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At least 19 recordsLinked to original sources

Preserved configural learning and spatial learning impairment in rats with hippocampal damage.

This study was undertaken to compare the effect of hippocampal neurotoxic lesions in rats on two behavioral tasks, one a test of spatial learning, and the other an operant discrimination task that is acquired by forming nonspatial configural associations. Lesions of the hippocampus were made with microinjections of ibotenic acid. After postoperative recovery, rats were trained initially to locate a camouflaged escape platform in a water maze using distal spatial cues. Rats also were trained in the maze apparatus with a visible escape platform under conditions in which spatial information was made irrelevant to performance, i.e., cue learning. In an operant task, the same rats were then trained on a discrimination that included simultaneous feature positive and feature negative components (trial types XA+, A-, XB-, B+). After completion of this nonspatial configural learning task, rats received additional training in the water maze using a new platform location for spatial learning. To the extent that proficient performance in both the maze and operant tasks depends on a common function of the hippocampus, i.e., configural learning, the expectation was that hippocampal lesions would prove equally detrimental to performance in both tasks. Contrary to this expectation, lesioned rats were severely impaired in spatial learning but readily acquired the operant discrimination, even exhibiting some evidence of enhanced performance on this nonspatial configural learning task. Performance of the lesioned rats during cue training in the water maze was also enhanced relative to the control group.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance

Hippocampal granule cells are necessary for normal spatial learning but not for spatially-selective pyramidal cell discharge.

The effects of massive destruction of granule cells of the fascia dentata on the spatial and temporal firing characteristics of pyramidal cells in the CA1 and CA3 subfields of the hippocampus were examined in freely moving rats. Microinjections of the neurotoxin colchicine were made at a number of levels along the septo-temporal axis of the dentate gyri of both hemispheres, resulting in destruction of over 75% of the granule cells. By contrast there was relatively little damage to the pyramidal cell fields. As assessed by three different behavioral tests, the colchicine treatment resulted in severe spatial learning deficits. Single units were recorded from the CA1 and CA3 subfields using the stereotrode recording method while the animals performed a forced choice behavioral task on the radial 8-arm maze. Considering the extent of damage to the dentate gyrus, which has hitherto been considered to be the main source of afferent information to the CA fields, there was remarkably little effect on the spatial selectivity of "place cell" discharge on the maze, as compared to recordings from control animals. There was, however, a change in the temporal firing characteristics of these cells, which was manifested primarily as an increase in the likelihood of burst discharge. The main conclusion derived from these findings is that most of the spatial information exhibited by hippocampal pyramidal cells is likely to be transmitted from the cortex by routes other than the traditional "trisynaptic circuit". These routes may include the direct projections from entorhinal layers II and III to CA3 and CA1, respectively.

Animals

The effects of concurrent manipulations of cholinergic and noradrenergic systems on neocortical EEG and spatial learning.

In the spatial learning test, young animals were divided into three groups receiving saline, scopolamine (0.15 mg/kg), or scopolamine (0.8 mg/kg). Half of the animals in each group were lesioned with DSP-4 to destroy noradrenergic fibers. DSP-4 lesions did not produce any significant impairment alone or in combination with a lower dose of scopolamine (0.15 mg/kg), but they did further augment the scopolamine (0.8 mg/kg)-induced defect. In the electroencephalography (EEG) experiment, both control rats and DSP-4-lesioned rats were recorded after receiving saline, scopolamine (0.15 mg/kg), and scopolamine (0.8 mg/kg) injections. Scopolamine induced a dose- and behavioral state-dependent EEG slowing, whereas DSP-4 lesions did not change either baseline EEG activity or EEG reactivity to scopolamine.

Age Factors

Heterosis and resistance to DFP effects on spatial learning in C57BL X DBA hybrids.

The inbred mouse strains C57BL/6Ibg and DBA/2Ibg differ in their ability to exhibit spatial learning in the Morris water task. C57BL mice learn the task well and show impairment of spatial learning following disruption of cholinergic function. DBA mice show rudimentary spatial learning ability, and are not further impaired when cholinergic function is decreased. These mice may carry genes regulating a noncholinergic spatial learning system. To test this hypothesis, first generation (F1) hybrids between DBA and C57BL mice were tested for spatial learning in the Morris water task. The hybrids performed better than either parental strain, suggesting that both parents contributed genes for spatial learning ability. Chronic treatment with diisopropylfluorophosphate (DFP), which abolished spatial learning ability in C57BL mice, produced only minor impairments in the hybrids. The behavioral resistance to DFP occurred despite significant reductions in hippocampal and cortical muscarinic binding. The results suggest either that the hybrids inherited a noncholinergic neurochemical system influencing spatial learning from their DBA parents or that the DFP treatment did not disrupt cholinergic function to a sufficient degree to impair the superior learning abilities of the F1 hybrids.

