探索学习对局灶性脑梗死大鼠行为学恢复及巢蛋白、神经生长因子、突触素表达的影响
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摘要
目的:脑血管意外是一类发病率、死亡率和致残率都很高的疾病,在中国,脑血管意外的致残率在众多疾病中居于首位,其发展快、恢复慢和高死亡率、致残率的特点,给患者和家庭、社会带来了极大的痛苦和沉重负担。有研究表明,康复治疗对缺血性脑梗死的患者在改善感觉、运动及行为能力方面已获得明显的疗效。长期以来,综合运用各种康复手段治疗疾病是康复医学理论的一个重要指导思想。在脑缺血动物实验方面,研究者们同样综合使用运动训练、丰富环境和药物辅助等方法观察疗效。在实验性卒中研究资料中,有确凿的证据表明将大鼠饲养于丰富环境中,即动物有机会进行社会交往,探索和进行各种体力活动,但不进行特殊训练,与饲养在标准的实验环境中相比,其功能后果改善更明显。
众所周知,中枢神经系统(central nerve system,CNS)具有可塑性。目前认为脑损伤后功能恢复与脑的结构和功能可塑性有关,且已发现一些可塑性相关分子。近十几年来,人们发现在成年脑组织内存在具有多种分化潜能的神经干细胞(neural stem cell,NSC),正常情况下处于静息状态,当其所处的微环境发生改变或在外来信号的刺激下,能自我更新,并在一定条件下分化为神经元、星形胶质细胞和少突胶质细胞,参与神经系统的修复,这表明了CNS具有一定自我修复潜能。脑缺血是引起神经功能障碍的常见病因,因此研究脑缺血后体内NSC的反应,具有重要的临床意义。巢蛋白(nestin)被认为是神经前体细胞的标志,已广泛用于NSC的鉴定。神经生长因子(nerve growth factor,NGF)具有促进神经细胞生长同时可以诱导NSC迁移的作用。突触素(synaptophysin,SYN)与神经递质的释放、突触形成及突触小泡离子通道密切相关,通过检测SYN表达含量的多少可直接反映突触功能。目前尚未见探索学习对实验性脑梗死大鼠脑内nestin、NGF、SYN影响的报道。阐明探索学习对脑损伤功能恢复的作用及其机理,对更科学地制定康复策略具有非常重要的意义。
方法:健康雄性SD大鼠80只,其中60只电凝法造成右侧大脑中动脉阻断(middle cerebral artery occlusion,MCAO)模型后,随机分为探索学习组(n=30)、对照组(n=30)。探索学习组15只一组群居于迷宫笼,对照组5只一组群居于标准笼。假手术组(n=20)仅开颅不电凝大脑中动脉,居于标准笼。各组随机选取15只在术后1天、7天、14天、28天进行行为学评测,21天始进行水迷宫评测。对照组与探索学习组于造模后1天、7天、14天及28天各取5只,假手术组于造模后7天、28天各取5只处死,剖颅取脑,石蜡包埋。用免疫组化染色观察梗死灶周围皮质nestin、NGF阳性细胞数及梗死灶周围皮质、海马CA3区SYN光密度。
结果:行为学评分:1.造模成功与否的判断:造模后1天,脑梗死大鼠均出现明显的偏瘫体征,Berderson评分多为2分,假手术组大鼠无明显异常。2. Berderson神经功能评分:造模后1～7天探索学习组与对照组评分差异无显著性意义(P>0.05),探索学习组于14～28天恢复明显优于对照组(P<0.05)。3.肌力测验及平衡木行走测验:造模后脑梗死大鼠均出现肌力、平衡木行走能力下降,造模后1～7天探索学习组与对照组评分差异无显著性意义(P>0.05),探索学习组于14～28天恢复明显优于对照组(P<0.05)。假手术组大鼠无明显异常。4.水迷宫试验:从潜伏期的变化可见,与假手术组比较,脑梗死大鼠第21～25天到达平台的潜伏期明显延长(P<0.05)。与对照组比较,探索学习组大鼠第21～25天达到平台的潜伏期明显缩短(P<0.05)。脑梗死大鼠测试前三天潜伏期迅速下降,从第24天开始趋于平缓。
nestin阳性细胞数的时程变化:假手术组大鼠可见少量nestin表达。脑梗死大鼠于造模后第7天阳性细胞最多,第14天和第28天阳性细胞逐渐减少。造模后7天和14天,探索学习组大鼠nestin阳性细胞较对照组增多有显著性差异(P<0.05)。而缺血后28天探索学习组与对照组阳性细胞数无显著差异(P>0.05)。
NGF的时程变化:假手术组大鼠可见少量NGF表达。脑梗死大鼠于造模后1天即可见NGF表达增加,于第7天达峰值,探索学习组较对照组增多有显著性差异(P<0.05),此后两组的NGF表达均呈下降趋势,于28天两组无明显差别(P>0.05)。
SYN光密度的时程变化:假手术组可见SYN呈点状或颗粒样分布。脑梗死大鼠的SYN表达在造模后7天已有所增加,探索学习组及对照组之间无明显差异(P>0.05)。第14天表达明显增强,28天最强。探索学习组SYN的表达在第14、28天较对照组有明显增强,两组之间差别显著(P<0.05)。
结论:
1.本研究采用开颅电凝嗅束近端至大脑下静脉之间一段MCA的方法,成功地制作了大鼠大脑中动脉分布区局灶性脑梗死模型。
2.局灶性脑梗死后给予探索学习可促进大鼠行为学和空间记忆能力的恢复。
3. nestin是NSC的标志,在脑损伤的修复中发挥重要作用。探索学习可增强局灶性脑梗死大鼠nestin的表达。
4. NGF是神经系统重要的生物活性分子,维持神经系统正常的生物学功能,参与损伤神经的再生与功能重组。探索学习促进了局灶性脑梗死后大鼠NGF的表达。
5. SYN与神经生长、修复、再生和突触重塑密切相关。脑梗死可使SYN表达升高,探索学习促进了SYN表达的增加。
Objective : Cerebral vascular accident is a common disease with a high rate of morbidity, mortality and mutilation. In China, the mutilation rate of cerebral vascular is the highest in the numerous diseases. The feature with fast developing, slow recovery and high rate of mortality, mutilation take galactic suffering and heavy burden to the patients, their family and society. The recent studies suggest that rehabilitative treatment has gained evident therapeutic effect in improving the sensation, movement and capability of patients with cerebral infarction. It is a important guidance thinking of rehabilitation medicine theory that making use of comprehensive rehabilitation maneuvers to treat the patients since a long-term ago. Samely in the animal experiments of cerebral ischemia, the researchers utilized movement training, enriched environment and medicine synthetically to observe therapeutic effect. In the animal experiments, there were irrefutably evidence indicated that: rats reared in enriched environment (EE) after MCAO revovered better than reared in standard environment. In the enriched environment, rats have the more chance for social communication, learning and various kinds of physical activity, but no special training.
