Non-spatial water radial-arm maze learning in mice

Recently, we published a method for examining working and reference memory in mice using a spatial version of the water radial-arm maze. Here we describe a non-spatial version of the same maze. BXSB mice were able to learn the maze as shown by the decrease in the number of working and reference memory errors over sessions. This maze was used to examine learning differences between males and females and between mice with misplaced clusters of neurons in layer I of cortex (ectopias) and those without. In a prior study using the spatial version of the water radial-arm maze, male BXSB mice had poorer working memory than females during the acquisition phase. Similarly, in this study male BXSB mice demonstrated impaired working memory during the asymptotic phase of non-spatial radial-arm maze learning. Two prior studies showed that mice with neocortical ectopias demonstrated working memory impairments compared to non-ectopic littermates in the spatial version of the water radial-arm maze. Contrary to this, in the non-spatial radial-arm maze used here, ectopic mice were not impaired in working memory and showed better memory when the working memory 'load' was the highest. Overall, both versions of the maze can be useful tools to assess spatial and non-spatial working and reference memory in mice.     

The effects of fear conditioning on cerebellar LTP and LTD

Long-term potentiation (LTP) and depression (LTD) at parallel fibre-Purkinje cell synapses have been described in vitro in the cerebellar cortex, but the physiological roles of these two forms of plasticity have not been well defined. Here we show that, in cerebellar slices taken from rats that had undergone fear conditioning, there was a significant occlusion of electrically induced LTP at parallel fibre-Purkinje cell synapses. This effect was long-lasting and related to associative processes, as LTP was not occluded in unpaired animals. Notably, in conditioned animals the LTP-inducing protocol produced LTD in some cells instead of LTP. Conversely, synaptic depression induced by conjunctive stimulation of parallel fibers and climbing fibres was impaired in tissue taken immediately following aversive stimulation in both paired and unpaired subjects. This effect was not, however, long-lasting as the incidence and extent of LTD returned to normal levels 24 h after behavioural testing. These findings suggest that LTP takes part in the mechanisms underlying aversive associative memories in the cerebellum.     

Use of sequence information in associative learning in control subjects and cerebellar patients

Previous studies of our group have shown that cerebellar patients are impaired in their ability to associate a color and a numeral or two colors with a button push. The aim of the present study was to examine whether control subjects make use of sequence information in visuomotor associative learning tasks and if this ability is impaired in cerebellar patients. A group of eight patients with degenerative cerebellar disease and eight age, sex and IQ matched controls were tested. Subjects had to learn the association between pairs of colored squares and a button push. Two colored squares were shown one after the other in a fixed or random order on a computer screen. Control subjects but not cerebellar patients took advantage of the fixed order information of colored squares in order to improve associative learning. Differences between groups could not be explained by differences in verbal and visuospatial short-term memory, color discrimination, affective state or motor disturbances. Results suggest that impaired sequencing of sensory stimuli may contribute to disorders in visuomotor associative learning in cerebellar patients.     

Stress impairs performance in spatial water maze learning tasks

The water maze task has been developed to test spatial learning abilities in rats or mice, and is widely used. Though it has been reported before that numerous cognitive abilities are of importance for learning this task, poor performance is usually interpreted as an impairment of spatial memory formation. Previous investigations that tried to correlate long-term potentiation (LTP) of synaptic transmission with spatial learning abilities in rats reported that injection of drugs or specific gene deletions which blocked the expression of LTP correlated with learning impairments of spatial tasks in a water maze. Recent studies, however, have shown that pretraining enables these animals to learn such spatial tasks even though LTP was still found to be blocked. I investigated to what degree altered fear condition and stress perception could account for the impaired spatial learning when no pretraining is given. In a fear habituation task, unhandled rats preferred a dark over a well lit chamber more than handled animals did, but unhandled rats favoured the lit chamber more in an active avoidance task. They also performed poorly in a spatial water maze task compared with handled rats. Rats pretrained in a radial arm maze performed better in a water maze than non-pretrained rats. No difference between groups was found in a non-spatial water maze task. On the other hand, when pretrained in a water maze, rats performed only marginally better in a radial arm maze compared to non-pretrained animals. Since animals have to be handled to learn a radial arm maze, the difference in this task was not due to stress but most probably due to getting accustomed to the room dimensions prior to learning the spatial task. The results suggest that impaired learning of spatial tasks in the water maze can be due to increased stress and decreased fear conditioning without actually affecting spatial learning abilities. These results question the interpretations of the results of some previously published results of spatial water maze tasks.     

