运动康复训练对大鼠缺氧缺血性脑损伤后学习记忆的影响及可能机制研究
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摘要
第一部分新生鼠缺氧缺血脑损伤模型的建立和验证
目的:成功建立新生鼠缺氧缺血性脑损伤模型并予以验证。
方法:选7日龄SD大鼠32只,分为假手术组和缺氧缺血脑损伤模型(HIBD)组。HIBD组大鼠经乙醚麻醉后结扎左侧颈总动脉,置于缺氧箱内持续通入8%的氮氧混合气体2 h进行缺氧缺血干预;假手术组只游离而不结扎左侧颈总动脉,亦不予缺氧处理。于缺氧结束后即刻观察行为学改变,24 h后进行感觉运动神经反射评定,随即断头取脑行TTC染色观察脑组织缺氧缺血梗死灶,各组剩余大鼠于缺氧结束4 w后断头取脑进行HE染色观察海马组织病理改变。
结果:与假手术组相比,HIBD组大鼠缺氧24 h后均有不同程度的异常行为学表现,其翻正反射、悬崖回避反射和趋地性反射均较假手术组明显延迟。脑组织切片TTC染色显示HIBD组大鼠皮层和皮层下脑组织出现面积不等的梗死灶,而假手术组大鼠未见确切梗死灶。缺氧4 w后行病理学检查显示HIBD组大鼠建模侧大脑半球体积较对侧半球缩小,并伴有液化和空洞的形成,H.E.染色后光镜检查发现HIBD组大鼠建模侧海马CA1区出现大量变性和坏死的神经元,胶质细胞增生,细胞排列结构紊乱;而假手术组大鼠脑组织肉眼及镜下观察均未见明显异常。
结论:本实验采用Rice-Vannucci法成功的建立新生鼠缺氧缺血性脑损伤模型。
第二部分运动康复训练对大鼠缺氧缺血性脑损伤后学习记忆的影响及可能机制研究
目的:探讨运动康复对缺氧缺血性脑损伤(HIBD)大鼠脑结构和空间学习记忆的影响。
方法:7日龄SD大鼠随机分为假手术组、HIBD非运动组及HIBD运动组。HIBD运动组于建模2 w后开始连续4 w的运动康复。而后通过神经功能评分和Morris水迷宫检测各组大鼠运动功能和空间学习记忆能力,称取双侧大脑半球重量,H.E.染色后光镜下计数海马CA1区存活神经元数目,透射电镜观察海马突触超微结构,最后通过免疫组织化学方法检测海马磷酸化CaMKII及BDNF表达水平。
结果:运动康复4 w后HIBD运动组大鼠神经功能评分(0.46±0.18)和假手术组大鼠评分(0.50±0.36)均明显优于HIBD非运动组(1.04±0.33) ,HIBD运动组与假手术组间无统计学差异。在各测试时间点HIBD非运动组大鼠水迷宫平均寻台潜伏期均较HIBD运动组和假手术组长,穿越平台次数(2.62±0.74次)较HIBD运动组(5.25±0.98次)和假手术组(4.62±1.19次)少,HIBD运动组和假手术组间平均寻台潜伏期及穿越平台次数无统计学差异。脑重测定示HIBD非运动组、HIBD运动组大鼠左侧平均脑重均低于假手术组(0.68±0.04 g) ,HIBD非运动组(0.46±0.02 g)又低于HIBD运动组(0.63±0.06 g) ;三组大鼠右侧平均脑重间无统计学差异。H.E.染色观察示HIBD非运动组大鼠左侧海马出现大量变性坏死的神经元,HIBD运动组大鼠左侧海马亦可见变性坏死神经元,但程度较HIBD非运动组减轻,假手术组左侧海马未见明显异常;HIBD非运动组和HIBD运动组大鼠左侧海马CA1区400倍光镜下平均每视野存活神经元数目均较假手术组(63.0±8.5个)明显减少,HIBD非运动组(47.1±6.32个)又较HIBD运动组(56.1±11.56个)少。此外,透射电镜示HIBD非运动组大鼠左侧海马突触前膜囊泡减少,突触间隙增宽,突触后致密物变薄,HIBD运动组和假手术组左侧海马突触结构未见明显异常。最后,免疫组化结果显示HIBD运动组大鼠左侧海马CA1区磷酸化CaMKII平均光密度值(0.2833±0.0208)和假手术组磷酸化CaMKII平均光密度值(0.2988±0.0196)均明显高于HIBD非运动组(0.2259±0.0201) ,HIBD运动组与假手术组间无统计学差异。而HIBD运动组、HIBD非运动组大鼠左侧海马CA1区BDNF平均光密度值均较假手术组(0.1363±0.0078)高,HIBD运动组(0.2352±0.0151)又明显高于HIBD非运动组(0.1788±0.0092)。
结论:HIBD运动组大鼠空间学习记忆能力明显优于HIBD非运动组,同时其海马CA1区磷酸化CaMKII和BDNF表达水平均明显高于HIBD非运动组,提示运动康复通过上调海马区磷酸化CaMKII和BDNF表达水平来促进缺氧缺血脑损伤后大鼠海马神经元存活,增强突触结构可塑性,改善受损的空间学习记忆能力。
PART I ESTABLISHMENT OF HYPOXIA-ISCHEMIA BRAIN DAMAGE MODEL IN NEONATAL RATS
Objective To establish a successful hypoxic-ischemic brain injury model in neonatal rats.
Methods Following Rice-Vannucci, thirty-two 7-day-old Sprague-Dawley rats were randomly divided into two groups: a group that was subjected to left carotid ligation followed by 2 hours hypoxic stress (HIBD) and a control group that was subjected to a sham-operation without ligation and hypoxic stress. Behavioral manners of rats were observed soon after hypoxic insult. Three developmental reflexes (righting, cliff aversion and geotaxis) of all rats were then assessed 24 hours later, after that 8 rats were randomly chosen from each group and their brains were prepared for TTC staining. Four weeks after the end of hypoxia, the remaining rats were decapitated and their brain slices were prepared for pathological examination.
