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PubMed2001

Normalization of spatial learning despite brain damage in rats receiving ketamine after seizure-induction: evidence for the neuromatrix.

The concept of the neuromatrix assumes that all behaviours are associated with complex spatiotemporal electromagnetic fields within the brain. The same complex magnetic field can be supported potentially by different mosaics of neuronal associations and result in the same behaviours. In the present study the accuracy of long-term and short-term spatial memory for rats that had been treated with 100 mg/kg of ketamine immediately after the induction of seizures by lithium and pilocarpine did not differ from normal rats despite the conspicuous multifocal neuronal loss. A 30-min. delay of treatment with ketamine resulted in significant memory impairment. Whereas deficits in short-term memory were significantly correlated with cell loss within the CA field of the hippocampus, deficits in long-term memory were related to cell loss within specific thalamic-amygdaloid structures. Implications for the concept of the neuromatrix, if valid, are discussed.

Analgesics↗
PubMed1993

Spatial learning deficit and reduced hippocampal ChAT activity in rats after an ICV injection of streptozotocin.

ICV injections of streptozotocin (STREP) lower the glucose utilization of the brain and affect the cholinergic system. The present study was designed to evaluate whether STREP-treated rats have an impaired spatial discrimination performance in the Morris spatial navigation task. Performance in this task is sensitive to treatment with cholinergic antagonists. In contrast to young rats, middle-aged STREP-treated rats tended to have an impaired spatial discrimination performance in the Morris task at the end of training. In middle-aged STREP-treated rats, but not in control rats, spatial discrimination performance was associated with hippocampal choline acetyltransferase (ChAT) activity. The correlation between spatial discrimination performance in the Morris task and the decrease in hippocampal ChAT activity resembles the relation between cognitive and biochemical changes observed in Alzheimer's disease. Our findings suggest that STREP treatment of middle-aged rats may provide a relevant model for dementia.

Animals↗
PubMed2000

Reversible inactivation of the hippocampal mossy fiber synapses in mice impairs spatial learning, but neither consolidation nor memory retrieval, in the Morris navigation task.

The role played by hippocampal mossy fibers in the learning and memory processes implemented in the Morris swimming navigation task has been studied in C57BL/6 mice by selective and reversible inactivation of mossy fiber synaptic fields by diethyldithiocarbamate. The functional integrity of the mossy fibers proved essential for the storage of the spatial representation on the modifiable synapses of the recurrent collaterals of the CA3 pyramidal cells, whereas it is not necessary for the consolidation and recall of spatial memories. The results suggest that mossy fibers are preferentially involved in new learning. They are consistent with the hypothesis that the hippocampal CA3 region might act as an autoassociation memory.

Animals↗
PubMed1992

8-Hydroxy-2-(di-n-propylamino)tetralin impairs spatial learning in a water maze: role of postsynaptic 5-HT1A receptors.

1. The effects of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a 5-HT1A receptor agonist, on place navigation was studied by use of two spatial tasks in a water maze. 2. In the first experiment, rats treated subcutaneously with 100 and 300 (but not 30) micrograms kg-1 8-OH-DPAT were impaired in their ability to locate a hidden platform. The probe test confirmed the impairment of spatial navigation but the effect (time spent in the training quadrant) was quantitatively different, depending on whether 8-OH-DPAT was administered only before each training session, only before the probe test or in both conditions. 3. In the second experiment, rats received 150 micrograms 5,7-dihydroxytryptamine (5,7-DHT) intracerebroventricularly to destroy 5-hydroxytryptamine (5-HT)-containing neurones and 24 days later were examined for choice accuracy in a two-platform spatial discrimination task. 4. At 100 (but not 30) micrograms kg-1 8-OH-DPAT impaired rats' accuracy with no effect on latency and no errors of omission. In 5,7-DHT-treated rats, this dose had a greater effect, including errors of omission. Sham-operated rats injected with 300 micrograms kg-1 8-OH-DPAT were markedly impaired in accuracy but they had longer latencies and made more errors than controls. All the effects were increased in 5,7-DHT treated rats. 5. The results suggest that, at doses causing no apparent changes in motor behaviour or motivation, 8-OH-DPAT impairs spatial navigation by stimulating postsynaptic 5-HT1A receptors in the rat brain.

5,7-Dihydroxytryptamine↗
PubMed2001

Finding a goal on dry land and in the water: differential effects of disorientation on spatial learning.