高同型半胱氨酸血症对大鼠在Morris水迷宫实验中学习记忆行为的影响

目的 研究高同型半胱氨酸血症对大鼠在Morris水迷宫实验中学习记忆能力的影响.方法 以高蛋氨酸饮食喂养大鼠,制作高同型半胱氨酸血症模型.进行隐藏平台获得实验、空间探索实验,比较高同型半胱氨酸组与对照组的学习记忆能力.结果 Z隐藏平台获得实验第3d高同型半胱氨酸血症组大鼠逃避潜伏期长于对照组(P＜ 0.05);空间探索实验高同型半胱氨酸血症组目的象限停留时间比及游程比、穿过原平台位置的次数均低于对照组(P＜0.05).结论 高同型半胱氨酸血症可致大鼠空间学习记忆能力下降.     

Differential effects of kindling and kindled seizures on place learning in the morris water maze

There is some controversy about the role of long-term potentiation (LTP) in spatial learning. The authors have found that triggering generalized kindled seizures with stimulation of the perforant path disrupts spatial learning in the Morris water maze but that kindling per se does not affect spatial learning. It is suggested that abnormal electrical activity induced by high-frequency stimulation of the perforant path may have been responsible for the disruption of spatial learning previously attributed to LTP saturation.     

Prefrontal cortical mediation of rats' place learning in a modified water maze

The acquisition of a place learning task in a water maze modified from the “standard” set-up by restriction of distal cues and addition of “proximal” cues (ping-pong balls in fixed positions on the surface of the water) was tested in three groups of rats: (I) animals subjected to bilateral ablation of the anteromedial prefrontal cortex, (II) rats in which the parietal “association” cortex had been removed bilaterally, and (III) a sham operated control group. The task acquisition of the prefrontaly ablated group was significantly impaired, whereas the animals in which the parietal cortex had been removed acquired the task as quickly as the control group. Upon reaching criterion level performance all animals were tested on “challenge” sessions on which the cues were manipulated. Such “challenges” demonstrated that the animals of all three groups discriminated between the distal cues and utilized such a discrimination for navigational purposes.     

Increase of the hippocampal theta activity in the Morris water maze reflects learning rather than motor activity

The change in the percentage of rat hippocampal high-frequency theta activity from being immobile and awake to swimming behaviour was calculated for three groups of rats, trained in either place learning, cue learning or egocentric learning in the Morris water maze. The place-learning-trained rats showed an increase in the percentage of theta activity, along with a significant reduction in escape latency over the last 3 days of training. No changes were observed in the other two groups. Because the motor activity displayed by the three groups of rats was similar, we suggest that the increase in the percentage of theta activity concomitant with place-learning training could be related to the processing of information by the hippocampus, rather than to the displayed motor activity.     

Preserved configural learning and spatial learning impairment in rats with hippocampal damage.

