Pre- and post-training infusion of prazosin into the bed nucleus of the stria terminalis impaired acquisition and retention in a Morris water maze task

The bed nucleus of the stria terminalis (BNST) is interconnected with the amygdala that is implicated in memory modulation. In view of the innervation of this structure by the hippocampus and brain stem noradrenergic nuclei, this study examined the role of BNST noradrenergic activity in acquisition, formation and expression of spatial memory. Male Wistar rats with indwelling cannulae in the BNST were trained on a spatial navigation task in the Morris water maze. Groups of rats received intra-BNST infusion of vehicle, norepinephrine, prazosin or both drugs shortly before or after each daily training session, or shortly before retention tests. Results showed that pre- or posttraining infusion of 1.0 microg prazosin impaired acquisition and retention, but the treatment had no effect on a cued response task. Posttraining infusion of 1.0 microg norepinephrine enhanced acquisition and retention, and this enhancing effect was blocked by simultaneous infusion of 0.3 microg prazosin. Pretest intra-BNST of prazosin or norepinephrine at a dose of 1.0 microg did not impair expression of the spatial navigation memory. These findings suggest that the BNST noradrengergic function is involved in modulating acquisition and formation of spatial memory that engage the hippocampus.     

Roles of oxytocin in spatial learning and memory in the nucleus basalis of Meynert in rats

The present study was performed to explore the role of oxytocin (OT) in spatial learning and memory in the nucleus basalis of Meynert (NBM) of rats. The latency, distance and swimming path to find the platform were tested by Morris water maze and recorded by a video camera connected to a computer. Intra-NBM injections of 2 or 10 nmol of OT, but not 0.2 nmol of OT, induced significant increase on the latency of spatial learning. Rats receiving intra-NBM administrations of 2 or 10 nmol of OT showed a more random search pattern. There were no significant changes in the swimming speed in Morris water maze test after the injection of OT. Furthermore, the impaired effect of OT on the latency of spatial learning was blocked by intra-NBM injection of the selective OT antagonist Atosiban, indicating that the effect of OT was mediated by OT receptor in the NBM of rats. Moreover, there were no influences of OT or Atosiban on the retention performance in rats. The results suggest that OT plays an inhibitory role in spatial learning in the NBM; the effect is mediated by OT receptor.     

Effects of physical fatigue in mice on learning performance in a water maze

We investigated the effects of physical fatigue produced by swimming exercise on learning the Morris water maze in BALB/c mice. We measured the escape latency in the maze immediately after the swimming exercise. The control group was soaked in the water but not fatigued. For easier tasks, like one with an obvious cue flag, the escape latency was not changed by exercise fatigue. However, escape latency was increased after exercise fatigue for more difficult tasks of spatial learning. These results appear to suggest that physical fatigue impaired learning performance. The effects of swimming exercise fatigue on learning efficiency were then investigated. Mice were continuously fatigued during the spatial learning period. This increased escape latency between the first and third sessions. The results suggest that learning efficiency was impaired by exercise fatigue. This system may be useful for screening new foods used to enhance brain function during exercise.     

Dexamethasone reverses the memory impairment induced by antagonism of hippocampal gastrin-releasing peptide receptors

Storage of emotionally influenced memory is regulated by activation of glucocorticoid receptors (GRs) as well as of gastrin-releasing peptide receptors (GRPRs) in the dorsal hippocampus. In the present study, male Wistar rats were given a bilateral infusion of saline or the GRPR antagonist (D-Tpi6, Leu13 psi[CH2NH]-Leu14) bombesin (6-14) (RC-3095) (1.0 microg/side) into the dorsal hippocampus 10 min before training on an inhibitory avoidance task, followed by an immediate post-training i.p. injection of vehicle or the GR agonist dexamethasone (0.3 mg/kg). A retention test trial, carried out 24 h after training, indicated that intrahippocampal infusion of RC-3095 impaired inhibitory avoidance retention. Post-training administration of dexamethasone induced an enhancement of retention regardless of whether the animals had received saline or RC-3095 into the hippocampus before training. The findings indicate that hippocampal GRPR blockade does not prevent memory enhancement induced by dexamethasone. Together with previous results, these findings suggest that endogenous activation of GRPRs in the hippocampus modulates the consolidation of emotional memory, but is not a critical receptor system mediating memory formation.     