Results Rats in HIBD group had various kinds of abnormal behavioral performances after hypoxic injury, and they also showed delayed developmental reflexes compared with rats in control group. TTC staining showed that rats submitted to hypoxia suffered extensive cortical and subcortical (including hippocampus) cerebral infarcts ipsilateral to the ligated carotid artery, while rats in sham control group did not develop brain infarcts. In gross anatomic examination, cerebral atrophy accompanied with liquefaction and cavitation was noticed in the hemisphere of rats submitted to ipsilateral carotid artery ligation followed by hypoxia, and microscopic examination of the cerebral sections showed significant loss of neurons in hippocampus ipsilateral to the side of carotid artery ligation in hypoxia-ischemia affected rats; while no abnormality was observed in both gross anatomic and microscopic examination in rats subjected to a sham-operation.
Conclusions A successful hypoxic-ischemic brain injury model in neonatal rats can be obtained following Rice-Vannucci.
PART II PHYSICAL TRAINING TASKS IMPROVE SPATIAL LEARNING IMPAIRMENTS FOLLOWING HYPOXIC ISCHEMIC INSULT IN NEONATAL RATS
Objective To investigate the effect of physical training on cerebral structure and spatial learning and memory in neonatal rats submitted to hypoxic-ischemic brain damage (HIBD).
Methods Forty-eight 7-day-old Sprague-Dawley rats were randomly divided into three groups: a group that was subjected to left carotid ligation followed by 2 hours hypoxic stress (HIBD), a group that received physical training 2 weeks after the HIBD event and a control group that was subjected to a sham-operation without ligation and hypoxic stress. After four weeks physical training, motor function test and water maze task were performed; thereafter, bilateral brain weight, cerebral morphology and left hippocampal ultrastructrue of the animals were examined. Finally, expression levels of phosphor calmodulin-dependent protein kinase II (CaMKII) and brain derived neurotrophic factor (BDNF) in left hippocampus of all rats were determined by immunohistochemistry.
