一氧化氮对大鼠舌下神经核的时相依赖性调控研究
发布时间：2018-08-01 16:21
【摘要】：[研究背景] 延髓舌下神经核(hypoglossal motor nuclei, HMN)的兴奋性改变对舌肌在不同脑时相(如睡眠-醒觉期或药物引致的麻醉状态)的活性起决定作用。由于睡眠中舌肌活动的抑制能使上气道狭窄和阻塞,对阻塞性睡眠呼吸暂停低通气综合征(obstructive sleep apnea-hypopnea syndrome,OSAHS)的发生起重要作用,所以确定对HMN兴奋性的神经影响因素和OSAHS的发病机制息息相关。一氧化氮(nitric oxide, NO)是一种可自由扩散的细胞间信号分子,研究发现有合成NO的神经元投射到HMN。HMN同时也含有可溶性腺苷环化酶(soluble guanylyl cyclase, sGC),一种主要的NO细胞内受体酶。虽然已确定NO可作为中枢神经系统几种神经元的调控因子,但它对HMN体内情况下的作用尚未得知。本研究拟验证体内情况下NO作为HMN兴奋性神经递质的假设。 [目的] 了解NO作为一种神经递质,在脑的麻醉、清醒、非快动眼(non-rapid eye movement, NREM)和快动眼(rapid eye movement, REM)睡眠等不同时相分别作用于舌下神经核,其调控作用如何以及通过何种通路进行调控。 [方法] 选用了麻醉和自由活动两种大鼠模型来观察NO对HMN的调控作用。 1、麻醉大鼠模型： 雄性成年wistar大鼠,行气管切开、获取膈肌、颏舌肌(genioglossus muscle, GG)肌电、动脉血压,在HMN插入微透析探针,麻醉情况下分别给予递增浓度的NO供体、NO清除剂、一氧化氮合成酶(nitric oxide synthase, NOS)抑制剂和可溶性腺苷环化酶(soluble guanylyl cyclase, sGC)抑制剂,以及持续浓度的NO供体和sGC抑制剂的混合物,观测GG及膈肌电活动、动脉血压和呼吸频率的变化。 2、自由活动大鼠模型： 手术埋植电极在大鼠GG、膈肌、颈肌及大脑皮层,并在舌下神经核上方埋植探针导管。术后第6-7天,连接GG、膈肌、颈肌及脑电图电极,实验前经导管插入探针到HMN。两组大鼠分别持续透析NO供体和清除剂,记录各肌电和脑电信号。经数字化处理后,以脑电图区分醒觉、NREM、REM睡眠,评估在不同脑时相时该药物对GG的影响作用。 [结果] 一、麻醉大鼠模型： 1、NO供体DEA使大鼠的节律性GG电活动呈浓度依赖性升高。在高浓度DEA(100mmol·L-1)时紧张性电活动亦出现增强。 2、NO清除剂、NOS抑制剂和sGC抑制剂组大鼠的节律性GG活动明显降低并呈浓度依赖性。这三组大鼠所有浓度的药物对紧张性GG活动都无显著影响。 3、在HMN给予NO供体和sGC抑制剂的混合物,后者有效地抑制了前者对HMN的兴奋作用。 二、自由活动大鼠模型： 1、NO供体作用于舌下神经核增加NREM睡眠中GG的紧张性活动,但对清醒和REM睡眠期没有影响。 2、在NO清除剂组的10只大鼠中,不论在哪个时相(NREM睡眠,REM睡眠和清醒),NO清除剂对GG节律性和紧张性活动的影响均无统计学意义。 [结论] 1、NO对舌下神经核总的来说存在兴奋作用。 2、NO在舌下神经核局部产生,通过舌下神经元的sGC-cGMP通路起作用。 3、NO对HMN兴奋作用的特点依赖于脑的不同时相(也就是说,麻醉、清醒、NREM睡眠、REM睡眠)而有所不同。在麻醉状态下,NO增强舌下神经核的节律性活动成分。在自由活动动物中,则可增强NREM睡眠期的紧张性活动。
[Abstract]:[research background]
Excitatory changes in the hypoglossal motor nuclei (HMN) of the medulla oblongata play a decisive role in the activity of the lingual muscles in different brain phases, such as sleep wake or drug induced narcotic state. The inhibition of the movement of the tongue in sleep can narrow and obstruct the upper airway, and the obstructive sleep apnea hypopnea syndrome (obstructiv E sleep apnea-hypopnea syndrome, OSAHS) plays an important role in determining the nerve effects on HMN excitability and the pathogenesis of OSAHS. Nitric oxide (nitric oxide, NO) is a free diffusion intercellular signal molecule. The study found that synthetic NO neurons projecting to HMN.HMN are also soluble. Soluble guanylyl cyclase (sGC), a major NO intracellular receptor enzyme. Although NO has been identified as a regulator of several neurons in the central nervous system, its role in the body of HMN has not been known. This study is to verify the hypothesis that NO is a HMN excitatory neurotransmitter in the body.
