通脉益智方对VD大鼠学习记忆行为和海马CA1区突触结构的影响

目的:观察通脉益智方对血管性痴呆模型大鼠学习记忆行为和海马CA1区突触超微结构的影响.方法:应用高脂血症大鼠,采用脑缺血再灌注的方法建立血管性痴呆动物模型,利用跳台实验和Y型迷宫实验检验大鼠的学习记忆能力,应用透射电镜和光镜观察分析海马CA1区神经细胞和突触形态结构的变化.结果:跳台实验和Y型迷宫实验表明模型大鼠学习记忆能力明显下降,而给予通脉益智方组学习记忆能力改善,与模型组相比有显著性差异(p＜0.05).形态学观察显示模型组大鼠海马CA1区神经细胞排列紊乱,核固缩、退化、变性、坏死、消失.突触结构不完整,突触小泡减少;突触间隙模糊,线粒体肿胀、空泡样变.通脉益智方组的神经细胞、突触的形态与模型组相比有明显改善.结论:通脉益智方通过减轻突触的损伤及对神经细胞的保护作用,从而改善了学习记忆能力.     

慢性应激对大鼠海马锥体细胞形态结构的效应

为研究慢性应激相关精神障碍的发病机制,采用尼氏（Nissl）染色法、高尔基（Golgi）镀染法和透射电镜技术,探讨慢性应激对大鼠海马CA1、CA3区锥体细胞形态结构的效应.结果显示应激组大鼠海马CA1区锥体细胞形态结构较对照组无明显变化.应激组海马CA3区锥体细胞数（35.14±3.85）较对照组(38.74±3.54)显著减少（P＜0.05）;顶树突的总长度（155.67 μm±33.32 μm）较对照组（195.63 μm±34.61 μm）显著缩短（P＜0.05）;应激组大鼠海马CA3区锥体细胞出现超微结构的改变,包括细胞固缩、体积缩小、核膜皱缩、线粒体变性和粗面内质网模糊不清.这提示海马CA3区锥体细胞形态结构的改变,可能是慢性应激相关精神障碍的病理生理基础.     

抑郁症模型大鼠学习记忆能力变化研究

为探讨抑郁症发生发展过程中学习记忆能力的变化模式及其可能机制．分别采用21天慢性非预见性刺激法和嗅球切除法建立的抑郁症模型大鼠．运用旷场行为实验（open—field behavior）检测大鼠主动性活动能力,用Morris水迷宫法检测大鼠空间学习记忆能力,HPLC—UV法测定大鼠血清皮质醇含量。电生理法记录海马CA1区LTP与LTD,观察海马神经元的突触可塑性。结果显示：与对照组相比,两种模型的自主活动性、空间探索兴趣和学习能力都明显降低,而记忆的反馈功能没有明显的变化。同时．两种模型大鼠海马神经细胞的突触可塑性显著下降,血清皮质醇的含量则明显上升。提示两种建模方法均导致大鼠产生抑郁症状和学习能力障碍．但对记忆反馈功能无明显影响。     

丹参酮ⅡA 预防慢性缺氧大鼠认知功能障碍的电生理机制

目的:探讨丹参酮ⅡA(TⅡA)预防慢性缺氧大鼠认知功能障碍的电生理机制。方法:将18只雄性SD大鼠(200-250 g)随机分为对照组、模型组(Model组)、TⅡA(10mg/kg.d)治疗组(TⅡA组)。复制慢性缺氧大鼠认知功能障碍模型,并给予相应治疗,在脑片水平运用膜片钳技术检测海马CA1区的LTP变化,并检测海马CA1区锥体细胞的兴奋性变化。结果:(1)给予高频强直刺激(HFS)后各组兴奋性突出后电位(fEPSP)斜率均显著增加,即均可诱发LTP并持续1h以上,但模型组LTP较对照组显著减弱(P<0.05),TⅡA治疗组LTP较模型组明显增强(P<0.05);(2)慢性缺氧使海马CA1锥体细胞放电所需的刺激电流幅度显著增加、阈电位升高、兴奋性降低,同样刺激强度条件下动作电位数量减少,TⅡA干预可明显减轻慢性缺氧对海马CA1锥体细胞的上述抑制。结论:TⅡA可能是通过维持海马CA1锥体细胞的兴奋性、维持海马的突出可塑性减轻慢性缺氧对认知功能的损害。     

