Spatial performance in a complex maze is associated with persistent long-term potentiation enhancement in mouse hippocampal slices at early training stages

Long-term potentiation (LTP) and long-term depression (LTD) are principal reflections of synaptic plasticity that have been implicated in learning and memory. We have previously shown that spatial learning in a newly validated complex maze is accompanied by depression of hippocampal CA1 synaptic activity in hippocampal slices of trained mice ("behavioral LTD"). In the present study, we investigated whether behavioral LTD is accompanied by alterations of subsequent LTP induced by high-frequency stimulation (HFS). Moreover, we were interested in the time course of such alterations in relation to training stage. Animals underwent 1, 2, and 8 days of spatial training in the complex maze, respectively. Hippocampal slices were taken 24 h after the last training session. We found a simultaneous decrease of basal synaptic response and increase of HFS induced LTP magnitude compared with slices of untrained animals. Synaptic plasticity was not influenced by repeated running wheel exercise in an additional control group without spatial learning. The mentioned alterations occurred already after day 2 of maze exploration parallel to the most pronounced improvement of behavioral performance but did not change thereafter until day 8 despite further learning progress. They were also found when animals were trained for 2 days and kept at rest for a subsequent 6 days. In conclusion, spatial learning may be reflected by distinct and persistent measurable alterations of synaptic plasticity in hippocampal CA1 neurons at early training stages.     

Effects of intrahippocampal l-NAME treatment on the behavioral long-term potentiation in dentate gyrus

Using a combination of electrophysiological recordings, behavioral tests and local pharmacological administration in hippocampus, we investigated in the present study the effects of nitric oxide (NO) synthase inhibitor N-nitro-l-arginine methyl ester (l-NAME) on the behavioral long-term potentiation (LTP) and maze learning performance in freely moving rats. The results showed as follows: (1) intrahippocampal l-NAME administration led to a defect in maze learning performance of the animals; (2) l-NAME treatment also substantially impaired the induction of the behavioral LTP in perforant pathway to dentate gyrus (PP-DG) pathway induced by maze learning task, while it had no significant effects on basic synaptic transmission in PP-DG pathway; Collectively, these results indicate that NO synthesis may be critical for the behavioral LTP in PP-DG pathway and maze learning performance.     

Sleep restriction suppresses neurogenesis induced by hippocampus-dependent learning

Sleep deprivation impairs hippocampal-dependent learning, which, in turn, is associated with increased survival of newborn cells in the hippocampus. We tested whether the deleterious effects of sleep restriction on hippocampus-dependent memory were associated with reduced cell survival in the hippocampus. We show that sleep restriction impaired hippocampus-dependent learning and abolished learning-induced neurogenesis. Animals were trained in a water maze on either a spatial learning (hippocampus-dependent) task or a nonspatial (hippocampus-independent) task for 4 days. Sleep-restricted animals were kept awake for one-half of their rest phase on each of the training days. Consistent with previous reports, animals trained on the hippocampus-dependent task expressed increased survival of newborn cells in comparison with animals trained on the hippocampus-independent task. This increase was abolished by sleep restriction that caused overall reduced cell survival in all animals. Sleep restriction also selectively impaired spatial learning while performance in the nonspatial task was, surprisingly, improved. Further analysis showed that in both training groups fully rested animals applied a spatial strategy irrespective of task requirements; this strategy interfered with performance in the nonspatial task. Conversely, in sleep-restricted animals, this preferred spatial strategy was eliminated, favoring the use of nonspatial information, and hence improving performance in the nonspatial task. These findings suggest that sleep loss altered behavioral strategies to those that do not depend on the hippocampus, concomitantly reversing the neurogenic effects of hippocampus-dependent learning.     

Effects of morphine dependence on the performance of rats in reference and working versions of the water maze

Numerous studies have dealt with the role of opiate system in tasks aimed at measurement of cognitive behavior, but the role of morphine dependence on learning and memory is still controversial. In this study chronic exposure to morphine was employed to evaluate learning ability and spatial short-term memory (working memory) and long-term memory (reference memory) in the water maze task. Male albino rats were made dependent by chronic administration of morphine in drinking water that lasted at least 21 days. In Experiment 1, the performance of animals was evaluated in reference memory version of the water maze. Rats were submitted to a session of 6 trials for 6 consecutive days to find the submerged platform that was located in the center of a quadrant. Latency and traveled distance to find the platform were measured as indexes of learning. Memory retention was tested 24 h after the last training session in a probe trial (60 s) in which there was no platform and the time spent in each quadrant of the water maze was recorded. Results indicated that latency and traveled distance to find the platform were same in control and dependent rats during training days, but during the probe test morphine-dependent group spent significantly less time in the target quadrant. In Experiment 2, training on working memory version of the water maze task was started. Only two trials per day were given until the performance of animals was stabilized (at least 5 days). Final test was done at day 6. Acquisition-retention interval was 75 min. No significant differences were found on acquisition and retention trials between morphine and control groups. Our findings indicate that chronic exposure to morphine did not impair learning ability, but partially impaired retention of spatial long-term (reference) memory. Moreover, dependence on morphine did not affect either acquisition or retention of spatial short (working) memory.     

