异亚丙基莽草酸对慢性低灌注大鼠突触可塑性的影响
|
摘要
血管性痴呆(Vascular Dementia, VD)是由一系列脑血管因素导致脑组织损害而引起的获得性智能损害综合征,是继阿尔茨海默氏症(Alzheimer’s Disease, AD)之后第二位最常见的痴呆类型,临床可表现出包括记忆障碍在内的一系列症状。慢性脑灌注不足是血管性痴呆,特别是低灌注性痴呆的主要病理基础。脑灌注减少影响了糖和氧的正常传递,导致大脑突触通路的能量代谢衰竭,最终引发包括记忆衰退在内的大脑整体功能的下降。记忆是中枢神经元的整合,其细胞和分子基础定位于突触。记忆形成的基础是突触效应的增强。在一定条件下,机体可调整突触功能,改变其形态以及数目,这被称之为突触可塑性。随着我国老龄人口比例加大,预防及治疗慢性低灌注引发的VD具有重大社会意义。
异亚丙基莽草酸(3,4-oxo-isopropylidene shikimic acid,ISA)是从中药八角属植物八角茴香中提取的有效成分莽草酸(shikimic acid,SA)的合成衍生物,本组前期研究结果显示,ISA能够明显抑制多种诱导剂所致的血小板聚集以及实验性血栓的形成,对培养的海马以及神经细胞具有直接的神经保护作用,可对抗脑缺血—再灌注诱导的急性炎症反应。本研究进一步从行为学、神经细胞突触结构、胆碱能神经递质合成水平、突触前标志物以及核内转录因子表达水平等环节探讨了ISA对VD模型大鼠海马突触可塑性的干预作用及其可能的作用机理。实验分为三部分。
第一部分建立光化学损伤以及慢性低灌注性VD大鼠模型,探讨慢性低灌注大鼠海马CA1区神经元以及突触结构的变化特点
目的:探讨建立光化学损伤以及慢性低灌注性VD大鼠模型的条件以及两种模型的特点,并探讨慢性低灌注大鼠海马CA1区神经元以及突触结构的变化特征。方法:采用舌下静脉注射4%玫瑰红与绿光照射顶叶皮层相结合的方法诱导大鼠局灶性脑缺血,建立光化学损伤性VD大鼠模型,术后30天通过Morris水迷宫对大鼠进行空间记忆测试;采用永久性结扎加切断大鼠双侧颈总动脉的方法诱导前脑慢性低灌注性VD大鼠模型,60天后通过Morris水迷宫对其进行空间记忆测试。将Morris水迷宫测试结束后的大鼠进行经心灌注固定,制成大脑石蜡切片后,进行HE染色以及Nissl染色,光镜下观察顶叶皮层神经元或海马CA1区锥体神经元的形态学改变。并采用透射电子显微镜观察慢性低灌注性VD模型大鼠海马CA1区突触结构的改变。
结果:①采用舌下静脉注射4%玫瑰红复合5mm直径绿光光纤照射顶叶皮层诱导的VD模型大鼠出现明显的学习记忆障碍,表现为在第2—4天定位航行测试中的逃避潜伏期明显长于假手术组(p<0.05;p<0.01);在空间探索测试中,大鼠游泳初始角度显著大于假手术组(p<0.05)。②光化学损伤造成大鼠顶叶皮质出现明显可见的圆形梗死灶。梗死灶内神经细胞消失,灶内无明显出血。外围的过渡区内从相对正常状态过渡到梗死灶,病变逐渐加重。③双侧颈总动脉永久性结扎加切断后8周,模型大鼠出现明显的学习记忆障碍,表现为在第3天定位航行测试中的路径长度显著长于假手术大鼠(p<0.05);在第2天以及第3天定位航行测试中的游泳错误初始角度显著大于假手术大鼠(p<0.05;p<0.01)。在空间探索测试中,模型大鼠的游泳错误初始角度显著大于假手术大鼠(p<0.05),但二者的原平台象限游泳距离百分比无显著差异(p>0.05)。④慢性低灌注大鼠海马CA1区的锥体细胞排列紊乱,部分脱失,胶质细胞增生显著。⑤进一步采用双侧颈总动脉结扎模型大鼠进行的透射电镜研究显示,8周后该模型大鼠海马CA1区突触间隙模糊,部分突触间隙增宽,突触前后膜肿胀、空化,囊泡数量减少。⑥光化学法VD模型大鼠死亡率较高,为25%;而双侧颈总动脉永久性结扎造成的VD模型大鼠死亡率较低,为10%。
结论:①成功建立了光化学损伤和慢性低灌注两种VD大鼠模型。光化学法与双侧颈总动脉永久性结扎造成的VD模型大鼠在学习记忆以及神经元形态学改变方面均较为显著。②慢性低灌注大鼠模型由于死亡率较低,且手术操作相对简便而更适用于进一步的药效学研究。
第二部分异亚丙基莽草酸对慢性低灌注大鼠的药效作用研究
目的:探讨ISA对双侧颈总动脉结扎造成的慢性低灌注大鼠空间学习记忆能力、海马CA1区神经元形态学以及突触超微结构的影响。
方法:采用永久性结扎大鼠双侧颈总动脉的方法诱导前脑慢性低灌注大鼠模型。实验动物分为假手术组、模型组、阳性对照药喜得镇组、ISA100mg/kg组、ISA50mg/kg组以及ISA25mg/kg组。造模后连续灌胃给予大鼠相应药物60天,通过Morris水迷宫对其进行4d定位航行及1d空间探索测试。水迷宫测试结束后,将部分大鼠进行经心灌注固定,制成大脑石蜡切片,进行HE染色。行为学测试结束后,另取部分大鼠经心灌注固定,取海马CA1区,制成超薄切片。采用透射电镜观察大鼠突触前及突触后结构参数的改变,包括突触界面曲率、活性区长度(length of active zone, L)、突触后致密物质(postsynaptic density,PSD)厚度、突触数密度(numerical density per unit volume of synapses, Nv)、面密度(surface density per unit volume, Sv)、入坞囊泡(docked vesicle, DV)的数量以及单位长度活性区中入坞囊泡的数量(DV/L)。
结果:①双侧颈总动脉结扎诱导的慢性低灌注模型大鼠出现明显的学习记忆障碍。与假手术组相比,模型大鼠在第2、3天定位航行实验中的游泳初始角度增加显著(p<0.05;p<0.01);在第3天定位航行实验中,游泳路径长度延长显著(p<0.05)。在空间探索实验中游泳初始角度明显大于假手术组(p<0.05)。其游泳策略在中早期一般以边缘式为主,后期大多表现为趋向式。造模后连续给与ISA100mg/kg可明显缩短第2天定位航行的游泳路径长度(p<0.05),而对定位航行中游泳初始角度以及其他时间点的游泳路径长度以及空间探索实验中游泳初始角度无显著影响(p>0.05)。ISA50mg/kg可明显减小空间探索实验中的游泳初始角度(p<0.05),而对定位航行中游泳路径长度以及初始角度无显著影响(p>0.05)。ISA25mg/kg可明显减小在第3天定位航行实验及空间探索实验中的游泳初始角度(p<0.01; p<0.05),而对定位航行中的游泳路径长度无显著影响(p>0.05)。ISA各组的游泳策略在中早期一般以趋向式为主,后期大多表现为直线式。喜得镇可明显减小在第3天定位航行实验中的游泳初始角度(p<0.05),而对定位航行中游泳路径长度、其他时间点的初始角度以及空间探索实验中游泳初始角度无显著影响(p>0.05)。其游泳策略在中早期一般以趋向式为主,后期大多表现为直线式。②慢性低灌注大鼠海马CA1区的锥体细胞排列紊乱,部分脱失,神经细胞数明显较少,部分神经细胞水肿,细胞核固缩,有的形成碎片,胶质细胞显著增加。ISA及喜得镇组大鼠的神经元损伤明显减轻,尤以ISA100mg/kg剂量组减轻更明显,表现为海马各区神经细胞胞浆丰富、排列紧密、结构完整,核仁、核膜清晰可见,胞浆染色正常。③慢性低灌注模型大鼠海马CA1区神经毡内突触间隙模糊,突触前后膜肿胀、空化。模型大鼠海马CA1区Nv、Sv、DV、L、DV/L以及突触界面曲率降低非常显著(p<0.01),但PSD厚度未见显著变化(p>0.05)。连续灌胃给与ISA及喜得镇65d后上述损伤明显减轻。与模型组相比,各剂量ISA以及喜得镇可使Nv、Sv、DV、L以及DV/L显著增加(p<0.05;p<0.01)。ISA100mg/kg以及ISA50mg/kg还可明显增加突触界面曲率(p<0.05;p<0.01)。ISA各剂量以及喜得镇组间无显著差异(p>0.05)。
结论:ISA连续灌胃给药8周后各剂量组均可提高慢性低灌注大鼠对空间记忆的获取以及保持能力;改善慢性低灌注大鼠海马CA1区神经细胞形态;显著改善慢性低灌注大鼠海马CA1区突触超微结构,促进突触的结构可塑性。
第三部分异亚丙基莽草酸增强慢性低灌注大鼠突触可塑性的可能作用机制
目的:探讨慢性低灌注大鼠海马CA1区突触可塑性相关蛋白突触素(synaptophysin, SYP)、胆碱乙酰转移酶(choline acetyltransferase, ChAT)、磷酸化cAMP反应元件结合蛋白(phosphorylated- cAMP responsive element binding protein, p-CREB)、脑源性神经营养因子(brain derived neurotrophic factor, BDNF)以及酪氨酸激酶B(tyrosine kinase B, TrkB)的蛋白表达以及基因转录水平的改变,并观察ISA对其影响。
方法:实验动物分为假手术组、模型组、阳性对照药喜得镇组、ISA100mg/kg组、ISA50mg/kg组以及ISA25mg/kg组。将Morris水迷宫测试结束后的慢性低灌注大鼠经心灌注固定,制备大脑石蜡切片后,进行免疫组织化学染色,测定海马CA1区SYP、ChAT、p-CREB、BDNF以及TrkB的定位以及相对定量表达。提取大鼠海马CA1区组织蛋白,利用Western Blot对SYP、p-CREB、BDNF以及TrkB的蛋白表达水平进行半定量测定。抽提大鼠海马CA1区组织总RNA,通过荧光定量实时PCR技术,对BDNF、ChAT、TrkB、SYP以及CREB的mRNA表达水平进行测定。
结果:①大鼠海马CA1区SYP免疫反应阳性产物主要分布于神经元周围,胞浆内颗粒状免疫反应产物少见,白质、血管及胶质细胞不着色。模型大鼠海马CA1区SYP蛋白表达水平以及SYP mRNA表达水平非常显著低于假手术组(p<0.01)。与模型组相比,ISA100mg/kg以及50mg/kg组大鼠的SYP蛋白表达水平显著增加(p<0.05);ISA100mg/kg连续灌胃给药65d可显著增加SYP mRNA表达水平(p<0.05);除ISA100mg/kg外,ISA其余各剂量以及喜得镇对SYP mRNA表达水平无显著影响(p>0.05)。
②大鼠海马CA1区ChAT免疫反应阳性产物主要分布于锥体细胞的胞浆及轴突。模型大鼠的ChAT蛋白表达水平以及ChAT mRNA表达水平非常显著低于假手术组(p<0.01)。与模型组相比,除ISA25mg/kg组外,各给药组的ChAT蛋白表达水平均升高显著(p<0.05;p<0.01);ISA100mg/kg组的ChAT mRNA表达水平增加非常显著(p<0.01),而ISA其余各剂量以及喜得镇对ChAT mRNA表达水平无显著影响(p>0.05)。
③p-CREB免疫反应阳性颗粒主要分布于锥体细胞的胞核中。模型组大鼠海马CA1区p-CREB蛋白表达水平以及CREB mRNA表达水平显著高于假手术组(p<0.05)。与模型组相比,ISA各剂量以及喜得镇对p-CREB蛋白表达水平无显著影响(p>0.05);ISA100mg/kg连续灌胃给药65d后,可显著增加大鼠海马CA1区CREB mRNA表达水平(p<0.05);ISA其余各剂量以及喜得镇对CREB mRNA表达水平无显著影响(p>0.05)。
④B DNF免疫反应阳性产物主要分布于神经元的胞浆、胞核以及长的轴突中。模型大鼠海马CA1区BDNF蛋白表达水平以及BDNF mRNA表达水平均显著高于假手术组(p<0.05)。与模型组相比,100mg/kg的ISA可显著增加BDNF蛋白表达水平以及BDNF mRNA表达水平(p<0.05);喜得镇、ISA50mg/kg与25mg/kg组的BDNF蛋白表达水平以及BDNF mRNA表达水平无显著改变(p>0.05)。
⑤TrkB的免疫反应阳性产物主要分布于神经元的胞浆及轴突内。模型大鼠海马CA1区TrkB mRNA表达水平显著高于假手术组(p<0.05),但是蛋白表达水平未发生显著改变(p>0.05)。各ISA组与喜得镇组的TrkB蛋白以及mRNA表达水平无显著变化(p>0.05)。
结论:①长期慢性低灌注导致大鼠海马CA1区ChAT以及SYP表达水平降低。胆碱能神经功能降低以及突触丢失造成了海马突触结构可塑性的降低,而突触结构可塑性的降低可能是导致慢性低灌注大鼠学习记忆下降的结构基础。②BDNF参与了慢性低灌注损伤后的补偿机制。ISA可通过上调内源性保护因子BDNF的表达,进而提高ChAT的活性以及SYP的含量,提高突触传递效能。③ISA可通过增强胆碱能神经功能以及保护突触结构而促进突触可塑性,进而提高慢性低灌注性痴呆动物的学习记忆能力。
全文结论:
1.本研究成功建立了两种VD大鼠模型,即光化学损伤以及慢性低灌注性VD大鼠模型。两种模型大鼠均表现出明显的空间学习记忆障碍,同时顶叶皮质或海马CA1区神经元严重脱失。并且慢性低灌注大鼠海马CA1区突触超微结构出现明显损伤。
2.相对于光化学损伤诱导的VD模型而言,慢性低灌注大鼠模型更稳定,动物成活率高,实验成本低,与人类VD的病理生理过程更加接近。本研究采用慢性低灌注大鼠模型进行ISA的药效学以及作用机制研究。
3.本研究提示ISA对抗慢性低灌注性VD具有良好的药效作用,表现为连续灌胃给药8周后可明显改善慢性低灌注大鼠的学习记忆功能;减少海马CA1区锥体神经元的脱失,保护神经元形态的完整;促进海马突触的结构可塑性。并以ISA100mg/kg剂量组的药效作用为更好。
4.本研究还提示突触丢失以及胆碱能神经功能障碍可能是导致慢性低灌注性痴呆动物学习记忆下降的主要原因。
5.ISA的作用可能是通过提高BDNF在CA1区的蛋白以及mRNA表达水平,从而进一步加强慢性低灌注本身引发的内源性神经保护机制。即ISA通过加强BDNF-TrkB对其下游靶蛋白SYP以及ChAT的调节,提高突触传递效能。(1)连续给与ISA 8周后,大鼠海马CA1区单位面积中ChAT免疫反应阳性细胞数、免疫反应阳性产物面积百分率以及ChA mRNA表达水平均显著高于模型组。说明给与外源性药物ISA后,胆碱能水平的增加为突触可塑性的增强提供了物质基础。(2)ISA连续用药8周后,大鼠海马CA1区SYP蛋白以及mRNA表达水平均显著提高。这提示ISA可能是通过提高SYP蛋白以及mRNA表达水平,进而提高突触传递效能而改善实验动物的学习记忆能力。6.综上所述,ISA可通过增强胆碱能神经功能以及保护突触结构而促进突触可塑性,进而提高慢性低灌注性痴呆动物的学习记忆能力。
本研究的创新点:
1.首先研究ISA对慢性低灌注大鼠模型的药效学作用;
2.首先采用慢性低灌注大鼠模型研究海马p-CREB表达水平,以及海马CA1区突触中入坞囊泡数量的改变。
Vascular dementia (VD), which is characterized by progressive intellectual decline induced by ischemia hypoxia or hemorrhage brain lesion, represents the second most common dementia accounting for about a quarter to a half of all cases of dementia in developed countries. Chronic cerebral hypoperfusion (CCH) is one of common pathophysiologic basis of VD and Alzheimer's disease. CCH impacts the delivery of glucose and oxygen, leading to the handicap of energy metabolism in the brain synaptic pathway, followed by the decline of the whole brain function including memory decline. The structural basis of memory is synapse. The enhancement of synaptic function contributes to the formation of memory. The rats with memory decline showed the changes in synaptic structural parameters, such as the decrease of numerical density of synapses (Nv) and docked vesicles (Dv).
With increasing number of the elderly in world populations, dementia, characterized by progressive descending of memory and cognition, has given rise to enormous socioeconomic burden. In the past few decades, a great deal of investigation has been conducted. However, the efficiency of currently available strategies for the prevention of VD remains poor. 3,4-oxo-isopropylidene-shikimic acid(ISA)was extracted from Illicium verum Hook. Fil, a traditional Chinese herb. Our preliminary work showed that ISA could suppress variously experimental thrombosis and platelet aggregation significantly, improve the morphology and decrease the apoptosis rate of cultured cortical and hippocampal neurons after hypoxia-reoxygenation injury, exert neuroprotective effects on rats subjected to middle cerebral artery occlusion (MCAO) and reperfusion by an intraluminal thread, as evidenced by decreasing the neurological severity score, infarct volume, brain water content and brain edema. It was indicated that the anti-free radical effects of ISA might account for the protection against cerebral ischemia. Thus, ISA appeared to be a promising drug to ameliorate cognitive deficits induced by cerebral ischemia. But to our knowledge, the effects and the mechanism of ISA on CCH in rats remain to be elucidated. In the present study, we made use of the permanent occlusion of bilateral common carotid arteries (two-vessel occlusion, 2VO) model of CCH to evaluate the effects of ISA on synaptic plasticity in dementia rats. The possible mechanism underlying its effect was also explored. To address this issue, a variety of multidisciplinary approaches including Morris water maze, transmission electron microscopy, immunohistochemical staining, Western blotting, fluorescent quantitative real-time polymerase chain reaction were used.
There are three stories in this thesis.
PartⅠCreation of two kinds of VD rat models and the investigation on the pathological changes in neurons and synaptic ultrastructure in hippocampal CA1 subfield
Objective: To explore the characteristics of the photochemical model and 2VO model, and to investigate the pathological changes of neurons and synaptic ultrastructure in hippocampal CA1 subfield.
Methods: A focal lesion in the left parietal cortex was induced photochemically by using Rose Bengal as a photosensitive dye and cold light beam, then the rats were treated with ISA orally once a day for 30 days. The cognitive effects of ISA were assessed in rats using the Morris water maze test for spatial learning and memory. HE staining and Nissl staining were used to study the neuronal alteration in left parietal cortex. For the reproduction of CCH as it occurs in VD, permanent occlusion of the bilateral common carotid arteries of rats (2-vessel occlusion, 2VO) was introduced. 60 days after 2VO surgery, the rats underwent spatial cognition test in Morris water maze. Subsequently the brain sections were subjected to HE staining and transmission electron microscopy. Results:①Photochemical lesion induced spatial cognition deficits, which was proven by prolonged escape latency on the 2-4 training days(p<0.05, p<0.01)and the larger initial angle in probe test, compared to the sham-operated group(p<0.05).②Photochemical lesion could induce round infarction in the left parietal cortex of rats. The neurons in the infarction almost disappeared. No obvious hemorrhage and edema existed. The pathological changes were gradiently severe from relatively normal brain region to the infarction.③8 weeks after 2VO surgery, the model rats showed significant cognition deficits, as evidenced by longer swimming path length on the third training day(p<0.05), the larger initial angles on the second and third training day(p<0.05, p<0.01), compared to the sham-operated group rats. In the probe test, the model rats exhibited larger initial angles(p<0.05), compared to the sham-operated group rats. No difference in the quadrant percentage was observed between the two groups(p>0.05).④Macroscopic evaluation of rat brains demonstrated that 2VO induced pyramidal neuron damage in hippocampus CA1 subfield 65 days after operation. The rats showed severe neuronal loss and the gliocyte proliferation in the hippocampal CA1 region.⑤The synaptic ultrastructures of neuropil field within CA1 stratum radiatum of the sham-operated group rats were intact. The synapses of GrayⅠtype showed clear synaptic clefts, typical asymmetric interfaces, intact structures of the pre- and postsynaptic membranes, round clear vesicles and thick postsynaptic densities (PSD). The synaptic ultrastructures of 2VO group presented the blurry synaptic clefts, swollen, vacuolated pre- and postsynaptic membranes and less synaptic vesicles in the synaptic terminals.⑥The mortality rate in the model rats with photochemical lesion was 25%, while 10% in the model rats with CCH. Conclusion:①Two VD models induced by the photochemical lesion and 2VO respectively in rats were created. The changes in the cognition and neuronal pathology in the 2VO rats were observed.②2VO model is more suitable for the investigating in the further pharmacodynamics research due to its lower mortality rate and easier surgical process.
PartⅡPharmacodynamics research of 3, 4-oxo-isopropylidene-shikimic acid in rats with vascular dementia induced by chronic cerebral hypoperfusion
Objective: To probe the effects of ISA on spatial cognition, neuronal pathology and synaptic ultrastructure within hippocampal CA1 subfield in rats with CCH.
Methods: We used 2VO to induce CCH in rats. Male Sprague Dawley rats were randomly divided into six groups including vehicle-treated sham-operated group, vehicle-treated operated group, ISA 100mg/kg-treated operated group, ISA 50mg/kg-treated operated group, ISA 25mg/kg-treated operated group and Hydergine 0.6mg/kg-treated operated group. Vehicle group rats’bilateral carotid arteries were occluded. The sham-operated rats received the same operation with the exception of ligation. Other rats were intragastricly administered relevant drugs once per day. Eight weeks after 2VO, Morris water maze was used to measure spatial learning and memory. Each rat received two trials everyday for 4 consecutive days. Length of swimming path to escape onto the hidden platform and initial angle were recorded. On the fifth day, each rat was subjected to a 20-second probe trial in which the platform was removed and the initial angle and typical swim-tracking path were recorded. Subsequently, the morphological changes in neurons were evaluated with HE staining in hippocampal CA1 subfield. Transmission electron microscopy was used to evaluate the following synaptic structural parameters in hippocampal CA1 subfield. Nv, surface density (Sv), DV and DV per unit length of active zone (L) were measured.
Results:①The sham-operated rats showed smaller initial angles on the second (p<0.05) and third (p< 0.01) training days, and the shorter path length on the third training day (p<0.05), compared to 2VO group. In the probe test, the initial angle of sham-operated group was smaller than 2VO rats (p<0.05). The swimming strategy was tendency at the early stage and straight at the late stage in sham-operated rats, and marginal at the early stage and random pattern at the late stage in 2VO rats. Administration of ISA at the dose of 100mg/kg could significantly shorten the path length on the second training day (p<0.05), but didn’t change the path length on other training days, and initial angle in navigation trails and probe trail, compared to 2VO group (all p>0.05). Administration of ISA at the dose of 50mg/kg could significantly reduce initial angle in probe trail (p<0.05), but didn’t change the path length and initial angle in navigation trails, compared to 2VO group (all p>0.05). Administration of ISA at the dose of 25mg/kg could significantly reduce initial angle on the third training day in navigation trail(p<0.01)and probe trail (p<0.05), but couldn’t change the path length in navigation trail, compared to 2VO group (all p>0.05). When treated with dihydroergotoxine at the dose of 0.6mg/kg, the rats showed smaller initial angle on the third training day, compared to 2VO group (p<0.05). No difference in swimming path length on other training days, and initial angle in probe trail were observed, compared to 2VO group (all p>0.05). The main swimming strategies in all drug-treated groups were tendency at the early stage and straight at the late stage.②Microscopic evaluation of rat brains demonstrated that 2VO induced pyramidal neuron damage in hippocampus CA1 subfield 65 days after operation. 2VO rats showed severe neuronal loss and the gliocyte proliferation in the hippocampal CA1 region. The structures of pyramidal neurons in all drug-treated groups were relatively intact.③The synaptic ultrastructures of neuropil field within CA1 stratum radiatum of the sham-operated group rats were intact. The synapses of GrayⅠtype showed clear synaptic clefts, typically asymmetric interfaces, intact structures of the pre- and postsynaptic membranes, round clear vesicles and thick PSD. The synaptic ultrastructures of 2VO rats presented the blurry synaptic clefts, swollen and vacuolated pre- and postsynaptic membranes. The synaptic ultrastructures were relatively intact in all drug-treated groups. There were more synaptic vesicles in the presynaptic terminals in ISA and dihydroergotoxine-treated groups, compared to 2VO group. Compared to the sham-operated group, the 2VO rats showed significantly reduced Nv, Sv, DV, DV/L and synaptic curvature (all p<0.01), but the thickness of PSD didin’t change markedly (p>0.05). All the ISA-treated and dihydroergotoxine-treated rats showed markedly increased Nv, Sv, DV and DV/L (p<0.05, p<0.01), compared to 2VO group. Administration of ISA at the dose of 50mg/kg (p<0.01) and 100mg/kg (p<0.05) could significantly increase the synaptic curvature.
Conclusions: Administration of ISA could improve the decline of learning and memory, and protect the neuronal morphology of the brain in rats with CCH. It improved the structural plasticity of CA1 synapses.
PartⅢProbe into the potential molecular mechanism of 3, 4-oxo-isopropylidene-shikimic acid underlying its synaptic plasticity effects on vacular dementia induced by chronic cerebral hypoperfusion
Objective: To probe effects of ISA on the expressions of brain derived neurotrophic factor (BDNF), its receptor tyrosine kinase B(TrkB), Choline acetyltransferase (ChAT), synaptophysin (SYP), phosphorylated cAMP response element binding protein (p-CREB) in the mRNA and protein levels within hippocampal CA1 region of CCH rats. Methods: Male Sprague Dawley rats were randomly divided into six groups including vehicle-treated sham-operated group, vehicle-treated operated group, ISA 100mg/kg-treated operated group, ISA 50mg/kg-treated operated group, ISA 25mg/kg-treated operated group and Hydergine 0.6mg/kg-treated operated group. After the behavioral test, rats were perfused intracardially. The paraffin sections were used for immunohistochemistry staining to probe the expression of p-CREB, BDNF, TrkB, ChAT and SYP in protein level within hippocampal CA1 subfield. The proteins were extracted and used for evaluation of the semi-quantitative expression of p-CREB, BDNF, TrkB, ChAT and SYP in protein level. Fluorescent quantitative real-time polymerase chain reaction was employed to measure the mRNA expression level of BDNF, TrkB, ChAT, SYP and CREB.
Results:①At week 9 after 2VO surgery, the immunoreactive products of p-CREB, some brown granules, distributed in the neucli of pyramidal neurons within hippocampal CA1 region. The expressions of p-CREB in protein level and CREB in mRNA level were higher in 2VO group than in sham-operated group (both p <0.05). Administration of ISA at the dose of 100mg/kg increased the CREB expression in mRNA level, compared to the 2VO group (p<0.05). Dihydroergotoxine and ISA at three doses didn’t significantly change the expressions of p-CREB in protein level and CREB in mRNA level (all p>0.05).②The immunoreactive products of BDNF distributed in the cytoplasm, neucli and axons of pyramidal neurons within hippocampal CA1 subfield. The BDNF expressions in protein and mRNA levels were higher in 2VO group than in sham-operated group (p<0.05). Administration of ISA at the dose of 100mg/kg could markedly increase BDNF expression in protein and mRNA levels, compared to the 2VO group (both p<0.05). Dihydroergotoxine and ISA at the doses of 50mg/kg and 25mg/kg didn’t significantly change BDNF expression in protein and mRNA levels (all p>0.05).③The immunoreactive products of TrkB distributed in the cytoplasm, neucli and axons of pyramidal neurons within hippocampal CA1 subfield. The TrkB mRNA expression was higher in 2VO group than in sham-operated group (p <0.05). But the protein expression level didn’t change significantly in 2VO rats. Administration of ISA at three dosages and Dihydroergotoxine didn’t significantly change TrkB expression in protein levels and mRNA levels (all p>0.05)④The immunoreactive products of ChAT distributed in the cytoplasm and axons of pyramidal neurons within hippocampal CA1 subfield. The ChAT expression in protein and mRNA levels were lower in 2VO group than in sham-operated group (p<0.01). Administration of Dihydroergotoxine and ISA at the dose of 50 mg/kg and 100mg/kg increased the ChAT expressions in protein level (all p<0.01). ISA significantly increased ChAT mRNA expression at the dose of 100mg/kg, compared to 2VO group (p<0.05, p<0.01). Dihydroergotoxine and ISA at the dose of 50 mg/kg and 25mg/kg didn’t change ChAT mRNA expression markedly (all p>0.05).⑤The immunoreactive products of SYP surrounded the pyramidal neurons, showing the profile of the cell body and axon in the hippocampal CA1 region. Few immunoreactive products were observed in the cytoplasm and nucleu. The SYP expression in protein and mRNA levels were lower in 2VO group than in sham-operated group (p<0.05). Administration of Dihydroergotoxine and ISA at all doses increased the SYP expressions in protein level (all p<0.01). ISA increased SYP mRNA expression at the dose of ISA100mg/kg (p<0.01). Administration of Dihydroergotoxine and ISA at other doses didn’t markedly change the SYP expressions in mRNA level (all p >0.05).
Conclusions:①The declines of cholinergic function and synaptic loss accounted for the cognition deficits in rats subjected to CCH.②ISA enhanced the activity of ChAT and expression of SYP via increasing BDNF expression, subsequently improved the synaptic transmission efficiency.③ISA improved the learning and memory through enhancing the cholinergic function and synaptic plasticity in hippocampus of CCH rats.