戊四氮点燃癫痫大鼠空间学习记忆改变及海马突触素、突触后致密物PSD-95表达的变化

目的探讨戊四氮点燃癫痫对大鼠空间学习记忆的影响及可能的分子机制。方法戊四氮(pentylenetet-razol,PTZ)点燃建立慢性癫痫(chronic epileptic,CEP)模型,Morris水迷宫进行行为学检测,免疫组织化学方法观察大鼠海马CA1、CA3区突触素(synaptophysin,P38)和突触后致密物95(postsynaptic density 95,PSD-95)的表达,并用计算机图像分析系统对免疫反应结果进行处理。结果水迷宫试验检测癫痫组大鼠空间学习记忆能力受损;免疫组化结果表明其海马CA1、CA3区P38和PSD-95免疫反应产物较对照组明显减少(P<0.01,P<0.05)。结论戊四氮点燃癫痫大鼠伴有学习记忆功能减退,其海马神经元P38和PSD-95的表达减少可能参与了空间学习记忆受损。     

二十五味珊瑚丸对D-半乳糖衰老大鼠神经元特异性烯醇化酶表达的影响

探讨二十五味珊瑚丸(25 Odors Coral Pills)对D-半乳糖(D-gal)衰老大鼠海马锥体细胞形态和神经元特异性烯醇化酶(NSE)表达的影响。采用颈背部皮下注射D-gal模拟衰老大鼠模型。治疗组于造模第6周,给予25 Odors Coral Pills灌胃2周,之后取各组脑组织行相关检测。与模型组比较,25 Odors Coral Pills组大鼠海马CA1、CA3区锥体细胞层细胞丢失较少,细胞排列较紧密、整齐;DG区NSE阳性的细胞减少,胞体较小,突起较细;海马NSE表达下降,有统计学差异(P0.05)。D-gal衰老模型鼠海马锥体细胞衰老变性且NSE的表达增多;25 Odors Coral Pills可抑制D-gal衰老鼠海马锥体细胞的衰老变性和NSE的表达。     

D-半乳糖合并Meynert基底核损毁对海马长时程增强和突触形态的影响

目的 :研究D 半乳糖合并Meynert基底核损毁Alzheimer病 (AD)大鼠模型海马突触可塑性的变化。方法 :通过0 .96 %D 半乳糖致亚急性损伤及鹅膏蕈氨酸损毁Meynert基底核建立AD动物模型 ,应用行为学测试、电生理学方法和电镜观察 ,研究AD模型大鼠海马突触形态结构和长时程增强现象 (long termpotentiation ,LTP)的变化。结果 :①AD模型大鼠在Morris水迷宫的学习记忆能力明显低于对照组 ;②AD大鼠海马CA1区突触的数密度、面密度明显减少 ;③AD模型大鼠海马齿状回产生的LTP较对照组明显降低。结论 :海马突触结构改变和功能可塑性的降低可能与AD大鼠的学习记忆能力下降有关     

姜黄素对自发性高血压大鼠脑缺血/再灌注后海马神经元损伤及RANTES表达的影响

目的：探讨姜黄素对自发性高血压大鼠（SHR）脑缺血/再灌注后认知功能及海马神经元损伤和调解活化正常T细胞表达和分泌的趋化因子（RANTES）表达的影响。方法：雄性Wistar-Kyoto大鼠（WKY）和SHR,随机分为5组：假手术组（W-Sham、S-Sham）、缺血/再灌注组（W-I/R、S-I/R）和姜黄素组（S-Cur）,各组按再灌注时间分为3h、12 h、1 d、3 d、7 d 5个亚组（n=6）。采用四血管阻断法制备全脑缺血/再灌注模型,HE染色观察海马CA1区神经细胞形态,Nissl染色计数海马CA1区平均锥体细胞密度,ELISA法检测海马RANTES表达,于再灌注后7 d观察行为学。结果：与假手术组大鼠比较,缺血/再灌注组大鼠学习和记忆能力下降,海马CA1区神经元损伤加重,海马RANTES蛋白表达上调（P〈0.05）;与W-I/R大鼠比较,S-I/R大鼠学习和记忆能力下降,海马CA1区神经元损伤加重,海马RANTES蛋白表达上调（P〈0.05）;姜黄素组大鼠学习和记忆能力明显改善,海马CA1区神经元损伤减轻,海马RANTES蛋白表达下调（P〈0.05）。结论：缺血/再灌注更易导致SHR海马神经元损伤。姜黄素减轻SHR脑缺血/再灌注海马神经元损伤,其机制可能与抑制RANTES蛋白的表达有关。     