Results Compared with the rats in control group and trained-HIBD group, rats in non-trained HIBD group had a remarkable worse performance in both motor function assessment and Morris water maze test, whereas there was no significant difference between the rats in trained-HIBD and control groups in motor function assessment and spatial learning test. Left hemisphere weight and survival neurons in left hippocampal CA1 zone of rats in both HIBD groups decreased sharply compared with rats in control group and rats in non-trained HIBD group had a even more significant reduction. The ultrastructure of left hippocampus of rats in non-trained HIBD group was remarkably abnormal, while the left hippocampal ultrastructure of rats in trained HIBD and control group had no certain abnormality. At last, phosphor-CaMKII and BDNF expression level in left hippocampus of rats in trained HIBD group increased significantly compared with rats in the non-trained HIBD group.
Conclusions Physical training can restrain brain damage and ameliorate the spatial learning and memory impairments of rats submitted to hypoxia-ischemia insult.
目的:成功建立新生鼠缺氧缺血性脑损伤模型并予以验证。
方法:选7日龄SD大鼠32只,分为假手术组和缺氧缺血脑损伤模型(HIBD)组。HIBD组大鼠经乙醚麻醉后结扎左侧颈总动脉,置于缺氧箱内持续通入8%的氮氧混合气体2 h进行缺氧缺血干预;假手术组只游离而不结扎左侧颈总动脉,亦不予缺氧处理。于缺氧结束后即刻观察行为学改变,24 h后进行感觉运动神经反射评定,随即断头取脑行TTC染色观察脑组织缺氧缺血梗死灶,各组剩余大鼠于缺氧结束4 w后断头取脑进行HE染色观察海马组织病理改变。
结果:与假手术组相比,HIBD组大鼠缺氧24 h后均有不同程度的异常行为学表现,其翻正反射、悬崖回避反射和趋地性反射均较假手术组明显延迟。脑组织切片TTC染色显示HIBD组大鼠皮层和皮层下脑组织出现面积不等的梗死灶,而假手术组大鼠未见确切梗死灶。缺氧4 w后行病理学检查显示HIBD组大鼠建模侧大脑半球体积较对侧半球缩小,并伴有液化和空洞的形成,H.E.染色后光镜检查发现HIBD组大鼠建模侧海马CA1区出现大量变性和坏死的神经元,胶质细胞增生,细胞排列结构紊乱;而假手术组大鼠脑组织肉眼及镜下观察均未见明显异常。
结论:本实验采用Rice-Vannucci法成功的建立新生鼠缺氧缺血性脑损伤模型。
第二部分运动康复训练对大鼠缺氧缺血性脑损伤后学习记忆的影响及可能机制研究
目的:探讨运动康复对缺氧缺血性脑损伤(HIBD)大鼠脑结构和空间学习记忆的影响。
方法:7日龄SD大鼠随机分为假手术组、HIBD非运动组及HIBD运动组。HIBD运动组于建模2 w后开始连续4 w的运动康复。而后通过神经功能评分和Morris水迷宫检测各组大鼠运动功能和空间学习记忆能力,称取双侧大脑半球重量,H.E.染色后光镜下计数海马CA1区存活神经元数目,透射电镜观察海马突触超微结构,最后通过免疫组织化学方法检测海马磷酸化CaMKII及BDNF表达水平。
结果:运动康复4 w后HIBD运动组大鼠神经功能评分(0.46±0.18)和假手术组大鼠评分(0.50±0.36)均明显优于HIBD非运动组(1.04±0.33) ,HIBD运动组与假手术组间无统计学差异。在各测试时间点HIBD非运动组大鼠水迷宫平均寻台潜伏期均较HIBD运动组和假手术组长,穿越平台次数(2.62±0.74次)较HIBD运动组(5.25±0.98次)和假手术组(4.62±1.19次)少,HIBD运动组和假手术组间平均寻台潜伏期及穿越平台次数无统计学差异。脑重测定示HIBD非运动组、HIBD运动组大鼠左侧平均脑重均低于假手术组(0.68±0.04 g) ,HIBD非运动组(0.46±0.02 g)又低于HIBD运动组(0.63±0.06 g) ;三组大鼠右侧平均脑重间无统计学差异。H.E.染色观察示HIBD非运动组大鼠左侧海马出现大量变性坏死的神经元,HIBD运动组大鼠左侧海马亦可见变性坏死神经元,但程度较HIBD非运动组减轻,假手术组左侧海马未见明显异常;HIBD非运动组和HIBD运动组大鼠左侧海马CA1区400倍光镜下平均每视野存活神经元数目均较假手术组(63.0±8.5个)明显减少,HIBD非运动组(47.1±6.32个)又较HIBD运动组(56.1±11.56个)少。此外,透射电镜示HIBD非运动组大鼠左侧海马突触前膜囊泡减少,突触间隙增宽,突触后致密物变薄,HIBD运动组和假手术组左侧海马突触结构未见明显异常。最后,免疫组化结果显示HIBD运动组大鼠左侧海马CA1区磷酸化CaMKII平均光密度值(0.2833±0.0208)和假手术组磷酸化CaMKII平均光密度值(0.2988±0.0196)均明显高于HIBD非运动组(0.2259±0.0201) ,HIBD运动组与假手术组间无统计学差异。而HIBD运动组、HIBD非运动组大鼠左侧海马CA1区BDNF平均光密度值均较假手术组(0.1363±0.0078)高,HIBD运动组(0.2352±0.0151)又明显高于HIBD非运动组(0.1788±0.0092)。
结论:HIBD运动组大鼠空间学习记忆能力明显优于HIBD非运动组,同时其海马CA1区磷酸化CaMKII和BDNF表达水平均明显高于HIBD非运动组,提示运动康复通过上调海马区磷酸化CaMKII和BDNF表达水平来促进缺氧缺血脑损伤后大鼠海马神经元存活,增强突触结构可塑性,改善受损的空间学习记忆能力。
