重复经颅刺激修复老年性痴呆大鼠记忆功能障碍的研究
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摘要
目的：
本论文以老年性痴呆大鼠(AD)为研究对象，从学习记忆行为学和海马神经元平均频率编码及ISI时间编码两个不同层次，探讨低频重复经颅磁刺激对AD大鼠记忆功能障碍的修复作用和可能机制。
方法：
(1)制备模型：将33只SD大鼠随机分为2组，正常对照组8只，另外25只均采用双侧Meynert核微量注射淀粉样蛋白Aβ方法，制备AD大鼠模型，从模型大鼠中随机选择15只做为rTMS组给予rTMS。
(2)施加rTMS：对rTMS组大鼠进行3个干预疗程的低频(1Hz)rTMS，每疗程连续5天，每天给予大鼠1次包含20个脉冲的20串刺激，各疗程间隔2天。刺激强度为0.5Tesla。
(3)Morris水迷宫学习记忆行为测试：在制备模型前、后以及rTMS后分别对正常组、模型组和rTMS组的大鼠进行Morris水迷宫的定向航行实验和空间探索实验。
(4)对各组大鼠海马CA3区进行神经元放电的细胞外记录。对原始信号进行取零均值等信号预处理后，应用Chart5.0软件选取神经元放电序列。
(5)三组大鼠神经元放电时间间隔(ISI)编码模式：将定性的ISI编码中的散点图编码、联合间隔直方图编码定量化，定量方法是采用70％ISI点密集区的I_(max)值来比较各组大鼠神经元放电分布情况。
(5)统计学处理：对三组大鼠的Morris水迷宫学习记忆行为实验结果进行统计比较，定向航行实验应用重复测量的Two-ways ANOVA分析，三组大鼠的空间探索实验数据和三组大鼠神经元放电ISI编码的I_(max)比较使用t test。P＜0.05认为差别有统计学意义。
结果：
(1)AD大鼠模型：
应用以下方法筛选AD大鼠模型：正常大鼠在第二次Morris水迷宫行为学实验中的定向航行实验的所有训练时段的逃避潜伏期平均值为9.17±1.89s，界值为11.06，将注射Aβ的25只大鼠的所有训练时段逃避潜伏期平均值与之比较，25只大鼠中有16只大鼠被选为AD模型大鼠组，AD大鼠模型制备成功率为64％。
(2)Morris水迷宫学习记忆行为实验：
①不同期组间比较：
在定向航行实验中，正常组、AD模型组和rTMS组比较的F值为7.577，P＜0.01。AD模型组的平均逃避潜伏期比正常组的明显延长(P＜0.01)，rTMS组的平均逃避潜伏期比AD模型组和正常组的均明显缩短(P＜0.01)；
空间探索实验中，AD模型组和rTMS组的平台象限游泳时间、平台象限游泳路程占总游泳路程的百分比和3环内记忆得分均比正常组的明显减少(P＜0.05)，rTMS组的平台象限游泳路程占总游泳路程的百分比与AD模型组比较明显减低(P＜0.05)，但平台象限游泳时间、和3环内记忆得分和AD模型组的无差别(P＞0.05)。
③同期组间比较：
定向航行实验中，AD模型大鼠与正常组大鼠的平均逃避潜伏期比较F值为14.48(P＜0.01)；rTMS组的平均逃避潜伏期与AD组的比较F值为5.64(P＜0.05)。
空间探索实验，AD模型组的平台象限游泳时间、平台象限游泳路程占总游泳路程的百分比和3环内记忆得分均比正常组的明显减少(P＜0.05)；rTMS组的平台象限游泳时间、平台象限游泳路程占总游泳路程的百分比和3环内记忆得分与AD组的接近(P＞0.05)。
(3)各组海马神经元放电ISI序列编码：
①ISI随时间变化的直方图编码：
与正常大鼠组ISI的分布状况相比，给予rTMS后AD大鼠海马CA3区ISI分布在100ms的时间间隔内出现的百分比明显减少(P＜0.05)，而在200ms间隔以后出现的百分比非常明显增加(P＜0.05)，而AD大鼠海马CA3区的ISI分布在50ms、100ms、150ms的时间间隔内出现的百分比明显减少(P＜0.05)，在大于200ms的间隔内出现的百分比明显增加(P＜0.05)；与不给予Rtm的AD大鼠相比，给予rTMS后的AD大鼠海马CA3区的ISI分布在100ms的间隔内出现的百分比明显增加(P＜0.05)，在150ms、200ms、250ms的时间间隔内出现的百分比较为接近(P＜0.05)，而在大于300ms的时间间隔内出现的百分比明显减少(P＜0.05)。
②ISI散点图编码：三组海马神经元放电ISI的量化指标结果为，正常组的海马神经元放电序列中，按ISI值从小到大排序，其中70％的ISI点对应的ISI值I_(max)为0.123±0.005ms；rTMS组的为0.163±0.013ms，AD组的为0.239±0.032ms，三组间比较P＜0.01。
