NMDA受体信号通路在晕动症适应—脱适应过程中的作用及机制
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摘要
晕动症是由于人体暴露于异常加速度环境所引起的多系统生理反应。反复暴露于该加速度环境，能使得晕动症症状减轻甚至消失，这就是适应现象。脱离加速度环境一定时间后，会出现脱适应现象。但是这种适应脱适应的周期性规律和其中枢机制却不清楚。众所周知，前庭系统是外界加速度信息的主要感受系统，前人的研究发现在前庭神经元中，谷氨酸是主要的神经递质，而NMDA受体也广泛地存在于前庭核的神经元中。大量的研究表明，NMDA受体介导的长时程增强是中枢学习记忆的神经基础，NMDA受体介导的胞内信号转导级联反应主要是通过谷氨酸激活NMDA受体后通过钙/钙调蛋白依赖型激酶II（Ca2+/CaMKII）途径，最终激活cAMP反应元件结合蛋白（CREB），而磷酸化的CREB也作为转录因子可进一步诱导及早基因c-fos以及脑源性神经生长因子（BDNF）等新基因的表达。我们的前期研究发现Fos蛋白能作为前庭核神经元激活的分子标志，并且谷氨酸能神经元前庭内脏投射通路能被旋转刺激所激活。另外，大量研究证实，海马是记忆相关的重要脑区，前庭与海马之间存在着广泛的联系，前庭系统的激活能影响海马的功能和海马相关的学习记忆能力。本研究首先观察了晕动症大鼠的行为学变化和适应-脱适应规律，进一步采用分子生物学方法观察NMDA受体信号通路在晕动症适应-脱适应过程中的变化，最后采用药理学手段阻断该信号通路，观察对晕动症适应-脱适应过程的影响。
方法
一、晕动症适应-脱适应动物模型的建立
1、实验动物及分组550只健康雄性SD大鼠，体重220-250g。
（1）长时刺激实验100只动物完全随机分为10组：旋转刺激4h组，静止对照4h组，1h旋转组，1h静止组，2h旋转组，2h静止组，3h旋转组，3h静止组，4h旋转组，4h静止组，每组10只。前2组记录每小时的实时行为学变化，后8组记录自发活动变化。
（2）东莨菪碱干预实验90只动物完全随机分为9组：自由活动对照组，静止对照组，旋转对照组，东莨菪碱旋转组（ISco0.5mg/kg），东莨菪碱静止组I，东莨菪碱旋转组I（ISco1.0mg/kg），东莨菪碱静止组II，溶剂旋转组，溶剂静止组，每组10只。药物及溶剂组为刺激前30min给药（1ml/只，i.g.）。
（3）双侧迷路切除实验40只动物完全随机分为4组：双侧迷路切除旋转组，双侧迷路切除静止组，假手术旋转组，假手术静止组，每组10只。手术后4周进行刺激实验。
（4）适应规律实验40只动物完全随机分为2组：旋转刺激2h/d组、静止对照2h/d组，每组20只，每天进行模拟晕动刺激，实时观察行为学变化。100只动物完全随机分为10组：旋转刺激2h-1d组、2h-4d组、2h-7d组、2h-10d组、2h-13d组，和与各自时间对应的静止对照组，每组10只，记录自发活动变化。
（5）脱适应规律实验180只动物完全随机分为18组：脱适应5d，7d，14d，21d，28d，35d组及相应天数刺激对照组，静止对照组，每组10只。脱适应组动物首先进行晕动刺激至适应，连续9d，每天2h，后正常饲养至相应脱适应天数，再进行一次2h晕动刺激，记录实时行为学变化和自发活动变化。
2、双侧迷路切除手术及假手术3%戊巴比妥那麻醉后，将大鼠侧卧位置于手术显微镜下，剪开耳后皮肤，钝性分离软组织，暴露外耳道外壁，剪开外耳道，暴露鼓膜及鼓室，观察听小骨清晰后，寻找圆窗及卵圆窗，用五号注射器针头挑开鼓泡，除去部分骨质，用尖头镊探查内耳，剪除内耳骨部，挑出内耳，用左氧氟沙星粉剂敷于内耳，防止感染，缝合外耳道及耳后部皮肤，存活24h后，重新进行另一侧内耳切除手术。假手术过程与双侧内耳切除手术相同，区别在于剪除内耳骨部后，不触及内耳半规管。动物正常饲养恢复4周后，进行旋转刺激。
3、模拟晕动症刺激及行为学测量晕动症模拟器根据Crampton等的报道仿制而成。将代谢盒放入晕动症模拟器的有机玻璃笼内，旋转刺激组大鼠无束缚的放置于代谢盒的铁丝网上进行旋转刺激。实时行为学测量：刺激结束后，立即计量铁丝网上的粪便颗粒数、尿液槽中的尿液量、饲料槽中饲料摄入量、高岭土槽中高岭土摄入量。高岭土摄入量（24h）测量：每天10:00自动动物代谢监测系统（CLAMS）自动记录。自发活动测量：采用DigBehav动物行为分析系统记录动物3min的运动。
二、前庭核NMDA受体信号通路在晕动症适应-脱适应过程中的作用
1、实验动物及分组128只健康雄性SD大鼠，体重220-250g。80只动物完全随机分为10组：旋转刺激组1d，4d，7d，10d，13d及相应的静止对照组，每组8只，用于进行western blot和实时定量PCR实验。48只动物完全随机分为6组：旋转刺激组1d，4d，7d，10d，13d及静止对照组，每组8只，用于进行免疫组织化学及免疫荧光组织化学实验。
2、分子生物学实验采用Western blot法测定尾侧前庭核内NMDA R1受体、NMDA R2A/B受体、GABAAα1亚基、CaMKIIα亚基、磷酸化CaMKIIα亚基、CREB、磷酸化CREB蛋白含量。
采用实时定量PCR法测定尾侧前庭核内Fos、Arc、BDNF mRNA表达水平。
采用免疫组织化学法观察尾侧前庭核内Fos标记神经元数量。
采用免疫荧光组织化学法观察尾侧前庭核内GABAAα1标记神经元、Arc标记神经元、GABAAα1/Arc共标记神经元数量。
三、海马NMDA受体信号通路在晕动症适应-脱适应过程中的作用
1、实验动物及分组260只健康雄性SD大鼠，体重220-250g。80只动物完全随机分为10组：旋转刺激组1d，4d，7d，10d，13d及相应的静止对照组，每组8只，用于进行western blot和实时定量PCR实验。30只动物完全随机分为6组：脱适应组1d，4d，7d，14d，21d及静止对照组（Sta），每组5只，用于进行western blot实验。150只动物完全随机分为15组：抑制剂组2d，4d，6d，8d，10d及相应生理盐水对照组、脱适应对照组，每组10只。
2、双侧海马内微注射3%戊巴比妥那麻醉后，将大鼠头部固定于脑立体定位仪上，切开颅顶部皮肤，暴露前囟点，以前囟点为原点定位双侧海马中心部（AP3.8mm；ML2.3mm；DV3.0mm），打开颅骨，插入进样导管，牙科水泥固定导管于颅骨表面，左氧氟沙星粉剂敷于颅骨表面，缝合颅顶部皮肤，盖上导管帽。后正常饲养7d，前3d每天腹腔注射1ml左氧氟沙星注射液防治感染。乙醚麻醉大鼠后，打开导管帽，以注射管将0.5μl20nmol/μl KN-93缓慢注射至海马中心部，留针1min，缓慢拔针，盖上导管帽。
3、行为学实验旋转刺激同第一部分，所有动物首先进行连续9d，每天2h的晕动刺激至适应；抑制剂组与生理盐水对照组动物每天双侧海马内微注射CaMKII抑制剂KN-93或生理盐水至相应脱适应天数后，进行2h晕动刺激记录实时行为学变化及自发活动变化；脱适应对照组正常饲养至相应脱适应天数后，进行2h晕动刺激记录实时行为学变化及自发活动变化。
4、分子生物学实验采用Western blot法测定海马内NMDA R1受体、NMDA R2A/B、CaMKIIα亚基、磷酸化CaMKII α亚基、CREB、磷酸化CREB蛋白含量。采用实时定量荧光PCR法测定海马内Fos、Arc、BDNF mRNA表达水平。
四、统计学分析采用SPSS v13.0软件进行统计分析。适应规律、脱适应规律、Western blot及PCR实验中，两因素多水平方差分析用来统计整个处理过程中旋转刺激、时间的主因素效应和交互作用效应有无显著性差异。当交互效应存在的情况下，单因素方差分析及Bonferroni检验用来分析相对应的时间点，旋转刺激组和静止对照组之间的差异。行为学指标筛选实验中，方差分析Bonferroni检验用来分析相对应的时间点，旋转刺激组和静止对照组之间的差异。免疫组织化学及免疫荧光组织化学实验中，单因素方差分析及Dunnett-t检验用来统计尾侧前庭核中标记神经元数目有无差别。
结果
一、晕动症适应-脱适应动物模型的建立
1、长时刺激对晕动症行为学的影响统计分析显示，与静止对照组（Sta）相比，粪便颗粒数在刺激的第1、2小时增加（P<0.05），在第3、4小时下降至对照水平（P>0.05）；自发活动量和活动次数均在第1、2小时降低（P<0.05），在第3、4小时上升到接近对照组水平（P>0.05）；24h高岭土摄入量在4h中均增加（P<0.05）。尿液量无显著变化（P>0.05）。
2、东莨菪碱对晕动症行为学的影响统计分析显示，与溶剂组相比，给予东莨菪碱0.5mg/kg和1.0mg/kg后，两个剂量均可以减少粪便颗粒数与24h高岭土摄入量，增加自发活动量和活动次数（P<0.05）。由于灌胃给予溶液的原因，使得所有动物的尿液量均增加（P<0.05）。
3、双侧内耳切除术对晕动症行为学的影响统计分析显示，双侧迷路切除组动物的粪便颗粒数、24h高岭土摄入量、自发活动量和自发活动次数均与静止对照组无明显差别（P>0.05），与晕动刺激对照组有差别（P<0.05）；假手术组动物各指标均与晕动刺激对照组无差别（P>0.05）。
4、适应规律观察实验统计分析显示晕动刺激组和静止对照组动物的粪便颗粒数在晕动刺激第1天到第8天有显著差异（P<0.05），在第9天到第14天无差别（P>0.05）；实时高岭土摄入量在晕动刺激第3天到第27天有显著差异（P<0.05），在第29天到第33天无差别（P>0.05）；24h高岭土摄入量在晕动刺激第3天到第29天有显著差异（P<0.05），在第31天到第33天无差别（P>0.05）。与静止对照组相比，自发活动量和活动次数均在晕动刺激第1、4天降低（P<0.05），第7天恢复到对照组水平（P>0.05）。
5、脱适应规律观察实验粪便颗粒数在脱适应5d仍维持在静止对照组水平（P>0.05），在脱适应7d达到旋转对照组水平。自发活动量和活动次数随着脱适应天数的增加而增加，在第21天显示与旋转对照组无明显差异（P>0.05），这说明其已经达到脱适应水平。其它指标也显示部分脱适应组与对照组有差别，但都没有规律性。
二、前庭核NMDA受体信号通路在晕动症适应-脱适应过程中的作用
