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PubMed1998

Posterior parietal cortex lesions severely disrupt spatial learning in DBA mice characterized by a genetic hippocampal dysfunction.

C57BL/6 (C57) and DBA/2 (DBA) inbred mice with posterior parietal cortex or sham lesions were tested in a radial eight-arm maze task with all the paths baited. In the high learner C57 strain, parietal lesions produced a limited impairment of performance without affecting maze-running strategies while the same lesions were found to affect more severely performance in the poor learner DBA strain. Because (1) the processing of spatial information has been found to depend on the conjunctive participation of the hippocampus and the posterior parietal cortex, and (2) DBA mice represent a genetic model of hippocampal dysfunction, the fact that parietal lesions impair spatial performance more severely in the DBA strain suggests that the contribution of the posterior parietal cortex to spatial learning depends on the degree of functionality of the hippocampus.

Animals↗
PubMed2004

Effects of hypothermia and hyperthermia on attentional and spatial learning deficits following neonatal hypoxia-ischemic insult in rats.

We previously reported that rats exposed to neonatal hypoxic-ischemic (HI) insult showed selective and long-lasting learning and memory impairments in the plus maze, 8-arm radial maze, choice reaction time (CRT) task, and water maze, and that they showed severe brain injury to areas such as parietal cortex, hippocampus, striatum and thalamus. In this study, we examined the effects of hypothermia and hyperthermia on learning and memory deficits following neonatal HI insult. Seven-day-old Wistar rats were subjected to left carotid artery ligation followed by 2 h of hypoxia (8% O2/92% N2) under three different temperature conditions: 27 degrees C (hypothermia), 33 degrees C (normothermia) and 37 degrees C (hyperthermia) in temperature-controlled chambers. Hypothermia significantly reduced attentional deficits in the CRT task and spatial learning deficits in the water maze, and protected against severe brain injury in comparison with the control temperature. On the other hand, hyperthermia aggravated the behavioral deficits and brain injury. These outcomes clearly show that temperature regulation during HI insult plays an important role in the induction of behavioral and histological changes following neonatal HI insult in rats.

Analysis of Variance↗
PubMed2002

Transgenic mice expressing the human C99 terminal fragment of betaAPP: effects on spatial learning, exploration, anxiety, and motor coordination.

The functional consequence of beta-amyloid precursor protein (betaAPP) manipulation on behavior was assessed in Tg13592 mice, characterized by transgene expression of the 99 amino acid C-terminal sequence of human betaAPP in brain and skeletal muscle but with plaque formation only in muscle. By comparison to the C57BL/6 background strain controlled for age and gender, Tg13592 transgenic mice had fewer movements in an automated chamber and fewer enclosed arm entries in the elevated plus-maze. This hypoactivity was probably due to a loss in the motivation to explore novel environmental stimuli rather than motor weakness or anxiety. In addition, the acquisition of place learning in the Morris water maze task was impaired in Tg13592 mice. The transgenic mice were not impaired in a probe trial or while swimming toward a visible platform. These results are concordant with the hypothesis that transgene expression of the C-terminal sequence of human betaAPP in brain is sufficient for causing behavioral abnormalities. The hypoactivity and the spatial learning deficit were associated with higher cytochrome oxidase activity seen in thalamic nuclei, indicating that altered regional brain metabolism caused by betaAPP transgene expression may be responsible for the behavioral changes.

Amyloid beta-Protein Precursor↗
PubMed2004

Chronic prenatal ethanol exposure alters hippocampal GABA(A) receptors and impairs spatial learning in the guinea pig.

Chronic prenatal ethanol exposure (CPEE) can injure the developing brain, and may lead to the fetal alcohol syndrome (FAS). Previous studies have demonstrated that CPEE upregulates gamma-aminobutyric acid type A (GABA(A)) receptor expression in the cerebral cortex, and decreases functional synaptic plasticity in the hippocampus, in the adult guinea pig. This study tested the hypothesis that CPEE increases GABA(A) receptor expression in the hippocampus of guinea pig offspring that exhibit cognitive deficits in a hippocampal-dependent spatial learning task. Timed, pregnant guinea pigs were treated with ethanol (4 g/kg maternal body weight per day), isocaloric-sucrose/pair-feeding, or water throughout gestation. GABA(A) receptor subunit protein expression in the hippocampus was measured at two development ages: near-term fetus and young adult. In young adult guinea pig offspring, CPEE increased spontaneous locomotor activity in the open-field and impaired task acquisition in the Morris water maze. CPEE did not change GABA(A) receptor subunit protein expression in the near-term fetal hippocampus, but increased expression of the beta2/3-subunit of the GABA(A) receptor in the hippocampus of young adult offspring. CPEE did not change either [(3)H]flunitrazepam binding or GABA potentiation of [(3)H]flunitrazepam binding, but decreased the efficacy of allopregnanolone potentiation of [(3)H]flunitrazepam binding, to hippocampal GABA(A) receptors in adult offspring. Correlational analysis revealed a relationship between increased spontaneous locomotor activity and growth restriction in the hippocampus induced by CPEE. Similarly, an inverse relationship was found between performance in the water maze and the efficacy of allopregnanolone potentiation of [(3)H]flunitrazepam binding in the hippocampus. These data suggest that alterations in hippocampal GABA(A) receptor expression and pharmacological properties contribute to hippocampal-related behavioral and cognitive deficits associated with CPEE.

