血管性痴呆大鼠学习记忆障碍及脑组织生长抑素的变化

目的探讨生长抑素（SS）参与血管性痴呆（VD）大鼠学习记忆障碍的作用机制。方法采用双侧颈总动脉结扎法制备慢性前脑缺血动物模型，随机分为假手术组（S）、模型组（M）。造模2月后进行水迷宫试验，观察2组大鼠空间学习记忆能力的差异，应用免疫组化方法检测造模2月后VD大鼠海马及颞叶皮层生长抑素表达变化。结果与假手术组比较，大鼠水迷宫学习记忆能力在造模2月后差异有显著性意义（P〈0．05），大鼠海马及颞叶皮层SS表达在造模2月后降低（P〈0．05）。结论脑组织SS表达降低，导致血管性痴呆大鼠学习记忆障碍。     

一氧化氮合酶抑制剂对大鼠学习记忆能力的影响及尼莫地平的作用研究

目的：研究一氧化氮合酶抑制剂对大鼠学习记忆障碍的影响，和其海马一氧化氮(NO)变化及尼莫地平的作用。方法：大鼠双侧海马注入N-ω-硝基—L精氨酸(LNA)建立学习记忆障碍模型，注完L-NA后再给大鼠腹腔内注射尼莫地平，用Y型电迷宫进行学习记忆能力测试。取大鼠海马部位组织检测N0含量。结果：模型组大鼠的学习记忆能力明显低于对照组大鼠，干预组大鼠的学习记忆能力与模型组无差异；模型组大鼠的海马N0含量明显低于对照组，干预组大鼠海马N0含量与模型组无显著差异。结论：双侧海马注入L-NA可使大鼠出现学习记忆障碍，海马N0浓度降低。尼莫地平对L-NA所致的学习记忆障碍无治疗作用。     

L—NA对大鼠学习记忆的影响及NO、SS相关性研究

目的 探讨一氧化氮（NO）和生长抑素（SS）在学习记忆过程中的作用及相互作用。方法 大鼠海马微量注射一氧化氮合酶（NOS）抑制剂N-ω硝基－L精氨酸（N-ω－Nitro-L-Arginine,L-NA) 后采用Y型电迷宫观察大鼠学习记忆能力的改变,以硝酸还原酶法测定海马NO含量,以放射免疫法测定海马SS含量,并进行学习记忆能力、NO含量和SS含量相关性分析。结果 海马微量注射L－NA组大鼠与生理盐水对照组和正常对照组比较,海马中NO、SS含量明显下降（P＜0．01）。Y型电迷宫测定次数明显增加（P＜0．01）,L－NA组大鼠海马NO水平和SS水平呈显著正相关,NO、SS水平均与Y型电迷宫测试次数呈显著负相关。结论 海马中NO、SS水平的正常是机体实现正常学习和记忆过程的重要因素;NO可能通过调节SS的合成和释放,共同促进学习和记忆过程。     

实验性癫痫大鼠脑组织中ATP酶含量变化的研究

本文采用戊四氮（ＰＴＺ）诱发大鼠癫痫模型，用化学比色法测定了癫痫大鼠额叶皮层及海马中Ｎａ＋－Ｋ＋－、Ｃａ２＋－、Ｍｇ２＋－ＡＴＰａｓｅ含量的变化。结果发现：癫痫大鼠脑组织中额叶皮层及海马的诸ＡＴＰａｓｅ含量显著降低。提示额叶皮层及海马中ＡＴＰａｓｅ下降与癫痫发作有关     

Alzheimer病大鼠局部脑血流量与行为学改变的研究

目的 研究Ａｌｚｈｅｉｍｅｒ病大鼠的局部脑血流量及学习记忆的改变及尼莫地平对其影响。方法β－淀粉样蛋白注入大鼠迈特基底核建立大鼠ＡＤ模型，氢清除法动态观察海马，额叶局部脑血流量，三等分Ｙ迷宫测定大鼠学习记忆能力。治疗组大鼠腹腔注射尼莫地平至实验结束。结果 实验组大鼠额叶和海马的ｒＣＢＦ的下降，学习记忆能力下降；治疗组ｒＣＢＦ均有改善，至第２周接近注射前；但与对照组比较仍有差异。β－ＡＰ注入ＮＢＭ能     

