Timosaponin B-II improves memory and learning dysfunction induced by cerebral ischemia in rats

Sapogenins from Anemarrhenae asphodeloides was reported to improve the learning and memory abilities. In this study, we investigated the effect of Timosaponin B-II(TB-II), a purified extract from A. asphodeloidesb on rat vascular dementia (VD) produced by transient (2 h) middle cerebral artery occlusion. The learning and memory abilities of rats were measured by water maze task and passive avoidance task. Daily oral administration of TB-II at two different dose levels of 100 and 200 mg/kg resulted in a significant improvement of the deficit in the learning of the water maze task, beginning 14 days after ischemia. Shortened mean escape latency was detected in TB-II group compared with model group during the same trial days. TB-II treatment also significantly reversed the ischemia-induced retention deficit determined by a one trial step-down type of passive avoidance task. Meanwhile, the expression of interleukin-10, an anti-inflammatory cytokine, and its receptor were significantly increased in TB-II treated VD rats. The results presented the first evidence of a neuroprotective effect of TB-II in the model of vascular dementia. We suggest that the anti-dementia effect by TB-II is derived at least in part from its anti-inflammatory properties.     

β淀粉样蛋白对大鼠学习记忆功能及tau蛋白异常磷酸化的影响

为了探讨β淀粉样蛋白对大鼠学习记忆功能和tau蛋白异常磷酸化的影响,本文在海马注射Aβ25-35建立阿尔茨海黙病(AD)大鼠模型的基础上,通过行为学检测、HE染色、免疫组化和免疫蛋白印迹技术对动物的学习能力、组织的病理改变和tau(pS202)、tau(pT231)和tau-5的表达情况进行了分析。在行为学检测中,Aβ注射组大鼠在穿梭箱实验中的主动回避次数和被动回避次数减少,失败次数增多,而在Morris水迷宫测试中的逃避潜伏期和游泳距离延长。HE染色显示Aβ注射组大鼠海马CA1、CA3、齿状回的神经细胞数目减少;而免疫组化和免疫印迹结果显示注射组tau(pS202)阳性细胞明显增加,tau(pS202)、tau(pT231)和tau-5蛋白表达增加。以上结果提示海马内注射Aβ25-35可引起大鼠学习记忆功能下降,可能与神经细胞减少,tau蛋白异常磷酸化增多有关。     

Involvement of dorsal hippocampal α1-adrenergic receptors in the effect of WIN55,212-2 on memory retrieval in inhibitory avoidance task

In the present study, the possible role of α1-adrenergic receptors of the dorsal hippocampus on WIN55,212-2-induced amnesia in male Wistar rats has been evaluated. As a model of learning, a step-down passive avoidance task was used. Results indicated that post-training or pre-test intra-CA1 administration of WIN55,212-2 (0.25 and 0.5 μg/rat) reduced the step-down latency, showing an amnestic response. Amnesia produced by post-training WIN55,212-2 (0.5 μg/rat) was reversed by pre-test administration of the same drug dose. Interestingly, pre-test intra-CA1 administration of α1-noradrenergic agonists, phenylephrine alone or with an ineffective dose of WIN55,212-2 (0.25 μg/rat) reversed post-training WIN55,212-2 (0.5 μg/rat)-induced retrieval impairment. On the other hand, pre-test intra-CA1 microinjection of an α1-adrenergic antagonist, prazosin (0.5 μg/rat), 2 min before administration of WIN55,212-2 (0.5 μg/rat) inhibited the pre-test WIN55,212-2 response. It may be concluded that α1-adrenergic receptors of the dorsal hippocampal CA1 regions play an important role in WIN55,212-2-induced amnesia and restoration of memory by pre-test WIN55,212-2 administration.     

