Non-spatial Learning Research Articles

Paired-associate learning is unaffected by combined hippocampal and parahippocampal lesions in homing pigeons.

To examine whether the avian hippocampus-parahippocampus (HF) is necessary for nonspatial, paired-associate learning, as has been suggested for rodents, HF-lesioned and control homing pigeons were tested on a visual paired-associate learning task. Both groups learned equally well to discriminate trials that consisted of a stimulus preceded by its paired associate from trials that consisted of a stimulus preceded by stimuli from other paired associates (mispair trials), even when a mispair was experienced for the first time. The groups also learned equally well not to respond to 2 stimuli that were never rewarded. The results demonstrate that HF lesions do not impair nonspatial paired-associate learning in birds, suggesting that the role of HF in nonspatial cognition differs between birds and mammals.

Cognitive impairment in spontaneously hypertensive rats: role of central nicotinic receptors. I

Both human essential hypertension and genetically induced hypertension in rats have been associated with a range of impairments of cognitive ability. The spontaneous hypertensive rat (SHR) previously has been shown to exhibit a decrease in the expression of brain nicotinic acetylcholine receptors, a factor that could play a role in the impaired ability of this strain in the performance of learning and memory-related tasks. The purpose of this study was to help determine whether task impairment by SHR was related to the reduced expression of central nicotinic acetylcholine receptors. Twelve-week-old SHR were tested in two phases of a water maze (spatial memory) task, and their performance was compared with that of two age-matched normotensive strains, Wistar Kyoto (WKY) and Wistar rats. During Phase 1, SHR exhibited significantly increased latencies to locate a hidden platform as compared with either WKY or Wistar rats. During Phase 2 (subsequent series of trials after a 4-day inter-phase period), where rats were required to find a new platform location, SHR again exhibited significantly impaired performance compared to the normotensive strains. In a single trial passive avoidance paradigm, SHR again displayed significantly reduced avoidance behavior as compared with both WKY and Wistar rats. In consecutive coronal sections, the density of [ 3H]cytisine binding sites was decreased in SHR by up to 25% in about half of the brain regions examined, with the deficits particularly apparent in cephalic regions. The binding of [ 125I]α-bungarotoxin to brain sections also was decreased in SHR; however, only certain brain areas exhibited significant interstrain differences. These alterations in the expression of putative nicotinic receptor subtypes in SHR were not due to changes in the density of cholinergic neurons since there were no interstrain differences in the binding densities for [ 3H]vesamicol, which labels the vesicular acetylcholine transporter. Moreover, the magnitude of nicotine-stimulated rubidium efflux from cortical and striatal synaptosomes in vitro was significantly reduced in samples derived from SHR as compared with those from normotensive rats. These results are consistent with the possibility that a reduction in the expression of cortical nicotinic receptors in SHR plays a role in this strain's impaired performance of both spatial and non-spatial learning and memory-related tasks.

Deficits in Water Escape Performance and Alterations in Hippocampal Cholinergic Mechanisms Associated With Neonatal Monosodium Glutamate Treatment in Mice

Mice treated neonatally with monosodium glutamate (MSG) were found to have learning and memory deficits in performing a non-spatial water escape task. Scopolamine impaired the water-escape performance of the control mice but not that of the MSG-treated mice. It was suggested that the water-escape performance deficit in the MSG-treated mice was a result of impaired central cholinergic mechanisms. As such, scopolamine was unable to further incapacitate an already impaired cholinergic system. This is strongly suppported by the decreased affinity of the sodium-dependent high-affinity choline uptake observed in the hippocampus. d-Cycloserine, a partial agonist at the glycine site of the NMDA receptor, did not affect the water-escape performance of the MSG-treated and control mice; nor did it alter the effects of scopolamine. This lack of effect of d-Cycloserine may imply that the NMDA receptors are not involved in non-spatial learning, in contrast to their reported involvement in spatial learning.

Effect of prenatal phenytoin exposure in rats on forms of spatial and non-spatial learning and memory as determined by the morris water maze and its modifications

Effect of prenatal phenytoin exposure in rats on forms of spatial and non-spatial learning and memory as determined by the morris water maze and its modifications

Spatial and nonspatial learning across the rat estrous cycle.