③直方图编码：三组海马神经元放电ISI的量化指标结果为，正常组海马神经元放电序列中，凝聚了70％ISI点的I_(max)为0.193±0.019ms，rTMS组的为0.253±0.020ms，AD组的为0.387±0.072ms，三组间比较P＜0.01。
(4)平均频率：
正常大鼠海马神经元放电的平均频率为9.51±0.86Hz，AD大鼠海马神经元放电平均频率为7.54±0.55Hz，rTMS大鼠海马神经元放电平均频率为5.31±0.50Hz，三组间比较P＜0.01。
结论：
(1)采用Meynert核微量注射淀粉样蛋白Aβ成功地制备AD大鼠模型，成功率为64％。支持了胆碱能损伤假说和Aβ级联学说。
(2) Morris水迷宫的定向航行实验和空间探索实验结果验证了AD大鼠的学习记忆能力明显降低，进行rTMS干预后的学习记忆能力有了提高，说明了rTMS对记忆障碍的修复作用。
(3)海马神经元放电ISI编码：三类大鼠ISI编码模式说明AD大鼠神经元放电模式比正常大鼠放电频率降低，放电间隔变大。rTMS组的平均放电频率较模型组增加，正常放电模式趋向正常；AD大鼠海马神经元放电ISI分布比正常大鼠发散，rTMS组大鼠海马神经元放电ISI分布趋于密集。
(4)大鼠海马超微结构：AD大鼠海马有大片神经组织坏死，神经元突起部位大片水肿溶解，染色质聚集成大团块状，尼氏体消失，较多空泡，轴突、树突内线粒体肿胀溶解，微丝稀疏。rTMS组大鼠海马CA3区中可见水肿、坏死的突起部位局限化，周边存在较密集的结构趋向正常的神经元突起，其中可见较多的有板层状嵴的线粒体。
(5) rTMS可以修复AD大鼠的学习记忆功能，可能机制是rTMS通过促进BDNF、sAPP、c-fos等的表达，增加AMPA、NMDA神经递质的活动等机制改善了突触功能，促进神经元的生成并增强其存活能力，导致记忆功能的修复。
Objection:
From the two different view of memory ethology and temporal coding ofhippocampal neuron, the preventing effect of low-frequency repetitive transcranialmagnetic stimulation (rTMS) on dysfunction of memory for Alzheimer's disease (AD)rat model is studied.
Methods:
(1)Making model: 33 normal SD rats were randomly divided into two groups. One isthe control(n=8), the left(n=25) would be microinjected amyloid protein into bilateralMeynert nucleus to make AD rat model. From the AD rat model, 15 rats would bechose to be given rTMS, as rTMS group.
(2)Giving rTMS: 3 sessions of rTMS with frequency of 1Hz were given to the rTMSgroup, with each session including 20 trains with 20 pules of it during continuous 5days. The time of inter-session is 2day. The stimulation intensity is 0.5 Tesla.
(3)Morris water maze test: Befor and after making model, and a third times, aftergiving rTMS, Morris water maze behavioral test, including place navigation andSpatial probe test, were performed among normal control group, AD group and rTMsgroup.
(4)Getting spontaneous spike in hippocampat CA3 neuron: Original signal of all threegroups were recorded using microelectrode extracellular recording technology.Spontaneous spike were chose via Chart5.0 software after pre-disposal.
