Spatial learning and the saturation of long-term potentiation.
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Role of heparin-binding growth-associated molecule (HB-GAM) in hippocampal LTP and spatial learning revealed by studies on overexpressing and knockout mice.
Heparin-binding growth-associated molecule (HB-GAM) is an extracellular matrix-associated protein with neurite outgrowth-promoting activity and which is suggested to be implicated in hippocampal synaptic plasticity. To study the functions of HB-GAM in adult brain we have produced HB-GAM overexpressing mice and compared phenotypic changes in the transgenic mice to those in the HB-GAM null mice. Both mutants were viable and displayed no gross morphological abnormalities. The basal synaptic transmission was normal in the area CA1 of hippocampal slices from the genetically modified mice. However, long-term potentiation (LTP) was attenuated in the mice overexpressing HB-GAM, whereas enhanced LTP was detected in the HB-GAM-deficient mice. Changes in LTP seen in vitro were paralleled by behavioral alterations in vivo. The animals overexpressing HB-GAM displayed faster learning in water maze and decreased anxiety in elevated plus-maze, while the HB-GAM knockouts demonstrated an opposite behavioral phenotype. These results show that HB-GAM suppresses LTP in hippocampus and plays a role in regulation of learning-related behavior.
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Pharmacological dissociation between the spatial learning deficits produced by morphine and diazepam.
This study sought to determine whether the place learning deficits produced by diazepam are a secondary result of opioid release. Rats pretreated with diazepam (3 mg/kg) or morphine (15 mg/kg) were trained in the Morris water maze. Diazepam impaired place learning-slowing acquisition and preventing the formation of a quadrant preference. Morphine also slowed acquisition, but did not prevent place learning, and impaired escape to a visible platform. Flumazenil blocked the deficits produced by diazepam, but not morphine. Naloxone (2 mg/kg) blocked the deficits produced by morphine, but not diazepam. A high dose of naloxone (10 mg/kg) slowed acquisition, and exacerbated the deficit produced by diazepam. These results demonstrate that diazepam interferes with mnemonic processes through endogenous benzodiazepine receptors, independently of opioidergic systems. Further, they suggest that morphine interferes with motivational processes through opioidergic systems, independently of endogenous benzodiazepine systems.
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Methamphetamine exposure during early postnatal development in rats: I. Acoustic startle augmentation and spatial learning deficits.
Methamphetamine (MA) induces neurotransmitter reductions and neurotoxicity at high doses in adult animals, but its effects on early brain development and behavior have received less attention. In this experiment the effects of MA exposure during a period equivalent to the human third trimester were examined. Rats (Sprague-Dawley CD) were injected subcutaneously with d-MA (30 mg/kg b.i.d.) early in postnatal development (days 1-10), later (postnatal days 11-20), or with water during both of these periods. Both early and later MA-exposed offspring exhibited augmented acoustic startle and impaired performance in a complex multiple-T water maze. Only the early MA exposure group showed a persistent deficit in weight while only the later MA exposure group showed impaired learning in the Morris hidden platform maze. Effects on locomoter activity are reported in the accompanying article. It was concluded that the effects of MA are both long lasting and stage dependent and involve cognitive as well as arousal functions.
Acoustic Stimulation↗
Chronic treatments with cholinoceptor drugs influence spatial learning in rats.
Nicotine, scopolamine, oxotremorine, diisopropyl-fluorophosphate (DFP) and tetrahydroaminoacridine (THA) were administered chronically to different groups of rats in doses reported to alter central muscarinic and/or nicotinic receptor numbers. Beginning 24 h after final drug injection, the groups were compared to a vehicle control group on acquisition of a hidden platform position in the Morris water maze over 20 trials with a 30-min inter-trial interval. Chronic treatment with either nicotine or scopolamine significantly improved the rate of learning, but oxotremorine and DFP retarded learning and THA had no effect on learning. The chronic drug effects on behaviour were consistent with known effects of the injected drugs on muscarinic and nicotinic binding in the forebrain and on the sensitivity of frontal cortex neurones to iontophoretically applied cholinoceptor agonists. However, alternative explanations for the observed changes cannot be ruled out, since the drugs used are known to have a wide range of effects on other neurotransmitters.