Acetylcholinesterase induces neuronal cell loss,astrocyte hypertrophy and behavioral deficits in mammalian hippocampus

Previous studies have demonstrated that acetylcholinesterase (AChE) promotes the assembly of amyloid-beta-peptides into neurotoxic amyloid fibrils and is toxic for chick retina neuronal cultures and neuroblastoma cells. Moreover, AChE is present in senile plaques in Alzheimer's disease (AD) brains. Here we have studied the effect of AChE on astrocytes and hippocampal neurons in vivo. Morphological as well as behavioral disturbances were analyzed after intrahippocampal injection of AChE. Rats were trained in the Morris water maze and assayed for behavioral parameters. Neuronal cell loss was found in the upper leaf of the dentate gyrus in rats injected with AChE in comparison with control animals. Glial fibrillary acidic protein immunoreactivity showed astrocytic hypertrophy and the magnitude of the response was associated with neuronal cell loss. Behavioral results show that injection of AChE produces cognitive impairment demonstrated by an altered water maze performance including (i) a higher escape latency score, (ii) a decreased spatial acuity and (iii) a shorter time of swimming in the platform quadrant. These findings indicate that a local increment in neuronal AChE concentration at the mammalian hippocampus, such as those present in amyloid deposits, may play a role in triggering neuropathological and behavioral changes such as those observed in AD brains.     

大鼠血管性痴呆模型海马组织中线粒体的变化

目的:观察血管性痴呆模型(Vascular dementia,VD)大鼠海马组织内线粒体超微结构、线粒体膜电位与空间学习记忆能力的变化。方法:健康成年雄性Wistar大鼠30只,随机分为假手术组(SHAM)和血管性痴呆(VD)组,每组15只。VD组行双侧颈总动脉结扎手术制备血管性痴呆动物模型,SHAM组手术步骤同VD组,但不结扎颈总动脉。于术后第29天起行Morris水迷宫测试大鼠空间学习记忆功能,第1-5天为定位航行试验,评估大鼠空间学习能力,第6天进行空间探索试验,评估大鼠空间记忆功能。采用透射电镜技术、流式细胞学技术分别检测大鼠海马组织线粒体形态和功能变化。结果:与SHAM组相比,血管性痴呆模型组大鼠Morris水迷宫试验中逃避潜伏期明显延长(P0.01),在目标象限中停留时间显著缩短(P0.01),空间学习记忆能力受损,血管性痴呆模型组大鼠海马组织线粒体超微结构有明显损伤,线粒体膜电位明显下降(P0.01)。结论:线粒体损伤是血管性痴呆空间学习记忆功能障碍的重要机制之一。     

TRP 对KA 诱导的AD 模型大鼠学习记忆的影响及其作用机制

目的:观察雷公藤甲素(Triptolide,TRP)对海人藻酸(Kainic acid,KA)海马内注射后大鼠学习记忆的影响及其作用机制。方法:采用Morris水迷宫筛选空间学习记忆能力正常的SD雄性大鼠90只(200～220g)。将实验动物分成3组:右侧海马注射生理盐水后生理盐水灌胃对照组(NS+NS)、右侧海马注射海人藻酸后生理盐水灌胃干预组(KA+NS)、右侧海马注射海人藻酸后雷公藤甲素灌胃干预组(KA+TRP)。动物存活1天,3天,5天,7天,14天,每个时间点6只,处死前分别于各相应时间点用Morris水迷宫检测各组动物空间位置记忆能力;免疫组织化学方法结合图像分析技术检测海马CA1区神经元COX-2的表达。结果:与NS组(NS+NS)比较,KA组(KA+NS)大鼠逃避潜伏期延长(P<0.05),跨越原平台次数减少(P<0.05);海马CA1区的神经元COX-2表达升高(P<0.05);TRP组(TRP+KA)与KA组比较,大鼠的平均逃避潜伏期从第5天起缩短(P<0.05),跨越原平台次数增多(P<0.05),海马CA1区神经元COX-2表达在5天,7天时下调(P<0.05)。结论:KA海马内注射,可以导致大鼠学习记忆功能障碍及上调海马CA1区神经元COX-2表达;雷公藤甲素干预治疗,能够改善动物的学习和记忆能力,能抑制KA诱导的海马CAl区神经元COX-2的表达。     

