Spatial learning and motor deficits in aged rats

Young (3 months) and aged (24 months) rats were compared on a range of behavioural tests. The aged animal were impaired in their acquisition of a spatial learining task in the Morris water maze, as well as showing deficits in motor coordination, swimming efficiency, and spontaneous locomotion and exploration in an open field. Qualitative observation and correlation analyses indicated that the aged group was heterogeneous in the degree of impairments manifested by the individual animals, and suggested that the development of impairments may progress with aging at different rates in the various tasks and possibly in different underlying neuroanatomical systems.     

Spatial learning deficits in old rats: a model for memory decline in the aged

Spatial learning tasks are sensitive to functional decline in aged laboratory rodents. This is a review of recent work that has examined both the nature of age-related impairments on spatial tasks, and the relation of such deficits to underlying neurobiological mechanisms. The review supports the notion that hippocampal dysfunction underlies the mild/moderate cognitive decline that often accompanies normal aging. Thus the spatial learning deficit in aged rodents is a promising model for understanding the effect of age on brain systems that serve a memory function in humans.     

The role of complement in inflammation during experimental pneumococcal meningitis

The mechanism whereby an effective bactericidal inflammatory reaction develops in the subarachnoid space is not clearly defined. While normal cerebrospinal fluid is deficient in complement, immunoglobulin and leukocytes, these serum components appear in cerebrospinal fluid (CSF) during the course of bacterial meningitis. Using a rabbit model of pneumococcal meningitis we examined the role of the alternate complement pathway in three early events important to the defense of the subarachnoid space: leukocyte chemotaxis, phagocyte mediated bacterial killing, and clearance of bacterial components from the cerebrospinal fluid space. Rabbits treated with cobra venom factor to deplete complement were inoculated intracisternally with encapsulated (type II or XIX) pneumococci. Following complement depletion, there was a dramatic (at least 100-fold) decrease in the LD50 for these strains. Nevertheless, complement depletion did not affect the magnitude of CSF leucocytosis or the rate of clearance of bacterial particles from CSF. A short delay in the appearance of leukocytes in CSF was found in the absence of complement. The major effect of complement depletion, however, was to diminish the efficiency of leukocyte mediated killing of encapsulated bacteria in the CSF. Although the short delay in the onset of leukocytosis in the complement depleted animals is consistent with a chemotactic role of complement in the normal animal, the quantitatively normal leukocytosis in the complement depleted rabbits clearly indicates that important chemotaxins other than complement function in CSF. Inhibition of leukocytosis by indomethacin and diclofenac suggests that metabolite(s) of the arachidonic acid pathway may perform such a chemotactic role. A major role of complement in the defense of the subarachnoid space appears to be as an opsonin needed for the effective bactericidal activity of leukocytes. It is the lack of this function that best explains the greatly decreased LD50 value of encapsulated pneumococci in the complement depleted animal.     

Matrix metalloproteinases contribute to brain damage in experimental pneumococcal meningitis

The present study was performed to evaluate the role of matrix metalloproteinases (MMP) in the pathogenesis of the inflammatory reaction and the development of neuronal injury in a rat model of bacterial meningitis. mRNA encoding specific MMPs (MMP-3, MMP-7, MMP-8, and MMP-9) and the inflammatory cytokine tumor necrosis factor alpha (TNF-alpha) were significantly (P < 0.04) upregulated, compared to the beta-actin housekeeping gene, in cortical homogenates at 20 h after infection. In parallel, concentrations of MMP-9 and TNF-alpha in cerebrospinal fluid (CSF) were significantly increased in rats with bacterial meningitis compared to uninfected animals (P = 0.002) and showed a close correlation (r = 0.76; P < 0. 001). Treatment with a hydroxamic acid-type MMP inhibitor (GM6001; 65 mg/kg intraperitoneally every 12 h) beginning at the time of infection significantly lowered the MMP-9 (P < 0.02) and TNF-alpha (P < 0.02) levels in CSF. Histopathology at 25.5 +/- 5.7 h after infection showed neuronal injury (median [range], 3.5% [0 to 17.5%] of the cortex), which was significantly (P < 0.01) reduced to 0% (0 to 10.8%) by GM6001. This is the first report to demonstrate that MMPs contribute to the development of neuronal injury in bacterial meningitis and that inhibition of MMPs may be an effective approach to prevent brain damage as a consequence of the disease.     