PART I ESTABLISHMENT OF HYPOXIA-ISCHEMIA BRAIN DAMAGE MODEL IN NEONATAL RATS
Objective To establish a successful hypoxic-ischemic brain injury model in neonatal rats.
Methods Following Rice-Vannucci, thirty-two 7-day-old Sprague-Dawley rats were randomly divided into two groups: a group that was subjected to left carotid ligation followed by 2 hours hypoxic stress (HIBD) and a control group that was subjected to a sham-operation without ligation and hypoxic stress. Behavioral manners of rats were observed soon after hypoxic insult. Three developmental reflexes (righting, cliff aversion and geotaxis) of all rats were then assessed 24 hours later, after that 8 rats were randomly chosen from each group and their brains were prepared for TTC staining. Four weeks after the end of hypoxia, the remaining rats were decapitated and their brain slices were prepared for pathological examination.
Results Rats in HIBD group had various kinds of abnormal behavioral performances after hypoxic injury, and they also showed delayed developmental reflexes compared with rats in control group. TTC staining showed that rats submitted to hypoxia suffered extensive cortical and subcortical (including hippocampus) cerebral infarcts ipsilateral to the ligated carotid artery, while rats in sham control group did not develop brain infarcts. In gross anatomic examination, cerebral atrophy accompanied with liquefaction and cavitation was noticed in the hemisphere of rats submitted to ipsilateral carotid artery ligation followed by hypoxia, and microscopic examination of the cerebral sections showed significant loss of neurons in hippocampus ipsilateral to the side of carotid artery ligation in hypoxia-ischemia affected rats; while no abnormality was observed in both gross anatomic and microscopic examination in rats subjected to a sham-operation.
Conclusions A successful hypoxic-ischemic brain injury model in neonatal rats can be obtained following Rice-Vannucci.
PART II PHYSICAL TRAINING TASKS IMPROVE SPATIAL LEARNING IMPAIRMENTS FOLLOWING HYPOXIC ISCHEMIC INSULT IN NEONATAL RATS
Objective To investigate the effect of physical training on cerebral structure and spatial learning and memory in neonatal rats submitted to hypoxic-ischemic brain damage (HIBD).
Methods Forty-eight 7-day-old Sprague-Dawley rats were randomly divided into three groups: a group that was subjected to left carotid ligation followed by 2 hours hypoxic stress (HIBD), a group that received physical training 2 weeks after the HIBD event and a control group that was subjected to a sham-operation without ligation and hypoxic stress. After four weeks physical training, motor function test and water maze task were performed; thereafter, bilateral brain weight, cerebral morphology and left hippocampal ultrastructrue of the animals were examined. Finally, expression levels of phosphor calmodulin-dependent protein kinase II (CaMKII) and brain derived neurotrophic factor (BDNF) in left hippocampus of all rats were determined by immunohistochemistry.