Animals↗
PubMed2004

Impaired SynGAP expression and long-term spatial learning and memory in hippocampal CA1 area from rats previously exposed to perinatal hypoxia-induced insults: beneficial effects of A68930.

Hypoxic encephalopathy is a common cause of neonatal seizures and long-term neurological cognitive deficits. In rats at postnatal days 10-12 (P10-P12), global hypoxia induced spontaneous seizures and chronic brain injury, mimicking clinical aspects of neonatal hypoxia. Synaptic Ras-GTPase activating protein (SynGAP) has important roles in RAS/MAPK-dependent synaptic plasticity and mammalian learning. We investigated possible alterations of SynGAP expression occurring in memory-impaired animals previously exposed to perinatal hypoxia insults. We also evaluated the therapeutic efficacy of A68930, a selective agonist of dopamine D1/D5 receptors, on perinatal hypoxia insults. In the hippocampal CA1 region, perinatal hypoxia insults (P10) led to a reduction in SynGAP expression associated with impairment in long-term spatial learning and memory performance at P45. The use of A68930 (at a dose of 1, 2, 3mg/kg, P17-P23) effectively attenuated the deleterious effects as described above. Our results may indicate the involvement of SynGAP in certain forms of brain injury, leading to long-term learning and memory deficits. A68930 may have clinical potential as a therapeutic agent for alleviation of long-term cognitive deficits in rats and other animal models.

Animals↗
PubMedDate not supplied

Influence of the shape of the experimental room on spatial learning in rats.

Rats and other mammals can orient themselves in their habitat and locate various goals using different learning strategies. When a cartographic or local strategy is used, the animals construct and store in their long-term memories a complex representation of the extramaze space. However, exactly what constitutes the behaviorally key components of the extramaze space is still little known. The purpose of this study was to investigate whether the shape of the environment that surrounds the animal is an informative factor when a cartographic strategy is used. Two experiments were performed in which the rats were trained to find food in the goal arm of a four-arm, plus-shaped maze. Experiment 1 shows that lesions to the hippocampus impair the acquisition of this task, which suggests that in fact, a cartographic strategy is necessary to solve it. In Experiment 2, in which only one group of neurologically intact rats was used, we directly manipulated the shape of the space around the maze. The results showed that once the animals have learned the task, the hiding of all the extramaze single landmarks while keeping intact the general shape of the experimental room does not affect performance. Only when the shape of the surrounding space was modified did the performance deteriorate significantly. These results are discussed in relation to the different components of the extramaze environment and the contribution of each of them to the spatial learning.

Animals↗
PubMed1993

Elevated seizure threshold and impaired spatial learning in transgenic mice with putrescine overproduction in the brain.

We have studied the role of putrescine by using transgenic mouse lines overexpressing the human ornithine decarboxylase gene in most of their tissues. The aberrant expression of the transgene is most strikingly manifested in the brain, leading to an increase of up to 20-fold in putrescine content. We report that the transgenic mice with grossly elevated putrescine in all brain regions analysed (cortex, striatum, hippocampus and cerebellum) showed a significantly elevated seizure threshold to chemical and electrical stimuli, and impaired performance in spatial learning and memory tests. The view that putrescine may be primarily responsible for these changes was supported by the fact that the concentrations of the major neurotransmitter amino acids, glutamate and GABA in the brain, were not changed in the transgenic animals, and by the finding that a further increase in brain putrescine, achieved by inhibition of the catabolism of L-ornithine, appeared to provide additional protection against electroshock-induced seizures. These results suggest that the commonly observed increase in ornithine decarboxylase activity and the massive increase in brain putrescine in connection with neuron damage is a neuroprotective measure rather than a cause of the damage.

