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PubMedDate not supplied

Overexpression of a calcium-binding protein, S100 beta, in astrocytes alters synaptic plasticity and impairs spatial learning in transgenic mice.

Recent evidence suggests that slowly propagating Ca2+ waves from astrocytes can modulate the function of neurons. Altering astrocytic calcium processes in vivo may therefore affect neuronal and behavioral phenotypes. Previously, we generated transgenic mice that overexpress an astrocytic calcium-binding protein, S100 beta. Immunocytochemistry and in situ hybridization showed elevated expression in the astrocytes of the hippocampus and other brain regions. Neurons in the hippocampus were negative for S100 beta. In this paper we analyze the hippocampal electrophysiology and learning properties of mice from two transgenic lines. Significant differences were found between the hippocampal slices of normal and transgenic mice in their response to high frequency (100 Hz) stimulation. The overall distribution of post-tetanic excitatory postsynaptic potentials (EPSP) of the slices from the transgenic mice was shifted significantly toward smaller values to a degree that 25% of slices exhibited depression. The altered hippocampal neurophysiology was accompanied by an impairment in a hippocampal-dependent learning task. Transgenic mice showed significant impairment in a spatial version of the Morris water maze, however, they performed normally in non-spatial tasks. Probe trials showed that transgenic mice, though significantly impaired, also acquired spatial information. The results suggested that the impairment was not due to motor dysfunction, impaired vision or motivation of the transgenic mice, findings compatible with a possible hippocampal mechanism. We conclude that overexpression of S100 beta in astrocytes impairs, but does not abolish, the ability to solve a spatial task, and it leads to a significantly decreased post-tetanic potentiation in the hippocampal slice. We hypothesize that the changes are due to calcium mediated processes. Our results support the notion that astrocytes are involved in higher brain functions.

Animals↗
PubMed2002

Place and matching-to-place spatial learning affected by rat inbreeding (Dark-Agouti, Fischer 344) and albinism (Wistar, Sprague-Dawley) but not domestication (wild rat vs. Long-Evans, Fischer-Norway).

Domestication has been shown to produce a shift in both morphological and behavioral characteristics of animals. While changes in body weight, brain size, reproductive rates, and temperament are well documented, the effects of domestication on learning and memory are not as clearly understood. This issue is of particular importance to the use of rodent models in learning and memory where the domestication of Rattus norvegicus for research has resulted in the availability of numerous strains. To investigate cognitive effects resulting frm domestication, we examined the spatial performance of a number of rat strains: wild, Long-Evans, Fischer-Norway, Dark-Agouti, Wistar, Fischer 344, Sprague-Dawley. The wild rats served as a baseline for comparing inbred and outbred domestic strains and pigmented and albino domestic strains. Place (a measure of nonspatial and procedural learning), matching-to-place (spatial working memory), and probe (retention) performance were measured in the Morris swimming pool task. The task is an ideal means for comparing different rat strains because place learning has not been selected for in the domestication of Rattus norvegicus and because the task is ethologically relevant. The results indicated that wild rats and Long-Evans rats did not differ on any measure, with Fischer-Norway rats being only slightly inferior. Larger impairments were found in Wistar > Fischer 344 > Dark-Agouti > Sprague-Dawley strains. Impairments were more obvious on place acquisition but also occurred in matching-to-place performance. Platform crosses, but not quadrant preference was found to be correlated with place learning. In general, although nonspatial and spatial deficits were associated with both inbreeding and albinism, impaired spatial performance is not a necessary result of domestication.

Animals↗
PubMed1991

Effect of exposure to high pressure on subsequent spatial learning and memory in rats.

The effects of high helium pressure on the subsequent acquisition of spatial memory were studied in male rats. Thirty-two rats were exposed to 65 ATA helium-oxygen pressure for 4.2 days, decompressed (total time in chamber 5 days), and then tested in an eight-arm radial maze. Thirty-two control rats were exposed in the chamber to 1 ATA air. Each rat had 20 sessions in the maze (2 sessions/day for 10 days), and the number of correct (visiting an arm not previously visited to obtain the reward pellet) and incorrect choices (visiting a previously visited arm) were recorded. Statistical analysis showed that the rats exposed to 65 ATA performed significantly better than 1-ATA controls during the first 8 of 20 sessions. This effect was most pronounced in sessions 5-8. Results for sessions 9-20 showed that the pressure-treated rats still made more correct choices but to an extent that did not always reach statistical significance. Possible explanations include the pressure-treated rats performing better because of hunger after a lower food consumption at pressure. Alternatively, pressure itself may enhance proposed mechanisms of spatial memory such as long-term potentiation.

Animals↗
PubMed1987

Exploration and spatial learning in staggerer mutant mice.

Staggerer mutant mice, that lose cerebellar Purkinje cells and granule cells and inferior olive neurons, were evaluated in tests of spontaneous alternation and maze learning. It was found that, contrary to normal mice, the staggerer mutants did not alternate spontaneously and had deficits in the acquisition of maze learning. It is hypothesized that the olivocerebellar system has a role in visuo-spatial organization.

