大鼠延髓中缝核群与前庭复合体之间纤维联系及其在运动病中作用的形态学研究
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摘要
一、研究意义
运动病(motion sickness,MS)是前庭器官受刺激而引起的中枢及植物神经系统功能紊乱的反应,其症状包括面色苍白、出汗、流涎、淡漠、嗜睡、眩晕、恶心或呕吐等前庭-植物神经系统功能紊乱症状。它发生于人们乘坐车、船、飞机、游乐设施或航海、航空、航天模拟和实际作业时,因所处的运动环境不同,MS又有不同的名称,如空晕病、晕船(航海MS)、航天病、模拟器病等。MS发病率较高,对人们生活的影响较大,同时,该病严重影响着部队的作战能力。然而迄今为止,由于本病的发病机制尚未完全阐明,目前所使用药物的防治效果还不十分令人满意,而且多具嗜睡、工作效率低等副作用。因此,深入研究本病的发病机制,对于提高人们生活质量,增强部队战斗力具有重要意义。
目前,关于MS发病机制存在多种假说,使人们对其发病机制有了深入了解。目前被人们广泛接受的是神经不匹配学说,该学说认为当人们进入到一个新的运动环境之后,来自视觉、耳石器、半规管和本体感觉器将信息传入到前庭神经核,由前庭复合体(vetibular nuclei complex,VNC)发出的神经纤维进一步向中枢其它核团投射,大脑将会对所获得的运动信息与原有的信息进行对照,一旦新的信息与过去的经验不符,或者和所“期望”的信号不一致,即可发生神经不匹配而引起MS。因此,可以说MS是由VNC始发,多个中枢核团参与的中枢神经系统功能紊乱疾病。中缝核群(raphe nuclei complex,RNC)是脑干五-羟色胺(5-hydroxytryptamine,5-HT)能神经元集中存在的部位,由于5-HT不能通过血脑屏障,因此中枢神经系统内源性的5-HT大部分来源于RNC。是否存在VNC向RNC的纤维投射还不十分明确,研究显示5-HT可以通过作用于VNC内5-HT1A受体抑制VN的活性,并且已经证实RNC存在向VNC投射的纤维联系。
在借鉴先前工作的基础上,本课题利用复杂旋转加速度刺激器刺激大鼠的前庭器官,建立MS动物模型,同时观察动物在旋转刺激下VNC、RNC中Fos、P物质受体(subsnance P receptor,SPR)的表达变化,同时,利用逆行追踪技术研究VNC与RNC之间的纤维联系,提供形态学依据,为进一步临床研究打下基础。
二、材料与方法
本研究主要以二级SD大鼠为研究对象,利用复杂旋转刺激器装置,采用免疫组化方法、免疫荧光技术、激光共聚焦技术以及荧光素追踪技术探讨MS可能的发生机理。
1、采用复杂旋转刺激器刺激大鼠的前庭器官,利用大鼠发生MS后异食高岭土等非营养性物质这一特征,验证建立的MS动物模型是否成功。
2、观察复杂旋转刺激后大鼠VNC内Fos蛋白表达情况及阳性细胞计数,分析Fos对MS模型中大鼠VNC作用。
3、计算复杂旋转刺激后大鼠RNC内Fos蛋白表达阳性细胞数目,分析Fos在MS模型中大鼠RNC的表达变化。
4、利用四甲基罗达明(tatramethyl thodamine,TMR)逆行标记追踪技术,研究VNC向延髓RNC的纤维投射联系,为进一步研究MS的发生机制提供形态学依据。
5、采用荧光金(fluorogold,FG)追踪、免疫荧光及激光共聚焦方法研究刺激后大鼠MVN内Fos、SP受体(NK-1R)在MVN内FG逆标神经元细胞的共表达情况,分析Fos、SPR在MS模型中的表达变化及意义。
三、结果
1、本试验采用复杂的双轴旋转刺激动物,引起显著的异食高岭土行为,而对照组动物行为学无改变。
2、双轴旋转刺激动物,观察VNC内Fos阳性标记细胞表达情况,结果显示MVN标记细胞最多,占VNC内阳性细胞的60 %左右,其余核团均有不同数目的阳性神经元,所占比率不同。
3、双轴旋转刺激动物,RNC同时出现较多Fos阳性标记细胞,主要相关核团内阳性细胞数目在150~300之间。
4、在延髓RNC区域微注射TMR,在荧光显微镜下观察到VNC中出现标记细胞,各个亚核中标记细胞数目存在明显差异,在同一亚核的不同部分标记细胞的分布也不一样。标记细胞主要存在于MVN吻端及LVN区域,SuVN区域数量较少。
5、在延髓RNC区域微注射FG 6 d后,旋转刺激动物1 h,观察到在MVN中存在FG、Fos与SPR共同标记神经元。
四、结论
1、利用复杂双轴旋转刺激装置成功建立MS动物模型,为MS的机理研究提供可靠方法。
2、双轴旋转刺激后,大鼠VNC及RNC内各亚核均出现数量不等的Fos阳性标记细胞,提示VNC、RNC共同参与了MS的发生过程。
3、VNC不但接受来自RNC发出的神经纤维支配,同时也发出纤维投射到RMg以及RPa等延髓RNC,提示两者之间存在双向纤维联系。
4、延髓RNC区域微注射FG后,MVN可见到FG、Fos、SPR共同标记阳性细胞。提示在复杂双轴旋转刺激引起的MS发生时,RNC内的部分神经元通过某种机制参与了MS的发生或者起到一定的调节作用。
Objective At present, it is believed that motion sickness happens in riding, navigation or aviation and is mostly induced by the abnormal activity of vestibular system. Signs and symptoms of motion sickness include headache, dizziness, and nausea, vomiting which influence remarkably the ability for navy or air members. Although there are many hypothesis for the pathogenesis, none of' them can thoroughly