用Morris全自动水迷宫评价Sprage Dawley鼠全脑反复缺血后学习记忆功能研究

目的　评价大鼠脑缺血后的学习、记忆功能及其与海马组织学变化的关系。方法　用Morris全自动新式水迷宫试验方法对反复脑缺血再灌注大鼠进行学习获得试验、记忆保持试验 ,光镜观察海马组织学变化 ,并计算海马神经元密度。结果　与对照组比较 ,反复脑缺血大鼠学习记忆成绩显著下降 ,潜伏期显著延长 ,游水迷宫形呈周边型 ;缺血后海马CA1、CA4 和PM区神经元大量丧失。结论　大鼠反复脑缺血出现严重的学习、记忆障碍。认知功能改变与海马神经元缺血性损害有关。用Morris全自动水迷宫评价缺血所致学习、记忆障碍简便、准确、真实。     

慢性前脑缺血大鼠学习、记忆功能的研究

目的 研究慢性持续性脑血流量下降对大鼠学习、记忆功能的影响。方法 采用双侧颈总动脉永久结扎方法制备慢性前脑缺血动物模型；利用激光多普勒血流仪检测各组大鼠术后不同时间点（术后24h、7d、15d、30d、60d、90d、120d）额叶皮质、海马枢局部及血流量(rCBF）；采用被动回避性条件反射－－跳台试验检验各组大鼠（时间点同前）学习能力；利用水迷宫方法检验各组大鼠记忆功能。结果 大鼠术后额叶皮质、海马区的cCBF明显下降，以术后24h最明显，主后120d时仍明显 于正常，呈慢性持续性下降的趋势。同时各实验组大鼠学习、记忆能力也明显下降，且有随时间推移而逐渐加重的倾向。结论 慢性持续性脑血流量下降可导致实验大鼠出现进行性认知功能障碍。     

灵芝多糖对模拟AD学习记忆障碍大鼠海马白细胞介素-6表达的影响

目的 研究灵芝多糖对模拟AD学习记忆障碍大鼠脑组织白细胞介素-6表达（IL-6）的影响。方法 采用双侧海马内一次性注射β-淀粉样多肽25～35片段（Aβ25～35）制作模拟AD学习记忆障碍大鼠模型，造模24h后治疗组腹腔注射灵芝多糖注射液，其余各组分别注射等量的生理盐水，1次/d，疗程7d，并于第8d开始进行Morris水迷宫实验观察其学习记忆能力，行为学检测后再通过免疫组化SABC法检测各组大鼠海马IL-6表达水平。结果 模型组大鼠较对照组学习记忆能力降低，海马IL-6表达明显增强；治疗组大鼠较模型组学习记忆能力显著提高，海马IL-6表达显著下调。结论 灵芝多糖可提高Aβ25-35诱导的模拟AD学习记忆障碍大鼠的学习记忆能力，抑制海马IL-6表达。     

实验性癫痫大鼠脑组织中生长抑素含量变化的研究

本文采用戊四氮（ｐｅｎｔｙｌｅｎｅｔｅｒａｚｏｌ，ＰＴＺ）诱发大鼠癫痫模型，用放射免疫方法测定了癫痫大鼠乳头体、额叶皮层及海马中生长抑素（ｓｏｍａｔｏｓｔａｔｉｎ，ＳＳ）含量的变化。结果发现，癫痫大鼠脑组织中乳头体及额叶皮层的ＳＳ含量显著升高，海马无明显。提示乳头体及额叶皮层中ＳＳＧ民癫痫发作有关，可能参与也癫痫的散过程。     