Results Compared with the rats in control group and trained-HIBD group, rats in non-trained HIBD group had a remarkable worse performance in both motor function assessment and Morris water maze test, whereas there was no significant difference between the rats in trained-HIBD and control groups in motor function assessment and spatial learning test. Left hemisphere weight and survival neurons in left hippocampal CA1 zone of rats in both HIBD groups decreased sharply compared with rats in control group and rats in non-trained HIBD group had a even more significant reduction. The ultrastructure of left hippocampus of rats in non-trained HIBD group was remarkably abnormal, while the left hippocampal ultrastructure of rats in trained HIBD and control group had no certain abnormality. At last, phosphor-CaMKII and BDNF expression level in left hippocampus of rats in trained HIBD group increased significantly compared with rats in the non-trained HIBD group.
Conclusions Physical training can restrain brain damage and ameliorate the spatial learning and memory impairments of rats submitted to hypoxia-ischemia insult.
引文
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[23] Murer M, Yan Q, Raisman VR. Brain-derived neurotrophic factor in the control human brain, and in Alzheimer′s disease and Parkinson′s disease [J]. Prog Neurobiol, 2001, 63 (1) : 71-74.
[24]左昕,邱太兴,潘奇波等.脑源性神经营养因子在学习记忆中作用机制的研究进展[J].海军医学杂志, 2009, 30 (3) :
[25] N.C. Berchtold, G. Chinn, M. Chou, et al. Exercise primes a molecular memory for brain-derived neurotrophic factor protein induction in the rat hippocampus [J]. Neuroscience, 2005, 133: 853-61.
[26] Li Y, Luikart BW, Birnbaum S, et al. TrkB regulates hippocampal neurogenesis and governs sensitivity to antidepressive treatment [J]. Neuron, 2008, 59: 399–412.
[1]刘瑾彦,娄淑杰,陈佩杰.跑台运动对不同月龄大鼠空间学习和记忆能力的影响[J].中国体育科技, 2009, 45(6): 87-90.
[2] R.M. O Callaghan, Robert Ohle, Aine M. Kelly. The effects of forced exercise on hippocampal plasticity in the rat: A comparison of LTP, spatial and non-spatial learning [J]. Behav Brain Res, 2007, 176: 362-366.
[3] H. van Praag. Neurogenesis and exercise: past and future directions [J]. Neuromolecular Med, 2008, 10: 128-140.
[4] H. van Praag, Tiffany Shubert, Chunmei Zhao, et al. Exercise enhances learning and hippocampal neurogenesis in aged mice [J]. J Neurosci, 2005, 25: 8680-8685.
[5]余茜,李晓红,吴士明等.运动康复对脑梗死大鼠学习记忆能力和LTP的影响[J].中华物理医学与康复杂志, 2002, 24(3): 140-143.
[6]赵燕燕,陈春生,刘新霞等.运动训练对亚硝酸钠致记忆障碍模型小鼠学习记忆能力的影响[J].中国康复医学杂志, 2009, 24(2): 110-112.
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[12] C.H. Hillman, Artem V. Belopolsky, Erin M. Snook, et al. Physical activity and executive control: implications for increased cognitive health during older adulthood [J]. Res Q Exerc Sport, 2004, 75: 176-185.
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[14] Prakash RS, Snook EM, Erickson KI, et al. Cardiorespiratory fitness: a predictor of cortical plasticity in multiple sclerosis [J]. Neuroimage, 2007, 34: 1238-44.
[15] P.J. Clark, W.J. Brzezinska, M.W. Thomas, et al. Intact neurogenesis is required for benefits of exercise on spatial memory but not motor performance or contextual fear conditioning in C57BL/6J mice [J]. Neuroscience, 2008, 155: 1048-1058.
[16] N. Kee, Ca′tia M Teixeira, Afra H Wang, et al. Preferential incorporation of adult-generated granule cells into spatial memory networks in the dentate gyrus [J]. Nat Neurosci, 2007, 10: 355-362.