1、晕动症适应过程中尾侧前庭核NR1、NR2A/B、GABAAα1蛋白水平和αCaMKII、CREB蛋白磷酸化水平的变化统计分析显示旋转刺激组动物的GABAAα1蛋白水平、αCaMKII蛋白磷酸化水平在晕动刺激第1、4天增加（P<0.05），第7天恢复到静止对照组水平（P>0.05）；CREB蛋白磷酸化水平在晕动刺激第1、4、7、10天增加（P<0.05），第13天恢复到静止对照组水平（P>0.05）；NR1和NR2A/B蛋白水平无显著变化（P>0.05）。
2、晕动症适应过程中尾侧前庭核Fos、Arc和BDNFmRNA表达水平的变化统计分析显示旋转刺激组动物的Fos mRNA表达水平在晕动刺激第1、4天增加（P<0.05），Arc mRNA表达水平在晕动症第1、4天减少（P<0.05），均在第7天恢复到静止对照水平（P>0.05）；BDNF mRNA表达水平无显著变化（P>0.05）。
3、晕动症适应过程中Fos在尾侧前庭核神经元中表达的变化方差分析显示SpVe和MVe中的Fos标记神经元在旋转刺激组和对照组之间均有显著差别（P<0.01）。Dunnett-t test显示在晕动刺激第1、4、7天，Fos标记神经元增加（P<0.05），在刺激第10天起恢复到对照水平（P>0.05）。
4、晕动症适应过程中GABAAα1和Arc在尾侧前庭核神经元中共表达方差分析显示Arc标记神经元、GABAAα1标记神经元和GABAAα1/Arc共标记神经元在旋转刺激组和对照组之间有显著差别（p<0.01）。Dunnett-t test显示在晕动刺激第1、4天，GABAAα1标记神经元增加（P<0.05），Arc标记神经元和GABAAα1/Arc共标记神经元减少（P<0.05），在刺激第7天起恢复到对照水平（P>0.05）。
三、海马NMDA受体信号通路在晕动症适应-脱适应过程中的作用
1、晕动症适应过程中海马NR1、NR2A/B蛋白水平和αCaMKII、CREB蛋白磷酸化水平的变化统计分析显示，旋转刺激组动物αCaMKII蛋白磷酸化水平在晕动刺激第1、4、7、10天无显著变化（P>0.05），第13天升高（P<0.05）；CREB蛋白磷酸化水平在晕动刺激第1、4、7、10天缓慢增加（P>0.05），第13天与静止对照组相比显著升高（P<0.05）；NR1和NR2A/B蛋白水平无显著变化（P>0.05）。
2、晕动症适应过程中海马Fos、Arc和BDNF mRNA表达水平的变化统计分析显示，Fos、Arc、BDNF mRNA表达水平在旋转刺激组和静止对照组之间无明显差别（P>0.05）。
3、晕动症脱适应过程中海马αCaMKII、CREB蛋白磷酸化水平变化统计分析显示，αCaMKII蛋白磷酸化水平在脱适应第1天无明显变化（P>0.05），在第4、7、14天升高（P<0.05），第21天恢复到对照水平（P>0.05）。统计分析显示， CREB蛋白磷酸化水平在晕动刺激第1、4天升高（P<0.05），第7、14、21天恢复到对照水平（P>0.05）。
4、KN-93对晕动症脱适应行为学的影响统计分析显示，粪便颗粒数、自发活动量、活动次数在各时间点的生理盐水组和脱适应组之间均无差别（P>0.05）。抑制剂组动物的粪便颗粒数在脱适应6、8、10d增加（P<0.05），自发活动量在脱适应6、10d降低（P<0.05），活动次数在脱适应6、8、10d降低（P<0.05）。
结论
1、与异嗜高岭土行为比较，排便量和自发活动是大鼠晕动症判断较为敏感和可靠的指标，其中粪便颗粒计数操作简单，不易出现测量误差；晕动刺激后的自发活动也是晕动症敏感的行为学指标，综合运用这些指标有利于提高大鼠晕动症严重程度判断的准确性，是较为可靠的晕动症行为学实验方法；24h高岭土摄入量作为使用广泛的指标，也能反映大鼠晕动症症状，但其表现具有一定的延迟性。
2、粪便颗粒数的适应时间为9d，脱适应时间为7d；自发活动量和活动次数的适应时间为7d，脱适应时间为21d。指标不一致的原因可能是由于中枢神经系统和自主神经系统反映的不一致性引起的，因此，晕动症完全适应时间为9d，完全脱适应时间为21d。
3、在晕动症症状期（1、4d），大鼠尾侧前庭核中CaMKIIα、CREB活性和FosmRNA、蛋白表达水平升高，GABAAα1受体蛋白水平升高，Arc mRNA表达水平下降；在适应期（13d），CaMKIIα活性，Fos、Arc mRNA表达水平和Fos、GABAAα1受体蛋白水平均恢复到对照组水平。并且这些分子的改变与晕动症适应过程中行为学改变有明显相关性，说明大鼠尾侧前庭核中NMDA受体信号通路活性和GABAAα1受体水平的升高与晕动症适应的形成是相关的，可能为晕动症的适应提供了分子基础。
4、在晕动症适应期，大鼠海马中CaMKIIα、CREB活性升高，并一直延续到脱适应期，并于晕动症脱适应行为学改变有一定相关性，采用CaMKIIα抑制剂KN-93预处理可以明显提前晕动症脱适应时间，说明大鼠海马中NMDA受体信号通路活性升高与晕动症适应的维持是相关的，在晕动症适应的维持中起一定作用。
Motion sickness (MS) refers to the normal universal physiological response tounusual perception of motion, whether real or apparent, and remains an important problemin modern traveling activities and virtual reality environments. Prolonged exposure to aprovocative motion stimulus leads to diminution and eventual disappearance of MSreactions. This character of MS was called habituation. Habituation effect would decreaseor even disappear with a long-term absence of stimulus. However, the periodical regularityand central mechanism of these MS characters still remains unclear.
As we know, the vestibular system is the major receptor system of the outsideinformation of acceleration. Glutamate is a major excitatory neurotransmitter of primaryvestibular afferents and N-methyl-D-aspartate (NMDA) type ionotropic glutamatereceptors are abundantly localized in vestibular nucleus neurons. Many studies showed thatNMDA receptor-mediated LTP was the neural basis of learning and memory in the centralnervous system. Studies had also shown that NMDA receptor-mediated intracellular signaltransduction cascade mainly through the activation of NMDA receptors by glutamate, bycalcium/calmodulin-dependent kinase II (Ca2+/CaMKII) pathway, and ultimately activationof cAMP response element binding protein (CREB). Phosphorylation of CREB couldfurther induce the expression of immediate early gene c-fos and brain derived neurotrophicfactor (BDNF) gene and other new genes. In our previous study that Fos protein can beused as a specific molecular marker for activation of vestibular nucleus neurons and theglutamatergic vestibule-visceral projection pathway might be activated during FWLrotation. Moreover, a lot of studies had shown that many connections between thevestibular nucleus complexes were found, and activation of the vestibular system couldaffect hippocampal function and spatial memory. The aim of present study was designed toinvestigate the behavioral changes during repeated rotation treatment, and further examinewhether NMDA signaling pathway involves in motion sickness habituation andde-habituation in rat caudal vestibular nucleus and hippocampus, and finally examine theeffect of blocking the signaling pathway using pharmacological techniques on motion sicknesshabituation and de-habituation.