铅暴露对大鼠学习和记忆的影响

目的:研究低水平铅暴露对大鼠学习和记忆的影响。方法:0.05%水平醋酸铅污染大鼠饮用水28天,用Morris水迷宫试验测定大鼠的学习记忆功能。结果:在定位导航任务两组之间没有差异(P>0.05);在探索试验和工作记忆任务中,铅暴露组和正常对照组大鼠成绩显著差异(P<0.01)。结论:铅暴露对大鼠空间参考记忆和工作记忆有明显损害作用,对空间学习未见明显影响。     

Neonatal hyperthyroidism disrupts hippocampal LTP and spatial learning

Summary Excess thyroid hormone at an early stage of development produces marked neurochemical and morphological alterations in the rat hippocampal formation. In order to better understand the functional significance of these changes, we tested adult rats treated neonatally with triiodothyronine (T3), and their control litter mates, in a spatial learning task and for the induction of longterm potentiation (LTP) in the dentate gyrus (DG) of the hippocampal formation. The T3-treated rats were significantly impaired in their performance on the spatial task in comparison to their matched controls. Similarly, the efficacy of LTP induction was significantly attenuated in the T3-treated animals. Further, a significant correlation was obtained between LTP induction and performance on the spatial learning task. Thus, a brief neonatal excess of thyroid hormone produces impairments in spatial learning along with decreases in LTP, long held as a model of learning and memory. This relationship provides a unique opportunity to study associations between behavioral, physiological, pharmacological and morphological processes intimately associated with the hippocampal formation     

新生期大鼠接种卡介苗对空间学习能力和海马突触可塑性的影响

目的检测免疫接种卡介苗（BCG）后大鼠行为学,电生理,海马神经元树突棘的变化。为进一步研究疫苗接种对突触传递和学习记忆的影响提供依据。方法实验分为卡介组和对照组。新生Sprague-Dawley（SD）大鼠于出生24h内背部皮下接种卡介苗,对照组皮下注射等量的PBS。4周时水迷宫检测其行为学的变化,在体LTP测其电生理的变化,并使用基因枪散射DiI染料法检测海马神经元树突棘的变化。结果与其对照组相比,卡介组空间学习记忆能力明显增强：LTP结果显著优于对照组;海马神经元树突棘的密度以及蘑菇样（mushroom）增多。结论新生期成功接种疫苗可以提高大鼠突触传递的可塑性并促进其学习记忆能力。     

The stress experience dependent long-term depression disassociated with stress effect on spatial memory task

Behavioral stress can either block or facilitate memory and affect the induction of long-term potentiation (LTP) and long-term depression (LTD). However, the relevance of the stress experience-dependent long-term depression (SLTD) to spatial memory task is unknown. Here we have investigated the effects of acute and sub-acute elevated platform (EP) and foot shock (FS) stress on LTD induction in CA1 region of the hippocampus of anesthetized rats and spatial memory in Morris water maze. We found that LTD was facilitated by acute EP stress, but not by sub-acute EP stress that may be due to the fast adaptation of the animals to this naturalistic mild stress. However, FS stress, an inadaptable strong stress, facilitated LTD induction both in acute and sub-acute treatment. In addition, with the same stress protocols, acute EP stress impaired spatial memory but the sub-acute EP stressed animals performed the spatial memory task as well as the controls, may due to the same reason of adaptation. However, acute FS stress slightly impaired learning but sub-acute FS even enhanced memory retrieval. Our results showed that SLTD was disassociated with the effect of stress on memory task but might be related to stress experience-dependent form of aberrant memory.     