Animals↗
PubMed2004

Bromocriptine reduces lipid peroxidation and enhances spatial learning and hippocampal neuron survival in a rodent model of focal brain trauma.

Oxidative stress is a significant contributor to the secondary sequelae of traumatic brain injury (TBI), and may mediate subsequent neurobehavioral deficits and histopathology. The present study examined the neuroprotective effects of bromocriptine (BRO), a dopamine D2 receptor agonist with significant antioxidant properties, on cognition, histopathology, and lipid peroxidation in a rodent model of focal brain trauma. BRO (5 mg/kg) or a comparable volume of vehicle (VEH) was administered intraperitoneally 15 min prior to cortical impact or sham injury. In experiment 1, spatial learning was assessed in an established water maze task on post-surgery days 14-18, followed by quantification of hippocampal cell survival and cortical lesion volume at 4 weeks. In experiment 2, rats were sacrificed 1 hr post-surgery, and malondialdehyde (MDA), the end product of lipid peroxidation, was measured in the frontal cortex, striatum, and substantia nigra using a thiobarbituric acid reactive substances assay. The TBI+BRO group was significantly more adept at locating a hidden platform in the water maze compared to the TBI+VEH group and also exhibited a greater percentage of surviving CA3 hippocampal neurons. TBI increased MDA in all examined regions of the VEH-treated, but not BRO-treated group versus SHAMs. MDA was significantly decreased in both the striatum (4.22 +/- 0.52 versus 5.60 +/- 0.44 nmol per mg/tissue +/- SEM) and substantia nigra (4.18 +/- 0.35 versus 7.76 +/- 2.05) of the TBI+BRO versus TBI+VEH groups, respectively, while only a trend toward decreased MDA was observed in the frontal cortex (5.44 +/- 0.44 versus 6.96 +/- 0.77). These findings suggest that TBI-induced oxidative stress is attenuated by acute BRO treatment, which may, in part, explain the benefit in cognitive and histological outcome.

Animals↗
PubMed2003

Repeated exposures to subthreshold doses of chlorpyrifos in rats: hippocampal damage, impaired axonal transport, and deficits in spatial learning.

Organophosphorus (OP) compounds are detectable in the environment for years after use and endanger many populations. Although the effects of acutely toxic doses of many OP compounds are well described, much less is known about repeated low-level exposures. The purpose of these studies was to further evaluate potential toxicological effects of the extensively used OP pesticide chlorpyrifos (CPF) in rats. CPF, across a range of subthreshold doses (i.e., for acute toxicity), reduced rearing and sniffing activity and the magnitude of weight gain over 14 days of repeated exposure. Performance in a spatial learning task was impaired after 14 days of exposure to CPF (18.0 and 25.0 mg/kg) when testing was initiated 24 h after the last injection but not after a 14-day washout. However, inhibition of both fast anterograde and retrograde axonal transport was observed for up to 20 days after exposure to 25.0 mg/kg CPF. Studies using hippocampal cultures indicated that 8 days of continuous exposure to the parent compound, CPF (> or =100 micro M), resulted in cell toxicity and death. Furthermore, a dose (2.5 mg/kg) of CPF that had no effects on weight gain or memory performance when administered 5 days per week over 38 days impaired forelimb grip strength in the later days of testing. Collectively, these results indicate that repeated exposures to subthreshold doses of CPF may lead to growth retardation, behavioral abnormalities, and muscle weakness. Some of these symptoms may be attributed to effects of the OP on axonal transport.

Animals↗
PubMed2005

[Chronic pain impairs spatial learning and memory ability and down-regulates Bcl-2 and BDNF mRNA expression in hippocampus of neonatal rats].

OBJECTIVE: To investigate the effect and possible mechanism of complete Freund's adjuvant induced chronic pain on later function of learning and memory in neonatal rats. METHODS: Sixty Sprague-Dewley rat pups (10 litters of 6 pups) were randomly divided into control group and chronic pain group (n = 30 in each group). In the chronic pain group, left hind paws of the rats were treated with subcutaneous injection of 20 microl of CFA on postnatal day-2. The control rat pups received normal saline. The hippocampus of rats were separated on postnatal days 10 and 21 (one rat in each group from every litter, n = 10). The expression of Bcl-2 and BDNF mRNA were investigated by RT-PCR. Morris water maze tests were performed on day 21 (one rat in each group from every litter, n = 10). RESULTS: In hidden-platform training of Morris water maze, the mean escape latency of rats in the chronic pain group were longer than that of the control rats. In spatial probe tests, the average percentages of the swimming time and distances in the platform quadrant in the pain group rats were less than those in the control group. There was no significant difference in visible-platform training between the two groups. The Bcl-2 and BDNF mRNA expressions in hippocampus of the pain group rats were lower than those in the control at day 10, but no significant difference at day 21. CONCLUSION: Chronic pain stress induced by CFA impairs the spatial learning and memory function in neonatal rats. These effects might exert through down-regulating Bcl-2 and BDNF mRNA expression in the hippocampus.