CNS plasticity is well known. At present thinking, the functional recovery post brain injury relates to the plasticity of brain structure and function, furthermore, some factors relate to plasticity have been discovered. For the recent years, people found that NSC possess various differentiated potentiality in the adult brain tissue. They occupy resting state in the standard condition, and self-renew when it comes foreign signal or the microenviorenment changing. Then they differentiate into neuron, astrocyte and oligodendrocyte in some conditions, and participate to the neurologic recovery. All of these indicate that the CNS has self recovery potentiality. Cerebral ischemia is the common factor that can cause nervous disfunction, so it is important to study and reaserch the reaction of NSC post cerebral ischemia. Nestin is known as the marker of nerve precursor cell, and utended as identifying NSC generally. NGF can promote nerve cell growth, and induce NSC migration. SYN correlates to neurotransmitter releasing, synapse formation and synaptic vesicle ion channel. The expression of SYN can reflect synapse function directly. There was no report about the effects of learning on nestin, NGF, SYN in rats after experimental cerebral infarction at present. Elucidating the effect of learning on functional recovery post brain injury and the mechanism is very significant for formulating rehabilitative strategy successfully.
Methods: 80 male Sprague-Dawley rats were adopted. After making the model of MCAO by electric coagulation successfully, 60 rats were divided into learning group (n=30, 15 as a group living in a maze cage), control group (n=30, 5 as a group living in a standard cage) randomly. Other 20 rats as sham group living in standard cage. 15 rats were chosen randomly from each group respectively for Berderson test at the 1st, 7th, 14th, 28th day after operation, and water maze test from 21st day after operation. At the 1st, 7th, 14th, 28th day after MCAO, 5 rats were randomly killed respectively in learning group and control group. 5 rats in sham group were randomly killed separately at the 7th, 28th day after operation. The expression of nestin, NGF in the peri-ischemic cortex and synaptophysin in the peri-ischemic cortex , CA3 area of hippocampus were examined using immunohistochemistry straining.
Results: 1.After MCAO, severe impairment of function occurred in operated groups and there was no significant abnormal in sham group. 2.Berderson test: In 1-7 days after MCAO, there were no significant difference among the operated groups (P>0.05). Since 14 to 28 days learning group scored better than control group (P<0.05). 3.Result of manual muscle test and balancing wood: The result of manual muscle test and balancing wood decreased in all the MCAO rats after operation. In 1-7 days after MCAO, there were no significant difference among the operated groups (P>0.05). Since 14 to 28 days learning group scored better than control group (P<0.05). There was no apparent abnormality in the sham group. 4.Water maze test: It is thus clear that the latent phase of the operated groups were longer than the sham group since 21st to 25th day in the testing phase (P<0.05). Compared to the control group, the latent phase of learning group was shorter since 21st to 25th day in the testing phase (P<0.05). The latent phase of the operated groups decrease quickly in the first 3 days, then tended to stable since the 24th day, and maintained at a constancy level.
The expression of nestin: Small amounts of nestin expressed in the sham group. The time distribution of nestin in the MCAO rats showed that the number of nestin labeled cells got to the peak at the 7th day and decreased since 14th to 28th day after operation. In the learning group, the expression was higher than the control group at 7th and 14th day after operation (P<0.05), and no significant difference at 28th day (P>0.05).
The expression of nerve growth factor: Small amounts of nerve growth factor expressed in the sham group. The expression of nerve grwoth factor increased at the 1st day after operation, and got to the peak at the 7th day. There was significant difference between learnig group and control group at 7th day (P<0.05). Then the expression of nerve growth factor decreased in the operated groups, and no significant difference between two groups at 28th day (P>0.05).
The expression of synaptophysin: Small amounts of synaptophysin expressed in the sham group. The expression of synaptophysin in the MCAO rats increased at the 7th day after operation, and no significant difference between two groups (P>0.05). The expression increased obviously at 14th day and got to peak at 28th day in learning group and control group. There was significant difference between learnig group and control group at 14th day and 28th day (P<0.05).