Post-weaning mice fed exclusively milk have deficits in induction of long-term depression in the CA1 hippocampal region and spatial learning and memory

Previously, we have found that post-weaning mice fed exclusively milk display low-frequency exploratory behavior compared to mice fed a food pellet diet (Ishii et al., 2005a). Because cognitive functions play a key role in animal exploration, in the present study we examined the effect of an exclusively milk formula diet on spatial learning and memory in a water maze and also on induction of long-term potentiation (LTP) and long-term depression (LTD) at the Schaffer collateral-CA1 synapse in the hippocampus. Exclusively milk-fed mice exhibited slower learning and memory deficits in hidden water maze tests as compared with pellet-fed mice. Moreover, milk-fed mice showed a significant inhibition of LTD but a normal induction of LTP. Despite these functional deficits, adult neurogenesis in the dentate gyrus of the hippocampus, which has been proposed to have a causal relationship to spatial memory, was stimulated in milk-fed mice. These result suggest that an exclusively milk formula diet after weaning leads to a stimulation of hippocampal neurogenesis but causes deficits in the induction of LTD in the CA1 hippocampal region and impairment of spatial learning and memory.     

Exercise effects stress-induced analgesia and spatial learning in rats

Previous studies indicated that intensity level may be a determining factor in the beneficial or detrimental effects of exercise on spatial memory, as chronic low-intensity level exercise appears to enhance learning and memory which stressful situations may impair. This study examines the effects of different intensity levels of acute exercise (treadmill running) on spatial memory in rats. Using the Morris water maze, spatial learning was measured in animals exposed to treadmill running at low- (20-22 m/min for 25 min daily) and high-intensity (25 m/min for 25 min daily) levels of exercise. A stress control using an electric foot shock was used to examine if the high-intensity exercise was sufficient to serve as a stressor. Stress level was estimated by examining tail flick latencies as a measure of stress-induced analgesia. The results indicate that high-intensity exercise at a level that may not induce an analgesic state is sufficient to impair early acquisition of spatial learning. However, with additional trials, all animals are capable of learning the task. Acute exposure to the electric foot shock impaired learning in the Morris water maze. Surprisingly, across all studies, there was a significantly higher analgesic state post-swim as compared to pre-swim. The results indicate that irrespective of stress level prior to water maze testing, swimming in the Morris water maze repeatedly for short durations of time is enough to induce an analgesic state.     

Age and Experience-Dependent Representational Reorganization During Spatial Learning

Previously, we found that aged rats showed a significant enhancement of hippocampal CA1 place cell spatial specificity, as well as a reduction of hilar place cell spatial specificity, during asymptote performance of a spatial memory task. Because such an age effect was not observed when animals performed a nonspatial task, the present study tested the hypothesis that the different patterns of spatial selectivity observed in memory and nonmemory tests reflected a redistribution of spatial representations that occurred in response to changing task demands. In the present experiment, after animals became familiar with the test environment and motor demands of performance on a radial maze, CA1 and hilar place cells were recorded as they learned a spatial memory task. CA1 place cells recorded from unimpaired old, but not impaired old or young, animals became more spatially selective as animals learned the task. Hilar spatial selectivity for both age groups was not significantly related to choice accuracy. These data support the hypothesis that at least a subpopulation of aged rats may benefit from reorganization of spatial representations in such a way that the normal age-related spatial learning deficit is attenuated.     

Intact neurogenesis is required for benefits of exercise on spatial memory but not motor performance or contextual fear conditioning in C57BL/6J mice

The mammalian hippocampus continues to generate new neurons throughout life. Experiences such as exercise, anti-depressants, and stress regulate levels of neurogenesis. Exercise increases adult hippocampal neurogenesis and enhances behavioral performance on rotarod, contextual fear and water maze in rodents. To directly test whether intact neurogenesis is required for gains in behavioral performance from exercise in C57BL/6J mice, neurogenesis was reduced using focal gamma irradiation (3 sessions of 5 Gy). Two months after treatment, mice (total n=42 males and 42 females) (Irradiated or Sham), were placed with or without running wheels (Runner or Sedentary) for 54 days. The first 10 days mice received daily injections of bromodeoxyuridine (BrdU) to label dividing cells. The last 14 days mice were tested on water maze (two trials per day for 5 days, then 1 h later probe test), rotarod (four trials per day for 3 days), and contextual fear conditioning (2 days), then measured for neurogenesis using immunohistochemical detection of BrdU and neuronal nuclear protein (NeuN) mature neuronal marker. Consistent with previous studies, in Sham animals, running increased neurogenesis fourfold and gains in performance were observed for the water maze (spatial learning and memory), rotarod (motor performance), and contextual fear (conditioning). These positive results provided the reference to determine whether gains in performance were blocked by irradiation. Irradiation reduced neurogenesis by 50% in both groups, Runner and Sedentary. Irradiation did not affect running or baseline performance on any task. Minimal changes in microglia associated with inflammation (using immunohistochemical detection of cd68) were detected at the time of behavioral testing. Irradiation did not reduce gains in performance on rotarod or contextual fear, however it eliminated gain in performance on the water maze. Results support the hypothesis that intact exercise-induced hippocampal neurogenesis is required for improved spatial memory, but not motor performance or contextual fear in C57BL/6J mice.     