Conclusions for the whole thesis:
1. The present research exhibited two kinds of VD rat model. The rats with photochemical lesion or CCH both showed significant declines in spatial learning and memory. The neuronal loss existed in the parietal cortex and hippocampal CA1 subfield respectively in the above-mentioned two sorts of model rats. The further transmission electron microscopy indicated the pathological changes of synaptic ultrastructure in hippocampal CA1 subfield of 2VO rats.
2. Compared to the photochemical lesion model, the 2VO rat model showed better stability, higher living rate and lower experimental costs. Most of all, it better mimiced the pathophysiologic process of VD in patients. So in the present research, we took use of the 2VO model to investigate the effects and mechanisms of ISA on rats with CCH.
3. The research showed that the treatment with ISA was benefit for rats with CCH, as evidenced by administration of ISA could ameliorate the spatial learning and memory, reduce the neuronal loss and enhance the structural plasticity of hippocampal synapse in rats. ISA showed better effects at the dose of 100mg/kg.
4. The research also indicated that the decline of cholinergic function and synaptic loss contributed to the cognition deficits in rats with CCH.
5. BDNF contributed to the compensation mechanism. ISA could enhance the endogenous neuroprotection induced by CCH through increasing the expression of BDNF in mRNA and protein levels in hippocampal CA1 subfield. Up-regulating the expressions of SYP and ChAT, two downstream proteins of BDNF-TrkB might be the main mechanism underlying the effects of ISA. (1) Administration of ISA for 8 weeks could significantly increase the number of ChAT immunoreaction-positive cell per unit area, the percentage of immunoreaction-positive area and ChAT mRNA expression in hippocampal CA1 subfield. This result indicated that the enhancement of cholinergic function induced by ISA could potentially supply the substance basis to the synaptic plasticity. (2) Administration of ISA could significantly increase the SYP expression in mRNA and protein levels, subsequently improved the learning and memory via enhancing synaptic transmission efficiency.
6. To conclude, ISA improved the learning and memory through enhancing the cholinergic function and protecting the synaptic structure in hippocampus of CCH rats.
异亚丙基莽草酸(3,4-oxo-isopropylidene shikimic acid,ISA)是从中药八角属植物八角茴香中提取的有效成分莽草酸(shikimic acid,SA)的合成衍生物,本组前期研究结果显示,ISA能够明显抑制多种诱导剂所致的血小板聚集以及实验性血栓的形成,对培养的海马以及神经细胞具有直接的神经保护作用,可对抗脑缺血—再灌注诱导的急性炎症反应。本研究进一步从行为学、神经细胞突触结构、胆碱能神经递质合成水平、突触前标志物以及核内转录因子表达水平等环节探讨了ISA对VD模型大鼠海马突触可塑性的干预作用及其可能的作用机理。实验分为三部分。
第一部分建立光化学损伤以及慢性低灌注性VD大鼠模型,探讨慢性低灌注大鼠海马CA1区神经元以及突触结构的变化特点
目的:探讨建立光化学损伤以及慢性低灌注性VD大鼠模型的条件以及两种模型的特点,并探讨慢性低灌注大鼠海马CA1区神经元以及突触结构的变化特征。方法:采用舌下静脉注射4%玫瑰红与绿光照射顶叶皮层相结合的方法诱导大鼠局灶性脑缺血,建立光化学损伤性VD大鼠模型,术后30天通过Morris水迷宫对大鼠进行空间记忆测试;采用永久性结扎加切断大鼠双侧颈总动脉的方法诱导前脑慢性低灌注性VD大鼠模型,60天后通过Morris水迷宫对其进行空间记忆测试。将Morris水迷宫测试结束后的大鼠进行经心灌注固定,制成大脑石蜡切片后,进行HE染色以及Nissl染色,光镜下观察顶叶皮层神经元或海马CA1区锥体神经元的形态学改变。并采用透射电子显微镜观察慢性低灌注性VD模型大鼠海马CA1区突触结构的改变。
结果:①采用舌下静脉注射4%玫瑰红复合5mm直径绿光光纤照射顶叶皮层诱导的VD模型大鼠出现明显的学习记忆障碍,表现为在第2—4天定位航行测试中的逃避潜伏期明显长于假手术组(p<0.05;p<0.01);在空间探索测试中,大鼠游泳初始角度显著大于假手术组(p<0.05)。②光化学损伤造成大鼠顶叶皮质出现明显可见的圆形梗死灶。梗死灶内神经细胞消失,灶内无明显出血。外围的过渡区内从相对正常状态过渡到梗死灶,病变逐渐加重。③双侧颈总动脉永久性结扎加切断后8周,模型大鼠出现明显的学习记忆障碍,表现为在第3天定位航行测试中的路径长度显著长于假手术大鼠(p<0.05);在第2天以及第3天定位航行测试中的游泳错误初始角度显著大于假手术大鼠(p<0.05;p<0.01)。在空间探索测试中,模型大鼠的游泳错误初始角度显著大于假手术大鼠(p<0.05),但二者的原平台象限游泳距离百分比无显著差异(p>0.05)。④慢性低灌注大鼠海马CA1区的锥体细胞排列紊乱,部分脱失,胶质细胞增生显著。⑤进一步采用双侧颈总动脉结扎模型大鼠进行的透射电镜研究显示,8周后该模型大鼠海马CA1区突触间隙模糊,部分突触间隙增宽,突触前后膜肿胀、空化,囊泡数量减少。⑥光化学法VD模型大鼠死亡率较高,为25%;而双侧颈总动脉永久性结扎造成的VD模型大鼠死亡率较低,为10%。
结论:①成功建立了光化学损伤和慢性低灌注两种VD大鼠模型。光化学法与双侧颈总动脉永久性结扎造成的VD模型大鼠在学习记忆以及神经元形态学改变方面均较为显著。②慢性低灌注大鼠模型由于死亡率较低,且手术操作相对简便而更适用于进一步的药效学研究。
第二部分异亚丙基莽草酸对慢性低灌注大鼠的药效作用研究
目的:探讨ISA对双侧颈总动脉结扎造成的慢性低灌注大鼠空间学习记忆能力、海马CA1区神经元形态学以及突触超微结构的影响。
方法:采用永久性结扎大鼠双侧颈总动脉的方法诱导前脑慢性低灌注大鼠模型。实验动物分为假手术组、模型组、阳性对照药喜得镇组、ISA100mg/kg组、ISA50mg/kg组以及ISA25mg/kg组。造模后连续灌胃给予大鼠相应药物60天,通过Morris水迷宫对其进行4d定位航行及1d空间探索测试。水迷宫测试结束后,将部分大鼠进行经心灌注固定,制成大脑石蜡切片,进行HE染色。行为学测试结束后,另取部分大鼠经心灌注固定,取海马CA1区,制成超薄切片。采用透射电镜观察大鼠突触前及突触后结构参数的改变,包括突触界面曲率、活性区长度(length of active zone, L)、突触后致密物质(postsynaptic density,PSD)厚度、突触数密度(numerical density per unit volume of synapses, Nv)、面密度(surface density per unit volume, Sv)、入坞囊泡(docked vesicle, DV)的数量以及单位长度活性区中入坞囊泡的数量(DV/L)。
结果:①双侧颈总动脉结扎诱导的慢性低灌注模型大鼠出现明显的学习记忆障碍。与假手术组相比,模型大鼠在第2、3天定位航行实验中的游泳初始角度增加显著(p<0.05;p<0.01);在第3天定位航行实验中,游泳路径长度延长显著(p<0.05)。在空间探索实验中游泳初始角度明显大于假手术组(p<0.05)。其游泳策略在中早期一般以边缘式为主,后期大多表现为趋向式。造模后连续给与ISA100mg/kg可明显缩短第2天定位航行的游泳路径长度(p<0.05),而对定位航行中游泳初始角度以及其他时间点的游泳路径长度以及空间探索实验中游泳初始角度无显著影响(p>0.05)。ISA50mg/kg可明显减小空间探索实验中的游泳初始角度(p<0.05),而对定位航行中游泳路径长度以及初始角度无显著影响(p>0.05)。ISA25mg/kg可明显减小在第3天定位航行实验及空间探索实验中的游泳初始角度(p<0.01; p<0.05),而对定位航行中的游泳路径长度无显著影响(p>0.05)。ISA各组的游泳策略在中早期一般以趋向式为主,后期大多表现为直线式。喜得镇可明显减小在第3天定位航行实验中的游泳初始角度(p<0.05),而对定位航行中游泳路径长度、其他时间点的初始角度以及空间探索实验中游泳初始角度无显著影响(p>0.05)。其游泳策略在中早期一般以趋向式为主,后期大多表现为直线式。②慢性低灌注大鼠海马CA1区的锥体细胞排列紊乱,部分脱失,神经细胞数明显较少,部分神经细胞水肿,细胞核固缩,有的形成碎片,胶质细胞显著增加。ISA及喜得镇组大鼠的神经元损伤明显减轻,尤以ISA100mg/kg剂量组减轻更明显,表现为海马各区神经细胞胞浆丰富、排列紧密、结构完整,核仁、核膜清晰可见,胞浆染色正常。③慢性低灌注模型大鼠海马CA1区神经毡内突触间隙模糊,突触前后膜肿胀、空化。模型大鼠海马CA1区Nv、Sv、DV、L、DV/L以及突触界面曲率降低非常显著(p<0.01),但PSD厚度未见显著变化(p>0.05)。连续灌胃给与ISA及喜得镇65d后上述损伤明显减轻。与模型组相比,各剂量ISA以及喜得镇可使Nv、Sv、DV、L以及DV/L显著增加(p<0.05;p<0.01)。ISA100mg/kg以及ISA50mg/kg还可明显增加突触界面曲率(p<0.05;p<0.01)。ISA各剂量以及喜得镇组间无显著差异(p>0.05)。
结论:ISA连续灌胃给药8周后各剂量组均可提高慢性低灌注大鼠对空间记忆的获取以及保持能力;改善慢性低灌注大鼠海马CA1区神经细胞形态;显著改善慢性低灌注大鼠海马CA1区突触超微结构,促进突触的结构可塑性。
第三部分异亚丙基莽草酸增强慢性低灌注大鼠突触可塑性的可能作用机制
目的:探讨慢性低灌注大鼠海马CA1区突触可塑性相关蛋白突触素(synaptophysin, SYP)、胆碱乙酰转移酶(choline acetyltransferase, ChAT)、磷酸化cAMP反应元件结合蛋白(phosphorylated- cAMP responsive element binding protein, p-CREB)、脑源性神经营养因子(brain derived neurotrophic factor, BDNF)以及酪氨酸激酶B(tyrosine kinase B, TrkB)的蛋白表达以及基因转录水平的改变,并观察ISA对其影响。
方法:实验动物分为假手术组、模型组、阳性对照药喜得镇组、ISA100mg/kg组、ISA50mg/kg组以及ISA25mg/kg组。将Morris水迷宫测试结束后的慢性低灌注大鼠经心灌注固定,制备大脑石蜡切片后,进行免疫组织化学染色,测定海马CA1区SYP、ChAT、p-CREB、BDNF以及TrkB的定位以及相对定量表达。提取大鼠海马CA1区组织蛋白,利用Western Blot对SYP、p-CREB、BDNF以及TrkB的蛋白表达水平进行半定量测定。抽提大鼠海马CA1区组织总RNA,通过荧光定量实时PCR技术,对BDNF、ChAT、TrkB、SYP以及CREB的mRNA表达水平进行测定。
结果:①大鼠海马CA1区SYP免疫反应阳性产物主要分布于神经元周围,胞浆内颗粒状免疫反应产物少见,白质、血管及胶质细胞不着色。模型大鼠海马CA1区SYP蛋白表达水平以及SYP mRNA表达水平非常显著低于假手术组(p<0.01)。与模型组相比,ISA100mg/kg以及50mg/kg组大鼠的SYP蛋白表达水平显著增加(p<0.05);ISA100mg/kg连续灌胃给药65d可显著增加SYP mRNA表达水平(p<0.05);除ISA100mg/kg外,ISA其余各剂量以及喜得镇对SYP mRNA表达水平无显著影响(p>0.05)。
②大鼠海马CA1区ChAT免疫反应阳性产物主要分布于锥体细胞的胞浆及轴突。模型大鼠的ChAT蛋白表达水平以及ChAT mRNA表达水平非常显著低于假手术组(p<0.01)。与模型组相比,除ISA25mg/kg组外,各给药组的ChAT蛋白表达水平均升高显著(p<0.05;p<0.01);ISA100mg/kg组的ChAT mRNA表达水平增加非常显著(p<0.01),而ISA其余各剂量以及喜得镇对ChAT mRNA表达水平无显著影响(p>0.05)。
③p-CREB免疫反应阳性颗粒主要分布于锥体细胞的胞核中。模型组大鼠海马CA1区p-CREB蛋白表达水平以及CREB mRNA表达水平显著高于假手术组(p<0.05)。与模型组相比,ISA各剂量以及喜得镇对p-CREB蛋白表达水平无显著影响(p>0.05);ISA100mg/kg连续灌胃给药65d后,可显著增加大鼠海马CA1区CREB mRNA表达水平(p<0.05);ISA其余各剂量以及喜得镇对CREB mRNA表达水平无显著影响(p>0.05)。
④B DNF免疫反应阳性产物主要分布于神经元的胞浆、胞核以及长的轴突中。模型大鼠海马CA1区BDNF蛋白表达水平以及BDNF mRNA表达水平均显著高于假手术组(p<0.05)。与模型组相比,100mg/kg的ISA可显著增加BDNF蛋白表达水平以及BDNF mRNA表达水平(p<0.05);喜得镇、ISA50mg/kg与25mg/kg组的BDNF蛋白表达水平以及BDNF mRNA表达水平无显著改变(p>0.05)。
⑤TrkB的免疫反应阳性产物主要分布于神经元的胞浆及轴突内。模型大鼠海马CA1区TrkB mRNA表达水平显著高于假手术组(p<0.05),但是蛋白表达水平未发生显著改变(p>0.05)。各ISA组与喜得镇组的TrkB蛋白以及mRNA表达水平无显著变化(p>0.05)。
结论:①长期慢性低灌注导致大鼠海马CA1区ChAT以及SYP表达水平降低。胆碱能神经功能降低以及突触丢失造成了海马突触结构可塑性的降低,而突触结构可塑性的降低可能是导致慢性低灌注大鼠学习记忆下降的结构基础。②BDNF参与了慢性低灌注损伤后的补偿机制。ISA可通过上调内源性保护因子BDNF的表达,进而提高ChAT的活性以及SYP的含量,提高突触传递效能。③ISA可通过增强胆碱能神经功能以及保护突触结构而促进突触可塑性,进而提高慢性低灌注性痴呆动物的学习记忆能力。
全文结论:
1.本研究成功建立了两种VD大鼠模型,即光化学损伤以及慢性低灌注性VD大鼠模型。两种模型大鼠均表现出明显的空间学习记忆障碍,同时顶叶皮质或海马CA1区神经元严重脱失。并且慢性低灌注大鼠海马CA1区突触超微结构出现明显损伤。
2.相对于光化学损伤诱导的VD模型而言,慢性低灌注大鼠模型更稳定,动物成活率高,实验成本低,与人类VD的病理生理过程更加接近。本研究采用慢性低灌注大鼠模型进行ISA的药效学以及作用机制研究。
3.本研究提示ISA对抗慢性低灌注性VD具有良好的药效作用,表现为连续灌胃给药8周后可明显改善慢性低灌注大鼠的学习记忆功能;减少海马CA1区锥体神经元的脱失,保护神经元形态的完整;促进海马突触的结构可塑性。并以ISA100mg/kg剂量组的药效作用为更好。
4.本研究还提示突触丢失以及胆碱能神经功能障碍可能是导致慢性低灌注性痴呆动物学习记忆下降的主要原因。
5.ISA的作用可能是通过提高BDNF在CA1区的蛋白以及mRNA表达水平,从而进一步加强慢性低灌注本身引发的内源性神经保护机制。即ISA通过加强BDNF-TrkB对其下游靶蛋白SYP以及ChAT的调节,提高突触传递效能。(1)连续给与ISA 8周后,大鼠海马CA1区单位面积中ChAT免疫反应阳性细胞数、免疫反应阳性产物面积百分率以及ChA mRNA表达水平均显著高于模型组。说明给与外源性药物ISA后,胆碱能水平的增加为突触可塑性的增强提供了物质基础。(2)ISA连续用药8周后,大鼠海马CA1区SYP蛋白以及mRNA表达水平均显著提高。这提示ISA可能是通过提高SYP蛋白以及mRNA表达水平,进而提高突触传递效能而改善实验动物的学习记忆能力。6.综上所述,ISA可通过增强胆碱能神经功能以及保护突触结构而促进突触可塑性,进而提高慢性低灌注性痴呆动物的学习记忆能力。
本研究的创新点:
1.首先研究ISA对慢性低灌注大鼠模型的药效学作用;
2.首先采用慢性低灌注大鼠模型研究海马p-CREB表达水平,以及海马CA1区突触中入坞囊泡数量的改变。
Vascular dementia (VD), which is characterized by progressive intellectual decline induced by ischemia hypoxia or hemorrhage brain lesion, represents the second most common dementia accounting for about a quarter to a half of all cases of dementia in developed countries. Chronic cerebral hypoperfusion (CCH) is one of common pathophysiologic basis of VD and Alzheimer's disease. CCH impacts the delivery of glucose and oxygen, leading to the handicap of energy metabolism in the brain synaptic pathway, followed by the decline of the whole brain function including memory decline. The structural basis of memory is synapse. The enhancement of synaptic function contributes to the formation of memory. The rats with memory decline showed the changes in synaptic structural parameters, such as the decrease of numerical density of synapses (Nv) and docked vesicles (Dv).
With increasing number of the elderly in world populations, dementia, characterized by progressive descending of memory and cognition, has given rise to enormous socioeconomic burden. In the past few decades, a great deal of investigation has been conducted. However, the efficiency of currently available strategies for the prevention of VD remains poor. 3,4-oxo-isopropylidene-shikimic acid(ISA)was extracted from Illicium verum Hook. Fil, a traditional Chinese herb. Our preliminary work showed that ISA could suppress variously experimental thrombosis and platelet aggregation significantly, improve the morphology and decrease the apoptosis rate of cultured cortical and hippocampal neurons after hypoxia-reoxygenation injury, exert neuroprotective effects on rats subjected to middle cerebral artery occlusion (MCAO) and reperfusion by an intraluminal thread, as evidenced by decreasing the neurological severity score, infarct volume, brain water content and brain edema. It was indicated that the anti-free radical effects of ISA might account for the protection against cerebral ischemia. Thus, ISA appeared to be a promising drug to ameliorate cognitive deficits induced by cerebral ischemia. But to our knowledge, the effects and the mechanism of ISA on CCH in rats remain to be elucidated. In the present study, we made use of the permanent occlusion of bilateral common carotid arteries (two-vessel occlusion, 2VO) model of CCH to evaluate the effects of ISA on synaptic plasticity in dementia rats. The possible mechanism underlying its effect was also explored. To address this issue, a variety of multidisciplinary approaches including Morris water maze, transmission electron microscopy, immunohistochemical staining, Western blotting, fluorescent quantitative real-time polymerase chain reaction were used.
There are three stories in this thesis.
PartⅠCreation of two kinds of VD rat models and the investigation on the pathological changes in neurons and synaptic ultrastructure in hippocampal CA1 subfield
Objective: To explore the characteristics of the photochemical model and 2VO model, and to investigate the pathological changes of neurons and synaptic ultrastructure in hippocampal CA1 subfield.
Methods: A focal lesion in the left parietal cortex was induced photochemically by using Rose Bengal as a photosensitive dye and cold light beam, then the rats were treated with ISA orally once a day for 30 days. The cognitive effects of ISA were assessed in rats using the Morris water maze test for spatial learning and memory. HE staining and Nissl staining were used to study the neuronal alteration in left parietal cortex. For the reproduction of CCH as it occurs in VD, permanent occlusion of the bilateral common carotid arteries of rats (2-vessel occlusion, 2VO) was introduced. 60 days after 2VO surgery, the rats underwent spatial cognition test in Morris water maze. Subsequently the brain sections were subjected to HE staining and transmission electron microscopy. Results:①Photochemical lesion induced spatial cognition deficits, which was proven by prolonged escape latency on the 2-4 training days(p<0.05, p<0.01)and the larger initial angle in probe test, compared to the sham-operated group(p<0.05).②Photochemical lesion could induce round infarction in the left parietal cortex of rats. The neurons in the infarction almost disappeared. No obvious hemorrhage and edema existed. The pathological changes were gradiently severe from relatively normal brain region to the infarction.③8 weeks after 2VO surgery, the model rats showed significant cognition deficits, as evidenced by longer swimming path length on the third training day(p<0.05), the larger initial angles on the second and third training day(p<0.05, p<0.01), compared to the sham-operated group rats. In the probe test, the model rats exhibited larger initial angles(p<0.05), compared to the sham-operated group rats. No difference in the quadrant percentage was observed between the two groups(p>0.05).④Macroscopic evaluation of rat brains demonstrated that 2VO induced pyramidal neuron damage in hippocampus CA1 subfield 65 days after operation. The rats showed severe neuronal loss and the gliocyte proliferation in the hippocampal CA1 region.⑤The synaptic ultrastructures of neuropil field within CA1 stratum radiatum of the sham-operated group rats were intact. The synapses of GrayⅠtype showed clear synaptic clefts, typical asymmetric interfaces, intact structures of the pre- and postsynaptic membranes, round clear vesicles and thick postsynaptic densities (PSD). The synaptic ultrastructures of 2VO group presented the blurry synaptic clefts, swollen, vacuolated pre- and postsynaptic membranes and less synaptic vesicles in the synaptic terminals.⑥The mortality rate in the model rats with photochemical lesion was 25%, while 10% in the model rats with CCH. Conclusion:①Two VD models induced by the photochemical lesion and 2VO respectively in rats were created. The changes in the cognition and neuronal pathology in the 2VO rats were observed.②2VO model is more suitable for the investigating in the further pharmacodynamics research due to its lower mortality rate and easier surgical process.
PartⅡPharmacodynamics research of 3, 4-oxo-isopropylidene-shikimic acid in rats with vascular dementia induced by chronic cerebral hypoperfusion
Objective: To probe the effects of ISA on spatial cognition, neuronal pathology and synaptic ultrastructure within hippocampal CA1 subfield in rats with CCH.
Methods: We used 2VO to induce CCH in rats. Male Sprague Dawley rats were randomly divided into six groups including vehicle-treated sham-operated group, vehicle-treated operated group, ISA 100mg/kg-treated operated group, ISA 50mg/kg-treated operated group, ISA 25mg/kg-treated operated group and Hydergine 0.6mg/kg-treated operated group. Vehicle group rats’bilateral carotid arteries were occluded. The sham-operated rats received the same operation with the exception of ligation. Other rats were intragastricly administered relevant drugs once per day. Eight weeks after 2VO, Morris water maze was used to measure spatial learning and memory. Each rat received two trials everyday for 4 consecutive days. Length of swimming path to escape onto the hidden platform and initial angle were recorded. On the fifth day, each rat was subjected to a 20-second probe trial in which the platform was removed and the initial angle and typical swim-tracking path were recorded. Subsequently, the morphological changes in neurons were evaluated with HE staining in hippocampal CA1 subfield. Transmission electron microscopy was used to evaluate the following synaptic structural parameters in hippocampal CA1 subfield. Nv, surface density (Sv), DV and DV per unit length of active zone (L) were measured.
Results:①The sham-operated rats showed smaller initial angles on the second (p<0.05) and third (p< 0.01) training days, and the shorter path length on the third training day (p<0.05), compared to 2VO group. In the probe test, the initial angle of sham-operated group was smaller than 2VO rats (p<0.05). The swimming strategy was tendency at the early stage and straight at the late stage in sham-operated rats, and marginal at the early stage and random pattern at the late stage in 2VO rats. Administration of ISA at the dose of 100mg/kg could significantly shorten the path length on the second training day (p<0.05), but didn’t change the path length on other training days, and initial angle in navigation trails and probe trail, compared to 2VO group (all p>0.05). Administration of ISA at the dose of 50mg/kg could significantly reduce initial angle in probe trail (p<0.05), but didn’t change the path length and initial angle in navigation trails, compared to 2VO group (all p>0.05). Administration of ISA at the dose of 25mg/kg could significantly reduce initial angle on the third training day in navigation trail(p<0.01)and probe trail (p<0.05), but couldn’t change the path length in navigation trail, compared to 2VO group (all p>0.05). When treated with dihydroergotoxine at the dose of 0.6mg/kg, the rats showed smaller initial angle on the third training day, compared to 2VO group (p<0.05). No difference in swimming path length on other training days, and initial angle in probe trail were observed, compared to 2VO group (all p>0.05). The main swimming strategies in all drug-treated groups were tendency at the early stage and straight at the late stage.②Microscopic evaluation of rat brains demonstrated that 2VO induced pyramidal neuron damage in hippocampus CA1 subfield 65 days after operation. 2VO rats showed severe neuronal loss and the gliocyte proliferation in the hippocampal CA1 region. The structures of pyramidal neurons in all drug-treated groups were relatively intact.③The synaptic ultrastructures of neuropil field within CA1 stratum radiatum of the sham-operated group rats were intact. The synapses of GrayⅠtype showed clear synaptic clefts, typically asymmetric interfaces, intact structures of the pre- and postsynaptic membranes, round clear vesicles and thick PSD. The synaptic ultrastructures of 2VO rats presented the blurry synaptic clefts, swollen and vacuolated pre- and postsynaptic membranes. The synaptic ultrastructures were relatively intact in all drug-treated groups. There were more synaptic vesicles in the presynaptic terminals in ISA and dihydroergotoxine-treated groups, compared to 2VO group. Compared to the sham-operated group, the 2VO rats showed significantly reduced Nv, Sv, DV, DV/L and synaptic curvature (all p<0.01), but the thickness of PSD didin’t change markedly (p>0.05). All the ISA-treated and dihydroergotoxine-treated rats showed markedly increased Nv, Sv, DV and DV/L (p<0.05, p<0.01), compared to 2VO group. Administration of ISA at the dose of 50mg/kg (p<0.01) and 100mg/kg (p<0.05) could significantly increase the synaptic curvature.
Conclusions: Administration of ISA could improve the decline of learning and memory, and protect the neuronal morphology of the brain in rats with CCH. It improved the structural plasticity of CA1 synapses.
PartⅢProbe into the potential molecular mechanism of 3, 4-oxo-isopropylidene-shikimic acid underlying its synaptic plasticity effects on vacular dementia induced by chronic cerebral hypoperfusion
Objective: To probe effects of ISA on the expressions of brain derived neurotrophic factor (BDNF), its receptor tyrosine kinase B(TrkB), Choline acetyltransferase (ChAT), synaptophysin (SYP), phosphorylated cAMP response element binding protein (p-CREB) in the mRNA and protein levels within hippocampal CA1 region of CCH rats. Methods: Male Sprague Dawley rats were randomly divided into six groups including vehicle-treated sham-operated group, vehicle-treated operated group, ISA 100mg/kg-treated operated group, ISA 50mg/kg-treated operated group, ISA 25mg/kg-treated operated group and Hydergine 0.6mg/kg-treated operated group. After the behavioral test, rats were perfused intracardially. The paraffin sections were used for immunohistochemistry staining to probe the expression of p-CREB, BDNF, TrkB, ChAT and SYP in protein level within hippocampal CA1 subfield. The proteins were extracted and used for evaluation of the semi-quantitative expression of p-CREB, BDNF, TrkB, ChAT and SYP in protein level. Fluorescent quantitative real-time polymerase chain reaction was employed to measure the mRNA expression level of BDNF, TrkB, ChAT, SYP and CREB.
Results:①At week 9 after 2VO surgery, the immunoreactive products of p-CREB, some brown granules, distributed in the neucli of pyramidal neurons within hippocampal CA1 region. The expressions of p-CREB in protein level and CREB in mRNA level were higher in 2VO group than in sham-operated group (both p <0.05). Administration of ISA at the dose of 100mg/kg increased the CREB expression in mRNA level, compared to the 2VO group (p<0.05). Dihydroergotoxine and ISA at three doses didn’t significantly change the expressions of p-CREB in protein level and CREB in mRNA level (all p>0.05).②The immunoreactive products of BDNF distributed in the cytoplasm, neucli and axons of pyramidal neurons within hippocampal CA1 subfield. The BDNF expressions in protein and mRNA levels were higher in 2VO group than in sham-operated group (p<0.05). Administration of ISA at the dose of 100mg/kg could markedly increase BDNF expression in protein and mRNA levels, compared to the 2VO group (both p<0.05). Dihydroergotoxine and ISA at the doses of 50mg/kg and 25mg/kg didn’t significantly change BDNF expression in protein and mRNA levels (all p>0.05).③The immunoreactive products of TrkB distributed in the cytoplasm, neucli and axons of pyramidal neurons within hippocampal CA1 subfield. The TrkB mRNA expression was higher in 2VO group than in sham-operated group (p <0.05). But the protein expression level didn’t change significantly in 2VO rats. Administration of ISA at three dosages and Dihydroergotoxine didn’t significantly change TrkB expression in protein levels and mRNA levels (all p>0.05)④The immunoreactive products of ChAT distributed in the cytoplasm and axons of pyramidal neurons within hippocampal CA1 subfield. The ChAT expression in protein and mRNA levels were lower in 2VO group than in sham-operated group (p<0.01). Administration of Dihydroergotoxine and ISA at the dose of 50 mg/kg and 100mg/kg increased the ChAT expressions in protein level (all p<0.01). ISA significantly increased ChAT mRNA expression at the dose of 100mg/kg, compared to 2VO group (p<0.05, p<0.01). Dihydroergotoxine and ISA at the dose of 50 mg/kg and 25mg/kg didn’t change ChAT mRNA expression markedly (all p>0.05).⑤The immunoreactive products of SYP surrounded the pyramidal neurons, showing the profile of the cell body and axon in the hippocampal CA1 region. Few immunoreactive products were observed in the cytoplasm and nucleu. The SYP expression in protein and mRNA levels were lower in 2VO group than in sham-operated group (p<0.05). Administration of Dihydroergotoxine and ISA at all doses increased the SYP expressions in protein level (all p<0.01). ISA increased SYP mRNA expression at the dose of ISA100mg/kg (p<0.01). Administration of Dihydroergotoxine and ISA at other doses didn’t markedly change the SYP expressions in mRNA level (all p >0.05).