Conclusions:
1. Modle of MCAO was made successfully by occluding MCA from the olfactory tract to lateral inferior cerebral vein with electric coagulation.
2. Learning could enhance the functional recovery of local infarcted rats.
3. Nestin is the identification marker of nerve stem cells, and it is important on recovery post brain injure. Learning could promote the expression of nestin in the rat post local cerebral infarction.
4. Nerve growth factor is a important bioactive molecule in the nervous system. It maintains the normal biological function of the nervous system, and participates the regeneration and the fuctional recombination of the injured nerve. Learning could promote the expression of nerve growth factor in the rat post local cerebral infarction.
5. Synaptophysin correlates to nerves growth, recovery, regeneration and synapsis remodeling closely. Cerebral infarction can promote the expression of synaptophysin. Learning could promote the expression of synaptophysin in the rat post local cerebral infarction.
众所周知,中枢神经系统(central nerve system,CNS)具有可塑性。目前认为脑损伤后功能恢复与脑的结构和功能可塑性有关,且已发现一些可塑性相关分子。近十几年来,人们发现在成年脑组织内存在具有多种分化潜能的神经干细胞(neural stem cell,NSC),正常情况下处于静息状态,当其所处的微环境发生改变或在外来信号的刺激下,能自我更新,并在一定条件下分化为神经元、星形胶质细胞和少突胶质细胞,参与神经系统的修复,这表明了CNS具有一定自我修复潜能。脑缺血是引起神经功能障碍的常见病因,因此研究脑缺血后体内NSC的反应,具有重要的临床意义。巢蛋白(nestin)被认为是神经前体细胞的标志,已广泛用于NSC的鉴定。神经生长因子(nerve growth factor,NGF)具有促进神经细胞生长同时可以诱导NSC迁移的作用。突触素(synaptophysin,SYN)与神经递质的释放、突触形成及突触小泡离子通道密切相关,通过检测SYN表达含量的多少可直接反映突触功能。目前尚未见探索学习对实验性脑梗死大鼠脑内nestin、NGF、SYN影响的报道。阐明探索学习对脑损伤功能恢复的作用及其机理,对更科学地制定康复策略具有非常重要的意义。
方法:健康雄性SD大鼠80只,其中60只电凝法造成右侧大脑中动脉阻断(middle cerebral artery occlusion,MCAO)模型后,随机分为探索学习组(n=30)、对照组(n=30)。探索学习组15只一组群居于迷宫笼,对照组5只一组群居于标准笼。假手术组(n=20)仅开颅不电凝大脑中动脉,居于标准笼。各组随机选取15只在术后1天、7天、14天、28天进行行为学评测,21天始进行水迷宫评测。对照组与探索学习组于造模后1天、7天、14天及28天各取5只,假手术组于造模后7天、28天各取5只处死,剖颅取脑,石蜡包埋。用免疫组化染色观察梗死灶周围皮质nestin、NGF阳性细胞数及梗死灶周围皮质、海马CA3区SYN光密度。
结果:行为学评分:1.造模成功与否的判断:造模后1天,脑梗死大鼠均出现明显的偏瘫体征,Berderson评分多为2分,假手术组大鼠无明显异常。2. Berderson神经功能评分:造模后1～7天探索学习组与对照组评分差异无显著性意义(P>0.05),探索学习组于14～28天恢复明显优于对照组(P<0.05)。3.肌力测验及平衡木行走测验:造模后脑梗死大鼠均出现肌力、平衡木行走能力下降,造模后1～7天探索学习组与对照组评分差异无显著性意义(P>0.05),探索学习组于14～28天恢复明显优于对照组(P<0.05)。假手术组大鼠无明显异常。4.水迷宫试验:从潜伏期的变化可见,与假手术组比较,脑梗死大鼠第21～25天到达平台的潜伏期明显延长(P<0.05)。与对照组比较,探索学习组大鼠第21～25天达到平台的潜伏期明显缩短(P<0.05)。脑梗死大鼠测试前三天潜伏期迅速下降,从第24天开始趋于平缓。
nestin阳性细胞数的时程变化:假手术组大鼠可见少量nestin表达。脑梗死大鼠于造模后第7天阳性细胞最多,第14天和第28天阳性细胞逐渐减少。造模后7天和14天,探索学习组大鼠nestin阳性细胞较对照组增多有显著性差异(P<0.05)。而缺血后28天探索学习组与对照组阳性细胞数无显著差异(P>0.05)。
NGF的时程变化:假手术组大鼠可见少量NGF表达。脑梗死大鼠于造模后1天即可见NGF表达增加,于第7天达峰值,探索学习组较对照组增多有显著性差异(P<0.05),此后两组的NGF表达均呈下降趋势,于28天两组无明显差别(P>0.05)。
SYN光密度的时程变化:假手术组可见SYN呈点状或颗粒样分布。脑梗死大鼠的SYN表达在造模后7天已有所增加,探索学习组及对照组之间无明显差异(P>0.05)。第14天表达明显增强,28天最强。探索学习组SYN的表达在第14、28天较对照组有明显增强,两组之间差别显著(P<0.05)。
结论:
1.本研究采用开颅电凝嗅束近端至大脑下静脉之间一段MCA的方法,成功地制作了大鼠大脑中动脉分布区局灶性脑梗死模型。
2.局灶性脑梗死后给予探索学习可促进大鼠行为学和空间记忆能力的恢复。
3. nestin是NSC的标志,在脑损伤的修复中发挥重要作用。探索学习可增强局灶性脑梗死大鼠nestin的表达。
4. NGF是神经系统重要的生物活性分子,维持神经系统正常的生物学功能,参与损伤神经的再生与功能重组。探索学习促进了局灶性脑梗死后大鼠NGF的表达。
5. SYN与神经生长、修复、再生和突触重塑密切相关。脑梗死可使SYN表达升高,探索学习促进了SYN表达的增加。
Objective : Cerebral vascular accident is a common disease with a high rate of morbidity, mortality and mutilation. In China, the mutilation rate of cerebral vascular is the highest in the numerous diseases. The feature with fast developing, slow recovery and high rate of mortality, mutilation take galactic suffering and heavy burden to the patients, their family and society. The recent studies suggest that rehabilitative treatment has gained evident therapeutic effect in improving the sensation, movement and capability of patients with cerebral infarction. It is a important guidance thinking of rehabilitation medicine theory that making use of comprehensive rehabilitation maneuvers to treat the patients since a long-term ago. Samely in the animal experiments of cerebral ischemia, the researchers utilized movement training, enriched environment and medicine synthetically to observe therapeutic effect. In the animal experiments, there were irrefutably evidence indicated that: rats reared in enriched environment (EE) after MCAO revovered better than reared in standard environment. In the enriched environment, rats have the more chance for social communication, learning and various kinds of physical activity, but no special training.