explain the occurrence, development and all kinds of symptoms in MS. The pathogenesis of MS is not clarificated. This study aims to observe the change of neurotrasmitter in the brain stem during motion sickness so as to render the foundation of the disease and investigate the relationship. The illumination of the mechanism has important academic and practical significance which to prevent and treat motion sickness.
Materials and methods
1. Establish and testify the MS model in rats. SD male rats were randomly divided into MS group and control group. We set up rat MS model using complex rotation stimulator made by our laboratory and gave rats one-hour stimulation everyday. The establishment of MS was measured by their kaolin consumption.
2. After one-hour simulation, the changes of Fos protein expression in VNC and RNC of rats were observed by immunohistochemitry.
3. TMR retrograde tracing technique was used to observe the position of stained positive cells in VNC.
4. After injecting FG to the RNC, we used antibodies against SPR and Fos to testify the co-expression by immunofluorescence histochemistry in MVN. The stained sections were observed using a confocal laser-scanning microscope.
Results
1. Compared with the control group, the kaolin consumption of MS group increased markedly. The results indicated the establishment of MS in rats is successful.
2. In the control group, we found the expression of Fos protein in cells of VNC and RNC were hardly observed. Compared with the control group, the number of Fos-positive cells increased markedly after the stimulation by complex rotation. The Fos protein were distributed in the different subnuclei of VNC and RNC. The results indicate that this stimulation can activate the vestibular neurons, some neurons in RNC were activated through direct or indirect connections with VNC.
3. After injected TMR to the RMg、RPa,a number of TMR retrogradely labeled neurons were mainly distributed in the MVN、LVN and IVN.
4. The rats were stimulated after 6-day injection of FG, triple-labeled neurons of FG/Fos/SPR were found in MVN.
Conclusion
1. The motion sickness model in rats was established successfully.
2. Fos protein were increased markedly in VNC and RNC by motion sickness model .This suggested that RNC play a role in MS.
3. There are reciprocal connection between VNC and RNC in medulla oblongata.
4. In the MVN, some neurons with Fos immunoreactivity transmitting the move information and projecting directly to the RNC might receive SPergic afferents.