Conclusions:①The declines of cholinergic function and synaptic loss accounted for the cognition deficits in rats subjected to CCH.②ISA enhanced the activity of ChAT and expression of SYP via increasing BDNF expression, subsequently improved the synaptic transmission efficiency.③ISA improved the learning and memory through enhancing the cholinergic function and synaptic plasticity in hippocampus of CCH rats.
Conclusions for the whole thesis:
1. The present research exhibited two kinds of VD rat model. The rats with photochemical lesion or CCH both showed significant declines in spatial learning and memory. The neuronal loss existed in the parietal cortex and hippocampal CA1 subfield respectively in the above-mentioned two sorts of model rats. The further transmission electron microscopy indicated the pathological changes of synaptic ultrastructure in hippocampal CA1 subfield of 2VO rats.
2. Compared to the photochemical lesion model, the 2VO rat model showed better stability, higher living rate and lower experimental costs. Most of all, it better mimiced the pathophysiologic process of VD in patients. So in the present research, we took use of the 2VO model to investigate the effects and mechanisms of ISA on rats with CCH.
3. The research showed that the treatment with ISA was benefit for rats with CCH, as evidenced by administration of ISA could ameliorate the spatial learning and memory, reduce the neuronal loss and enhance the structural plasticity of hippocampal synapse in rats. ISA showed better effects at the dose of 100mg/kg.
4. The research also indicated that the decline of cholinergic function and synaptic loss contributed to the cognition deficits in rats with CCH.
5. BDNF contributed to the compensation mechanism. ISA could enhance the endogenous neuroprotection induced by CCH through increasing the expression of BDNF in mRNA and protein levels in hippocampal CA1 subfield. Up-regulating the expressions of SYP and ChAT, two downstream proteins of BDNF-TrkB might be the main mechanism underlying the effects of ISA. (1) Administration of ISA for 8 weeks could significantly increase the number of ChAT immunoreaction-positive cell per unit area, the percentage of immunoreaction-positive area and ChAT mRNA expression in hippocampal CA1 subfield. This result indicated that the enhancement of cholinergic function induced by ISA could potentially supply the substance basis to the synaptic plasticity. (2) Administration of ISA could significantly increase the SYP expression in mRNA and protein levels, subsequently improved the learning and memory via enhancing synaptic transmission efficiency.
6. To conclude, ISA improved the learning and memory through enhancing the cholinergic function and protecting the synaptic structure in hippocampus of CCH rats.
引文
[1] Abel, T., Lattal, K.M. Molecular mechanisms of memory acquisition, consolidation and retrieval. Curr Opin Neurobiol, 2001,11(2);180-187.
[2] Schimanski, L.A., Nguyen, P.V. Multidisciplinary approaches for investigating the mechanisms of hippocampus-dependent memory: a focus on inbred mouse strains. Neurosci Biobehav Rev, 2004,28(5);463-483.
[3] Okada, T., Yamada, N., Tsuzuki, K., et al. Long-term potentiation in the hippocampal CA1 area and dentate gyrus plays different roles in spatial learning. Eur J Neurosci, 2003,17(2);341-349.
[4] Schinder, A.F., Poo, M. The neurotrophin hypothesis for synaptic plasticity. Trends Neurosci, 2000,23(12);639-645.
[5] Thoenen, H. Neurotrophins and activity-dependent plasticity. Prog Brain Res, 2000,128;183-191.
[6] Poo, M.M. Neurotrophins as synaptic modulators. Nat Rev Neurosci, 2001,2(1);24-32.
[7] Mowla, S.J., Farhadi, H.F., Pareek, S., et al. Biosynthesis and post-translational processing of the precursor to brain-derived neurotrophic factor. J Biol Chem, 2001,276(16);12660-12666.
[8] Murer, M.G., Yan, Q., Raisman-Vozari, R. Brain-derived neurotrophic factor in the control human brain, and in Alzheimer's disease and Parkinson's disease. Prog Neurobiol, 2001,63(1);71-124.
[9] Tao, X., West, A.E., Chen, W.G., et al. A calcium-responsive transcription factor, CaRF, that regulates neuronal activity-dependent expression of BDNF. Neuron, 2002,33(3);383-395.
[10] Aliaga, E., Arancibia, S., Givalois, L., et al. Osmotic stress increases brain-derived neurotrophic factor messenger RNA expression in the hypothalamic supraoptic nucleus with differential regulation of its transcripts. Relation to arginine-vasopressin content. Neuroscience, 2002,112(4);841-850.
[11] Dias, B.G., Banerjee, S.B., Duman, R.S., et al. Differential regulation of brain derived neurotrophic factor transcripts by antidepressant treatments in the adult rat brain. Neuropharmacology, 2003,45(4);553-563.
[12] Rattiner, L.M., Davis, M., Ressler, K.J. Differential regulation of brain-derived neurotrophic factor transcripts during the consolidation of fear learning. Learn Mem, 2004,11(6);727-731.
[13] Tabuchi, A., Sakaya, H., Kisukeda, T., et al. Involvement of an upstream stimulatory factor as well as cAMP-responsive element-binding protein in the activation of brain-derived neurotrophic factor gene promoter I. J Biol Chem, 2002,277(39);35920-35931.
[14] Righi, M., Tongiorgi, E., Cattaneo, A. Brain-derived neurotrophic factor (BDNF) induces dendritic targeting of BDNF and tyrosine kinase B mRNAs in hippocampal neurons through a phosphatidylinositol-3 kinase-dependent pathway. J Neurosci, 2000,20(9);3165-3174.
[15] Patterson, S.L., Pittenger, C., Morozov, A., et al. Some forms of cAMP-mediated long-lasting potentiation are associated with release of BDNF and nuclear translocation of phospho-MAP kinase. Neuron, 2001,32(1);123-140.
[16] Miller, S., Yasuda, M., Coats, J.K., et al. Disruption of dendritic translation of CaMKIIalpha impairs stabilization of synaptic plasticity and memory consolidation. Neuron, 2002,36(3);507-519.
[17] Villarreal, D.M., Do, V., Haddad, E., et al. NMDA receptor antagonists sustain LTP and spatial memory: active processes mediate LTP decay. Nat Neurosci, 2002,5(1);48-52.
[18] Kandel, E.R. The molecular biology of memory storage: a dialogue between genes and synapses. Science, 2001,294(5544);1030-1038.
[19] Hansson, A.C., Cintra, A., Belluardo, N., et al. Gluco- and mineralocorticoid receptor-mediated regulation of neurotrophic factor gene expression in the dorsal hippocampus and the neocortex of the rat. Eur J Neurosci, 2000,12(8);2918-2934.
[20] Russo-Neustadt, A.A., Beard, R.C., Huang, Y.M., et al. Physical activity and antidepressant treatment potentiate the expression of specific brain-derived neurotrophic factor transcripts in the rat hippocampus. Neuroscience, 2000,101(2);305-312.
[21] Ickes, B.R., Pham, T.M., Sanders, L.A., et al. Long-term environmental enrichment leads to regional increases in neurotrophin levels in rat brain. Exp Neurol, 2000,164(1);45-52.
[22] Miyake, K., Yamamoto, W., Tadokoro, M., et al. Alterations in hippocampal GAP-43, BDNF, and L1 following sustained cerebral ischemia. Brain Res, 2002,935(1-2);24-31.
[23] Drake, C.T., Milner, T.A., Patterson, S.L. Ultrastructural localization of full-length trkB immunoreactivity in rat hippocampus suggests multiple roles in modulating activity-dependent synaptic plasticity. J Neurosci, 1999,19(18);8009-8026.
[24] Tyler, W.J., Pozzo-Miller, L.D. BDNF enhances quantal neurotransmitter release and increases the number of docked vesicles at the active zones of hippocampal excitatory synapses. J Neurosci, 2001,21(12);4249-4258.
[25] Larsson, E., Nanobashvili, A., Kokaia, Z., et al. Evidence for neuroprotective effects of endogenous brain-derived neurotrophic factor after global forebrain ischemia in rats. J Cereb Blood Flow Metab, 1999,19(11);1220-1228.
[26] Keenan, J.P., Nelson, A., O'Connor, M., et al. Self-recognition and the right hemisphere. Nature, 2001,409(6818);305.
[27] Hartmann, M., Heumann, R., Lessmann, V. Synaptic secretion of BDNF after high-frequency stimulation of glutamatergic synapses. Embo J, 2001,20(21);5887-5897.
[28] Kohara, K., Kitamura, A., Morishima, M., et al. Activity-dependent transfer of brain-derived neurotrophic factor to postsynaptic neurons. Science,2001,291(5512);2419-2423.
[29] Kojima, M., Takei, N., Numakawa, T., et al. Biological characterization and optical imaging of brain-derived neurotrophic factor-green fluorescent protein suggest an activity-dependent local release of brain-derived neurotrophic factor in neurites of cultured hippocampal neurons. J Neurosci Res, 2001,64(1);1-10.
[30] Fawcett, J.P., Bamji, S.X., Causing, C.G., et al. Functional evidence that BDNF is an anterograde neuronal trophic factor in the CNS. J Neurosci, 1998,18(8);2808-2821.
[31] Griesbeck, O., Canossa, M., Campana, G., et al. Are there differences between the secretion characteristics of NGF and BDNF? Implications for the modulatory role of neurotrophins in activity-dependent neuronal plasticity. Microsc Res Tech, 1999,45(4-5);262-275.
[32] Rose, C.R., Blum, R., Kafitz, K.W., et al. From modulator to mediator: rapid effects of BDNF on ion channels. Bioessays, 2004,26(11);1185-1194.
[33] Teng, H.K., Teng, K.K., Lee, R., et al. ProBDNF induces neuronal apoptosis via activation of a receptor complex of p75NTR and sortilin. J Neurosci, 2005,25(22);5455-5463.
[34] Glombik, M.M., Gerdes, H.H. Signal-mediated sorting of neuropeptides and prohormones: secretory granule biogenesis revisited. Biochimie, 2000,82(4);315-326.
[35] Binder, D.K., Routbort, M.J., McNamara, J.O. Immunohistochemical evidence of seizure-induced activation of trk receptors in the mossy fiber pathway of adult rat hippocampus. J Neurosci, 1999,19(11);4616-4626.
[36] Ying, S.W., Futter, M., Rosenblum, K., et al. Brain-derived neurotrophic factor induces long-term potentiation in intact adult hippocampus: requirement for ERK activation coupled to CREB and upregulation of Arc synthesis. J Neurosci, 2002,22(5);1532-1540.
[37] Sweatt, J.D. The neuronal MAP kinase cascade: a biochemical signal integration system subserving synaptic plasticity and memory. J Neurochem, 2001,76(1);1-10.
[38] Iwasaki, Y., Gay, B., Wada, K., et al. Association of the Src family tyrosine kinase Fyn with TrkB. J Neurochem, 1998,71(1);106-111.
[39] Kaplan, D.R., Miller, F.D. Neurotrophin signal transduction in the nervous system. Curr Opin Neurobiol, 2000,10(3);381-391.
[40] Patapoutian, A., Reichardt, L.F. Trk receptors: mediators of neurotrophin action. Curr Opin Neurobiol, 2001,11(3);272-280.
[41] Finkbeiner, S., Tavazoie, S.F., Maloratsky, A., et al. CREB: a major mediator of neuronal neurotrophin responses. Neuron, 1997,19(5);1031-1047.
[42] Vaynman, S., Ying, Z., Gomez-Pinilla, F. Interplay between brain-derived neurotrophic factor and signal transduction modulators in the regulation of the effects of exercise on synaptic-plasticity. Neuroscience, 2003,122(3);647-657.
[43] Orban, P.C., Chapman, P.F., Brambilla, R. Is the Ras-MAPK signalling pathway necessary for long-term memory formation? Trends Neurosci, 1999,22(1);38-44.
[44] Schafe, G.E., Nadel, N.V., Sullivan, G.M., et al. Memory consolidation for contextual and auditory fear conditioning is dependent on protein synthesis, PKA, and MAP kinase. Learn Mem, 1999,6(2);97-110.
[45] Sherwood, N.T., Lo, D.C. Long-term enhancement of central synaptic transmission by chronic brain-derived neurotrophic factor treatment. J Neurosci, 1999,19(16);7025-7036.
[46] Tartaglia, N., Du, J., Tyler, W.J., et al. Protein synthesis-dependent and -independent regulation of hippocampal synapses by brain-derived neurotrophic factor. J Biol Chem, 2001,276(40);37585-37593.
[47] Messaoudi, E., Bardsen, K., Srebro, B., et al. Acute intrahippocampal infusion of BDNF induces lasting potentiation of synaptic transmission in the rat dentate gyrus. J Neurophysiol, 1998,79(1);496-499.
[48] Ernfors, P., Bramham, C.R. The coupling of a trkB tyrosine residue to LTP. Trends Neurosci, 2003,26(4);171-173.
[49] Kelleher, R.J., 3rd, Govindarajan, A., Tonegawa, S. Translational regulatory mechanisms in persistent forms of synaptic plasticity. Neuron, 2004,44(1);59-73.
[50] Alsina, B., Vu, T., Cohen-Cory, S. Visualizing synapse formation in arborizing optic axons in vivo: dynamics and modulation by BDNF. Nat Neurosci, 2001,4(11);1093-1101.
[51] Bramham, C.R., Messaoudi, E. BDNF function in adult synaptic plasticity: the synaptic consolidation hypothesis. Prog Neurobiol, 2005,76(2);99-125.
[52] Schratt, G.M., Nigh, E.A., Chen, W.G., et al. BDNF regulates the translation of a select group of mRNAs by a mammalian target of rapamycin-phosphatidylinositol 3-kinase-dependent pathway during neuronal development. J Neurosci, 2004,24(33);7366-7377.
[53] Collin, C., Vicario-Abejon, C., Rubio, M.E., et al. Neurotrophins act at presynaptic terminals to activate synapses among cultured hippocampal neurons. Eur J Neurosci, 2001,13(7);1273-1282.
[54] Aakalu, G., Smith, W.B., Nguyen, N., et al. Dynamic visualization of local protein synthesis in hippocampal neurons. Neuron, 2001,30(2);489-502.
[55] Eberwine, J., Miyashiro, K., Kacharmina, J.E., et al. Local translation of classes of mRNAs that are targeted to neuronal dendrites. Proc Natl Acad Sci U S A, 2001,98(13);7080-7085.
[56] Yin, Y., Edelman, G.M., Vanderklish, P.W. The brain-derived neurotrophic factor enhances synthesis of Arc in synaptoneurosomes. Proc Natl Acad Sci U S A, 2002,99(4);2368-2373.
[57] Zybailov, B., Coleman, M.K., Florens, L., et al. Correlation of relative abundance ratios derived from peptide ion chromatograms and spectrum counting for quantitative proteomic analysis using stable isotope labeling. Anal Chem, 2005,77(19);6218-6224.
[58] Liao, L., Pilotte, J., Xu, T., et al. BDNF induces widespread changes in synaptic proteincontent and up-regulates components of the translation machinery: an analysis using high-throughput proteomics. J Proteome Res, 2007,6(3);1059-1071.
[59] Lisman, J., Schulman, H., Cline, H. The molecular basis of CaMKII function in synaptic and behavioural memory. Nat Rev Neurosci, 2002,3(3);175-190.
[60] Steward, O., Schuman, E.M. Protein synthesis at synaptic sites on dendrites. Annu Rev Neurosci, 2001,24(299-325.
[61] Martinez, A., Alcantara, S., Borrell, V., et al. TrkB and TrkC signaling are required for maturation and synaptogenesis of hippocampal connections. J Neurosci, 1998,18(18);7336-7350.
[62] Pozzo-Miller, L.D., Gottschalk, W., Zhang, L., et al. Impairments in high-frequency transmission, synaptic vesicle docking, and synaptic protein distribution in the hippocampus of BDNF knockout mice. J Neurosci, 1999,19(12);4972-4983.
[63] Korte, M., Griesbeck, O., Gravel, C., et al. Virus-mediated gene transfer into hippocampal CA1 region restores long-term potentiation in brain-derived neurotrophic factor mutant mice. Proc Natl Acad Sci U S A, 1996,93(22);12547-12552.
[64] Minichiello, L., Korte, M., Wolfer, D., et al. Essential role for TrkB receptors in hippocampus-mediated learning. Neuron, 1999,24(2);401-414.
[65] Xu, B., Gottschalk, W., Chow, A., et al. The role of brain-derived neurotrophic factor receptors in the mature hippocampus: modulation of long-term potentiation through a presynaptic mechanism involving TrkB. J Neurosci, 2000,20(18);6888-6897.
[66] Kossel, A.H., Cambridge, S.B., Wagner, U., et al. A caged Ab reveals an immediate/instructive effect of BDNF during hippocampal synaptic potentiation. Proc Natl Acad Sci U S A, 2001,98(25);14702-14707.
[67] Levine, E.S., Dreyfus, C.F., Black, I.B., et al. Brain-derived neurotrophic factor rapidly enhances synaptic transmission in hippocampal neurons via postsynaptic tyrosine kinase receptors. Proc Natl Acad Sci U S A, 1995,92(17);8074-8077.
[68] Chang, S., Popov, S.V. Long-range signaling within growing neurites mediated by neurotrophin-3. Proc Natl Acad Sci U S A, 1999,96(7);4095-4100.
[69] Gottschalk, W., Pozzo-Miller, L.D., Figurov, A., et al. Presynaptic modulation of synaptic transmission and plasticity by brain-derived neurotrophic factor in the developing hippocampus. J Neurosci, 1998,18(17);6830-6839.
[70] Patterson, S.L., Abel, T., Deuel, T.A., et al. Recombinant BDNF rescues deficits in basal synaptic transmission and hippocampal LTP in BDNF knockout mice. Neuron, 1996,16(6);1137-1145.
[71] Figurov, A., Pozzo-Miller, L.D., Olafsson, P., et al. Regulation of synaptic responses to high-frequency stimulation and LTP by neurotrophins in the hippocampus. Nature, 1996,381(6584);706-709.
[72] Kang, H., Welcher, A.A., Shelton, D., et al. Neurotrophins and time: different roles forTrkB signaling in hippocampal long-term potentiation. Neuron, 1997,19(3);653-664.
[73] Canales, J.J., Graybiel, A.M. A measure of striatal function predicts motor stereotypy. Nat Neurosci, 2000,3(4);377-383.
[74] Lessmann, V. Neurotrophin-dependent modulation of glutamatergic synaptic transmission in the mammalian CNS. Gen Pharmacol, 1998,31(5);667-674.
[75] Schikorski, T., Stevens, C.F. Quantitative ultrastructural analysis of hippocampal excitatory synapses. J Neurosci, 1997,17(15);5858-5867.
[76] Dobrunz, L.E., Stevens, C.F. Heterogeneity of release probability, facilitation, and depletion at central synapses. Neuron, 1997,18(6);995-1008.
[77] Alonso, M., Vianna, M.R., Depino, A.M., et al. BDNF-triggered events in the rat hippocampus are required for both short- and long-term memory formation. Hippocampus, 2002,12(4);551-560.
[78] Kafitz, K.W., Rose, C.R., Thoenen, H., et al. Neurotrophin-evoked rapid excitation through TrkB receptors. Nature, 1999,401(6756);918-921.
[79] McAllister, A.K., Katz, L.C., Lo, D.C. Neurotrophins and synaptic plasticity. Annu Rev Neurosci, 1999,22;295-318.
[80] Frerking, M., Malenka, R.C., Nicoll, R.A. Brain-derived neurotrophic factor (BDNF) modulates inhibitory, but not excitatory, transmission in the CA1 region of the hippocampus. J Neurophysiol, 1998,80(6);3383-3386.
[81] Kovalchuk, Y., Hanse, E., Kafitz, K.W., et al. Postsynaptic Induction of BDNF-Mediated Long-Term Potentiation. Science, 2002,295(5560);1729-1734.
[82] Chen, C., Tonegawa, S. Molecular genetic analysis of synaptic plasticity, activity-dependent neural development, learning, and memory in the mammalian brain. Annu Rev Neurosci, 1997,20;157-184.
[83] Levine, E.S., Crozier, R.A., Black, I.B., et al. Brain-derived neurotrophic factor modulates hippocampal synaptic transmission by increasing N-methyl-D-aspartic acid receptor activity. Proc Natl Acad Sci U S A, 1998,95(17);10235-10239.
[84] Suen, P.C., Wu, K., Levine, E.S., et al. Brain-derived neurotrophic factor rapidly enhances phosphorylation of the postsynaptic N-methyl-D-aspartate receptor subunit 1. Proc Natl Acad Sci U S A, 1997,94(15);8191-8195.
[85] Lin, S.Y., Wu, K., Levine, E.S., et al. BDNF acutely increases tyrosine phosphorylation of the NMDA receptor subunit 2B in cortical and hippocampal postsynaptic densities. Brain Res Mol Brain Res, 1998,55(1);20-27.
[86] Yu, X.M., Askalan, R., Keil, G.J., 2nd, et al. NMDA channel regulation by channel-associated protein tyrosine kinase Src. Science, 1997,275(5300);674-678.
[87] Li, Y.X., Zhang, Y., Lester, H.A., et al. Enhancement of neurotransmitter release induced by brain-derived neurotrophic factor in cultured hippocampal neurons. J Neurosci, 1998,18(24);10231-10240.
[88] Engert, F., Bonhoeffer, T. Dendritic spine changes associated with hippocampal long-term synaptic plasticity. Nature, 1999,399(6731);66-70.
[89] Toni, N., Buchs, P.A., Nikonenko, I., et al. LTP promotes formation of multiple spine synapses between a single axon terminal and a dendrite. Nature, 1999,402(6760);421-425.
[90] Gallo, G., Letourneau, P.C. Localized sources of neurotrophins initiate axon collateral sprouting. J Neurosci, 1998,18(14);5403-5414.
[91] Shimada, A., Mason, C.A., Morrison, M.E. TrkB signaling modulates spine density and morphology independent of dendrite structure in cultured neonatal Purkinje cells. J Neurosci, 1998,18(21);8559-8570.
[92] Alonso, M., Medina, J.H., Pozzo-Miller, L. ERK1/2 activation is necessary for BDNF to increase dendritic spine density in hippocampal CA1 pyramidal neurons. Learn Mem, 2004,11(2);172-178.
[93]Inoue, A., Sanes, J.R. Lamina-specific connectivity in the brain: regulation by N-cadherin, neurotrophins, and glycoconjugates. Science, 1997,276(5317);1428-1431.
[94] Lein, E.S., Shatz, C.J. Rapid regulation of brain-derived neurotrophic factor mRNA within eye-specific circuits during ocular dominance column formation. J Neurosci, 2000,20(4);1470-1483.
[95] Craig, A.M., Lichtman, J. W. Synapse formation and maturation. Johns Hopkins Univ. Press,2001,571–612.
[96] Mozhayeva, M.G., Sara, Y., Liu, X., et al. Development of vesicle pools during maturation of hippocampal synapses. J Neurosci, 2002,22(3);654-665.
[97] Genoud, C., Knott, G.W., Sakata, K., et al. Altered synapse formation in the adult somatosensory cortex of brain-derived neurotrophic factor heterozygote mice. J Neurosci, 2004,24(10);2394-2400.
[98] Jovanovic, J.N., Czernik, A.J., Fienberg, A.A., et al. Synapsins as mediators of BDNF-enhanced neurotransmitter release. Nat Neurosci, 2000,3(4);323-329.
[99] Graham, K.S., Patterson, K., Pratt, K.H., et al. Relearning and subsequent forgetting of semantic category exemplars in a case of semantic dementia. Neuropsychology, 1999,13(3);359-380.
[100] McGaugh, J.L. Memory--a century of consolidation. Science, 2000,287(5451);248-251.
[101] Hoffman, K.L., McNaughton, B.L. Coordinated reactivation of distributed memory traces in primate neocortex. Science, 2002,297(5589);2070-2073.
[102] Izquierdo, I., Vianna, M.R., Izquierdo, L.A., et al. Memory retrieval and its lasting consequences. Neurotox Res, 2002,4(5-6);573-593.
[103] Qiao, X., Chen, L., Gao, H., et al. Cerebellar brain-derived neurotrophic factor-TrkB defect associated with impairment of eyeblink conditioning in Stargazer mutant mice. J Neurosci, 1998;18(17);6990-6999.
[104] Aloe, L., Properzi, F., Probert, L., et al. Learning abilities, NGF and BDNF brain levelsin two lines of TNF-alpha transgenic mice, one characterized by neurological disorders, the other phenotypically normal. Brain Res, 1999,840(1-2);125-137.
[105] Croll, S.D., Suri, C., Compton, D.L., et al. Brain-derived neurotrophic factor transgenic mice exhibit passive avoidance deficits, increased seizure severity and in vitro hyperexcitability in the hippocampus and entorhinal cortex. Neuroscience, 1999,93(4);1491-1506.
[106] Tokuyama, W., Okuno, H., Hashimoto, T., et al. BDNF upregulation during declarative memory formation in monkey inferior temporal cortex. Nat Neurosci, 2000,3(11);1134-1142.
[107] Akutagawa, E., Konishi, M. Transient expression and transport of brain-derived neurotrophic factor in the male zebra finch's song system during vocal development. Proc Natl Acad Sci U S A, 1998,95(19);11429-11434.
[108] Wade, J. TrkB-like immunoreactivity in the song system of developing zebra finches. J Chem Neuroanat, 2000,19(1);33-39.
[109] Johnston, A.N., Clements, M.P., Rose, S.P. Role of brain-derived neurotrophic factor and presynaptic proteins in passive avoidance learning in day-old domestic chicks. Neuroscience, 1999,88(4);1033-1042.
[110] Mizuno, M., Yamada, K., Olariu, A., et al. Involvement of brain-derived neurotrophic factor in spatial memory formation and maintenance in a radial arm maze test in rats. J Neurosci, 2000,20(18);7116-7121.
[111] Hall, J., Thomas, K.L., Everitt, B.J. Rapid and selective induction of BDNF expression in the hippocampus during contextual learning. Nat Neurosci, 2000,3(6);533-535.
[112] Mu, J.S., Li, W.P., Yao, Z.B., et al. Deprivation of endogenous brain-derived neurotrophic factor results in impairment of spatial learning and memory in adult rats. Brain Res, 1999,835(2);259-265.
[113] Ma, Y.L., Wang, H.L., Wu, H.C., et al. Brain-derived neurotrophic factor antisense oligonucleotide impairs memory retention and inhibits long-term potentiation in rats. Neuroscience, 1998,82(4);957-967.
[114] DiCarlo, J.J., Johnson, K.O. Velocity invariance of receptive field structure in somatosensory cortical area 3b of the alert monkey. J Neurosci, 1999,19(1);401-419.
[115] Agnès Gruart, C.S., Mauricio Valenzuela-Harrington. Mutation at the TrkB PLC-docking site affects hippocampal LTP and associative learning in conscious mice. Learning& Memory, 2006,14;54-62.
[116] Mizuno, M., Yamada, K., Takei, N., et al. Phosphatidylinositol 3-kinase: a molecule mediating BDNF-dependent spatial memory formation. Mol Psychiatry, 2003,8(2);217-224.
[117] Alonso, M., Bekinschtein, P., Cammarota, M., et al. Endogenous BDNF is required for long-term memory formation in the rat parietal cortex. Learn Mem, 2005,12(5);504-510.
[118] Liu, J., Fukunaga, K., Yamamoto, H., et al. Differential roles of Ca(2+)/calmodulin-dependent protein kinase II and mitogen-activated protein kinaseactivation in hippocampal long-term potentiation. J Neurosci, 1999,19(19);8292-8299.
[119] Blanquet, P.R. Identification of two persistently activated neurotrophin-regulated pathways in rat hippocampus. Neuroscience, 2000,95(3);705-719.
[120] Saarelainen, T., Pussinen, R., Koponen, E., et al. Transgenic mice overexpressing truncated trkB neurotrophin receptors in neurons have impaired long-term spatial memory but normal hippocampal LTP. Synapse, 2000,38(1);102-104.
[121] Huang, E.J., Reichardt, L.F. Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci, 2001,24;677-736.
[122] Yamada, K., Mizuno, M., Nabeshima, T. Role for brain-derived neurotrophic factor in learning and memory. Life Sci, 2002,70(7);735-744.
[123] Kiprianova, I., Freiman, T.M., Desiderato, S., et al. Brain-derived neurotrophic factor prevents neuronal death and glial activation after global ischemia in the rat. J Neurosci Res, 1999,56(1);21-27.
[124] Bhave, S.V., Ghoda, L., Hoffman, P.L. Brain-derived neurotrophic factor mediates the anti-apoptotic effect of NMDA in cerebellar granule neurons: signal transduction cascades and site of ethanol action. J Neurosci, 1999,19(9);3277-3286.
[125] Zhao, L.R., Mattsson, B., Johansson, B.B. Environmental influence on brain-derived neurotrophic factor messenger RNA expression after middle cerebral artery occlusion in spontaneously hypertensive rats. Neuroscience, 2000,97(1);177-184.