绿茶多酚对脑缺血大鼠血脑屏障及学习记忆功能的影响

目的 研究绿茶多酚(Green tea polyphenols,GTPs)对脑缺血大鼠血脑屏障(Blood-brain barrier,BBB)及学习记忆功能的影响.方法 双侧颈总动脉结扎法制备脑缺血大鼠模型,大鼠随机分为假手术组、模型组和GTPs治疗组,每组8只,观察GTPs的保护作用.应用Morris水迷宫测试大鼠学习记忆能力,甲苯胺蓝染色法观察大鼠海马CA1区神经元形态变化,透射电镜观察BBB的变化以及海马CA1区神经元超微结构改变.结果模型组与假手术组相比BBB破坏,海马CA1区结构紊乱,学习记忆能力明显下降(P＜o.05),GTPs治疗组与模型组相比,缺血性脑损伤明显减轻,学习记忆能力明显改善(P＜0.05).结论 GTPs能够减轻缺血性脑损伤,从而发挥改善脑缺血SD大鼠学习记忆能力的作用.     

预缺血通过NMDA受体抑制海马CA1区Bcl-2磷酸化的研究

目的:研究预缺血以及联合给予预缺血和NMDA(N-甲基-D-天冬氨酸)受体抑制剂MK801后对大鼠海马CA1区Bcl-2的磷酸化以及海马CA1区锥体细胞凋亡的影响。方法:采用SD大鼠四动脉结扎全脑缺血及预缺血模型,给药组大鼠在预缺血前1h给予腹腔注射MK801 3mg/kg。用免疫印迹法分析不同处理下大鼠海马CA1区Bcl-2的蛋白表达及其磷酸化水平,焦油紫染色法分析海马CA1区锥体细胞的凋亡情况。结果:脑缺血再灌注组相对于Sham组Bcl-2的磷酸化水平以及海马CA1区锥体细胞的凋亡水平显著增高,预缺血组相对于缺血再灌注组Bcl-2的磷酸化水平以及海马CA1区锥体细胞的凋亡水平显著降低;而预缺血前给予MK801组相对于预缺血组Bcl-2磷酸化水平以及海马CA1区锥体细胞的凋亡水平显著增高;而Bcl-2的蛋白表达水平在以上不同处理条件下均无明显变化。结论:NMDA受体介导了预缺血抑制脑缺血再灌注诱导增加Bcl-2磷酸化以及海马CA1区锥体细胞凋亡。     

围产期食物限制对子代成年大鼠海马CA1区突触可塑性的影响

围产期食物限制导致子代大鼠学习和记忆能力等的神经生物学变化,但其机制并不清楚。将成年Wistar雌性大鼠与雄性大鼠同笼,受孕后随机分为对照组 (n=9) 和食物限制组 (n=8) 。对照组母鼠在妊娠期和哺乳期自由进食和饮水,食物限制组母鼠从妊娠的第7天到子代大鼠出生后21天进行食物限制,食物限制量为对照组大鼠的50%。子代雄性大鼠成年后,通过Morris 水迷宫测试空间学习和记忆能力。之后,在海马CA1区在体记录场兴奋性突触后电位 (field excitatory postsynaptic potential,fEPSP),并采用免疫组织化学方法观察海马CA1区神经元型一氧化氮合酶 (nNOS) 阳性细胞密度的变化。结果表明,围产期食物限制降低了子代大鼠出生后第1、7、10、14和21天的体重,并减弱了成年子代大鼠的学习和记忆能力,海马CA1区fEPSP的斜率和nNOS阳性细胞的密度也明显降低。结果提示,围产期食物限制可能通过抑制NO的产生降低了海马突触可塑性,从而影响了子代大鼠的学习和记忆能力。     

Corticosterone replacement restores normal morphological features to the hippocampal dendrites, axons and synapses of adrenalectomized rats