Ganglioside GQ1b improves spatial learning and memory of rats as measured by the Y-maze and the Morris water maze tests

Gangliosides are major components of cell membranes and are particularly enriched in the mammalian brain where they represent the major lipid constituents of the neuronal cell surface. In the central nervous system, gangliosides have a close connection to many neurophysiological functions related to neurogenesis, proliferation, synaptogenesis, and synaptic transmission. The previously reported effect of the tetra-sialoganglioside GQ1b in hippocampal CA1 neurons of brain slices showed that GQ1b enhanced ATP-induced long-term potentiation (LTP). However, there has been no clear evidence of the effects of GQ1b on learning and memory as measured using behavioral test. In the present study, we performed the Y-maze and the Morris water maze (MWM) tests to reveal the effects of GQ1b on spatial learning and memory following intracerebroventricular (ICV) injection of GQ1b. GQ1b-treated rats showed highly increased performance on the Y-maze and the MWM tests without any significant alteration of basal locomotor activity. Therefore, our behavioral data strongly suggest that GQ1b improves spatial learning and memory in rats. Also, these data support the previous finding that GQ1b treatment in hippocampal CA1 neurons of rodent brain slices increased ATP-induced LTP.     

The synthetic cannabinoid WIN 55212-2 differentially modulates thigmotaxis but not spatial learning in adolescent and adult animals

Unlike Δ(9)-THC, the synthetic compound WIN 55212-2 (WIN) is a full agonist of endogenous cannabinoid receptors. Previous work has shown Δ(9)-THC to affect adolescent and adult animals differently on numerous behavioral measures of spatial memory, anxiety, and locomotor activity. However, far less is known about the developmental and neurobehavioral effects of WIN. To address this, we assessed the effect of WIN (1mg/kg) on spatial learning in adolescent and adult rats using the Morris water maze. While all animals demonstrated decreased swim distance across days, WIN affected adolescents and adults differently. It improved performance in adolescents and resulted in a nearly significant performance decrement in adults. However, these effects were significantly related to thigmotaxis, which declined across days in the water maze testing protocol. WIN reduced thigmotaxis on days 1 and 2 (but not days 3-5) only in adolescents. The effect of age, treatment, and the age×treatment interaction was eliminated after controlling for thigmotaxis. These results indicate that WIN affects thigmotaxis rather than spatial reference memory. More importantly, these findings indicate a dissociation between the developmental effects of THC and the synthetic CB1 receptor agonist, WIN 55212-2. We suggest that the role of thigmotaxis be carefully evaluated in future neurodevelopmental studies of spatial learning, especially those investigating the endocannabinoid system.     

Early postnatal hyperthyroidism improves both working and reference memory in a spatial radial-maze task in adult mice

Newborn male pups of the inbred mouse strain DBA/2J were injected with a buffered solution of L-thyroxine, known to induce a hyperplasia of the intra- and infrapyramidal mossy fiber terminal fields (iip-MF). Because previous studies have shown that the size of the iip-MF correlates positively with both reference memory and working memory in a spatial radial maze task, we expected improved performance on such a task in the treated animals. Such an improvement was in fact found for both reference and working memory. We conclude that the iip-MF are functionally involved in the regulation of spatial learning and memory in mice.     

Hippocampal spine-associated Rap-specific GTPase-activating protein induces enhancement of learning and memory in postnatally hypoxia-exposed mice

Spine-associated Rap-specific GTPase-activating protein (SPAR) is a postsynaptic protein that forms a complex with postsynaptic density (PSD)-95 and N-methyl-d-aspartate receptors (NMDARs), and morphologically regulates dendritic spines. Mild intermittent hypoxia (IH, 16.0% O₂, 4 h/day for 4 weeks) is known to markedly enhance spatial learning and memory in postnatal developing mice. Here, we report that this effect is correlated with persistent increases in SPAR expression as well as long-term potentiation (LTP) in the hippocampus of IH-exposed mice. Furthermore, an infusion of SPAR antisense oligonucleotides into the dorsal hippocampus disrupted elevation of SPAR expression, preventing enhanced hippocampal LTP in IH-exposed developing mice and also reducing LTP in normoxic mice, without altering basal synaptic transmission. In SPAR antisense-treated mice, acquisition of the Morris water maze spatial learning task was impaired, as was memory retention in probe trails following training. This study provides the first evidence that SPAR is functionally required for synaptic plasticity and contributes to the IH-induced enhancement of spatial learning and memory in postnatal developing mice.     