Spatial learning deficits in rats after injection of vincristine into the dorsal hippocampus.

In the present study, performance in the Morris water escape task after bilateral lesioning of the dorsal hippocampus induced by the microtubule poison vincristine is discussed as a cognitive deficit model in rats. As we are especially interested in spontaneous or pharmacologically induced recovery processes after experimentally induced cognitive dysfunctions, the model should fulfil a number of criteria. Firstly, a clear dose-effect relationship between the dose of vincristine and the amount of spatial learning impairments should be present. Secondly, lesions must remain within the target area. Thirdly, there should be an observable behavioural recovery or compensation of the induced deficit. Two experiments evaluated the influence of the application volume (experiment 1) and the concentration of vincristine (experiment 2) on lesion location and size, and on spatial learning. The results of both experiments demonstrated that the effect of vincristine on the performance in the Morris water escape task seems to be characterized by an "all-or-none" relationship. Concentrations above a "threshold" value induced severe damage in the hippocampus and adjacent brain structures, whereas concentrations below the "threshold" value had marginal or no effects. The non-selective and highly toxic properties of vincristine make this neurotoxin an unsuitable tool for the establishment of a learning and memory deficit model.     

Spatial learning deficits in adult children of alcoholic parents

This study investigated whether the visuospatial deficits displayed by chronic alcoholics are present in persons at risk for alcoholism. Participants were 34 matched social drinkers, half of whom were children of alcoholic parents and half of whom had no family alcoholism history. Ss with a family history of alcoholism displayed visuospatial learning that was significantly poorer than that displayed by Ss with no family alcoholism history. The learning patterns displayed by those with a family alcoholism history were similar to those displayed by previously studied detoxified alcoholics and young children of alcoholics using a similar learning task. Data suggest that visuospatial learning deficits may reflect an antecedent to rather than a consequence of chronic alcohol abuse.     

卡托普利对小鼠学习记忆能力具有促进作用

目的:研究实验小鼠经卡托普利给药后,小鼠的学习记忆能力的变化及海马区多聚唾液酸神经细胞黏附因子(polysialylated neural cell adhesion molecule,PSA-NCAM)的表达情况。方法:BALB/c小鼠随机分为给药组和对照组,各6只。给药组小鼠腹腔注射卡托普利,每日30 mg/kg,连续7 d;对照组注射等量的无菌生理盐水。给药后对小鼠进行Morris水迷宫试验检测小鼠的学习记忆能力,后取脑切片进行PSA-NCAM免疫组织化学染色。结果:给药组小鼠逃避潜伏期较对照组缩短,而目标象限停留时间及经过平台次数较对照组增加(P0.05)。免疫组织化学法显示两组小鼠海马区PSA-NCAM表达没有明显差异。结论:对实验小鼠给药卡托普利可促进小鼠学习记忆能力,但该药对小鼠海马区PSA-NCAM表达没有明显作用。     

Lashley maze learning deficits in NZB mice.

In a prior study we found excellent Lashley III maze learning in BXSB mice and poor learning in NZB mice, despite the fact that both strains are autoimmune and develop cortical ectopias. This prompted us to examine NZB Lashley maze performance in detail, including comparisons to other strains and attempts to improve performance by giving additional trials with or without additional intramaze visual cues. In conventional Lashley testing (10 trials), RF mice (non-autoimmune and nonectopic) and BXSBs performed well in the Lashley maze. They had high learning indices and few errors. NZB mice performed poorly, with low learning indices and many errors. Even with additional trials or additional trials plus intramaze cues, NZB performance remained poor. The number of backward and forward errors stayed high; learning indices were low. Since both BXSB and NZB mice develop autoimmune disorders and cortical ectopias, it is unlikely that differential Lashley performance is the result of the presence of these phenomena. NZB mice are known to have alterations in their hippocampal morphology, and this is a possible mediator of the Lashley deficit.     