This study was undertaken to compare the effect of hippocampal neurotoxic lesions in rats on two behavioral tasks, one a test of spatial learning, and the other an operant discrimination task that is acquired by forming nonspatial configural associations. Lesions of the hippocampus were made with microinjections of ibotenic acid. After postoperative recovery, rats were trained initially to locate a camouflaged escape platform in a water maze using distal spatial cues. Rats also were trained in the maze apparatus with a visible escape platform under conditions in which spatial information was made irrelevant to performance, i.e., cue learning. In an operant task, the same rats were then trained on a discrimination that included simultaneous feature positive and feature negative components (trial types XA+, A-, XB-, B+). After completion of this nonspatial configural learning task, rats received additional training in the water maze using a new platform location for spatial learning. To the extent that proficient performance in both the maze and operant tasks depends on a common function of the hippocampus, i.e., configural learning, the expectation was that hippocampal lesions would prove equally detrimental to performance in both tasks. Contrary to this expectation, lesioned rats were severely impaired in spatial learning but readily acquired the operant discrimination, even exhibiting some evidence of enhanced performance on this nonspatial configural learning task. Performance of the lesioned rats during cue training in the water maze was also enhanced relative to the control group.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of apparatus design and test procedure on learning and memory performance of C57BL/6J mice on the Barnes maze

The Barnes maze is a visuo-spatial learning and memory test originally designed for use with rats, and later adapted for use with mice. The Barnes maze design and test procedure vary across studies using mice, but the effects of variation in Barnes maze design and test procedure on learning and memory in mice have not yet been investigated. Therefore the present experiment investigates whether test procedures, such as the number of habituation trials and parameters of the probe trial (correct zone size and trial length) influence learning and memory performance on three Barnes maze designs that differed in size and the presence of a wall with intra-maze visual cues. Performance was compared across the three mazes to determine how apparatus design influences visuo-spatial cue use. The number of habituation trials and parameters of the probe trial had small effects on learning and memory performance. Apparatus design, had little effect on acquisition performance but had a significant effect on memory performance. Mice on a maze with a small diameter, external wall and intra-maze visual cues had very poor visuo-spatial memory relative to mice tested on small and large diameter mazes without a wall or intra-maze visual cues. Assessment of visuo-spatial cue use indicated that mice do not rely on visuo-spatial cues to locate the escape hole on the small-diameter maze with a wall and intra-maze visual cues, but show reliable visuo-spatial cue use on small or large diameter mazes with no wall. These results indicate that apparatus design influences search strategy use and memory performance on the Barnes maze, and that including a wall around the edge of the Barnes maze decreases visuo-spatial cue use.     

Applications of the Morris water maze in the study of learning and memory

The Morris water maze (MWM) was described 20 years ago as a device to investigate spatial learning and memory in laboratory rats. In the meanwhile, it has become one of the most frequently used laboratory tools in behavioral neuroscience. Many methodological variations of the MWM task have been and are being used by research groups in many different applications. However, researchers have become increasingly aware that MWM performance is influenced by factors such as apparatus or training procedure as well as by the characteristics of the experimental animals (sex, species/strain, age, nutritional state, exposure to stress or infection). Lesions in distinct brain regions like hippocampus, striatum, basal forebrain, cerebellum and cerebral cortex were shown to impair MWM performance, but disconnecting rather than destroying brain regions relevant for spatial learning may impair MWM performance as well. Spatial learning in general and MWM performance in particular appear to depend upon the coordinated action of different brain regions and neurotransmitter systems constituting a functionally integrated neural network. Finally, the MWM task has often been used in the validation of rodent models for neurocognitive disorders and the evaluation of possible neurocognitive treatments. Through its many applications, MWM testing gained a position at the very core of contemporary neuroscience research.     

Spatial learning and memory, maze running strategies and cholinergic mechanisms in two inbred strains of mice

The acquisition process of the radial maze task was studied in two inbred strains of mice, C57BL/6 and DBA/2. A quantitative and qualitative evaluation of performance was performed and the pretest level of activity was measured. The results showed a significant correlation between activity and performance since the highly active C57BL/6 mice exhibited better performance of the radial maze task than the less active DBA/2 mice. Moreover, for correct trials, strain-dependent maze-running strategies were observed: while both strains displayed about the same percentage of clockwise and spatial strategies, it was observed that among the spatial strategies C57BL/6 used a larger number of different correct solutions. Subsequently, the effect of scopolamine administration on working memory processes was assessed in sequential and discrete trials. A different reactivity of each strain to anti-cholinergic treatment was found in discrete trials since only DBA/2 mice were impaired. The effect of scopolamine is discussed in relation to the different models of information processing involved in learning and memorizing the experimental rule.     