[126] Arai, S., Kinouchi, H., Akabane, A., et al. Induction of brain-derived neurotrophic factor (BDNF) and the receptor trk B mRNA following middle cerebral artery occlusion in rat. Neurosci Lett, 1996,211(1);57-60.
[127] Imai, F., Suzuki, H., Oda, J., et al. Neuroprotective effect of exogenous microglia in global brain ischemia. J Cereb Blood Flow Metab, 2007,27(3);488-500.
[128] Kiprianova I.. Sandkühler J.. Schwab S, e.a. Brain-Derived Neurotrophic Factorimproves Long-Term Potentiation and cognitive functions after transient forebrain ischemia in the rat Experimental Neurology 1999,159(2);511-519.
[129] 巴迎春, 王廷华, 潘兴华.等. 慢性脑缺血大鼠海马 CA1 区中的 BDNF 表达. 神经解剖学杂志, 2005,21(6);664-666.
[130] Irina Kiprianova, T.M.F., Stephanie Desiderato, et al. Brain-Derived Neurotrophic Factor Prevents. Neuronal Death and Glial Activation After. Global Ischemia in the Rat. J Neurosci Res 1999,56(1);21-27.
[1] Soderling, T.R. CaM-kinases: modulators of synaptic plasticity. Curr Opin Neurobiol, 2000,10(3);375-380.
[2] Soderling, T.R., Derkach, V.A. Postsynaptic protein phosphorylation and LTP. Trends Neurosci, 2000,23(2);75-80.
[3] Winder, D.G., Sweatt, J.D. Roles of serine/threonine phosphatases in hippocampal synaptic plasticity. Nat Rev Neurosci, 2001,2(7);461-474.
[4] Weeber, E.J., Sweatt, J.D. Molecular neurobiology of human cognition. Neuron, 2002,33(6);845-848.
[5] Coupry, I., Monnet, L., Attia, A.A., et al. Analysis of CBP (CREBBP) gene deletions in Rubinstein-Taybi syndrome patients using real-time quantitative PCR. Hum Mutat, 2004,23(3);278-284.
[6] Servillo, G., Della Fazia, M.A., Sassone-Corsi, P. Coupling cAMP signaling to transcription in the liver: pivotal role of CREB and CREM. Exp Cell Res, 2002,275(2);143-154.
[7] Shaywitz, A.J., Greenberg, M.E. CREB: a stimulus-induced transcription factor activated by a diverse array of extracellular signals. Annu Rev Biochem, 1999,68;821-861.
[8] Walton, M.R., Dragunow, I. Is CREB a key to neuronal survival? Trends Neurosci, 2000,23(2);48-53.
[9] Shaywitz, A.J., Dove, S.L., Kornhauser, J.M., et al. Magnitude of the CREB-dependent transcriptional response is determined by the strength of the interaction between the kinase-inducible domain of CREB and the KIX domain of CREB-binding protein. Mol Cell Biol, 2000,20(24);9409-9422.
[10] Wu, G.Y., Deisseroth, K., Tsien, R.W. Activity-dependent CREB phosphorylation: convergence of a fast, sensitive calmodulin kinase pathway and a slow, less sensitive mitogen-activated protein kinase pathway. Proc Natl Acad Sci U S A, 2001,98(5);2808-2813.
[11] Hardingham, G.E., Arnold, F.J., Bading, H. Nuclear calcium signaling controls CREB-mediated gene expression triggered by synaptic activity. Nat Neurosci, 2001,4(3);261-267.
[12] Sakaguchi, H., Wada, K., Maekawa, M., et al. Song-induced phosphorylation of cAMP response element-binding protein in the songbird brain. J Neurosci, 1999,19(10);3973-3981.
[13] Screaton, R.A., Conkright, M.D., Katoh, Y., et al. The CREB coactivator TORC2 functions as a calcium- and cAMP-sensitive coincidence detector. Cell, 2004,119(1);61-74.
[14] Pittenger, C., Huang, Y.Y., Paletzki, R.F., et al. Reversible inhibition of CREB/ATF transcription factors in region CA1 of the dorsal hippocampus disruptshippocampus-dependent spatial memory. Neuron, 2002,34(3);447-462.
[15] Kogan, J.H., Frankland, P.W., Silva, A.J. Long-term memory underlying hippocampus-dependent social recognition in mice. Hippocampus, 2000,10(1);47-56.
[16] Genoux, D., Haditsch, U., Knobloch, M., et al. Protein phosphatase 1 is a molecular constraint on learning and memory. Nature, 2002,418(6901);970-975.
[17] Blanquet, P.R., Mariani, J., Derer, P. A calcium/calmodulin kinase pathway connects brain-derived neurotrophic factor to the cyclic AMP-responsive transcription factor in the rat hippocampus. Neuroscience, 2003,118(2);477-490.
[18] Swank, M.W. Phosphorylation of MAP kinase and CREB in mouse cortex and amygdala during taste aversion learning. Neuroreport, 2000,11(8);1625-1630.
[19] LeDoux, J.E. Emotion circuits in the brain. Annu Rev Neurosci, 2000;23;155-184.
[20] Graves, L., Dalvi, A., Lucki, I., et al. Behavioral analysis of CREB alphadelta mutation on a B6/129 F1 hybrid background. Hippocampus, 2002,12(1);18-26.
[21] Falls, W.A., Kogan, J.H., Silva, A.J., et al. Fear-potentiated startle, but not prepulse inhibition of startle, is impaired in CREBalphadelta-/- mutant mice. Behav Neurosci, 2000,114(5);998-1004.
[22] Nguyen, P.V., Gerlai, R. Behavioural and physiological characterization of inbred mouse strains: prospects for elucidating the molecular mechanisms of mammalian learning and memory. Genes Brain Behav, 2002,1(2);72-81.
[23] Schimanski, L.A., Nguyen, P.V. Multidisciplinary approaches for investigating the mechanisms of hippocampus-dependent memory: a focus on inbred mouse strains. Neurosci Biobehav Rev, 2004,28(5);463-483.
[24] Athos, J., Impey, S., Pineda, V.V., et al. Hippocampal CRE-mediated gene expression is required for contextual memory formation. Nat Neurosci, 2002,5(11);1119-1120.
[25] Wiltgen, B.J., Sanders, M.J., Behne, N.S., et al. Sex differences, context preexposure, and the immediate shock deficit in Pavlovian context conditioning with mice. Behav Neurosci, 2001,115(1);26-32.
[26] Barrientos, R.M., O'Reilly, R.C., Rudy, J.W. Memory for context is impaired by injecting anisomycin into dorsal hippocampus following context exploration. Behav Brain Res, 2002,134(1-2);299-306.
[27] Cammarota, M., Bevilaqua, L.R., Ardenghi, P., et al. Learning-associated activation of nuclear MAPK, CREB and Elk-1, along with Fos production, in the rat hippocampus after a one-trial avoidance learning: abolition by NMDA receptor blockade. Brain Res Mol Brain Res, 2000,76(1);36-46.
[28] Josselyn, S.A., Shi, C., Carlezon, W.A., Jr., et al. Long-term memory is facilitated by cAMP response element-binding protein overexpression in the amygdala. J Neurosci, 2001,21(7);2404-2412.
[29] Wallace, T.L., Stellitano, K.E., Neve, R.L., et al. Effects of cyclic adenosinemonophosphate response element binding protein overexpression in the basolateral amygdala on behavioral models of depression and anxiety. Biol Psychiatry, 2004,56(3);151-160.
[30] Brodie, C.R., Khaliq, M., Yin, J.C., et al. Overexpression of CREB reduces CRE-mediated transcription: behavioral and cellular analyses in transgenic mice. Mol Cell Neurosci, 2004,25(4);602-611.
[31] Bozon, B., Kelly, A., Josselyn, S.A., et al. MAPK, CREB and zif268 are all required for the consolidation of recognition memory. Philos Trans R Soc Lond B Biol Sci, 2003,358(1432);805-814.
[32] Yang, S.N., Huang, L.T., Wang, C.L., et al. Prenatal administration of morphine decreases CREBSerine-133 phosphorylation and synaptic plasticity range mediated by glutamatergic transmission in the hippocampal CA1 area of cognitive-deficient rat offspring. Hippocampus, 2003,13(8);915-921.
[33] Pandey, S.C., Mittal, N., Silva, A.J. Blockade of cyclic AMP-responsive element DNA binding in the brain of CREB delta/alpha mutant mice. Neuroreport, 2000,11(11);2577-2580.
[34] Mantamadiotis, T., Lemberger, T., Bleckmann, S.C., et al. Disruption of CREB function in brain leads to neurodegeneration. Nat Genet, 2002,31(1);47-54.
[35] Rammes, G., Steckler, T., Kresse, A., et al. Synaptic plasticity in the basolateral amygdala in transgenic mice expressing dominant-negative cAMP response element-binding protein (CREB) in forebrain. Eur J Neurosci, 2000,12(7);2534-2546.
[36] Kida, S., Josselyn, S.A., de Ortiz, S.P., et al. CREB required for the stability of new and reactivated fear memories. Nat Neurosci, 2002,5(4);348-355.
[37] Barco, A., Alarcon, J.M., Kandel, E.R. Expression of constitutively active CREB protein facilitates the late phase of long-term potentiation by enhancing synaptic capture. Cell, 2002,108(5);689-703.
[38] Simonato, M., Manservigi, R., Marconi, P., et al. Gene transfer into neurones for the molecular analysis of behaviour: focus on herpes simplex vectors. Trends Neurosci, 2000,23(5);183-190.
[39] Barrot, M., Olivier, J.D., Perrotti, L.I., et al. CREB activity in the nucleus accumbens shell controls gating of behavioral responses to emotional stimuli. Proc Natl Acad Sci U S A, 2002,99(17);11435-11440.
[40] Marie, H., Morishita, W., Yu, X., et al. Generation of silent synapses by acute in vivo expression of CaMKIV and CREB. Neuron, 2005,45(5);741-752.
[41] Taubenfeld, S.M., Milekic, M.H., Monti, B., et al. The consolidation of new but not reactivated memory requires hippocampal C/EBPbeta. Nat Neurosci, 2001,4(8);813-818.
[42] Walters, C.L., Blendy, J.A. Different requirements for cAMP response element binding protein in positive and negative reinforcing properties of drugs of abuse. J Neurosci, 2001,21(23);9438-9444.
[43] Balschun, D., Wolfer, D.P., Gass, P., et al. Does cAMP response element-binding proteinhave a pivotal role in hippocampal synaptic plasticity and hippocampus-dependent memory? J Neurosci, 2003,23(15);6304-6314.
[44] Carlezon, W.A., Jr., Thome, J., Olson, V.G., et al. Regulation of cocaine reward by CREB. Science, 1998,282(5397);2272-2275.
[45] Bourtchuladze, R., Frenguelli, B., Blendy, J., et al. Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein. Cell, 1994,79(1);59-68.
[46] Gass, P., Wolfer, D.P., Balschun, D., et al. Deficits in memory tasks of mice with CREB mutations depend on gene dosage. Learn Mem, 1998,5(4-5);274-288.
[47] Zhang, J.J., Okutani, F., Inoue, S., et al. Activation of the cyclic AMP response element-binding protein signaling pathway in the olfactory bulb is required for the acquisition of olfactory aversive learning in young rats. Neuroscience, 2003,117(3);707-713.
[48] Frankland, P.W.J., S. A. In Memories are made of these: from messengers to molecules. Landes Bioscience, 2004.
[49] Brightwell, J.J., Smith, C.A., Countryman, R.A., et al. Hippocampal overexpression of mutant creb blocks long-term, but not short-term memory for a socially transmitted food preference. Learn Mem, 2005,12(1);12-17.
[50] Cho, Y.H., Giese, K.P., Tanila, H., et al. Abnormal hippocampal spatial representations in alphaCaMKIIT286A and CREBalphaDelta- mice. Science, 1998,279(5352);867-869.
[51] Guzowski, J.F., McGaugh, J.L. Antisense oligodeoxynucleotide-mediated disruption of hippocampal cAMP response element binding protein levels impairs consolidation of memory for water maze training. Proc Natl Acad Sci U S A, 1997,94(6);2693-2698.
[52] Florian, C., Mons, N., Roullet, P. CREB antisense oligodeoxynucleotide administration into the dorsal hippocampal CA3 region impairs long- but not short-term spatial memory in mice. Learn Mem, 2006,13(4);465-472.
[53] Huang, Y.Y., Pittenger, C., Kandel, E.R. A form of long-lasting, learning-related synaptic plasticity in the hippocampus induced by heterosynaptic low-frequency pairing. Proc Natl Acad Sci U S A, 2004,101(3);859-864.
[54] Brightwell, J.J., Smith, C.A., Neve, R.L., et al. Long-term memory for place learning is facilitated by expression of cAMP response element-binding protein in the dorsal hippocampus. Learn Mem, 2007,14(3);195-199.
[55] Wood, M.A., Kaplan, M.P., Park, A., et al. Transgenic mice expressing a truncated form of CREB-binding protein (CBP) exhibit deficits in hippocampal synaptic plasticity and memory storage. Learn Mem, 2005,12(2);111-119.
[56] Bach, M.E., Barad, M., Son, H., et al. Age-related defects in spatial memory are correlated with defects in the late phase of hippocampal long-term potentiation in vitro and are attenuated by drugs that enhance the cAMP signaling pathway. Proc Natl Acad Sci U S A, 1999,96(9);5280-5285.
[57] Brightwell, J.J., Gallagher, M., Colombo, P.J. Hippocampal CREB1 but not CREB2 is decreased in aged rats with spatial memory impairments. Neurobiol Learn Mem, 2004,81(1);19-26.
[58] Mouravlev, A., Dunning, J., Young, D., et al. Somatic gene transfer of cAMP response element-binding protein attenuates memory impairment in aging rats. Proc Natl Acad Sci U S A, 2006,103(12);4705-4710.
[59] Johannessen, M., Delghandi, M.P., Moens, U. What turns CREB on? Cell Signal, 2004,16(11);1211-1227.
[60] Mayr, B., Montminy, M. Transcriptional regulation by the phosphorylation-dependent factor CREB. Nat Rev Mol Cell Biol, 2001,2(8);599-609.
[61] Lonze, B.E., Ginty, D.D. Function and regulation of CREB family transcription factors in the nervous system. Neuron, 2002,35(4);605-623.
[62] Salas, T.R., Reddy, S.A., Clifford, J.L., et al. Alleviating the suppression of glycogen synthase kinase-3beta by Akt leads to the phosphorylation of cAMP-response element-binding protein and its transactivation in intact cell nuclei. J Biol Chem, 2003,278(42);41338-41346.
[63] Hansen, T.O., Rehfeld, J.F., Nielsen, F.C. GSK-3beta reduces cAMP-induced cholecystokinin gene expression by inhibiting CREB binding. Neuroreport, 2004,15(5);841-845.
[64] Hotte, M., Thuault, S., Dineley, K.T., et al. Phosphorylation of CREB and DARPP-32 during late LTP at hippocampal to prefrontal cortex synapses in vivo. Synapse, 2007,61(1);24-28.
[65] Taubenfeld, S.M., Wiig, K.A., Bear, M.F., et al. A molecular correlate of memory and amnesia in the hippocampus. Nat Neurosci, 1999,2(4);309-310.
[66] Ehlers, M.D. Activity level controls postsynaptic composition and signaling via the ubiquitin-proteasome system. Nat Neurosci, 2003,6(3);231-242.
[67] Schafe, G.E., Atkins, C.M., Swank, M.W., et al. Activation of ERK/MAP kinase in the amygdala is required for memory consolidation of pavlovian fear conditioning. J Neurosci, 2000,20(21);8177-8187.
[68] Deisseroth, K., Tsien, R.W. Dynamic multiphosphorylation passwords for activity-dependent gene expression. Neuron, 2002,34(2);179-182.
[69] Barco, A., Patterson, S., Alarcon, J.M., et al. Gene expression profiling of facilitated L-LTP in VP16-CREB mice reveals that BDNF is critical for the maintenance of LTP and its synaptic capture. Neuron, 2005,48(1);123-137.
[70] Tang, Y.P., Shimizu, E., Dube, G.R., et al. Genetic enhancement of learning and memory in mice. Nature, 1999,401(6748);63-69.
[71] Malleret, G., Haditsch, U., Genoux, D., et al. Inducible and reversible enhancement of learning, memory, and long-term potentiation by genetic inhibition of calcineurin. Cell,2001,104(5);675-686.
[72] Wang, H., Ferguson, G.D., Pineda, V.V., et al. Overexpression of type-1 adenylyl cyclase in mouse forebrain enhances recognition memory and LTP. Nat Neurosci, 2004,7(6);635-642.
[73] Huang, Y.Y., Li, X.C., Kandel, E.R. cAMP contributes to mossy fiber LTP by initiating both a covalently mediated early phase and macromolecular synthesis-dependent late phase. Cell, 1994,79(1);69-79.
[74] Abel, T., Nguyen, P.V., Barad, M., et al. Genetic demonstration of a role for PKA in the late phase of LTP and in hippocampus-based long-term memory. Cell, 1997,88(5);615-626.
[75] Impey, S., Mark, M., Villacres, E.C., et al. Induction of CRE-mediated gene expression by stimuli that generate long-lasting LTP in area CA1 of the hippocampus. Neuron, 1996,16(5);973-982.
[76] Kitagawa, K. CREB and cAMP response element-mediated gene expression in the ischemic brain. Febs J, 2007,274(13);3210-3217.
[77] Meller, R., Minami, M., Cameron, J.A., et al. CREB-mediated Bcl-2 protein expression after ischemic preconditioning. J Cereb Blood Flow Metab, 2005,25(2);234-246.
[78] Ding, Y., Li, J., Luan, X., et al. Exercise pre-conditioning reduces brain damage in ischemic rats that may be associated with regional angiogenesis and cellular overexpression of neurotrophin. Neuroscience, 2004,124(3);583-591.
[79] Tanaka, K., Nogawa, S., Nagata, E., et al. Persistent CREB phosphorylation with protection of hippocampal CA1 pyramidal neurons following temporary occlusion of the middle cerebral artery in the rat. Exp Neurol, 2000,161(2);462-471.
[80] Zhu, D.Y., Lau, L., Liu, S.H., et al. Activation of cAMP-response-element-binding protein (CREB) after focal cerebral ischemia stimulates neurogenesis in the adult dentate gyrus. Proc Natl Acad Sci U S A, 2004,101(25);9453-9457.
[81] Hu, B.R., Fux, C.M., Martone, M.E., et al. Persistent phosphorylation of cyclic AMP responsive element-binding protein and activating transcription factor-2 transcription factors following transient cerebral ischemia in rat brain. Neuroscience, 1999,89(2);437-452.
[82] Irving, E.A., Barone, F.C., Reith, A.D., et al. Differential activation of MAPK/ERK and p38/SAPK in neurones and glia following focal cerebral ischaemia in the rat. Brain Res Mol Brain Res, 2000,77(1);65-75.
[83] Tanaka, K., Nagata, E., Suzuki, S., et al. Immunohistochemical analysis of cyclic AMP response element binding protein phosphorylation in focal cerebral ischemia in rats. Brain Res, 1999,818(2);520-526.
[84] Takeo, S., Niimura, M., Miyake-Takagi, K., et al. A possible mechanism for improvement by a cognition-enhancer nefiracetam of spatial memory function and cAMP-mediated signal transduction system in sustained cerebral ischaemia in rats. Br J Pharmacol, 2003,138(4);642-654.
[85] Jin, K., Mao, X.O., Simon, R.P., et al. Cyclic AMP response element binding protein(CREB) and CREB binding protein (CBP) in global cerebral ischemia. J Mol Neurosci, 2001,16(1);49-56.
[86] 葛巍, 沈霞, 刘永海, 等. 磷酸化 cAMP 反应元件结合蛋白在全脑缺血大鼠海马中的表达. 中风与神经疾病杂志, 2004, (3);7-9,97.
[87] Nagakura, A., Niimura, M., Takeo, S. Effects of a phosphodiesterase IV inhibitor rolipram on microsphere embolism-induced defects in memory function and cerebral cyclic AMP signal transduction system in rats. Br J Pharmacol, 2002,135(7);1783-1793.
[88] Nagakura, A., Takagi, N., Takeo, S. Impairment of cerebral cAMP-mediated signal transduction system and of spatial memory function after microsphere embolism in rats. Neuroscience, 2002,113(3);519-528.
[1] 吴彦,孙建宁,张宁,等.芪龙胶囊对大鼠脑缺血的保护作用.中成药, 2004,26(5); 386-389.
[2] Dahlqvist, P., Ronnback, A., Bergstrom, S.A., 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.
[3] Farkas, E., Institoris, A., Domoki, F., et al. Diazoxide and dimethyl sulphoxide prevent cerebral hypoperfusion-related learning dysfunction and brain damage after carotid artery occlusion. Brain Res, 2004,1008(2);252-260.
[4] 包新民,舒斯云. 大鼠脑立体定位图谱. 人民卫生出版社, 1991.
[5] Lee, V.M., Burdett, N.G., Carpenter, A., et al. Evolution of photochemically induced focal cerebral ischemia in the rat. Magnetic resonance imaging and histology. Stroke, 1996,27(11);2110-2118; discussion 2118-2119.
[6] Rogers, D.C., Wright, P.W., Roberts, J.C., et al. Photothrombotic lesions of the frontal cortex impair the performance of the delayed non-matching to position task by rats. Behav Brain Res, 1992,49(2);231-235.
[7] Chao Liu, J.W., Jun Gu, et al. . Baicalein improves cognitive deficits induced by chronic cerebral hypoperfusion in rats Pharmacology Biochemistry and Behavior. , 2007,86(3);423-430.
[8] Otori, T., Katsumata, T., Katayama, Y., et al. Measurement of regional cerebral blood flow and glucose utilization in rat brain under chronic hypoperfusion conditions following bilateral carotid artery occlusion. Analyzed by autoradiographical methods. Nippon Ika Daigaku Zasshi, 1997,64(5);428-439.
[9] Tanaka, K., Ogawa, N., Asanuma, M., et al. Relationship between cholinergic dysfunction and discrimination learning disabilities in Wistar rats following chronic cerebral hypoperfusion. Brain Res, 1996,729(1);55-65.
[10] de Wilde, M.C., Farkas, E., Gerrits, M., et al. The effect of n-3 polyunsaturated fatty acid-rich diets on cognitive and cerebrovascular parameters in chronic cerebral hypoperfusion. Brain Res, 2002,947(2);166-173.
[11] Busch, H.J., Buschmann, I.R., Mies, G., et al. Arteriogenesis in hypoperfused rat brain. J Cereb Blood Flow Metab, 2003,23(5);621-628.
[12] De Jong, G.I., De Vos, R.A., Steur, E.N., et al. Cerebrovascular hypoperfusion: a risk factor for Alzheimer's disease? Animal model and postmortem human studies. Ann N Y Acad Sci, 1997,826;56-74.
[13] Farkas, E., Luiten, P.G., Bari, F. Permanent, bilateral common carotid artery occlusion in the rat: a model for chronic cerebral hypoperfusion-related neurodegenerative diseases. Brain Res Rev, 2007,54(1);162-180.
[1] McDonald, R.J., White, N.M. Information acquired by the hippocampus interferes with acquisition of the amygdala-based conditioned-cue preference in the rat. Hippocampus, 1995,5(3);189-197.
[2] 韩太真. 学习与记忆的神经生物学. 北京大学医学出版社, 1998 年,208.
[3] Jones, D.G., Calverley, R.K. Frequency of occurrence of perforated synapses in developing rat neocortex. Neurosci Lett, 1991,129(2);189-192.
[4] Pozzo-Miller, L.D., Gottschalk, W., Zhang, L., et al. Impairments in high-frequency transmission, synaptic vesicle docking, and synaptic protein distribution in the hippocampus of BDNF knockout mice. J Neurosci, 1999,19(12);4972-4983.
[5] Markus, E.J., Petit, T.L. Synaptic structural plasticity: role of synaptic shape. Synapse, 1989,3(1);1-11.
[6] Jones, D.G., Devon, R.M. An ultrastructural study into the effects of pentobarbitone on synaptic organization. Brain Res, 1978,147(1);47-63.
[7] Guldner, F.H., Ingham, C.A. Increase in postsynaptic density material in optic target neurons of the rat suprachiasmatic nucleus after bilateral enucleation. Neurosci Lett, 1980,17(1-2);27-31.
[8] Jiang, M.L., Han, T.Z., Yang, D.W., et al. Morphological alteration of the hippocampal synapses in rats prenatally exposed to magnetic resonance imaging magnetic fields. Sheng Li Xue Bao, 2003,55(6);705-710.
[9] D'Hooge, R., De Deyn, P.P. Applications of the Morris water maze in the study of learning and memory. Brain Res Brain Res Rev, 2001,36(1);60-90.
[10] Redish, A.D., Touretzky, D.S. The role of the hippocampus in solving the Morris water maze. Neural Comput, 1998,10(1);73-111.
[11] Chao Liu, J.W., Jun Gu, et al. . Baicalein improves cognitive deficits induced by chronic cerebral hypoperfusion in rats Pharmacology Biochemistry and Behavior. , 2007,86(3);423-430.
[12] Ni, J., Ohta, H., Matsumoto, K., et al. Progressive cognitive impairment following chronic cerebral hypoperfusion induced by permanent occlusion of bilateral carotid arteries in rats. Brain Res, 1994,653(1-2);231-236.
[13] Pappas, B.A., de la Torre, J.C., Davidson, C.M., et al. Chronic reduction of cerebral blood flow in the adult rat: late-emerging CA1 cell loss and memory dysfunction. Brain Res, 1996,708(1-2);50-58.
[14] Martin, S.J., Grimwood, P.D., Morris, R.G. Synaptic plasticity and memory: an evaluation of the hypothesis. Annu Rev Neurosci, 2000,23;649-711.
[15] Yakel, J.L. Desensitization of 5-HT3 receptors expressed in Xenopus oocytes: dependence on voltage and primary structure. Behav Brain Res, 1996,73(1-2);269-272.
[16] Steckler, T., Drinkenburg, W.H., Sahgal, A., et al. Recognition memory in rats--II.Neuroanatomical substrates. Prog Neurobiol, 1998,54(3);313-332.
[17] Nakazawa, K., McHugh, T.J., Wilson, M.A., et al. NMDA receptors, place cells and hippocampal spatial memory. Nat Rev Neurosci, 2004,5(5);361-372.
[18] Farkas, E., Luiten, P.G., Bari, F. Permanent, bilateral common carotid artery occlusion in the rat: a model for chronic cerebral hypoperfusion-related neurodegenerative diseases. Brain Res Rev, 2007,54(1);162-180.
[19] Hunter, A.J., Mackay, K.B., Rogers, D.C. To what extent have functional studies of ischaemia in animals been useful in the assessment of potential neuroprotective agents? Trends Pharmacol Sci, 1998,19(2);59-66.
[20] 李露斯,刘之荣,肖桃元. 大鼠慢性脑血流灌注不足脑的病理组织学和超微结构变化. 第三军医大学学报 1999, 21(11); 805-808.
[21] Tanaka, K., Wada, N., Ogawa, N. Chronic cerebral hypoperfusion induces transient reversible monoaminergic changes in the rat brain. Neurochem Res, 2000,25(2);313-320.
[22] Ohtaki, H., Fujimoto, T., Sato, T., et al. Progressive expression of vascular endothelial growth factor (VEGF) and angiogenesis after chronic ischemic hypoperfusion in rat. Acta Neurochir, 2006,96(Suppl); 283-287.
[23] Farkas, E., Institoris, A., Domoki, F., et al. The effect of pre- and posttreatment with diazoxide on the early phase of chronic cerebral hypoperfusion in the rat. Brain Res, 2006,1087(1);168-174.
[24] Schmidt-Kastner, R., Truettner, J., Lin, B., et al. Transient changes of brain-derived neurotrophic factor (BDNF) mRNA expression in hippocampus during moderate ischemia induced by chronic bilateral common carotid artery occlusions in the rat. Brain Res Mol Brain Res, 2001,92(1-2);157-166.
[25] Farkas, E., Institoris, A., Domoki, F., et al. Diazoxide and dimethyl sulphoxide prevent cerebral hypoperfusion-related learning dysfunction and brain damage after carotid artery occlusion. Brain Res, 2004,1008(2);252-260.
[26] Liu, J., Jin, D.Z., Xiao, L., et al. Paeoniflorin attenuates chronic cerebral hypoperfusion-induced learning dysfunction and brain damage in rats. Brain Res, 2006,1089(1);162-170.
[27] Nanri, M., Watanabe, H. [Availability of 2VO rats as a model for chronic cerebrovascular disease]. Nippon Yakurigaku Zasshi, 1999,113(2);85-95.
[28] Ni, J.W., Matsumoto, K., Li, H.B., et al. Neuronal damage and decrease of central acetylcholine level following permanent occlusion of bilateral common carotid arteries in rat. Brain Res, 1995,673(2);290-296.
[29] De Jong, G.I., De Vos, R.A., Steur, E.N., et al. Cerebrovascular hypoperfusion: a risk factor for Alzheimer's disease? Animal model and postmortem human studies. Ann N Y Acad Sci, 1997,826;56-74.
[30] Ohta, H., Nishikawa, H., Kimura, H., et al. Chronic cerebral hypoperfusion by permanentinternal carotid ligation produces learning impairment without brain damage in rats. Neuroscience, 1997,79(4);1039-1050.
[31] Harukuni, I., Bhardwaj, A. Mechanisms of brain injury after global cerebral ischemia. Neurol Clin, 2006,24(1);1-21.
[32] Ueda, H., Fujita, R. Cell death mode switch from necrosis to apoptosis in brain. Biol Pharm Bull, 2004,27(7);950-955.