(5)Temporal coding of interspike interval of spontaneous spike: The qualitativeindex——interspike interval was quantified in scatterplot coding and joint intervalhistogram coding by using I_(MAX) which is the max of interspike interval in 70%intensive point of interspike interval.
(6)Statistics: Repeated Two-ways ANOVA analysis was used to compare the result ofplace navigation of three groups; t test was used to compare the result of spatial probetest and the I_(MAX) of three groups. P＜0.05 means there have statistic meaning.
Results:
(1) AD rat model: AD rat model were chose as followed criteria. The average latencyof all normal rats were 9.17±1.89s, the criteria was 11.06s, and the average latency ofeach rat microinjecting Aβcompared with it. Finally 16 out of 25 rats were regardedas AD rat model. The success rate was 64%.
(2)Morris water maze behavioral test:
①Out of syn comparison among three groups:
In the place navigation, F is 7.58(P＜0.01). The average latency of AD was muchlonger than that of normal group (P＜0.01); the average latency of rTMS group wasmuch decreased than that of normal group and AD group (P＜0.01).
In spatial probe test, the swim time in platform quadrant, the swim distance precentin platform quadrant, the memory mark of 3 circles in AD group and rTMS groupwere much lower than that of normal group (P＜0.05); the corresponding parameter inrTMS group were much lower than that of AD group(P＜0.05).
③Synchronic comparison among three groups:
In place navigation, F between AD and normal group is 14.48 (P＜0.01); F betweenrTMS group and AD group is 5.64(P＜0.05).
In spatial probe test, the swim time in platform quadrant, the swim distance precentin platform quadrant, the memory mark of 3 circles in AD group were much lowerthan that of normal group (P＜0.05); the corresponding parameter in rTMS group weresimilar with that of AD group(P＞0.05).
(3)ISI coding of neuron spike among three groups:
①ISI histogram coding: Comparing with normal spike, the percent of 100ms intervalof ISI in rTMS group decreased markedly, while increased highly in the intervallarger than 200ms; the percent of 50ms、100ms、150ms interval of ISI in AD group decreased highly, much increased in the interval larger than 200ms. Comparing withAD group, the percent of 100ms interval of ISI in rTMS group increased markedly,similar at the interval of 150ms、200ms、250ms,decreased highly at the interval largerthan 300ms. (All: P＜0.05)
②ISI scatterplot coding: I_(max) in normal group, AD group and rTMS group wererespectively 0.123±0.005ms, 0.163±0.013ms, 0.239±0.032ms. P＜0.01③ISI histogram coding: I_(max) in normal group, AD group and rTMS group wererespectively 0.193±0.019ms, 0.253±0.020ms, 0.387±0.072ms. P＜0.01(4)average frequency coding: The average frequency coding of normal group, ADgroup and rTMS group were respectively 9.51±0.86Hz, 7.54±0.55Hz, 5.31±0.50Hz.P＜0.01
Conclusion:
(1) The AD rat model was successfully made via microinjecting Aβinto bilateralMeynert nucleus, with rate of 64%, which support the cholinergic damaged theoryand Aβdeposited theory.
(2)Learning and memory of the AD rat model decreased markedly, and improvedafter rTMS verified by the result of place navigation and spatial probe test of Morriswater maze, indicating that rTMS can repair the failed learning and memory.
(3)From the ISI coding mode of three group rats, the spike mode of AD rats presentlower spike frequency and larger interspike interval. While the spike mode of rTMSrats shows increasing spike frequency and shorter interspike interval; The ISIdistribution of AD rats scattered more than normal rats, while rTMS rats show theassembly trend toward normal rats.
(4)The ultrastructure of hippocampus: There are bulks of cellular necrosis, neurite edema, and lack of tigroid body, much vacuole, swelled and dissolved chondrosome,and rare microfilament in hippocampus of AD rat model. After rTMS, edemalocalized, and conferted neurite including chondrosome with cristal could be seenhere and there around edema area.
(5) rTMS can improve the learning and memory function of AD rat. The probablereason is that rTMS could promote the expression of BDNF, c-fos and sAPP; andincrease the activation of AMPA and NMDA in hippocampus. In all, rTMS canimprove the memory failure in AD rat.