1.Animal model of motion sickness habituation and dehabituation
1.1Animals and grouping
Adult male Sprague–Dawley (SD) rats weighing220–250g were used in thisexperiment.
1.1.1Long-time experiment
Twenty male SD rats were used in this experiment and divided into rotation group andstatic control group (n=10). They were used to measure the number of fecal granule, thevolume of urine and the amount of kaolin and food intake during the1st,2nd,3rd, and4thhour of consecutive4-hour treatment. Another eighty male rats were randomly divided intoeight groups including rotation groups which received1h,2h,3h and4h rotationstimulation respectively and correspondent static control group without rotation (n=10).Spontaneous activity of each group was measured immediately after treatment.
1.1.2Scopolamine experiment
Thirty male SD rats were used in this experiment. They were divided into threegroups: static control group, rotation control group, and free moving control group inwhich animals were maintained in individual cage without rotation and restraintstimulation (n=10).
Sixty male SD rats were used in this experiment. They were randomly divided intosolvent control group, scopolamine I group (Sco0.5mg/kg) and scopolamine II group (Sco1.0mg/kg)(n=20), in which animals received solvent or scopolamine (i.g.) with the samevolume30minutes before each treatment session and then they were subdivided into staticand rotation groups, respectively (n=10in each subgroup).
1.1.3Labyrinthectomy experiment
Forty male SD rats were used in this experiment. They were randomly divided intobilateral labyrinthectomy group and sham-lesioned group (n=20), in which animalsreceived operation4weeks before experiment started. Then they were subdivided intostatic and rotation groups, respectively (n=10in each subgroup).
1.1.4Habituation experiment
Forty male rats were randomly divided into rotation treatment and static control group. (n=20). Animals in Rot group received daily2-hour static treatment for3days prior to thebeginning of the rotation sessions. Then they were rotated for2-hours per day at the sametime on the following days. Animals in static control group were treated similarly to theRot group except that they were not rotated. Defecation and urination responses and kaolinconsumption were measured daily during3-day prerotation and the following rotationsessions in all animals. To test the spontaneous activity during daily rotation sessions,another100male rats were used and assigned to5rotation groups receiving1,4,7,10and13daily2-hour rotation sessions, respectively and5corresponding Sta control groups(n=10).
1.1.5De-habituation experiment
In this experiment, de-habituation treatment procedure was divided into threedifferent phases—2h/d repeated rotation to achieve habituation, no-rotation to getde-habituation, and re-rotation to test MS symptoms. At first, animals were rotated for2h/d and MS symptoms were measured daily (n=60). When the MS symptoms of animalsrecovered to normal level, rotation treatment ended temporally and animals were assignedto several subgroups which were re-rotated on day5,7,14,21,28and35after habituationachieved, respectively (n=10in each subgroup). In the meantime, another120animalsmatched in age and body weight with de-habituation experiment subgroups were dividedinto5rotation control and5static control groups which were rotated or not on thecorresponding re-rotation day (n=10in each group).
1.2Labyrinthectomy experiment and Sham lesion experiment
Bilateral labyrinthectomy (BL) was performed under anesthesia4weeks beforeexperiment started. In brief, animals were initially anesthetized with sodium pentobarbital(40mg/kg, i.p.). Under an operating microscope, the mastoid was exposed by the retroauricular approach. Dental burr were then used to open the bony horizontal semicircularcanal. Then the membranous labyrinth was surgically removed with a small hook and thenthoroughly destroyed by injection of100%ethanol into the opened bony canal. Tympanicmembrane and ossicular chain remained intact during operation. At the end of surgery,antibiotic powder (Levofloxacin) was topically applied to the opened labyrinth to preventinfection and the temporal bone was sealed with dental cement. The operative wound wassutured and the animal was allowed to recover in the light. For the bilaterallabyrinthectomy, the second operation for controlateral labyrinth was performed24h after the first one. In sham-lesioned (SL) control animals, same procedures as above wereconducted excepted that only the bony horizontal semicircular canal was opened and innerear structure remained intact.
1.3Rotation method and behavioral test
Each conscious rat was rotated by a Forris-wheel like method. The rotation deviceused in the present experiment was modified based on that for cats by Crampton and Lucot.In brief, plexiglass containers suspended on a metal frame revolved about an axis parallelto the floor. Animals in static groups (Sta) were only enclosed in the restrainer for the sameperiod of time as rotation animals but not rotated. The consumption data of kaolin wascollected automated by the Comprehensive Lab Animal Monitoring System (CLAMS;Columbus Instruments, Columbus, OH) daily between10:00–11:00a.m. Spontaneousactivity test over the3min period was recorded using a computer-based event recorder andanalyzed by its software. This test was carried out immediately after the end of everyrotation or static treatment session.
2. Effect of NMDA signaling pathway in vestibular nucleus neuronsduring habituation and de-habituation
2.1Animals and grouping
Adult male Sprague–Dawley (SD) rats weighing220–250g were used. Eighty animalswere used for western blot and real-time quantitative PCR (RT-PCR) test and randomlydivided into five rotation treatment (Rot) groups receiving1,4,7,10or13rotationsessions on a daily basis (2h/d), respectively, and five corresponding static control (Sta)groups (kept in the restrainer near the rotation device when Rot animals were being rotated)(n=8in each group). Forty eight animals were used for immunohistochemistry andimmunofluorescence study and divided into five Rot groups treated the same as above anda Sta group (kept in the restrainer for2h but not rotated)(n=8in each group).
2.2Molecular biology experiment
During habituation and de-habituation treatment procedure, the concentrations ofNMDA R1receptor (NR1), NMDA R2A/B receptor (NR2A/B), GABAAα1, calmodulinprotein kinaseIIα subunit (αCaMKII), phosphorylation of αCaMKII (p-αCaMKII), thenuclear transcription factor cAMP response element-binding (CREB), phosphorylation ofCREB (p-CREB) protein in the caudal vestibular nucleus were assessed by Western blot. Fos, Arc and brain-derived neurotrophic factor (BDNF) mRNA level in the caudalvestibular nucleus were assessed by real-time quantitative PCR. Fos expression in thecaudal vestibular nucleus were analyses by immunohistochemistry. During daily rotationtreatment sessions, co-expression of GABAAα1subunit with Arc in the caudal vestibularnucleus neurons was analyses by immunofluorescence.
3. Effect of NMDA signaling pathway in hippocampal neurons duringhabituation and de-habituation
3.1Animals and grouping
Adult male Sprague–Dawley (SD) rats weighing220–250g were used. Eighty animalswere used for western blot and real-time quantitative PCR (RT-PCR) test and randomlydivided into five rotation treatment (Rot) groups receiving1,4,7,10or13rotationsessions on a daily basis (2h/d), respectively, and five corresponding static control (Sta)groups (kept in the restrainer near the rotation device when Rot animals were being rotated)(n=8in each group).
Thirty animals were divided into five dehabituation groups receiving1,4,7,14or21no rotation sessions after habituation achieved, respectively, and a Sta group (n=5in eachgroup). One hundred and fifty animals were divided into five KN-93(KN) groupsreceiving2,4,6,8,10no rotation sessions after habituation achieved, and fivecorresponding sodium chloride control (SC) groups and five dehabituation control (dehab)groups (n=10in each group). On no rotation day, animals in KN and SC groups weremicroinjected KN-93and sodium chloride into the center of happocampus, respectively.
3.2Microinjection
Rats were anesthetized with diethyl ether and placed in a rodent stereotaxic apparatus.The skin over the skull was incised and burr holes were drilled manually. Needles wereinserted through the burr holes, animals were bilaterally implanted with indwelling guidecannulae stereotaxically aimed center of the hippocampus (coordinates AP3.8mm；ML2.3mm；DV3.0mm from bregma point). Animals were allowed to recover from surgeryduring7days before submitting them to any other procedure. At the time of drug delivery,a infusion cannula was tightly ftted into the guides. Infusions (0.5μl/side) were carried outover60s, frst on one side and then on the other; the infusion cannula was left in place for60additional seconds to minimize backfow.
3.3Behaviour experiment
Rotation produce was same as produce1.4. De-habituation treatment procedure weredescribed in3.1. Fecal granule, total distance and total activity were detected after rotation.
3.4Molecular biology experiment
During habituation and de-habituation treatment procedure, the concentrations of NR1,NR2A/B, αCaMKII, p-αCaMKII, CREB, p-CREB protein in the hippocampus wereassessed by Western blot. Fos, Arc and BDNF mRNA level in the hippocampus wereassessed by real-time quantitative PCR.
4. Statistical analysis
Statistical analysis was performed using the SPSS v13.0statistical program.Two-factorial analysis of variance (ANOVA) was performed using General Linear Protocolto examine whether there were any significant effect of rotation, time and/or interactioneffect of rotation×time throughout the whole treatment process. Bonferroni post hoc testwas used to analyze the difference between Rot and Sta group, when a significant rotation×time interaction effect was obtained. The data for each Rot group were expressed as foldchange of the mean±SEM relative to the mean of the corresponding Sta group inhabituation, de-habituation, western blot and RT-PCR experiments.
In behavioral response experiment, ANOVA and bonferroni post hoc test was used toanalyze the difference between Rot and Sta group. In immunohistochemistry experiment,one-way ANOVA combined with Dunnett-t test was performed to analyze the number ofFos-LI, GABAAα1-LI, GABAAα1/Arc-LI neurons and Arc/neuron in the caudalvestibular nuclei (MVe and SpVe). All data presented were expressed as mean±SEM.Statistical significance was judged at p<0.05.