Two previous studies, Martin et al. (J. Exp. Psychol. Anim. Behav. Process. 23 (1997) 183) and Dudchenko et al. (J. Exp. Psychol. Anim. Behav. Process. 23 (1997) 194), report that, compared to non-disoriented controls, rats disoriented before testing were disrupted in their ability to learn the location of a goal on a dry radial-arm maze task, but that both groups learned at the same rate in the Morris water maze. However, the radial-arm maze task was much more difficult than the water maze. In the current set of experiments, we examined the performance of control and disoriented rats on more comparable dry land and water maze tasks. Compared to non-disoriented rats, rats that were disoriented before testing were significantly impaired in locating a goal in a circular dry arena, but not a water tank. The results constrain theoretical explanations for the differential effects of disorientation on different spatial tasks.

Animals↗
PubMed2006

Spatial learning induces presynaptic structural remodeling in the hippocampal mossy fiber system of two rat strains.

Hebb (1949) proposed that after learning both presynaptic and postsynaptic structural changes form the neural substrate of long-lasting memory. Despite this, there are few instances linking presynaptic remodeling with learning. Here the authors demonstrate in two different rat strains that learning the location of a hidden platform induces expansion of the presynaptic hippocampal mossy fiber terminal field (MFTF) from the stratum lucidum to the distal stratum oriens (dSO). Prior to any training, Long Evans rats (LER) showed an extensive endogenous MFTF innervation of DSO, in contrast to Wistar rats (WR) that showed minimal innervation. LER showed better recall than WR on the hidden platform water maze task and a visible reversal water maze task. In both strains, significant MFTF expansion to dSO, spanning approximately 200 mum, was detected 7 days after training on the hidden platform task, but only LER showed significant MFTF expansion 24 h after training. It is attractive to think that the MFTF expansion to dSO contributes both to long-lasting memory formation and to facilitating spatial navigation strategies. The present results establish learning-induced axonal remodeling of the hippocampal MF system in adult rats as an especially useful system for exploring presynaptic morphological adjustments consequent to learning.

Animals↗
PubMed2006

High and low temperatures have unequal reinforcing properties in Drosophila spatial learning.

Small insects regulate their body temperature solely through behavior. Thus, sensing environmental temperature and implementing an appropriate behavioral strategy can be critical for survival. The fly Drosophila melanogaster prefers 24 degrees C, avoiding higher and lower temperatures when tested on a temperature gradient. Furthermore, temperatures above 24 degrees C have negative reinforcing properties. In contrast, we found that flies have a preference in operant learning experiments for a low-temperature-associated position rather than the 24 degrees C alternative in the heat-box. Two additional differences between high- and low-temperature reinforcement, i.e., temperatures above and below 24 degrees C, were found. Temperatures equally above and below 24 degrees C did not reinforce equally and only high temperatures supported increased memory performance with reversal conditioning. Finally, low- and high-temperature reinforced memories are similarly sensitive to two genetic mutations. Together these results indicate the qualitative meaning of temperatures below 24 degrees C depends on the dynamics of the temperatures encountered and that the reinforcing effects of these temperatures depend on at least some common genetic components. Conceptualizing these results using the Wolf-Heisenberg model of operant conditioning, we propose the maximum difference in experienced temperatures determines the magnitude of the reinforcement input to a conditioning circuit.

Adenylyl Cyclases↗
PubMed2006

Behaviorally induced synaptogenesis and dendritic growth in the hippocampal region following transient global cerebral ischemia are accompanied by improvement in spatial learning.

Reports have shown that damage to the adult brain can result in adaptive changes in regions adjacent or surrounding the site of the principal injury and that these changes may be modulated by rehabilitation training. In this study, we examined the influence of complex environment housing as a rehabilitation strategy on ischemia-induced synaptic and dendritic changes in the hippocampus. Thirty-six adult male Wistar rats were included in the study and assigned to either transient global cerebral ischemia or sham group. Following ischemic or sham surgery, rats were randomized to either complex environment housing (EC) or social condition (SC, paired housing) group during the rehabilitation period. Following 14 days of rehabilitation, rats were tested in the water maze. Our results showed that: (1) ischemic injury and EC housing were able to independently influence synaptogenesis and dendritic growth in the hippocampal area adjacent to the site of injury, and (2) EC housing-induced synaptic and dendritic changes were accompanied by enhanced functional recovery after transient global cerebral ischemia. These data suggest that behavioral experience during the rehabilitation period may be able to alter the neuronal circuitry in the surrounding region where primary neuronal damage was seen and that such modification may have contributed to functional improvement.

