Delta 活性；
DOI：
10.1038/npp.2016.13
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发表时间：
2016-07-01
影响因子：
7.6
通讯作者：
Huang, Zhi-Li
中科院分区：
文献类型：
--
作者：
Chen, Li;Yin, Dou;Huang, Zhi-Li
基底前脑（BF）胆碱能神经元一直被认为参与行为觉醒和皮层激活。然而，由于BF神经元的异质性和传统方法的选择性差，BF胆碱能神经元在调节睡眠-觉醒周期中的确切作用尚不清楚。我们研究了细胞选择性操作BF胆碱能神经元对睡眠觉醒行为和脑电图（EEG）功率谱的影响，使用药物遗传学技术，“设计师受体专门激活的设计师药物（DREADD）”的方法，和ChAT-IRES-Cre小鼠。我们的研究结果表明，表达hM 3Dq受体的BF胆碱能神经元的激活显着和持久地降低了EEG的δ功率谱，产生低δ非快速眼动睡眠，并轻微增加清醒在光明和黑暗阶段，而表达hM 4Di受体的BF胆碱能神经元的抑制显着增加EEG的δ功率谱，并轻微减少清醒。接着，通过人源化海肾绿色荧光蛋白（hrGFP）追踪BF胆碱能神经元的投射。在次级运动皮质和扣带皮质中观察到丰富和高度密集的hrGFP阳性纤维，在腹外侧视前核（一种已知的睡眠相关结构）中观察到稀疏的hrGFP阳性纤维。最后，我们发现激活BF胆碱能神经元显著增加了次级运动皮层和扣带回皮层的c-Fos表达，但降低了腹外侧视前核的c-Fos表达。综上所述，这些发现表明BF胆碱能神经元的主要功能是通过激活大脑皮层来抑制EEG δ活动，而不是诱导行为觉醒。
The basal forebrain (BF) cholinergic neurons have long been thought to be involved in behavioral wakefulness and cortical activation. However, owing to the heterogeneity of BF neurons and poor selectivity of traditional methods, the precise role of BF cholinergic neurons in regulating the sleep wake cycle remains unclear. We investigated the effects of cell-selective manipulation of BF cholinergic neurons on the sleep wake behavior and electroencephalogram (EEG) power spectrum using the pharmacogenetic technique, the 'designer receptors exclusively activated by designer drugs (DREADD)' approach, and ChAT-IRES-Cre mice. Our results showed that activation of BF cholinergic neurons expressing hM3Dq receptors significantly and lastingly decreased the EEG delta power spectrum, produced low-delta non-rapid eye movement sleep, and slightly increased wakefulness in both light and dark phases, whereas inhibition of BF cholinergic neurons expressing hM4Di receptors significantly increased EEG delta power spectrum and slightly decreased wakefulness. Next, the projections of BF cholinergic neurons were traced by humanized Renilla green fluorescent protein (hrGFP). Abundant and highly dense hrGFP-positive fibers were observed in the secondary motor cortex and cingulate cortex, and sparse hrGFP-positive fibers were observed in the ventrolateral preoptic nucleus, a known sleep-related structure. Finally, we found that activation of BF cholinergic neurons significantly increased c-Fos expression in the secondary motor cortex and cingulate cortex, but decreased c-Fos expression in the ventrolateral preoptic nucleus. Taken together, these findings reveal that the primary function of BF cholinergic neurons is to inhibit EEG delta activity through the activation of cerebral cortex, rather than to induce behavioral wakefulness.