促红细胞生成素对血管性痴呆大鼠行为学及脑组织形态学的影响

目的永久性结扎双侧颈总动脉（2-VO）建立血管性痴呆（VaD）动物模型,观察EPO治疗对VaD大鼠行为学及脑组织形态学的影响。方法选用14～15月龄Wistar大鼠,应用水迷宫进行空间定向学习训练,将达到学会标准者随机分为3组：假手术（Sham）组、VaD组、VaD＋EPO腹部皮下注射治疗（EPO）组。2-VO制作VaD模型,应用水迷宫检测空间定向学习能力;行HE染色,透射电镜观察海马组织病理学变化。结果与Sham组比较,VaD组、EPO组2-VO后8周学习记忆能力均明显下降;VaD组2-VO术后8周海马CA1区锥体神经元细胞稀疏、肿胀,与VaD组相比,EPO组脑组织损伤程度明显减轻,学习记忆能力增强。结论2-VO可引起大鼠学习记忆能力下降,EPO治疗的VaD大鼠学习记忆能力明显增强;海马CA1区神经元的缺血损伤减轻可能是EPO改善VaD大鼠认知功能障碍的组织病理学基础。     

Postnatal phencyclidine-induced deficit in adult water maze performance is associated with N-methyl- -aspartate receptor upregulation

The N-methyl-D-aspartate (NMDA) receptor plays an important role in developmental plasticity. Earlier, we have shown that blocking the NMDA receptor with the non-competitive antagonist phencyclidine (PCP), during a brief postnatal period, disrupts the water maze performance in young juvenile rats (starting at 25 days of age). We now show the long-term effects of postnatal phencyclidine exposure on spatial learning and memory. Male and female rats were exposed to PCP (1 and 5mg/kg) or saline, from postnatal days 5-15, and their performance in the Morris water maze (MWM) was tested both as adolescents (starting on postnatal day (PD) 35) and as adults (starting on postnatal day 60). Separate groups of adult male and female postnatal PCP-treated and saline-treated rats were sacrificed and saturation [3H]MK-801 binding experiments were carried out in their hippocampi and frontal cortices; hippocampus and frontal cortex have high densities of NMDA receptors and both regions are important in spatial learning and memory. Postnatal PCP administration disrupted the water maze performance both in adolescent and adult rats of both sexes. Adult male and female rats treated postnatally with PCP had increased maximal [3H]MK-801 binding in the hippocampus and frontal cortex compared to same-sex saline-treated controls. Taken together, repeated postnatal PCP (RPP) administration impaired the acquisition of spatial learning in adolescent and adult male and female rats, and this cognitive deficit was associated with increased [3H]MK-801 labeled NMDA receptor in the hippocampus and frontal cortex. These findings are consistent with the hypothesis that PCP treatment during the postnatal period produces deficits in the water maze performance by disrupting the developing glutamatergic system.     

Effects of chronic intraventricular infusion of heparin glycosaminoglycan on learning and brain acetylcholine parameters in aged rats

We reported previously that the glycosaminoglycan heparin (HP) has the facility to improve learning in adult rodents when administered into the nucleus basalis of the ventral pallidum. Here we gauged the effects of chronic intraventricular infusion of HP (20 ng per day over 28 days) in 26-month-old rats in terms of Morris water maze performance, habituation to a novel open field, retention of a step-through inhibitory avoidance task and changes in forebrain acetylcholine (ACh) levels. Control groups included vehicle-infused old and adult (3-month-old) rats. The chronic infusion of HP did not significantly influence the performance of the old animals in any of the learning and memory tasks employed. HP only slightly facilitated the retention of the inhibitory avoidance task and the rate of habituation in the open-field paradigm. In the water maze, the glycosaminoglycan did not counteract the navigation deficits observed for aged controls and even impaired performance during the initial place-learning trials. After behavioural testing, tissue levels of ACh were determined in frontal cortex, ventral striatum, neostriatum and hippocampus without detecting any obvious neurochemical differences between groups. The current results, together with our previous work, indicate that HP differentially affects learning and memory parameters in adult and aged rats. Thus, whereas the glycosaminoglycan proved effective in facilitating mnemonic functions in normal adult animals, no such a clear-cut beneficial effect was observed in behaviourally impaired old rats.     