Glucosamine alleviates scopolamine induced spatial learning and memory deficits in rats

Introduction and objectiveBeneficial effects of glucosamine in spatial learning and memory impairment induced by scopolamine has been evaluated in rats by using Morris water maze.MethodsMale Wistar rats were randomly divided into control, scopolamine and scopolamine plus glucosamine groups. All injections were given in 5 consecutive days and 30 min after each injection, the rats were tested in the Morris water maze test. Escape latency and path length to reach the hidden platform were subjected to analysis of variance [ANOVA].ResultsThe rats treated with scopolamine showed increased escape latency and path length to reach the hidden platform compared to control group (P < 0.001). Both escape latency and traveled path length to reach the hidden platform in glucosamine treated animals (1 and 2 g/kg) were significantly lower (P < 0.05 to P < 0.001) than in the scopolamine group.ConclusionThe results of this study showed that the glucosamine can inhibit scopolamine-induced impairments of spatial learning and memory in rats. Glucosamine might offer a promise in either the prevention or the treatment of neurodegenerative diseases such as Alzheimer's disease.     

Morphological correlates of acute and permanent hearing loss during experimental pneumococcal meningitis

In patients with acute bacterial meningitis, hearing loss can be transient but is often permanent. The mechanisms underlying meningitis-associated hearing loss are not fully understood. Therefore, we investigated the morphological correlates of hearing loss in a rat model of pneumococcal meningitis. Transcutaneous intracisternal injection of Streptococcus pneumoniae resulted in a dose-dependent hearing loss (determined by auditory brainstem response audiometry), which was partially reversible during the acute stage. Nevertheless, a severe permanent hearing loss persisted until 2 weeks after infection. Suppurative labyrinthitis was accompanied by blood-labyrinth barrier disruption (determined by cochlear Evans blue extravasation), which correlated closely with hearing loss during the acute stage but not after recovery. Two weeks after infection, spiral ganglion neuronal density was markedly decreased and correlated with the severity of permanent hearing loss. Neuronal loss can be explained by the new finding of meningitis-associated spiral ganglion neuronal necrosis rather than apoptosis (determined by morphology, TUNEL staining, and immunohistochemistry).     

Grafted neuronal precursor cells differentiate and integrate in injured hippocampus in experimental pneumococcal meningitis

Bacterial meningitis (BM) frequently causes persisting neurofunctional sequelae. Autopsy studies in patients dying from BM show characteristic apoptotic brain injury to the stem cell niche in the subgranular zone of the hippocampal dentate gyrus (DG), and this form of brain damage is associated with learning and memory deficits in experimental BM. With an eye to potential regenerative therapies, the survival, migration, and differentiation of neuronal precursor cells (NPCs) were evaluated after engraftment into the injured hippocampus in vitro and in vivo in an infant rat model of pneumococcal meningitis. Green fluorescent protein (GFP)-expressing NPCs were grafted into the DG of organotypic hippocampal slice cultures injured by challenge with live Streptococcus pneumoniae. Seven days after engraftment, NPCs had migrated from the site of injection into the injured granular layer of the DG and electro-functionally integrated into the hippocampal network. In vivo, GFP-expressing NPCs migrated within 1 week from the injection site in the hilus region to the injured granular layer of the hippocampal DG and showed neuronal differentiation at 2 and 4 weeks after transplantation. Hippocampal injury induced by BM guides grafted NPCs to the area of brain damage and provides a microenvironment for neuronal differentiation and functional integration.     

Doxycycline reduces mortality and injury to the brain and cochlea in experimental pneumococcal meningitis