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Rats with low levels of brain docosahexaenoic acid show impaired performance in olfactory-based and spatial learning tasks.
Studies were carried out to determine if decreased levels of central nervous system docosahexaenoic acid (DHA), a result of consuming an n-3-deficient diet, had an effect on learning- and memory-related behaviors in adult male rats. Females were reared on an n-3-deficient or n-3-adequate diet beginning at 21 d of life. Their male pups, the F2 generation, were weaned to the diet of the dam and tested at 9-12 wk of age. An olfactory-based discrimination and Morris water maze task were used to assess performance. Whole brain was collected after the behavioral experiments and central nervous system fatty acid content was analyzed in olfactory bulb total lipid extracts. F2 generation male rats consuming the n-3-deficient diet had an 82% decrease in DHA compared to rats consuming the n-3-adequate diet. The n-3-deficient animals made significantly more total errors in a 7-problem, 2-odor discrimination task compared to the n-3-adequate group. Furthermore, the escape latency in the Morris water maze task was significantly longer for the n-3-deficient rats compared to the n-3-adequate rats. These results indicate that rats with decreased DHA levels in the central nervous system perform poorer in these tasks compared to rats with higher DHA levels and suggest the presence of learning deficits in these animals.
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Similar target, different effects: late-onset ataxia and spatial learning in prion protein-deficient mouse lines.
Several lines of mice with targeted deletion of the prion protein gene (Prnp) have been produced, some of them appearing phenotypically normal, others developing late-onset ataxia. This has been tentatively attributed to the size of the targeted deletion in the Prnp gene. but a masking role of genetic background could not be excluded. Thus, we have crossed an ataxic mutant line with large deletion of Prnp (Ngsk Prnp0/0) with a knockout line showing only partial deletion of Prnp and no neurological deficits (Zrchl Prnp0/0). A F2 generation was then studied for up to 70 weeks for co-segregation of lesion size and behavioral phenotype, including cognitive and neurological anomalies. These mice were later crossed with a recently generated PrP-deficient line also having a large deletion and late-onset ataxia (Zrch2 Prnp0/0). They underwent similar testing for up to 90 weeks. The ataxic phenotype always co-segregates with large homozygous deletions involving either the Ngsk or the Zrch2 allele, independent of genetic background or sex. Compound heterozygous Zrchl/Ngsk mice or Zrch1/Zrch2 mice showed intermediate neurological phenotypes, suggesting a gene-dosage effect of large deletions. At 12 weeks of age, large deletions were also associated with minor non-cognitive impairments in water maze learning, and hyperactivity in open field and elevated zero maze. These impairments were not predictive for the development of ataxia. Thus, the neurological deficits are closely associated with large deletions, which entail an upregulation of the recently discovered prion Doppel protein (Dpl), while genetic background factors seem to be responsible for shifting the onset of neurological symptoms.
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Effect of ultralow doses of antibodies to S-100 antigen (Proproten-100) on spatial learning in rats.
In experiments on rats we studied the effect of potentiated antibodies against S-100 antigen on training a step-down passive avoidance task and choice between drinking bowls with sucrose solution. Peroral treatment with antibodies accelerated inhibition of ineffective and punished locomotor reactions in animals.
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The nootropic compound BMY-21502 improves spatial learning ability in brain injured rats.
Although long-lasting cognitive dysfunction often follows clinical traumatic brain injury (TBI), few pharmacologic regimens have been developed to treat post-traumatic cognitive deficits. We have previously shown that, in the rat, experimental lateral fluid-percussion (FP) brain injury induces a profound impairment in retrograde memory. In the present study, we characterized alterations in the ability of rats to learn a novel task following lateral FP brain injury and examined the potential modulatory effects of the nootropic cognitive enhancer BMY-21502 on post-injury learning. Male Sprague-Dawley rats were subjected to lateral (parasagittal) FP brain injury of moderate severity (2.4 atm) or sham surgery (no injury). On days 7 and 8 post-injury, animals were tested in a Morris water maze for their ability to learn to navigate to a submerged, invisible platform using external visual cues. BMY-21502 (10 mg/kg) or vehicle was administered 30 min prior to the first trial on both days. A highly significant (P < 0.001) impairment in post-injury learning was observed in vehicle-treated brain-injured animals compared with vehicle-treated sham animals. Injured animals treated with BMY-21502 at one week post-injury showed significantly (P < 0.05) improvement in post-injury learning ability compared to injured animals treated with vehicle. Paradoxically, in uninjured control animals BMY-21502 treatment appeared to worsen learning scores. The results of this study indicate that BMY-21502 may be useful for attenuating the dysfunction in learning ability that occurs following TBI.