Influence of electroconvulsive shock and naloxone on acquisition and retention of a spatial navigation task in rats

The effects of electroconvulsive shock (ECS) on learning and memory were examined in rats using the Morris navigation task. Rats were trained to escape from a large pool of water onto an invisible underwater platform. Application of ECS at various intervals before training (15 to 120 min) induced a significant time-dependent impairment of the acquisition of escape behavior; naloxone (1 mg/kg IP 15 min before ECS) did not prevent the ECS-induced impairment. One single active escape trial preceding ECS prevented ECS-interference with the subsequent acquisition of the task. Spatial navigation in well trained animals was significantly impaired 30 and 60 min after ECS. It is concluded that ECS disturbs the disturbs the formation of a spatial memory trace more than the retrieval of a previously formed spatial trace. Release of opioid peptides do not seem to contribute substantially to the amnesic effects of ECS in the spatial navigation task.     

Preserved LTP and water maze learning in hyperglycaemic-hyperinsulinemic ZDF rats

Previous investigations have demonstrated that cognitive deficits as well as hippocampal dysfunctions are generated in animals presenting manifestations of Type 1 diabetes (T1D) mellitus. The present study examined whether such deficits can also be reproduced in the Zucker Diabetic Fatty (ZDF) rats after they developed symptoms of Type 2 diabetes (T2D). Learning and memory assessments were performed using the Morris water maze 5 weeks after the animals presented symptoms of Type 1 diabetes for Experiment 1 (Exp 1) and after 8 weeks for Experiment 2 (Exp 2). Testing in the water maze revealed that ZDF rats learned the task normally, although control rats were found to swim significantly faster after 5 or 8 weeks of untreated diabetes. From an electrophysiological perspective, we observed that the integrity of synaptic function was also preserved in ZDF rats as no alterations in long-term potentiation (LTP) were observed in the area CA1 of hippocampal slices. It is concluded that hyperglycaemia is not the only factor influencing water maze learning and LTP in this animal model of Type 2 diabetes (T2D). The experiments suggest that the resistance of ZDF rats to cognitive and electrophysiological dysfunctions might be related to the protective action of hyperinsulinemia. Indeed, measurements of the plasma insulin level at the end of testing were significantly superior in ZDF rats in comparison to control rats.     

Correlation between cognitive deficits and Abeta deposits in transgenic APP+PS1 mice

Doubly transgenic mAPP+mPS1 mice (15-16 months) had impaired cognitive function in a spatial learning and memory task that combined features of a water maze and a radial arm maze. Nontransgenic mice learned a new platform location each day during 4 consecutive acquisition trials, and exhibited memory for this location in a retention trial administered 30 min later. In contrast, transgenic mice were, on average, unable to improve their performance in finding the hidden platform over trials. The cognitive performance of individual mice within the transgenic group were inversely related to the amount of Abeta deposited in the frontal cortex and hippocampus. These findings imply that mAPP+mPS1 transgenic mice develop deficits in cognitive ability as Abeta deposits increase. These data argue that radial arm water maze testing of doubly transgenic mice may be a useful behavioral endpoint in evaluating the functional consequences of potential AD therapies, especially those designed to reduce Abeta load.     

Task-dependent strain difference of spatial learning in C57BL/6N and BALB/c mice

In the present study, we used a dry maze task to assess the spatial learning ability of C57BL/6N and BALB/cA mice besides the water maze task. In Experiment 1, the performance of C57BL/6N and BALB/cA mice in the water maze task and dry maze task were investigated. In the former task, the mice had to learn the position of a hidden platform submerged below the water surface and they had to learn the position of a baited hole on the circular maze in the latter task. C57BL/6N mice showed significant learning in both maze tasks, whereas BALB/cA mice showed learning in a dry maze but not in water maze as reported before. In Experiment 2, a dry maze task was conducted on a circular open field which contained 16 holes arranged symmetrically and which was put on the same height as the surface of the water maze. In Experiment 2, BALB/cA mice showed significant improvement in latency and path length to reach the food hole. The poor performance of the BALB/cA in the water maze task may reflect a weak motivation, escaping from water, rather than the poor spatial memory in this strain.