Acetylcholinesterase

Inheritance of spatial learning ability in inbred mice: a classical genetic analysis.

The inheritance of spatial learning ability in inbred mice was examined by performance of a classical genetic cross between the 2 inbred strains C57BL/6Ibg and DBA/2Ibg. The inbreds were crossed to produce the 1st filial generation (F1) hybrids. F1 mice were bred to each other and were backcrossed to the parental strains to produce 3 hybrid generations with recombinant genotypes. The animals were tested for spatial learning ability in the Morris water task. All hybrid generations showed greater spatial learning ability than the inbreds, with F1 hybrids showing the greatest degree of spatial learning. The inheritance pattern for spatial learning differed between male and female mice, with males showing a type of inheritance in which dominant genes made the major contribution to the expression of the behavior. Females showed equal contributions of dominance deviation and additive genetic effects. The results are discussed in terms of fitness value to the animals.

Animals

Interaction between raphe dorsalis and nucleus basalis magnocellularis in spatial learning.

We compared the effects on spatial learning of an ibotenic acid lesion of the nucleus basalis magnocellularis (NBM), a 5, 7-dihydroxytryptamine lesion of the raphe dorsalis (RD) and a combined NBM and RD lesion. The RD lesion reduced serotonin levels, and the NBM lesion reduced cholineacetyltransferase (ChAT) activity in the cortex. Although RD lesions alone did not affect spatial learning in the water-maze, the lesion aggravated the spatial navigation deficit produced by NMB lesioning. The current results suggest a functional interaction between the RD and NBM in spatial navigation.

Animals

Chronic neonatal MK-801 treatment results in an impairment of spatial learning in the adult rat.

Chronic neonatal treatment with the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 from postnatal day 8 through 19 has been shown to affect hippocampal NMDA receptor function of adult rats. Since many studies have shown that NMDA receptors play a crucial role in learning and memory, and since one of the hippocampal functions is spatial learning, we have examined whether this changed response of hippocampal neurons is associated with changes in its normal function. We therefore tested spatial learning and memory using a water maze in adult rats neonatally treated with MK-801. MK-801-treated rats were able to learn the spatial task as well as control rats but at a significantly slower rate. Performance in a visual cue task was not affected by the neonatal treatment, suggesting that the slower spatial learning is not caused by locomotor or sensory deficits. These results suggest that chronic NMDA receptor blockade during the neonatal period leads to long-lasting disturbances of hippocampal function.

Animals

Bilateral knife cuts to the perforant path disrupt spatial learning in the Morris water maze.

Both the hippocampus and the entorhinal cortex are known to be crucial for spatial learning, but the contribution of the pathway linking the two structures, the perforant path (PP), has never been tested in a spatial learning paradigm. The present study examined the role of the PP in spatial learning using the Morris water maze. Seven days after bilateral transection of the PP with a fine-bladed knife, rats were habituated to the pool, then trained to swim from varying start locations to a platform submerged in a fixed location. After 28 training trials over 5 days, probe trials (without any platform present) were given to assess spatial memory for the location. Compared to sham-operated controls, lesioned rats showed slower learning and poorer asymptotic performance in terms of both swim path distance and escape latency, and less preference for the correct quadrant during probe trials. When the platform location was "reversed" to the opposite quadrant, the lesioned rats again showed poorer learning, poorer asymptotic performance, and reduced preference for the correct quadrant on the probe trial. When tested with a visible platform whose position varied from trial to trial, lesioned rats performed as well as controls. These results are congruent with previous analyses of the contributions of the entorhinal cortex and hippocampus to spatial learning and suggest that for spatial learning, the PP is a critical functional link between these two structures.

Animals

Enhancement of spatial learning in F344 rats by physical activity and related learning-associated alterations in hippocampal and cortical cholinergic functioning.

