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Selectivity of the spatial learning deficit after lesions of the mammillary region in rats.

Rats with lesions of the mammillary region (MB-R) or a control group (C) were trained on a visual-spatial conditional associative learning task in which they had to learn to go to one of two locations depending on the particular visual cue presented on each trial; the rats approached the cues from different directions. The animals were subsequently tested on a spatial working memory task, the eight-arm radial maze. Rats with damage to the MB-R were able to acquire the conditional associative task at a rate comparable to that of the C animals. By contrast, lesions of the MB-R led to a severe impairment on the radial maze. The present finding of a dissociation between the effects of MB-R lesions on two different classes of behavior suggest that the spatial learning deficit following damage of this region may be specific to remembering one or more places over a given time but not the ability to form associations between visual and spatial stimuli.

Animals↗

Pharmacological protection of synaptic function, spatial learning, and memory from transient hypoxia in rats.

Hypoxia significantly reduced cholinergic theta activity in rat CA1 field and intracellular theta in the CA1 pyramidal cells, recorded in hippocampal slices. The hypoxic responses of the hippocampal CA1 pyramidal cells to a brief hypoxia consisted of a short period of "synaptic arrest", observed as an elimination of excitatory postsynaptic current under voltage clamp and recovered immediately as oxygenation was reinitiated. The hypoxic synaptic arrest was not associated with reduced postsynaptic responses of the pyramidal cells to externally applied L-glutamate, suggesting that the synaptic arrest might result from a presynaptic mechanism. The hypoxic synaptic arrest was abolished in the presence of 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), a specific adenosine A(1) receptor antagonist. Blocking adenosine A(1) receptors also eliminated effects of hypoxia on the hippocampal CA1 field theta activity and intracellular theta of the CA1 pyramidal cells. In behaving rats, brief hypoxia impaired their water maze performance in both the escape latency and probe tests. The impairment was prevented by intralateral cerebroventricular injections of DPCPX. These results suggest that hypoxia releases adenosine and produces an inhibition of synaptic transmission and intracellular signal cascade(s) involved in generation/maintenance of hippocampal CA1 theta activity. This protection of synaptic efficacy and spatial learning through adenosine A(1) receptor antagonism may represent an effective therapeutic strategy to eliminate functional interruption due to transient hypoxic episodes and/or chronic hypoxia secondary to compromise of respiratory function.

Animals↗

Enhanced hippocampal CA1 LTP but normal spatial learning in inositol 1,4,5-trisphosphate 3-kinase(A)-deficient mice.

To define the physiological role of IP(3)3-kinase(A) in vivo, we have generated a mouse strain with a null mutation of the IP(3)3-kinase(A) locus by gene targeting. Homozygous mutant mice were fully viable, fertile, apparently normal, and did not show any morphological anomaly in brain sections. In the mutant brain, the IP4 level was significantly decreased whereas the IP3 level did not change, demonstrating a major role of IP(3)3-kinase(A) in the generation of IP4. Nevertheless, no significant difference was detected in the hippocampal neuronal cells of the wild-type and the mutant mice in the kinetics of Ca2+ regulation after glutamate stimulation. Electrophysiological analyses carried out in hippocampal slices showed that the mutation significantly enhanced the LTP in the hippocampal CA1 region, but had no effect on the LTP in dentate gyrus (DG). No difference was noted, however, between the mutant and the wild-type mice in the Morris water maze task. Our results indicate that IP(3)3-kinase(A) may play an important role in the regulation of LTP in hippocampal CA1 region through the generation of IP4, but the enhanced LTP in the hippocampal CA1 does not affect spatial learning and memory.

Animals↗

Enhanced acquisition of reversal training in a spatial learning task in rats treated with chronic nimodipine.

Nimodipine levels were measured in blood and brain of rats implanted SC with sustained-release pellets of nimodipine (0, 10, 20, or 40 mg). Dose-dependent levels of nimodipine were detected in both plasma and brain. These results indicated the possible usefulness of these pellets in behavioral studies where long-term treatment is required. Therefore, the effects of chronic nimodipine, using 40-mg pellets, were examined on the performance of young, middle-aged, and aged rats in the Morris water maze. Following implantation of either nimodipine or placebo pellets, rats were trained for 6 days (three sessions/day) followed by 6 days of reversal training. During both initial and reversal training, every sixth trial was a probe trial. During initial training, there were clear age-related acquisition deficits in place training, with no effects of chronic nimodipine. Nimodipine did, however, enhance performance of rats during the first and second probe trials of reversal training. Time spent in the training quadrant by nimodipine-treated rats was approximately 30% longer on the first reversal probe and 35% longer on the second reversal probe than time spent in this quadrant by placebo-treated animals. These results indicate that chronic nimodipine enhances the performance of normal animals in reversal training on a spatial learning task.