[33] Briede, J., Duburs, G. Protective effect of cerebrocrast on rat brain ischaemia induced by occlusion of both common carotid arteries. Cell Biochem Funct, 2007,25(2);203-210.
[34] 韩太真. 学习与记忆的神经生物学. 北京大学医学出版社, 1998 年,222.
[35] Moser, E.I., Krobert, K.A., Moser, M.B., et al. Impaired spatial learning after saturation of long-term potentiation. Science, 1998,281(5385);2038-2042.
[36] Lue, L.F., Kuo, Y.M., Roher, A.E., et al. Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer's disease. Am J Pathol, 1999,155(3);853-862.
[37] Tiraboschi, P., Hansen, L.A., Alford, M., et al. The decline in synapses and cholinergic activity is asynchronous in Alzheimer's disease. Neurology, 2000;55(9);1278-1283.
[38] 丰岩清,郭云良,梁秀龄. 脑缺血再灌注后突触素的表达及其与神经生长因子的关系 中国神经精神疾病杂志, 2000,26(4);251-252.
[39] Aarts, M.M., Tymianski, M. Molecular mechanisms underlying specificity of excitotoxic signaling in neurons. Curr Mol Med, 2004,4(2);137-147.
[40] Petit, T.L., LeBoutillier, J.C. Quantifying synaptic number and structure: effects of stain and post-mortem delay. Brain Res, 1990,517(1-2);269-275.
[41] Ghaffari-Farazi T, L.J., Berger TW Consequence of morphological alterations on synaptic function. Neurocomput, 1999,26;17-27.
[42] 吴馥梅, 杜红燕, 章子贵. 突触界面曲率及其生理意义. 神经解剖学杂志, 1994,10(1);89-92.
[43] Dyson, S.E., Jones, D.G. Quantitation of terminal parameters and their inter-relationships in maturing central synapses: a perspective for experimental studies. Brain Res, 1980,183(1);43-59.
[44] Rizzoli, S.O., Betz, W.J. Synaptic vesicle pools. Nat Rev Neurosci, 2005,6(1);57-69.
[45] Schikorski, T., Stevens, C.F. Quantitative ultrastructural analysis of hippocampal excitatory synapses. J Neurosci, 1997,17(15);5858-5867.
[46] Harata, N., Pyle, J.L., Aravanis, A.M., et al. Limited numbers of recycling vesicles in small CNS nerve terminals: implications for neural signaling and vesicular cycling. Trends Neurosci, 2001,24(11);637-643.
[47] B, K. The release of neural transmitter substances. Liverpool UP., 1969.
[48] Highstein, S.M., Bennett, M.V. Fatigue and recovery of transmission at the Mauthner fiber-giant fiber synapse of the hatchetfish. Brain Res, 1975,98(2);229-242.
[49] Tyler, W.J., Pozzo-Miller, L.D. BDNF enhances quantal neurotransmitter release andincreases the number of docked vesicles at the active zones of hippocampal excitatory synapses. J Neurosci, 2001,21(12);4249-4258.
[50] G.-Y. Wu, J.K., D.F. Marrone, T.W. et al. . Winter Conference on Neural Plasticity, Guadeloupe, French Antilles, 2003.
[1] J.萨姆布鲁克, D.W.拉. 分子克隆实验指南. 科学出版社, 2002.
[2] Johansson, A.C., Visse, E., Widegren, B., et al. Computerized image analysis as a tool to quantify infiltrating leukocytes: a comparison between high- and low-magnification images. J Histochem Cytochem, 2001,49(9);1073-1079.
[3] O'Leary, T.J. Standardization in immunohistochemistry. Appl Immunohistochem Mol Morphol, 2001,9(1);3-8.
[4] Kirino, T. Ischemic tolerance. J Cereb Blood Flow Metab, 2002,22(11);1283-1296.
[5] 董伟为. 神经保护的基础与临床. 科学出版社, 2002,197-203.
[6] Benfenati, F. Synaptic plasticity and the neurobiology of learning and memory. Acta Biomed, 2007,78(Suppl); 58-66.
[7] De Cesare, D., Fimia, G.M., Sassone-Corsi, P. Signaling routes to CREM and CREB: plasticity in transcriptional activation. Trends Biochem Sci, 1999,24(7);281-285.
[8] Sato-Bigbee, C., Pal, S., Chu, A.K. Different neuroligands and signal transduction pathways stimulate CREB phosphorylation at specific developmental stages along oligodendrocyte differentiation. J Neurochem, 1999,72(1);139-147.
[9] Lonze, B.E., Ginty, D.D. Function and regulation of CREB family transcription factors in the nervous system. Neuron, 2002,35(4);605-623.
[10] Jin, K., Mao, X.O., Simon, R.P., et al. Cyclic AMP response element binding protein (CREB) and CREB binding protein (CBP) in global cerebral ischemia. J Mol Neurosci, 2001,16(1);49-56.
[11] Tanaka, K., Nogawa, S., Nagata, E., et al. Persistent CREB phosphorylation with protection of hippocampal CA1 pyramidal neurons following temporary occlusion of the middle cerebral artery in the rat. Exp Neurol, 2000,161(2);462-471.
[12] Hu, B.R., Fux, C.M., Martone, M.E., et al. Persistent phosphorylation of cyclic AMP responsive element-binding protein and activating transcription factor-2 transcription factors following transient cerebral ischemia in rat brain. Neuroscience, 1999,89(2);437-452.
[13] Zhu, D.Y., Lau, L., Liu, S.H., et al. Activation of cAMP-response-element-binding protein (CREB) after focal cerebral ischemia stimulates neurogenesis in the adult dentate gyrus. Proc Natl Acad Sci U S A, 2004,101(25);9453-9457.
[14] Paxinos G, W.C. The rat nervous system. Academic Press, 1995.
[15] de la Torre, J.C., Fortin, T., Park, G.A., et al. Brain blood flow restoration 'rescues' chronically damaged rat CA1 neurons. Brain Res, 1993,623(1);6-15.
[16] Finkbeiner, S., Tavazoie, S.F., Maloratsky, A., et al. CREB: a major mediator of neuronal neurotrophin responses. Neuron, 1997,19(5);1031-1047.
[17] Tao, X., Finkbeiner, S., Arnold, D.B., et al. Ca2+ influx regulates BDNF transcription by a CREB family transcription factor-dependent mechanism. Neuron, 1998,20(4);709-726.
[18] Binder, D.K., Routbort, M.J., McNamara, J.O. Immunohistochemical evidence of seizure-induced activation of trk receptors in the mossy fiber pathway of adult rat hippocampus. J Neurosci, 1999,19(11);4616-4626.
[19] Ying, S.W., Futter, M., Rosenblum, K., et al. Brain-derived neurotrophic factor induces long-term potentiation in intact adult hippocampus: requirement for ERK activation coupled to CREB and upregulation of Arc synthesis. J Neurosci, 2002,22(5);1532-1540.
[20] Lo, D.C. Neurotrophic factors and synaptic plasticity. Neuron, 1995,15(5);979-981.
[21] Thoenen, H. Neurotrophins and neuronal plasticity. Science, 1995,270(5236);593-598.
[22] McAllister, A.K., Katz, L.C., Lo, D.C. Neurotrophins and synaptic plasticity. Annu Rev Neurosci, 1999,22;295-318.
[23] Lu, B., Chow, A. Neurotrophins and hippocampal synaptic transmission and plasticity. J Neurosci Res, 1999,58(1);76-87.
[24] Levine, E.S., Dreyfus, C.F., Black, I.B., et al. Brain-derived neurotrophic factor rapidly enhances synaptic transmission in hippocampal neurons via postsynaptic tyrosine kinase receptors. Proc Natl Acad Sci U S A, 1995,92(17);8074-8077.
[25] Murphy, D.D., Cole, N.B., Segal, M. Brain-derived neurotrophic factor mediates estradiol-induced dendritic spine formation in hippocampal neurons. Proc Natl Acad Sci U S A, 1998,95(19);11412-11417.
[26] Patel, M.N., McNamara, J.O. Selective enhancement of axonal branching of cultured dentate gyrus neurons by neurotrophic factors. Neuroscience, 1995,69(3);763-770.
[27] Lowenstein, D.H., Arsenault, L. The effects of growth factors on the survival and differentiation of cultured dentate gyrus neurons. J Neurosci, 1996,16(5);1759-1769.
[28] Bradley, J., Sporns, O. BDNF-dependent enhancement of exocytosis in cultured cortical neurons requires translation but not transcription. Brain Res, 1999,815(1);140-149.
[29] Lessmann, V., Gottmann, K., Heumann, R. BDNF and NT-4/5 enhance glutamatergic synaptic transmission in cultured hippocampal neurones. Neuroreport, 1994,6(1);21-25.
[30] Bartrup, J.T., Moorman, J.M., Newberry, N.R. BDNF enhances neuronal growth and synaptic activity in hippocampal cell cultures. Neuroreport, 1997,8(17);3791-3794.
[31] Lessmann, V., Heumann, R. Modulation of unitary glutamatergic synapses by neurotrophin-4/5 or brain-derived neurotrophic factor in hippocampal microcultures: presynaptic enhancement depends on pre-established paired-pulse facilitation. Neuroscience, 1998,86(2);399-413.
[32] Pozzo-Miller, L.D., Gottschalk, W., Zhang, L., et al. Impairments in high-frequency transmission, synaptic vesicle docking, and synaptic protein distribution in the hippocampus of BDNF knockout mice. J Neurosci, 1999,19(12);4972-4983.
[33] Mocchetti, I., Wrathall, J.R. Neurotrophic factors in central nervous system trauma. J Neurotrauma, 1995,12(5);853-870.
[34] Ivanova, T., Beyer, C. Pre- and postnatal expression of brain-derived neurotrophic factormRNA/protein and tyrosine protein kinase receptor B mRNA in the mouse hippocampus. Neurosci Lett, 2001,307(1);21-24.
[35] Farkas, E., Donka, G., de Vos, R.A., et al. Experimental cerebral hypoperfusion induces white matter injury and microglial activation in the rat brain. Acta Neuropathol, 2004,108(1);57-64.
[36] Farkas, E., Institoris, A., Domoki, F., et al. Diazoxide and dimethyl sulphoxide prevent cerebral hypoperfusion-related learning dysfunction and brain damage after carotid artery occlusion. Brain Res, 2004,1008(2);252-260.
[37] Farkas, E., Institoris, A., Domoki, F., et al. The effect of pre- and posttreatment with diazoxide on the early phase of chronic cerebral hypoperfusion in the rat. Brain Res, 2006,1087(1);168-174.
[38] Schmidt-Kastner, R., Aguirre-Chen, C., Saul, I., et al. Astrocytes react to oligemia in the forebrain induced by chronic bilateral common carotid artery occlusion in rats. Brain Res, 2005,1052(1);28-39.
[39] Xi Kuang, J.-R.D., Yan-Xin Liu, et al. . Postischemic administration of Z-Ligustilide ameliorates cognitive dysfunction and brain damage induced by permanent forebrain ischemia in rats. . Pharmacology, Biochemistry and Behavior, 2008,88;213-221.
[40] 李世泽,刘其强,白宏英,等. 丁咯地尔对慢性脑缺血大鼠海马 CA1 区星形胶质细胞及认知障碍的影响. 中国实用神经疾病杂志,2006,(3);40-41.
[41] 赵世刚,姜玉武,罗强,等. 脑源性神经营养因子与海马苔藓状纤维突触重组的关系. 中华医学杂志, 2001,81(5);283-287.
[42] Schratt, G.M., Nigh, E.A., Chen, W.G., et al. BDNF regulates the translation of a select group of mRNAs by a mammalian target of rapamycin-phosphatidylinositol 3-kinase-dependent pathway during neuronal development. J Neurosci, 2004,24(33);7366-7377.
[43] Collin, C., Vicario-Abejon, C., Rubio, M.E., et al. Neurotrophins act at presynaptic terminals to activate synapses among cultured hippocampal neurons. Eur J Neurosci, 2001,13(7);1273-1282.
[44] Aakalu, G., Smith, W.B., Nguyen, N., et al. Dynamic visualization of local protein synthesis in hippocampal neurons. Neuron, 2001,30(2);489-502.
[45] Eberwine, J., Miyashiro, K., Kacharmina, J.E., et al. Local translation of classes of mRNAs that are targeted to neuronal dendrites. Proc Natl Acad Sci U S A, 2001,98(13);7080-7085.
[46] Yin, Y., Edelman, G.M., Vanderklish, P.W. The brain-derived neurotrophic factor enhances synthesis of Arc in synaptoneurosomes. Proc Natl Acad Sci U S A, 2002,99(4);2368-2373.
[47] Alsina, B., Vu, T., Cohen-Cory, S. Visualizing synapse formation in arborizing optic axons in vivo: dynamics and modulation by BDNF. Nat Neurosci, 2001,4(11);1093-1101.
[48] Bramham, C.R., Messaoudi, E. BDNF function in adult synaptic plasticity: the synaptic consolidation hypothesis. Prog Neurobiol, 2005,76(2);99-125.
[49] Gottschalk, W., Pozzo-Miller, L.D., Figurov, A., et al. Presynaptic modulation of synaptic transmission and plasticity by brain-derived neurotrophic factor in the developing hippocampus. J Neurosci, 1998,18(17);6830-6839.
[50] Lessmann, V. Neurotrophin-dependent modulation of glutamatergic synaptic transmission in the mammalian CNS. Gen Pharmacol, 1998,31(5);667-674.
[51] Jovanovic, J.N., Czernik, A.J., Fienberg, A.A., et al. Synapsins as mediators of BDNF-enhanced neurotransmitter release. Nat Neurosci, 2000,3(4);323-329.
[52] Poo, M.M. Neurotrophins as synaptic modulators. Nat Rev Neurosci, 2001,2(1);24-32.
[53] Merlio, J.P., Ernfors, P., Kokaia, Z., et al. Increased production of the TrkB protein tyrosine kinase receptor after brain insults. Neuron, 1993,10(2);151-164.
[54] Muly, S.M., Gross, J.S., Morest, D.K., et al. Synaptophysin in the cochlear nucleus following acoustic trauma. Exp Neurol, 2002,177(1);202-221.
[55] Torrealba, F., Carrasco, M.A. A review on electron microscopy and neurotransmitter systems. Brain Res Brain Res Rev, 2004,47(1-3);5-17.
[56] Becher, A., Drenckhahn, A., Pahner, I., et al. The synaptophysin-synaptobrevin complex: a hallmark of synaptic vesicle maturation. J Neurosci, 1999,19(6);1922-1931.
[57] Hannah, M.J., Schmidt, A.A., Huttner, W.B. Synaptic vesicle biogenesis. Annu Rev Cell Dev Biol, 1999,15;733-798.
[58] Thiele, C., Hannah, M.J., Fahrenholz, F., et al. Cholesterol binds to synaptophysin and is required for biogenesis of synaptic vesicles. Nat Cell Biol, 2000,2(1);42-49.
[59] Regnier-Vigouroux, A., Tooze, S.A., Huttner, W.B. Newly synthesized synaptophysin is transported to synaptic-like microvesicles via constitutive secretory vesicles and the plasma membrane. Embo J, 1991,10(12);3589-3601.
[60] Deken, S.L., Wang, D., Quick, M.W. Plasma membrane GABA transporters reside on distinct vesicles and undergo rapid regulated recycling. J Neurosci, 2003,23(5);1563-1568.
[61] Lauri, S.E., Lamsa, K., Pavlov, I., et al. Activity blockade increases the number of functional synapses in the hippocampus of newborn rats. Mol Cell Neurosci, 2003,22(1);107-117.
[62] Kadish, I., Van Groen, T. Differences in lesion-induced hippocampal plasticity between mice and rats. Neuroscience, 2003,116(2);499-509.
[63] Sze, C.I., Bi, H., Kleinschmidt-DeMasters, B.K., et al. Selective regional loss of exocytotic presynaptic vesicle proteins in Alzheimer's disease brains. J Neurol Sci, 2000,175(2);81-90.
[64] Thomas, L., Hartung, K., Langosch, D., et al. Identification of synaptophysin as a hexameric channel protein of the synaptic vesicle membrane. Science, 1988,242(4881);1050-1053.
[65] Daly, C., Sugimori, M., Moreira, J.E., et al. Synaptophysin regulates clathrin-independent endocytosis of synaptic vesicles. Proc Natl Acad Sci U S A, 2000,97(11);6120-6125.
[66] Pennuto, M., Dunlap, D., Contestabile, A., et al. Fluorescence resonance energy transfer detection of synaptophysin I and vesicle-associated membrane protein 2 interactions during exocytosis from single live synapses. Mol Biol Cell, 2002,13(8);2706-2717.
[67] 韩济生,关新民. 医用神经生物学. 武汉出版社, 1996 年,17.
[68] Alder, J., Xie, Z.P., Valtorta, F., et al. Antibodies to synaptophysin interfere with transmitter secretion at neuromuscular synapses. Neuron, 1992,9(4);759-768.
[69] Alder, J., Kanki, H., Valtorta, F., et al. Overexpression of synaptophysin enhances neurotransmitter secretion at Xenopus neuromuscular synapses. J Neurosci, 1995,15(1 Pt 2);511-519.
[70] Alder, J., Lu, B., Valtorta, F., et al. Calcium-dependent transmitter secretion reconstituted in Xenopus oocytes: requirement for synaptophysin. Science, 1992,257(5070);657-661.
[71] Marks, B., Stowell, M.H., Vallis, Y., et al. GTPase activity of dynamin and resulting conformation change are essential for endocytosis. Nature, 2001,410(6825);231-235.
[72] Valtorta, F., Pennuto, M., Bonanomi, D., et al. Synaptophysin: leading actor or walk-on role in synaptic vesicle exocytosis? Bioessays, 2004,26(4);445-453.
[73] Bonanomi, D., Pennuto, M., Rigoni, M., et al. Taipoxin induces synaptic vesicle exocytosis and disrupts the interaction of synaptophysin I with VAMP2. Mol Pharmacol, 2005,67(6);1901-1908.
[74] Scarr, E., Gray, L., Keriakous, D., et al. Increased levels of SNAP-25 and synaptophysin in the dorsolateral prefrontal cortex in bipolar I disorder. Bipolar Disord, 2006,8(2);133-143.
[75] Mitter, D., Reisinger, C., Hinz, B., et al. The synaptophysin/synaptobrevin interaction critically depends on the cholesterol content. J Neurochem, 2003,84(1);35-42.
[76] Royle, S.J., Lagnado, L. Endocytosis at the synaptic terminal. J Physiol, 2003,553(Pt 2);345-355.
[77] Granseth, B., Odermatt, B., Royle, S.J., et al. Clathrin-mediated endocytosis is the dominant mechanism of vesicle retrieval at hippocampal synapses. Neuron, 2006,51(6);773-786.
[78] Daly, C., Ziff, E.B. Ca2+-dependent formation of a dynamin-synaptophysin complex: potential role in synaptic vesicle endocytosis. J Biol Chem, 2002,277(11);9010-9015.
[79]Cousin, M.A. Synaptic vesicle endocytosis: calcium works overtime in the nerve terminal. Mol Neurobiol, 2000,22(1-3);115-128.
[80] Spiwoks-Becker, I., Vollrath, L., Seeliger, M.W., et al. Synaptic vesicle alterations in rod photoreceptors of synaptophysin-deficient mice. Neuroscience, 2001,107(1);127-142.
[81] Janz, R., Sudhof, T.C., Hammer, R.E., et al. Essential roles in synaptic plasticity for synaptogyrin I and synaptophysin I. Neuron, 1999,24(3);687-700.
[82] Mullany, P.M., Lynch, M.A. Evidence for a role for synaptophysin in expression oflong-term potentiation in rat dentate gyrus. Neuroreport, 1998,9(11);2489-2494.
[83] Mullany, P., Lynch, M.A. Changes in protein synthesis and synthesis of the synaptic vesicle protein, synaptophysin, in entorhinal cortex following induction of long-term potentiation in dentate gyrus: an age-related study in the rat. Neuropharmacology, 1997,36(7);973-980.
[84] Murdoch, I., Perry, E.K., Court, J.A., et al. Cortical cholinergic dysfunction after human head injury. J Neurotrauma, 1998,15(5);295-305.
[85] Smith, T.D., Adams, M.M., Gallagher, M., et al. Circuit-specific alterations in hippocampal synaptophysin immunoreactivity predict spatial learning impairment in aged rats. J Neurosci, 2000,20(17);6587-6593.
[86] 王守春,吴江,孙莉,等. 慢性脑缺血大鼠海马区和齿状回突触素表达变化与其认知功能关系的研究. 现代神经疾病杂志, 2003,3;142-145.
[87] Korematsu, K., Goto, S., Nagahiro, S., et al. Changes of immunoreactivity for synaptophysin ('protein p38') following a transient cerebral ischemia in the rat striatum. Brain Res, 1993,616(1-2);320-324.
[88] Tartaglia, N., Du, J., Tyler, W.J., et al. Protein synthesis-dependent and -independent regulation of hippocampal synapses by brain-derived neurotrophic factor. J Biol Chem, 2001,276(40);37585-37593.
[89] Tyler, W.J., Pozzo-Miller, L.D. BDNF enhances quantal neurotransmitter release and increases the number of docked vesicles at the active zones of hippocampal excitatory synapses. J Neurosci, 2001,21(12);4249-4258.
[90] Mesulam, M.M., Geula, C. Nucleus basalis (Ch4) and cortical cholinergic innervation in the human brain: observations based on the distribution of acetylcholinesterase and choline acetyltransferase. J Comp Neurol, 1988,275(2);216-240.
[91] Hasselmo, M. Expecting the unexpected: modeling of neuromodulation. Neuron, 2005,46(4);526-528.
[92] Shinoe, T., Matsui, M., Taketo, M.M., et al. Modulation of synaptic plasticity by physiological activation of M1 muscarinic acetylcholine receptors in the mouse hippocampus. J Neurosci, 2005,25(48);11194-11200.
[93] Rasmusson, D.D., Dykes, R.W. Long-term enhancement of evoked potentials in cat somatosensory cortex produced by co-activation of the basal forebrain and cutaneous receptors. Exp Brain Res, 1988,70(2);276-286.
[94] Galey, D., Destrade, C., Jaffard, R. Relationships between septo-hippocampal cholinergic activation and the improvement of long-term retention produced by medial septal electrical stimulation in two inbred strains of mice. Behav Brain Res, 1994,60(2);183-189.
[95] Abe, K., Nakata, A., Mizutani, A., et al. Facilitatory but nonessential role of the muscarinic cholinergic system in the generation of long-term potentiation of population spikes in the dentate gyrus in vivo. Neuropharmacology, 1994,33(7);847-852.
[96] Barnes, C.A., Jung, M.W., McNaughton, B.L., et al. LTP saturation and spatial learning disruption: effects of task variables and saturation levels. J Neurosci, 1994,14(10);5793-5806.
[97] Kotani, S., Yamauchi, T., Teramoto, T., et al. Pharmacological evidence of cholinergic involvement in adult hippocampal neurogenesis in rats. Neuroscience, 2006,142(2);505-514.
[98] Van der Borght, K., Mulder, J., Keijser, J.N., et al. Input from the medial septum regulates adult hippocampal neurogenesis. Brain Res Bull, 2005,67(1-2);117-125.
[99] Oda, Y. Choline acetyltransferase: the structure, distribution and pathologic changes in the central nervous system. Pathol Int, 1999,49(11);921-937.
[100] Tiraboschi, P., Hansen, L.A., Alford, M., et al. The decline in synapses and cholinergic activity is asynchronous in Alzheimer's disease. Neurology, 2000,55(9);1278-1283.
[101] Salvaterra, P.M., Vaughn, J.E. Regulation of choline acetyltransferase. Int Rev Neurobiol, 1989,31;81-143.
[102] Hruschak, K.A., Friedrich, V.L., Jr., Giacobini, E. Synaptogenesis in chick paravertebral sympathetic ganglia: a morphometric analysis. Brain Res, 1982,256(2);229-240.
[103] Auld, D.S., Mennicken, F., Quirion, R. Nerve growth factor rapidly induces prolonged acetylcholine release from cultured basal forebrain neurons: differentiation between neuromodulatory and neurotrophic influences. J Neurosci, 2001,21(10);3375-3382.
[104] Berse, B., Szczecinska, W., Lopez-Coviella, I., et al. Expression of high affinity choline transporter during mouse development in vivo and its upregulation by NGF and BMP-4 in vitro. Brain Res Dev Brain Res, 2005,157(2);132-140.
[105] Nonner, D., Barrett, E.F., Barrett, J.N. Brief exposure to neurotrophins produces a calcium-dependent increase in choline acetyltransferase activity in cultured rat septal neurons. J Neurochem, 2000,74(3);988-999.
[106] Ha, D.H., Robertson, R.T., Roshanaei, M., et al. Enhanced survival and morphological features of basal forebrain cholinergic neurons in vitro: role of neurotrophins and other potential cortically derived cholinergic trophic factors. J Comp Neurol, 1999,406(2);156-170.
[107] Nonner, D., Barrett, E.F., Barrett, J.N. Neurotrophin effects on survival and expression of cholinergic properties in cultured rat septal neurons under normal and stress conditions. J Neurosci, 1996,16(21);6665-6675.
[108] Knipper, M., da Penha Berzaghi, M., Blochl, A., et al. Positive feedback between acetylcholine and the neurotrophins nerve growth factor and brain-derived neurotrophic factor in the rat hippocampus. Eur J Neurosci, 1994v6(4);668-671.
[109] 金国华,田美玲,秦建兵,等. BDNF、NGF 对体外长期培养的胚基底前脑胆碱能神经元的影响. 神经解剖学杂志, 2001,17(4);337-341.
[110] Jezierski, M.K., Sohrabji, F. Estrogen enhances retrograde transport of brain-derived neurotrophic factor in the rodent forebrain. Endocrinology, 2003,144(11);5022-5029.
[111] Grosse, G., Djalali, S., Deng, D.R., et al. Area-specific effects of brain-derived neurotrophic factor (BDNF) genetic ablation on various neuronal subtypes of the mouse brain.Brain Res Dev Brain Res, 2005,156(2);111-126.
[112] 范文辉,刘之荣. 血管性痴呆的动物模型及其胆碱能机制研究. 第三军医大学学报, 2000,22 (4);314-316.
[113] Erkinjuntti, T., Roman, G., Gauthier, S., et al. Emerging therapies for vascular dementia and vascular cognitive impairment. Stroke, 2004,35(4);1010-1017.
[114] Saez-Valero, J., Mok, S.S., Small, D.H. An unusually glycosylated form of acetylcholinesterase is a CSF biomarker for Alzheimer's disease. Acta Neurol Scand, 2000,176(Suppl );49-52.
[115] Buttini, M., Yu, G.Q., Shockley, K., et al. Modulation of Alzheimer-like synaptic and cholinergic deficits in transgenic mice by human apolipoprotein E depends on isoform, aging, and overexpression of amyloid beta peptides but not on plaque formation. J Neurosci, 2002,22(24);10539-10548.
[116] Hellstrom-Lindahl, E., Mousavi, M., Zhang, X., et al. Regional distribution of nicotinic receptor subunit mRNAs in human brain: comparison between Alzheimer and normal brain. Brain Res Mol Brain Res, 1999,66(1-2);94-103.
[117] Hulette, C., Nochlin, D., McKeel, D., et al. Clinical-neuropathologic findings in multi-infarct dementia: a report of six autopsied cases. Neurology, 1997,48(3);668-672.
[118] Amenta, F., Di Tullio, M.A., Tomassoni, D. The cholinergic approach for the treatment of vascular dementia: evidence from pre-clinical and clinical studies. Clin Exp Hypertens, 2002,24(7-8);697-713.
[119] 肖军,韦永胜,黄雨兰,等. 卡巴拉汀对血管性痴呆认知功能的影响. 实用医院临床杂志 2004,1(2);22-23.
[120] Ni, J.W., Matsumoto, K., Li, H.B., et al. Neuronal damage and decrease of central acetylcholine level following permanent occlusion of bilateral common carotid arteries in rat. Brain Res, 1995,673(2);290-296.
[121] Tanaka, K., Wada, N., Hori, K., et al. Chronic cerebral hypoperfusion disrupts discriminative behavior in acquired-learning rats. J Neurosci Methods, 1998,84(1-2);63-68.
[122] Kondo, Y., Ogawa, N., Asanuma, M., et al. Preventive effects of bifemelane hydrochloride on decreased levels of muscarinic acetylcholine receptor and its mRNA in a rat model of chronic cerebral hypoperfusion. Neurosci Res, 1996,24(4);409-414.
[123] 吴 启 伟 . 血 管 性 痴 呆 的 基 础 性 研 究 进 展 . 中 华 医 学 研 究 杂 志 , 2005,5(10);1009-1011.
[124] 王哲,张昱,李华军,等. 痴呆大鼠模型的行为学、脑内胆碱乙酰转移酶及突触素改变. 神经疾病与精神卫生, 2003,3(4);253-255.
[125] 徐莉,李铃,陈景藻,等. 康复训练对大鼠脑梗塞神经功能恢复的影响. 中华物理医学与康复杂志, 2000,2(33);86.
[126] Macdonald RL, S.M. Pathophysiology of cerebral ischemia. Neurol Med Chir (Tokyo) 1998,38(1);1-11.
[127] 王宏涛,靳洪涛,孙建宁,等. 异亚丙基莽草酸抗血栓作用的实验研究. 药学学报, 2002,37(4);245-248.
[128] 马怡,孙建宁,徐秋萍,等. 异亚丙基莽草酸对血管内皮细胞释放前列环素的影响 北京中医药大学学报, 2003,26(4);25-27.
[129] Ma, Y., Sun, J.N., Xu, Q.P., et al. 3,4-oxo-isopropylidene-shikimic acid inhibits adhesion of polymorphonuclear leukocyte to TNF-alpha-induced endothelial cells in vitro. Acta Pharmacol Sin, 2004,25(2);246-250.