早期游泳运动对慢性温和应激抑郁大鼠学习和记忆能力的影响

目的:探讨早期游泳运动对慢性温和应激(chronic mild stress,CMS)大鼠学习和记忆能力的影响。方法:50只SD大鼠随机分成5组:对照组、模型组、低强度运动组、中等强度运动组、高强度运动组。运动组大鼠按照游泳运动方案运动4 w,糖水消耗实验和强迫游泳实验评价大鼠抑郁程度;Morris水迷宫实验评价大鼠学习记忆能力。结果:模型组大鼠糖水消耗量和游泳不动时间较对照组明显降低(P0.01),低强度运动组和中等强度运动组大鼠较模型组糖水消耗量和游泳不动时间明显增加(P0.05或P0.01);模型组大鼠较对照组逃避潜伏期明显延长,目标象限搜索时间占总游泳时间的百分比和目标象限穿过次数减少,体质量、双侧海马质量和海马相对质量下降(P0.05或P0.01);低强度运动组和中等强度运动组大鼠较模型组比较,潜伏期缩短明显,目标象限搜索时间占总游泳时间的百分比和目标象限穿过次数增加,体质量、双侧海马质量和海马相对质量增加(P0.05或P0.01)。结论:早期游泳运动能减轻慢性温和应激抑郁大鼠的学习记忆的损害,其中低强度和中等强度运动训练作用效果最佳。     

Positive impact of levetiracetam on emotional learning and memory in naive mice

AimsThe effect of an antiepileptic drug on cognitive function is of primary importance with respect to the patient's quality of life. Levetiracetam (LEV) is a novel antiepileptic drug used to treat epilepsy, but its effects on spatial and emotional learning and memory are not yet well understood. The goal of our study was to establish the effects of LEV (17 and 54 mg/kg, intraperitoneally (IP)) on spatial memory retrieval in the Morris water maze test and on acquisition and memory formation in the passive avoidance (PA) test in naive mice.Main methodsThe subjects were adult male BALB/c mice. Spatial learning and memory was established with the Morris water maze (MWM) test. The ‘time spent in escape platforms quadrant’ and the ‘distance to platform’ analyses were measured using a video tracking system to determine spatial memory function. Emotional learning and memory were determined with a one-trial, step-through passive avoidance test.Key findingsIn the MWM test, LEV (17 and 54 mg/kg) neither affected the time spent in the target quadrant nor altered the distance to platform. Moreover, LEV had no effect on swim speed. In the PA task, LEV (17 and 54 mg/kg) significantly prolonged retention latency.SignificanceOur results indicate that LEV did not alter spatial memory retrieval in the MWM test, but it did show some ameliorating effects on acquisition and memory formation in the PA test in naive mice.     

Protective effects of Ginkgo biloba leaf extract on aluminum-induced brain dysfunction in rats

This study examined the protective effects of Ginkgo biloba extract (GbE) on the learning and memory function in aluminum-treated rats and potential mechanisms. Wistar rats were given daily aluminum chloride 500 mg/kg, i.g, for one month, followed by continuous exposure via the drinking water containing 1600 ppm aluminum chloride for up to 5 months. The ability of spatial learning and memory was tested by Morris water maze. Aluminum administration significantly increased escape latency and searching distance, indicative of brain dysfunction. GbE treatment (50-200 mg/kg, i.g) significantly protected against aluminum-induced brain dysfunction, as evidenced by decreased escape latency and searching distance compared with the Al alone group. To examine the mechanisms of the protection, the expressions of amyloid precursor protein (APP) and caspase-3 in brain regions were examined by immunohistochemistry. GbE treatment reduced the contents of APP and caspase-3 in hippocampus of aluminum-treated rats in a dose-dependent manner. At the highest dose of GbE (200 mg/kg), the immunostain for APP and caspase-3 was returned to normal levels. In summary, this study demonstrates that GbE is effective in improving the ability of spatial learning and memory of aluminum-intoxicated rats. This protection appears to be due to a decreased expression of APP and caspase-3 in rat brain, resulting in a decrease in the production of insoluble fragments of Abeta-amyloid.     