[17] G. Kronenberg, Anika Bick-Sander, Eva Bunk, et al. Physical exercise prevents age-related decline in precursor cell activity in the mouse dentate gyrus [J]. Neurobiol Aging, 2006, 27: 1505-1513.
[18] Z. Kohl, Mahesh Kandasamy, Beate Winner, et al. Physical activity fails to rescue hippocampal neurogenesis deficits in the R6/2 mouse model of Huntington’s disease [J]. Brain Res, 2007, 1155: 24-33.
[19] V.A. Redila, B.R. Christie. Exercise-induced changes in dendritic structure andcomplexity in the adult hippocampal dentate gyrus [J]. Neuroscience, 2006, 137: 1299-1307.
[20] Fabel K, Tam B, Kaufer D, et al. VEGF is necessary for exercise-induced adult hippocampal neurogenesis [J]. Eur. J. Neurosci, 2003, 18: 2803–2812.
[21] J.L. Trejo, Eva Carro, Ignacio Torres-Alema′n. Circulating insulin-like growth factor I mediates exercise-induced increases in the number of new neurons in the adult hippocampus [J]. J Neurosci, 2001, 21: 1628-1634.
[22] T. Kitamura, M. Mishina, H. Sugiyama. Enhancement of neurogenesis by running wheel exercises is suppressed in mice lacking NMDA receptorε1 subunit [J]. Neurosci Res, 2003, 47: 55-63.
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[25] Li Y, Luikart BW, Birnbaum S, et al. TrkB regulates hippocampal neurogenesis and governs sensitivity to antidepressive treatment [J]. Neuron, 2008, 59: 399–412.
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[22] Giese KP, Fedorov NB, Filipkowski RK, Silva AJ. Autophosphorylation at Thr286 of the alpha calcium-calmodulin kinase II in LTP and learning [J]. Science, 1998, 279 (5352) : 870-873.
[23] Murer M, Yan Q, Raisman VR. Brain-derived neurotrophic factor in the control human brain, and in Alzheimer′s disease and Parkinson′s disease [J]. Prog Neurobiol, 2001, 63 (1) : 71-74.
[24]左昕,邱太兴,潘奇波等.脑源性神经营养因子在学习记忆中作用机制的研究进展[J].海军医学杂志, 2009, 30 (3) :
[25] N.C. Berchtold, G. Chinn, M. Chou, et al. Exercise primes a molecular memory for brain-derived neurotrophic factor protein induction in the rat hippocampus [J]. Neuroscience, 2005, 133: 853-61.
[26] Li Y, Luikart BW, Birnbaum S, et al. TrkB regulates hippocampal neurogenesis and governs sensitivity to antidepressive treatment [J]. Neuron, 2008, 59: 399–412.
[1]刘瑾彦,娄淑杰,陈佩杰.跑台运动对不同月龄大鼠空间学习和记忆能力的影响[J].中国体育科技, 2009, 45(6): 87-90.
[2] R.M. O Callaghan, Robert Ohle, Aine M. Kelly. The effects of forced exercise on hippocampal plasticity in the rat: A comparison of LTP, spatial and non-spatial learning [J]. Behav Brain Res, 2007, 176: 362-366.
[3] H. van Praag. Neurogenesis and exercise: past and future directions [J]. Neuromolecular Med, 2008, 10: 128-140.
[4] H. van Praag, Tiffany Shubert, Chunmei Zhao, et al. Exercise enhances learning and hippocampal neurogenesis in aged mice [J]. J Neurosci, 2005, 25: 8680-8685.
[5]余茜,李晓红,吴士明等.运动康复对脑梗死大鼠学习记忆能力和LTP的影响[J].中华物理医学与康复杂志, 2002, 24(3): 140-143.
[6]赵燕燕,陈春生,刘新霞等.运动训练对亚硝酸钠致记忆障碍模型小鼠学习记忆能力的影响[J].中国康复医学杂志, 2009, 24(2): 110-112.
[7] P.A. Adlard, Victoria M. Perreau, Viorela Pop, et al. Voluntary exercise decreases amyloid load in a transgenic model of Alzheimer’s disease [J]. J Neurosci, 2005, 25: 4217-4221.