Animals↗
PubMed1999

Effects of nicotine on spatial learning in C57BL mice.

In the present study, the effects of nicotine on spatial memory in C57BL/6J mice was evaluated. Mice were trained in a water maze during four daily sessions of three trials each. In the first experiment, nicotine (0.7 and 0.35 mg/kg) or saline was administered once daily for 4 days, 15 min before the start of daily training: an impairment of performance of the water maze was observed in the group treated with 0.7 mg/kg of nicotine. In the second experiment, nicotine (0.7 and 0.35 mg/kg) or saline was administered from the 5 days prior to the beginning of the task and during the 4 days of acquisition. The results indicated an improvement in the rate of learning in the 9-day nicotine treated groups. The comparison between 4-day and 9-day treated groups revealed that the group receiving 0.35 mg/kg of nicotine for 9 days displayed significantly shorter latencies than all the other groups, while the group receiving 0.7 mg/kg of nicotine for 4 days performed significantly worse than all the other groups. The most noteworthy result is that nicotine was more effective after a more prolonged administration than when administered only during the training days.

Animals↗
PubMed2006

Sleep after spatial learning promotes covert reorganization of brain activity.

Sleep promotes the integration of recently acquired spatial memories into cerebral networks for the long term. In this study, we examined how sleep deprivation hinders this consolidation process. Using functional MRI, we mapped regional cerebral activity during place-finding navigation in a virtual town, immediately after learning and 3 days later, in subjects either allowed regular sleep (RS) or totally sleep-deprived (TSD) on the first posttraining night. At immediate and delayed retrieval, place-finding navigation elicited increased brain activity in an extended hippocampo-neocortical network in both RS and TSD subjects. Behavioral performance was equivalent between groups. However, striatal navigation-related activity increased more at delayed retrieval in RS than in TSD subjects. Furthermore, correlations between striatal response and behavioral performance, as well as functional connectivity between the striatum and the hippocampus, were modulated by posttraining sleep. These data suggest that brain activity is restructured during sleep in such a way that navigation in the virtual environment, initially related to a hippocampus-dependent spatial strategy, becomes progressively contingent in part on a response-based strategy mediated by the striatum. Both neural strategies eventually relate to equivalent performance levels, indicating that covert reorganization of brain patterns underlying navigation after sleep is not necessarily accompanied by overt changes in behavior.

Adult↗
PubMed2002

Long-term monitoring of hippocampus-dependent behavior in naturalistic settings: mutant mice lacking neurotrophin receptor TrkB in the forebrain show spatial learning but impaired behavioral flexibility.

Previous behavioral studies (Minichiello et al., Neuron 1999;24:401-414) showed that mice deficient for the TrkB receptor in the forebrain were unable to learn a swimming navigation task with an invisible platform and were severely impaired in finding a visible platform in the same setup. Likewise, additional behavioral deficits suggested a malfunction of the hippocampus and proximally connected forebrain structures. In order to discriminate whether the behavioral impairment was caused either by deficits in spatial memory and learning, or alternatively by loss of behavioral flexibility, 8 trkB mutant, 13 wild-type, and 22 heterozygous mice were implanted with transponders and released for 21 days into a large outdoor pen (10 x 10 m). The enclosure contained 2 shelters and 8 computer-controlled feeder boxes, delivering food portions for every mouse only during their first visit. Every third day, mice received food ad libitum inside the shelters. All mice learned to patrol the boxes correctly within a few days. However, significant differences emerged during those days with free food available. Wild-type mice remained inside the shelters, while all homozygous mutants continued to patrol the boxes in their habitual way, the heterozygous mutants showing intermediate scores. These and previous data suggest that one of the natural functions of the mouse hippocampus is to comediate behavioral flexibility, and that TrkB receptors might play an essential role in maintaining the neuronal short-term plasticity necessary for this capacity.

Animals↗
PubMed2000

Transient spine density increases in the mid-molecular layer of hippocampal dentate gyrus accompany consolidation of a spatial learning task in the rodent.

In previous studies, we observed a transient increase in dendritic spine frequency in the molecular layer of the dentate gyrus at 6h following passive avoidance training [O'Malley A., O'Connell C. and Regan C. M. (1998) Neuroscience 87, 607-613]. To determine if a similar change is associated with spatial forms of learning, we have estimated time-dependent modulations of spine number in the dentate gyrus of the adult rat following water maze training. All animals exhibited significant reductions in the latency to locate the platform over the five training sessions of the single trial (median and interquartile ranges of 60, 8 versus 8, 3 s for trials 1 and 5, respectively) and this improved performance was retained just prior to killing at the 6h post-training time. The unbiased dissector stereological procedure was used to estimate spine number in serial pairs of ultrathin coronal sections obtained at a point 3.3 mm caudal of Bregma. This analysis revealed a significant learning-associated increase in spine number at the 6h post-training time (1.32+/-0.18 spines/microm(3)) as it was not observed in paired controls exposed to the water maze for a similar swim-time (0.66+/-0.11 spines/microm(3)). The increase was transient as spine number returned to control levels at the 72 h post-training time. These spine frequency changes are proposed to reflect increased synapse turnover rate and concomitant change in connectivity pattern in the processing of information for long-term storage.