本论文以老年性痴呆大鼠(AD)为研究对象，从学习记忆行为学和海马神经元平均频率编码及ISI时间编码两个不同层次，探讨低频重复经颅磁刺激对AD大鼠记忆功能障碍的修复作用和可能机制。
方法：
(1)制备模型：将33只SD大鼠随机分为2组，正常对照组8只，另外25只均采用双侧Meynert核微量注射淀粉样蛋白Aβ方法，制备AD大鼠模型，从模型大鼠中随机选择15只做为rTMS组给予rTMS。
(2)施加rTMS：对rTMS组大鼠进行3个干预疗程的低频(1Hz)rTMS，每疗程连续5天，每天给予大鼠1次包含20个脉冲的20串刺激，各疗程间隔2天。刺激强度为0.5Tesla。
(3)Morris水迷宫学习记忆行为测试：在制备模型前、后以及rTMS后分别对正常组、模型组和rTMS组的大鼠进行Morris水迷宫的定向航行实验和空间探索实验。
(4)对各组大鼠海马CA3区进行神经元放电的细胞外记录。对原始信号进行取零均值等信号预处理后，应用Chart5.0软件选取神经元放电序列。
(5)三组大鼠神经元放电时间间隔(ISI)编码模式：将定性的ISI编码中的散点图编码、联合间隔直方图编码定量化，定量方法是采用70％ISI点密集区的I_(max)值来比较各组大鼠神经元放电分布情况。
(5)统计学处理：对三组大鼠的Morris水迷宫学习记忆行为实验结果进行统计比较，定向航行实验应用重复测量的Two-ways ANOVA分析，三组大鼠的空间探索实验数据和三组大鼠神经元放电ISI编码的I_(max)比较使用t test。P＜0.05认为差别有统计学意义。
结果：
(1)AD大鼠模型：
应用以下方法筛选AD大鼠模型：正常大鼠在第二次Morris水迷宫行为学实验中的定向航行实验的所有训练时段的逃避潜伏期平均值为9.17±1.89s，界值为11.06，将注射Aβ的25只大鼠的所有训练时段逃避潜伏期平均值与之比较，25只大鼠中有16只大鼠被选为AD模型大鼠组，AD大鼠模型制备成功率为64％。
(2)Morris水迷宫学习记忆行为实验：
①不同期组间比较：
在定向航行实验中，正常组、AD模型组和rTMS组比较的F值为7.577，P＜0.01。AD模型组的平均逃避潜伏期比正常组的明显延长(P＜0.01)，rTMS组的平均逃避潜伏期比AD模型组和正常组的均明显缩短(P＜0.01)；
空间探索实验中，AD模型组和rTMS组的平台象限游泳时间、平台象限游泳路程占总游泳路程的百分比和3环内记忆得分均比正常组的明显减少(P＜0.05)，rTMS组的平台象限游泳路程占总游泳路程的百分比与AD模型组比较明显减低(P＜0.05)，但平台象限游泳时间、和3环内记忆得分和AD模型组的无差别(P＞0.05)。
③同期组间比较：
定向航行实验中，AD模型大鼠与正常组大鼠的平均逃避潜伏期比较F值为14.48(P＜0.01)；rTMS组的平均逃避潜伏期与AD组的比较F值为5.64(P＜0.05)。
空间探索实验，AD模型组的平台象限游泳时间、平台象限游泳路程占总游泳路程的百分比和3环内记忆得分均比正常组的明显减少(P＜0.05)；rTMS组的平台象限游泳时间、平台象限游泳路程占总游泳路程的百分比和3环内记忆得分与AD组的接近(P＞0.05)。
(3)各组海马神经元放电ISI序列编码：
①ISI随时间变化的直方图编码：
与正常大鼠组ISI的分布状况相比，给予rTMS后AD大鼠海马CA3区ISI分布在100ms的时间间隔内出现的百分比明显减少(P＜0.05)，而在200ms间隔以后出现的百分比非常明显增加(P＜0.05)，而AD大鼠海马CA3区的ISI分布在50ms、100ms、150ms的时间间隔内出现的百分比明显减少(P＜0.05)，在大于200ms的间隔内出现的百分比明显增加(P＜0.05)；与不给予Rtm的AD大鼠相比，给予rTMS后的AD大鼠海马CA3区的ISI分布在100ms的间隔内出现的百分比明显增加(P＜0.05)，在150ms、200ms、250ms的时间间隔内出现的百分比较为接近(P＜0.05)，而在大于300ms的时间间隔内出现的百分比明显减少(P＜0.05)。
②ISI散点图编码：三组海马神经元放电ISI的量化指标结果为，正常组的海马神经元放电序列中，按ISI值从小到大排序，其中70％的ISI点对应的ISI值I_(max)为0.123±0.005ms；rTMS组的为0.163±0.013ms，AD组的为0.239±0.032ms，三组间比较P＜0.01。
③直方图编码：三组海马神经元放电ISI的量化指标结果为，正常组海马神经元放电序列中，凝聚了70％ISI点的I_(max)为0.193±0.019ms，rTMS组的为0.253±0.020ms，AD组的为0.387±0.072ms，三组间比较P＜0.01。