The effects of physical activity on spatial memory performance and associated cholinergic function were examined in F344 rats. Cholinergic analysis included resting and depolarization-induced activation of high-affinity choline uptake and muscarinic receptor binding in the hippocampus, parietal cortex and frontal cortex. Rats that were physically trained, using chronic treadmill running, demonstrated significantly enhanced performance on the spatial learning task, both in second trial latency and first and second trial proximity ratio scores (P less than 0.002). Concomitant with enhanced behavioral performance were neurochemical changes of a reduction in hippocampal high-affinity choline uptake, an upregulation of muscarinic receptor density, and an increase in high-affinity choline uptake 24 h after spatial memory testing (P less than 0.05). Spatial memory tested rats demonstrated enhanced depolarization-induced activation of high-affinity choline uptake (P less than 0.001). Rats that were yoked for swim time to spatial memory tested rats did not show any spatial learning-induced alterations in high affinity choline uptake. These spatial learning- and physical activity-induced cholinergic alterations were observed only in the hippocampus, not in the parietal or frontal cortex. These data indicate that the chronic running-induced alterations in hippocampal high-affinity choline uptake and upregulation of muscarinic receptor density, in combination with enhancement of high-affinity choline uptake related to spatial learning, may contribute to the enhanced spatial learning performance of chronic-run rats.

Animals

Markers for biogenic amines in the aged rat brain: relationship to decline in spatial learning ability.

The major goal of the study was to evaluate the relationship of brain aging to individual differences in functional decline in rats. Forebrain choline-acetyltransferase (ChAT) and monoamines, including their metabolites, were examined in young and aged male Long-Evans rats in relation to their spatial learning ability. Aged rats that were unimpaired on a spatial learning task exhibited few changes in neurochemistry relative to the young group: each change in this subgroup was also evident in the remaining aged animals that were behaviorally impaired. Additional changes in neurochemical measures only found in the behaviorally impaired aged animals included decreased ChAT in the basal forebrain, striatum, and frontal cortex. A cluster analysis using the 15 neurochemical measures that were sensitive to aging yielded groupings of aged animals that differed with respect to their spatial learning ability, but not in their cue learning latencies. In this analysis the activity of ChAT in the basal forebrain and striatum appeared to be the best predictors of spatial learning impairment.

Aging

Elevated dynorphin in the hippocampal formation of aged rats: relation to cognitive impairment on a spatial learning task.

Radioimmunoassay revealed increased dynorphin A(1-8)-like immunoreactivity [dynA(1-8)LI] in the aged rat brain. Among a number of brain regions examined, an age-related dynA(1-8)LI elevation was found only in the hippocampal formation and frontal cortex. Moreover, the increase in dynA(1-8)LI in the aged hippocampus was associated with a decline in spatial learning ability: dynA(1-8)LI distinguished aged rats that were behaviorally impaired from aged cohorts that learned the spatial task as rapidly as younger animals. Northern blot hybridization using a 32P-labeled complementary RNA probe encoding rat prodynorphin indicated that the abundance of prodynorphin mRNA was also significantly increased in the hippocampal formation of aged rats with identified spatial learning impairments.

Aging

Effects of haloperidol on recall and information processing in verbal and spatial learning.

1. Normal male subjects were tested with either a multi-trial word list learning test or a spatial analogue prior to administration of either 4 mg. or 10 mg. of oral haloperidol. Six hours after drug administration subjects who had previously received the verbal test were administered the spatial test, and vice versa, so for each test there was a no-drug control group, a group tested after receiving 4 mg. of haloperidol, and a group tested after a 10 mg. dose. 2. Both the verbal and spatial learning tests yield multidimensional measures of components of memory and learning, including measures sensitive to effort-demanding and more automatic information processing operations. 3. Results showed no differences for either test among the pre-drug control group and the 4 mg. and 10 mg. groups, with only one minor exception. 4. The lack of significant results cannot be attributed to insensitivity of the test instruments used, since previous studies have documented sensitivity to a number of clinical conditions and to aging. 5. Results have implications regarding clinical effects of haloperidol. A theory that links dopaminergic functioning with effortful information processing underlying memory and learning was not supported.

Adult

Spatial learning deficits in old rats: a model for memory decline in the aged.

Spatial learning tasks are sensitive to functional decline in aged laboratory rodents. This is a review of recent work that has examined both the nature of age-related impairments on spatial tasks, and the relation of such deficits to underlying neurobiological mechanisms. The review supports the notion that hippocampal dysfunction underlies the mild/moderate cognitive decline that often accompanies normal aging. Thus the spatial learning deficit in aged rodents is a promising model for understanding the effect of age on brain systems that serve a memory function in humans.

Aging

Rats acquire spatial learning sets.