围产期慢性尼古丁摄入对子代小鼠学习与记忆的影响

尼古丁对学习记忆间接作用的研究鲜有报道。昆明小鼠母鼠受孕后随机分为对照组(CON)和尼古丁组(NIC)。CON组母鼠自由饮水,NIC组母鼠饮水中给予浓度为50μg/mL的尼古丁。子代小鼠60日龄时,进行Morris水迷宫实验,之后在体记录海马区穿通纤维通路(perforant pathway,PP)至齿状回(dentate gyrus,DG)的长时程增强(long-term potentiation,LTP)。结果显示,NIC组仔鼠的逃避潜伏期从第3天开始明显大于CON组,目标象限停留时间所占百分比和穿越平台次数均低于CON组,LTP群峰电位幅值和场兴奋性突触后电位斜率也都显著低于CON组。说明由母体摄入的尼古丁,可经胎盘和乳汁明显作用于其子代,导致子代学习记忆功能的明显损伤,其可能机制是因为海马神经元突触传递可塑性的效率显著降低。     

Effects of a Cardiotonic Medicine,Danshen Pills,on Cognitive Ability and Expression of PSD-95 in a Vascular Dementia Rat Model

A widely used Chinese cardiotonic proprietary medicine, compound Danshen dripping pills (CDDP, Fufang Danshen Diwan) has also begun to be used for treatment of vascular dementia (VaD). We tried to explore the mechanism of CDDP action in this case. A VaD experimental model was built in rats by bilateral ligation of the common carotid arteries. The cognitive ability of experimental animals was evaluated in the Morris water maze test. Synaptic ultrastructural changes in the hippocampus were detected by transmission electron microscopy; expression of PSD-95 mRNA in the hippocampus was examined using hybridization in situ. The latter index (mRNA expression) in the VaD group was significantly lower than those in the CDDP and sham-operated groups (P < 0.05). CDDP treatment considerably improved disturbed ultrastructural synaptic characteristics in the hippocampus of VaD rats. The mean escape latency in the Morris water maze test was significantly shorter in CDDP-treated VaD rats, compared with that those of the VaD group (P < 0.05). In the CDDP group compared to the VaD one, escape strategies improved from edge and random searches to more linear swim pathway (P < 0.05). Thus, decreasing expression of PSD-95 plays an important role in the pathogenesis of VaD. CDDP treatment improves the learning and memory ability of VaD rats by improving neural synaptic ultrastructural characteristics and increasing expression of PSD-95 mRNA in the hippocampus.     

水迷宫实验中不同性别树鼩学习记忆能力的比较

目的研究雌雄树鼩空间学习和记忆能力的差异。方法随机选择自繁F1代树鼩20只（雄11只,雌9只）,在相同条件下进行8 d的水迷宫实验,包括前7 d的定位航行实验和第8天的空间探索实验。结果定位航行实验中雌雄逃避潜伏期、游泳总路程差异无显著性（P〉0.05）,但不同时间水平差异有显著性（P〈0.05）;平均游泳速度雌雄差异无显著性（P〉0.05）。空间探索实验中目标象限游泳时间和总时间之比、目标象限游泳路程和总路程之比雌雄差异无显著性（P〉0.05）;穿越目标象限次数和搜索策略雌雄差异有显著性（P〈0.05）。结论水迷宫实验中树鼩在空间学习能力上雌雄无差异,但在空间探索实验中雄性的表现优于雌性。     

硫辛酸对卵巢切除小鼠学习记忆的影响

目的:探讨硫辛酸(Lipoic acid,LA)对卵巢切除(ovariectomized,OVX)小鼠学习记忆的影响。方法:2月龄雌性昆明小鼠随机分为4组:假手术(Sham)组、OVX组、OVX+LA组、OVX+LA+左旋硝基精氨酸甲酯(L-NAME)组。建立卵巢切除模型并给药,Morris水迷宫检测各组小鼠学习记忆能力。结果:前4天定位巡航实验中,OVX组与Sham组相比,逃避潜伏期明显延长(P0.05),第5天撤除平台后,OVX组在目的象限游泳距离及时间百分比较Sham组明显缩短(P0.05);OVX+LA组与OVX组相比,逃避潜伏期明显缩短(P0.05),撤除平台后,在目的象限游泳距离及时间百分比明显延长(P0.05);OVX+LA+L-NAME组与Sham组相比,逃避潜伏期明显延长(P0.05),撤除平台后,在目的象限游泳距离及时间百分比明显缩短(P0.05)。结论:OVX损伤小鼠的学习记忆,LA可改善这种损伤,内皮型一氧化氮合酶(e NOS)抑制剂L-NAME可削弱LA的这种保护作用。     