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The effects of NGF and fetal cell transplants on spatial learning after intradentate administration of colchicine.
This study was performed to assess the effects of NGF infusion alone or in combination with fetal hippocampal transplants on recovery of function after damage to hippocampal dentate granule cells. Two groups of male Fischer-344 rats received bilateral infusions of colchicine (COLCH; 2.5 micrograms/site) or artificial cerebrospinal fluid (ACSF; 0.5 microliter) through chronic indwelling cannulae into the dentate gyrus. At the time of COLCH injection, a unilateral intracerebroventricular (ICV) cannula was implanted. One week later, when animals were tested in activity chambers for 60 min, COLCH-treated rats showed a significant increase in spontaneous locomotor activity. Two weeks after COLCH treatment, animals were assigned to various post-treatment groups and received 1.0 microliter of rat fetal hippocampal cell suspensions (ED-17 or 18) or Earle's basic salt solution in the same site as previous hippocampal infusions. Modified Alzet miniosmotic pumps (0.25 microliter/h) containing NGF (10 ng/microliter) or ACSF with cytochrome C (20 ng/microliter) were implanted subcutaneously and attached to the previously implanted ICV cannulae. The animals were tested for learning ability in a Morris water maze task starting 6 or 12 weeks post-COLCH. During both test periods, COLCH lesions significantly impaired acquisition and retention. At 6 weeks postlesion, NGF treatment ameliorated this COLCH-induced behavioral deficit while the presence of transplants did not ameliorate the COLCH-induced learning deficit. COLCH/transplant/NGF-treated rats performed better than both COLCH-lesioned rats with or without transplants. At 12 weeks postlesion COLCH-induced behavioral deficits were not ameliorated by NGF or transplants. Morphological examination performed after behavioral testing confirmed the presence of viable transplants and COLCH-induced granule cell loss. Exogenous NGF infusions appeared to have no effect on the morphological measures taken. These data demonstrate a time-dependent facilitative effect of exogenously applied NGF on functional deficiencies produced by experimentally induced neurodegeneration in the dentate gyrus of the hippocampus.
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A non-modality specific impairment in spatial learning after fornix lesions in monkeys.
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Animals↗
A novel NMDA antagonist, MK-801, impairs performance in a hippocampal-dependent spatial learning task.
N-Methyl-d-aspartate (NMDA) receptors have been implicated with the triggering of long-term potentiation, a currently studied physiological model of learning and memory. The compound (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate (MK-801) has recently been classified as a potent and selective NMDA antagonist acting at the associated ion channel. After determination of the highest intraperitoneal dose of MK-801 at which increases in activity (measured in photocell activity cages and 3-arm maze) were not observed (0.2 mg/kg), rats that had been previously trained to obtain food pellets in an 8-arm radial maze up to criterion were tested with 0.1 and 0.2 mg/kg doses. Dose-related decreases in "efficiency" in the task were found. The present findings support the suggestion that NMDA antagonists cause impairments in "working memory" and also support the status of long-term potentiation as a physiological model of memory.
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Effect of oxiracetam on scopolamine-induced amnesia in the rat in a spatial learning task.
The effects of the nootropic agent 4-hydroxy-2-oxopyrrolidinoacetamide (oxiracetam) on memory and performance impairments induced by scopolamine were evaluated in the Morris water maze task. No effect was seen on the performance of rats when treated with oxiracetam (30 mg/kg, IP) alone. Task performance of scopolamine (0.2 mg/kg, SC)-treated rats was impaired as compared to that of control animals. The behavioral deficits expressed in the task by scopolamine treatment were attenuated by the same dose of oxiracetam.
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Effect of DAU 6215, a novel 5-HT3 receptor antagonist, on scopolamine-induced amnesia in the rat in a spatial learning task.