Results
1.Animal model of motion sickness habituation and dehabituation
1.1Effect of long time on MS behavior index
During4h rotation treatment, the number of fecal granule significantly increased inthe first and second hour (P<0.05) and decreased in the following third and fourth hourcompared with the static control group (P>0.05).24h kaolin consumption increasedthrough the4hours (P<0.05). Other indexes measured per hour showed no difference between rotation and static control data during the consecutive4h rotation (P>0.05). Inspontaneous activity test, the total activity and movement were significantly decreased in1h,2h rotation group compared with corresponding static control group (P<0.05), while itwas increased in3h and4h rotation group and showed no significant difference to staticgroup (P>0.05).
1.2Effect of scopolamine on MS behavior index
Anti-MS medication pretreatment experiment was signed by using a single dose ofscopolamine at0.5or1.0mg/kg (i.g.). Both doses showed effect on decrease in defecationand24h kaolin consumption compared with solvent controls (P<0.05), and they evenrecovered to static control level. However, agent application (solvent or scopolamine)slightly increased the urine volume probably due to the dieresis effect of the solute(P<0.05). In spontaneous activity test, compared to the static control,2h rotation led tosignificant decrease in exploring behavior and total activity (P<0.05). In the meantime,scopolamine treatment at both doses attenuated the reduction effect on spontaneousactivity after rotation compared to the rotation control group.
1.3Effect of labyrinthectomy on MS behavior index
In sham operated animals, compared with static control group, the number of fecalgranules and24h kaolin consumption were increased, and the total activity and movementwas decreased significantly (P<0.05), and reached to the level of rotation control group(P>0.05). In bilateral labyrinthectomy (BL) group, no obvious change of MS symptomsand spontaneous activity was observed after rotation compared with static control group(P>0.05).
1.4Habituation effect on MS behavior index
Statistical analysis found significant difference in number of fecal granules betweenRot and Sta groups from rotation session1to rotation session8(P<0.05), no differencewas found during9-14session (P>0.05). Statistical analysis revealed significant increase indaily24h kaolin consumption of Rot group from rotation session3to rotation session29(P<0.05), when compared with Sta group, while no difference was found when animalsreceived31rotation sessions (P>0.05). There is a significant decrease in total travelingdistance and total activity in animals receiving1and4rotation sessions when compared tocorresponding static controls (P<0.05). It recovered to static control level in animalsreceiving7,10and13rotation sessions (P>0.05).
1.5De-habituation effect on MS behavior index
After9days of2h/d rotation treatment, fecal granule recovered to base level inde-habituation (De-hab) group. It still remained at control level after5days withoutrotation, indicating that the animals maintained habituation state during these days(P>0.05). While, after7days without rotation, re-stimulation induced significant increasein fecal granule back to rotation control (Rot-con) level compared with static control group(P>0.05). Although, other behavior responses also showed some difference betweende-habituation and control groups on certain days after rotation paused, no character ortrend of de-habituation effect was observed. In spontaneous activity test, de-habituationeffect was observed in exploring behavior and total activity after21days without rotation,which recovered to rotation control level but lower than static control level indicated thatmotion sickness signs showed again.
2. Effect of NMDA signaling pathway in vestibular nucleus neuronsduring habituation and de-habituation
2.1Effect of daily rotation on NR1, NR2A/B and GABAAα1protein level andαCaMKII and CREB phosphorylation in the caudal vestibular nucleus
In rat caudal vestibular nucleus, statistical analysis found that GABAAα1andp-αCaMKII/αCaMKII increased significantly in animals receiving1or4rotation sessions(P<0.05) compared with corresponding Sta controls and reduced to baseline level after7sessions (P>0.05). Compared with the Sta control animals, p-CREB/CREB increased inanimals exposed to1,4,7or10rotation sessions (P<0.05) and reduced to baseline levelafter13sessions (P>0.05). There was no significant effect of rotation or time on NR1andNR2A/B level in Rot groups during the whole process during the13rotation sessions(P>0.05).
2.2Effect of daily rotation on Fos, Arc and BDNF mRNA transcription in thecaudal vestibular nucleus
In rat caudal vestibular nucleus, statistical analysis revealed that compared with Stacontrol animals, c-fos mRNA increased in animals exposed to1and4rotation sessions(P<0.05). Arc mRNA decreased in animals exposed to1and4rotation sessions comparedwith corresponding Sta controls (P<0.05). No significant effect of rotation or time on BDNF mRNAlevel was found in Rot groups during the whole process (P>0.05).
2.3Effect of daily rotation on Fos expression in the caudal vestibular nucleus
One-way ANOVA revealed that there was an overall difference in the amount ofFos-LI neurons in the MVe and the SpVe among Rot and Sta control group (P<0.01).Bonferroni post hoc analysis found that the amount of Fos-LI neurons increased in theMVe and the SpVe of animals receiving1,4or7rotation sessions (P<0.05) and reduced tobaseline in animals receiving10,13rotation sessions (P>0.05).
2.4Co-expression of GABAAα1subunit with Arc in the caudal vestibularnucleus neurons during repeated rotation session
One-way ANOVA revealed that the amount of GABAAα1-LI and GABAAα1/Arc-LIneurons and Arc/neuron was significantly different between Rot and Sta control groups(P<0.01). Dunnett-t test analysis found that the number of GABAAα1-LI neurons in thecaudal vestibular nucleus were increased while GABAAα1/Arc-LI neurons and Arc/neuron were decreased in animals receiving1or4rotation sessions (P<0.05) andrecovered to Sta control level in animals receiving more than7rotation sessions (P>0.05).
3. Effect of NMDA signaling pathway in hippocampal neurons duringhabituation and de-habituation
3.1Effect of daily rotation on NR1and NR2A/B protein level and αCaMKIIand CREB phosphorylation in the hippocampus
In rat hippocampus, statistical analysis found that p-αCaMKII/αCaMKII increasedsignificantly in animals receiving13rotation sessions (P<0.05) compared withcorresponding Sta controls, and on day1,4,7,10, it had no change (P>0.05).P-CREB/CREB increased slowly in animals exposed to1,4,7or10rotation sessions(P>0.05) and increased significantly on day13(P<0.05) compared with the Sta controlanimals. There was no significant effect of rotation or time on NR1and NR2A/B level inRot groups during the whole process during the13rotation sessions (P>0.05).
3.2Effect of daily rotation on Fos, Arc and BDNF mRNA transcription in thehippocampus
In rat hippocampus, there was no significant effect of rotation or time on Fos, Arc, BDNF mRNA level in Rot groups during the whole process during the13rotation sessions(P>0.05).
3.3Effect of de-habituation on αCaMKII and CREB phosphorylation in thehippocampus
In rat hippocampus, statistical analysis found that p-αCaMKII/αCaMKII increasedsignificantly in animals after5,7,14day without rotation (P<0.05) compared withcorresponding Sta controls, and reduced to baseline level after21days (P>0.05).Compared with the Sta control animals, p-CREB/CREB increased in animals after1,4daywithout rotation (P<0.05) and reduced to baseline level after7days (P>0.05).
3.4Effect of KN-93on behavior response of MS de-habituation
After9days of2h/d rotation treatment, fecal granule recovered to base level inKN-93(KN) group, sodium chloride control (SC) group and de-habituation control (Dehab)group. As the result of1.5, fecal granule in SC and Dehab group still remained at controllevel after2,4,6days without rotation, indicating that the animals maintained habituationstate during these days (P>0.05). While, after8days without rotation, re-stimulationinduced significant increase in fecal granule back to rotation control level compared withstatic control group (P>0.05). Fecal granule in KN group increased after6days withoutrotation, indicating that de-habituation time was6days. In spontaneous activity test,de-habituation effect was observed in exploring behavior and total activity after6dayswithout rotation, which lower than dehab control group (P<0.05) indicated that motionsickness signs showed again.
Conclusions
1. In the present study, defecation during simulated motion sickness stimulation is asensitive MS specific symptom of rats. It is also suggested that counting the number offecal granule excreted during MS stimulation in rats can be an easy and reliable method forevaluating MS closely related characterizations including habituation and de-habituation.In the meantime, spontaneous activity test immediately after MS stimulation is also aneffective assay indicative of MS development. These indexes could be used to enhance theefficiency for judgment of motion sickness symptom. Pica, which was widely used as aspecie relevant paradigm of motion sickness in rodents by examining the kaolin intakeduring24hours after MS stimulation for many years, did not increase when the rats was firstly exposed to rotation, and not recover as rapidly as other behavioral response.Because of it, pica did not fit to research habituation and de-habituation of motionsickness.
2. In the present study, after repeated exposure to MS stimulation, defecation andspontaneous activity response were gradually alleviated and almost returns to control levelon treatment day9and7, respectively. When the stimulation paused for about7and21days after habituation achieved, defecation and spontaneous activity response wasre-activated back to the pretreatment level indicative of the retrieval of the susceptibility toMS stimulation. Although these two indexes were not consistent with each otherthoroughly on the judgment of habituation and de-habituation progress, it might reflect theasynchronous response of the autonomic nerve system and cerebrum during MSstimulation. In conclusion, habituation time of rat was9days, and de-habituation time was21days.