Spatial and nonspatial learning across the rat estrous cycle.

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.

The Essential Role of Hippocampal CA1 NMDA Receptor–Dependent Synaptic Plasticity in Spatial Memory

Summary We have produced a mouse strain in which the deletion of the NMDAR1 gene is restricted to the CA1 pyramidal cells of the hippocampus by using a new and general method that allows CA1-restricted gene knockout. The mutant mice grow into adulthood without obvious abnormalities. Adult mice lack NMDA receptor–mediated synaptic currents and long-term potentiation in the CA1 synapses and exhibit impaired spatial memory but unimpaired nonspatial learning. Our results strongly suggest that activity-dependent modifications of CA1 synapses, mediated by NMDA receptors, play an essential role in the acquisition of spatial memories.

Spatial and Nonspatial Learning in Mice: Effects of S100β Overexpression and Age

S100β, a Ca2+binding astrocytic brain protein implicated in brain development and neurophysiology, has elevated levels in progressive neurodegenerative diseases, Down's Syndrome, and Alzheimer Disease. Transgenic mice carrying multiple S100β gene copies exhibited abnormal exploratory behaviors and synaptic processes suggesting hippocampal dysfunction. Here we analyze learning in a hippocampal-dependent (spatial) as well as a non-hippocampal-dependent (nonspatial) version of the Morris water maze and compare CD1 control and CD1-derived S100β transgenic mice. We also investigate possible progressive age-dependent effects of S100β overexpression by comparing two age groups of the above mice: 3- and 16-month-old. We show that 3-month-old S100β transgenic mice have a spatial task-specific impairment confirming a hippocampal dysfunction. However, we found the 16-month-old transgenic mice statistically indistinguishable from their normal counterparts, a result that does not confirm progressive S100β transgene effects. We also show that age, independently of the transgene, impairs spatial learning, spares nonspatial learning and reference memory, but leads to behavioral rigidity.

The NMDA antagonist MK-801 affects nonspatial learning in preweanling rats.

The NMDA antagonist MK-801 affects nonspatial learning in preweanling rats.

Dorsal striatal lesions in rats. 2: Effects on spatial and non-spatial learning.

Rats with small electrolytic lesions of the dorsal striatum were evaluated in acquisition of spatial learning, sensorimotor learning, and a straight runway food approach response and its extinction. No differences were detected between rats with dorsal striatal lesions and sham-operated controls during acquisition of hidden and visible trials in the Morris water maze. Neither was an intergroup difference observed during acquisition of the rotorod test of motor coordination. Lesioned rats were not impaired in running for a food reward, but their running latencies on day 2 of extinction were lower than those of controls, an indication of perseveration. These results indicate that perseverative responding may occur in dorsal striatal lesioned rats in the absence of spatial or sensorimotor defects.

The NMDA antagonist MK-801 affects nonspatial learning in preweanling rats.

The N-methyl-D-aspartate (NMDA) subtype of the excitatory amino acid receptor has been implicated in several kinds of learning and memory, as well as in long-term potentiation (LTP), a putative cellular mechanism for learning and memory. This experiment examined the role of the NMDA receptor in patterned single-alternation (PSA) learning in preweanling rats following intraperitoneal injections of 0.05 mg/kg MK-801, a selective NMDA antagonist. MK-801 significantly inhibited PSA at both 60-s and 30-s intertrial intervals (ITIs), and attenuated, but did not block, learning at 8-s ITI. These results are compared with effects on PSA, a form of nonspatial, memory-based learning, observed after early postnatal exposure to alcohol, infant hippocampal lesions, and infant exposure to X-irradiation, and they add strongly to these earlier demonstrations of the role of the hippocampus in learning and memory that is clearly nonspatial and non-cognitive-map-related.