[8] B.A. Sibley, J.L. Etnier. The relationship between physical activity and cognition in children: a meta-analysis [J]. Pediatric Exercise Science, 2003, 15: 243-256.
[9] B. Winter, Caterina Breitenstein, Frank C, et al. Mooren. High impact running improves learning [J]. Neurobiol Learn Mem, 2007, 87: 597-609.
[10] A.C. Pereira, Dan E. Huddleston, Adam M. Brickman, et al. An in vivo correlate of exercise-induced neurogenesis in the adult dentate gyrus [J]. Proc Natl Acad Sci USA, 2007, 104: 5638-5643.
[11] C.H. Hillman, Kirk I. Erickson, Arthur F. Kramer. Be smart, exercise your heart: exercise effects on brain and cognition [J]. Nat Rev Neurosci, 2008, 9: 58-65.
[12] C.H. Hillman, Artem V. Belopolsky, Erin M. Snook, et al. Physical activity and executive control: implications for increased cognitive health during older adulthood [J]. Res Q Exerc Sport, 2004, 75: 176-185.
[13] S.P. Deeny, David Poeppel, Jo B. Zimmerman, et al. Exercise, APOE, and working memory: MEG and behavioral evidence for benefit of exercise in epsilon4 carriers [J]. Biol Psychol, 2008, 78: 179-187.
[14] Prakash RS, Snook EM, Erickson KI, et al. Cardiorespiratory fitness: a predictor of cortical plasticity in multiple sclerosis [J]. Neuroimage, 2007, 34: 1238-44.
[15] P.J. Clark, W.J. Brzezinska, M.W. Thomas, et al. Intact neurogenesis is required for benefits of exercise on spatial memory but not motor performance or contextual fear conditioning in C57BL/6J mice [J]. Neuroscience, 2008, 155: 1048-1058.
[16] N. Kee, Ca′tia M Teixeira, Afra H Wang, et al. Preferential incorporation of adult-generated granule cells into spatial memory networks in the dentate gyrus [J]. Nat Neurosci, 2007, 10: 355-362.
[17] G. Kronenberg, Anika Bick-Sander, Eva Bunk, et al. Physical exercise prevents age-related decline in precursor cell activity in the mouse dentate gyrus [J]. Neurobiol Aging, 2006, 27: 1505-1513.
[18] Z. Kohl, Mahesh Kandasamy, Beate Winner, et al. Physical activity fails to rescue hippocampal neurogenesis deficits in the R6/2 mouse model of Huntington’s disease [J]. Brain Res, 2007, 1155: 24-33.
[19] V.A. Redila, B.R. Christie. Exercise-induced changes in dendritic structure andcomplexity in the adult hippocampal dentate gyrus [J]. Neuroscience, 2006, 137: 1299-1307.
[20] Fabel K, Tam B, Kaufer D, et al. VEGF is necessary for exercise-induced adult hippocampal neurogenesis [J]. Eur. J. Neurosci, 2003, 18: 2803–2812.
[21] J.L. Trejo, Eva Carro, Ignacio Torres-Alema′n. Circulating insulin-like growth factor I mediates exercise-induced increases in the number of new neurons in the adult hippocampus [J]. J Neurosci, 2001, 21: 1628-1634.
[22] T. Kitamura, M. Mishina, H. Sugiyama. Enhancement of neurogenesis by running wheel exercises is suppressed in mice lacking NMDA receptorε1 subunit [J]. Neurosci Res, 2003, 47: 55-63.
[23] J.J. Radley, B.L. Jacobs. 5-HT1A receptor antagonist administration decreases cell proliferation in the dentate gyrus [J]. Brain Res, 2002, 955: 264-267.
[24] N.C. Berchtold, G. Chinn, M. Chou, et al. Exercise primes a molecular memory for brain-derived neurotrophic factor protein induction in the rat hippocampus [J]. Neuroscience, 2005, 133: 853-61.
[25] Li Y, Luikart BW, Birnbaum S, et al. TrkB regulates hippocampal neurogenesis and governs sensitivity to antidepressive treatment [J]. Neuron, 2008, 59: 399–412.