Bacterial meningitis is characterized by an inflammatory reaction to the invading pathogens that can ultimately lead to sensorineural hearing loss, permanent brain injury, or death. The matrix metalloproteinases (MMPs) and tumor necrosis factor alpha-converting enzyme (TACE) are key mediators that promote inflammation, blood-brain barrier disruption, and brain injury in bacterial meningitis. Doxycycline is a clinically used antibiotic with anti-inflammatory effects that lead to reduced cytokine release and the inhibition of MMPs. Here, doxycycline inhibited TACE with a 50% inhibitory dose of 74 microM in vitro and reduced the amount of tumor necrosis factor alpha released into the cerebrospinal fluid by 90% in vivo. In an infant rat model of pneumococcal meningitis, a single dose of doxycycline (30 mg/kg) given as adjuvant therapy in addition to ceftriaxone 18 h after infection significantly reduced the mortality, the blood-brain barrier disruption, and the extent of cortical brain injury. Adjuvant doxycycline (30 mg/kg given subcutaneously once daily for 4 days) also attenuated hearing loss, as assessed by auditory brainstem response audiometry, and neuronal death in the cochlear spiral ganglion at 3 weeks after infection. Thus, doxycycline, probably as a result of its anti-inflammatory properties, had broad beneficial effects in the brain and the cochlea and improved survival in this model of pneumococcal meningitis in infant rats.     

Early detection of age-related memory deficits in individual mice

To date, no consensus has been reached concerning the age of the earliest onset of age-related cognitive deficits in rodents. Our aim was to develop a behavioral model allowing early and individual detection of age-related cognitive impairments. We tested young (3 months), middle-aged (10 months) and aged (17 months) C57Bl/6 mice in the starmaze, a task allowing precise analysis of the search pattern of mice via standardized calculation of two navigation indices. We performed mouse-per-mouse analyses and compared each mouse's performance to a threshold based on young mice's performances. Using this method we identified impaired mice from the age of 10 months old. Their deficits were independent of any sensorimotor dysfunctions and were associated with an alteration of the maintenance of the hippocampal CA1 late-LTP. This study develops reliable methodology for early detection of age-related memory disorders and provides evidence that memory can decline in some individuals as early as from the age of 10 months.     

Working memory deficits in BXSB mice with neocortical ectopias

Approximately 40-60% of BXSB/MpJ-Yaa mice exhibit neocortical ectopias, which are misplaced clusters of neurons in layer I of cortex. These ectopias are usually located in the prefrontal and/or motor region of cortex in BXSB mice, and are similar in appearance to those found in postmortem analyses of the brains of dyslexic humans. Several within-strain learning differences between mice with ectopias and those without have been reported. In particular, ectopic BXSB mice exhibited superior reference memory learning, but inferior working memory learning in several studies from our laboratory. This study used the Morris water maze delayed matching-to sample task and the water radial-arm maze to asses working memory in female BXSB mice with and without ectopias. In the delayed matching-to sample task, a hidden escape platform remained in a constant position for each four-trial session, but changed position between sessions. Trial 2 was the measure of working memory, i.e., how well did the mouse remember where the platform was located for that session. In the water version of the eight-arm radial maze, hidden escape platforms were located in four of the eight arms, and each platform was removed from the maze once found. This enabled us to assess working and reference memory simultaneously. Ectopic mice demonstrated working memory deficits during the first part of the delayed matching-to sample task compared to nonectopics. Similarly, ectopics made more working memory errors during the latter half of radial-arm maze testing, while not differing from nonectopics in reference memory performance. Additionally, there were significant correlations between measures of working memory in the radial-arm maze and working memory in a delayed matching-to-sample task. These findings are in agreement with other studies demonstrating working memory deficits in ectopic BXSB mice.     

Development of learning and memory in mice after brief paradoxical sleep deprivation.

The effects of three hour paradoxical sleep deprivation (3 hr PSD) via the water tank procedure to produce retrograde amnesia of active avoidance and inhibitory avoidance learning was examined in mice. Results indicated no memory impairment in experimentally treated groups. An attempt was then made to induce amnesia by administering ECS immediately after 3 hr PSD thereby increasing the susceptibility of the memory trace to disruption. This procedure, however, also results in good retention. We conclude that the paradoxical sleep (PS) phase immediately after aversively motivated training is not essential for subsequent development of learning and memory. These results do not, however, detract from previously reported protracted PSD effects on memory storage processes.     