硫胺素缺乏对小鼠学习记忆能力的影响

为研究硫胺素缺乏对小鼠学习记忆能力的影响，我们随机地将４０只昆明雄性小鼠分成对照、对饲和硫胺素缺乏组。经２４天饲养后，硫胺素缺乏组小鼠毛发稀疏、体重显著性地低于对照和对饲组，ＴＰＤ效应值显著地高于对照和对饲组。硫胺素缺乏组小鼠完成水迷宫所需要的时间和平均错误次数均显著性地高于对照和对饲组。在一次性回避反应的跳台和避暗测验中，硫胺素缺乏组小鼠避暗反应的平均潜伏期显著显著性地短于对照组，且平均错误次数     

大鼠纹状体边缘区与海马逃避性学习记忆功能的比较

为了比较纹状体边缘区 (Mr D)与海马在逃避性学习记忆方面的差别 ,藉以探讨 Mr D与海马两个不同脑区在大脑学习记忆功能上的区别和作用地位。应用 Y迷宫训练大鼠后 2 4h,化学损毁大鼠双侧 Mr D或切断双侧穹窿海马伞 (fornix/fimbria,FF ) ,手术 5 d后再观察大鼠在 Y迷宫中学习记忆的行为表现。结果表明 ,化学损毁 Mr D组大鼠在 Y迷宫中的记忆能力和对照组相比 ,明显降低 ,差别显著 (P<0 .0 1) ;而切断双侧穹窿海马伞组大鼠与对照组相比 ,无显著性差异 (P>0 .0 5 )。说明大鼠在 Y迷宫中的逃避性学习记忆行为主要和 Mr D有关 ,和海马无明显关系。提示 Mr D和海马两个脑区在参与大脑的学习记忆功能方面 ,并非处于相同的位置     

免疫应答过程对小鼠习得性行为的影响及其相关分子机制的研究

目的探讨免疫应答和免疫记忆的建立对大脑学习记忆能力的影响及分子机制。方法以绵羊红细胞作为外源性抗原激发小鼠免疫应答,建立免疫记忆;同时注射生理盐水作为对照组。应用跳台法对两组小鼠进行被动回避行为训练,以步下潜伏期为学习记忆成绩指标比较分析两组的差异。再取行为训练后小鼠脑做石蜡切片采用免疫组化法检测其海马结构内cFos蛋白的表达。结果小鼠经被动行为训练后学习记忆成绩免疫组优于对照组,有统计学显著性差异(P<0.05);小鼠海马内cFos蛋白表达免疫组显著高于对照组(P<0.05);相关性分析发现实验组小鼠抗SRBC抗体效价与海马cFos蛋白表达的免疫组化灰度值之间,实验组小鼠抗SRBC抗体效价与行为训练后学习记忆成绩之间不呈统计学相关(P>0.05)。结论免疫应答和免疫记忆的建立可以提高大脑的学习记忆能力,免疫应答过程增强小鼠脑海马内的cFos蛋白的表达可能是免疫系统对大脑高级活动产生影响的重要因素。     

Changes in cognition induced by social isolation in the mouse are restored by electro-acupuncture

Social isolation by individual housing the mice eliminates social interaction and induces pathophysiological changes including decreased learning capabilities. Acupuncture with the manipulation of the needles according to traditional Chinese medicine or with the electrical stimulation applied on needles inserted into the acupoints (referred as electro-acupuncture, EA) may modulate stress response, mood, learning and memory process. We investigated whether or not EA could reverse memory impairments induced in the male mouse by social isolation. We also studied any changes due to EA or social isolation in neurotrophic factors as nerve growth factor (NGF) or brain-derived neurotrophic factor (BDNF) known to have a role in regulating memory and learning processes. We found that 30 min daily session of EA for a period of 4 days at the acupoint Zusanli (low burst frequency of 2 Hz, each pulse was a square electric wave and had a duration of 180, length of 0.1, and internal burst frequency of 80 Hz; intensity 1.0-1.5 mA) reverses the changes in the passive avoidance responses of isolated mice. These findings were associated with decreased NGF and BDNF in the hippocampus and decreased NGF in the striatum of isolated mice exposed to EA. In conclusion the present data in the mouse show that EA may modulate cognition in mice subjected to social isolation.     