A thorough evaluation of hippocampal dendrites, axons and synaptic contacts has not been undertaken following prolonged periods of absence of corticosteroids despite the marked granule cell loss which occurs in the dentate gyrus of adrenalectomized rats. Thus, we have applied morphometric techniques to analyse the dendrites of granule and pyramidal cells, the mossy fiber system, and the number and morphology of synapses between the mossy fibers and the excrescences of CA3 pyramidal cells in rats submitted to different periods of adrenalectomy. In addition, to search for the presence of neuritic reorganisation in the hippocampal formation once normal corticosteroid levels were re-established, we incorporated in this study a group of rats replaced with corticosterone one month after adrenalectomy. The results obtained in adrenalectomized rats showed a striking impoverishment of the dendrites of surviving granule cells, subtle alterations in the apical dendritic arborization of CA3 pyramidal cells and no changes in the apical dendrites of CA1 pyramidal cells. In addition, in adrenalectomized rats there was a progressive reduction in the total number of synapses established between mossy fibers and CA3 pyramids, as a consequence of a reduction in the volume of the suprapyramidal part of the mossy fiber system, and profound changes in the morphology of mossy fiber terminals and CA3 dendritic excrescences. A remarkable reorganisation of neurites was found to occur following the administration of low doses of corticosterone, completely reversing the adrenalectomy-induced synaptic loss and partially restoring the morphology of hippocampal axons and dendrites. These plastic mechanisms provide a sound structural basis for the reversibility of cognitive deficits observed after corticosterone administration to adrenalectomized rats.     

Dehydroevodiamine.HCl prevents impairment of learning and memory and neuronal loss in rat models of cognitive disturbance

We previously reported that dehydroevodiamine.HCl (DHED) has anticholinesterase and antiamnesic activities. To verify the effects of DHED on cognitive deficits further, we tested it on the scopolamine-induced amnesia model of the rat using the passive avoidance and eight-arm radial maze tests. A single (20 mg/kg p.o.) and repeated (10 mg/kg p.o.) administrations of DHED could significantly reverse the latency time shortened by scopolamine (1 mg/kg i.p.) to control level. The impaired spatial working memory induced by scopolamine (1 mg/kg i.p.) was also improved significantly by a single injection (6.25 mg/kg i.p.) and repeated administrations of DHED (10 mg/kg p.o.) in the eight-arm radial maze test. In addition, we examined the effects of DHED on the memory impairment and the histological changes of the brain after unilateral electrolytic lesion of the entorhinal cortex (EC) and middle cerebral artery occlusion in rats. The cognitive deficits caused by EC lesion and middle cerebral artery occlusion were improved significantly by repeated administrations of DHED (6.25 mg/kg i.p.) after EC lesion or ischemic insult once a day for 7 days in the passive avoidance test. Histological analysis showed that the neuronal loss in the DHED-treated group was notably reduced in the hippocampal area (CA1) of ischemic rats and in the dentate gyrus and hippocampal area (CA1 and CA3) of EC-lesioned rats compared with the nontreated group. The infarction area was decreased significantly by a single administration of DHED (6.25 mg/kg i.p.) 30 min before ischemic insult for 6 h. These results suggest that DHED might be an effective drug for not only the Alzheimer's disease type, but also the vascular type of dementia.     

Neural stem cell apoptosis after low‐methylmercury exposures in postnatal hippocampus produce persistent cell loss and adolescent memory deficits

The developing brain is particularly sensitive to exposures to environmental contaminants. In contrast to the adult, the developing brain contains large numbers of dividing neuronal precursors, suggesting that they may be vulnerable targets. The postnatal day 7 (P7) rat hippocampus has populations of both mature neurons in the CA1–3 region as well as neural stem cells (NSC) in the dentate gyrus (DG) hilus, which actively produce new neurons that migrate to the granule cell layer (GCL). Using this well‐characterized NSC population, we examined the impact of low levels of methylmercury (MeHg) on proliferation, neurogenesis, and subsequent adolescent learning and memory behavior. Assessing a range of exposures, we found that a single subcutaneous injection of 0.6 µg/g MeHg in P7 rats induced caspase activation in proliferating NSC of the hilus and GCL. This acute NSC death had lasting impact on the DG at P21, reducing cell numbers in the hilus by 22% and the GCL by 27%, as well as reductions in neural precursor proliferation by 25%. In contrast, non‐proliferative CA1–3 pyramidal neuron cell number was unchanged. Furthermore, animals exposed to P7 MeHg exhibited an adolescent spatial memory deficit as assessed by Morris water maze. These results suggest that environmentally relevant levels of MeHg exposure may decrease NSC populations and, despite ongoing neurogenesis, the brain may not restore the hippocampal cell deficits, which may contribute to hippocampal‐dependent memory deficits during adolescence. © 2013 Wiley Periodicals, Inc. Develop Neurobiol 73: 936–949, 2013     