CNS plasticity is well known. At present thinking, the functional recovery post brain injury relates to the plasticity of brain structure and function, furthermore, some factors relate to plasticity have been discovered. For the recent years, people found that NSC possess various differentiated potentiality in the adult brain tissue. They occupy resting state in the standard condition, and self-renew when it comes foreign signal or the microenviorenment changing. Then they differentiate into neuron, astrocyte and oligodendrocyte in some conditions, and participate to the neurologic recovery. All of these indicate that the CNS has self recovery potentiality. Cerebral ischemia is the common factor that can cause nervous disfunction, so it is important to study and reaserch the reaction of NSC post cerebral ischemia. Nestin is known as the marker of nerve precursor cell, and utended as identifying NSC generally. NGF can promote nerve cell growth, and induce NSC migration. SYN correlates to neurotransmitter releasing, synapse formation and synaptic vesicle ion channel. The expression of SYN can reflect synapse function directly. There was no report about the effects of learning on nestin, NGF, SYN in rats after experimental cerebral infarction at present. Elucidating the effect of learning on functional recovery post brain injury and the mechanism is very significant for formulating rehabilitative strategy successfully.
Methods: 80 male Sprague-Dawley rats were adopted. After making the model of MCAO by electric coagulation successfully, 60 rats were divided into learning group (n=30, 15 as a group living in a maze cage), control group (n=30, 5 as a group living in a standard cage) randomly. Other 20 rats as sham group living in standard cage. 15 rats were chosen randomly from each group respectively for Berderson test at the 1st, 7th, 14th, 28th day after operation, and water maze test from 21st day after operation. At the 1st, 7th, 14th, 28th day after MCAO, 5 rats were randomly killed respectively in learning group and control group. 5 rats in sham group were randomly killed separately at the 7th, 28th day after operation. The expression of nestin, NGF in the peri-ischemic cortex and synaptophysin in the peri-ischemic cortex , CA3 area of hippocampus were examined using immunohistochemistry straining.
Results: 1.After MCAO, severe impairment of function occurred in operated groups and there was no significant abnormal in sham group. 2.Berderson test: In 1-7 days after MCAO, there were no significant difference among the operated groups (P>0.05). Since 14 to 28 days learning group scored better than control group (P<0.05). 3.Result of manual muscle test and balancing wood: The result of manual muscle test and balancing wood decreased in all the MCAO rats after operation. In 1-7 days after MCAO, there were no significant difference among the operated groups (P>0.05). Since 14 to 28 days learning group scored better than control group (P<0.05). There was no apparent abnormality in the sham group. 4.Water maze test: It is thus clear that the latent phase of the operated groups were longer than the sham group since 21st to 25th day in the testing phase (P<0.05). Compared to the control group, the latent phase of learning group was shorter since 21st to 25th day in the testing phase (P<0.05). The latent phase of the operated groups decrease quickly in the first 3 days, then tended to stable since the 24th day, and maintained at a constancy level.
The expression of nestin: Small amounts of nestin expressed in the sham group. The time distribution of nestin in the MCAO rats showed that the number of nestin labeled cells got to the peak at the 7th day and decreased since 14th to 28th day after operation. In the learning group, the expression was higher than the control group at 7th and 14th day after operation (P<0.05), and no significant difference at 28th day (P>0.05).
The expression of nerve growth factor: Small amounts of nerve growth factor expressed in the sham group. The expression of nerve grwoth factor increased at the 1st day after operation, and got to the peak at the 7th day. There was significant difference between learnig group and control group at 7th day (P<0.05). Then the expression of nerve growth factor decreased in the operated groups, and no significant difference between two groups at 28th day (P>0.05).
The expression of synaptophysin: Small amounts of synaptophysin expressed in the sham group. The expression of synaptophysin in the MCAO rats increased at the 7th day after operation, and no significant difference between two groups (P>0.05). The expression increased obviously at 14th day and got to peak at 28th day in learning group and control group. There was significant difference between learnig group and control group at 14th day and 28th day (P<0.05).
Conclusions:
1. Modle of MCAO was made successfully by occluding MCA from the olfactory tract to lateral inferior cerebral vein with electric coagulation.