Animals↗
PubMed1999

Deletion of the ryanodine receptor type 3 (RyR3) impairs forms of synaptic plasticity and spatial learning.

Deletion of the ryanodine receptor type 3 (RyR3) results in specific changes in hippocampal synaptic plasticity, without affecting hippocampal morphology, basal synaptic transmission or presynaptic function. Robust long-term potentiation (LTP) induced by repeated, strong tetanization in the CA1 region and in the dentate gyrus was unaltered in hippocampal slices in vitro, whereas weak forms of plasticity generated by either a single weak tetanization or depotentiation of a robust LTP were impaired. These distinct physiological deficits were paralleled by a reduced flexibility in re-learning a new target in the water-maze. In contrast, learning performance in the acquisition phase and during probe trial did not differ between the mutants and their wild-type littermates. In the open-field, RyR3(-/-) mice displayed a normal exploration and habituation, but had an increased speed of locomotion and a mild tendency to circular running. The observed physiological and behavioral effects implicate RyR3-mediated Ca(2+) release in the intracellular processes underlying spatial learning and hippocampal synaptic plasticity.

Animals↗
PubMed1992

Genotype-dependent involvement of limbic areas in spatial learning and postlesion recovery.

Male C57BL/6 (C57) and DBA/2 (DBA) mice with hippocampal, amygdaloid, or sham lesions were tested in a radial eight-arm maze 1 or 4 weeks after surgery. The results show that the effect of the lesions varied according to the performance level of the strain considered. In the high-learner C57 strain, the two lesions impaired acquisition at both postlesion intervals. Conversely, in the low-learner DBA strain, only hippocampal lesions impaired acquisition 1 week but not 4 weeks after lesioning. It is hypothesized that if more limbic areas are involved in controlling spatial learning in C57 mice, these structures could be processing distinct but complementary memory attributes, thus contributing to a high baseline performance. This, however, also entails an increased sensitivity of C57 performance to brain damage with reduced possibilities of long-term recovery.

Amygdala↗
PubMed1990

Org2766 improves performance of rats with unilateral lesions in the fimbria fornix in a spatial learning task.

ACTH and related peptides are known for their effects on behavior and for their efficacy on peripheral nerve regeneration. More recently, evidence demonstrating neurotrophic effects of Org2766 on recovery after damage of the central nervous system has become available. Aging studies indicated that particularly the hippocampus appears susceptible to peptide treatment. Therefore, in this study the neurotrophic influence of Org2766 on recovery of hippocampal functioning was studied after transection of the fimbria fornix connection. Analogous to results obtained with recovery of sensorimotor function following peripheral nerve damage a chronic treatment with Org2766 facilitates recovery of the impaired function, i.e. spatial learning in a Morris maze. However, the lesion-induced impairment of avoidance behavior was not influenced by the peptide treatment.

Adrenocorticotropic Hormone↗
PubMed2005

Age-dependent enhancement of hippocampal long-term potentiation and impairment of spatial learning through the Rho-associated kinase pathway in protein tyrosine phosphatase receptor type Z-deficient mice.

Although protein tyrosine phosphatases (PTPs) are expressed abundantly in the brain, their roles in synaptic plasticity have not been well elucidated. In this study, we have examined the physiological functions of Ptprz, which is a receptor-type PTP expressed predominantly in the brain as a chondroitin sulfate proteoglycan. We have examined phenotypes of mutant mice deficient in Ptprz using electrophysiological, pharmacological, and behavioral approaches. Mutant mice exhibit enhanced long-term potentiation (LTP) in the CA1 region of hippocampal slices and impaired spatial learning abilities in an age-dependent manner: young adult (<10 weeks old) mutant mice show normal LTP and learning abilities in the Morris water maze task, whereas adult (>13 weeks old) mutant mice exhibit enhanced LTP and impairment in the task. The enhanced LTP is specifically canceled out by pharmacological inhibition of Rho-associated kinase (ROCK), a major downstream effector of Rho. These findings suggest that the lack of Ptprz leads to aberrant activation of ROCK and resultantly to enhanced LTP in the slice and learning impairments in the animal.