[130] Farkas, E., Luiten, P.G., Bari, F. Permanent, bilateral common carotid artery occlusion in the rat: a model for chronic cerebral hypoperfusion-related neurodegenerative diseases. Brain Res Rev, 2007,54(1);162-180.
[131] Aytac, E., Seymen, H.O., Uzun, H., et al. Effects of iloprost on visual evoked potentials and brain tissue oxidative stress after bilateral common carotid artery occlusion. Prostaglandins Leukot Essent Fatty Acids, 2006,74(6);373-378.
[132] Ozacmak, V.H., Sayan, H., Cetin, A., et al. AT1 receptor blocker candesartan-induced attenuation of brain injury of rats subjected to chronic cerebral hypoperfusion. Neurochem Res, 2007,32(8);1314-1321.
[133] Wang, H.T., Sun, J.N., Xu, Q.P. Effect of 3,4-oxo-isopropylidene shikimic acid on brain edema and energy metabolism in rats subjected to middle cerebral artery thrombosis Chinese Journal of Pharmacology and Toxicology,2002,16;270-272.
[134] Ma, Y., Sun, J.N., Xu, Q.P. Protective effect of 3,4-oxo-isopropylidene-shikimic acid on vascular endothelial cell injury Pharmacology and Clinics of Chinese Materia Medica, 2002,18(supplement);78-79.
[135] Wang, H.T., Sun, J.N., Xu, Q.P. Efect of 3,4-OXO-isopropylidene-shikimic acid on free radical metabolism in the brain tissue of rats subjected to middle cerebral artery thrombosis Chin Pharmacol Bull, 2002,18(5);569.
[2] Schimanski, L.A., Nguyen, P.V. Multidisciplinary approaches for investigating the mechanisms of hippocampus-dependent memory: a focus on inbred mouse strains. Neurosci Biobehav Rev, 2004,28(5);463-483.
[3] Okada, T., Yamada, N., Tsuzuki, K., et al. Long-term potentiation in the hippocampal CA1 area and dentate gyrus plays different roles in spatial learning. Eur J Neurosci, 2003,17(2);341-349.
[4] Schinder, A.F., Poo, M. The neurotrophin hypothesis for synaptic plasticity. Trends Neurosci, 2000,23(12);639-645.
[5] Thoenen, H. Neurotrophins and activity-dependent plasticity. Prog Brain Res, 2000,128;183-191.
[6] Poo, M.M. Neurotrophins as synaptic modulators. Nat Rev Neurosci, 2001,2(1);24-32.
[7] Mowla, S.J., Farhadi, H.F., Pareek, S., et al. Biosynthesis and post-translational processing of the precursor to brain-derived neurotrophic factor. J Biol Chem, 2001,276(16);12660-12666.
[8] Murer, M.G., Yan, Q., Raisman-Vozari, R. Brain-derived neurotrophic factor in the control human brain, and in Alzheimer's disease and Parkinson's disease. Prog Neurobiol, 2001,63(1);71-124.
[9] Tao, X., West, A.E., Chen, W.G., et al. A calcium-responsive transcription factor, CaRF, that regulates neuronal activity-dependent expression of BDNF. Neuron, 2002,33(3);383-395.
[10] Aliaga, E., Arancibia, S., Givalois, L., et al. Osmotic stress increases brain-derived neurotrophic factor messenger RNA expression in the hypothalamic supraoptic nucleus with differential regulation of its transcripts. Relation to arginine-vasopressin content. Neuroscience, 2002,112(4);841-850.
[11] Dias, B.G., Banerjee, S.B., Duman, R.S., et al. Differential regulation of brain derived neurotrophic factor transcripts by antidepressant treatments in the adult rat brain. Neuropharmacology, 2003,45(4);553-563.
[12] Rattiner, L.M., Davis, M., Ressler, K.J. Differential regulation of brain-derived neurotrophic factor transcripts during the consolidation of fear learning. Learn Mem, 2004,11(6);727-731.
[13] Tabuchi, A., Sakaya, H., Kisukeda, T., et al. Involvement of an upstream stimulatory factor as well as cAMP-responsive element-binding protein in the activation of brain-derived neurotrophic factor gene promoter I. J Biol Chem, 2002,277(39);35920-35931.
[14] Righi, M., Tongiorgi, E., Cattaneo, A. Brain-derived neurotrophic factor (BDNF) induces dendritic targeting of BDNF and tyrosine kinase B mRNAs in hippocampal neurons through a phosphatidylinositol-3 kinase-dependent pathway. J Neurosci, 2000,20(9);3165-3174.
[15] Patterson, S.L., Pittenger, C., Morozov, A., et al. Some forms of cAMP-mediated long-lasting potentiation are associated with release of BDNF and nuclear translocation of phospho-MAP kinase. Neuron, 2001,32(1);123-140.
[16] Miller, S., Yasuda, M., Coats, J.K., et al. Disruption of dendritic translation of CaMKIIalpha impairs stabilization of synaptic plasticity and memory consolidation. Neuron, 2002,36(3);507-519.
[17] Villarreal, D.M., Do, V., Haddad, E., et al. NMDA receptor antagonists sustain LTP and spatial memory: active processes mediate LTP decay. Nat Neurosci, 2002,5(1);48-52.
[18] Kandel, E.R. The molecular biology of memory storage: a dialogue between genes and synapses. Science, 2001,294(5544);1030-1038.
[19] Hansson, A.C., Cintra, A., Belluardo, N., et al. Gluco- and mineralocorticoid receptor-mediated regulation of neurotrophic factor gene expression in the dorsal hippocampus and the neocortex of the rat. Eur J Neurosci, 2000,12(8);2918-2934.
[20] Russo-Neustadt, A.A., Beard, R.C., Huang, Y.M., et al. Physical activity and antidepressant treatment potentiate the expression of specific brain-derived neurotrophic factor transcripts in the rat hippocampus. Neuroscience, 2000,101(2);305-312.
[21] Ickes, B.R., Pham, T.M., Sanders, L.A., et al. Long-term environmental enrichment leads to regional increases in neurotrophin levels in rat brain. Exp Neurol, 2000,164(1);45-52.
[22] Miyake, K., Yamamoto, W., Tadokoro, M., et al. Alterations in hippocampal GAP-43, BDNF, and L1 following sustained cerebral ischemia. Brain Res, 2002,935(1-2);24-31.
[23] Drake, C.T., Milner, T.A., Patterson, S.L. Ultrastructural localization of full-length trkB immunoreactivity in rat hippocampus suggests multiple roles in modulating activity-dependent synaptic plasticity. J Neurosci, 1999,19(18);8009-8026.
[24] Tyler, W.J., Pozzo-Miller, L.D. BDNF enhances quantal neurotransmitter release and increases the number of docked vesicles at the active zones of hippocampal excitatory synapses. J Neurosci, 2001,21(12);4249-4258.
[25] Larsson, E., Nanobashvili, A., Kokaia, Z., et al. Evidence for neuroprotective effects of endogenous brain-derived neurotrophic factor after global forebrain ischemia in rats. J Cereb Blood Flow Metab, 1999,19(11);1220-1228.
[26] Keenan, J.P., Nelson, A., O'Connor, M., et al. Self-recognition and the right hemisphere. Nature, 2001,409(6818);305.
[27] Hartmann, M., Heumann, R., Lessmann, V. Synaptic secretion of BDNF after high-frequency stimulation of glutamatergic synapses. Embo J, 2001,20(21);5887-5897.
[28] Kohara, K., Kitamura, A., Morishima, M., et al. Activity-dependent transfer of brain-derived neurotrophic factor to postsynaptic neurons. Science,2001,291(5512);2419-2423.
[29] Kojima, M., Takei, N., Numakawa, T., et al. Biological characterization and optical imaging of brain-derived neurotrophic factor-green fluorescent protein suggest an activity-dependent local release of brain-derived neurotrophic factor in neurites of cultured hippocampal neurons. J Neurosci Res, 2001,64(1);1-10.
[30] Fawcett, J.P., Bamji, S.X., Causing, C.G., et al. Functional evidence that BDNF is an anterograde neuronal trophic factor in the CNS. J Neurosci, 1998,18(8);2808-2821.
[31] Griesbeck, O., Canossa, M., Campana, G., et al. Are there differences between the secretion characteristics of NGF and BDNF? Implications for the modulatory role of neurotrophins in activity-dependent neuronal plasticity. Microsc Res Tech, 1999,45(4-5);262-275.
[32] Rose, C.R., Blum, R., Kafitz, K.W., et al. From modulator to mediator: rapid effects of BDNF on ion channels. Bioessays, 2004,26(11);1185-1194.
[33] Teng, H.K., Teng, K.K., Lee, R., et al. ProBDNF induces neuronal apoptosis via activation of a receptor complex of p75NTR and sortilin. J Neurosci, 2005,25(22);5455-5463.
[34] Glombik, M.M., Gerdes, H.H. Signal-mediated sorting of neuropeptides and prohormones: secretory granule biogenesis revisited. Biochimie, 2000,82(4);315-326.
[35] Binder, D.K., Routbort, M.J., McNamara, J.O. Immunohistochemical evidence of seizure-induced activation of trk receptors in the mossy fiber pathway of adult rat hippocampus. J Neurosci, 1999,19(11);4616-4626.
[36] Ying, S.W., Futter, M., Rosenblum, K., et al. Brain-derived neurotrophic factor induces long-term potentiation in intact adult hippocampus: requirement for ERK activation coupled to CREB and upregulation of Arc synthesis. J Neurosci, 2002,22(5);1532-1540.
[37] Sweatt, J.D. The neuronal MAP kinase cascade: a biochemical signal integration system subserving synaptic plasticity and memory. J Neurochem, 2001,76(1);1-10.
[38] Iwasaki, Y., Gay, B., Wada, K., et al. Association of the Src family tyrosine kinase Fyn with TrkB. J Neurochem, 1998,71(1);106-111.
[39] Kaplan, D.R., Miller, F.D. Neurotrophin signal transduction in the nervous system. Curr Opin Neurobiol, 2000,10(3);381-391.
[40] Patapoutian, A., Reichardt, L.F. Trk receptors: mediators of neurotrophin action. Curr Opin Neurobiol, 2001,11(3);272-280.
[41] Finkbeiner, S., Tavazoie, S.F., Maloratsky, A., et al. CREB: a major mediator of neuronal neurotrophin responses. Neuron, 1997,19(5);1031-1047.
[42] Vaynman, S., Ying, Z., Gomez-Pinilla, F. Interplay between brain-derived neurotrophic factor and signal transduction modulators in the regulation of the effects of exercise on synaptic-plasticity. Neuroscience, 2003,122(3);647-657.
[43] Orban, P.C., Chapman, P.F., Brambilla, R. Is the Ras-MAPK signalling pathway necessary for long-term memory formation? Trends Neurosci, 1999,22(1);38-44.
[44] Schafe, G.E., Nadel, N.V., Sullivan, G.M., et al. Memory consolidation for contextual and auditory fear conditioning is dependent on protein synthesis, PKA, and MAP kinase. Learn Mem, 1999,6(2);97-110.
[45] Sherwood, N.T., Lo, D.C. Long-term enhancement of central synaptic transmission by chronic brain-derived neurotrophic factor treatment. J Neurosci, 1999,19(16);7025-7036.
[46] Tartaglia, N., Du, J., Tyler, W.J., et al. Protein synthesis-dependent and -independent regulation of hippocampal synapses by brain-derived neurotrophic factor. J Biol Chem, 2001,276(40);37585-37593.
[47] Messaoudi, E., Bardsen, K., Srebro, B., et al. Acute intrahippocampal infusion of BDNF induces lasting potentiation of synaptic transmission in the rat dentate gyrus. J Neurophysiol, 1998,79(1);496-499.
[48] Ernfors, P., Bramham, C.R. The coupling of a trkB tyrosine residue to LTP. Trends Neurosci, 2003,26(4);171-173.
[49] Kelleher, R.J., 3rd, Govindarajan, A., Tonegawa, S. Translational regulatory mechanisms in persistent forms of synaptic plasticity. Neuron, 2004,44(1);59-73.
[50] Alsina, B., Vu, T., Cohen-Cory, S. Visualizing synapse formation in arborizing optic axons in vivo: dynamics and modulation by BDNF. Nat Neurosci, 2001,4(11);1093-1101.
[51] Bramham, C.R., Messaoudi, E. BDNF function in adult synaptic plasticity: the synaptic consolidation hypothesis. Prog Neurobiol, 2005,76(2);99-125.
[52] Schratt, G.M., Nigh, E.A., Chen, W.G., et al. BDNF regulates the translation of a select group of mRNAs by a mammalian target of rapamycin-phosphatidylinositol 3-kinase-dependent pathway during neuronal development. J Neurosci, 2004,24(33);7366-7377.
[53] Collin, C., Vicario-Abejon, C., Rubio, M.E., et al. Neurotrophins act at presynaptic terminals to activate synapses among cultured hippocampal neurons. Eur J Neurosci, 2001,13(7);1273-1282.
[54] Aakalu, G., Smith, W.B., Nguyen, N., et al. Dynamic visualization of local protein synthesis in hippocampal neurons. Neuron, 2001,30(2);489-502.
[55] Eberwine, J., Miyashiro, K., Kacharmina, J.E., et al. Local translation of classes of mRNAs that are targeted to neuronal dendrites. Proc Natl Acad Sci U S A, 2001,98(13);7080-7085.
[56] Yin, Y., Edelman, G.M., Vanderklish, P.W. The brain-derived neurotrophic factor enhances synthesis of Arc in synaptoneurosomes. Proc Natl Acad Sci U S A, 2002,99(4);2368-2373.
[57] Zybailov, B., Coleman, M.K., Florens, L., et al. Correlation of relative abundance ratios derived from peptide ion chromatograms and spectrum counting for quantitative proteomic analysis using stable isotope labeling. Anal Chem, 2005,77(19);6218-6224.
[58] Liao, L., Pilotte, J., Xu, T., et al. BDNF induces widespread changes in synaptic proteincontent and up-regulates components of the translation machinery: an analysis using high-throughput proteomics. J Proteome Res, 2007,6(3);1059-1071.
[59] Lisman, J., Schulman, H., Cline, H. The molecular basis of CaMKII function in synaptic and behavioural memory. Nat Rev Neurosci, 2002,3(3);175-190.
[60] Steward, O., Schuman, E.M. Protein synthesis at synaptic sites on dendrites. Annu Rev Neurosci, 2001,24(299-325.
[61] Martinez, A., Alcantara, S., Borrell, V., et al. TrkB and TrkC signaling are required for maturation and synaptogenesis of hippocampal connections. J Neurosci, 1998,18(18);7336-7350.
[62] Pozzo-Miller, L.D., Gottschalk, W., Zhang, L., et al. Impairments in high-frequency transmission, synaptic vesicle docking, and synaptic protein distribution in the hippocampus of BDNF knockout mice. J Neurosci, 1999,19(12);4972-4983.
[63] Korte, M., Griesbeck, O., Gravel, C., et al. Virus-mediated gene transfer into hippocampal CA1 region restores long-term potentiation in brain-derived neurotrophic factor mutant mice. Proc Natl Acad Sci U S A, 1996,93(22);12547-12552.
[64] Minichiello, L., Korte, M., Wolfer, D., et al. Essential role for TrkB receptors in hippocampus-mediated learning. Neuron, 1999,24(2);401-414.
[65] Xu, B., Gottschalk, W., Chow, A., et al. The role of brain-derived neurotrophic factor receptors in the mature hippocampus: modulation of long-term potentiation through a presynaptic mechanism involving TrkB. J Neurosci, 2000,20(18);6888-6897.
[66] Kossel, A.H., Cambridge, S.B., Wagner, U., et al. A caged Ab reveals an immediate/instructive effect of BDNF during hippocampal synaptic potentiation. Proc Natl Acad Sci U S A, 2001,98(25);14702-14707.
[67] Levine, E.S., Dreyfus, C.F., Black, I.B., et al. Brain-derived neurotrophic factor rapidly enhances synaptic transmission in hippocampal neurons via postsynaptic tyrosine kinase receptors. Proc Natl Acad Sci U S A, 1995,92(17);8074-8077.
[68] Chang, S., Popov, S.V. Long-range signaling within growing neurites mediated by neurotrophin-3. Proc Natl Acad Sci U S A, 1999,96(7);4095-4100.
[69] Gottschalk, W., Pozzo-Miller, L.D., Figurov, A., et al. Presynaptic modulation of synaptic transmission and plasticity by brain-derived neurotrophic factor in the developing hippocampus. J Neurosci, 1998,18(17);6830-6839.
[70] Patterson, S.L., Abel, T., Deuel, T.A., et al. Recombinant BDNF rescues deficits in basal synaptic transmission and hippocampal LTP in BDNF knockout mice. Neuron, 1996,16(6);1137-1145.
[71] Figurov, A., Pozzo-Miller, L.D., Olafsson, P., et al. Regulation of synaptic responses to high-frequency stimulation and LTP by neurotrophins in the hippocampus. Nature, 1996,381(6584);706-709.
[72] Kang, H., Welcher, A.A., Shelton, D., et al. Neurotrophins and time: different roles forTrkB signaling in hippocampal long-term potentiation. Neuron, 1997,19(3);653-664.
[73] Canales, J.J., Graybiel, A.M. A measure of striatal function predicts motor stereotypy. Nat Neurosci, 2000,3(4);377-383.
[74] Lessmann, V. Neurotrophin-dependent modulation of glutamatergic synaptic transmission in the mammalian CNS. Gen Pharmacol, 1998,31(5);667-674.
[75] Schikorski, T., Stevens, C.F. Quantitative ultrastructural analysis of hippocampal excitatory synapses. J Neurosci, 1997,17(15);5858-5867.
[76] Dobrunz, L.E., Stevens, C.F. Heterogeneity of release probability, facilitation, and depletion at central synapses. Neuron, 1997,18(6);995-1008.
[77] Alonso, M., Vianna, M.R., Depino, A.M., et al. BDNF-triggered events in the rat hippocampus are required for both short- and long-term memory formation. Hippocampus, 2002,12(4);551-560.
[78] Kafitz, K.W., Rose, C.R., Thoenen, H., et al. Neurotrophin-evoked rapid excitation through TrkB receptors. Nature, 1999,401(6756);918-921.
[79] McAllister, A.K., Katz, L.C., Lo, D.C. Neurotrophins and synaptic plasticity. Annu Rev Neurosci, 1999,22;295-318.
[80] Frerking, M., Malenka, R.C., Nicoll, R.A. Brain-derived neurotrophic factor (BDNF) modulates inhibitory, but not excitatory, transmission in the CA1 region of the hippocampus. J Neurophysiol, 1998,80(6);3383-3386.
[81] Kovalchuk, Y., Hanse, E., Kafitz, K.W., et al. Postsynaptic Induction of BDNF-Mediated Long-Term Potentiation. Science, 2002,295(5560);1729-1734.
[82] Chen, C., Tonegawa, S. Molecular genetic analysis of synaptic plasticity, activity-dependent neural development, learning, and memory in the mammalian brain. Annu Rev Neurosci, 1997,20;157-184.
[83] Levine, E.S., Crozier, R.A., Black, I.B., et al. Brain-derived neurotrophic factor modulates hippocampal synaptic transmission by increasing N-methyl-D-aspartic acid receptor activity. Proc Natl Acad Sci U S A, 1998,95(17);10235-10239.
[84] Suen, P.C., Wu, K., Levine, E.S., et al. Brain-derived neurotrophic factor rapidly enhances phosphorylation of the postsynaptic N-methyl-D-aspartate receptor subunit 1. Proc Natl Acad Sci U S A, 1997,94(15);8191-8195.
[85] Lin, S.Y., Wu, K., Levine, E.S., et al. BDNF acutely increases tyrosine phosphorylation of the NMDA receptor subunit 2B in cortical and hippocampal postsynaptic densities. Brain Res Mol Brain Res, 1998,55(1);20-27.
[86] Yu, X.M., Askalan, R., Keil, G.J., 2nd, et al. NMDA channel regulation by channel-associated protein tyrosine kinase Src. Science, 1997,275(5300);674-678.
[87] Li, Y.X., Zhang, Y., Lester, H.A., et al. Enhancement of neurotransmitter release induced by brain-derived neurotrophic factor in cultured hippocampal neurons. J Neurosci, 1998,18(24);10231-10240.
[88] Engert, F., Bonhoeffer, T. Dendritic spine changes associated with hippocampal long-term synaptic plasticity. Nature, 1999,399(6731);66-70.
[89] Toni, N., Buchs, P.A., Nikonenko, I., et al. LTP promotes formation of multiple spine synapses between a single axon terminal and a dendrite. Nature, 1999,402(6760);421-425.
[90] Gallo, G., Letourneau, P.C. Localized sources of neurotrophins initiate axon collateral sprouting. J Neurosci, 1998,18(14);5403-5414.
[91] Shimada, A., Mason, C.A., Morrison, M.E. TrkB signaling modulates spine density and morphology independent of dendrite structure in cultured neonatal Purkinje cells. J Neurosci, 1998,18(21);8559-8570.
[92] Alonso, M., Medina, J.H., Pozzo-Miller, L. ERK1/2 activation is necessary for BDNF to increase dendritic spine density in hippocampal CA1 pyramidal neurons. Learn Mem, 2004,11(2);172-178.
[93]Inoue, A., Sanes, J.R. Lamina-specific connectivity in the brain: regulation by N-cadherin, neurotrophins, and glycoconjugates. Science, 1997,276(5317);1428-1431.
[94] Lein, E.S., Shatz, C.J. Rapid regulation of brain-derived neurotrophic factor mRNA within eye-specific circuits during ocular dominance column formation. J Neurosci, 2000,20(4);1470-1483.
[95] Craig, A.M., Lichtman, J. W. Synapse formation and maturation. Johns Hopkins Univ. Press,2001,571–612.
[96] Mozhayeva, M.G., Sara, Y., Liu, X., et al. Development of vesicle pools during maturation of hippocampal synapses. J Neurosci, 2002,22(3);654-665.
[97] Genoud, C., Knott, G.W., Sakata, K., et al. Altered synapse formation in the adult somatosensory cortex of brain-derived neurotrophic factor heterozygote mice. J Neurosci, 2004,24(10);2394-2400.
[98] Jovanovic, J.N., Czernik, A.J., Fienberg, A.A., et al. Synapsins as mediators of BDNF-enhanced neurotransmitter release. Nat Neurosci, 2000,3(4);323-329.
[99] Graham, K.S., Patterson, K., Pratt, K.H., et al. Relearning and subsequent forgetting of semantic category exemplars in a case of semantic dementia. Neuropsychology, 1999,13(3);359-380.
[100] McGaugh, J.L. Memory--a century of consolidation. Science, 2000,287(5451);248-251.
[101] Hoffman, K.L., McNaughton, B.L. Coordinated reactivation of distributed memory traces in primate neocortex. Science, 2002,297(5589);2070-2073.
[102] Izquierdo, I., Vianna, M.R., Izquierdo, L.A., et al. Memory retrieval and its lasting consequences. Neurotox Res, 2002,4(5-6);573-593.
[103] Qiao, X., Chen, L., Gao, H., et al. Cerebellar brain-derived neurotrophic factor-TrkB defect associated with impairment of eyeblink conditioning in Stargazer mutant mice. J Neurosci, 1998;18(17);6990-6999.
[104] Aloe, L., Properzi, F., Probert, L., et al. Learning abilities, NGF and BDNF brain levelsin two lines of TNF-alpha transgenic mice, one characterized by neurological disorders, the other phenotypically normal. Brain Res, 1999,840(1-2);125-137.
[105] Croll, S.D., Suri, C., Compton, D.L., et al. Brain-derived neurotrophic factor transgenic mice exhibit passive avoidance deficits, increased seizure severity and in vitro hyperexcitability in the hippocampus and entorhinal cortex. Neuroscience, 1999,93(4);1491-1506.
[106] Tokuyama, W., Okuno, H., Hashimoto, T., et al. BDNF upregulation during declarative memory formation in monkey inferior temporal cortex. Nat Neurosci, 2000,3(11);1134-1142.
[107] Akutagawa, E., Konishi, M. Transient expression and transport of brain-derived neurotrophic factor in the male zebra finch's song system during vocal development. Proc Natl Acad Sci U S A, 1998,95(19);11429-11434.
[108] Wade, J. TrkB-like immunoreactivity in the song system of developing zebra finches. J Chem Neuroanat, 2000,19(1);33-39.
[109] Johnston, A.N., Clements, M.P., Rose, S.P. Role of brain-derived neurotrophic factor and presynaptic proteins in passive avoidance learning in day-old domestic chicks. Neuroscience, 1999,88(4);1033-1042.
[110] Mizuno, M., Yamada, K., Olariu, A., et al. Involvement of brain-derived neurotrophic factor in spatial memory formation and maintenance in a radial arm maze test in rats. J Neurosci, 2000,20(18);7116-7121.
[111] Hall, J., Thomas, K.L., Everitt, B.J. Rapid and selective induction of BDNF expression in the hippocampus during contextual learning. Nat Neurosci, 2000,3(6);533-535.
[112] Mu, J.S., Li, W.P., Yao, Z.B., et al. Deprivation of endogenous brain-derived neurotrophic factor results in impairment of spatial learning and memory in adult rats. Brain Res, 1999,835(2);259-265.
[113] Ma, Y.L., Wang, H.L., Wu, H.C., et al. Brain-derived neurotrophic factor antisense oligonucleotide impairs memory retention and inhibits long-term potentiation in rats. Neuroscience, 1998,82(4);957-967.
[114] DiCarlo, J.J., Johnson, K.O. Velocity invariance of receptive field structure in somatosensory cortical area 3b of the alert monkey. J Neurosci, 1999,19(1);401-419.
[115] Agnès Gruart, C.S., Mauricio Valenzuela-Harrington. Mutation at the TrkB PLC-docking site affects hippocampal LTP and associative learning in conscious mice. Learning& Memory, 2006,14;54-62.
[116] Mizuno, M., Yamada, K., Takei, N., et al. Phosphatidylinositol 3-kinase: a molecule mediating BDNF-dependent spatial memory formation. Mol Psychiatry, 2003,8(2);217-224.
[117] Alonso, M., Bekinschtein, P., Cammarota, M., et al. Endogenous BDNF is required for long-term memory formation in the rat parietal cortex. Learn Mem, 2005,12(5);504-510.
[118] Liu, J., Fukunaga, K., Yamamoto, H., et al. Differential roles of Ca(2+)/calmodulin-dependent protein kinase II and mitogen-activated protein kinaseactivation in hippocampal long-term potentiation. J Neurosci, 1999,19(19);8292-8299.
[119] Blanquet, P.R. Identification of two persistently activated neurotrophin-regulated pathways in rat hippocampus. Neuroscience, 2000,95(3);705-719.
[120] Saarelainen, T., Pussinen, R., Koponen, E., et al. Transgenic mice overexpressing truncated trkB neurotrophin receptors in neurons have impaired long-term spatial memory but normal hippocampal LTP. Synapse, 2000,38(1);102-104.
[121] Huang, E.J., Reichardt, L.F. Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci, 2001,24;677-736.
[122] Yamada, K., Mizuno, M., Nabeshima, T. Role for brain-derived neurotrophic factor in learning and memory. Life Sci, 2002,70(7);735-744.
[123] Kiprianova, I., Freiman, T.M., Desiderato, S., et al. Brain-derived neurotrophic factor prevents neuronal death and glial activation after global ischemia in the rat. J Neurosci Res, 1999,56(1);21-27.
[124] Bhave, S.V., Ghoda, L., Hoffman, P.L. Brain-derived neurotrophic factor mediates the anti-apoptotic effect of NMDA in cerebellar granule neurons: signal transduction cascades and site of ethanol action. J Neurosci, 1999,19(9);3277-3286.
[125] Zhao, L.R., Mattsson, B., Johansson, B.B. Environmental influence on brain-derived neurotrophic factor messenger RNA expression after middle cerebral artery occlusion in spontaneously hypertensive rats. Neuroscience, 2000,97(1);177-184.
[126] Arai, S., Kinouchi, H., Akabane, A., et al. Induction of brain-derived neurotrophic factor (BDNF) and the receptor trk B mRNA following middle cerebral artery occlusion in rat. Neurosci Lett, 1996,211(1);57-60.
[127] Imai, F., Suzuki, H., Oda, J., et al. Neuroprotective effect of exogenous microglia in global brain ischemia. J Cereb Blood Flow Metab, 2007,27(3);488-500.
[128] Kiprianova I.. Sandkühler J.. Schwab S, e.a. Brain-Derived Neurotrophic Factorimproves Long-Term Potentiation and cognitive functions after transient forebrain ischemia in the rat Experimental Neurology 1999,159(2);511-519.
[129] 巴迎春, 王廷华, 潘兴华.等. 慢性脑缺血大鼠海马 CA1 区中的 BDNF 表达. 神经解剖学杂志, 2005,21(6);664-666.
[130] Irina Kiprianova, T.M.F., Stephanie Desiderato, et al. Brain-Derived Neurotrophic Factor Prevents. Neuronal Death and Glial Activation After. Global Ischemia in the Rat. J Neurosci Res 1999,56(1);21-27.
[1] Soderling, T.R. CaM-kinases: modulators of synaptic plasticity. Curr Opin Neurobiol, 2000,10(3);375-380.
[2] Soderling, T.R., Derkach, V.A. Postsynaptic protein phosphorylation and LTP. Trends Neurosci, 2000,23(2);75-80.
[3] Winder, D.G., Sweatt, J.D. Roles of serine/threonine phosphatases in hippocampal synaptic plasticity. Nat Rev Neurosci, 2001,2(7);461-474.