Spatial and non-spatial learning in the rat following lesions to the nucleus locus coeruleus

NeuroReport is a channel for rapid communication of new findings in neuroscience. It is a forum for the publication of short but complete reports of important studies that require very fast publication. Papers are accepted on the basis of the novelty of their finding, on their significance for neuroscience and on a clear need for rapid publication. Preliminary communications are not suitable for the Journal. Submitted articles undergo a preliminary review by the editor. Some articles may be returned to authors without further consideration. Those being considered for publication will undergo further assessment and peer-review by the editors and those invited to do so from a reviewer pool. The core interest of the Journal is on studies that cast light on how the brain (and the whole of the nervous system) works.

Spatial and non-spatial learning in the rat following lesions to the nucleus locus coeruleus

The present experiment examined the effects of unilateral or bilateral locus coeruleus lesions on general activity, acquisition of a non-monotonic serial pattern (14-0-3-7 food pellets, respectively), and response learning acquisition in a Greek cross version of the Morris water maze. Sham-operated control rats were capable of tracking the elements of the serial pattern while rats with a unilateral locus coeruleus lesion were moderately impaired, and those with bilateral locus coeruleus lesions were severely impaired. A similar pattern of working memory deficits emerged in an analysis of the response-learning data in the Greek cross. The results are discussed in terms of the current understanding of norepinephrine and the locus coeruleus in learning and memory processes.

8-OH-DPAT impairs spatial but not visual learning in a water maze by stimulating 5-HT 1A receptors in the hippocampus

The effect of 8-hydroxy-2-(di- n-propylamino) tetralin (8-OH-DPAT), a 5-HT 1A receptor agonist, on spatial and non-spatial learning in a water maze was studied using two tasks of equal difficulty, with the same motor, motivational and reinforcement demands. Rats were examined for choice accuracy in a two-platform spatial discrimination task. Rats treated subcutaneously with 100 μg/kg 8-OH-DPAT were impaired in choice accuracy with no effect on latency. Treated rats made more errors of omission than controls only on days 1 and 2 of training. Infusion of 1 μg/μl spiroxatrine (SPX) or 5 μg/μl of (+) WAY100135, two potent 5-HT 1A receptor antagonists, in the CA1 region of the dorsal hippocampus antagonized the impairment in choice accuracy caused by 8-OH-DPAT. The effect on errors of omission on days 1 and 2 of training were not significantly modified by spiroxatrine or (+) WAY100135. Rats treated with 8-OH-DPAT were not impaired in their ability to learn a visual discrimination in a water maze. The results suggest that stimulation of 5-HT 1A receptors in the CA1 region of the dorsal hippocampus impairs spatial but not visual discrimination in rats.

Correlations between radial-maze learning and structural variations of septum and hippocampus in rodents

Large, but non-pathological, individual differences in neuroanatomy of the brain exist in rodents, which have been shown to covary with behavioral traits. In the present review, we explore the relationship between variations in the extent of the intra- and infrapyramidal mossy fiber projection of the hippocampus and spatial and non-spatial learning capacities in mice and rats. Preliminary data concerning anatomical variation in the septo-hippocampal cholinergic system and its consequences for individual behavior are also presented. We conclude that the hippocampal intra- and infrapyramidal mossy fiber projection is intimately involved in the regulation of spatial, but not of non-spatial learning capabilities. Although lesion studies have shown that a well-functioning cholinergic system is a pre-requisite for performance in spatial learning tasks, our preliminary data suggest that individual differences in the cholinergic system do not explain individual differences in learning.

Metabotropic glutamate receptors in spatial and nonspatial learning in rats studied by means of agonist and antagonist application.

We examined the effects of both the metabotropic glutamate receptor (mGluR) antagonist MCPG and the agonist tADA in two behavioral paradigms in rats: (1) brightness discrimination and (2) spatial alternation. Compounds were applied intracerebroventricularly at different times, either 30 min prior to training or immediately after training, and rats were tested for retention 24 hr later in the same paradigms. Both MCPG and tADA caused amnesia in the spatial alternation test, when applied pretraining, but no effect was obtained in the brightness discrimination paradigm. Drug-induced amnesia was shown not to be attributable to state-dependent effects of MCPG or tADA. Moreover, the memory inhibiting effect of MCPG was dose dependent, with a low dose (20 mM/5 ml) having no effect on learning and memory and a 10 times higher concentration (200 mM/5 ml) causing complete amnesia. Application of both saline and MCPG immediately post-training prevented memory formation, which may be attributable to an interference by the injection procedure with the process of memory formation. The mGluR agonist tADA, however, facilitated memory formation in the spatial alternation task, when injected immediately after training. Post-training application of the compounds had no effect on retention in the brightness discrimination task. On the basis of these data we conclude that (1) mGluRs are of particular importance for spatial learning and play no role in visual discrimination; (2) both the block and the activation of mGluRs inhibit spatial learning, suggesting that saturated activation prevents further modulation of mGluRs, which may be required during learning or memory formation; and (3) mGluR agonist tADA may be memory facilitating when applied after training, thus enhancing the establishment of the memory trace.