Aging↗
PubMed1994

A GABAergic mechanism in the medial septum influences cortical arousal and locomotor activity but not a previously learned spatial discrimination task.

The effect of perfusion of the medial septum (MS) with artificial cerebrospinal fluid (CSF) on three consecutive daily trials was assessed on the amount of sleep/wake as determined by measurement of electro-encephalographic activity (EEG), spontaneous locomotor activity as determined by open field test and spatial discrimination task as determined by Morris water maze performance. Perfusion of the MS on the fourth trial with the GABAA agonist, muscimol (10-100 microM) produced an increase in cortical arousal and increased spontaneous locomotor activity. Perfusion with muscimol (5 microM) had an effect not distinguishable from perfusion with CSF alone. However doses of muscimol that reduced slow wave sleep (SWS) and increased locomotion had no effect on the memory and performance of a learned spatial discrimination task.

Animals↗
PubMed1998

Dissociation between genes activated in long-term potentiation and in spatial learning in the rat.

We have compared changes in mRNA of three genes, zif268, raf B, and syntaxin 1 B, following the unilateral induction of long-term potentiation (LTP) in rats previously trained in a water maze, and in behaviourally naive animals. mRNA of all three genes was enhanced in the potentiated dentate gyrus of naive animals 3 h after the induction of LTP. Training did not affect expression of mRNA for zif268 or for syntaxin 1 B. Expression of raf B was enhanced by training, and in trained animals the LTP-associated increase in expression of raf B was occluded. These results suggest that LTP and spatial training engage a common pathway utilizing an increase in mRNA for raf B, and demonstrate a dissociation between LTP and spatial learning with respect to expression of zif268 and syntaxin 1B.

Animals↗
PubMedDate not supplied

CYP2D1 polymorphism in methamphetamine-treated rats: genetic differences in neonatal mortality and effects on spatial learning and acoustic startle.

d-Methamphetamine (MA) is one of more than two dozen drugs included in the cytochrome P450-mediated "debrisoquine oxidation polymorphism" panel. The human gene (CYP2D6) is responsible for the "poor metabolizer" (PM) and "extensive metabolizer" (EM) phenotypes for drugs such as MA; a similar polymorphism (the CYP2D1 gene) exists in rats. Female Black or Dark Agouti rats exhibit the PM phenotype, whereas Sprague-Dawley (SD) rats show the EM trait. We sought to test the possibility that these strains of rats might exhibit altered MA-induced developmental neurotoxicity. Neonatal exposure to MA on days 11-20 has previously been shown to induce spatial learning deficits in Sprague-Dawley rats when tested as adults. Therefore, in the present experiment, on postpartum days 11 through 20, ACI (Black Agouti) and SD progeny were administered 30 mg/kg MA twice daily. MA treatment caused larger increases in mortality in ACI than in SD rats, suggesting that decreased MA metabolism leads to enhanced toxicity and lethality. Female offspring were assessed behaviorally as adults. No differences were observed in acoustic startle or straight swimming channel performance. In the Morris maze, both MA-treated rat strains showed longer latencies to find the hidden platform during acquisition, reinstatement, and shift trials, and spent less time in the target quadrant on probe trials; no strain differences in learning were found. Although these data do not support our hypothesis that MA-induced developmental neurotoxicity might be enhanced in the ACI rat, this interpretation is tempered by the high mortality rate (65%) of MA-treated ACI neonates, suggesting a possible "survivor effect" in this strain.

Acoustic Stimulation↗
PubMed1996

Detailed behavioral analysis of water maze acquisition under systemic NMDA or muscarinic antagonism: nonspatial pretraining eliminates spatial learning deficits.

A detailed behavioral analysis of water-maze acquisition showed that the N-methyl-D-aspartate (NMDA) antagonist NPC17742 and the muscarinic antagonist scopolamine caused sensorimotor disturbances in behaviors required for maze performances and that these correlated with acquisition impairments in both hidden and visible platform versions of the maze in male rats. Behavioral disturbances included thigmotaxic swimming, swimming over and deflecting off the platform, abnormal swim behavior, and hyperactivity. Rats familiar with the behavioral strategies involved in the task performed normally under NPC17742 or scopolamine. The results indicated that drug-induced sensorimotor disturbances contributed to poor acquisition scores in naive rats. NMDA or muscarinic activity may contribute to but do not appear to be essential for spatial learning in the water maze.

Amino Acids↗