Supplementation of Cr Methionine During Dry Period of Dairy Cows and Its Effect on Some Production and Biochemical Parameters During Early Lactation and on Immunity of Their Offspring

Previous studies have shown the inhibitory effect of the in vitro application of copper sulfate on hippocampal long-term potentiation. While in vivo administration of copper did not affect spatial learning and memory. To find possible answers to this controversial issue, we evaluate the effect of different doses of copper sulfate on in vivo long-term potentiation, synaptic transmission, and paired-pulse behavior of CA1 pyramidal cells. Thirty-two male Wistar rats were divided into four groups: control, 5, 10, and 15 mg of copper sulfate. Field excitatory postsynaptic potential from the stratum radiatum of CA1 neurons was recorded following Schaffer collateral stimulation in rats. Spike amplitude, long-term potentiation and paired-pulse index were measured in all groups. The results of this study showed that 5 mg/kg copper sulfate increased synaptic transmission and inhibited long-term potentiation and decreased the hippocampal paired-pulse ratio, while 10 and 15 mg/kg copper sulfate did not affect CA1 synaptic transmission properties. Low, but not high, doses of copper sulfate affect synaptic plasticity. This finding may explain the difference between the effect of copper on synaptic plasticity and spatial learning and memory.     

Leptin attenuates the detrimental effects of β-amyloid on spatial memory and hippocampal later-phase long term potentiation in rats

β-Amyloid (Aβ) is the main component of amyloid plaques developed in the brain of patients with Alzheimer's disease (AD). The increasing burden of Aβ in the cortex and hippocampus is closely correlated with memory loss and cognition deficits in AD. Recently, leptin, a 16 kD peptide derived mainly from white adipocyte tissue, has been appreciated for its neuroprotective function, although less is known about the effects of leptin on spatial memory and synaptic plasticity. The present study investigated the neuroprotective effects of leptin against Aβ-induced deficits in spatial memory and in vivo hippocampal late-phase long-term potentiation (L-LTP) in rats. Y maze spontaneous alternation was used to assess short term working memory, and the Morris water maze task was used to assess long term reference memory. Hippocampal field potential recordings were performed to observe changes in L-LTP. We found that chronically intracerebroventricular injection of leptin (1 μg) effectively alleviated Aβ1–42 (20 μg)-induced spatial memory impairments of Y maze spontaneous alternation and Morris water maze. In addition, chronic administration of leptin also reversed Aβ1–42-induced suppression of in vivo hippocampal L-LTP in rats. Together, these results suggest that chronic leptin treatments reversed Aβ-induced deficits in learning and memory and the maintenance of L-LTP.     

Selective cholinergic depletion in medial septum leads to impaired long term potentiation and glutamatergic synaptic currents in the hippocampus

Cholinergic depletion in the medial septum (MS) is associated with impaired hippocampal-dependent learning and memory. Here we investigated whether long term potentiation (LTP) and synaptic currents, mediated by alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA) and N-methyl-D-aspartate (NMDA) receptors in the CA1 hippocampal region, are affected following cholinergic lesions of the MS. Stereotaxic intra-medioseptal infusions of a selective immunotoxin, 192-saporin, against cholinergic neurons or sterile saline were made in adult rats. Four days after infusions, hippocampal slices were made and LTP, whole cell, and single channel (AMPA or NMDA receptor) currents were recorded. Results demonstrated impairment in the induction and expression of LTP in lesioned rats. Lesioned rats also showed decreases in synaptic currents from CA1 pyramidal cells and synaptosomal single channels of AMPA and NMDA receptors. Our results suggest that MS cholinergic afferents modulate LTP and glutamatergic currents in the CA1 region of the hippocampus, providing a potential synaptic mechanism for the learning and memory deficits observed in the rodent model of selective MS cholinergic lesioning.     