2. Learning could enhance the functional recovery of local infarcted rats.
3. Nestin is the identification marker of nerve stem cells, and it is important on recovery post brain injure. Learning could promote the expression of nestin in the rat post local cerebral infarction.
4. Nerve growth factor is a important bioactive molecule in the nervous system. It maintains the normal biological function of the nervous system, and participates the regeneration and the fuctional recombination of the injured nerve. Learning could promote the expression of nerve growth factor in the rat post local cerebral infarction.
5. Synaptophysin correlates to nerves growth, recovery, regeneration and synapsis remodeling closely. Cerebral infarction can promote the expression of synaptophysin. Learning could promote the expression of synaptophysin in the rat post local cerebral infarction.
引文
1 Berderson JB, Pitis LH, Tsun M, et al. Rat middle cerebral artery occlusion: evaluation of the model and development of a neurologic examination. Stroke, 1986, 17(3): 472-476
2 陈景藻主编. 康复医学. 北京:高等教育出版社, 2001, 26-32
3 缪鸿石主编. 康复医学理论与实践. 上海: 上海科学技术出版社, 2000, 21-22; 49-100
4 高俊淑,李阔,李娜,等. 探索学习对局灶性脑梗死大鼠梗死灶周围皮质 BDNF 表达的影响. 中国康复医学杂志, 2007, 22(7): 584-585
5 贾子善,李阔,槐雅萍,等. 不同环境干预对局灶性脑梗死大鼠行为学恢复的影响. 中国康复医学杂志, 2007, 22(7): 578-580
6 Johansson BB. Brain plasticity and stroke rehabilitation. Stroke, 2000, 31(1): 223-230
7 Buzsaki G, Chen LS, Goge FH. Spatial organization of physiological activity in the hippocampal region: Relevance to memory formation. Prog Brain Res, 1990, 83: 257-268
8 Treves A, Rolls ET. Computational analysis of the role of the hippocampus in memory. Hippocampus, 1994, 4 (3):374-391
9 韩太真,吴馥梅主编. 学习记忆的神经生物学. 北京 : 北京医科大学、中国协和医科大学联合出版社, 1998, 61 ; 146 ; 206-322
10 Block F. Global ischemia and behavioural deficits. Prog Neurobiol, 1999, 58 (3): 279-295
11 吴为平, 匡培根, 张风英,等. 缺血性脑血管病患者的记忆障碍与脑脊液中三种神经肽关系的研究. 心理学报, 1992, 24(1): 103-107
12 Reynolds BA, Tetzlaff W, Weiss S. A multipotent EGF-responsive striatal embryonic progenitor cell produces neurons and astrocytes. J Neurosc,1992, 12: 4565-4574
13 Reynolds BA, Seiss S. Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science, 1992, 255: 1707-1710
14 Li Y,Chopp M. Temporal profile of nestin expression after focal cerebral ischemia in adult rat. Brain Res, 1999, 838(1-2 ): 1-10
15 Abe K. Therapeutic potential of neurotrophic factors and neural stem cells against ischemic brain injury. Cereb Blood Flow Metab,2000,20(10 ): 1393-1408
16 Lai C, Feng L. Neuregulin induces proliferation of neural progenitor cells via PLC/PKC pathway. Biochem Biophys Res Commun, 2004, 319(2): 603-611
17 Mohammed AH, Zhu SW, Darmopil S, et al. Environmental enrichment and the brain. Prog Brain Res, 2002, 138: 109-133
18 Raner MS , Priestley JV , Mcmahon SB. Functional regeneration of sensory axons into the adult spinal cord. Nature,2000,403(6767): 312-316
19 Ishida A, Kawakami H, Yasuzumi F, et al. Gene therapy for cerebral infarction (cerebral ischemia). No To Shinkei, 2002, 54(3): 213-219
20 胡志云,王洪津,姜长斌,等. 脑缺血再灌注后海马谷氨酸和神经生长因子的表达. 大连医科大学学报, 2005, 27(3): 170-173
21 卢宏,宋志宇,王建平,等. 外源性雌二醇对脑缺血再灌注损伤大鼠脑源性神经营养因子和神经生长因子表达的影响. 中国临床康复, 2005, 9(25): 96-98
22 Cattaneo E, McKay R. Proliferation and differentiation of neuronal stem cells regulated by nerve growth factor. Nature, 1990, 347: 762-765
23 施英唐,马骥,袁崇刚. 神经生长因子诱导神经干细胞定向迁移. 解剖学报, 2004, 35: 22-25
24 Faverjon S, Silveira DC, Fu DD, et al. Beneficial effects of enriched environment following status epilepticus in immature rats. Neurology, 2002, 59(9): 1356-1364
25 Auvergne R, Lere C, El-bahh B, et al. Delayed kindling epileptogenesis and increased neurogenesis in adult rats housed in an riched environment. Brain Res, 2002, 954(2): 277-285
26 Dipiero V, Chollet FM, Maccarthy P, et al. Motor recoveryafter acute ischemic stroke: a metabolic study. Neurol Neurosurg Psychiatty, 1992, 55: 990-996
27 Chen YC, Chen QS, Lei JL, et al. Physical training modifies the age-related decrease of GAP-43 and synaptophysin in the hippocampal formation in C57BL/6J mouse. Brain Res, 1998, 806(2): 238-245
1 Liu J, Solway K, Messing RO, et al. Increased neurogenesis in the dentate gyrus after transient global ischemia in gerbils. Neurosci, 1998, 18(19): 7768-7778