Urine formaldehyde level is inversely correlated to mini mental state examination scores in senile dementia

It is widely known that exogenous formaldehyde exposure induces human cognitive impairment and animal memory loss; and recent studies show that formaldehyde at pathological levels induces Aβ deposition and misfolding of tau protein to form globular amyloid-like aggregates. Endogenous formaldehyde may be a marker for progressive senile dementia.The aim of this study was to investigate the correlation of endogenous formaldehyde in urine of senile dementia and mini mental state examination (MMSE) scores.Formaldehyde level was analyzed by high-performance liquid chromatography (with fluorescence detection) in human urine from dementia patients (n = 141), patients with hypertension (n = 33) or diabetes (n = 16) and healthy individuals (n = 38), autopsy hippocampus samples from Alzheimer's disease (AD) patients and brains of three types of AD animal model: namely, senescence accelerated mice (SAMP8), APP-transgenic mice and APP/PS1-transgenic mice.In a double-blind study, there was marked elevation of urine formaldehyde levels in patients (n = 91) with dementia, and a slight increase in patients (n = 50) with mild cognitive impairment. Urine formaldehyde level was inversely correlated with mini mental state examination scores (Rs = −0.441, p < 0.0001). Furthermore, formaldehyde levels were significantly increased in the autopsy hippocampus from Alzheimer's patients (n = 4). In SAMP8 brains the formaldehyde level was significantly increased, suggesting that the endogenous formaldehyde is related to aging in mice. The brain formaldehyde level in APP/PS1-transgenic (n = 8) mice at age of 3 months and APP-transgenic (n = 8) mice at age of 6 months was increased (0.56 ± 0.02 mM), respectively, as compared with their respective age-matched controls, when these two types of AD-like animals, respectively, started to form Aβ deposits and memory loss obviously. According to the level of formaldehyde in the brain of the transgenic mice, we treated normal mice with formaldehyde (0.5 mM, intraperitoneal administration) and observed the memory loss of the animal in Morris water maze trial.Cognitive impairments for the senile dementia are probably related to endogenous formaldehyde levels; and the mini mental state examination scores referred to the evaluation of urine formaldehyde level in dementia patients may be used as a non-invasive method for the investigation and diagnosis of senile dementia.     

Progesterone enhances performance of aged mice in cortical or hippocampal tasks

Ovarian steroids alter cognitive performance of young individuals. Whether progesterone enhances learning and memory in tasks involving the prefrontal cortex and/or hippocampus in aged mice was investigated. Aged mice received progesterone (10 mg/kg, SC) or vehicle and were tested for cortical and/or hippocampal learning and memory. Progesterone increased spontaneous alterations in the T-maze and time spent exploring novel objects in the object recognition task. Progesterone increased the time mice spent in the quadrant of the water maze where the hidden platform had been during training, increased latencies to crossover to the shock-associated side of the inhibitory avoidance chamber, and increased freezing in the contextual fear conditioning task. Progesterone did not enhance performance in tasks mediated by the amygdala (cued conditioning), striatum (conditioned place preference), or cerebellum (rotarod) in these aged mice. Thus, progesterone improved learning and memory in tasks mediated by the prefrontal cortex and/or hippocampus of aged mice.     

Progesterone enhances learning and memory of aged wildtype and progestin receptor knockout mice

Progesterone can enhance cognitive performance among young and aged mice; however, the mechanisms underlying these effects of progesterone are not well-understood. Aged, mice which lack functional progestin receptors (PRKO), or wildtype mice were administered progesterone (10 mg/kg, SC), or vehicle, and learning/memory was evaluated. Progesterone, compared to vehicle, produced a conditioned place preference in PRKO and wildtype mice. Progesterone improved performance of PRKO and wildtype mice in the object placement, water maze, contextual and cued fear conditioning tasks. PRKO, compared to wildtype, mice performed better in the inhibitory avoidance task, irrespective of progesterone. Thus, progesterone to aged mice enhances performance across a variety of tasks and this may not require actions at PRs.     

