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Repeated stress causes reversible impairments of spatial memory performance.

Restraint stress, 6 h/day for 21 days, caused an impairment, during acquisition, of the performance of a spatial memory task, the eight-arm radial maze. The impairment was reversible, temporally limited and blocked by phenytoin, a blocker of excitatory amino acid action, or tianeptine, an antidepressant, which lowers extracellular serotonin. These effects on behavior parallel the reversible stress-induced atrophy of dendrites of hippocampal CA3 neurons that are also blocked by the drugs.

Animals↗

Apoptotic morphology of dentate gyrus granule cells following experimental cortical impact injury in rats: possible role in spatial memory deficits.

Loss of hippocampal neurons as a result of traumatic brain injury (TBI) is thought to contribute to the observed spatial memory deficits. Using a rodent model of experimental brain injury, we have examined the nature of hippocampal cell death following TBI. Light microscope examination of stained sections showed the presence of a large number of hyperchromatic and dystrophic neurons in the dentate gyrus of the hippocampus. These cells appeared to be undergoing nuclear condensation. Electron microscope examination demonstrated the presence of cell shrinkage, condensed chromatin, nuclear segmentation, and cytoplasmic vacuolization. Detection of a DNA ladder and in situ labeling (TUNEL) were also consistent with the process of apoptosis. However, in some dystrophic neurons these morphologies were also accompanied by the presence of swollen mitochondria and a lack of distinctive rough endoplasmic reticulum which are typically associated with necrosis. These findings show that cortical impact injury produces cell death in the hippocampus which has both apoptotic and necrotic features.

Animals↗

Altered hippocampal transcript profile accompanies an age-related spatial memory deficit in mice.

We have carried out a global survey of age-related changes in mRNA levels in the C57BL/6NIA mouse hippocampus and found a difference in the hippocampal gene expression profile between 2-month-old young mice and 15-month-old middle-aged mice correlated with an age-related cognitive deficit in hippocampal-based explicit memory formation. Middle-aged mice displayed a mild but specific deficit in spatial memory in the Morris water maze. By using Affymetrix GeneChip microarrays, we found a distinct pattern of age-related change, consisting mostly of gene overexpression in the middle-aged mice, suggesting that the induction of negative regulators in the middle-aged hippocampus could be involved in impairment of learning. Interestingly, we report changes in transcript levels for genes that could affect synaptic plasticity. Those changes could be involved in the memory deficits we observed in the 15-month-old mice. In agreement with previous reports, we also found altered expression in genes related to inflammation, protein processing, and oxidative stress.

Aging↗

Lateralized fascia dentata lesion and blockade of one hippocampus: effect on spatial memory in rats.

Unilateral blockade of the dorsal hippocampus by tetrodotoxin makes it possible to form lateralized spatial memories, which rapidly transfer to the naive hippocampus when training continues with intact brain. Unilateral X-ray irradiation of newborn rats causes irreversible destruction of granule cells in the ipsilateral fascia dentata (FD). Possible compensation of poor learning in the lesioned hemisphere by commissural transfer of memories from the intact hippocampus was examined in seven rats with unilateral FD lesion, which were first trained in the Morris water maze to asymptotic performance (mean escape latency 6+/-1 s). Subsequent testing during functional ablation either of the intact or of the lesioned hippocampus by tetrodotoxin revealed escape latencies 35+/-8 s or 8+/-1 s, respectively. Probe trial tests during inactivation of the intact and lesioned hippocampus showed target quadrant preference of 32+/-2% or 54+/-3%, respectively. The results indicate: (a) that one intact hippocampus alone can support the water maze task, (b) that no, or only a very weak, memory trace is available in the lesioned hippocampus. It is concluded that the above results are due to the inability of the FD lesioned hippocampus to process the information received from the ipsilateral entorhinal cortex.

Animals↗

Progressive entorhinal cortex lesions accelerate hippocampal sprouting and spare spatial memory in rats.