[Objective]
To understand how NO acts as a neurotransmitter in brain anesthesia, awake, non fast moving eyes (non-rapid eye movement, NREM) and fast moving eye (rapid eye movement, REM) sleep respectively on the hypoglossal nucleus, and how and through which pathway it is regulated.
[method]
Two models of anaesthesia and free movement were used to observe the regulatory effect of NO on HMN.
1, the rat model of anaesthetized rats:
Male adult Wistar rats were treated with tracheotomy, phrenic muscle, geniclingual muscle (genioglossus muscle, GG) myoelectric, arterial blood pressure, and HMN inserted microdialysis probe. Under anesthesia, the increasing concentration of NO donor, NO scavenger, nitric oxide synthase (nitric oxide synthase, NOS) inhibitor and soluble adenosine cyclase (soluble) The changes of GG and diaphragm electromyographic activity, arterial blood pressure and respiratory rate were observed with a mixture of YL cyclase, sGC inhibitor and a continuous concentration of NO donor and sGC inhibitor.
2, free active rat model:
The electrodes were implanted in GG, diaphragm, neck and cerebral cortex in rats, and the probe catheter was implanted above the hypoglossal nucleus. After 6-7 days, GG, diaphragm, neck muscle and electroencephalogram electrode were connected. The NO donor and scavenger were continuously dialysed into HMN. two rats by catheter insertion probe before the experiment. The electromyography and electroencephalogram were recorded. After the EEG was used to distinguish wakefulness, NREM and REM sleep, the effect of the drug on GG was evaluated at different brain phases.
[results]
1. The model of anesthetized rats:
1. NO donor DEA increased the rhythmic GG electrical activity in a concentration-dependent manner, and increased the tension electrical activity at high concentration of DEA (100 mmol.L-1).
2, the rhythmic GG activity of the NO scavenger, the NOS inhibitor and the sGC inhibitor group was significantly reduced and showed a concentration dependence. All the concentrations of the three groups had no significant effect on the activity of tension GG.
3, a mixture of NO donor and sGC inhibitor was given in HMN, which effectively inhibited the excitatory effect of the former on HMN.
Two, free active rat model:
1, the NO donor acts on the hypoglossal nucleus to increase the tension activity of GG in NREM sleep, but has no effect on wakefulness and REM sleep period.
2, in the 10 rats of the NO scavenger group, no matter which phase (NREM sleep, REM sleep and sober), the effect of NO scavenger on GG rhythmic and tension activity was not statistically significant.
[Conclusion]
1, NO has an excitatory effect on the hypoglossal nucleus.
2, NO is localized in the hypoglossal nucleus and plays a role through the sGC-cGMP pathway in hypoglossal neurons.
3, the characteristics of NO's excitatory effect on HMN depend on different phases of the brain (that is, anesthesia, sobriety, NREM sleep, REM sleep). In anaesthetized state, NO enhances the rhythmic activity of the hypoglossal nucleus. In free active animals, it can enhance the tension in the NREM sleep period.