2 Tureyen k, Vemuganti R, Sailor KA, et al. Transient focal cerebral ischemia-induced neurogenesis in the dentate gyrus of the adult mouse. Neurosurgery, 2004, 101(5): 799-805
3 Ruilan Z, Zhenggang Z, Lei W, et al. Activated neural stem cells contribute to stroke-induced neurogenesis and neuroblast migration toward the infarct boundary in adult rats. Cereb Blood Flow Metab, 2004, 24: 441-448
4 Zhang RL, Zhang ZG, Zhang L, et al. Proliferation and differentiation of progenitor cells in the cortex and the subventricular zone in the adult rat after focal cerebralischemia. Neurosci, 2001, 105(1): 33-41
5 Arvidsson A, Collin T, Kirik D, et al. Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med, 2002, 8: 963-970
6 Takasawa K, Kitagawa K, Yagita Y, et al. Increased proliferation of neural progenitor cells but reduced survival of newborn cells in the contralateral hippocampus after focal cerebral ischemia in rats. Cereb Blood Flow Metab, 2002, 22 (3): 299-307
7 Li Y, Chopp M. Temporal profile of nestin expression after focal cerebral ischemia in adult rat. Brain Res, 1999, 838 (1-2): 1-10
8 Abe K. Therapeutic potential of neurotrophic factors and neural stem cells against ischemic brain injury. Cereb Blood Flow Metab, 2000, 20(10): 1393-1408
9 李玲, 徐莉, 晏培松, 等. 脑梗死大鼠康复训练后脑的增殖细胞核抗原的表达及病理学改变. 中华物理医学与康复杂志, 2000, 22: 339-342
10 王卫东,王洪典,王津存,等. 康复训练对成年大鼠脑梗死后海马齿状回神经前体细胞增殖的影响. 中华物理医学与康复杂志, 2003, 25: 386-389
11 Kitagawa K, Matsumoto M, Hori M. Protective and regenerative response endogenously induced in the ischemic brain. Can J Physiol Pharmacol, 2001, 79(3): 262-265
12 周晓琳,赵永波,段淑荣,等. 脑梗死后康复训练对成年大鼠海马结构中神经干细胞的影响. 神经疾病与精神卫生, 2004, 4: 430-434
13 Will B, Galani R, Kelch C, et al. Recovery from brain injury in animals: relative efficacy of environmental enrichment,physical exercise or formal training(1990-2002). Prog Neurobiol, 2004, 72(3): 167-182
14 Dahlqvist P, Ronnback A, Bergstrom SA, et al. Environmental enrichment reverses learning impairment in the Morris water maze after focal cerebral ischemia in rats. Eur J Neurosci, 2004, 19(8): 2288-2298
15 Biernaskie J, Chernenko G, Corbett D. Efficacy of rehabilitative experience declines with time after focal ischemic brain injury. Neurosci, 2004, 24(5): 1245-1254
16 Yasuhiko M,Shwuhuey MH,Yang F,et al. Enriched environment and spatial learning enhance hippocampal neurogenesis and salvages ischemic penumbra after focal cerebral ischemia. Neurobiol Dis, 2006, 22(1): 187-198
17 Pencea V, Bingaman KD, Wiegand SJ, et al. Infusion of brain-derived neurotrophic factor into the lateral ventricle of the adult rat leads to new neurons in the parenchyma of the striatum, septum, thalamus, and hypothalamus. Neurosci, 2001, 21(17): 6706-6717
18 Benraiss A, Chmielnicki E, Lerner K, et al. Adenoviral brain-derived neurotrophic factor induces both neostriatal and olfactory neuronal recruitment from endogenous progenitor cells in the adult forebrain. Neurosci, 2001, 21(17): 6718-6731
19 吴永超,郑启新,胡东,等. 骨髓间充质干细胞表达神经营养因子及对神经干细胞的保护作用. 中国康复理论与实践, 2006, 12(9): 780-782
20 Larsson E, Mandel RJ, Klein RL, et al. Suppression of insult-induced neurogenesis in adult rat brain by brain-derived neurotrophic factor. Exp Neurol, 2002, 177(1): 1-8
21 Shingo T, Sorokan ST, Shimazaki T, et al. Erythropoietin regulates the in vitro and in vivo production of neuronal progenitors by mammalian forebrain neural stem cells. Neurosci, 2001, 21(24): 9733-9743
22 Teramoto T, Qiu J, Plumier JC, et al. EGF amplifies the replacement of parvalbumin-expressin striatal interneurons after ischemia. Clin Invest, 2003, 111 (8): 1125-1132
23 Nakatomi H,Kuriu T,Okabe S,et al. Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors. Cell,2002,110:429-441
24 历俊华,郑淑荣,万虹,等. 血清预培养促进神经干细胞的增殖. 中国康复理论与实践, 2005, 11(5): 339-340
25 王力平,樊东升,王荫华,等. 神经干细胞脑脊液移植后存活及迁移规律研究. 中国康复理论与实践, 2005, 11(5): 337-338
26 Toda H, Takahashi J, Iwakami N, et al. Grafting neural stem cells improved the impaired spatial recognition in ischemic rats. Neurosci Lett, 2001, 316 (1): 9-12
27 Chu K, Kim M, Chae SH, et al. Distribution and in situ proliferation patterns of intravenously injected immortalized human neural stem-like cells in rats with focal cerebral ischemia. Neurosci Res, 2004, 50(4): 459-465