The effects of different doses (1, 10, 30, and 100 micrograms/kg, IP) of a new 5-hydroxytryptamine3 (5-HT3) receptor antagonist, 3-alpha-tropanyl)1H-benzimidazolone-3-carboxamide chloride (DAU 6215), on memory and performance deficits induced by SC 0.2 mg/kg scopolamine were assessed in the Morris water maze task. No effect was observed on the performance of rats treated with DAU 6215 alone. The doses of 10 and 30 micrograms/kg DAU 6215 attenuated these scopolamine-induced behavioral deficits.
Amnesia↗
The effects of dorsal noradrenergic bundle lesions on spatial learning, locomotor activity, and reaction to novelty.
The dorsal noradrenergic bundle (DNB) of male Wistar rats was lesioned bilaterally using intracerebral injections of 6-hydroxydopamine neurotoxin. Some of the rats were trained in a water maze using an "alternation" strategy, where the two positions of the hidden platform in the pool were changed between successive trials in the daily tests, and other rats in a water maze, where the temperature of the water was lowered to about 11 degrees C. The rats trained in the cold-water maze were also tested in open-field and saccharin neophobia tests. No differences were found between the two groups in learning of water maze tasks or in locomotor activity in the open-field tests. However, the saccharin neophobia test revealed an increased neophobia in the DNB-lesioned rats.
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The effects of forebrain ischaemia on spatial learning.
Rats were subjected to 15 min of forebrain ischaemia using the 4-vessel occlusion method. Following recovery they were trained using place navigation learning in a Morris water maze and forced choice rewarded alternation in a T-maze. Ischaemic rats were impaired in place navigation learning but the deficit was transient and there was no impairment of subsequent transfer test performance. Food-rewarded forced-choice alternation in a T-maze revealed a persistent impairment in ischaemic rats. The behavioural deficits were associated with neuropathological damage in the CA1 cell layer of the dorsal hippocampus with varying degrees of damage in layers CA2, CA3 and CA4. Granule cells in the dentate gyrus were not visibly affected. Variable amounts of lesion damage were found in the dorsolateral striatum. Ischaemic rats are therefore impaired on both place navigation and forced choice rewarded alternation, suggesting that ischaemic brain damage affects reference and working memory processes to different extents. Forced choice alternation may be the more sensitive method of assessing cognitive changes caused by forebrain ischaemia.
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Spatial learning during the course of autoimmune disease in MRL mice.
The present study examines whether autoimmune MRL-lpr mice develop impairments in learning and memory that correlate with changing severity of lupus-like disease. MRL-lpr mice (n = 20) were tested in the Morris water-maze at 12, 14, 16 and 18 weeks of age. Age-matched controls were congenic MRL +/+ mice (n = 20) that develop the disease much later. Immune status was assessed by the presence of anti-nuclear antibodies (ANA), brain-reactive antibodies, proteinuria, and haematocrit. Learning rates and memory retention did not differ between the substrains, and did not correlate or deteriorate with advancing age and autoimmunity. However, the baseline performance level in autoimmune MRL-lpr mice was shifted, as evidenced by a consistently longer task-solving latencies. Thigmotaxic swimming (along the pool wall) was pronounced in the MRL-lpr group, and was associated with the observed difference in performance. The present study does not support the notion that learning/memory abilities of autoimmune MRL-lpr mice are impaired per se, but may support the hypothesis that the rapid progress of humoral autoimmunity affects the emotionality of lupus-prone mice.
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Stimulus configuration, spatial learning, and hippocampal function.
Schmajuk and DiCarlo (Psychol. Rev., 99 (1992) 268-305) introduced a neural network, which utilizes a biologically plausible backpropagation procedure, to describe configural paradigms in classical conditioning. The model correctly describes many experimental results under the assumption that aspiration lesions of the hippocampus eliminate (a) the competition between simple and configural stimuli to gain association with the unconditioned stimulus and (b) the adjustment of initially random configural stimuli. The present study extends the network to describe place learning. Under the assumption that ibotenic acid lesions of the hippocampus only impair the adjustment of initially random configural stimuli, the model correctly shows that ibotenic acid lesions might spare a configural discrimination but impair place learning. In general, the results are taken to support a hippocampal role in the modulation of stimulus configuration.
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