龟龄集对 AD 小鼠皮层和海马 Fas/ FasL 表达及神经元凋亡的影响

目的 探究龟龄集对阿尔茨海默病 (Alzheimer’s disease, AD) 小鼠皮层和海马 Fas/ FasL 表达及 神经元凋亡的影响。 方法 构建 AD 小鼠模型, 小鼠随机分为对照组、 模型组、 多奈哌齐组及龟龄集低、 中、 高剂量组。 Morris 水迷宫检测干预前后小鼠的学习记忆能力; HE 染色检测小鼠皮层、 海马神经元病理 学改变情况; TUNEL 染色检测神经元凋亡情况; Western 印迹及 Real time PCR 分别检测 Fas、 FasL 的蛋白 表达水平及 mRNA 表达水平。 结果 与模型组比较, 龟龄集各组和多奈哌齐组小鼠学习记忆能力明显提高 (P< 0. 05), 皮层和海马神经元病理学损害及神经元凋亡改善 (P< 0. 05), Fas、 FasL 蛋白和 mRNA 水平下 降 (P< 0. 05)。 结论 龟龄集可能通过抑制 Fas/ FasL 表达抑制 AD 模型小鼠皮层、 海马神经元凋亡, 并改 善其学习记忆能力。     

Effects of age and spatial learning on adenylyl cyclase mRNA expression in the mouse hippocampus

Adenylyl cyclase (AC) subtypes have been implicated in memory processes and synaptic plasticity. In the present study, the effects of aging and learning on Ca2+/calmodulin-stimulable AC1, Ca2+-insensitive AC2 and Ca2+/calcineurin-inhibited AC9 mRNA level were compared in the dorsal hippocampus of young-adult and aged C57BL/6 mice using in situ hybridization. Both AC1 and AC9 mRNA expression were downregulated in aged hippocampus, whereas AC2 mRNA remained unchanged, suggesting differential sensitivities to the aging process. We next examined AC mRNA expression in the hippocampus after spatial learning in the Morris water maze. Acquisition of the spatial task was associated with an increase of AC1 and AC9 mRNA levels in both young-adult and aged groups, suggesting that Ca2+-sensitive ACs are oppositely regulated by aging and learning. However, aged-trained mice had reduced AC1 and AC9, but greater AC2, mRNA levels relative to young-trained mice and age-related learning impairments were correlated with reduced AC1 expression in area CA1. We suggest that reduced levels of hippocampal AC1 mRNA may greatly contribute to age-related defects in spatial memory.     

Rapid,specific and active site-catalyzed effect of tissue-plasminogen activator on hippocampus-dependent learning in mice

In the present study we trained tissue-plasminogen activator (tPA)-knockout (tPA -/-) and wild-type (tPA +/+) male mice in step-down inhibitory avoidance learning, a hippocampus-dependent task. tPA -/- displayed significantly shorter latencies to step down at 90 min, one, two and seven days after training indicating the learning deficit in these animals (P < 0.05 vs tPA +/+). The locomotor activity, the level of anxiety in an elevated-plus maze, as well as the pain threshold did not differ between the two strains of mice. The learning disability of tPA -/- was overcome by more intense training. The learning deficit was also partially restored by limited intrahippocampal delivery of tPA (infused for 2 h before training; P < 0.05 vs control), but not by the delivery of urokinase plasminogen activator, indicating the acute need for tPA in learning. The beneficial effect of tPA was abolished by co-infusion of its inhibitor tPA-STOP, indicating that the facilitatory effect of tPA on learning requires a proteolytic step. However, tPA activity in the hippocampus was not indispensable for effective memory retrieval in tPA-infused tPA -/- mice. Thus, rapid, specific and proteolytic action of tPA facilitates hippocampus-dependent learning, but not retrieval of previously acquired information.     

Novel age-dependent learning deficits in a mouse model of Alzheimer's disease: Implications for translational research

Computational modeling predicts that the hippocampus plays an important role in the ability to apply previously learned information to novel problems and situations (referred to as the ability to generalize information or simply as ‘transfer learning’). These predictions have been tested in humans using a computer-based task on which individuals with hippocampal damage are able to learn a series of complex discriminations with two stimulus features (shape and color), but are impaired in their ability to transfer this information to newly configured problems in which one of the features is altered. This deficit occurs despite the fact that the feature predictive of the reward (the relevant information) is not changed. The goal of the current study was to develop a mouse analog of transfer learning and to determine if this new task was sensitive to pathological changes in a mouse model of AD. We describe a task in which mice were able to learn a series of concurrent discriminations that contained two stimulus features (odor and digging media) and could transfer this learned information to new problems in which the irrelevant feature in each discrimination pair was altered. Moreover, we report age-dependent deficits specific to transfer learning in APP + PS1 mice relative to non-transgenic littermates. The robust impairment in transfer learning may be more sensitive to AD-like pathology than traditional cognitive assessments in that no deficits were observed in the APP + PS1 mice on the widely used Morris water maze task. These data describe a novel and sensitive paradigm to evaluate mnemonic decline in AD mouse models that has unique translational advantages over standard species-specific cognitive assessments (e.g., water maze for rodent and delayed paragraph recall for humans).     