28 Dinsmore JH,Martin J,Siegan J,et al. CNS gragts for treatment of neurologic disorders. San Diego: Academic Press, 2002: 1127-1134
29 Li Y, Chopp M, Chen J, et al. Intrastriatal transplantation of bone marrow nonhematopoietic cells improves functional recovery after stroke in adult mice. Cereb Blood Flow Metab, 2000, 20(9): 1311-1319
30 Shen LH, Li Y, Chen J, et al. Intracarotid transplantation of bone marrow stromal cells increases axon-myelin remodeling after stroke. Neuroscience, 2006, 137: 393-399
2 陈景藻主编. 康复医学. 北京:高等教育出版社, 2001, 26-32
3 缪鸿石主编. 康复医学理论与实践. 上海: 上海科学技术出版社, 2000, 21-22; 49-100
4 高俊淑,李阔,李娜,等. 探索学习对局灶性脑梗死大鼠梗死灶周围皮质 BDNF 表达的影响. 中国康复医学杂志, 2007, 22(7): 584-585
5 贾子善,李阔,槐雅萍,等. 不同环境干预对局灶性脑梗死大鼠行为学恢复的影响. 中国康复医学杂志, 2007, 22(7): 578-580
6 Johansson BB. Brain plasticity and stroke rehabilitation. Stroke, 2000, 31(1): 223-230
7 Buzsaki G, Chen LS, Goge FH. Spatial organization of physiological activity in the hippocampal region: Relevance to memory formation. Prog Brain Res, 1990, 83: 257-268
8 Treves A, Rolls ET. Computational analysis of the role of the hippocampus in memory. Hippocampus, 1994, 4 (3):374-391
9 韩太真,吴馥梅主编. 学习记忆的神经生物学. 北京 : 北京医科大学、中国协和医科大学联合出版社, 1998, 61 ; 146 ; 206-322
10 Block F. Global ischemia and behavioural deficits. Prog Neurobiol, 1999, 58 (3): 279-295
11 吴为平, 匡培根, 张风英,等. 缺血性脑血管病患者的记忆障碍与脑脊液中三种神经肽关系的研究. 心理学报, 1992, 24(1): 103-107
12 Reynolds BA, Tetzlaff W, Weiss S. A multipotent EGF-responsive striatal embryonic progenitor cell produces neurons and astrocytes. J Neurosc,1992, 12: 4565-4574
13 Reynolds BA, Seiss S. Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science, 1992, 255: 1707-1710
14 Li Y,Chopp M. Temporal profile of nestin expression after focal cerebral ischemia in adult rat. Brain Res, 1999, 838(1-2 ): 1-10
15 Abe K. Therapeutic potential of neurotrophic factors and neural stem cells against ischemic brain injury. Cereb Blood Flow Metab,2000,20(10 ): 1393-1408
16 Lai C, Feng L. Neuregulin induces proliferation of neural progenitor cells via PLC/PKC pathway. Biochem Biophys Res Commun, 2004, 319(2): 603-611
17 Mohammed AH, Zhu SW, Darmopil S, et al. Environmental enrichment and the brain. Prog Brain Res, 2002, 138: 109-133
18 Raner MS , Priestley JV , Mcmahon SB. Functional regeneration of sensory axons into the adult spinal cord. Nature,2000,403(6767): 312-316
19 Ishida A, Kawakami H, Yasuzumi F, et al. Gene therapy for cerebral infarction (cerebral ischemia). No To Shinkei, 2002, 54(3): 213-219
20 胡志云,王洪津,姜长斌,等. 脑缺血再灌注后海马谷氨酸和神经生长因子的表达. 大连医科大学学报, 2005, 27(3): 170-173
21 卢宏,宋志宇,王建平,等. 外源性雌二醇对脑缺血再灌注损伤大鼠脑源性神经营养因子和神经生长因子表达的影响. 中国临床康复, 2005, 9(25): 96-98
22 Cattaneo E, McKay R. Proliferation and differentiation of neuronal stem cells regulated by nerve growth factor. Nature, 1990, 347: 762-765
23 施英唐,马骥,袁崇刚. 神经生长因子诱导神经干细胞定向迁移. 解剖学报, 2004, 35: 22-25
24 Faverjon S, Silveira DC, Fu DD, et al. Beneficial effects of enriched environment following status epilepticus in immature rats. Neurology, 2002, 59(9): 1356-1364
25 Auvergne R, Lere C, El-bahh B, et al. Delayed kindling epileptogenesis and increased neurogenesis in adult rats housed in an riched environment. Brain Res, 2002, 954(2): 277-285
26 Dipiero V, Chollet FM, Maccarthy P, et al. Motor recoveryafter acute ischemic stroke: a metabolic study. Neurol Neurosurg Psychiatty, 1992, 55: 990-996
27 Chen YC, Chen QS, Lei JL, et al. Physical training modifies the age-related decrease of GAP-43 and synaptophysin in the hippocampal formation in C57BL/6J mouse. Brain Res, 1998, 806(2): 238-245
1 Liu J, Solway K, Messing RO, et al. Increased neurogenesis in the dentate gyrus after transient global ischemia in gerbils. Neurosci, 1998, 18(19): 7768-7778
2 Tureyen k, Vemuganti R, Sailor KA, et al. Transient focal cerebral ischemia-induced neurogenesis in the dentate gyrus of the adult mouse. Neurosurgery, 2004, 101(5): 799-805
3 Ruilan Z, Zhenggang Z, Lei W, et al. Activated neural stem cells contribute to stroke-induced neurogenesis and neuroblast migration toward the infarct boundary in adult rats. Cereb Blood Flow Metab, 2004, 24: 441-448
4 Zhang RL, Zhang ZG, Zhang L, et al. Proliferation and differentiation of progenitor cells in the cortex and the subventricular zone in the adult rat after focal cerebralischemia. Neurosci, 2001, 105(1): 33-41