Accelerating hippocampal sprouting by making unilateral progressive lesions of the entorhinal cortex spared the spatial memory of rats tested for retention of a learned alternation task. Subsequent transection of the sprouted crossed temporodentate pathway (CTD), as well as a simultaneous CTD transection and progressive entorhinal lesion, produced a persistent deficit on the memory task. These results suggest that CTD sprouting, which is homologous to the original perforant path input to the dentate gyrus of the hippocampus, is behaviorally significant and can ameliorate at least some of the memory deficits associated with hippocampal deafferentation.

Animals↗

Spatial memory in rats: a cross validation study.

Two experiments were performed to investigate whether two measures of spatial memory, working memory (WM) and reference memory (RM), can be generalized over learning situations. In the first experiment, outbred WU rats were used; in the second four inbred strains. In both experiments rats were given 50 training trials in both a holeboard and a high-sided radial maze: 4 out of 16 holes and 4 out of 8 arms were baited. The number of WM (revisits to baited holes/arms) and RM (visits and revisits to never baited holes/arms) errors were calculated for 5 blocks of 10 trials; odd-even reliabilities were determined for the last 20 trials and were shown to be satisfactory for both measures in both types of apparatus. Error-decrements were analyzed by trend components. For both WM and RM, simple and canonical correlations were determined between means and significant trends in maze and holeboard as a test for construct validity; in both experiments r's and Rr's were very low. It was concluded that the concepts WM and RM are not validly generalizable over tests.

Animals↗

Hippocampal function and spatial memory: evidence from functional neuroimaging in healthy participants and performance of patients with medial temporal lobe resections.

Several strategies can be used to find a destination in the environment. Using a virtual environment, the authors identified 2 strategies dependent on 2 different memory systems. A spatial strategy involved the use of multiple landmarks available in the environment, and a response strategy involved right and left turns from a given start position. Although a probe trial provided an objective measure of the strategy used, classification that was based on verbal reports was used in small groups to avoid risks of misclassification. The authors first demonstrated that the spatial strategy led to a significant activity of the hippocampus, whereas the response strategy led to a sustained activity in the caudate nucleus. Then, the authors administered the task to 15 patients with lesions to the medial temporal lobe, showing an impaired ability using the spatial strategy. Imaging and neuropsychological results are discussed to shed light on the human navigation system.

Adult↗

Orientation specificity in spatial memory: what makes a path different from a map of the path?

Three studies investigated the factors that lead spatial information to be stored in an orientation-specific versus orientation-free manner. In Experiment 1, we replicated the findings of Presson and Hazelrigg (1984) that learning paths from a small map versus learning the paths directly from viewing a world leads to different functional characteristics of spatial memory. Whether the route display was presented as the path itself or as a large map of the path did not affect how the information was stored. In Experiment 2, we examined the effects of size of stimulus display, size of world, and scale transformations on how spatial information in maps is stored and available for use in later judgments. In Experiment 3, we examined the effect of size on the orientation specificity of the spatial coding of paths that are viewed directly. The major determinant of whether spatial information was stored and used in an orientation-specific or an orientation-free manner was the size of the display. Small displays were coded in an orientation-specific way, whereas very large displays were coded in a more orientation-free manner. These data support the view that there are distinct spatial representations, one more perceptual and episodic and one more integrated and model-like, that have developed to meet different demands faced by mobile organisms.

Adult↗

Geometric determinants of human spatial memory.