Effects of ketamine and L-glutamic acid diethyl ester on spatial and nonspatial learning tasks in rats

An NMDA antagonist, ketamine, at the highest dose tested (15 mg/kg), impaired the acquisition of a hole-board spatial learning task but not the acquisition of a left-right alternation task. A non-NMDA (quisqualate) antagonist, L-glutamic acid diethyl ester (LGDE), did not impair the acquisition of either task. Both drugs had effects on different aspects of a go-no go discrimination task and a straight runway task, ketamine tending to activate and LGDE tending to slow rats. These results concur with previous research regarding the sensitivity of some spatial tasks to NMDA antagonism. Non-NMDA antagonists affect behavior without causing spatial deficits.

Impaired spatial learning in alpha-calcium-calmodulin kinase II mutant mice.

Although long-term potentiation (LTP) has been studied as the mechanism for hippocampus-dependent learning and memory, evidence for this hypothesis is still incomplete. The mice with a mutation in the alpha-calcium-calmodulin-dependent kinase II (alpha-CaMKII), a synaptic protein enriched in the hippocampus, are appropriate for addressing this issue because the hippocampus of these mice is deficient in LTP but maintains intact postsynaptic mechanisms. These mutant mice exhibit specific learning impairments, an indication that alpha-CaMKII has a prominent role in spatial learning, but that it is not essential for some types of non-spatial learning. The data considerably strengthen the contention that the synaptic changes exhibited in LTP are the basis for spatial memory.

Cytochrome oxidase inhibition: a novel animal model of Alzheimer's disease.

A profound decrease in activity of the mitochondrial enzyme cytochrome oxidase in blood platelets is a recently identified concomitant of Alzheimer's disease (AD). We investigated a possible pathogenic link between this finding and the symptoms of AD by mimicking this mitochondrial enzyme deficiency in rats. Rats were infused chronically with a selective inhibitor of cytochrome oxidase, sodium azide, or with saline delivered via subcutaneously implanted osmotic minipumps. The azide treatment impaired both spatial and nonspatial learning. Further, the azide treatment inhibited a low-threshold form of hippocampal long-term potentiation, primed burst potentiation. The behavioral deficits were not secondary to a sensory or motor impairment. Thus, chronic azide treatment of rats models some characteristics of AD.

Effects of N-methyl-d-aspartate antagonism on spatial learning in mice

C57BL/6Ibg mice were treated with the N-methyl-D-aspartate (NMDA) receptor antagonist 3-(2-carboxypiperazin-4-yl) propyl-1-phosphonic acid (CPP) and tested for selective deficits in spatial learning ability in the Morris water task. Two types of training protocols were used during the initial exposure to the training environment. In protocol 1, animals were given four massed trials before being returned to their home cages. In protocol 2, animals were returned to their home cages after each of the first four trials. Following the initial four trials, both sets of animals were given massed trials in blocks of four. CPP had minor effects on nonspatial learning, with greater impairment seen in animals trained according to protocol 1 than in animals trained according to protocol 2. The drug increased latency to find the platform in the spatial learning form of the task, with no effect of training protocol on latency. When spatial learning ability was measured in terms of the search behavior exhibited by the animals after the platform was removed from the pool, animals trained according to protocol 1 showed a severe CPP-induced impairment in search accuracy. Animals trained according to protocol 2 showed no effect of drug treatment. The results suggest that CPP does not have a reliable effect on place learning and that factors other than the type of learning being tested may contribute to performance deficits following CPP treatment.