5 Arvidsson A, Collin T, Kirik D, et al. Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med, 2002, 8: 963-970
6 Takasawa K, Kitagawa K, Yagita Y, et al. Increased proliferation of neural progenitor cells but reduced survival of newborn cells in the contralateral hippocampus after focal cerebral ischemia in rats. Cereb Blood Flow Metab, 2002, 22 (3): 299-307
7 Li Y, Chopp M. Temporal profile of nestin expression after focal cerebral ischemia in adult rat. Brain Res, 1999, 838 (1-2): 1-10
8 Abe K. Therapeutic potential of neurotrophic factors and neural stem cells against ischemic brain injury. Cereb Blood Flow Metab, 2000, 20(10): 1393-1408
9 李玲, 徐莉, 晏培松, 等. 脑梗死大鼠康复训练后脑的增殖细胞核抗原的表达及病理学改变. 中华物理医学与康复杂志, 2000, 22: 339-342
10 王卫东,王洪典,王津存,等. 康复训练对成年大鼠脑梗死后海马齿状回神经前体细胞增殖的影响. 中华物理医学与康复杂志, 2003, 25: 386-389
11 Kitagawa K, Matsumoto M, Hori M. Protective and regenerative response endogenously induced in the ischemic brain. Can J Physiol Pharmacol, 2001, 79(3): 262-265
12 周晓琳,赵永波,段淑荣,等. 脑梗死后康复训练对成年大鼠海马结构中神经干细胞的影响. 神经疾病与精神卫生, 2004, 4: 430-434
13 Will B, Galani R, Kelch C, et al. Recovery from brain injury in animals: relative efficacy of environmental enrichment,physical exercise or formal training(1990-2002). Prog Neurobiol, 2004, 72(3): 167-182
14 Dahlqvist P, Ronnback A, Bergstrom SA, et al. Environmental enrichment reverses learning impairment in the Morris water maze after focal cerebral ischemia in rats. Eur J Neurosci, 2004, 19(8): 2288-2298
15 Biernaskie J, Chernenko G, Corbett D. Efficacy of rehabilitative experience declines with time after focal ischemic brain injury. Neurosci, 2004, 24(5): 1245-1254
16 Yasuhiko M,Shwuhuey MH,Yang F,et al. Enriched environment and spatial learning enhance hippocampal neurogenesis and salvages ischemic penumbra after focal cerebral ischemia. Neurobiol Dis, 2006, 22(1): 187-198
17 Pencea V, Bingaman KD, Wiegand SJ, et al. Infusion of brain-derived neurotrophic factor into the lateral ventricle of the adult rat leads to new neurons in the parenchyma of the striatum, septum, thalamus, and hypothalamus. Neurosci, 2001, 21(17): 6706-6717
18 Benraiss A, Chmielnicki E, Lerner K, et al. Adenoviral brain-derived neurotrophic factor induces both neostriatal and olfactory neuronal recruitment from endogenous progenitor cells in the adult forebrain. Neurosci, 2001, 21(17): 6718-6731
19 吴永超,郑启新,胡东,等. 骨髓间充质干细胞表达神经营养因子及对神经干细胞的保护作用. 中国康复理论与实践, 2006, 12(9): 780-782
20 Larsson E, Mandel RJ, Klein RL, et al. Suppression of insult-induced neurogenesis in adult rat brain by brain-derived neurotrophic factor. Exp Neurol, 2002, 177(1): 1-8
21 Shingo T, Sorokan ST, Shimazaki T, et al. Erythropoietin regulates the in vitro and in vivo production of neuronal progenitors by mammalian forebrain neural stem cells. Neurosci, 2001, 21(24): 9733-9743
22 Teramoto T, Qiu J, Plumier JC, et al. EGF amplifies the replacement of parvalbumin-expressin striatal interneurons after ischemia. Clin Invest, 2003, 111 (8): 1125-1132
23 Nakatomi H,Kuriu T,Okabe S,et al. Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors. Cell,2002,110:429-441
24 历俊华,郑淑荣,万虹,等. 血清预培养促进神经干细胞的增殖. 中国康复理论与实践, 2005, 11(5): 339-340
25 王力平,樊东升,王荫华,等. 神经干细胞脑脊液移植后存活及迁移规律研究. 中国康复理论与实践, 2005, 11(5): 337-338
26 Toda H, Takahashi J, Iwakami N, et al. Grafting neural stem cells improved the impaired spatial recognition in ischemic rats. Neurosci Lett, 2001, 316 (1): 9-12
27 Chu K, Kim M, Chae SH, et al. Distribution and in situ proliferation patterns of intravenously injected immortalized human neural stem-like cells in rats with focal cerebral ischemia. Neurosci Res, 2004, 50(4): 459-465
28 Dinsmore JH,Martin J,Siegan J,et al. CNS gragts for treatment of neurologic disorders. San Diego: Academic Press, 2002: 1127-1134
29 Li Y, Chopp M, Chen J, et al. Intrastriatal transplantation of bone marrow nonhematopoietic cells improves functional recovery after stroke in adult mice. Cereb Blood Flow Metab, 2000, 20(9): 1311-1319
30 Shen LH, Li Y, Chen J, et al. Intracarotid transplantation of bone marrow stromal cells increases axon-myelin remodeling after stroke. Neuroscience, 2006, 137: 393-399