This experiment was designed to examine the development of a spatial learning set in rats and some of the variables influencing the retention of individual problems. The apparatus was a plus maze. At the beginning of each test, the rat was put on two arms, each in a different place. Food was present in one of the arms, but not in the other. The rat was then given a choice between these two places; the correct response was to return to the place that previously contained food (win-stay, lose-shift, response-reinforcement contingency). Fifty different two-choice spatial discriminations were given, each in a different location. At the end of testing, the mean percentage of correct responding for the first choice between the two places was 83%. Control procedures showed that the discriminative stimuli were distal, extramaze spatial stimuli. Variations of the procedure examined the influence of proactive interference and temporal delay on the memory for each discrimination. These results demonstrate that rats can develop a spatial learning set and provide new information about the characteristics of the memory underlying learning sets.

Animals

Combined cholinergic and serotonergic denervation of the forebrain produces severe deficits in a spatial learning task in the rat.

The purpose of the present experiments was to study the effects of a combined cholinergic and serotonergic denervation of the rat forebrain on spatial learning using the Morris water maze task. Experiment 1 compared the acute effects of a radiofrequency lesion of the septum, an intraventricular 5,7-dihydroxytryptamine (5,7-DHT) lesion, and a combined septal plus 5,7-DHT lesion. Although the 5,7-DHT lesion alone did not produce any significant deficits in the water maze task, the lesion greatly potentiated the learning impairments produced by the septal lesion. Thus, the rats with both lesions combined showed severe difficulties in finding the platform and they did not develop any place navigational search strategy. This effect was not dependent on any effect on swimming ability or locomotor activity. The long-term effects of the combined septal and 5,7-DHT lesion was investigated in experiment 2, where the rats were tested in the water maze both 5 and 24-25 weeks after surgery. In this experiment, the rats showed the same severe deficits in spatial learning in both tests, showing that the impairments remain for long periods and after extended training. The results show that a combination of a cholinergic and a serotonergic denervation of the rat forebrain produces pronounced impairments in spatial learning in the Morris water maze task, and that this effect is long-lasting. This indicates that the recently proposed serotonergic deficit in patients with Alzheimer's disease may contribute importantly to the cognitive disabilities in these patients.

5,7-Dihydroxytryptamine

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.

Animals

Relation of rotation to egocentric and allocentric spatial learning in the rat.

In this experiment, we asked whether the relation between amphetamine-induced rotation and the learning and retention of left-right discrimination extends to allocentric spatial learning or is limited to egocentric spatial tasks. Rotation was established following injections of d-amphetamine sulfate, and rats were classified as nonrotators, midrotators, or strong rotators. Animals were successively trained on navigation in the Morris water maze (allocentric) and delayed spatial alternation in a water T-maze (egocentric). There were no rotation effects in water maze learning but rotators and nonrotators differed significantly in delayed spatial alternation learning but not relearning. Strong rotators learned more slowly than midrotators, clearly implying that rotational bias and directional learning are not linearly related. We show that it is egocentric spatial learning that is facilitated by a nigrostriatal dopamine asymmetry and extend the generality of the left-right discrimination findings.

Amphetamine

Progressive decline in spatial learning and integrity of forebrain cholinergic neurons in rats during aging.

Rats distributed over five different age groups, 3, 12, 18, 24 and 30 months of age, were screened for their spatial learning and memory ability in the Morris water maze, and the degree of place navigational impairments was correlated with morphological changes in the four major forebrain cholinergic cell groups (medial septum, MS; vertical limb of the diagonal band of Broca, VDB; nucleus basalis magnocellularis, NBM; and striatum) using choline acetyltransferase (ChAT) and nerve growth factor receptor (NGFr) histochemistry. Impaired place navigation developed progressively with age, such that 8% of the 12-month-old rats, 45% of the 18-month-old, 53% of the 24-month-old, and over 90% of the 30-month-old rats were behaviorally impaired. Significant reductions in the number of ChAT/NGFr-positive cell bodies, amounting to between 19 and 45%, were observed in all four cell groups, and the remaining cells were reduced in size (6-24% reduction in cross-sectional area in the oldest age groups). Although the morphological changes were less severe and tended to develop later than the behavioral impairments, there was overall a significant correlation between water maze performance and ChAT/NGFr-positive cell counts, and to a lesser degree also cell size in all four cell groups. These changes were also highly correlated with age. The highest correlations were seen in MS, VDB and NBM, which are known to play a role in spatial memory performance in young rats. The results indicate that degenerative and/or atrophic changes in the forebrain cholinergic system and decline in spatial learning ability are parallel processes during aging. Although the magnitude of the morphological changes does not appear to be substantial enough, by itself, to explain the severe spatial learning impairments that develop in the oldest animals, the present data are consistent with the view that impaired function in the forebrain cholinergic system can contribute to age-dependent cognitive decline in rodents.

Aging