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.     

Neonatal hippocampal damage in rats: Long-term spatial memory deficits and associations with magnitude of hippocampal damage

This study investigated the effects of neonatal hippocampal ablation on the development of spatial learning and memory abilities in rats. Newborn rats sustained bilateral electrolytic lesions of the hippocampus or were sham-operated on postnatal day 1 (PN1). At PN20–25, PN50–55, or PN90–95, separate groups of rats were tested in a Morris water maze on a visible “cue” condition (visible platform in a fixed location of the maze), a spatial “place” condition (submerged platform in a fixed location), or a no-contingency “random” condition (submerged platform in a random location). Rats were tested for 6 consecutive days, with 12 acquisition trials and 1 retention (probe) trial per day. During acquisition trials, the rat's latency to escape the maze was recorded. During retention trials (last trial for each day, no escape platform available), the total time the rat spent in the probe quadrant was recorded. Data from rats with hippocampal lesions tested as infants (PN20–25) or as adults (PN50–55 and PN90–95) converged across measures to reveal that 1) spatial (place) memory deficits were evident throughout developmental testing, suggesting that the deficits in spatial memory were long-lasting, if not permanent, and 2) behavioral performance measures under the spatial (place) condition were significantly correlated with total volume of hippocampal tissue damage, and with volume of damage to the right and anterior hippocampal regions. These results support the hypothesis that hippocampal integrity is important for the normal development of spatial learning and memory functions, and show that other brain structures do not assume hippocampal-spatial memory functions when the hippocampus is damaged during the neonatal period (even when testing is not begun until adulthood). Thus, neonatal hippocampal damage in rats may serve as a rodent model for assessing treatment strategies (e.g., pharmacological) relevant to human perinatal brain injury and developmental disabilities within the learning and memory realm. Hippocampus 7:403–415, 1997. © 1997 Wiley-Liss, Inc.     

Online and offline effects of cerebellar transcranial direct current stimulation on motor learning in healthy older adults: a randomized double‐blind sham‐controlled study

The aim of this randomized double blinded sham‐controlled study was to determine the effect of cerebellar anodal transcranial direct current stimulation (a‐tDCS) on online and offline motor learning in healthy older individuals. Thirty participants were randomly assigned in experimental (n = 15) or sham tDCS (n = 15) groups. Participants in experimental group received 2 mA cerebellar a‐tDCS for 20 min. However, the tDCS was turned off after 30 seconds in sham group. Response time (RT) and error rate (ER) in serial RT test were assessed before, during 35 minutes and 48 h after the intervention. Reduction of RT and ER following the intervention session was considered as short‐term (35 min post intervention) and long‐term offline learning (48 h post intervention), respectively. Online RT and ER reduction were similar in both groups (P > 0.05). RT was significantly reduced 48 hours post intervention in cerebellar a‐tDCS group (P = 0.03). Moreover, RT was significantly increased after 35 minutes and 48 hours in sham tDCS group (P = 0.03, P = 0.007), which indicates a lack of short‐term and long‐term offline learning in older adults. A‐tDCS on cerebellar region produced more short‐term and long‐term offline improvement in RT (P = 0.014, P = 0.01) compared to sham tDCS. In addition, online, short‐term and long‐term (48 h) offline error reduced in cerebellar a‐tDCS as compared to sham‐control group, although this reduction was not significant (P > 0.05). A deficit suggests that a direct comparison to a younger group was made. The findings suggested that cerebellar a‐tDCS might be useful for improvement of offline motor learning in older individuals.     