[4] Weeber, E.J., Sweatt, J.D. Molecular neurobiology of human cognition. Neuron, 2002,33(6);845-848.
[5] Coupry, I., Monnet, L., Attia, A.A., et al. Analysis of CBP (CREBBP) gene deletions in Rubinstein-Taybi syndrome patients using real-time quantitative PCR. Hum Mutat, 2004,23(3);278-284.
[6] Servillo, G., Della Fazia, M.A., Sassone-Corsi, P. Coupling cAMP signaling to transcription in the liver: pivotal role of CREB and CREM. Exp Cell Res, 2002,275(2);143-154.
[7] Shaywitz, A.J., Greenberg, M.E. CREB: a stimulus-induced transcription factor activated by a diverse array of extracellular signals. Annu Rev Biochem, 1999,68;821-861.
[8] Walton, M.R., Dragunow, I. Is CREB a key to neuronal survival? Trends Neurosci, 2000,23(2);48-53.
[9] Shaywitz, A.J., Dove, S.L., Kornhauser, J.M., et al. Magnitude of the CREB-dependent transcriptional response is determined by the strength of the interaction between the kinase-inducible domain of CREB and the KIX domain of CREB-binding protein. Mol Cell Biol, 2000,20(24);9409-9422.
[10] Wu, G.Y., Deisseroth, K., Tsien, R.W. Activity-dependent CREB phosphorylation: convergence of a fast, sensitive calmodulin kinase pathway and a slow, less sensitive mitogen-activated protein kinase pathway. Proc Natl Acad Sci U S A, 2001,98(5);2808-2813.
[11] Hardingham, G.E., Arnold, F.J., Bading, H. Nuclear calcium signaling controls CREB-mediated gene expression triggered by synaptic activity. Nat Neurosci, 2001,4(3);261-267.
[12] Sakaguchi, H., Wada, K., Maekawa, M., et al. Song-induced phosphorylation of cAMP response element-binding protein in the songbird brain. J Neurosci, 1999,19(10);3973-3981.
[13] Screaton, R.A., Conkright, M.D., Katoh, Y., et al. The CREB coactivator TORC2 functions as a calcium- and cAMP-sensitive coincidence detector. Cell, 2004,119(1);61-74.
[14] Pittenger, C., Huang, Y.Y., Paletzki, R.F., et al. Reversible inhibition of CREB/ATF transcription factors in region CA1 of the dorsal hippocampus disruptshippocampus-dependent spatial memory. Neuron, 2002,34(3);447-462.
[15] Kogan, J.H., Frankland, P.W., Silva, A.J. Long-term memory underlying hippocampus-dependent social recognition in mice. Hippocampus, 2000,10(1);47-56.
[16] Genoux, D., Haditsch, U., Knobloch, M., et al. Protein phosphatase 1 is a molecular constraint on learning and memory. Nature, 2002,418(6901);970-975.
[17] Blanquet, P.R., Mariani, J., Derer, P. A calcium/calmodulin kinase pathway connects brain-derived neurotrophic factor to the cyclic AMP-responsive transcription factor in the rat hippocampus. Neuroscience, 2003,118(2);477-490.
[18] Swank, M.W. Phosphorylation of MAP kinase and CREB in mouse cortex and amygdala during taste aversion learning. Neuroreport, 2000,11(8);1625-1630.
[19] LeDoux, J.E. Emotion circuits in the brain. Annu Rev Neurosci, 2000;23;155-184.
[20] Graves, L., Dalvi, A., Lucki, I., et al. Behavioral analysis of CREB alphadelta mutation on a B6/129 F1 hybrid background. Hippocampus, 2002,12(1);18-26.
[21] Falls, W.A., Kogan, J.H., Silva, A.J., et al. Fear-potentiated startle, but not prepulse inhibition of startle, is impaired in CREBalphadelta-/- mutant mice. Behav Neurosci, 2000,114(5);998-1004.
[22] Nguyen, P.V., Gerlai, R. Behavioural and physiological characterization of inbred mouse strains: prospects for elucidating the molecular mechanisms of mammalian learning and memory. Genes Brain Behav, 2002,1(2);72-81.
[23] Schimanski, L.A., Nguyen, P.V. Multidisciplinary approaches for investigating the mechanisms of hippocampus-dependent memory: a focus on inbred mouse strains. Neurosci Biobehav Rev, 2004,28(5);463-483.
[24] Athos, J., Impey, S., Pineda, V.V., et al. Hippocampal CRE-mediated gene expression is required for contextual memory formation. Nat Neurosci, 2002,5(11);1119-1120.
[25] Wiltgen, B.J., Sanders, M.J., Behne, N.S., et al. Sex differences, context preexposure, and the immediate shock deficit in Pavlovian context conditioning with mice. Behav Neurosci, 2001,115(1);26-32.
[26] Barrientos, R.M., O'Reilly, R.C., Rudy, J.W. Memory for context is impaired by injecting anisomycin into dorsal hippocampus following context exploration. Behav Brain Res, 2002,134(1-2);299-306.
[27] Cammarota, M., Bevilaqua, L.R., Ardenghi, P., et al. Learning-associated activation of nuclear MAPK, CREB and Elk-1, along with Fos production, in the rat hippocampus after a one-trial avoidance learning: abolition by NMDA receptor blockade. Brain Res Mol Brain Res, 2000,76(1);36-46.
[28] Josselyn, S.A., Shi, C., Carlezon, W.A., Jr., et al. Long-term memory is facilitated by cAMP response element-binding protein overexpression in the amygdala. J Neurosci, 2001,21(7);2404-2412.
[29] Wallace, T.L., Stellitano, K.E., Neve, R.L., et al. Effects of cyclic adenosinemonophosphate response element binding protein overexpression in the basolateral amygdala on behavioral models of depression and anxiety. Biol Psychiatry, 2004,56(3);151-160.
[30] Brodie, C.R., Khaliq, M., Yin, J.C., et al. Overexpression of CREB reduces CRE-mediated transcription: behavioral and cellular analyses in transgenic mice. Mol Cell Neurosci, 2004,25(4);602-611.
[31] Bozon, B., Kelly, A., Josselyn, S.A., et al. MAPK, CREB and zif268 are all required for the consolidation of recognition memory. Philos Trans R Soc Lond B Biol Sci, 2003,358(1432);805-814.
[32] Yang, S.N., Huang, L.T., Wang, C.L., et al. Prenatal administration of morphine decreases CREBSerine-133 phosphorylation and synaptic plasticity range mediated by glutamatergic transmission in the hippocampal CA1 area of cognitive-deficient rat offspring. Hippocampus, 2003,13(8);915-921.
[33] Pandey, S.C., Mittal, N., Silva, A.J. Blockade of cyclic AMP-responsive element DNA binding in the brain of CREB delta/alpha mutant mice. Neuroreport, 2000,11(11);2577-2580.
[34] Mantamadiotis, T., Lemberger, T., Bleckmann, S.C., et al. Disruption of CREB function in brain leads to neurodegeneration. Nat Genet, 2002,31(1);47-54.
[35] Rammes, G., Steckler, T., Kresse, A., et al. Synaptic plasticity in the basolateral amygdala in transgenic mice expressing dominant-negative cAMP response element-binding protein (CREB) in forebrain. Eur J Neurosci, 2000,12(7);2534-2546.
[36] Kida, S., Josselyn, S.A., de Ortiz, S.P., et al. CREB required for the stability of new and reactivated fear memories. Nat Neurosci, 2002,5(4);348-355.
[37] Barco, A., Alarcon, J.M., Kandel, E.R. Expression of constitutively active CREB protein facilitates the late phase of long-term potentiation by enhancing synaptic capture. Cell, 2002,108(5);689-703.
[38] Simonato, M., Manservigi, R., Marconi, P., et al. Gene transfer into neurones for the molecular analysis of behaviour: focus on herpes simplex vectors. Trends Neurosci, 2000,23(5);183-190.
[39] Barrot, M., Olivier, J.D., Perrotti, L.I., et al. CREB activity in the nucleus accumbens shell controls gating of behavioral responses to emotional stimuli. Proc Natl Acad Sci U S A, 2002,99(17);11435-11440.
[40] Marie, H., Morishita, W., Yu, X., et al. Generation of silent synapses by acute in vivo expression of CaMKIV and CREB. Neuron, 2005,45(5);741-752.
[41] Taubenfeld, S.M., Milekic, M.H., Monti, B., et al. The consolidation of new but not reactivated memory requires hippocampal C/EBPbeta. Nat Neurosci, 2001,4(8);813-818.
[42] Walters, C.L., Blendy, J.A. Different requirements for cAMP response element binding protein in positive and negative reinforcing properties of drugs of abuse. J Neurosci, 2001,21(23);9438-9444.
[43] Balschun, D., Wolfer, D.P., Gass, P., et al. Does cAMP response element-binding proteinhave a pivotal role in hippocampal synaptic plasticity and hippocampus-dependent memory? J Neurosci, 2003,23(15);6304-6314.
[44] Carlezon, W.A., Jr., Thome, J., Olson, V.G., et al. Regulation of cocaine reward by CREB. Science, 1998,282(5397);2272-2275.
[45] Bourtchuladze, R., Frenguelli, B., Blendy, J., et al. Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein. Cell, 1994,79(1);59-68.
[46] Gass, P., Wolfer, D.P., Balschun, D., et al. Deficits in memory tasks of mice with CREB mutations depend on gene dosage. Learn Mem, 1998,5(4-5);274-288.
[47] Zhang, J.J., Okutani, F., Inoue, S., et al. Activation of the cyclic AMP response element-binding protein signaling pathway in the olfactory bulb is required for the acquisition of olfactory aversive learning in young rats. Neuroscience, 2003,117(3);707-713.
[48] Frankland, P.W.J., S. A. In Memories are made of these: from messengers to molecules. Landes Bioscience, 2004.
[49] Brightwell, J.J., Smith, C.A., Countryman, R.A., et al. Hippocampal overexpression of mutant creb blocks long-term, but not short-term memory for a socially transmitted food preference. Learn Mem, 2005,12(1);12-17.
[50] Cho, Y.H., Giese, K.P., Tanila, H., et al. Abnormal hippocampal spatial representations in alphaCaMKIIT286A and CREBalphaDelta- mice. Science, 1998,279(5352);867-869.
[51] Guzowski, J.F., McGaugh, J.L. Antisense oligodeoxynucleotide-mediated disruption of hippocampal cAMP response element binding protein levels impairs consolidation of memory for water maze training. Proc Natl Acad Sci U S A, 1997,94(6);2693-2698.
[52] Florian, C., Mons, N., Roullet, P. CREB antisense oligodeoxynucleotide administration into the dorsal hippocampal CA3 region impairs long- but not short-term spatial memory in mice. Learn Mem, 2006,13(4);465-472.
[53] Huang, Y.Y., Pittenger, C., Kandel, E.R. A form of long-lasting, learning-related synaptic plasticity in the hippocampus induced by heterosynaptic low-frequency pairing. Proc Natl Acad Sci U S A, 2004,101(3);859-864.
[54] Brightwell, J.J., Smith, C.A., Neve, R.L., et al. Long-term memory for place learning is facilitated by expression of cAMP response element-binding protein in the dorsal hippocampus. Learn Mem, 2007,14(3);195-199.
[55] Wood, M.A., Kaplan, M.P., Park, A., et al. Transgenic mice expressing a truncated form of CREB-binding protein (CBP) exhibit deficits in hippocampal synaptic plasticity and memory storage. Learn Mem, 2005,12(2);111-119.
[56] Bach, M.E., Barad, M., Son, H., et al. Age-related defects in spatial memory are correlated with defects in the late phase of hippocampal long-term potentiation in vitro and are attenuated by drugs that enhance the cAMP signaling pathway. Proc Natl Acad Sci U S A, 1999,96(9);5280-5285.
[57] Brightwell, J.J., Gallagher, M., Colombo, P.J. Hippocampal CREB1 but not CREB2 is decreased in aged rats with spatial memory impairments. Neurobiol Learn Mem, 2004,81(1);19-26.
[58] Mouravlev, A., Dunning, J., Young, D., et al. Somatic gene transfer of cAMP response element-binding protein attenuates memory impairment in aging rats. Proc Natl Acad Sci U S A, 2006,103(12);4705-4710.
[59] Johannessen, M., Delghandi, M.P., Moens, U. What turns CREB on? Cell Signal, 2004,16(11);1211-1227.
[60] Mayr, B., Montminy, M. Transcriptional regulation by the phosphorylation-dependent factor CREB. Nat Rev Mol Cell Biol, 2001,2(8);599-609.
[61] Lonze, B.E., Ginty, D.D. Function and regulation of CREB family transcription factors in the nervous system. Neuron, 2002,35(4);605-623.
[62] Salas, T.R., Reddy, S.A., Clifford, J.L., et al. Alleviating the suppression of glycogen synthase kinase-3beta by Akt leads to the phosphorylation of cAMP-response element-binding protein and its transactivation in intact cell nuclei. J Biol Chem, 2003,278(42);41338-41346.
[63] Hansen, T.O., Rehfeld, J.F., Nielsen, F.C. GSK-3beta reduces cAMP-induced cholecystokinin gene expression by inhibiting CREB binding. Neuroreport, 2004,15(5);841-845.
[64] Hotte, M., Thuault, S., Dineley, K.T., et al. Phosphorylation of CREB and DARPP-32 during late LTP at hippocampal to prefrontal cortex synapses in vivo. Synapse, 2007,61(1);24-28.
[65] Taubenfeld, S.M., Wiig, K.A., Bear, M.F., et al. A molecular correlate of memory and amnesia in the hippocampus. Nat Neurosci, 1999,2(4);309-310.
[66] Ehlers, M.D. Activity level controls postsynaptic composition and signaling via the ubiquitin-proteasome system. Nat Neurosci, 2003,6(3);231-242.
[67] Schafe, G.E., Atkins, C.M., Swank, M.W., et al. Activation of ERK/MAP kinase in the amygdala is required for memory consolidation of pavlovian fear conditioning. J Neurosci, 2000,20(21);8177-8187.
[68] Deisseroth, K., Tsien, R.W. Dynamic multiphosphorylation passwords for activity-dependent gene expression. Neuron, 2002,34(2);179-182.
[69] Barco, A., Patterson, S., Alarcon, J.M., et al. Gene expression profiling of facilitated L-LTP in VP16-CREB mice reveals that BDNF is critical for the maintenance of LTP and its synaptic capture. Neuron, 2005,48(1);123-137.
[70] Tang, Y.P., Shimizu, E., Dube, G.R., et al. Genetic enhancement of learning and memory in mice. Nature, 1999,401(6748);63-69.
[71] Malleret, G., Haditsch, U., Genoux, D., et al. Inducible and reversible enhancement of learning, memory, and long-term potentiation by genetic inhibition of calcineurin. Cell,2001,104(5);675-686.
[72] Wang, H., Ferguson, G.D., Pineda, V.V., et al. Overexpression of type-1 adenylyl cyclase in mouse forebrain enhances recognition memory and LTP. Nat Neurosci, 2004,7(6);635-642.
[73] Huang, Y.Y., Li, X.C., Kandel, E.R. cAMP contributes to mossy fiber LTP by initiating both a covalently mediated early phase and macromolecular synthesis-dependent late phase. Cell, 1994,79(1);69-79.
[74] Abel, T., Nguyen, P.V., Barad, M., et al. Genetic demonstration of a role for PKA in the late phase of LTP and in hippocampus-based long-term memory. Cell, 1997,88(5);615-626.
[75] Impey, S., Mark, M., Villacres, E.C., et al. Induction of CRE-mediated gene expression by stimuli that generate long-lasting LTP in area CA1 of the hippocampus. Neuron, 1996,16(5);973-982.
[76] Kitagawa, K. CREB and cAMP response element-mediated gene expression in the ischemic brain. Febs J, 2007,274(13);3210-3217.
[77] Meller, R., Minami, M., Cameron, J.A., et al. CREB-mediated Bcl-2 protein expression after ischemic preconditioning. J Cereb Blood Flow Metab, 2005,25(2);234-246.
[78] Ding, Y., Li, J., Luan, X., et al. Exercise pre-conditioning reduces brain damage in ischemic rats that may be associated with regional angiogenesis and cellular overexpression of neurotrophin. Neuroscience, 2004,124(3);583-591.
[79] Tanaka, K., Nogawa, S., Nagata, E., et al. Persistent CREB phosphorylation with protection of hippocampal CA1 pyramidal neurons following temporary occlusion of the middle cerebral artery in the rat. Exp Neurol, 2000,161(2);462-471.
[80] Zhu, D.Y., Lau, L., Liu, S.H., et al. Activation of cAMP-response-element-binding protein (CREB) after focal cerebral ischemia stimulates neurogenesis in the adult dentate gyrus. Proc Natl Acad Sci U S A, 2004,101(25);9453-9457.
[81] Hu, B.R., Fux, C.M., Martone, M.E., et al. Persistent phosphorylation of cyclic AMP responsive element-binding protein and activating transcription factor-2 transcription factors following transient cerebral ischemia in rat brain. Neuroscience, 1999,89(2);437-452.
[82] Irving, E.A., Barone, F.C., Reith, A.D., et al. Differential activation of MAPK/ERK and p38/SAPK in neurones and glia following focal cerebral ischaemia in the rat. Brain Res Mol Brain Res, 2000,77(1);65-75.
[83] Tanaka, K., Nagata, E., Suzuki, S., et al. Immunohistochemical analysis of cyclic AMP response element binding protein phosphorylation in focal cerebral ischemia in rats. Brain Res, 1999,818(2);520-526.
[84] Takeo, S., Niimura, M., Miyake-Takagi, K., et al. A possible mechanism for improvement by a cognition-enhancer nefiracetam of spatial memory function and cAMP-mediated signal transduction system in sustained cerebral ischaemia in rats. Br J Pharmacol, 2003,138(4);642-654.
[85] Jin, K., Mao, X.O., Simon, R.P., et al. Cyclic AMP response element binding protein(CREB) and CREB binding protein (CBP) in global cerebral ischemia. J Mol Neurosci, 2001,16(1);49-56.
[86] 葛巍, 沈霞, 刘永海, 等. 磷酸化 cAMP 反应元件结合蛋白在全脑缺血大鼠海马中的表达. 中风与神经疾病杂志, 2004, (3);7-9,97.
[87] Nagakura, A., Niimura, M., Takeo, S. Effects of a phosphodiesterase IV inhibitor rolipram on microsphere embolism-induced defects in memory function and cerebral cyclic AMP signal transduction system in rats. Br J Pharmacol, 2002,135(7);1783-1793.
[88] Nagakura, A., Takagi, N., Takeo, S. Impairment of cerebral cAMP-mediated signal transduction system and of spatial memory function after microsphere embolism in rats. Neuroscience, 2002,113(3);519-528.
[1] 吴彦,孙建宁,张宁,等.芪龙胶囊对大鼠脑缺血的保护作用.中成药, 2004,26(5); 386-389.
[2] Dahlqvist, P., Ronnback, A., Bergstrom, S.A., 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.
[3] Farkas, E., Institoris, A., Domoki, F., et al. Diazoxide and dimethyl sulphoxide prevent cerebral hypoperfusion-related learning dysfunction and brain damage after carotid artery occlusion. Brain Res, 2004,1008(2);252-260.
[4] 包新民,舒斯云. 大鼠脑立体定位图谱. 人民卫生出版社, 1991.
[5] Lee, V.M., Burdett, N.G., Carpenter, A., et al. Evolution of photochemically induced focal cerebral ischemia in the rat. Magnetic resonance imaging and histology. Stroke, 1996,27(11);2110-2118; discussion 2118-2119.
[6] Rogers, D.C., Wright, P.W., Roberts, J.C., et al. Photothrombotic lesions of the frontal cortex impair the performance of the delayed non-matching to position task by rats. Behav Brain Res, 1992,49(2);231-235.
[7] Chao Liu, J.W., Jun Gu, et al. . Baicalein improves cognitive deficits induced by chronic cerebral hypoperfusion in rats Pharmacology Biochemistry and Behavior. , 2007,86(3);423-430.
[8] Otori, T., Katsumata, T., Katayama, Y., et al. Measurement of regional cerebral blood flow and glucose utilization in rat brain under chronic hypoperfusion conditions following bilateral carotid artery occlusion. Analyzed by autoradiographical methods. Nippon Ika Daigaku Zasshi, 1997,64(5);428-439.
[9] Tanaka, K., Ogawa, N., Asanuma, M., et al. Relationship between cholinergic dysfunction and discrimination learning disabilities in Wistar rats following chronic cerebral hypoperfusion. Brain Res, 1996,729(1);55-65.
[10] de Wilde, M.C., Farkas, E., Gerrits, M., et al. The effect of n-3 polyunsaturated fatty acid-rich diets on cognitive and cerebrovascular parameters in chronic cerebral hypoperfusion. Brain Res, 2002,947(2);166-173.
[11] Busch, H.J., Buschmann, I.R., Mies, G., et al. Arteriogenesis in hypoperfused rat brain. J Cereb Blood Flow Metab, 2003,23(5);621-628.
[12] De Jong, G.I., De Vos, R.A., Steur, E.N., et al. Cerebrovascular hypoperfusion: a risk factor for Alzheimer's disease? Animal model and postmortem human studies. Ann N Y Acad Sci, 1997,826;56-74.
[13] Farkas, E., Luiten, P.G., Bari, F. Permanent, bilateral common carotid artery occlusion in the rat: a model for chronic cerebral hypoperfusion-related neurodegenerative diseases. Brain Res Rev, 2007,54(1);162-180.
[1] McDonald, R.J., White, N.M. Information acquired by the hippocampus interferes with acquisition of the amygdala-based conditioned-cue preference in the rat. Hippocampus, 1995,5(3);189-197.
[2] 韩太真. 学习与记忆的神经生物学. 北京大学医学出版社, 1998 年,208.
[3] Jones, D.G., Calverley, R.K. Frequency of occurrence of perforated synapses in developing rat neocortex. Neurosci Lett, 1991,129(2);189-192.
[4] Pozzo-Miller, L.D., Gottschalk, W., Zhang, L., et al. Impairments in high-frequency transmission, synaptic vesicle docking, and synaptic protein distribution in the hippocampus of BDNF knockout mice. J Neurosci, 1999,19(12);4972-4983.
[5] Markus, E.J., Petit, T.L. Synaptic structural plasticity: role of synaptic shape. Synapse, 1989,3(1);1-11.
[6] Jones, D.G., Devon, R.M. An ultrastructural study into the effects of pentobarbitone on synaptic organization. Brain Res, 1978,147(1);47-63.
[7] Guldner, F.H., Ingham, C.A. Increase in postsynaptic density material in optic target neurons of the rat suprachiasmatic nucleus after bilateral enucleation. Neurosci Lett, 1980,17(1-2);27-31.
[8] Jiang, M.L., Han, T.Z., Yang, D.W., et al. Morphological alteration of the hippocampal synapses in rats prenatally exposed to magnetic resonance imaging magnetic fields. Sheng Li Xue Bao, 2003,55(6);705-710.
[9] D'Hooge, R., De Deyn, P.P. Applications of the Morris water maze in the study of learning and memory. Brain Res Brain Res Rev, 2001,36(1);60-90.
[10] Redish, A.D., Touretzky, D.S. The role of the hippocampus in solving the Morris water maze. Neural Comput, 1998,10(1);73-111.
[11] Chao Liu, J.W., Jun Gu, et al. . Baicalein improves cognitive deficits induced by chronic cerebral hypoperfusion in rats Pharmacology Biochemistry and Behavior. , 2007,86(3);423-430.
[12] Ni, J., Ohta, H., Matsumoto, K., et al. Progressive cognitive impairment following chronic cerebral hypoperfusion induced by permanent occlusion of bilateral carotid arteries in rats. Brain Res, 1994,653(1-2);231-236.
[13] Pappas, B.A., de la Torre, J.C., Davidson, C.M., et al. Chronic reduction of cerebral blood flow in the adult rat: late-emerging CA1 cell loss and memory dysfunction. Brain Res, 1996,708(1-2);50-58.
[14] Martin, S.J., Grimwood, P.D., Morris, R.G. Synaptic plasticity and memory: an evaluation of the hypothesis. Annu Rev Neurosci, 2000,23;649-711.
[15] Yakel, J.L. Desensitization of 5-HT3 receptors expressed in Xenopus oocytes: dependence on voltage and primary structure. Behav Brain Res, 1996,73(1-2);269-272.
[16] Steckler, T., Drinkenburg, W.H., Sahgal, A., et al. Recognition memory in rats--II.Neuroanatomical substrates. Prog Neurobiol, 1998,54(3);313-332.
[17] Nakazawa, K., McHugh, T.J., Wilson, M.A., et al. NMDA receptors, place cells and hippocampal spatial memory. Nat Rev Neurosci, 2004,5(5);361-372.
[18] Farkas, E., Luiten, P.G., Bari, F. Permanent, bilateral common carotid artery occlusion in the rat: a model for chronic cerebral hypoperfusion-related neurodegenerative diseases. Brain Res Rev, 2007,54(1);162-180.
[19] Hunter, A.J., Mackay, K.B., Rogers, D.C. To what extent have functional studies of ischaemia in animals been useful in the assessment of potential neuroprotective agents? Trends Pharmacol Sci, 1998,19(2);59-66.
[20] 李露斯,刘之荣,肖桃元. 大鼠慢性脑血流灌注不足脑的病理组织学和超微结构变化. 第三军医大学学报 1999, 21(11); 805-808.
[21] Tanaka, K., Wada, N., Ogawa, N. Chronic cerebral hypoperfusion induces transient reversible monoaminergic changes in the rat brain. Neurochem Res, 2000,25(2);313-320.
[22] Ohtaki, H., Fujimoto, T., Sato, T., et al. Progressive expression of vascular endothelial growth factor (VEGF) and angiogenesis after chronic ischemic hypoperfusion in rat. Acta Neurochir, 2006,96(Suppl); 283-287.
[23] Farkas, E., Institoris, A., Domoki, F., et al. The effect of pre- and posttreatment with diazoxide on the early phase of chronic cerebral hypoperfusion in the rat. Brain Res, 2006,1087(1);168-174.
[24] Schmidt-Kastner, R., Truettner, J., Lin, B., et al. Transient changes of brain-derived neurotrophic factor (BDNF) mRNA expression in hippocampus during moderate ischemia induced by chronic bilateral common carotid artery occlusions in the rat. Brain Res Mol Brain Res, 2001,92(1-2);157-166.
[25] Farkas, E., Institoris, A., Domoki, F., et al. Diazoxide and dimethyl sulphoxide prevent cerebral hypoperfusion-related learning dysfunction and brain damage after carotid artery occlusion. Brain Res, 2004,1008(2);252-260.
[26] Liu, J., Jin, D.Z., Xiao, L., et al. Paeoniflorin attenuates chronic cerebral hypoperfusion-induced learning dysfunction and brain damage in rats. Brain Res, 2006,1089(1);162-170.
[27] Nanri, M., Watanabe, H. [Availability of 2VO rats as a model for chronic cerebrovascular disease]. Nippon Yakurigaku Zasshi, 1999,113(2);85-95.
[28] Ni, J.W., Matsumoto, K., Li, H.B., et al. Neuronal damage and decrease of central acetylcholine level following permanent occlusion of bilateral common carotid arteries in rat. Brain Res, 1995,673(2);290-296.
[29] De Jong, G.I., De Vos, R.A., Steur, E.N., et al. Cerebrovascular hypoperfusion: a risk factor for Alzheimer's disease? Animal model and postmortem human studies. Ann N Y Acad Sci, 1997,826;56-74.
[30] Ohta, H., Nishikawa, H., Kimura, H., et al. Chronic cerebral hypoperfusion by permanentinternal carotid ligation produces learning impairment without brain damage in rats. Neuroscience, 1997,79(4);1039-1050.
[31] Harukuni, I., Bhardwaj, A. Mechanisms of brain injury after global cerebral ischemia. Neurol Clin, 2006,24(1);1-21.
[32] Ueda, H., Fujita, R. Cell death mode switch from necrosis to apoptosis in brain. Biol Pharm Bull, 2004,27(7);950-955.
[33] Briede, J., Duburs, G. Protective effect of cerebrocrast on rat brain ischaemia induced by occlusion of both common carotid arteries. Cell Biochem Funct, 2007,25(2);203-210.
[34] 韩太真. 学习与记忆的神经生物学. 北京大学医学出版社, 1998 年,222.
[35] Moser, E.I., Krobert, K.A., Moser, M.B., et al. Impaired spatial learning after saturation of long-term potentiation. Science, 1998,281(5385);2038-2042.
[36] Lue, L.F., Kuo, Y.M., Roher, A.E., et al. Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer's disease. Am J Pathol, 1999,155(3);853-862.
[37] Tiraboschi, P., Hansen, L.A., Alford, M., et al. The decline in synapses and cholinergic activity is asynchronous in Alzheimer's disease. Neurology, 2000;55(9);1278-1283.
[38] 丰岩清,郭云良,梁秀龄. 脑缺血再灌注后突触素的表达及其与神经生长因子的关系 中国神经精神疾病杂志, 2000,26(4);251-252.
[39] Aarts, M.M., Tymianski, M. Molecular mechanisms underlying specificity of excitotoxic signaling in neurons. Curr Mol Med, 2004,4(2);137-147.
[40] Petit, T.L., LeBoutillier, J.C. Quantifying synaptic number and structure: effects of stain and post-mortem delay. Brain Res, 1990,517(1-2);269-275.
[41] Ghaffari-Farazi T, L.J., Berger TW Consequence of morphological alterations on synaptic function. Neurocomput, 1999,26;17-27.
[42] 吴馥梅, 杜红燕, 章子贵. 突触界面曲率及其生理意义. 神经解剖学杂志, 1994,10(1);89-92.