3. The present study showed that repeated rotation stimulation lead to change inNMDA receptor signaling and GABAAα1receptor expression in caudal vestibular nucleusneurons. During sickness phrase, αCaMKII and CREB activity and Fos mRNA levelincreased; GABAAreceptor α1subunit protein level increased and Arc mRNA leveldecreased. During habituation phrase, αCaMKII activity, Fos and Arc mRNA and GABAAα1protein level recovered back to control level. These results suggested that activation ofNMDA receptor and increment of GABAAα1receptor level in caudal vestibular nucleusassociate with motion sickness habituation development, and may provide a kind ofbiological basis for habituation of motion sickness.
4. In the present study, αCaMKII and CREB activity increased during habituationphrase, and lasted to de-habituation phrase. Microinjection of CaMKII inhibitor KN-93could obviously advance de-habituation time of motion sickness. These results suggestedthat activation of NMDA receptor in rat hippocampus associated with the maintenance ofhabituation, and may play a part in habituation of motion sickness.
方法
一、晕动症适应-脱适应动物模型的建立
1、实验动物及分组550只健康雄性SD大鼠，体重220-250g。
（1）长时刺激实验100只动物完全随机分为10组：旋转刺激4h组，静止对照4h组，1h旋转组，1h静止组，2h旋转组，2h静止组，3h旋转组，3h静止组，4h旋转组，4h静止组，每组10只。前2组记录每小时的实时行为学变化，后8组记录自发活动变化。
（2）东莨菪碱干预实验90只动物完全随机分为9组：自由活动对照组，静止对照组，旋转对照组，东莨菪碱旋转组（ISco0.5mg/kg），东莨菪碱静止组I，东莨菪碱旋转组I（ISco1.0mg/kg），东莨菪碱静止组II，溶剂旋转组，溶剂静止组，每组10只。药物及溶剂组为刺激前30min给药（1ml/只，i.g.）。
（3）双侧迷路切除实验40只动物完全随机分为4组：双侧迷路切除旋转组，双侧迷路切除静止组，假手术旋转组，假手术静止组，每组10只。手术后4周进行刺激实验。
（4）适应规律实验40只动物完全随机分为2组：旋转刺激2h/d组、静止对照2h/d组，每组20只，每天进行模拟晕动刺激，实时观察行为学变化。100只动物完全随机分为10组：旋转刺激2h-1d组、2h-4d组、2h-7d组、2h-10d组、2h-13d组，和与各自时间对应的静止对照组，每组10只，记录自发活动变化。
（5）脱适应规律实验180只动物完全随机分为18组：脱适应5d，7d，14d，21d，28d，35d组及相应天数刺激对照组，静止对照组，每组10只。脱适应组动物首先进行晕动刺激至适应，连续9d，每天2h，后正常饲养至相应脱适应天数，再进行一次2h晕动刺激，记录实时行为学变化和自发活动变化。
2、双侧迷路切除手术及假手术3%戊巴比妥那麻醉后，将大鼠侧卧位置于手术显微镜下，剪开耳后皮肤，钝性分离软组织，暴露外耳道外壁，剪开外耳道，暴露鼓膜及鼓室，观察听小骨清晰后，寻找圆窗及卵圆窗，用五号注射器针头挑开鼓泡，除去部分骨质，用尖头镊探查内耳，剪除内耳骨部，挑出内耳，用左氧氟沙星粉剂敷于内耳，防止感染，缝合外耳道及耳后部皮肤，存活24h后，重新进行另一侧内耳切除手术。假手术过程与双侧内耳切除手术相同，区别在于剪除内耳骨部后，不触及内耳半规管。动物正常饲养恢复4周后，进行旋转刺激。
3、模拟晕动症刺激及行为学测量晕动症模拟器根据Crampton等的报道仿制而成。将代谢盒放入晕动症模拟器的有机玻璃笼内，旋转刺激组大鼠无束缚的放置于代谢盒的铁丝网上进行旋转刺激。实时行为学测量：刺激结束后，立即计量铁丝网上的粪便颗粒数、尿液槽中的尿液量、饲料槽中饲料摄入量、高岭土槽中高岭土摄入量。高岭土摄入量（24h）测量：每天10:00自动动物代谢监测系统（CLAMS）自动记录。自发活动测量：采用DigBehav动物行为分析系统记录动物3min的运动。
二、前庭核NMDA受体信号通路在晕动症适应-脱适应过程中的作用
1、实验动物及分组128只健康雄性SD大鼠，体重220-250g。80只动物完全随机分为10组：旋转刺激组1d，4d，7d，10d，13d及相应的静止对照组，每组8只，用于进行western blot和实时定量PCR实验。48只动物完全随机分为6组：旋转刺激组1d，4d，7d，10d，13d及静止对照组，每组8只，用于进行免疫组织化学及免疫荧光组织化学实验。
2、分子生物学实验采用Western blot法测定尾侧前庭核内NMDA R1受体、NMDA R2A/B受体、GABAAα1亚基、CaMKIIα亚基、磷酸化CaMKIIα亚基、CREB、磷酸化CREB蛋白含量。
采用实时定量PCR法测定尾侧前庭核内Fos、Arc、BDNF mRNA表达水平。
采用免疫组织化学法观察尾侧前庭核内Fos标记神经元数量。
采用免疫荧光组织化学法观察尾侧前庭核内GABAAα1标记神经元、Arc标记神经元、GABAAα1/Arc共标记神经元数量。
三、海马NMDA受体信号通路在晕动症适应-脱适应过程中的作用
1、实验动物及分组260只健康雄性SD大鼠，体重220-250g。80只动物完全随机分为10组：旋转刺激组1d，4d，7d，10d，13d及相应的静止对照组，每组8只，用于进行western blot和实时定量PCR实验。30只动物完全随机分为6组：脱适应组1d，4d，7d，14d，21d及静止对照组（Sta），每组5只，用于进行western blot实验。150只动物完全随机分为15组：抑制剂组2d，4d，6d，8d，10d及相应生理盐水对照组、脱适应对照组，每组10只。
2、双侧海马内微注射3%戊巴比妥那麻醉后，将大鼠头部固定于脑立体定位仪上，切开颅顶部皮肤，暴露前囟点，以前囟点为原点定位双侧海马中心部（AP3.8mm；ML2.3mm；DV3.0mm），打开颅骨，插入进样导管，牙科水泥固定导管于颅骨表面，左氧氟沙星粉剂敷于颅骨表面，缝合颅顶部皮肤，盖上导管帽。后正常饲养7d，前3d每天腹腔注射1ml左氧氟沙星注射液防治感染。乙醚麻醉大鼠后，打开导管帽，以注射管将0.5μl20nmol/μl KN-93缓慢注射至海马中心部，留针1min，缓慢拔针，盖上导管帽。
3、行为学实验旋转刺激同第一部分，所有动物首先进行连续9d，每天2h的晕动刺激至适应；抑制剂组与生理盐水对照组动物每天双侧海马内微注射CaMKII抑制剂KN-93或生理盐水至相应脱适应天数后，进行2h晕动刺激记录实时行为学变化及自发活动变化；脱适应对照组正常饲养至相应脱适应天数后，进行2h晕动刺激记录实时行为学变化及自发活动变化。
4、分子生物学实验采用Western blot法测定海马内NMDA R1受体、NMDA R2A/B、CaMKIIα亚基、磷酸化CaMKII α亚基、CREB、磷酸化CREB蛋白含量。采用实时定量荧光PCR法测定海马内Fos、Arc、BDNF mRNA表达水平。
四、统计学分析采用SPSS v13.0软件进行统计分析。适应规律、脱适应规律、Western blot及PCR实验中，两因素多水平方差分析用来统计整个处理过程中旋转刺激、时间的主因素效应和交互作用效应有无显著性差异。当交互效应存在的情况下，单因素方差分析及Bonferroni检验用来分析相对应的时间点，旋转刺激组和静止对照组之间的差异。行为学指标筛选实验中，方差分析Bonferroni检验用来分析相对应的时间点，旋转刺激组和静止对照组之间的差异。免疫组织化学及免疫荧光组织化学实验中，单因素方差分析及Dunnett-t检验用来统计尾侧前庭核中标记神经元数目有无差别。
结果
一、晕动症适应-脱适应动物模型的建立
1、长时刺激对晕动症行为学的影响统计分析显示，与静止对照组（Sta）相比，粪便颗粒数在刺激的第1、2小时增加（P<0.05），在第3、4小时下降至对照水平（P>0.05）；自发活动量和活动次数均在第1、2小时降低（P<0.05），在第3、4小时上升到接近对照组水平（P>0.05）；24h高岭土摄入量在4h中均增加（P<0.05）。尿液量无显著变化（P>0.05）。
2、东莨菪碱对晕动症行为学的影响统计分析显示，与溶剂组相比，给予东莨菪碱0.5mg/kg和1.0mg/kg后，两个剂量均可以减少粪便颗粒数与24h高岭土摄入量，增加自发活动量和活动次数（P<0.05）。由于灌胃给予溶液的原因，使得所有动物的尿液量均增加（P<0.05）。
3、双侧内耳切除术对晕动症行为学的影响统计分析显示，双侧迷路切除组动物的粪便颗粒数、24h高岭土摄入量、自发活动量和自发活动次数均与静止对照组无明显差别（P>0.05），与晕动刺激对照组有差别（P<0.05）；假手术组动物各指标均与晕动刺激对照组无差别（P>0.05）。
4、适应规律观察实验统计分析显示晕动刺激组和静止对照组动物的粪便颗粒数在晕动刺激第1天到第8天有显著差异（P<0.05），在第9天到第14天无差别（P>0.05）；实时高岭土摄入量在晕动刺激第3天到第27天有显著差异（P<0.05），在第29天到第33天无差别（P>0.05）；24h高岭土摄入量在晕动刺激第3天到第29天有显著差异（P<0.05），在第31天到第33天无差别（P>0.05）。与静止对照组相比，自发活动量和活动次数均在晕动刺激第1、4天降低（P<0.05），第7天恢复到对照组水平（P>0.05）。
5、脱适应规律观察实验粪便颗粒数在脱适应5d仍维持在静止对照组水平（P>0.05），在脱适应7d达到旋转对照组水平。自发活动量和活动次数随着脱适应天数的增加而增加，在第21天显示与旋转对照组无明显差异（P>0.05），这说明其已经达到脱适应水平。其它指标也显示部分脱适应组与对照组有差别，但都没有规律性。
二、前庭核NMDA受体信号通路在晕动症适应-脱适应过程中的作用
1、晕动症适应过程中尾侧前庭核NR1、NR2A/B、GABAAα1蛋白水平和αCaMKII、CREB蛋白磷酸化水平的变化统计分析显示旋转刺激组动物的GABAAα1蛋白水平、αCaMKII蛋白磷酸化水平在晕动刺激第1、4天增加（P<0.05），第7天恢复到静止对照组水平（P>0.05）；CREB蛋白磷酸化水平在晕动刺激第1、4、7、10天增加（P<0.05），第13天恢复到静止对照组水平（P>0.05）；NR1和NR2A/B蛋白水平无显著变化（P>0.05）。
2、晕动症适应过程中尾侧前庭核Fos、Arc和BDNFmRNA表达水平的变化统计分析显示旋转刺激组动物的Fos mRNA表达水平在晕动刺激第1、4天增加（P<0.05），Arc mRNA表达水平在晕动症第1、4天减少（P<0.05），均在第7天恢复到静止对照水平（P>0.05）；BDNF mRNA表达水平无显著变化（P>0.05）。
