舌肌训练对不同程度慢性间歇低氧大鼠颏舌肌调控和上气道的影响及机制

Obstructive sleep apnea syndrome (OSAS) is characterized by repetitive collapse of upper airway during sleep. Currently, the common treatment for moderate and severe OSAS is continuous positive airway pressure (CPAP), but the compliance is less than 50%. Surgery such as UPPP is restrained because the only indication is for OSAS patients with narrow anatomic structure of upper airway. It is quite necessary to find a new method to treat OSAS patients easily and safely. The contractile force of the upper airway dilator muscles (for example, genioglossus) plays an important role to maintain the stability of upper airway, so the new target for OSAS treatment mainly focuses on improving the function of upper airway dilator muscles. In recent years, some scholars found that tongue exercise in daytime could induce the plasticity of genioglossus corticomotor excitability, and greatly alleviate OSAS severity. However, it is still unknown whether tongue exercise can change genioglossus central control and upper airway dynamics. Chronic intermittent hypoxia is the main pathophysiological manifestation of OSAS. How does different severity of hypoxia influence the changes induced by tongue exercise? No study has been reported. With the previous national natural science fund, by applying TMS techniques, we discovered that raphe 5-HT neurons participated in the central control of genioglossus in rats during intermittent hypoxia. It has been reported that tongue exercise could induce a significant increase in 5-HT immunoreactivity in the hypoglossal nucleus. Schaser et al. has observed that in the rat hypoglossal nucleus, the immunoreactivity levels of brain-derived neurotrophic factor (BDNF) and its receptor TrkB significantly increased and were positively correlated with tongue exercise in young and middle aged rats. Thus, we hypothesize that tongue exercise could actively increase the corticomotor activity of genioglossus and enhance the stability of upper airway. These effects may depend on 5-HT/5-HT2A receptor-PKC-BDNF/TrkB in hypoglossal nucleus. This study is designed to evaluate the effect of tongue exercise on genioglossus structure, central control, and the dynamics of upper airway in rats, especially during different severity of chronic intermittent hypoxia, so as to find the new methods to manage OSAS patients by stabilizing the upper airway.

阻塞性睡眠呼吸暂停综合征（OSAS）表现为睡眠中反复发生上气道塌陷和慢性间歇低氧，中重度OSAS主要通过无创正压通气治疗，但依从性不到50%，手术治疗受限，所以改善患者上气道扩张肌的功能成为治疗新靶点。有学者发现舌肌训练可以引起OSAS患者颏舌肌运动皮质区调控重塑，减轻患者病情，但是，舌肌训练通过什么机制改变中枢调控？在何种低氧模式下有助于维持上气道开放？目前尚无探讨。在之前国家自然科学基金的资助下，申请者发现慢性间歇低氧时中缝核5-HT在舌下神经核参与介导颏舌肌的中枢调控，有研究观察到舌肌训练后大鼠舌下神经核脑源性神经营养因子及酪氨酸蛋白激酶受体B表达增高。本课题拟通过慢性间歇低氧动物模型、经颅磁刺激、核团定位等技术探讨舌肌训练对大鼠颏舌肌结构、中枢调控、上气道动力学的影响和5-HT系统的介导通路，以及在不同程度慢性间歇低氧条件下上述影响的变化，探索通过稳定上气道来治疗OSAS的新途径。

阻塞性睡眠呼吸暂停（OSA）表现为睡眠中反复发生上气道塌陷和慢性间歇低氧，中重度OSA主要通过无创正压通气治疗，但依从性不到50%，手术治疗受限，所以改善患者上气道扩张肌的功能成为治疗新靶点。有学者发现舌肌训练可以引起OSA患者颏舌肌运动皮质区调控重塑，那么，能否通过舌肌训练来达到治疗OSA的目的呢？又怎样避免训练所带来的肌肉疲劳呢？舌肌训练通过什么机制改变舌肌的中枢调控？目前尚无探讨。本研究以大鼠颏舌肌为代表，应用慢性间歇低氧动物模型、经颅磁刺激、原位杂交、核团定位、舌下神经核微透析、免疫荧光等技术探讨不同模式舌肌训练对颏舌肌调控和上气道动力学的影响和介导机制，以及在不同程度慢性间歇低氧条件下上述影响的变化，发现：（1）在常氧状态下，舌肌力量训练8周可以提高大鼠的伸舌力量，引起颏舌肌结构、功能损伤和适应性改变，且8周的力量训练可以引起颏舌肌运动皮质区对TMS反应增强；舌肌功能训练可以显著提高舌肌力量的控制能力，且颏舌肌皮质中枢兴奋性的持续性增高可达120min，对气道塌陷的改善程度更好；（2）两种不同模式的舌肌训练均可增加大鼠颏舌肌在急性低氧刺激后的长时程易化反应；慢性间歇低氧时，舌肌训练可以减轻颏舌肌结构损伤，上气道可塌陷性下降；（3）两种不同模式舌肌训练对大鼠颏舌肌及其中枢调控的影响是通过舌下神经核5-HT—5-HT2AR—BDNF/TrkB通路介导的。本研究在既往研究的基础上，通过两种不同模式的舌肌训练动物模型的比较，在国际上新建了舌肌功能训练模式，在避免肌肉疲劳的同时更加优化了训练效果，不仅并且改善了上气道的可塌陷性，也使得肌肉的中枢调控重塑，为OSA的治疗建立了新途径，受到国际、国内的广泛关注，目前已应用于临床。