运动病(motion sickness,MS)是前庭器官受刺激而引起的中枢及植物神经系统功能紊乱的反应,其症状包括面色苍白、出汗、流涎、淡漠、嗜睡、眩晕、恶心或呕吐等前庭-植物神经系统功能紊乱症状。它发生于人们乘坐车、船、飞机、游乐设施或航海、航空、航天模拟和实际作业时,因所处的运动环境不同,MS又有不同的名称,如空晕病、晕船(航海MS)、航天病、模拟器病等。MS发病率较高,对人们生活的影响较大,同时,该病严重影响着部队的作战能力。然而迄今为止,由于本病的发病机制尚未完全阐明,目前所使用药物的防治效果还不十分令人满意,而且多具嗜睡、工作效率低等副作用。因此,深入研究本病的发病机制,对于提高人们生活质量,增强部队战斗力具有重要意义。
目前,关于MS发病机制存在多种假说,使人们对其发病机制有了深入了解。目前被人们广泛接受的是神经不匹配学说,该学说认为当人们进入到一个新的运动环境之后,来自视觉、耳石器、半规管和本体感觉器将信息传入到前庭神经核,由前庭复合体(vetibular nuclei complex,VNC)发出的神经纤维进一步向中枢其它核团投射,大脑将会对所获得的运动信息与原有的信息进行对照,一旦新的信息与过去的经验不符,或者和所“期望”的信号不一致,即可发生神经不匹配而引起MS。因此,可以说MS是由VNC始发,多个中枢核团参与的中枢神经系统功能紊乱疾病。中缝核群(raphe nuclei complex,RNC)是脑干五-羟色胺(5-hydroxytryptamine,5-HT)能神经元集中存在的部位,由于5-HT不能通过血脑屏障,因此中枢神经系统内源性的5-HT大部分来源于RNC。是否存在VNC向RNC的纤维投射还不十分明确,研究显示5-HT可以通过作用于VNC内5-HT1A受体抑制VN的活性,并且已经证实RNC存在向VNC投射的纤维联系。
在借鉴先前工作的基础上,本课题利用复杂旋转加速度刺激器刺激大鼠的前庭器官,建立MS动物模型,同时观察动物在旋转刺激下VNC、RNC中Fos、P物质受体(subsnance P receptor,SPR)的表达变化,同时,利用逆行追踪技术研究VNC与RNC之间的纤维联系,提供形态学依据,为进一步临床研究打下基础。
二、材料与方法
本研究主要以二级SD大鼠为研究对象,利用复杂旋转刺激器装置,采用免疫组化方法、免疫荧光技术、激光共聚焦技术以及荧光素追踪技术探讨MS可能的发生机理。
1、采用复杂旋转刺激器刺激大鼠的前庭器官,利用大鼠发生MS后异食高岭土等非营养性物质这一特征,验证建立的MS动物模型是否成功。
2、观察复杂旋转刺激后大鼠VNC内Fos蛋白表达情况及阳性细胞计数,分析Fos对MS模型中大鼠VNC作用。
3、计算复杂旋转刺激后大鼠RNC内Fos蛋白表达阳性细胞数目,分析Fos在MS模型中大鼠RNC的表达变化。
4、利用四甲基罗达明(tatramethyl thodamine,TMR)逆行标记追踪技术,研究VNC向延髓RNC的纤维投射联系,为进一步研究MS的发生机制提供形态学依据。
5、采用荧光金(fluorogold,FG)追踪、免疫荧光及激光共聚焦方法研究刺激后大鼠MVN内Fos、SP受体(NK-1R)在MVN内FG逆标神经元细胞的共表达情况,分析Fos、SPR在MS模型中的表达变化及意义。
三、结果
1、本试验采用复杂的双轴旋转刺激动物,引起显著的异食高岭土行为,而对照组动物行为学无改变。
2、双轴旋转刺激动物,观察VNC内Fos阳性标记细胞表达情况,结果显示MVN标记细胞最多,占VNC内阳性细胞的60 %左右,其余核团均有不同数目的阳性神经元,所占比率不同。
3、双轴旋转刺激动物,RNC同时出现较多Fos阳性标记细胞,主要相关核团内阳性细胞数目在150~300之间。
4、在延髓RNC区域微注射TMR,在荧光显微镜下观察到VNC中出现标记细胞,各个亚核中标记细胞数目存在明显差异,在同一亚核的不同部分标记细胞的分布也不一样。标记细胞主要存在于MVN吻端及LVN区域,SuVN区域数量较少。
5、在延髓RNC区域微注射FG 6 d后,旋转刺激动物1 h,观察到在MVN中存在FG、Fos与SPR共同标记神经元。
四、结论
1、利用复杂双轴旋转刺激装置成功建立MS动物模型,为MS的机理研究提供可靠方法。
2、双轴旋转刺激后,大鼠VNC及RNC内各亚核均出现数量不等的Fos阳性标记细胞,提示VNC、RNC共同参与了MS的发生过程。
3、VNC不但接受来自RNC发出的神经纤维支配,同时也发出纤维投射到RMg以及RPa等延髓RNC,提示两者之间存在双向纤维联系。
4、延髓RNC区域微注射FG后,MVN可见到FG、Fos、SPR共同标记阳性细胞。提示在复杂双轴旋转刺激引起的MS发生时,RNC内的部分神经元通过某种机制参与了MS的发生或者起到一定的调节作用。
Objective At present, it is believed that motion sickness happens in riding, navigation or aviation and is mostly induced by the abnormal activity of vestibular system. Signs and symptoms of motion sickness include headache, dizziness, and nausea, vomiting which influence remarkably the ability for navy or air members. Although there are many hypothesis for the pathogenesis, none of' them can thoroughly explain the occurrence, development and all kinds of symptoms in MS. The pathogenesis of MS is not clarificated. This study aims to observe the change of neurotrasmitter in the brain stem during motion sickness so as to render the foundation of the disease and investigate the relationship. The illumination of the mechanism has important academic and practical significance which to prevent and treat motion sickness.