2R,4R-APDC,a Metabotropic Glutamate Receptor Agonist,Reduced Neuronal Apoptosis by Upregulating MicroRNA-128 in a Rat Model After Seizures

This study aimed to study the protective effect of (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (2R,4R-APDC), a selective metabotropic glutamate receptor agonist, against hippocampal neuronal apoptosis induced by seizures in a rat model of pilocarpine-induced epilepsy. The Morris water maze test was used to assess the spatial memory abilities of epileptic rats with or without 2R,4R-APDC treatment. TUNEL assay was performed to examine neuronal apoptosis in hippocampus. Western blot was conducted to evaluate changes in the levels of caspase-3 and caspase-9 in hippocampus. Real-time PCR was used to determine the levels of microRNA-128 (miR-128) in hippocampus. The results of the Morris water maze test showed that the 2R,4R-APDC treatment reduced the escape latencies and swimming lengths of rats after seizures. The TUNEL assay showed that 2R,4R-APDC significantly counteracted seizure-induced cell apoptosis. The western blot confirmed this finding, demonstrating that the levels of cleaved caspase-3 and cleaved caspase-9 were potently decreased by 2R,4R-APDC in rat hippocampus after seizures. In addition, 2R,4R-APDC upregulated miR-128 expression levels in the hippocampus. A miR-128 mimic or inhibitor decreased or increased the percentage of TUNEL-positive cells in rats after seizures and 2R,4R-APDC treatment, respectively. The levels of both cleaved caspase-3 and cleaved caspase-9 were decreased in hippocampus exposed to the miR-128 mimic, whereas they were markedly increased in miR-128 inhibitor-treated hippocampus. In conclusion, 2R,4R-APDC protected hippocampal cells from cell apoptosis after seizures, possibly by upregulating miR-128.     

Spatial memory in the rat requires the dorsolateral band of the entorhinal cortex

The extensive connections of the entorhinal cortex with the hippocampus and the neocortex point to this region as a major interface in the hippocampal-neocortical interactions underlying memory. We asked whether hippocampal-dependent recall of spatial memory depends on the entorhinal cortex, and, if so, which parts are critical. After training in a Morris water maze, rats received fiber-sparing lesions in the dorsolateral band of the entorhinal cortex, which mediates much of the visuospatial input to the dorsal hippocampus. These lesions entirely disrupted retention and retarded new learning. Spatial memory was spared by lesions in the ventromedial band, which connects primarily with ventral hippocampus, but these lesions reduced defensive behavior on an elevated plus maze, mirroring the effects of damage to ventral hippocampus. The results suggest that the functional differences between dorsal and ventral hippocampus reflect their connectivity with modules of the entorhinal cortex that are differently linked to the rest of the cortex.     

Z-Guggulsterone Improves the Scopolamine-Induced Memory Impairments Through Enhancement of the BDNF Signal in <Emphasis Type="Italic">C57BL</Emphasis>/<Emphasis Type="Italic">6J</Emphasis> Mice

Memory impairment is a common symptom in patients with neurodegenerative disorders, and its suppression could be beneficial to improve the quality of life of those patients. Z-guggulsterone, a compound extracted from the resin of plant Commiphora whighitii, exhibits numerous pharmacological effects in clinical practice, such as treatment of inflammation, arthritis, obesity and lipid metabolism disorders. However, the role and possible mechanism of Z-guggulsterone on brain-associated memory impairments are largely unknown. This issue was addressed in the present study in a memory impairment model induced by scopolamine, a muscarinic acetylcholine receptor antagonist, using the passive avoidance, Y-maze and Morris water maze tests. Results showed that scopolamine significantly decreased the step-through latency and spontaneous alternation of C57BL/6J mice in passive avoidance and Y-maze test, whereas increased the mean escape latency and decreased the swimming time in target quadrant in Morris water maze test. Pretreatment of mice with Z-guggulsterone at doses of 30 and 60 mg/kg effectively reversed the scopolamine-induced memory impairments. Mechanistic studies revealed that Z-guggulsterone pretreatment reversed the scopolamine-induced increase in acetylcholinesterase (AchE) activity, as well as decreases in brain-derived neurotrophic factor (BDNF) protein expression and cAMP response element-binding protein (CREB), extracellular regulated kinase 1/2 (ERK1/2) and protein kinase B (Akt) phosphorylation levels in the hippocampus and cortex. Inhibition of the BDNF signal, however, blocked the memory-enhancing effect of Z-guggulsterone. Therefore, these findings demonstrate that Z-guggulsterone attenuates the scopolamine-induced memory impairments mainly through activation of the CREB-BDNF signaling pathway, thereby exhibiting memory-improving effects.     