Selective cognitive dysfunction in mice lacking histamine H1 and H2 receptors

Previous pharmacological experiments provide conflicting findings that describe both facilitatory and inhibitory effects of neuronal histamine on learning and memory. Here, we examined learning and memory and synaptic plasticity in mice with a null mutation of gene coding histamine H1 or H2 receptor in order to clarify the role of these receptors in learning and memory processes. Learning and memory were evaluated by several behavioral tasks including object recognition, Barnes maze and fear conditioning. These behavioral tasks are highly dependent on the function of prefrontal cortex, hippocampus or amygdala. Object recognition and Barnes maze performance were significantly impaired in both H1 receptor gene knockout (H1KO) and H2 receptor gene knockout (H2KO) mice when compared to the respective wild-type (WT) mice. Conversely, both H1KO and H2KO mice showed better auditory and contextual freezing acquisition than their respective WT mice. Furthermore, we also examined long-term potentiation (LTP) in the CA1 area of hippocampus in H1KO and H2KO mice and their respective WT mice. LTP in the CA1 area of hippocampus was significantly reduced in both H1KO and H2KO mice when compared with their respective WT mice. In conclusion, our results demonstrate that both H1 and H2 receptors are involved in learning and memory processes for which the frontal cortex, amygdala and hippocampus interact.     

姜黄素对东莨菪碱所致小鼠记忆功能障碍的影响(英文)

目的：探讨中药单体姜黄素对东莨菪碱致小鼠记忆障碍的影响及其可能的机制。方法：用东莨菪碱建立昆明小鼠记忆获得性障碍模型,通过跳台和水迷宫实验观察姜黄素对小鼠学习记忆能力的影响,同时测定其脑组织中乙酰胆碱酯酶、谷胱甘肽过氧化物酶和丙二醛的活性。结果：姜黄素可以减少东莨菪碱所致的记忆获得性障碍小鼠跳台回避反应的错误次数（P<0.05）,延长其逃避潜伏期（P<0.05）,也可以缩短记忆获得障碍小鼠水迷宫中寻找平台的潜伏期（P<0.05）,撤去平台后可以延长小鼠在原平台象限的停留时间（P<0.05）。姜黄素可以降低小鼠脑乙酰胆碱酯酶活性（P<0.01）、提高抗氧化酶谷胱甘肽过氧化物酶活性（P<0.01）、降低脂质过氧化产物丙二醛含量（P<0.01）。结论：姜黄素对记忆获得性障碍有明显的改善作用,其机制可能与影响中枢胆碱能系统、抗氧化损伤有关。     

Hippocampal heterogeneity in spatial memory revealed by cytochrome oxidase

The oxidative metabolism was assessed in the septal, intermediate and temporal hippocampus in Wistar rats that were trained following a working memory schedule in the Morris water maze. The cytochrome oxidase histochemistry was measured at 90 min, 6, 24 and 48 h post-training. We found an increase in the septal dentate gyrus at 90 min, at 6 h the increase was also found in CA3 and CA1 regions and returned to basal levels at 24 h. In contrast, the intermediate region showed lower increase, limited to the dentate gyrus and CA3 at 24 h post-training. No changes were found in the temporal hippocampus. These findings suggest that septal and intermediate hippocampal zones participate in this spatial learning and contribute at different moments to process this information.     