3、晕动症适应过程中Fos在尾侧前庭核神经元中表达的变化方差分析显示SpVe和MVe中的Fos标记神经元在旋转刺激组和对照组之间均有显著差别（P<0.01）。Dunnett-t test显示在晕动刺激第1、4、7天，Fos标记神经元增加（P<0.05），在刺激第10天起恢复到对照水平（P>0.05）。
4、晕动症适应过程中GABAAα1和Arc在尾侧前庭核神经元中共表达方差分析显示Arc标记神经元、GABAAα1标记神经元和GABAAα1/Arc共标记神经元在旋转刺激组和对照组之间有显著差别（p<0.01）。Dunnett-t test显示在晕动刺激第1、4天，GABAAα1标记神经元增加（P<0.05），Arc标记神经元和GABAAα1/Arc共标记神经元减少（P<0.05），在刺激第7天起恢复到对照水平（P>0.05）。
三、海马NMDA受体信号通路在晕动症适应-脱适应过程中的作用
1、晕动症适应过程中海马NR1、NR2A/B蛋白水平和αCaMKII、CREB蛋白磷酸化水平的变化统计分析显示，旋转刺激组动物αCaMKII蛋白磷酸化水平在晕动刺激第1、4、7、10天无显著变化（P>0.05），第13天升高（P<0.05）；CREB蛋白磷酸化水平在晕动刺激第1、4、7、10天缓慢增加（P>0.05），第13天与静止对照组相比显著升高（P<0.05）；NR1和NR2A/B蛋白水平无显著变化（P>0.05）。
2、晕动症适应过程中海马Fos、Arc和BDNF mRNA表达水平的变化统计分析显示，Fos、Arc、BDNF mRNA表达水平在旋转刺激组和静止对照组之间无明显差别（P>0.05）。
3、晕动症脱适应过程中海马αCaMKII、CREB蛋白磷酸化水平变化统计分析显示，αCaMKII蛋白磷酸化水平在脱适应第1天无明显变化（P>0.05），在第4、7、14天升高（P<0.05），第21天恢复到对照水平（P>0.05）。统计分析显示， CREB蛋白磷酸化水平在晕动刺激第1、4天升高（P<0.05），第7、14、21天恢复到对照水平（P>0.05）。
4、KN-93对晕动症脱适应行为学的影响统计分析显示，粪便颗粒数、自发活动量、活动次数在各时间点的生理盐水组和脱适应组之间均无差别（P>0.05）。抑制剂组动物的粪便颗粒数在脱适应6、8、10d增加（P<0.05），自发活动量在脱适应6、10d降低（P<0.05），活动次数在脱适应6、8、10d降低（P<0.05）。
结论
1、与异嗜高岭土行为比较，排便量和自发活动是大鼠晕动症判断较为敏感和可靠的指标，其中粪便颗粒计数操作简单，不易出现测量误差；晕动刺激后的自发活动也是晕动症敏感的行为学指标，综合运用这些指标有利于提高大鼠晕动症严重程度判断的准确性，是较为可靠的晕动症行为学实验方法；24h高岭土摄入量作为使用广泛的指标，也能反映大鼠晕动症症状，但其表现具有一定的延迟性。
2、粪便颗粒数的适应时间为9d，脱适应时间为7d；自发活动量和活动次数的适应时间为7d，脱适应时间为21d。指标不一致的原因可能是由于中枢神经系统和自主神经系统反映的不一致性引起的，因此，晕动症完全适应时间为9d，完全脱适应时间为21d。
3、在晕动症症状期（1、4d），大鼠尾侧前庭核中CaMKIIα、CREB活性和FosmRNA、蛋白表达水平升高，GABAAα1受体蛋白水平升高，Arc mRNA表达水平下降；在适应期（13d），CaMKIIα活性，Fos、Arc mRNA表达水平和Fos、GABAAα1受体蛋白水平均恢复到对照组水平。并且这些分子的改变与晕动症适应过程中行为学改变有明显相关性，说明大鼠尾侧前庭核中NMDA受体信号通路活性和GABAAα1受体水平的升高与晕动症适应的形成是相关的，可能为晕动症的适应提供了分子基础。
4、在晕动症适应期，大鼠海马中CaMKIIα、CREB活性升高，并一直延续到脱适应期，并于晕动症脱适应行为学改变有一定相关性，采用CaMKIIα抑制剂KN-93预处理可以明显提前晕动症脱适应时间，说明大鼠海马中NMDA受体信号通路活性升高与晕动症适应的维持是相关的，在晕动症适应的维持中起一定作用。
Motion sickness (MS) refers to the normal universal physiological response tounusual perception of motion, whether real or apparent, and remains an important problemin modern traveling activities and virtual reality environments. Prolonged exposure to aprovocative motion stimulus leads to diminution and eventual disappearance of MSreactions. This character of MS was called habituation. Habituation effect would decreaseor even disappear with a long-term absence of stimulus. However, the periodical regularityand central mechanism of these MS characters still remains unclear.
As we know, the vestibular system is the major receptor system of the outsideinformation of acceleration. Glutamate is a major excitatory neurotransmitter of primaryvestibular afferents and N-methyl-D-aspartate (NMDA) type ionotropic glutamatereceptors are abundantly localized in vestibular nucleus neurons. Many studies showed thatNMDA receptor-mediated LTP was the neural basis of learning and memory in the centralnervous system. Studies had also shown that NMDA receptor-mediated intracellular signaltransduction cascade mainly through the activation of NMDA receptors by glutamate, bycalcium/calmodulin-dependent kinase II (Ca2+/CaMKII) pathway, and ultimately activationof cAMP response element binding protein (CREB). Phosphorylation of CREB couldfurther induce the expression of immediate early gene c-fos and brain derived neurotrophicfactor (BDNF) gene and other new genes. In our previous study that Fos protein can beused as a specific molecular marker for activation of vestibular nucleus neurons and theglutamatergic vestibule-visceral projection pathway might be activated during FWLrotation. Moreover, a lot of studies had shown that many connections between thevestibular nucleus complexes were found, and activation of the vestibular system couldaffect hippocampal function and spatial memory. The aim of present study was designed toinvestigate the behavioral changes during repeated rotation treatment, and further examinewhether NMDA signaling pathway involves in motion sickness habituation andde-habituation in rat caudal vestibular nucleus and hippocampus, and finally examine theeffect of blocking the signaling pathway using pharmacological techniques on motion sicknesshabituation and de-habituation.
1.Animal model of motion sickness habituation and dehabituation
1.1Animals and grouping
Adult male Sprague–Dawley (SD) rats weighing220–250g were used in thisexperiment.
1.1.1Long-time experiment
Twenty male SD rats were used in this experiment and divided into rotation group andstatic control group (n=10). They were used to measure the number of fecal granule, thevolume of urine and the amount of kaolin and food intake during the1st,2nd,3rd, and4thhour of consecutive4-hour treatment. Another eighty male rats were randomly divided intoeight groups including rotation groups which received1h,2h,3h and4h rotationstimulation respectively and correspondent static control group without rotation (n=10).Spontaneous activity of each group was measured immediately after treatment.
1.1.2Scopolamine experiment
Thirty male SD rats were used in this experiment. They were divided into threegroups: static control group, rotation control group, and free moving control group inwhich animals were maintained in individual cage without rotation and restraintstimulation (n=10).
