Chemogenetic stimulation of the hypoglossal neurons improves upper airway patency.
Chemogenetic stimulation of the hypoglossal neurons improves upper airway patency.
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DOI：
10.1038/srep44392
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发表时间：
2017-03-10
影响因子：
4.6
通讯作者：
Polotsky VY
中科院分区：
文献类型：
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作者：
Fleury Curado T;Fishbein K;Pho H;Brennick M;Dergacheva O;Sennes LU;Pham LV;Ladenheim EE;Spencer R;Mendelowitz D;Schwartz AR;Polotsky VY
阻塞性睡眠呼吸暂停（OSA）的特征是睡眠期间反复出现上呼吸道阻塞。OSA导致高心血管发病率和死亡率。OSA的发病机制与咽部神经肌肉控制的缺陷有关。没有有效的药物治疗OSA。本研究的目的是确定是否可以使用化学遗传学方法通过在舌下神经运动神经元中部署由设计者药物专门激活的设计者受体（DREADD）来改善上气道通畅性。将DREADD（rAAV 5-hSyn-hM 3（Gq）-mCherry）和对照病毒（rAAV 5-hSyn-EGFP）立体定向施用至C57 BL/6 J小鼠的舌下神经核。在6-8周内，在施用DREADD配体氯氮平-N-氧化物（CNO）或载体（盐水）之前和之后进行颏舌肌EMG和上气道的动态MRI。在DREADD治疗的小鼠中，CNO激活了颏舌肌并显著扩张了咽部，而盐水则没有影响。对照病毒处理的小鼠未显示CNO的影响。我们的研究结果表明，化学遗传学方法可以被认为是一种治疗选择OSA和其他运动神经元疾病。
Obstructive sleep apnea (OSA) is characterized by recurrent upper airway obstruction during sleep. OSA leads to high cardiovascular morbidity and mortality. The pathogenesis of OSA has been linked to a defect in neuromuscular control of the pharynx. There is no effective pharmacotherapy for OSA. The objective of this study was to determine whether upper airway patency can be improved using chemogenetic approach by deploying designer receptors exclusively activated by designer drug (DREADD) in the hypoglossal motorneurons. DREADD (rAAV5-hSyn-hM3(Gq)-mCherry) and control virus (rAAV5-hSyn-EGFP) were stereotactically administered to the hypoglossal nucleus of C57BL/6J mice. In 6–8 weeks genioglossus EMG and dynamic MRI of the upper airway were performed before and after administration of the DREADD ligand clozapine-N-oxide (CNO) or vehicle (saline). In DREADD-treated mice, CNO activated the genioglossus muscle and markedly dilated the pharynx, whereas saline had no effect. Control virus treated mice showed no effect of CNO. Our results suggest that chemogenetic approach can be considered as a treatment option for OSA and other motorneuron disorders.