Geometric alterations to the boundaries of a virtual environment were used to investigate the representations underlying human spatial memory. Subjects encountered a cue object in a simple rectangular enclosure, with distant landmarks for orientation. After a brief delay, during which they were removed from the arena, subjects were returned to it at a new location and orientation and asked to mark the place where the cue had been. On some trials the geometry (size, aspect ratio) of the arena was varied between presentation and testing. Responses tended to lie somewhere between a location that maintained fixed distances from nearby walls and a location that maintained fixed ratios of the distances between opposing walls. The former were more common after expansions and for cued locations nearer to the edge while the latter were more common after contractions and for locations nearer to the center. The spatial distributions of responses predicted by various simple geometric models were compared to the data. The best fitting model was one derived from the response properties of 'place cells' in the rat hippocampus, which matches the 'proximities' 1/(d+c) of the cue to the four walls of the arena, where d is the distance to a wall and c is a global constant. Subjects also tended to adopt the same orientation at presentation and testing, although this was not due to using a view matching strategy, which could be ruled out in 50% of responses. Disoriented responses were most often seen where the cued location was near the center of the arena or where the long axis of a rectangular arena was changed between presentation and testing, suggesting that the geometry of the arena acts as a weak cue to orientation. Overall, the results suggest a process of visual landmark matching to determine orientation, combined with an abstract representation of the proximity of the cued location to the walls of the arena consistent with the neural representation of location in the hippocampus.

Adult↗

Neonatal hippocampal damage in rats: long-term spatial memory deficits and associations with magnitude of hippocampal damage.

This study investigated the effects of neonatal hippocampal ablation on the development of spatial learning and memory abilities in rats. Newborn rats sustained bilateral electrolytic lesions of the hippocampus or were sham-operated on postnatal day 1 (PN1). At PN20-25, PN50-55, or PN90-95, separate groups of rats were tested in a Morris water maze on a visible "cue" condition (visible platform in a fixed location of the maze), a spatial "place" condition (submerged platform in a fixed location), or a no-contingency "random" condition (submerged platform in a random location). Rats were tested for 6 consecutive days, with 12 acquisition trials and 1 retention (probe) trial per day. During acquisition trials, the rat's latency to escape the maze was recorded. During retention trials (last trial for each day, no escape platform available), the total time the rat spent in the probe quadrant was recorded. Data from rats with hippocampal lesions tested as infants (PN20-25) or as adults (PN50-55 and PN90-95) converged across measures to reveal that 1) spatial (place) memory deficits were evident throughout developmental testing, suggesting that the deficits in spatial memory were long-lasting, if not permanent, and 2) behavioral performance measures under the spatial (place) condition were significantly correlated with total volume of hippocampal tissue damage, and with volume of damage to the right and anterior hippocampal regions. These results support the hypothesis that hippocampal integrity is important for the normal development of spatial learning and memory functions, and show that other brain structures do not assume hippocampal-spatial memory functions when the hippocampus is damaged during the neonatal period (even when testing is not begun until adulthood). Thus, neonatal hippocampal damage in rats may serve as a rodent model for assessing treatment strategies (e.g., pharmacological) relevant to human perinatal brain injury and developmental disabilities within the learning and memory realm.

Age Factors↗

Performance of four seed-caching corvid species in operant tests of nonspatial and spatial memory.

The performance of 4 seed-caching corvid species was tested using 2 different operant nonmatching tasks. These species differ in their dependence on stored food, and differences in spatial memory tests have been correlated with better performance by the more cache-dependent species. Acquisition and retention of a color non-matching-to-sample task was tested in Experiment 1. Acquisition of the color task was not correlated with cache dependence, and no differences between species in performance during memory testing were found. Acquisition and retention of an operant spatial non-matching-to-sample task was tested in Experiment 2. Species differences in the spatial task were found for acquisition and during retention testing. The influence of natural history on the evolution of memory is discussed.

Animals↗

Partial hippocampal inactivation: effects on spatial memory performance in aged and young rats.

Changes in anatomical or functional connectivity during normal aging are thought to contribute to cognitive alterations over the lifespan. Neural network theories predict that synaptic loss in an aging brain could place the organism near the point of dysfunction in the nonlinear curve defining neural compromise versus performance. The present experiments examined whether aged rats are closer to this point of behavioral dysfunction by reversibly inactivating one or both hippocampal hemispheres. As expected, bilateral tetracaine inactivation of the hippocampus disrupted spatial memory in both age groups. Unilateral left hippocampal inactivation significantly increased errors only in aged rats; however, unilateral inactivation of the right hippocampus had no effect. The present outcome could reflect more extensive synaptic dysfunction in the aged right hippocampus or a greater involvement of the left hippocampus in spatial working memory problems.