慢性复合应激对大鼠学习和记忆及海马神经元神经颗粒素表达的影响

目的探讨慢性复合应激对大鼠学习和记忆功能及海马内神经元神经颗粒素(neurogranin,Ng)表达的影响。方法成年雄性Wistar大鼠随机分为对照组和复合应激组,复合应激组动物每天无规律交替暴露于复合应激原环境中,为期6周。应激结束后,用Morris水迷宫测试大鼠空间学习和记忆成绩,同时用免疫组织化学方法观察海马各亚区Ng表达的变化,并用RT-PCR技术分析各组大鼠海马Ng mRNA水平的变化。结果Morris水迷宫测试显示,应激组动物寻找隐蔽平台潜伏期明显短于对照组(P<0.05);应激组大鼠海马DG和CA3区Ng的蛋白表达水平明显高于对照组(P<0.05),而两组海马CA1区的Ng的免疫反应性无明显差别;与对照组相比,应激组动物的Ng mRNA水平亦明显上调(P<0.05)。结论慢性复合性应激大鼠的学习与记忆能力增强;Ng在海马中的表达和Ng mRNA转录水平增高,提示Ng参与了该增强机制。     

慢性复合应激增强大鼠空间学习和记忆能力

本文观察了慢性复合应激对大鼠学习与记忆功能的影响。实验采用成年 Wistar 大鼠, 将其随机分成应激组和对照组。采用垂直旋转、睡眠剥夺、噪音刺激和夜间光照4 种应激原, 无规律地交替刺激动物 6 周, 每天6 h, 制作慢性复合应激动物模型。采用 Morris 水迷宫和 Y- 迷宫测试大鼠学习与记忆成绩,并用 Cresyl violet 染色法对大鼠海马结构进行神经细胞计数。结果显示,应激组动物慢性复合应激后, 在 Morris 水迷宫内寻找隐蔽平台所需的时间(潜伏期)比对照组的明显地短(P<0.05), 表明应激鼠的空间记忆能力明显强于对照鼠;在 Y- 迷宫内寻找安全区的正确率比对照组的明显地高(P<0.05), 表明应激鼠的明暗分辨学习能力明显强于对照鼠; 应激鼠慢性复合应激后, 其海马结构齿状回、CA3 和CA1 区神经细胞密度极明显地高于对照鼠(P<0.001)。这些结果提示, 慢性复合应激可增强大鼠空间记忆能力和明暗分辨学习能力。本文并对慢性复合应激模式增强大鼠学习和记忆能力的可能原因进行了讨论。     

两种水迷宫在测试拟阿尔茨海默病小鼠学习记忆能力中的比较

目的采用两种水迷宫对拟阿尔茨海默病小鼠学习记忆功能进行比较。方法将小鼠分为正常对照组、模型组及给药组。用Morris水迷宫和MS-2水迷宫自动控制仪分别测试各组小鼠的学习记忆能力。结果在Morris水迷宫测试中,模型组与对照组,给药组与模型组比较,逃避潜伏期均有显著性差异（P〈0.01）,在MS-2水迷宫自动控制仪测试中,模型组与对照组比较有明显差异（P〈0.05）,而给药组与模型组比较,游出水迷路的时间均有所减少,但没有显著性差异（P〉0.05）。结论Morris水迷宫和MS-2水迷宫自动控制仪测试方法均能反映动物学习和记忆功能,而前者能更敏感地反映出动物的学习记忆能力。因此,Morris水迷宫应为实验首选,当然在实验需要时,两种水迷宫最好结合使用,以得到客观的结果。