Analysis of Variance↗
PubMed1998

Differential involvement of the lateral and medial divisions of the septal area on spatial learning processes as revealed by intracranial self-administration of morphine in mice.

The present study was conducted to investigate the effects of morphine self-administration into either the medial or lateral divisions of the septal region on spatial discrimination abilities in mice. To this end, BALB/c mice received a dose of 5 ng/50 nl of morphine sulfate, via a stainless steel injection cannula, inserted into either the medial septal area (MS) or the lateral septal nucleus (LS), when they are close to the end of one of the two choice arms of a Y-maze (acquisition period). In these conditions a discrimination between the reinforced arm and the neutral arm is acquired in MS as well as in LS mice. However both acquisition and subsequent extinction (vehicle only available) was more rapid in the LS group than in the MS group. Moreover, during the extinction period, numerous escape attempts from the Y-maze were observed for MS mice. When the dose of morphine was raised to 50 ng the pattern of acquisition was unchanged in the LS group. In contrast animals of the MS group learned to avoid the arm where the higher dose of morphine was delivered thus allowing us to conclude that in MS animals the drug effect became aversive at this higher dose. This possibility was directly investigated in a second experiment by closing the access to the neutral arm. Thus, for a 5-ng dose the rewarding effect of morphine was demonstrated in both MS and LS groups by the decrease of self-administration latencies which, furthermore, were notably lower than in the discrimination situation. Moreover, with the dose of 50 ng of morphine the latencies were identical for the two groups and at their lowest value thus indicating that morphine had similar appetitive effects in MS as well as in LS mice in this situation. Thus, the previously observed deficit of MS subjects, including escape attempts, disappeared when the dose of morphine was raised and the experimental context simplified. These results which demonstrate differential functional properties of these two septal divisions are discussed in terms of conflict resulting from the strongly appetitive effects of the morphine which induces, in parallel, deleterious consequences on cognitive processing in MS self-injected mice.

Animals↗
PubMed1998

Stimulation of alpha-1 adrenergic receptors facilitates spatial learning in rats.

The present experiments were designed to examine the effects of alpha-1 adrenergic stimulation and inhibition on memory encoding and to investigate whether the alpha-1 adrenergic and muscarinic cholinergic systems interact in the regulation of spatial navigation behavior in the Morris water maze test and we also studied the effects of D-cycloserine, a partial agonist at the glycine binding site on the N-methyl-D-aspartate (NMDA) receptor complex, on the performance of scopolamine-treated rats in this task. Pre-training subcutaneous administration of St-587 (a putative alpha-1 agonist) at 1000 micrograms kg-1 or 1500 micrograms kg-1 improved water maze navigation to a hidden platform. Prazosin (an alpha-1 antagonist), 300-2000 micrograms kg-1, did not significantly impair the spatial navigation performance. Pre-training administration of prazosin 1000 micrograms kg-1, but not 300 micrograms kg-1, slightly potentiated the deficit in water maze navigation seen after scopolamine (200 micrograms kg-1, pre-training intraperitoneal injection). Pre-training administration of St-587 at a dose 1500 micrograms kg-1, but not 500 micrograms kg-1, slightly ameliorated the scopolamine-induced (200 micrograms kg-1) impairment in performance of rats. Pre-training administration of prazosin at doses 300 or 1000 micrograms kg-1 or St-587 at doses 500 micrograms kg-1 or 1500 micrograms kg-1 did not have any significant influence on the scopolamine-induced (200 micrograms kg-1) increase of swimming speed. Furthermore, D-cycloserine at the dose of 300 micrograms kg-1 but not 1000 or 3000 micrograms kg-1 reversed the scopolamine (200 micrograms kg-1)-induced deficit in acquisition of the water maze task but not the increase in motor output (increased swimming speed). These results indicate that the stimulation of alpha-1 adrenoceptors may facilitate the encoding of new information. These findings suggest that alpha-1 adrenergic mechanisms do not participate or at least are not the most critical part of the noradrenergic system in the interaction between noradrenaline and muscarinic receptors in the modulation of learning and memory. In addition, these results suggest that D-cycloserine may be effective in alleviating states of central cholinergic hypofunction.