Therapeutic efficacy of meropenem for treatment of experimental penicillin-resistant pneumococcal meningitis

With the widespread emergence of antimicrobial resistance, combination regimens of ceftriaxone and vancomycin (C+V) or ceftriaxone and rifampin (C+R) are recommended for empirical treatment of pneumococcal meningitis. To evaluate the therapeutic efficacy of meropenem (M), we compared various treatment regimens in a rabbit model of meningitis caused by penicillin-resistant Streptococcus pneumoniae (PRSP). Therapeutic efficacy was also evaluated by the final bacterial concentration in the cerebrospinal fluid (CSF) at 24 hr. Each group consisted of six rabbits. C+V cleared the CSF at 10 hr, but regrowth was noted in 3 rabbits at 24 hr. Meropenem monotherapy resulted in sterilization at 10 hr, but regrowth was observed in all 6 rabbits at 24 hr. M+V also resulted in sterilization at 10 hr, but regrowth was observed in 2 rabbits at 24 hr. M+V was superior to the meropenem monotherapy at 24 hr (reduction of 4.8 vs. 1.8 log10 cfu/mL, respectively; p=0.003). The therapeutic efficacy of M+V was comparable to that of C+V (reduction of 4.8 vs. 4.0 log10 cfu/mL, respectively; p=0.054). The meropenem monotherapy may not be a suitable choice for PRSP meningitis, while combination of meropenem and vancomycin could be a possible alternative in the treatment of PRSP meningitis.     

Using knockout mice to study experimental meningitis

Despite the use of antibiotics, the prognosis of bacterial meningitis is still poor due to central nervous system (CNS) complications, such as brain edema formation, cerebrovascular alterations, and intracranial hemorrhage. Experimental studies with animal models have given new insights into its pathophysiology during the acute phase of the disease. In recent years, genetically engineered mice have become a powerful tool in investigating the role of particular genes by targeted deletion and have also been applied in bacterial meningitis research. By using knockout mice, new knowledge of the roles of the different cytokines, proteases, and oxidants involved in the inflammatory cascade has emerged. In the future, temporal and cell type-specific control of gene expression will provide even more information on the impact of a particular gene on meningitis-induced brain damage.     

Reduced spiral ganglion neuronal loss by adjunctive neurotrophin-3 in experimental pneumococcal meningitis

Background  

Hearing loss is a frequent long-term complication of pneumococcal meningitis (PM). Its main pathological correlate is damage to the organ of Corti and loss of spiral ganglion neurons. The only current treatment option is cochlear implants which require surviving neurons. Here, we investigated the impact of systemically applied neurotrophin-3 (NT-3) on long-term hearing loss and the survival of neurons.     

Tyrosine kinase inhibition reduces inflammation in the acute stage of experimental pneumococcal meningitis

Bacterial meningitis is an acute inflammatory disease of the central nervous system with a mortality rate of up to 30%. Excessive stimulation of the host immune system by bacterial surface components contributes to this devastating outcome. In vitro studies have shown that protein tyrosine kinase inhibitors are highly effective in preventing the release of proinflammatory cytokines induced by pneumococcal cell walls in microglia. In a well-established rat model, intracisternal injection of purified pneumococcal cell walls induced meningitis characterized by increases in the regional cerebral blood flow and intracranial pressure, an influx of leukocytes, and high concentrations of tumor necrosis factor alpha (TNF-alpha) in the cerebrospinal fluid. Compared with the values at the beginning of the experiment, intraperitoneal injection of tyrphostin AG 126 reduced the increases in regional cerebral blood flow (at 6 h, 127% +/- 14% versus 222% +/- 51% of the baseline value; P < 0.05) and intracranial pressure (at 6 h, 0.8 +/- 2.4 versus 5.4 +/- 2.0 mm of Hg; P < 0.05), the influx of leukocytes (at 6 h, 1,336 +/- 737 versus 4,350 +/- 2,182 leukocytes/microl; P < 0.05), and the TNF-alpha concentration (at 6 h, 261 +/- 188 versus 873 +/- 135 pg/microl; P < 0.05). These results demonstrate that inhibition of AG 126-sensitive tyrosine kinase pathways may provide new approaches for preventing excessive inflammation and reducing the increases in blood flow and intracranial pressure in the acute phase of bacterial meningitis.     

Morphology of pneumococcal meningitis in adults

Morphologically, acute pneumococcal meningitis runs like meningoencephalitis. A major part of pneumococcal meningitides belongs to primary ones. Liquor bacterioscopy using Gram's smear staining is an early method for their diagnosis.