Sixty male SD rats were used in this experiment. They were randomly divided intosolvent control group, scopolamine I group (Sco0.5mg/kg) and scopolamine II group (Sco1.0mg/kg)(n=20), in which animals received solvent or scopolamine (i.g.) with the samevolume30minutes before each treatment session and then they were subdivided into staticand rotation groups, respectively (n=10in each subgroup).
1.1.3Labyrinthectomy experiment
Forty male SD rats were used in this experiment. They were randomly divided intobilateral labyrinthectomy group and sham-lesioned group (n=20), in which animalsreceived operation4weeks before experiment started. Then they were subdivided intostatic and rotation groups, respectively (n=10in each subgroup).
1.1.4Habituation experiment
Forty male rats were randomly divided into rotation treatment and static control group. (n=20). Animals in Rot group received daily2-hour static treatment for3days prior to thebeginning of the rotation sessions. Then they were rotated for2-hours per day at the sametime on the following days. Animals in static control group were treated similarly to theRot group except that they were not rotated. Defecation and urination responses and kaolinconsumption were measured daily during3-day prerotation and the following rotationsessions in all animals. To test the spontaneous activity during daily rotation sessions,another100male rats were used and assigned to5rotation groups receiving1,4,7,10and13daily2-hour rotation sessions, respectively and5corresponding Sta control groups(n=10).
1.1.5De-habituation experiment
In this experiment, de-habituation treatment procedure was divided into threedifferent phases—2h/d repeated rotation to achieve habituation, no-rotation to getde-habituation, and re-rotation to test MS symptoms. At first, animals were rotated for2h/d and MS symptoms were measured daily (n=60). When the MS symptoms of animalsrecovered to normal level, rotation treatment ended temporally and animals were assignedto several subgroups which were re-rotated on day5,7,14,21,28and35after habituationachieved, respectively (n=10in each subgroup). In the meantime, another120animalsmatched in age and body weight with de-habituation experiment subgroups were dividedinto5rotation control and5static control groups which were rotated or not on thecorresponding re-rotation day (n=10in each group).
1.2Labyrinthectomy experiment and Sham lesion experiment
Bilateral labyrinthectomy (BL) was performed under anesthesia4weeks beforeexperiment started. In brief, animals were initially anesthetized with sodium pentobarbital(40mg/kg, i.p.). Under an operating microscope, the mastoid was exposed by the retroauricular approach. Dental burr were then used to open the bony horizontal semicircularcanal. Then the membranous labyrinth was surgically removed with a small hook and thenthoroughly destroyed by injection of100%ethanol into the opened bony canal. Tympanicmembrane and ossicular chain remained intact during operation. At the end of surgery,antibiotic powder (Levofloxacin) was topically applied to the opened labyrinth to preventinfection and the temporal bone was sealed with dental cement. The operative wound wassutured and the animal was allowed to recover in the light. For the bilaterallabyrinthectomy, the second operation for controlateral labyrinth was performed24h after the first one. In sham-lesioned (SL) control animals, same procedures as above wereconducted excepted that only the bony horizontal semicircular canal was opened and innerear structure remained intact.
1.3Rotation method and behavioral test
Each conscious rat was rotated by a Forris-wheel like method. The rotation deviceused in the present experiment was modified based on that for cats by Crampton and Lucot.In brief, plexiglass containers suspended on a metal frame revolved about an axis parallelto the floor. Animals in static groups (Sta) were only enclosed in the restrainer for the sameperiod of time as rotation animals but not rotated. The consumption data of kaolin wascollected automated by the Comprehensive Lab Animal Monitoring System (CLAMS;Columbus Instruments, Columbus, OH) daily between10:00–11:00a.m. Spontaneousactivity test over the3min period was recorded using a computer-based event recorder andanalyzed by its software. This test was carried out immediately after the end of everyrotation or static treatment session.
2. Effect of NMDA signaling pathway in vestibular nucleus neuronsduring habituation and de-habituation
2.1Animals and grouping
Adult male Sprague–Dawley (SD) rats weighing220–250g were used. Eighty animalswere used for western blot and real-time quantitative PCR (RT-PCR) test and randomlydivided into five rotation treatment (Rot) groups receiving1,4,7,10or13rotationsessions on a daily basis (2h/d), respectively, and five corresponding static control (Sta)groups (kept in the restrainer near the rotation device when Rot animals were being rotated)(n=8in each group). Forty eight animals were used for immunohistochemistry andimmunofluorescence study and divided into five Rot groups treated the same as above anda Sta group (kept in the restrainer for2h but not rotated)(n=8in each group).
2.2Molecular biology experiment
During habituation and de-habituation treatment procedure, the concentrations ofNMDA R1receptor (NR1), NMDA R2A/B receptor (NR2A/B), GABAAα1, calmodulinprotein kinaseIIα subunit (αCaMKII), phosphorylation of αCaMKII (p-αCaMKII), thenuclear transcription factor cAMP response element-binding (CREB), phosphorylation ofCREB (p-CREB) protein in the caudal vestibular nucleus were assessed by Western blot. Fos, Arc and brain-derived neurotrophic factor (BDNF) mRNA level in the caudalvestibular nucleus were assessed by real-time quantitative PCR. Fos expression in thecaudal vestibular nucleus were analyses by immunohistochemistry. During daily rotationtreatment sessions, co-expression of GABAAα1subunit with Arc in the caudal vestibularnucleus neurons was analyses by immunofluorescence.
3. Effect of NMDA signaling pathway in hippocampal neurons duringhabituation and de-habituation
3.1Animals and grouping
Adult male Sprague–Dawley (SD) rats weighing220–250g were used. Eighty animalswere used for western blot and real-time quantitative PCR (RT-PCR) test and randomlydivided into five rotation treatment (Rot) groups receiving1,4,7,10or13rotationsessions on a daily basis (2h/d), respectively, and five corresponding static control (Sta)groups (kept in the restrainer near the rotation device when Rot animals were being rotated)(n=8in each group).
Thirty animals were divided into five dehabituation groups receiving1,4,7,14or21no rotation sessions after habituation achieved, respectively, and a Sta group (n=5in eachgroup). One hundred and fifty animals were divided into five KN-93(KN) groupsreceiving2,4,6,8,10no rotation sessions after habituation achieved, and fivecorresponding sodium chloride control (SC) groups and five dehabituation control (dehab)groups (n=10in each group). On no rotation day, animals in KN and SC groups weremicroinjected KN-93and sodium chloride into the center of happocampus, respectively.
3.2Microinjection
Rats were anesthetized with diethyl ether and placed in a rodent stereotaxic apparatus.The skin over the skull was incised and burr holes were drilled manually. Needles wereinserted through the burr holes, animals were bilaterally implanted with indwelling guidecannulae stereotaxically aimed center of the hippocampus (coordinates AP3.8mm；ML2.3mm；DV3.0mm from bregma point). Animals were allowed to recover from surgeryduring7days before submitting them to any other procedure. At the time of drug delivery,a infusion cannula was tightly ftted into the guides. Infusions (0.5μl/side) were carried outover60s, frst on one side and then on the other; the infusion cannula was left in place for60additional seconds to minimize backfow.
3.3Behaviour experiment
Rotation produce was same as produce1.4. De-habituation treatment procedure weredescribed in3.1. Fecal granule, total distance and total activity were detected after rotation.
3.4Molecular biology experiment
During habituation and de-habituation treatment procedure, the concentrations of NR1,NR2A/B, αCaMKII, p-αCaMKII, CREB, p-CREB protein in the hippocampus wereassessed by Western blot. Fos, Arc and BDNF mRNA level in the hippocampus wereassessed by real-time quantitative PCR.
4. Statistical analysis
Statistical analysis was performed using the SPSS v13.0statistical program.Two-factorial analysis of variance (ANOVA) was performed using General Linear Protocolto examine whether there were any significant effect of rotation, time and/or interactioneffect of rotation×time throughout the whole treatment process. Bonferroni post hoc testwas used to analyze the difference between Rot and Sta group, when a significant rotation×time interaction effect was obtained. The data for each Rot group were expressed as foldchange of the mean±SEM relative to the mean of the corresponding Sta group inhabituation, de-habituation, western blot and RT-PCR experiments.
In behavioral response experiment, ANOVA and bonferroni post hoc test was used toanalyze the difference between Rot and Sta group. In immunohistochemistry experiment,one-way ANOVA combined with Dunnett-t test was performed to analyze the number ofFos-LI, GABAAα1-LI, GABAAα1/Arc-LI neurons and Arc/neuron in the caudalvestibular nuclei (MVe and SpVe). All data presented were expressed as mean±SEM.Statistical significance was judged at p<0.05.
Results
1.Animal model of motion sickness habituation and dehabituation
1.1Effect of long time on MS behavior index
During4h rotation treatment, the number of fecal granule significantly increased inthe first and second hour (P<0.05) and decreased in the following third and fourth hourcompared with the static control group (P>0.05).24h kaolin consumption increasedthrough the4hours (P<0.05). Other indexes measured per hour showed no difference between rotation and static control data during the consecutive4h rotation (P>0.05). Inspontaneous activity test, the total activity and movement were significantly decreased in1h,2h rotation group compared with corresponding static control group (P<0.05), while itwas increased in3h and4h rotation group and showed no significant difference to staticgroup (P>0.05).