【学位授予单位】：昆明医科大学
【学位级别】：博士
【学位授予年份】：2012
【分类号】：R766.4
本文编号：2158148
[Abstract]:[research background]
Excitatory changes in the hypoglossal motor nuclei (HMN) of the medulla oblongata play a decisive role in the activity of the lingual muscles in different brain phases, such as sleep wake or drug induced narcotic state. The inhibition of the movement of the tongue in sleep can narrow and obstruct the upper airway, and the obstructive sleep apnea hypopnea syndrome (obstructiv E sleep apnea-hypopnea syndrome, OSAHS) plays an important role in determining the nerve effects on HMN excitability and the pathogenesis of OSAHS. Nitric oxide (nitric oxide, NO) is a free diffusion intercellular signal molecule. The study found that synthetic NO neurons projecting to HMN.HMN are also soluble. Soluble guanylyl cyclase (sGC), a major NO intracellular receptor enzyme. Although NO has been identified as a regulator of several neurons in the central nervous system, its role in the body of HMN has not been known. This study is to verify the hypothesis that NO is a HMN excitatory neurotransmitter in the body.
[Objective]
To understand how NO acts as a neurotransmitter in brain anesthesia, awake, non fast moving eyes (non-rapid eye movement, NREM) and fast moving eye (rapid eye movement, REM) sleep respectively on the hypoglossal nucleus, and how and through which pathway it is regulated.
[method]
Two models of anaesthesia and free movement were used to observe the regulatory effect of NO on HMN.
1, the rat model of anaesthetized rats:
Male adult Wistar rats were treated with tracheotomy, phrenic muscle, geniclingual muscle (genioglossus muscle, GG) myoelectric, arterial blood pressure, and HMN inserted microdialysis probe. Under anesthesia, the increasing concentration of NO donor, NO scavenger, nitric oxide synthase (nitric oxide synthase, NOS) inhibitor and soluble adenosine cyclase (soluble) The changes of GG and diaphragm electromyographic activity, arterial blood pressure and respiratory rate were observed with a mixture of YL cyclase, sGC inhibitor and a continuous concentration of NO donor and sGC inhibitor.
2, free active rat model:
The electrodes were implanted in GG, diaphragm, neck and cerebral cortex in rats, and the probe catheter was implanted above the hypoglossal nucleus. After 6-7 days, GG, diaphragm, neck muscle and electroencephalogram electrode were connected. The NO donor and scavenger were continuously dialysed into HMN. two rats by catheter insertion probe before the experiment. The electromyography and electroencephalogram were recorded. After the EEG was used to distinguish wakefulness, NREM and REM sleep, the effect of the drug on GG was evaluated at different brain phases.
[results]
1. The model of anesthetized rats:
1. NO donor DEA increased the rhythmic GG electrical activity in a concentration-dependent manner, and increased the tension electrical activity at high concentration of DEA (100 mmol.L-1).
2, the rhythmic GG activity of the NO scavenger, the NOS inhibitor and the sGC inhibitor group was significantly reduced and showed a concentration dependence. All the concentrations of the three groups had no significant effect on the activity of tension GG.
3, a mixture of NO donor and sGC inhibitor was given in HMN, which effectively inhibited the excitatory effect of the former on HMN.
Two, free active rat model:
1, the NO donor acts on the hypoglossal nucleus to increase the tension activity of GG in NREM sleep, but has no effect on wakefulness and REM sleep period.
2, in the 10 rats of the NO scavenger group, no matter which phase (NREM sleep, REM sleep and sober), the effect of NO scavenger on GG rhythmic and tension activity was not statistically significant.
[Conclusion]
1, NO has an excitatory effect on the hypoglossal nucleus.
2, NO is localized in the hypoglossal nucleus and plays a role through the sGC-cGMP pathway in hypoglossal neurons.
3, the characteristics of NO's excitatory effect on HMN depend on different phases of the brain (that is, anesthesia, sobriety, NREM sleep, REM sleep). In anaesthetized state, NO enhances the rhythmic activity of the hypoglossal nucleus. In free active animals, it can enhance the tension in the NREM sleep period.
【学位授予单位】：昆明医科大学
【学位级别】：博士
【学位授予年份】：2012
【分类号】：R766.4
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