Aging↗

Effect of chronic nimodipine on spatial learning and on long-term potentiation.

The present study examined the effect of nimodipine on a reference memory task and on the induction and maintenance of long-term potentiation (LTP) in the hippocampal dentate gyrus. Young rats, subcutaneously implanted with either a 30 mg nimodipine or placebo pellet, were trained on the Barnes circular platform task. Retention was tested 15 days following acquisition. Following behavioural testing, recording and stimulating electrodes were implanted in the granule cell layer of the dentate gyrus and the perforant path, respectively. Pre-pellet baseline evoked potentials were collected. Nimodipine or placebo pellets were again subcutaneously implanted, according to the original groupings, and post-pellet baseline evoked potentials were obtained. LTP was then induced in the granule cell population by perforant path tetanization and the decay of LTP was followed for 15 days. Nimodipine significantly decreased the number of trials to reach both the acquisition and the retention criterion on the circular platform task, but did not alter granule cell excitability, LTP threshold, or the magnitude of LTP. Sustained nimodipine administration, however, increased the decay rate of LTP of the population spike, but did not affect the decay rate for LTP of the EPSP. No significant correlations were obtained between behavioural and electrophysiological measures. These results provide further evidence against a simple direct relationship between LTP and spatial learning.

Animals↗

Baclofen infused in rat hippocampal formation impairs spatial learning.

Recent studies show that baclofen, a selective GABA(B) agonist, impairs different kinds of learning. In the present study we investigated the effect of microinfused baclofen into the hippocampus of male Wistar rats, on the performance in the Morris water maze. Rats of 8-10 weeks of age were implanted with cannulae aimed bilaterally at the hippocampal formation. Baclofen (1 microl of 0.2 mM, 2.0 mM, and 20.0 mM) or sterilized saline was microinfused 1 h before each daily session (3 trials/session, 1 session/day) for 4 days. On the fifth day, the animals did not receive drug or saline injections and the retention of the location of the escape platform was tested in a 30 s free swim trial. Results from the free swim trial indicate that the doses of baclofen used during training affected the ability of the rats to swim to the target quadrant. Although no significant difference compared with the saline group was observed, the experimental rats showed a more generalized swim trajectory in the area of the target and both adjacent quadrants. Moreover, 1 microl of 20.0 mM baclofen also impaired the acquisition. We suggest that baclofen has an impairing action on spatial learning, although more studies should be conducted to reach a more precise conclusion.

Animals↗

Neurogranin null mutant mice display performance deficits on spatial learning tasks with anxiety related components.

Neurogranin/RC3 is a protein that binds calmodulin and serves as a substrate for protein kinase C. Neuronally distributed in the hippocampus and forebrain, neurogranin is highly expressed in dendritic spines of hippocampal pyramidal cells, implicating this protein in long-term potentiation and in learning and memory processes. Null mutation of the neurogranin gene Ng generated viable knockout mice for analysis of the behavioral phenotype resulting from the absence of neurogranin protein. Ng -/- mice were normal on measures of general health, neurological reflexes, sensory abilities, and motor functions, as compared to wild type littermate controls. On the Morris water task, Ng -/- mice failed to reach acquisition criterion on the hidden platform test and did not show selective search on the probe trial. In the Barnes circular maze, another test for spatial navigation learning, Ng -/- mice showed impairments on some components of transfer, but normal performance on time spent around the target hole. Abnormal and idiosyncratic behaviors were detected, that appeared to represent an anxiogenic phenotype in Ng -/- mice, as measured in the light<-->dark exploration test and the open field center time parameter. These findings of apparent deficits in spatial learning and anxiety-like tendencies in Ng -/- support a role for neurogranin in the hippocampally-mediated interaction between stress and performance.

Animals↗

Spatial learning deficit in the rat after exposure to a 60 Hz magnetic field.