The effect of chronic restraint stress on spatial learning and memory: relation to oxidant stress

The aim of this study was to investigate the effect of chronic restraint stress (RS) on spatial learning and memory. Fifty healthy male Wistar rats, aged three months were used. They were equally divided into five groups--C: Control, W: Water Maze, CS-1: Restrained for 21 days (1 h/day) + water maze protocol following stress period, CS-2: Restrained for 28 days (1 h/day) + water maze protocol during last 7 days of stress period, CS-3: Restrained for 21 days and allowed to recovery for 7 days (1 h/day). Corticosterone levels were higher in all stress groups than in C and W groups. Nitrite levels of frontal cortex and hippocampus were found to be elevated in chronic stress groups with respect to C and W groups. Thiobarbituric acid reactive substances (TBARS) of both tissues were increased significantly in CS1 and CS2 groups compared with C, W, and CS3 groups. Escape latencies of CS1 and CS2 groups were longer than those of the W group on each day of acquisition. In transfer test, CS1 and CS2 groups stayed significantly shorter in target quadrant according to the W group. Significant correlations between corticosterone and either nitrite or TBARS of hippocampus and frontal cortex were found. Both acquisition and memory performances were negatively correlated with plasma corticosterone level, nitrite, and TBARS levels of hippocampus and frontal cortex. The results of this study suggest that stress-induced lipid peroxidation may affect the acquisition and memory performances.     

Enhancement of spatial learning in F344 rats by physical activity and related learning-associated alterations in hippocampal and cortical cholinergic functioning.

The effects of physical activity on spatial memory performance and associated cholinergic function were examined in F344 rats. Cholinergic analysis included resting and depolarization-induced activation of high-affinity choline uptake and muscarinic receptor binding in the hippocampus, parietal cortex and frontal cortex. Rats that were physically trained, using chronic treadmill running, demonstrated significantly enhanced performance on the spatial learning task, both in second trial latency and first and second trial proximity ratio scores (P less than 0.002). Concomitant with enhanced behavioral performance were neurochemical changes of a reduction in hippocampal high-affinity choline uptake, an upregulation of muscarinic receptor density, and an increase in high-affinity choline uptake 24 h after spatial memory testing (P less than 0.05). Spatial memory tested rats demonstrated enhanced depolarization-induced activation of high-affinity choline uptake (P less than 0.001). Rats that were yoked for swim time to spatial memory tested rats did not show any spatial learning-induced alterations in high affinity choline uptake. These spatial learning- and physical activity-induced cholinergic alterations were observed only in the hippocampus, not in the parietal or frontal cortex. These data indicate that the chronic running-induced alterations in hippocampal high-affinity choline uptake and upregulation of muscarinic receptor density, in combination with enhancement of high-affinity choline uptake related to spatial learning, may contribute to the enhanced spatial learning performance of chronic-run rats.     

Water maze learning and hippocampal synaptic plasticity in streptozotocin-diabetic rats: effects of insulin treatment

Streptozotocin-diabetic rats express deficits in water maze learning and hippocampal synaptic plasticity. The present study examined whether these deficits could be prevented and/or reversed with insulin treatment. In addition, the water maze learning deficit in diabetic rats was further characterized. Insulin treatment was commenced at the onset of diabetes in a prevention experiment, and 10 weeks after diabetes induction in a reversal experiment. After 10 weeks of treatment, insulin-treated diabetic rats, untreated diabetic rats and non-diabetic controls were tested in a spatial version of the Morris water maze. Next, hippocampal long-term potentiation (LTP) was measured in vitro. To further characterize the effects of diabetes on water maze learning, a separate group of rats was pre-trained in a non-spatial version of the maze, prior to exposure to the spatial version. Both water maze learning and hippocampal LTP were impaired in diabetic rats. Insulin treatment commenced at the onset of diabetes prevented these impairments. In the reversal experiment, insulin treatment failed to reverse established deficits in maze learning and restored LTP only partially. Non-spatial pre-training abolished the performance deficit of diabetic rats in the spatial version of the maze. It is concluded that insulin treatment may prevent but not reverse deficits in water maze learning and LTP in streptozotocin-diabetic rats. The pre-training experiment suggests that the performance deficit of diabetic rats in the spatial version of the water maze is related to difficulties in learning the procedures of the maze rather than to impairments of spatial learning.     