(4)平均频率：
正常大鼠海马神经元放电的平均频率为9.51±0.86Hz，AD大鼠海马神经元放电平均频率为7.54±0.55Hz，rTMS大鼠海马神经元放电平均频率为5.31±0.50Hz，三组间比较P＜0.01。
结论：
(1)采用Meynert核微量注射淀粉样蛋白Aβ成功地制备AD大鼠模型，成功率为64％。支持了胆碱能损伤假说和Aβ级联学说。
(2) Morris水迷宫的定向航行实验和空间探索实验结果验证了AD大鼠的学习记忆能力明显降低，进行rTMS干预后的学习记忆能力有了提高，说明了rTMS对记忆障碍的修复作用。
(3)海马神经元放电ISI编码：三类大鼠ISI编码模式说明AD大鼠神经元放电模式比正常大鼠放电频率降低，放电间隔变大。rTMS组的平均放电频率较模型组增加，正常放电模式趋向正常；AD大鼠海马神经元放电ISI分布比正常大鼠发散，rTMS组大鼠海马神经元放电ISI分布趋于密集。
(4)大鼠海马超微结构：AD大鼠海马有大片神经组织坏死，神经元突起部位大片水肿溶解，染色质聚集成大团块状，尼氏体消失，较多空泡，轴突、树突内线粒体肿胀溶解，微丝稀疏。rTMS组大鼠海马CA3区中可见水肿、坏死的突起部位局限化，周边存在较密集的结构趋向正常的神经元突起，其中可见较多的有板层状嵴的线粒体。
(5) rTMS可以修复AD大鼠的学习记忆功能，可能机制是rTMS通过促进BDNF、sAPP、c-fos等的表达，增加AMPA、NMDA神经递质的活动等机制改善了突触功能，促进神经元的生成并增强其存活能力，导致记忆功能的修复。
Objection:
From the two different view of memory ethology and temporal coding ofhippocampal neuron, the preventing effect of low-frequency repetitive transcranialmagnetic stimulation (rTMS) on dysfunction of memory for Alzheimer's disease (AD)rat model is studied.
Methods:
(1)Making model: 33 normal SD rats were randomly divided into two groups. One isthe control(n=8), the left(n=25) would be microinjected amyloid protein into bilateralMeynert nucleus to make AD rat model. From the AD rat model, 15 rats would bechose to be given rTMS, as rTMS group.
(2)Giving rTMS: 3 sessions of rTMS with frequency of 1Hz were given to the rTMSgroup, with each session including 20 trains with 20 pules of it during continuous 5days. The time of inter-session is 2day. The stimulation intensity is 0.5 Tesla.
(3)Morris water maze test: Befor and after making model, and a third times, aftergiving rTMS, Morris water maze behavioral test, including place navigation andSpatial probe test, were performed among normal control group, AD group and rTMsgroup.
(4)Getting spontaneous spike in hippocampat CA3 neuron: Original signal of all threegroups were recorded using microelectrode extracellular recording technology.Spontaneous spike were chose via Chart5.0 software after pre-disposal.