Interactive effects of a protein kinase AII inhibitor and testosterone on spatial learning in the Morris water maze

Neurohormones such as testosterone (TE) are important in modulation of learning and memory. In the present study, we investigated the interactive effects of pre-training bilateral intra-hippocampal infusions of testosterone and H-89, a selective PKAII inhibitor, on spatial acquisition in the Morris water maze (MWM). Different doses of TE (20, 40 and 80 μg/side) and H-89 (5 and 10 μM/side) were administered 30 min before start of the training each day. Control animals received bilateral intra-hippocampal infusions of DMSO as vehicle for TE and H-89. Animals were trained for 4 days and each day included one block of four trials. The results of this study showed that bilateral infusion of TE (40 and 80 μg/side) or H-89 (10 μM/side) impaired spatial learning as indicated by significant increases in escape latency and traveled distance compared to the control group. Although pre-training bilateral infusions of a low concentration of either TE (20 μg/side) or H-89 (5 μM/side) into the CA1 region of the hippocampus did not affect learning capabilities, but the combination of the low doses of the drugs led to significant deficits in spatial acquisition. Overall, our data suggest that spatial acquisition was affected by PKAII inhibition or TE administration. Moreover, when co-administered, these drugs had a negative synergistic impact on acquisition.     

Radial maze learning in two inbred mouse strains and their reciprocal congenics for the non-pseudoautosomal region of the Y chromosome

The effect of the non-pseudoautosomal region of the Y chromosome on spatial learning in a radial maze task was examined in two inbred mouse strains, NZB and CBA/H, and their respective congenics for the Y(NPAR). Seven variables reflecting learning performance, learning strategy and lateralisation were measured. We found no substantial effect of the Y(NPAR) on radial maze learning, but modest influences on behavioral strategies. These findings are in agreement with previous results regarding the sizes of the intra- and infrapyramidal mossy fiber (IIPMF) terminal fields.     

Allopregnanolone inhibits learning in the Morris water maze

The progesterone metabolite allopregnanolone (3alpha-OH-5alpha-pregnane-20-one) inhibits neural functions, enhancing the GABA induced GABA(A) receptor activation. This effect is benzodiazepine like and benzodiazepines are known to impair memory. Acute effects of allopregnanolone on the hippocampus dependent spatial learning in the Morris water maze have not been studied. Adult male Wistar rats where injected (i.v.) with allopregnanolone (2 mg/kg), or vehicle, daily for 11 days. At 8 or 20 min after each injection, studies of place navigation were performed in the Morris water maze. Allopregnanolone concentrations in plasma and in nine different brain areas where analyzed by radioimmunoassay. The latency to find the platform was increased 8 min after the allopregnanolone injection, while normal learning was seen after 20 min. Swim speed did not differ between groups. A higher number of rats were swimming close to the pool wall (thigmotaxis) in the 8 min allopregnanolone group compared to the other groups. Allopregnanolone concentrations in the brain tissue at 8 min were 1.5 to 2.5 times higher then at 20 min after the allopregnanolone injections. After vehicle injections the brain concentrations of allopregnanolone were at control levels. Plasma concentrations of allopregnanolone followed the same pattern as in the brain, with the exception of an increase 8 min after vehicle injections. The natural progesterone metabolite allopregnanolone can inhibit learning in the Morris water maze, an effect not caused by motor impairment. The learning impairment might be due to a combination of changed swimming behavior and difficulties in navigation.     

Ipsilateral cerebellar lesions prevent learning of the classically conditioned nictitating membrane/eyelid response

Unilateral lesions of the cerebellum in the rabbit prior to any training completely prevented learning of the classically conditioned eyelid and nictitating membrane responses of the eye ipsilateral to the lesion. In marked contrast, subsequent training of the eye contralateral to the lesion yields normal learning.