Behavior alters the uptake of [3h]choline into acetylcholinergic neurons of the nucleus basalis magnocellularis and medial septal area

Behavioral experience changed sodium-dependent high affinity choline uptake (SDHACU) in the hippocampus and frontal cortex. Rats were trained on various behavioral tasks and sacrificed after testing. SDHACU was determined in frontal cortex and hippocampus, areas that receive cholinergic innervation from the nucleus basalis magnocellularis (NBM) and the medial septal area (MSA), respectively. Untrained rats taken directly from their home cages had fairly consistent levels of SDHACU in the hippocampus (1.76 ± 0.45, X ± S.E.) and frontal cortex (1.46 ± 0.37). In the hippocampus of rats performing in a radial maze and T-maze and in rats that surpassed a criterion level in an active avoidance task, SDHACU increased significantly above Cage (untrained) group levels. In the cortex of rats performing the radial maze task, SDHACU decreased slightly. There were no other changes in frontal cortical SDHACU. After behavioral testing ceased, SDHACU in rats performing the radial maze task remained elevated above Control and Treadmill group levels for 20 days, but returned to near control levels 40 days later. Our data demonstrate that a functional differentiation exists between the MSA and NBM cholinergic systems, and that the measurement of SDHACU in central cholinergic neurons is a useful tool to identify the influences of behavior and environment upon changes in neurochemical events and neuronal activity.     

Long-term effects of cysteamine on cognitive and locomotor behavior in rats: relationship to hippocampal glial pathology and somatostatin levels

Peroxidase-positive astrocytic inclusions, derived from effete, iron-laden mitochondria, accumulate in the rat hippocampus, striatum and other subcortical brain regions as a function of advancing age. The sulfhydryl agent, cysteamine (CSH), accelerates the appearance of this senescent glial phenotype both in primary astrocyte cultures and in the aging subcortical brain in situ. Earlier experiments have shown that short-term administration of CSH results in reversible depletion of brain somatostatin (SS) levels, cognitive deficits and decreases in locomotor activity. In the present study, we tested spatial learning/memory and motor functioning in rats at 4–5 weeks following cessation of chronic (6 week) CSH treatment to determine whether behavioral deficits may be associated with gliopathic changes within the dorsal hippocampus distinct from the behavioral abnormalities accruing to the immediate effects of the drug. CSH-treated rats displayed significantly impaired performance in the Morris water maze 4–5 weeks following termination of prolonged CSH treatment. In contrast, locomotor activity was not affected in this experimental paradigm. CSH-treated animals exhibited significantly higher numbers of peroxidase-positive astrocyte granules as well as total numbers of GFAP-positive astrocytes in the CA1 sector of the dorsal hippocampus relative to saline-treated controls. In the hilus of the dentate gyrus, numbers of both peroxidase-positive glial inclusions and astrocytes were unaffected by CSH exposure. At 5 weeks following cessation of CSH treatment, SS levels in the hippocampus and hypothalamus (but not cerebral cortex) were elevated relative to those of saline-treated controls. Our results indicate that chronic CSH exposure induces senescence-like changes in CA1 astrocytes which are associated with deficits in cognitive, but not locomotor, behavior and elevated levels of hippocampal and hypothalamic SS. Pathological glial-neuronal interactions within the hippocampus and other subcortical brain regions may play an important role in the cognitive decline observed during normal senescence and in aging-related neurodegenerative disorders.     