Adrenergic alpha-1 Receptor Agonists↗
PubMed2005

Competition between landmarks in spatial learning: the role of proximity to the goal.

In two experiments, rats were trained to find a hidden platform in a Morris pool in the presence of two landmarks. Landmark B was present on all training trials, on half the trials accompanied by landmark A, on the remainder by landmark C. For rats in Group Bn, B was near the location of the platform; for those in Group Bf, B was far from the platform. Group Bn performed better than Group Bf on test trials to B alone, but significantly worse on test trials to a new configuration formed by A and C. Thus, the spatial proximity of B to the platform affected not only how well it could be used to locate the platform, but also its ability to prevent learning about other landmarks.

Animals↗
PubMed1994

Perinatal undernutrition impairs spatial learning in recovered adult rats.

Learning ability of adult rats undernourished at perinatal age and nutritionally recovered (D-rats) was assayed in the Morris water maze test as compared with controls (C-rats). D-rats showed longer escape latencies to locate a hidden platform in absence of proximal cues during the acquisition period. Swimming pre-training experience did not improve this shortcoming. Retention scores obtained 1, 3, 10 and 30 days after training showed that spatial information was efficiently consolidated after acquisition since D-rats performed as well as C-rats on retention tests. A cue learning task revealed no significant differences between both groups. These results suggest that perinatal undernutrition induces, even after a long period of nutritional recovery, a deficit in efficient place navigation in adult rats.

Analysis of Variance↗
PubMed2002

Pentylenetetrazol-induced recurrent seizures in rat pups: time course on spatial learning and long-term effects.

PURPOSE: Recurrent seizures in infants are associated with a high incidence of neurocognitive deficits. Animal models have suggested that the immature brain is less vulnerable to seizure-induced injury than is that in adult animals. We studied the effects of recurrent neonatal seizures on cognitive tasks performed when the animals were in adolescence and adulthood. METHODS: Seizures were induced by intraperitoneal injection of pentylenetetrazol (PTZ) for 5 consecutive days, starting from postnatal day 10 (P10). At P35 and P60, rats were tested for spatial memory by using the Morris water maze task. In adulthood, motor performance was examined by the Rotarod test, and activity level was assessed by the open field test. Seizure threshold was examined by inhalant flurothyl. To assess presence or absence of spontaneous seizures, rats were video recorded for 4 h/day for 10 consecutive days for the detection of spontaneous seizures. Finally, brains were examined for histologic evidence of injury with cresyl violet stain and Timm staining in the supragranular zone and CA3 pyramidal cell layers of the hippocampus. RESULTS: PTZ-treated rats showed significant spatial deficits in the Morris water maze at both P35 and P60. There were no differences in seizure threshold, motor balance, or activity level during the open field test. Spontaneous seizures were not recorded in any rat. The cresyl violet stain showed no cell loss in either the control or experimental rats. PTZ-treated rats exhibited more Timm staining in the CA3 subfield. However, the control and experimental rats showed similar Timm staining within the supragranular zone. CONCLUSIONS: Our findings indicate that recurrent PTZ-induced seizures result in long-term cognitive deficits and morphologic changes in the developing brain. Furthermore, these cognitive deficits could be detected during pubescence.

Age Factors↗
PubMed1992

Competitive and non-competitive NMDA receptor antagonists in spatial learning tasks.

The effects of the competitive N-methyl-D-aspartate (NMDA) receptor antagonists, CGP37849 (3 or 6 mg/kg i.p.) and its ethyl ester CGP39551 (5 or 15 mg/kg i.p.) and of the non-competitive NMDA receptor antagonist, dizocilpine (0.16 mg/kg; i.p.) on acquisition by rats of different spatial orientation tasks in an 8-arm radial maze were evaluated. Neither of the CGP compounds influenced locomotor activity during spontaneous alternation, only dizocilpine increased the number of arm entries (locomotion). Preferred angles between consecutive arm entries were changed by the high doses of CGP37849 (6 mg/kg), CGP39551 (15 mg/kg) and dizocilpine (0.16 mg/kg). The high doses of both CGP compounds as well as dizocilpine produced impairments in the acquisition of an egocentric orientation task and an allocentric reversal task indicated by an increased number of arm entries and re-entries. Such amnesic effects did not occur after administration of low doses of CGP37849 (3 mg/kg) and CGP39551 (5 mg/kg), doses which are sufficient to produce anticonvulsant and anticataleptic effects. In contrast, the non-competitive NMDA receptor antagonist, dizocilpine, produced amnesic effects over the entire behaviourally effective dose range.