1.2Effect of scopolamine on MS behavior index
Anti-MS medication pretreatment experiment was signed by using a single dose ofscopolamine at0.5or1.0mg/kg (i.g.). Both doses showed effect on decrease in defecationand24h kaolin consumption compared with solvent controls (P<0.05), and they evenrecovered to static control level. However, agent application (solvent or scopolamine)slightly increased the urine volume probably due to the dieresis effect of the solute(P<0.05). In spontaneous activity test, compared to the static control,2h rotation led tosignificant decrease in exploring behavior and total activity (P<0.05). In the meantime,scopolamine treatment at both doses attenuated the reduction effect on spontaneousactivity after rotation compared to the rotation control group.
1.3Effect of labyrinthectomy on MS behavior index
In sham operated animals, compared with static control group, the number of fecalgranules and24h kaolin consumption were increased, and the total activity and movementwas decreased significantly (P<0.05), and reached to the level of rotation control group(P>0.05). In bilateral labyrinthectomy (BL) group, no obvious change of MS symptomsand spontaneous activity was observed after rotation compared with static control group(P>0.05).
1.4Habituation effect on MS behavior index
Statistical analysis found significant difference in number of fecal granules betweenRot and Sta groups from rotation session1to rotation session8(P<0.05), no differencewas found during9-14session (P>0.05). Statistical analysis revealed significant increase indaily24h kaolin consumption of Rot group from rotation session3to rotation session29(P<0.05), when compared with Sta group, while no difference was found when animalsreceived31rotation sessions (P>0.05). There is a significant decrease in total travelingdistance and total activity in animals receiving1and4rotation sessions when compared tocorresponding static controls (P<0.05). It recovered to static control level in animalsreceiving7,10and13rotation sessions (P>0.05).
1.5De-habituation effect on MS behavior index
After9days of2h/d rotation treatment, fecal granule recovered to base level inde-habituation (De-hab) group. It still remained at control level after5days withoutrotation, indicating that the animals maintained habituation state during these days(P>0.05). While, after7days without rotation, re-stimulation induced significant increasein fecal granule back to rotation control (Rot-con) level compared with static control group(P>0.05). Although, other behavior responses also showed some difference betweende-habituation and control groups on certain days after rotation paused, no character ortrend of de-habituation effect was observed. In spontaneous activity test, de-habituationeffect was observed in exploring behavior and total activity after21days without rotation,which recovered to rotation control level but lower than static control level indicated thatmotion sickness signs showed again.
2. Effect of NMDA signaling pathway in vestibular nucleus neuronsduring habituation and de-habituation
2.1Effect of daily rotation on NR1, NR2A/B and GABAAα1protein level andαCaMKII and CREB phosphorylation in the caudal vestibular nucleus
In rat caudal vestibular nucleus, statistical analysis found that GABAAα1andp-αCaMKII/αCaMKII increased significantly in animals receiving1or4rotation sessions(P<0.05) compared with corresponding Sta controls and reduced to baseline level after7sessions (P>0.05). Compared with the Sta control animals, p-CREB/CREB increased inanimals exposed to1,4,7or10rotation sessions (P<0.05) and reduced to baseline levelafter13sessions (P>0.05). There was no significant effect of rotation or time on NR1andNR2A/B level in Rot groups during the whole process during the13rotation sessions(P>0.05).
2.2Effect of daily rotation on Fos, Arc and BDNF mRNA transcription in thecaudal vestibular nucleus
In rat caudal vestibular nucleus, statistical analysis revealed that compared with Stacontrol animals, c-fos mRNA increased in animals exposed to1and4rotation sessions(P<0.05). Arc mRNA decreased in animals exposed to1and4rotation sessions comparedwith corresponding Sta controls (P<0.05). No significant effect of rotation or time on BDNF mRNAlevel was found in Rot groups during the whole process (P>0.05).
2.3Effect of daily rotation on Fos expression in the caudal vestibular nucleus
One-way ANOVA revealed that there was an overall difference in the amount ofFos-LI neurons in the MVe and the SpVe among Rot and Sta control group (P<0.01).Bonferroni post hoc analysis found that the amount of Fos-LI neurons increased in theMVe and the SpVe of animals receiving1,4or7rotation sessions (P<0.05) and reduced tobaseline in animals receiving10,13rotation sessions (P>0.05).
2.4Co-expression of GABAAα1subunit with Arc in the caudal vestibularnucleus neurons during repeated rotation session
One-way ANOVA revealed that the amount of GABAAα1-LI and GABAAα1/Arc-LIneurons and Arc/neuron was significantly different between Rot and Sta control groups(P<0.01). Dunnett-t test analysis found that the number of GABAAα1-LI neurons in thecaudal vestibular nucleus were increased while GABAAα1/Arc-LI neurons and Arc/neuron were decreased in animals receiving1or4rotation sessions (P<0.05) andrecovered to Sta control level in animals receiving more than7rotation sessions (P>0.05).
3. Effect of NMDA signaling pathway in hippocampal neurons duringhabituation and de-habituation
3.1Effect of daily rotation on NR1and NR2A/B protein level and αCaMKIIand CREB phosphorylation in the hippocampus
In rat hippocampus, statistical analysis found that p-αCaMKII/αCaMKII increasedsignificantly in animals receiving13rotation sessions (P<0.05) compared withcorresponding Sta controls, and on day1,4,7,10, it had no change (P>0.05).P-CREB/CREB increased slowly in animals exposed to1,4,7or10rotation sessions(P>0.05) and increased significantly on day13(P<0.05) compared with the Sta controlanimals. There was no significant effect of rotation or time on NR1and NR2A/B level inRot groups during the whole process during the13rotation sessions (P>0.05).
3.2Effect of daily rotation on Fos, Arc and BDNF mRNA transcription in thehippocampus
In rat hippocampus, there was no significant effect of rotation or time on Fos, Arc, BDNF mRNA level in Rot groups during the whole process during the13rotation sessions(P>0.05).
3.3Effect of de-habituation on αCaMKII and CREB phosphorylation in thehippocampus
In rat hippocampus, statistical analysis found that p-αCaMKII/αCaMKII increasedsignificantly in animals after5,7,14day without rotation (P<0.05) compared withcorresponding Sta controls, and reduced to baseline level after21days (P>0.05).Compared with the Sta control animals, p-CREB/CREB increased in animals after1,4daywithout rotation (P<0.05) and reduced to baseline level after7days (P>0.05).
3.4Effect of KN-93on behavior response of MS de-habituation
After9days of2h/d rotation treatment, fecal granule recovered to base level inKN-93(KN) group, sodium chloride control (SC) group and de-habituation control (Dehab)group. As the result of1.5, fecal granule in SC and Dehab group still remained at controllevel after2,4,6days without rotation, indicating that the animals maintained habituationstate during these days (P>0.05). While, after8days without rotation, re-stimulationinduced significant increase in fecal granule back to rotation control level compared withstatic control group (P>0.05). Fecal granule in KN group increased after6days withoutrotation, indicating that de-habituation time was6days. In spontaneous activity test,de-habituation effect was observed in exploring behavior and total activity after6dayswithout rotation, which lower than dehab control group (P<0.05) indicated that motionsickness signs showed again.
Conclusions
1. In the present study, defecation during simulated motion sickness stimulation is asensitive MS specific symptom of rats. It is also suggested that counting the number offecal granule excreted during MS stimulation in rats can be an easy and reliable method forevaluating MS closely related characterizations including habituation and de-habituation.In the meantime, spontaneous activity test immediately after MS stimulation is also aneffective assay indicative of MS development. These indexes could be used to enhance theefficiency for judgment of motion sickness symptom. Pica, which was widely used as aspecie relevant paradigm of motion sickness in rodents by examining the kaolin intakeduring24hours after MS stimulation for many years, did not increase when the rats was firstly exposed to rotation, and not recover as rapidly as other behavioral response.Because of it, pica did not fit to research habituation and de-habituation of motionsickness.
2. In the present study, after repeated exposure to MS stimulation, defecation andspontaneous activity response were gradually alleviated and almost returns to control levelon treatment day9and7, respectively. When the stimulation paused for about7and21days after habituation achieved, defecation and spontaneous activity response wasre-activated back to the pretreatment level indicative of the retrieval of the susceptibility toMS stimulation. Although these two indexes were not consistent with each otherthoroughly on the judgment of habituation and de-habituation progress, it might reflect theasynchronous response of the autonomic nerve system and cerebrum during MSstimulation. In conclusion, habituation time of rat was9days, and de-habituation time was21days.
3. The present study showed that repeated rotation stimulation lead to change inNMDA receptor signaling and GABAAα1receptor expression in caudal vestibular nucleusneurons. During sickness phrase, αCaMKII and CREB activity and Fos mRNA levelincreased; GABAAreceptor α1subunit protein level increased and Arc mRNA leveldecreased. During habituation phrase, αCaMKII activity, Fos and Arc mRNA and GABAAα1protein level recovered back to control level. These results suggested that activation ofNMDA receptor and increment of GABAAα1receptor level in caudal vestibular nucleusassociate with motion sickness habituation development, and may provide a kind ofbiological basis for habituation of motion sickness.
4. In the present study, αCaMKII and CREB activity increased during habituationphrase, and lasted to de-habituation phrase. Microinjection of CaMKII inhibitor KN-93could obviously advance de-habituation time of motion sickness. These results suggestedthat activation of NMDA receptor in rat hippocampus associated with the maintenance ofhabituation, and may play a part in habituation of motion sickness.
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