Rats were trained in ten daily sessions to perform in a 12-arm radial maze, which is a behavioral test for spatial memory functions. Exposure to a 60 Hz magnetic field (45 min, 0.75 mT) immediately before each training session retarded learning significantly. Pretreatment with the cholinergic agonist physostigmine before magnetic field exposure reversed the field's effect on spatial learning. Data from this experiment indicate that magnetic field-induced spatial learning deficit is caused by the effect of the field on cholinergic systems.

Analysis of Variance↗

SR 141716A prevents delta 9-tetrahydrocannabinol-induced spatial learning deficit in a Morris-type water maze in mice.

This study reports a series of spatial discrimination procedures in a Morris-type maze to investigate the effects of delta9-tetrahydrocannabinol (delta9-THC) on different phases of learning and memory in mice. Adult male mice were given training trails to find the submerged platform at a fixed location in the water maze adapted for mice. In additional experiments, mice were trained with the repeated acquisition procedure to test the working memory. Results indicate that delta9-THC (8 mg/kg i.p.) 30 min pretest impaired specifically the acquisition of spatial learning and the performance of mice in the working memory task, while consolidation and retrieval of a previously learned task were not affected. There was no evidence of motoric difficulty, as the number of quadrant line crossings was not decreased and no visible sign of sensorimotor disturbance was observed during swimming. Pretreatment with SR 141716A (1 mg/kg i.p.), a CB1 cannabinoid receptor antagonist, significantly prevented the learning deficits in the water maze. These findings show that delta9-THC impairs spatial discrimination learning in a selective way in the water maze in mice and that these deficits may be mediated by cannabinoid receptors.

Animals↗

Spatial learning and memory in calpastatin-deficient rats.

The present experiments were concerned with the examination of the hypothesis that a deficiency in calpastatin, the endogenous inhibitor of calpain, enhances learning and memory performance. In the first experiment we used rats with an altered calpain/calpastatin balance (Milan hypertensive strain, MHS, low calpastatin) to investigate the learning and memory of a spatial task in the Morris water maze in comparison with control rats with a normal calpain/calpastatin balance (Milan normotensive strain, MNS). Since the two strains also differ in blood pressure, a third strain of rats was included to assess the role of hypertension (spontaneously hypertensive rats, SHR). Although the acquisition rate of the spatial task was better in the low-calpastatin MHS rats than in their normal-calpastatin MNS controls, their performance was similar to that of the SHR rats, thus thwarting the conclusion that differences were due to the low level of calpastatin. The availability of another mutant strain, low-calpastatin level and normotensive (MH.NE), allowed a further examination of the hypothesis. In the second experiment rats of the MH.NE strain acquired the spatial task as well as their normotensive controls, but their memory retrieval was clearly less than that of their normal-calpastatin controls. This deficiency was not due to impaired visual function or a slower swimming speed. The conclusion is that an inbalanced calpain/calpastatin ratio, although favoring calpain activity, is disadvantageous for remembering a spatial task. This disadvantage is clearly overruled when this inbalance is accompanied by hypertension.

Animals↗

Spatial learning and performance in the radial arm maze is impaired after N-methyl-D-aspartate (NMDA) receptor blockade in striatal subregions.

These experiments addressed the role of striatal N-methyl-D-aspartate (NMDA) receptors in spatial behavior in the radial arm maze. Rats treated with the NMDA antagonist D-2-amino-5-phosphonopentanoic acid (AP-5) in the nucleus accumbens core, medial caudate, and posterior caudate were all significantly impaired in acquiring the correct spatial responses. In contrast, rats infused with AP-5 in the nucleus accumbens shell showed little impairment. When rats in all groups had learned the maze and were performing at similar levels, AP-5 had relatively little effect except in the posterior caudate group, where errors and trial times were again increased. These findings demonstrate the importance of NMDA receptor-dependent activity within the accumbens and caudate in spatial learning and performance. The neural processes necessary for adaptive spatial learning in complex environments may recruit multiple cortical systems having specialized functions, which in turn are integrated in widespread striatal regions.

2-Amino-5-phosphonovalerate↗

Spatial learning, discrimination learning, paw preference and neocortical ectopias in two autoimmune strains of mice.