Effects of prenatal low-dose beta radiation from tritiated water on learning and memory in rats and their possible mechanisms.

Pregnant adult Wistar rats were randomly divided into four groups. Three of these groups were irradiated with beta rays by a single intraperitoneal injection of tritiated water ((3)H(2)O) administered on the 13th day of gestation. The doses absorbed by their offspring were estimated to be 4.6, 9.2 and 27.3 cGy. The influence of radiation on the postnatal learning ability and memory behavior and on brain development of the offspring was investigated. The number of pyramidal cells (in areas CA1, CA2, CA3 and CA4) and neurons in the hippocampus of the offspring was also measured. In addition, the Ca(++) conductance of hippocampal pyramidal cells cultured in vitro was observed. The results showed that an exposure to 4.6 cGy could prolong avoidance response time significantly and decrease the number of hippocampal pyramidal cells in the CA1 area compared to controls. An exposure to 9.2 cGy significantly decreased the establishment of conditioned reflexes and the number of hippocampal pyramidal cells in the CA3 area. This exposure also induced the degeneration and malformation of hippocampal neurons cultured in vitro, in addition to decreasing the number of hippocampal neurons observed on each culture day. A dose of 27.3 cGy significantly decreased brain and body weights and the maximum electric conductance of Ca(++) in hippocampal pyramidal neurons. In general, dose-dependent effects were observed for most of the parameters assessed in the present study. Possible mechanisms are discussed.     

Maternal infection and fever during late gestation are associated with altered synaptic transmission in the hippocampus of juvenile offspring rats

Prenatal exposure to infection is known to affect brain development and has been linked to increased risk for schizophrenia. The goal of this study was to investigate whether maternal infection and associated fever near term disrupts synaptic transmission in the hippocampus of the offspring. We used LPS to mimic bacterial infection and trigger the maternal inflammatory response in near-term rats. LPS was administered to rats on embryonic days 15 and 16 and hippocampal synaptic transmission was evaluated in the offspring on postnatal days 20-25. Only offspring from rats that showed a fever in response to LPS were tested. Schaffer collateral-evoked field excitatory postsynaptic potentials (fEPSPs) and fiber volleys in CA1 of hippocampal slices appeared smaller in offspring from the LPS group compared with controls, but, when the fEPSPs were normalized to the amplitude of fiber volleys, they were larger in the LPS group. In addition, intrinsic excitability of CA1 pyramidal neurons was heightened, as antidromic field responses in the LPS group were greater than those from control. Short-, but not long-term plasticity was impaired since paired-pulse facilitation of the fEPSP was attenuated in the LPS group, whereas no differences in long-term potentiation were noted. These results suggest that LPS-induced inflammation during pregnancy produces in the offspring a reduction in presynaptic input to CA1 with compensatory enhancements in postsynaptic glutamatergic response and pyramidal cell excitability. Neurodevelopmental disruption triggered by prenatal infection can have profound effects on hippocampal synaptic transmission, likely contributing to the memory and cognitive deficits observed in schizophrenia.     

Intact LTP and fear memory but impaired spatial memory in mice lacking Ca(v)2.3 (alpha(IE)) channel

To investigate the functional roles of the Ca(v)2.3 (alpha(1E)) channel in hippocampal CA1 pyramidal neurons, we studied in vitro synaptic properties and in vivo behaviors of the Ca(v)2.3 gene deficient mice. The Ca(v)2.3 channel mRNA was identified in the hippocampal formation of the wild-type mouse by in situ hybridization. The basic excitatory synaptic transmission and long-term potentiation by theta-burst stimulation were intact in CA1 region of Ca(v)2.3-/- mice. We performed two forms of behavioral tests to examine the hippocampus-dependent function, i.e., emotional and spatial learning tests. The Ca(v)2.3-/- mice were able to establish and maintain fear memories. Although general improvement in the performance of Morris water maze test was seen in Ca(v)2.3-/- mice, they displayed an obvious impairment in the probe test. These results suggest that the Ca(v)2.3 channel plays some role in formation of the accurate spatial memory but not of the fear memory.