(5)Temporal coding of interspike interval of spontaneous spike: The qualitativeindex——interspike interval was quantified in scatterplot coding and joint intervalhistogram coding by using I_(MAX) which is the max of interspike interval in 70%intensive point of interspike interval.
(6)Statistics: Repeated Two-ways ANOVA analysis was used to compare the result ofplace navigation of three groups; t test was used to compare the result of spatial probetest and the I_(MAX) of three groups. P＜0.05 means there have statistic meaning.
Results:
(1) AD rat model: AD rat model were chose as followed criteria. The average latencyof all normal rats were 9.17±1.89s, the criteria was 11.06s, and the average latency ofeach rat microinjecting Aβcompared with it. Finally 16 out of 25 rats were regardedas AD rat model. The success rate was 64%.
(2)Morris water maze behavioral test:
①Out of syn comparison among three groups:
In the place navigation, F is 7.58(P＜0.01). The average latency of AD was muchlonger than that of normal group (P＜0.01); the average latency of rTMS group wasmuch decreased than that of normal group and AD group (P＜0.01).
In spatial probe test, the swim time in platform quadrant, the swim distance precentin platform quadrant, the memory mark of 3 circles in AD group and rTMS groupwere much lower than that of normal group (P＜0.05); the corresponding parameter inrTMS group were much lower than that of AD group(P＜0.05).
③Synchronic comparison among three groups:
In place navigation, F between AD and normal group is 14.48 (P＜0.01); F betweenrTMS group and AD group is 5.64(P＜0.05).
In spatial probe test, the swim time in platform quadrant, the swim distance precentin platform quadrant, the memory mark of 3 circles in AD group were much lowerthan that of normal group (P＜0.05); the corresponding parameter in rTMS group weresimilar with that of AD group(P＞0.05).
(3)ISI coding of neuron spike among three groups:
①ISI histogram coding: Comparing with normal spike, the percent of 100ms intervalof ISI in rTMS group decreased markedly, while increased highly in the intervallarger than 200ms; the percent of 50ms、100ms、150ms interval of ISI in AD group decreased highly, much increased in the interval larger than 200ms. Comparing withAD group, the percent of 100ms interval of ISI in rTMS group increased markedly,similar at the interval of 150ms、200ms、250ms,decreased highly at the interval largerthan 300ms. (All: P＜0.05)
②ISI scatterplot coding: I_(max) in normal group, AD group and rTMS group wererespectively 0.123±0.005ms, 0.163±0.013ms, 0.239±0.032ms. P＜0.01③ISI histogram coding: I_(max) in normal group, AD group and rTMS group wererespectively 0.193±0.019ms, 0.253±0.020ms, 0.387±0.072ms. P＜0.01(4)average frequency coding: The average frequency coding of normal group, ADgroup and rTMS group were respectively 9.51±0.86Hz, 7.54±0.55Hz, 5.31±0.50Hz.P＜0.01
Conclusion:
(1) The AD rat model was successfully made via microinjecting Aβinto bilateralMeynert nucleus, with rate of 64%, which support the cholinergic damaged theoryand Aβdeposited theory.
(2)Learning and memory of the AD rat model decreased markedly, and improvedafter rTMS verified by the result of place navigation and spatial probe test of Morriswater maze, indicating that rTMS can repair the failed learning and memory.
(3)From the ISI coding mode of three group rats, the spike mode of AD rats presentlower spike frequency and larger interspike interval. While the spike mode of rTMSrats shows increasing spike frequency and shorter interspike interval; The ISIdistribution of AD rats scattered more than normal rats, while rTMS rats show theassembly trend toward normal rats.
(4)The ultrastructure of hippocampus: There are bulks of cellular necrosis, neurite edema, and lack of tigroid body, much vacuole, swelled and dissolved chondrosome,and rare microfilament in hippocampus of AD rat model. After rTMS, edemalocalized, and conferted neurite including chondrosome with cristal could be seenhere and there around edema area.
(5) rTMS can improve the learning and memory function of AD rat. The probablereason is that rTMS could promote the expression of BDNF, c-fos and sAPP; andincrease the activation of AMPA and NMDA in hippocampus. In all, rTMS canimprove the memory failure in AD rat.
引文
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