2-Amino-5-phosphonovalerate↗
PubMed1993

Sex-related spatial learning differences after prenatal cocaine exposure in the young adult rat.

Prenatal cocaine exposure in humans is associated with a variety of adverse neurobehavioral effects. In the rat, in utero cocaine exposure has been shown to elicit learning impairment during early postnatal development. However, little research has focused on the persistence of these behavioral disruptions. The current study examines the long-term effects of prenatal cocaine exposure on learning performance during young adulthood. Fetal cocaine exposure evoked differential effects in male and female rats on radial-arm maze learning performance. Cocaine-treated females showed significantly impaired choice accuracy during acquisition of radial-arm maze performance when compared to control females. In contrast, cocaine-treated males showed no impairment and in fact showed significantly improved performance on one measure of choice accuracy. For both sexes, this effect was apparent during the final third of acquisition. No evidence was found to suggest altered sensitivity to anticholinergic drugs. While both nicotinic and muscarinic cholinergic antagonists caused significant impairments in memory performance, control and cocaine-exposed rats were effected equally. Single doses of these drugs which caused moderate memory deficits were chosen for use in the current study. The entire dose range should be evaluated to determine the relative sensitivity of cocaine-exposed and control animals to these drugs. The results of this study indicate that there are cognitive effects of prenatal cocaine exposure which persist into adulthood and the sex of the offspring seems to be critical.

Animals↗
PubMed1985

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.

Animals↗
PubMedDate not supplied

7-Nitro indazole, a selective neuronal nitric oxide synthase inhibitor in vivo, impairs spatial learning in the rat.

Nitric oxide (NO) is an intercellular messenger that has been suggested to have a role in learning and memory formation. Previous studies with nonselective NO synthase inhibitors have produced contradictory results in learning experiments. However, these drugs also produced blood pressure changes, as NO is an endothelial-derived relaxing factor. A novel NO synthase inhibitor, 7-nitro indazole (7-NI), as a dose (30 mg/kg i.p.) shown previously to inhibit neuronal NO synthase by 85% without affecting blood pressure, produced amnesic effects both in a water maze and in an 8-arm radial maze. Latency as well as distance was greater in the 7-NI group in the water maze while swim speed was not affected. Latency, working memory (WM), and reference memory (RF) errors were also higher in the 7-NI group in the 8-arm maze. At the end of the second training day, these differences were no longer apparent. However, on the fourth training day, a transfer test in the water maze showed that 7-NI had produced a spatial memory deficit, reducing quadrant bias and the number of annulus crossings. Learning of a visual cue task was not affected. No difference between groups was visible in an open field test. We conclude that neuronal NO synthase activity plays a role in learning and memory formation in the rat.

Animals↗
PubMed2005

Effects of estradiol on spatial learning, hippocampal cytochrome P450 19, and estrogen alpha and beta mRNA levels in ovariectomized female mice.

The brain is an important target organ for peripherally synthesized estrogen but it also has its own steroid biosynthesis producing estrogen from testosterone catalyzed by the aromatase enzyme. This study examined the effects of estrogen treatment in two spatial memory tasks, one-arm-baited radial arm maze and a position discrimination task in the T-maze in ovariectomized female mice. Hippocampal cytochrome P450 19 (encoding aromatase), and estrogen receptor alpha and beta gene expressions were also measured using real time quantitative polymerase chain reaction analysis. Estrogen (17beta-estradiol) was administered either tonically via s.c. minipellets or phasically via daily i.p. injections. In ovariectomized mice, the tonic estrogen decreased the number of reference memory errors in radial arm maze. Tonic estrogen treatment also up-regulated the expression of cytochrome P450 19 and estrogen receptors. In contrast, estrogen injections decreased the expression of cytochrome P450 19 and estrogen receptor alpha genes. The number of reference memory errors correlated negatively with estrogen receptor alpha expression. These findings indicate that peripheral estrogen levels affect neuronal estrogen synthesis by regulating the cytochrome P450 19 gene expression and also influence estrogen receptor alpha expression. The results also suggest that tonic rather than cyclic estrogen treatment might be more beneficial for cognitive functions.

Animals↗