Age Factors↗

A study on the role of the dorsal striatum and the nucleus accumbens in allocentric and egocentric spatial memory consolidation.

There is now accumulating evidence that the striatal complex in its two major components, the dorsal striatum and the nucleus accumbens, contributes to spatial memory. However, the possibility that different striatal subregions might modulate specific aspects of spatial navigation has not been completely elucidated. Therefore, in this study, two different learning procedures were used to determine whether the two striatal components could be distinguished on the basis of their involvement in spatial learning using different frames of reference: allocentric and egocentric. The task used involved the detection of a spatial change in the configuration of four objects placed in an arena, after the mice had had the opportunity to experience the objects in a constant position for three previous sessions. In the first part of the study we investigated whether changes in the place where the animals were introduced into the arena during habituation and testing could induce a preferential use of an egocentric or an allocentric frame of reference. In the second part of the study we performed focal injections of the N-methyl-d-aspartate (NMDA) receptors' antagonist, AP-5, within the two subregions immediately after training. The results indicate that using the two behavioral procedures, the animals rely on an egocentric and an allocentric spatial frame of reference. Furthermore, they demonstrate that AP-5 (37.5, 75, and 150 ng/side) injections into the dorsal striatum selectively impaired consolidation of spatial information in the egocentric but not in the allocentric procedure. Intra-accumbens AP-5 administration, instead, impaired animals trained using both procedures.

Analysis of Variance↗

Influence of gender on working and spatial memory in the novel object recognition task in the rat.

Gender differences in many behavioural tasks have been observed in both humans and laboratory animals. The novel object recognition (NOR) task is increasingly used to investigate drug effects on working memory processes, although, the influence of sexually dimorphic behaviours have not yet been evaluated. In addition, the role of natural fluctuations in the sex steroids during the oestrous cycle has received little attention during object recognition tasks. Therefore, the aim of the current study was to investigate the influence of gender and oestrous cycle phase on working and spatial memory using the NOR task. Animals were tested in the NOR task and the spatial NOR task. Male and female rats completed an acquisition trial followed by an inter-trial interval of a specified length, then a final retention trial. Vaginal cytology enabled the influence of oestrous cycle phase to be determined in both the NOR and spatial NOR, each animal was tested during one phase of their regular oestrous cycle only. It was found that female rats performed significantly better than male rats in the standard NOR paradigm (p<0.05 compared to no significance (NS) at 3h, respectively), while male rats showed improved memory in the spatial NOR paradigm compared with female rats (p<0.05 compared to NS at 3h, respectively). There was no influence of phase of oestrous cycle on the NOR task, however, during the spatial NOR there was a significant improvement in ability when oestrogen and progesterone levels have been shown to be at their lowest (i.e. p<0.05 during oestrous compared to NS at other stages). In conclusion, it is clear that gonadal hormones can influence components of memory and gender is an important consideration in experimental design.

Analysis of Variance↗

Spatial memory and orientation strategies in the elasmobranch Potamotrygon motoro.

We investigated whether juvenile freshwater stingrays (Potamotrygon motoro) can solve spatial tasks by constructing a cognitive map of their environment. Two experimental conditions were run: allocentric and ego-allocentric. Rays were trained to locate food within a four-arm maze placed in a room with visual spatial cues. The feeding location (goal) within the maze (room) remained constant while the starting position varied for the allocentrically but not for the ego-allocentrically trained group. After training, all rays solved the experimental tasks; however, different orientation strategies were used within and between groups. Allocentrically trained rays reached the goal via novel routes starting from unfamiliar locations, while ego-allocentrically trained rays primarily solved the task on the basis of an egocentric turn response. Our data suggest that P. motoro orients by constructing a visual cognitive map of its environment, but also uses egocentric and/or other orientation strategies alone or in combination for spatial orientation, a choice which may be governed by the complexity of the problem. We conclude that spatial memory functions are a general feature of the vertebrate brain.