[43] Dyson, S.E., Jones, D.G. Quantitation of terminal parameters and their inter-relationships in maturing central synapses: a perspective for experimental studies. Brain Res, 1980,183(1);43-59.
[44] Rizzoli, S.O., Betz, W.J. Synaptic vesicle pools. Nat Rev Neurosci, 2005,6(1);57-69.
[45] Schikorski, T., Stevens, C.F. Quantitative ultrastructural analysis of hippocampal excitatory synapses. J Neurosci, 1997,17(15);5858-5867.
[46] Harata, N., Pyle, J.L., Aravanis, A.M., et al. Limited numbers of recycling vesicles in small CNS nerve terminals: implications for neural signaling and vesicular cycling. Trends Neurosci, 2001,24(11);637-643.
[47] B, K. The release of neural transmitter substances. Liverpool UP., 1969.
[48] Highstein, S.M., Bennett, M.V. Fatigue and recovery of transmission at the Mauthner fiber-giant fiber synapse of the hatchetfish. Brain Res, 1975,98(2);229-242.
[49] Tyler, W.J., Pozzo-Miller, L.D. BDNF enhances quantal neurotransmitter release andincreases the number of docked vesicles at the active zones of hippocampal excitatory synapses. J Neurosci, 2001,21(12);4249-4258.
[50] G.-Y. Wu, J.K., D.F. Marrone, T.W. et al. . Winter Conference on Neural Plasticity, Guadeloupe, French Antilles, 2003.
[1] J.萨姆布鲁克, D.W.拉. 分子克隆实验指南. 科学出版社, 2002.
[2] Johansson, A.C., Visse, E., Widegren, B., et al. Computerized image analysis as a tool to quantify infiltrating leukocytes: a comparison between high- and low-magnification images. J Histochem Cytochem, 2001,49(9);1073-1079.
[3] O'Leary, T.J. Standardization in immunohistochemistry. Appl Immunohistochem Mol Morphol, 2001,9(1);3-8.
[4] Kirino, T. Ischemic tolerance. J Cereb Blood Flow Metab, 2002,22(11);1283-1296.
[5] 董伟为. 神经保护的基础与临床. 科学出版社, 2002,197-203.
[6] Benfenati, F. Synaptic plasticity and the neurobiology of learning and memory. Acta Biomed, 2007,78(Suppl); 58-66.
[7] De Cesare, D., Fimia, G.M., Sassone-Corsi, P. Signaling routes to CREM and CREB: plasticity in transcriptional activation. Trends Biochem Sci, 1999,24(7);281-285.
[8] Sato-Bigbee, C., Pal, S., Chu, A.K. Different neuroligands and signal transduction pathways stimulate CREB phosphorylation at specific developmental stages along oligodendrocyte differentiation. J Neurochem, 1999,72(1);139-147.
[9] Lonze, B.E., Ginty, D.D. Function and regulation of CREB family transcription factors in the nervous system. Neuron, 2002,35(4);605-623.
[10] Jin, K., Mao, X.O., Simon, R.P., et al. Cyclic AMP response element binding protein (CREB) and CREB binding protein (CBP) in global cerebral ischemia. J Mol Neurosci, 2001,16(1);49-56.
[11] Tanaka, K., Nogawa, S., Nagata, E., et al. Persistent CREB phosphorylation with protection of hippocampal CA1 pyramidal neurons following temporary occlusion of the middle cerebral artery in the rat. Exp Neurol, 2000,161(2);462-471.
[12] Hu, B.R., Fux, C.M., Martone, M.E., et al. Persistent phosphorylation of cyclic AMP responsive element-binding protein and activating transcription factor-2 transcription factors following transient cerebral ischemia in rat brain. Neuroscience, 1999,89(2);437-452.
[13] Zhu, D.Y., Lau, L., Liu, S.H., et al. Activation of cAMP-response-element-binding protein (CREB) after focal cerebral ischemia stimulates neurogenesis in the adult dentate gyrus. Proc Natl Acad Sci U S A, 2004,101(25);9453-9457.
[14] Paxinos G, W.C. The rat nervous system. Academic Press, 1995.
[15] de la Torre, J.C., Fortin, T., Park, G.A., et al. Brain blood flow restoration 'rescues' chronically damaged rat CA1 neurons. Brain Res, 1993,623(1);6-15.
[16] Finkbeiner, S., Tavazoie, S.F., Maloratsky, A., et al. CREB: a major mediator of neuronal neurotrophin responses. Neuron, 1997,19(5);1031-1047.
[17] Tao, X., Finkbeiner, S., Arnold, D.B., et al. Ca2+ influx regulates BDNF transcription by a CREB family transcription factor-dependent mechanism. Neuron, 1998,20(4);709-726.
[18] Binder, D.K., Routbort, M.J., McNamara, J.O. Immunohistochemical evidence of seizure-induced activation of trk receptors in the mossy fiber pathway of adult rat hippocampus. J Neurosci, 1999,19(11);4616-4626.
[19] Ying, S.W., Futter, M., Rosenblum, K., et al. Brain-derived neurotrophic factor induces long-term potentiation in intact adult hippocampus: requirement for ERK activation coupled to CREB and upregulation of Arc synthesis. J Neurosci, 2002,22(5);1532-1540.
[20] Lo, D.C. Neurotrophic factors and synaptic plasticity. Neuron, 1995,15(5);979-981.
[21] Thoenen, H. Neurotrophins and neuronal plasticity. Science, 1995,270(5236);593-598.
[22] McAllister, A.K., Katz, L.C., Lo, D.C. Neurotrophins and synaptic plasticity. Annu Rev Neurosci, 1999,22;295-318.
[23] Lu, B., Chow, A. Neurotrophins and hippocampal synaptic transmission and plasticity. J Neurosci Res, 1999,58(1);76-87.
[24] Levine, E.S., Dreyfus, C.F., Black, I.B., et al. Brain-derived neurotrophic factor rapidly enhances synaptic transmission in hippocampal neurons via postsynaptic tyrosine kinase receptors. Proc Natl Acad Sci U S A, 1995,92(17);8074-8077.
[25] Murphy, D.D., Cole, N.B., Segal, M. Brain-derived neurotrophic factor mediates estradiol-induced dendritic spine formation in hippocampal neurons. Proc Natl Acad Sci U S A, 1998,95(19);11412-11417.
[26] Patel, M.N., McNamara, J.O. Selective enhancement of axonal branching of cultured dentate gyrus neurons by neurotrophic factors. Neuroscience, 1995,69(3);763-770.
[27] Lowenstein, D.H., Arsenault, L. The effects of growth factors on the survival and differentiation of cultured dentate gyrus neurons. J Neurosci, 1996,16(5);1759-1769.
[28] Bradley, J., Sporns, O. BDNF-dependent enhancement of exocytosis in cultured cortical neurons requires translation but not transcription. Brain Res, 1999,815(1);140-149.
[29] Lessmann, V., Gottmann, K., Heumann, R. BDNF and NT-4/5 enhance glutamatergic synaptic transmission in cultured hippocampal neurones. Neuroreport, 1994,6(1);21-25.
[30] Bartrup, J.T., Moorman, J.M., Newberry, N.R. BDNF enhances neuronal growth and synaptic activity in hippocampal cell cultures. Neuroreport, 1997,8(17);3791-3794.
[31] Lessmann, V., Heumann, R. Modulation of unitary glutamatergic synapses by neurotrophin-4/5 or brain-derived neurotrophic factor in hippocampal microcultures: presynaptic enhancement depends on pre-established paired-pulse facilitation. Neuroscience, 1998,86(2);399-413.
[32] Pozzo-Miller, L.D., Gottschalk, W., Zhang, L., et al. Impairments in high-frequency transmission, synaptic vesicle docking, and synaptic protein distribution in the hippocampus of BDNF knockout mice. J Neurosci, 1999,19(12);4972-4983.
[33] Mocchetti, I., Wrathall, J.R. Neurotrophic factors in central nervous system trauma. J Neurotrauma, 1995,12(5);853-870.
[34] Ivanova, T., Beyer, C. Pre- and postnatal expression of brain-derived neurotrophic factormRNA/protein and tyrosine protein kinase receptor B mRNA in the mouse hippocampus. Neurosci Lett, 2001,307(1);21-24.
[35] Farkas, E., Donka, G., de Vos, R.A., et al. Experimental cerebral hypoperfusion induces white matter injury and microglial activation in the rat brain. Acta Neuropathol, 2004,108(1);57-64.
[36] Farkas, E., Institoris, A., Domoki, F., et al. Diazoxide and dimethyl sulphoxide prevent cerebral hypoperfusion-related learning dysfunction and brain damage after carotid artery occlusion. Brain Res, 2004,1008(2);252-260.
[37] Farkas, E., Institoris, A., Domoki, F., et al. The effect of pre- and posttreatment with diazoxide on the early phase of chronic cerebral hypoperfusion in the rat. Brain Res, 2006,1087(1);168-174.
[38] Schmidt-Kastner, R., Aguirre-Chen, C., Saul, I., et al. Astrocytes react to oligemia in the forebrain induced by chronic bilateral common carotid artery occlusion in rats. Brain Res, 2005,1052(1);28-39.
[39] Xi Kuang, J.-R.D., Yan-Xin Liu, et al. . Postischemic administration of Z-Ligustilide ameliorates cognitive dysfunction and brain damage induced by permanent forebrain ischemia in rats. . Pharmacology, Biochemistry and Behavior, 2008,88;213-221.
[40] 李世泽,刘其强,白宏英,等. 丁咯地尔对慢性脑缺血大鼠海马 CA1 区星形胶质细胞及认知障碍的影响. 中国实用神经疾病杂志,2006,(3);40-41.
[41] 赵世刚,姜玉武,罗强,等. 脑源性神经营养因子与海马苔藓状纤维突触重组的关系. 中华医学杂志, 2001,81(5);283-287.
[42] Schratt, G.M., Nigh, E.A., Chen, W.G., et al. BDNF regulates the translation of a select group of mRNAs by a mammalian target of rapamycin-phosphatidylinositol 3-kinase-dependent pathway during neuronal development. J Neurosci, 2004,24(33);7366-7377.
[43] Collin, C., Vicario-Abejon, C., Rubio, M.E., et al. Neurotrophins act at presynaptic terminals to activate synapses among cultured hippocampal neurons. Eur J Neurosci, 2001,13(7);1273-1282.
[44] Aakalu, G., Smith, W.B., Nguyen, N., et al. Dynamic visualization of local protein synthesis in hippocampal neurons. Neuron, 2001,30(2);489-502.
[45] Eberwine, J., Miyashiro, K., Kacharmina, J.E., et al. Local translation of classes of mRNAs that are targeted to neuronal dendrites. Proc Natl Acad Sci U S A, 2001,98(13);7080-7085.
[46] Yin, Y., Edelman, G.M., Vanderklish, P.W. The brain-derived neurotrophic factor enhances synthesis of Arc in synaptoneurosomes. Proc Natl Acad Sci U S A, 2002,99(4);2368-2373.
[47] Alsina, B., Vu, T., Cohen-Cory, S. Visualizing synapse formation in arborizing optic axons in vivo: dynamics and modulation by BDNF. Nat Neurosci, 2001,4(11);1093-1101.
[48] Bramham, C.R., Messaoudi, E. BDNF function in adult synaptic plasticity: the synaptic consolidation hypothesis. Prog Neurobiol, 2005,76(2);99-125.
[49] Gottschalk, W., Pozzo-Miller, L.D., Figurov, A., et al. Presynaptic modulation of synaptic transmission and plasticity by brain-derived neurotrophic factor in the developing hippocampus. J Neurosci, 1998,18(17);6830-6839.
[50] Lessmann, V. Neurotrophin-dependent modulation of glutamatergic synaptic transmission in the mammalian CNS. Gen Pharmacol, 1998,31(5);667-674.
[51] Jovanovic, J.N., Czernik, A.J., Fienberg, A.A., et al. Synapsins as mediators of BDNF-enhanced neurotransmitter release. Nat Neurosci, 2000,3(4);323-329.
[52] Poo, M.M. Neurotrophins as synaptic modulators. Nat Rev Neurosci, 2001,2(1);24-32.
[53] Merlio, J.P., Ernfors, P., Kokaia, Z., et al. Increased production of the TrkB protein tyrosine kinase receptor after brain insults. Neuron, 1993,10(2);151-164.
[54] Muly, S.M., Gross, J.S., Morest, D.K., et al. Synaptophysin in the cochlear nucleus following acoustic trauma. Exp Neurol, 2002,177(1);202-221.
[55] Torrealba, F., Carrasco, M.A. A review on electron microscopy and neurotransmitter systems. Brain Res Brain Res Rev, 2004,47(1-3);5-17.
[56] Becher, A., Drenckhahn, A., Pahner, I., et al. The synaptophysin-synaptobrevin complex: a hallmark of synaptic vesicle maturation. J Neurosci, 1999,19(6);1922-1931.
[57] Hannah, M.J., Schmidt, A.A., Huttner, W.B. Synaptic vesicle biogenesis. Annu Rev Cell Dev Biol, 1999,15;733-798.
[58] Thiele, C., Hannah, M.J., Fahrenholz, F., et al. Cholesterol binds to synaptophysin and is required for biogenesis of synaptic vesicles. Nat Cell Biol, 2000,2(1);42-49.
[59] Regnier-Vigouroux, A., Tooze, S.A., Huttner, W.B. Newly synthesized synaptophysin is transported to synaptic-like microvesicles via constitutive secretory vesicles and the plasma membrane. Embo J, 1991,10(12);3589-3601.
[60] Deken, S.L., Wang, D., Quick, M.W. Plasma membrane GABA transporters reside on distinct vesicles and undergo rapid regulated recycling. J Neurosci, 2003,23(5);1563-1568.
[61] Lauri, S.E., Lamsa, K., Pavlov, I., et al. Activity blockade increases the number of functional synapses in the hippocampus of newborn rats. Mol Cell Neurosci, 2003,22(1);107-117.
[62] Kadish, I., Van Groen, T. Differences in lesion-induced hippocampal plasticity between mice and rats. Neuroscience, 2003,116(2);499-509.
[63] Sze, C.I., Bi, H., Kleinschmidt-DeMasters, B.K., et al. Selective regional loss of exocytotic presynaptic vesicle proteins in Alzheimer's disease brains. J Neurol Sci, 2000,175(2);81-90.
[64] Thomas, L., Hartung, K., Langosch, D., et al. Identification of synaptophysin as a hexameric channel protein of the synaptic vesicle membrane. Science, 1988,242(4881);1050-1053.
[65] Daly, C., Sugimori, M., Moreira, J.E., et al. Synaptophysin regulates clathrin-independent endocytosis of synaptic vesicles. Proc Natl Acad Sci U S A, 2000,97(11);6120-6125.
[66] Pennuto, M., Dunlap, D., Contestabile, A., et al. Fluorescence resonance energy transfer detection of synaptophysin I and vesicle-associated membrane protein 2 interactions during exocytosis from single live synapses. Mol Biol Cell, 2002,13(8);2706-2717.
[67] 韩济生,关新民. 医用神经生物学. 武汉出版社, 1996 年,17.
[68] Alder, J., Xie, Z.P., Valtorta, F., et al. Antibodies to synaptophysin interfere with transmitter secretion at neuromuscular synapses. Neuron, 1992,9(4);759-768.
[69] Alder, J., Kanki, H., Valtorta, F., et al. Overexpression of synaptophysin enhances neurotransmitter secretion at Xenopus neuromuscular synapses. J Neurosci, 1995,15(1 Pt 2);511-519.
[70] Alder, J., Lu, B., Valtorta, F., et al. Calcium-dependent transmitter secretion reconstituted in Xenopus oocytes: requirement for synaptophysin. Science, 1992,257(5070);657-661.
[71] Marks, B., Stowell, M.H., Vallis, Y., et al. GTPase activity of dynamin and resulting conformation change are essential for endocytosis. Nature, 2001,410(6825);231-235.
[72] Valtorta, F., Pennuto, M., Bonanomi, D., et al. Synaptophysin: leading actor or walk-on role in synaptic vesicle exocytosis? Bioessays, 2004,26(4);445-453.
[73] Bonanomi, D., Pennuto, M., Rigoni, M., et al. Taipoxin induces synaptic vesicle exocytosis and disrupts the interaction of synaptophysin I with VAMP2. Mol Pharmacol, 2005,67(6);1901-1908.
[74] Scarr, E., Gray, L., Keriakous, D., et al. Increased levels of SNAP-25 and synaptophysin in the dorsolateral prefrontal cortex in bipolar I disorder. Bipolar Disord, 2006,8(2);133-143.
[75] Mitter, D., Reisinger, C., Hinz, B., et al. The synaptophysin/synaptobrevin interaction critically depends on the cholesterol content. J Neurochem, 2003,84(1);35-42.
[76] Royle, S.J., Lagnado, L. Endocytosis at the synaptic terminal. J Physiol, 2003,553(Pt 2);345-355.
[77] Granseth, B., Odermatt, B., Royle, S.J., et al. Clathrin-mediated endocytosis is the dominant mechanism of vesicle retrieval at hippocampal synapses. Neuron, 2006,51(6);773-786.
[78] Daly, C., Ziff, E.B. Ca2+-dependent formation of a dynamin-synaptophysin complex: potential role in synaptic vesicle endocytosis. J Biol Chem, 2002,277(11);9010-9015.
[79]Cousin, M.A. Synaptic vesicle endocytosis: calcium works overtime in the nerve terminal. Mol Neurobiol, 2000,22(1-3);115-128.
[80] Spiwoks-Becker, I., Vollrath, L., Seeliger, M.W., et al. Synaptic vesicle alterations in rod photoreceptors of synaptophysin-deficient mice. Neuroscience, 2001,107(1);127-142.
[81] Janz, R., Sudhof, T.C., Hammer, R.E., et al. Essential roles in synaptic plasticity for synaptogyrin I and synaptophysin I. Neuron, 1999,24(3);687-700.
[82] Mullany, P.M., Lynch, M.A. Evidence for a role for synaptophysin in expression oflong-term potentiation in rat dentate gyrus. Neuroreport, 1998,9(11);2489-2494.
[83] Mullany, P., Lynch, M.A. Changes in protein synthesis and synthesis of the synaptic vesicle protein, synaptophysin, in entorhinal cortex following induction of long-term potentiation in dentate gyrus: an age-related study in the rat. Neuropharmacology, 1997,36(7);973-980.
[84] Murdoch, I., Perry, E.K., Court, J.A., et al. Cortical cholinergic dysfunction after human head injury. J Neurotrauma, 1998,15(5);295-305.
[85] Smith, T.D., Adams, M.M., Gallagher, M., et al. Circuit-specific alterations in hippocampal synaptophysin immunoreactivity predict spatial learning impairment in aged rats. J Neurosci, 2000,20(17);6587-6593.
[86] 王守春,吴江,孙莉,等. 慢性脑缺血大鼠海马区和齿状回突触素表达变化与其认知功能关系的研究. 现代神经疾病杂志, 2003,3;142-145.
[87] Korematsu, K., Goto, S., Nagahiro, S., et al. Changes of immunoreactivity for synaptophysin ('protein p38') following a transient cerebral ischemia in the rat striatum. Brain Res, 1993,616(1-2);320-324.
[88] Tartaglia, N., Du, J., Tyler, W.J., et al. Protein synthesis-dependent and -independent regulation of hippocampal synapses by brain-derived neurotrophic factor. J Biol Chem, 2001,276(40);37585-37593.
[89] Tyler, W.J., Pozzo-Miller, L.D. BDNF enhances quantal neurotransmitter release and increases the number of docked vesicles at the active zones of hippocampal excitatory synapses. J Neurosci, 2001,21(12);4249-4258.
[90] Mesulam, M.M., Geula, C. Nucleus basalis (Ch4) and cortical cholinergic innervation in the human brain: observations based on the distribution of acetylcholinesterase and choline acetyltransferase. J Comp Neurol, 1988,275(2);216-240.
[91] Hasselmo, M. Expecting the unexpected: modeling of neuromodulation. Neuron, 2005,46(4);526-528.
[92] Shinoe, T., Matsui, M., Taketo, M.M., et al. Modulation of synaptic plasticity by physiological activation of M1 muscarinic acetylcholine receptors in the mouse hippocampus. J Neurosci, 2005,25(48);11194-11200.
[93] Rasmusson, D.D., Dykes, R.W. Long-term enhancement of evoked potentials in cat somatosensory cortex produced by co-activation of the basal forebrain and cutaneous receptors. Exp Brain Res, 1988,70(2);276-286.
[94] Galey, D., Destrade, C., Jaffard, R. Relationships between septo-hippocampal cholinergic activation and the improvement of long-term retention produced by medial septal electrical stimulation in two inbred strains of mice. Behav Brain Res, 1994,60(2);183-189.
[95] Abe, K., Nakata, A., Mizutani, A., et al. Facilitatory but nonessential role of the muscarinic cholinergic system in the generation of long-term potentiation of population spikes in the dentate gyrus in vivo. Neuropharmacology, 1994,33(7);847-852.
[96] Barnes, C.A., Jung, M.W., McNaughton, B.L., et al. LTP saturation and spatial learning disruption: effects of task variables and saturation levels. J Neurosci, 1994,14(10);5793-5806.
[97] Kotani, S., Yamauchi, T., Teramoto, T., et al. Pharmacological evidence of cholinergic involvement in adult hippocampal neurogenesis in rats. Neuroscience, 2006,142(2);505-514.
[98] Van der Borght, K., Mulder, J., Keijser, J.N., et al. Input from the medial septum regulates adult hippocampal neurogenesis. Brain Res Bull, 2005,67(1-2);117-125.
[99] Oda, Y. Choline acetyltransferase: the structure, distribution and pathologic changes in the central nervous system. Pathol Int, 1999,49(11);921-937.
[100] Tiraboschi, P., Hansen, L.A., Alford, M., et al. The decline in synapses and cholinergic activity is asynchronous in Alzheimer's disease. Neurology, 2000,55(9);1278-1283.
[101] Salvaterra, P.M., Vaughn, J.E. Regulation of choline acetyltransferase. Int Rev Neurobiol, 1989,31;81-143.
[102] Hruschak, K.A., Friedrich, V.L., Jr., Giacobini, E. Synaptogenesis in chick paravertebral sympathetic ganglia: a morphometric analysis. Brain Res, 1982,256(2);229-240.
[103] Auld, D.S., Mennicken, F., Quirion, R. Nerve growth factor rapidly induces prolonged acetylcholine release from cultured basal forebrain neurons: differentiation between neuromodulatory and neurotrophic influences. J Neurosci, 2001,21(10);3375-3382.
[104] Berse, B., Szczecinska, W., Lopez-Coviella, I., et al. Expression of high affinity choline transporter during mouse development in vivo and its upregulation by NGF and BMP-4 in vitro. Brain Res Dev Brain Res, 2005,157(2);132-140.
[105] Nonner, D., Barrett, E.F., Barrett, J.N. Brief exposure to neurotrophins produces a calcium-dependent increase in choline acetyltransferase activity in cultured rat septal neurons. J Neurochem, 2000,74(3);988-999.
[106] Ha, D.H., Robertson, R.T., Roshanaei, M., et al. Enhanced survival and morphological features of basal forebrain cholinergic neurons in vitro: role of neurotrophins and other potential cortically derived cholinergic trophic factors. J Comp Neurol, 1999,406(2);156-170.
[107] Nonner, D., Barrett, E.F., Barrett, J.N. Neurotrophin effects on survival and expression of cholinergic properties in cultured rat septal neurons under normal and stress conditions. J Neurosci, 1996,16(21);6665-6675.
[108] Knipper, M., da Penha Berzaghi, M., Blochl, A., et al. Positive feedback between acetylcholine and the neurotrophins nerve growth factor and brain-derived neurotrophic factor in the rat hippocampus. Eur J Neurosci, 1994v6(4);668-671.
[109] 金国华,田美玲,秦建兵,等. BDNF、NGF 对体外长期培养的胚基底前脑胆碱能神经元的影响. 神经解剖学杂志, 2001,17(4);337-341.
[110] Jezierski, M.K., Sohrabji, F. Estrogen enhances retrograde transport of brain-derived neurotrophic factor in the rodent forebrain. Endocrinology, 2003,144(11);5022-5029.
[111] Grosse, G., Djalali, S., Deng, D.R., et al. Area-specific effects of brain-derived neurotrophic factor (BDNF) genetic ablation on various neuronal subtypes of the mouse brain.Brain Res Dev Brain Res, 2005,156(2);111-126.
[112] 范文辉,刘之荣. 血管性痴呆的动物模型及其胆碱能机制研究. 第三军医大学学报, 2000,22 (4);314-316.
[113] Erkinjuntti, T., Roman, G., Gauthier, S., et al. Emerging therapies for vascular dementia and vascular cognitive impairment. Stroke, 2004,35(4);1010-1017.
[114] Saez-Valero, J., Mok, S.S., Small, D.H. An unusually glycosylated form of acetylcholinesterase is a CSF biomarker for Alzheimer's disease. Acta Neurol Scand, 2000,176(Suppl );49-52.
[115] Buttini, M., Yu, G.Q., Shockley, K., et al. Modulation of Alzheimer-like synaptic and cholinergic deficits in transgenic mice by human apolipoprotein E depends on isoform, aging, and overexpression of amyloid beta peptides but not on plaque formation. J Neurosci, 2002,22(24);10539-10548.
[116] Hellstrom-Lindahl, E., Mousavi, M., Zhang, X., et al. Regional distribution of nicotinic receptor subunit mRNAs in human brain: comparison between Alzheimer and normal brain. Brain Res Mol Brain Res, 1999,66(1-2);94-103.
[117] Hulette, C., Nochlin, D., McKeel, D., et al. Clinical-neuropathologic findings in multi-infarct dementia: a report of six autopsied cases. Neurology, 1997,48(3);668-672.
[118] Amenta, F., Di Tullio, M.A., Tomassoni, D. The cholinergic approach for the treatment of vascular dementia: evidence from pre-clinical and clinical studies. Clin Exp Hypertens, 2002,24(7-8);697-713.
[119] 肖军,韦永胜,黄雨兰,等. 卡巴拉汀对血管性痴呆认知功能的影响. 实用医院临床杂志 2004,1(2);22-23.
[120] Ni, J.W., Matsumoto, K., Li, H.B., et al. Neuronal damage and decrease of central acetylcholine level following permanent occlusion of bilateral common carotid arteries in rat. Brain Res, 1995,673(2);290-296.
[121] Tanaka, K., Wada, N., Hori, K., et al. Chronic cerebral hypoperfusion disrupts discriminative behavior in acquired-learning rats. J Neurosci Methods, 1998,84(1-2);63-68.
[122] Kondo, Y., Ogawa, N., Asanuma, M., et al. Preventive effects of bifemelane hydrochloride on decreased levels of muscarinic acetylcholine receptor and its mRNA in a rat model of chronic cerebral hypoperfusion. Neurosci Res, 1996,24(4);409-414.
[123] 吴 启 伟 . 血 管 性 痴 呆 的 基 础 性 研 究 进 展 . 中 华 医 学 研 究 杂 志 , 2005,5(10);1009-1011.
[124] 王哲,张昱,李华军,等. 痴呆大鼠模型的行为学、脑内胆碱乙酰转移酶及突触素改变. 神经疾病与精神卫生, 2003,3(4);253-255.
[125] 徐莉,李铃,陈景藻,等. 康复训练对大鼠脑梗塞神经功能恢复的影响. 中华物理医学与康复杂志, 2000,2(33);86.
[126] Macdonald RL, S.M. Pathophysiology of cerebral ischemia. Neurol Med Chir (Tokyo) 1998,38(1);1-11.
[127] 王宏涛,靳洪涛,孙建宁,等. 异亚丙基莽草酸抗血栓作用的实验研究. 药学学报, 2002,37(4);245-248.
[128] 马怡,孙建宁,徐秋萍,等. 异亚丙基莽草酸对血管内皮细胞释放前列环素的影响 北京中医药大学学报, 2003,26(4);25-27.
[129] Ma, Y., Sun, J.N., Xu, Q.P., et al. 3,4-oxo-isopropylidene-shikimic acid inhibits adhesion of polymorphonuclear leukocyte to TNF-alpha-induced endothelial cells in vitro. Acta Pharmacol Sin, 2004,25(2);246-250.
[130] Farkas, E., Luiten, P.G., Bari, F. Permanent, bilateral common carotid artery occlusion in the rat: a model for chronic cerebral hypoperfusion-related neurodegenerative diseases. Brain Res Rev, 2007,54(1);162-180.
[131] Aytac, E., Seymen, H.O., Uzun, H., et al. Effects of iloprost on visual evoked potentials and brain tissue oxidative stress after bilateral common carotid artery occlusion. Prostaglandins Leukot Essent Fatty Acids, 2006,74(6);373-378.
[132] Ozacmak, V.H., Sayan, H., Cetin, A., et al. AT1 receptor blocker candesartan-induced attenuation of brain injury of rats subjected to chronic cerebral hypoperfusion. Neurochem Res, 2007,32(8);1314-1321.
[133] Wang, H.T., Sun, J.N., Xu, Q.P. Effect of 3,4-oxo-isopropylidene shikimic acid on brain edema and energy metabolism in rats subjected to middle cerebral artery thrombosis Chinese Journal of Pharmacology and Toxicology,2002,16;270-272.
[134] Ma, Y., Sun, J.N., Xu, Q.P. Protective effect of 3,4-oxo-isopropylidene-shikimic acid on vascular endothelial cell injury Pharmacology and Clinics of Chinese Materia Medica, 2002,18(supplement);78-79.
[135] Wang, H.T., Sun, J.N., Xu, Q.P. Efect of 3,4-OXO-isopropylidene-shikimic acid on free radical metabolism in the brain tissue of rats subjected to middle cerebral artery thrombosis Chin Pharmacol Bull, 2002,18(5);569.