NZB and BXSB mice were given a battery of behavioral tests including paw preference, water escape, Lashley III maze, and discrimination learning. Their brains were then evaluated for cortical ectopias. The incidence of ectopias was 40.5% in NZBs and 48.5% in BXSBs. In the NZB strain left-pawed ectopic mice (both male and female) had the fastest swimming time in the water escape test, while right-pawed ectopics were the slowest. The same findings were obtained for left- and right-pawed ectopic BXSB males, but not for the females. However, on discrimination learning the BXSB males had the exact opposite pattern: right-pawed ectopics were the best learners while left-pawed ectopics were the worst. Male BXSBs and both male and female NZBs were manifesting autoimmune disease at the time of testing, while female BXSBs were not, suggesting that autoimmunity is a necessary background condition for the differential expression of ectopias and paw preference upon learning processes. The finding that the left-pawed ectopic BXSB mice, who were the poorest learners in the non-spatial discrimination learning test, learned best in the spatial water escape test is in agreement with the Geschwind hypothesis that pathological events during brain development may, in some instances, produce superiority of function.

Animals↗

Spatial learning and physical activity contribute to the induction of fibroblast growth factor: neural substrates for increased cognition associated with exercise.

New evidence indicates that neural activity regulates the expression of trophic factors in the brain but regulation of these molecules by select aspects of behaviour remains solely a fascinating possibility. We report that following training in the Morris water maze, a spatial memory task, the hippocampus and cerebellum of learning rats exhibited an increase in basic fibroblast growth factor messenger RNA. Basic fibroblast growth factor messenger RNA levels were higher during the learning of the task and decreased once asymptotic performance was reached, suggesting an involvement of basic fibroblast growth factor in learning/memory. An active control group, which exercised for the same time as the learning group but the spatial learning component of the task was minimized, exhibited a minor increase in basic fibroblast growth factor messenger RNA. The intensification of the physical activity component of the task by massed or intensive training resulted in greater increases in basic fibroblast growth factor messenger RNA for both learning and yoked groups, but levels of basic fibroblast growth factor messenger RNA in the learning group remained higher than yoked only in the cerebellum. Changes in basic fibroblast growth factor were accompanied by an increase in astrocyte density in the hippocampus in agreement with described roles of basic fibroblast growth factor in astrocyte proliferation/reactivity. Results suggest that learning potentiates the effects of physical activity on trophic factor induction in select brain regions. Trophic factor involvement in behaviour may provide a molecular basis for the enhanced cognitive function associated with active lifestyles, and guide development of strategies to improve rehabilitation and successful ageing.

Animals↗

Spatial learning induces differential changes in calcium/calmodulin-stimulated (ACI) and calcium-insensitive (ACII) adenylyl cyclases in the mouse hippocampus.

Several lines of evidence indicate that Ca2+/calmodulin-stimulated isoforms of adenylyl cyclase (AC) are involved in long-term potentiation and in certain forms of learning. Recently, we found that training in different types of learning task differentially activates Ca2+-sensitive versus Ca2+-insensitive AC activities in certain brain regions, indicating that AC species other than those stimulated by Ca2+/calmodulin may play an important role in learning processes (Guillou, Rose, & Cooper, 1999). Here, we report the effects of spatial reference memory training in a radial arm maze on the levels of AC1 and AC2 mRNA in the dorsal hippocampus of C57BL/6 mice. Acquisition of the task was associated with a learning-specific and time-dependent increase of AC1 mRNA expression selectively in subfields CA1-CA2. In contrast, AC2 mRNA levels were either reduced or not reliably affected depending on the stage of acquisition. Moreover, no significant changes in AC expression were observed either in the dorsal hippocampus of mice trained in a non-spatial (procedural) version of the task or in cortical regions of mice learning the spatial or procedural task. The regional specificity of these effects indicates that the formation of spatial and non-spatial memory requires distinct contributions from Ca2+-sensitive and Ca2+-insensitive AC in the hippocampus. It is suggested that downregulation of AC2 throughout all hippocampal subfields may play a permissive role during the acquisition of spatial learning whereas an upregulation of AC1 specifically in subfield CA1, may be critical to accurately encode, store or use spatial information.

Adenylyl Cyclases↗

Experience-dependent gene expression in the rat hippocampus after spatial learning: a comparison of the immediate-early genes Arc, c-fos, and zif268.