Animals↗

Spatial memory in young and elderly adults: category structure of stimulus sets.

In 1987, Sharps and Gollin reported that the spatial memory of older adults is aided more than that of young adults by visually distinctive cues to location. In 1990, Park, Cherry, Smith, and Lafronza failed to reproduce these results. In the present study, strong category structure yielded results analogous to those of Park et al., and weak category structure similar to that of Sharps and Gollin yielded the same pattern of results as those in their study. The categorical interrelatedness of stimulus items was shown to be of potential importance in the resolution of the discrepancy between the 2 reports.

Adult↗

Selective loss of hippocampal granule cells following adrenalectomy: implications for spatial memory.

We examined the effects of long-term adrenalectomy (ADX) on hippocampal anatomy and behavioral learning in two spatial memory tasks. We assessed damage throughout the hippocampus by stereological analysis of the dentate gyrus and Ammon's horn. Rats were ADX or sham operated, and then tested in the Morris water maze 12 weeks after surgery, followed by testing on an eight-arm, alternating-baited radial maze at 22 weeks postsurgery. Animals were killed 7 1/2 months after surgery. ADX rats had selective volume reduction in the dentate gyrus with no changes in pyramidal regions CA1, CA2, CA3, or CA4. Dentate gyrus damage in some cases occurred throughout the entire rostrocaudal extent of the hippocampus. Analysis of corticosterone serum levels, serum Na+/K+ ratios, and body weight gain suggested that individual differences in dentate gyrus damage appear to be due to incomplete adrenalectomies or remaining ectopic tissue. ADX rats were able to learn in both the Morris water maze and eight-arm radial maze, even when the dentate gyrus was severely damaged (80% volume reduction). However, in the Morris water maze, the ADX rats' learning rate was significantly slower compared to controls. There was no difference between ADX and controls during reversal in either task. These data indicate that damage to the dentate gyrus following long-term ADX is severe enough to cause learning impairment in selected learning tasks. Such damage is restricted to the dentate gyrus and can occur throughout the rostrocaudal regions of the hippocampus.

Adrenalectomy↗

A possible mechanism for improvement by a cognition-enhancer nefiracetam of spatial memory function and cAMP-mediated signal transduction system in sustained cerebral ischaemia in rats.

1. Accumulated evidence indicates that the adenylyl cyclase (AC)/cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/cAMP-responsive element binding protein (CREB) signal transduction system may be linked to learning and memory function. 2. The effects of nefiracetam, which has been developed as a cognition enhancer, on spatial memory function and the AC/cAMP/PKA/CREB signal transduction system in rats with sustained cerebral ischaemia were examined. 3. Microsphere embolism (ME)-induced sustained cerebral ischaemia was produced by injection of 700 microspheres (48 micro m in diameter) into the right hemisphere of rats. Daily oral administration of nefiracetam (10 mg kg(-1) day(-1)) was started from 15 h after the operation. 4. The delayed treatment with nefiracetam attenuated the ME-induced prolongation of the escape latency in the water maze task that was examined on day 7 to 9 after ME, but it did not reduce the infarct size. 5. ME decreased Ca(2+)/calmodulin (CaM)-stimulated AC (AC-I) activity, cAMP content, cytosolic PKA Cbeta level, nuclear PKA Calpha and Cbeta levels, and reduced the phosphorylation and DNA-binding activity of CREB in the nucleus in the right parietal cortex and hippocampus on day 3 after ME. The ME-induced changes in these variables did not occur by the delayed treatment with nefiracetam. 6. These results suggest that nefiracetam preserved cognitive function, or prevented cognitive dysfunction, after sustained cerebral ischaemia and that the effect is, in part, attributable to the prevention of the ischaemia-induced impairment of the AC/cAMP/PKA/CREB signal transduction pathway.

Animals↗