Electroacupuncture restores learning and memory impairment induced by both diabetes mellitus and cerebral ischemia in rats

Previous investigations have demonstrated that electroacupunctural stimulation can ameliorate primary and secondary symptoms such as peripheral neuropathy and diabetic encephalopathy in diabetic rats. In this study, we investigated whether electroacupuncture could improve learning and memory which was typically impaired in diabetic rats with cerebral ischemia. Furthermore, we investigated the mechanisms underlying its effects using passive avoidance test, active avoidance test, Morris water maze and electrophysiology. Electroacupuncture increased the step-down latency in passive avoidance test and accurate rate in active avoidance test, decreased the escape latency in Morris water maze. After electroacupuncture treatment, the long-term potentiation (LTP) impaired by both diabetes and cerebral ischemia was restored significantly. These results suggest that electroacupuncture can ameliorate learning and memory capacity impaired by hyperglycemia and ischemia. LTP plays a very important role in this beneficial effect.     

Influence of intracerebral administration of NO agents in dorsal hippocampus (CA1) on cannabinoid state-dependent memory in the step-down passive avoidance test

In the present study, the effects of nitric oxide agents on WIN55, 212-2 induced state-dependent memory of passive avoidance task were examined in mice. One-trial step-down paradigm was used for the assessment of memory retention in adult male NMRI mice. Post-training intra-CA1 administration of CB1 and CB2 receptor agonists, WIN55, 212-2 (0.25, 0.5 and 1 µg/mouse), dose-dependently decreased memory retrieval. The memory impairment induced by post-training administration of WIN55, 212-2 (1 µg/mouse) was restored by pre-test administration of the same dose of the drug (1 μg/mouse, intra-CA1), showing the WIN55, 212-2 state-dependent memory. Single intra-CA1 administration of l-arginine (0.3, 1 and 3 µg/mouse) or L-NAME (0.3, 1 and 3 µg/mouse), 5 min pre-test could not alter memory retrieval. On the other hand, in the animals in which retrieval was impaired due to post-training administration of WIN55, 212-2 (1 µg/mouse), pre-test intra-CA1 administration of l-arginine (1 and 3 µg/mouse), but not L-NAME (0.3, 1 and 3 µg/mouse) 24 h after training restored memory retrieval. Also, in the animals which received both post-training (1 µg/mouse) and pre-test injections of WIN55, 212-2 (1 µg/mouse), the injection of L-NAME (3 µg/mouse, intra-CA1), 2 min before pre-test administration decreased retrieval. Furthermore, in the animals under the influence of post-training administration of WIN55, 212-2 (1 µg/mouse), pre-test co-administration of non-effective doses of WIN55, 212-2 (0.25 µg/mouse) and l-arginine (0.3 and 1 µg/mouse), increased the restoration of memory by pre-test WIN55, 212-2. These findings may demonstrate the involvement of NO in state-dependent memory induced by intra-CA1 administration of WIN55, 212-2.     

母鼠孕哺期铅暴露及补充铁、钙对子代神经系统的影响

目的观察孕哺期铅暴露及补充铁和钙对子代学习记忆能力及海马细胞中生长抑素（SS）表达的影响。方法母鼠从孕期第1天至仔鼠出生第30天哺乳期间给以下干预：对照组（A）：饮用去离子水;染铅组（B）：饮用浓度为0．1％醋酸铅去离子水;铁＋铅组（C）：饮用浓度为0．1％醋酸铅的去离子水同时每天灌胃3．0mg／kg铁;铁＋钙＋铅组（D）：饮用浓度为0．1％醋酸铅的去离子水同时每天灌胃3．0mg／kg铁和250mg／kg钙。Y-迷宫试验用于检测仔鼠的学习记忆能力,采用免疫组织化学的方法观察仔鼠海马细胞中生长抑素（SS）阳性神经元。结果B组与A组比较,仔鼠Y-迷宫试验的错误次数明显增多（P〈0．05）,海马CA1、CA3区SS阳性神经元数量减少（P〈0．05）。D组Y-迷宫试验的错误次数比B组明显减少（P〈0．05）,海马CAI区SS阳性神经元数量增多,有统计学意义（P〈0．05）。C组则未表现上述变化。结论孕哺期母体铅暴露会损害仔鼠的学习记忆能力,补充钙剂可有所改善,而补充铁则没有明显改变,并能从海马组织中SS表达的改变得到印证。