Materials and methods
1. Establish and testify the MS model in rats. SD male rats were randomly divided into MS group and control group. We set up rat MS model using complex rotation stimulator made by our laboratory and gave rats one-hour stimulation everyday. The establishment of MS was measured by their kaolin consumption.
2. After one-hour simulation, the changes of Fos protein expression in VNC and RNC of rats were observed by immunohistochemitry.
3. TMR retrograde tracing technique was used to observe the position of stained positive cells in VNC.
4. After injecting FG to the RNC, we used antibodies against SPR and Fos to testify the co-expression by immunofluorescence histochemistry in MVN. The stained sections were observed using a confocal laser-scanning microscope.
Results
1. Compared with the control group, the kaolin consumption of MS group increased markedly. The results indicated the establishment of MS in rats is successful.
2. In the control group, we found the expression of Fos protein in cells of VNC and RNC were hardly observed. Compared with the control group, the number of Fos-positive cells increased markedly after the stimulation by complex rotation. The Fos protein were distributed in the different subnuclei of VNC and RNC. The results indicate that this stimulation can activate the vestibular neurons, some neurons in RNC were activated through direct or indirect connections with VNC.
3. After injected TMR to the RMg、RPa,a number of TMR retrogradely labeled neurons were mainly distributed in the MVN、LVN and IVN.
4. The rats were stimulated after 6-day injection of FG, triple-labeled neurons of FG/Fos/SPR were found in MVN.
Conclusion
1. The motion sickness model in rats was established successfully.
2. Fos protein were increased markedly in VNC and RNC by motion sickness model .This suggested that RNC play a role in MS.
3. There are reciprocal connection between VNC and RNC in medulla oblongata.
4. In the MVN, some neurons with Fos immunoreactivity transmitting the move information and projecting directly to the RNC might receive SPergic afferents.
引文
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