Controlled contusion injury alters molecular systems associated with cognitive performance

We investigated whether a learning impairment after a controlled cortical impact (CCI) injury was associated with alterations in molecules involved in synaptic plasticity and learning and memory. Adult male rats with moderate CCI to the left parietal cortex, tested in a Morris water maze (MWM) beginning at postinjury day 10, showed impaired cognitive performance compared with sham-treated rats. Tissue was extracted for mRNA analysis on postinjury day 21. The expression of brain-derived neurotrophic factor (BDNF), synapsin I, cyclic-AMP response element binding protein (CREB), and calcium-calmodulin-dependent protein kinase II (alpha-CAMKII) were all significantly decreased compared with sham injury levels within the ipsilateral hippocampus after CCI. No significant molecular level changes were found in the contralateral hippocampus. Decreased expression of BDNF and synapsin I was also found within the ipsilateral parietal cortex of CCI-injured rats compared with shams. However, BDNF and synapsin I expressions were significantly increased in the contralateral parietal cortex of the CCI rats. CREB expression was significantly decreased within the contralateral cortex of the CCI group. These findings show enduring reductions in the expression of BDNF, synapsin I, CREB, and alpha-CAMKII ipsilateral to a CCI injury, which seem associated with the spatial learning deficits observed in this injury model. In addition, the delayed increase in the expression of BDNF and synapsin I within the cortex contralateral to CCI may reflect restorative processes in areas homotypical to the injury.     

Agmatine, an endogenous ligand of imidazoline receptor protects against memory impairment and biochemical alterations in streptozotocin-induced diabetic rats

Agmatine, a polycationic amine synthesized via decarboxylation of l-arginine by arginine decarboxylase is reported to exhibit anti-hyperglycemic, antioxidant and memory enhancing effects. Therefore, we tested its influence against cognitive dysfunction in streptozotocin-induced diabetic rats using Morris water maze and object recognition paradigm. Lipid peroxidation and glutathione levels as parameters of oxidative stress and choline esterase (ChE) activity as a marker of cholinergic function were assessed in the cerebral cortex and hippocampus. Thirty days after diabetes induction rats showed a severe deficit in learning and memory associated with increased lipid peroxidation, decreased reduced glutathione, and elevated ChE activity. In contrast, chronic treatment with agmatine (5-10mg/kg, i.p. for 30 days) improved cognitive performance, lowered hyperglycemia, oxidative stress, and ChE activity in diabetic rats. Further, memory improving effects of agmatine were independent of adrenal I(2) imidazoline receptors. In a separate set, agmatine treatment for an initial 15 days after diabetes confirmation also significantly reduced memory impairment during training trials after 30 days of diabetes confirmation. Moreover, treatment during training trials (30 days after diabetes) also significantly reduced memory impairment in diabetic rats. In conclusion, the present study demonstrates that treatment with agmatine prevents changes in oxidative stress and ChE activity, and probably consequent memory impairment in diabetic rats.     

Effect of selective cholinergic denervation on the serotonergic system: implications for learning and memory

The cholinergic system has been widely implicated in cognitive processes and cholinergic loss is a classical hallmark in Alzheimer disease. Increasing evidence supports a role of the serotonergic system in cognition, possibly through a modulation of cholinergic activity. We compared selective cholinergic denervation by administration of the immunotoxin 192 IgG-saporin in the nucleus basalis of Meynert (NBM) with intracerebroventricular (ICV) lesions of the basal forebrain in male rats 7 days after lesioning. NBM lesions induced significant changes in cholinergic markers in the frontal cortex, whereas ICV lesions produced significant decreases in cholinergic markers both in the frontal cortex and hippocampus. Only ICV lesions lead to memory impairments in passive avoidance and Morris water maze tasks. Both models lead to reductions of serotonin levels in the frontal cortex. Similar changes in 5-hydroxytriptophan levels were observed, suggesting a downregulation of the rate-limiting enzyme for the synthesis of serotonin along with the cholinergic deficit. Neither 5-HT1A nor 5-HT1B receptors seem to mediate this process. These data imply that the serotonergic system in the frontal cortex can compensate for diminished cholinergic function and support the investigation of the serotonergic system as a therapeutic target to treat Alzheimer disease.