Neuronal immediate-early gene (IEG) expression is regulated by synaptic activity and plays an important role in the neuroplastic mechanisms critical to memory consolidation. IEGs can be divided into two functional classes: (1) regulatory transcription factors (RTFs), which can broadly influence cell function depending on the "downstream" genes they regulate, and (2) "effector" proteins, which may directly modulate specific cellular functions. The objective of the current study was to determine whether the expression of an effector IEG (Arc) was similar to, or different from, that of two well characterized RTF IEGs (c-fos and zif268) after learning. IEG RNA levels from rats trained in spatial and nonspatial water tasks were determined using RNase protection assays and in situ hybridization. Overall, the regulation of the three IEGs was similar in the hippocampus and the entorhinal and primary visual cortices. Consequently, IEG RNA levels were positively correlated within a structure. By contrast, Arc and zif268 RNA levels were not correlated or only weakly correlated across structures, although c-fos RNA levels were moderately correlated across structures. Arc RNA expression differed from that of zif268 and c-fos in two regards: (1) hippocampal Arc RNA levels were correlated with learning of the hippocampal-dependent spatial, but not hippocampal-independent cued response, water task, and (2) Arc RNA levels in the hippocampus and entorhinal cortex increased after spatial reversal learning relative to an asymptotic performance group. Thus, although the expression of Arc, zif268, and c-fos exhibited many similarities, Arc was most responsive to differences in behavioral task demands.

Animals↗

Spatial learning and memory at defined points of the estrous cycle: effects on performance of a hippocampal-dependent task.

Learning based on hippocampal-dependent spatial navigation in female rats was assessed at identified points in the estrous cycle corresponding to low (estrus) and high (proestrus) circulating estrogen. With background training in water-maze procedures, rats learned the location of an escape platform in the maze in a single session of 8 training trials. A strong spatial bias for the escape platform was also evident in a probe trial used to assess retention of learning 30 min after the training session. This entire protocol was completed in less than an hour. The performance of the estrus and proestrus rats was indistinguishable on all behavioral measures, irrespective of the stage of estrous cycle during the task. These results indicate that rapid learning and retention for spatial information over a relatively short interval may be preserved despite morphological alterations in hippocampal dendritic spine density in the normally cycling female rat.

Animals↗

Posttraining paradoxical sleep in rats is increased after spatial learning in the Morris water maze.

The role of posttraining paradoxical sleep (PS) in spatial or nonspatial learning in the Morris water maze was evaluated. Sprague-Dawley rats were given a 12-trial training session in either the hidden or the visible platform versions of the task. Subgroups then underwent paradoxical sleep deprivation (PSD) beginning at different times after training. Rats with PSD imposed from 1-4 hr after spatial training had poorer retest scores than any other group. Other rats, implanted with electrodes to permit continuous recording of sleep electroencephalography, were found to undergo a prolonged period of elevated PS after spatial training. By contrast, rats trained in the nonspatial version of the water maze task did not show retention deficits after PSD or elevated PS after training. These results support a role for PS in spatial, but not nonspatial, learning in the Morris water maze.

Animals↗

Buspirone impairment of performance of passive avoidance and spatial learning tasks in the rat.

The effects of buspirone on the execution of step-through passive avoidance and spatial navigation learning tasks were assessed. In view of the anxiolytic properties of the drug, its effects on shock induced ultrasonic vocalizations and shock suppressed locomotor activity in a hole-board were also determined. Doses (0.5, 1 and 2 mg/kg, IP) which did not affect exploratory activity in a novel environment (light/dark box and hole-board apparatus) were used. Buspirone (1 and 2 mg/kg) impaired performance on the 24 h passive avoidance recall test when given prior to the training and the test sessions or prior to the test session only but not when given before the training trial only. The stress response to the mild footshock, as measured in terms of suppressed locomotor activity in the hole-board apparatus and post-shock ultrasonic vocalizations, was reduced by buspirone (at 1 and 2 mg/kg, respectively), indicating that its effect on behavior in the passive avoidance learning task is probably due to its anxiolytic properties. Evidence for a possible amnesic effect of buspirone (2 mg/kg) was found on the acquisition and probe test trials in the spatial navigation task. During training the latency to find a submerged escape platform in a water maze was increased. Performance on a probe test was also impaired but this effect was not apparent in animals which had received buspirone only prior to the probe test. Although these changes may be attributable to alterations in many aspects of cognitive processing, the possibility of a direct effect on memory warrants further investigation.

Animals↗