Animals↗
PubMed2005

The effect of intrahippocampal injection of testosterone enanthate (an androgen receptor agonist) and anisomycin (protein synthesis inhibitor) on spatial learning and memory in adult, male rats.

In most mammals, the hippocampus has a well-documented role in spatial memory acquisition. High concentration of androgen receptors in fundamental centers of learning and memory in brain such as hippocampus shows that there may be some relationships between androgen receptors and cognitive aspects of brain. Previous studies, which have shown sex-dependent differences in hippocampal morphology and physiology, suggest a modulatory role for sex steroids in hippocampal function. Androgens have been shown to modulate some hippocampal-mediated behaviors including learning and memory. To study the mechanism of action of androgens in processes underlying learning and memory, anisomycin, a protein synthesis inhibitor was used to prevent the genomic effects of testosterone. Therefore, the effects of anisomycin and testosterone together were assessed on rat's performance in MWM. Rats received anisomycin (2.5 microg/0.5 microl), testosterone (80 microg/0.5 microl) or both anisomycin (2.5 microg/0.5 microl) and testosterone (80 microg/0.5 microl) through the connulas in the CA1 region. Anisomycin was injected 20 min and testosterone was injected 35 min before training each day. The results showed that anisomycin (2.5 microg/0.5 microl) and testosterone (80 microg/0.5 microl) increased latencies to find the invisible platform. But the group that received testosterone and anisomycin together was decrease in latency and traveled distance to find the invisible platform.

Androgen Receptor Antagonists↗
PubMedDate not supplied

Spatial learning in the 5-HT1B receptor knockout mouse: selective facilitation/impairment depending on the cognitive demand.

Age-related memory decline is associated with a combined dysfunction of the cholinergic and serotonergic systems in the hippocampus and frontal cortex, in particular. The 5-HT1B receptor occupies strategic cellular and subcellular locations in these structures, where it plays a role in the modulation of ACh release. In an attempt to characterize the contribution of this receptor to memory functions, 5-HT1B receptor knockout (KO) mice were submitted to various behavioral paradigms carried out in the same experimental context (water maze), which were aimed at exposing mice to various levels of memory demand. 5-HT1BKO mice exhibited a facilitation in the acquisition of a hippocampal-dependent spatial reference memory task in the Morris water maze. This facilitation was selective of task difficulty, showing thus that the genetic inactivation of the 5-HT1B receptor is associated with facilitation when the complexity of the task is increased, and reveals a protective effect on age-related hippocampal-dependent memory decline. Young-adult and aged KO and wild-type (WT) mice were equally able to learn a delayed spatial matching-to-sample working memory task in a radial-arm water maze with short (0 or 5 min) delays. However, 5-HT1BKO mice, only, exhibited a selective memory impairment at intermediate and long (15, 30, and 60 min) delays. Treatment by scopolamine induced the same pattern of performance in wild type as did the mutation for short (5 min, no impairment) and long (60 min, impairment) delays. Taken together, these studies revealed a beneficial effect of the mutation on the acquisition of a spatial reference memory task, but a deleterious effect on a working memory task for long delays. This 5-HT1BKO mouse story highlights the problem of the potential existence of "global memory enhancers."

Animals↗
PubMed2006

Wayfinding with words: spatial learning and navigation using dynamically updated verbal descriptions.

This work investigates whether large-scale indoor layouts can be learned and navigated non-visually, using verbal descriptions of layout geometry that are updated, e.g. contingent on a participant's location in a building. In previous research, verbal information has been used to facilitate route following, not to support free exploration and wayfinding. Our results with blindfolded-sighted participants demonstrate that accurate learning and wayfinding performance is possible using verbal descriptions and that it is sufficient to describe only local geometric detail. In addition, no differences in learning or navigation performance were observed between the verbal study and a control study using visual input. Verbal learning was also compared to the performance of a random walk model, demonstrating that human search behavior is not based on chance decision-making. However, the model performed more like human participants after adding a constraint that biased it against reversing direction.

Adolescent↗
PubMed2006

Spatial learning based on the shape of the environment is influenced by properties of the objects forming the shape.

In 3 experiments rats had to find a submerged platform that was located in a corner of a kite-shaped pool. The color of the walls creating this corner provided an additional cue for finding the platform in the shape + color condition but not the shape-only condition. During tests in a pool with walls of a uniform color but no platform, more time was spent in the corner where the platform was originally located after training in the shape + color than in the shape-only condition. The results challenge theories that assume either that learning about the shape of the environment takes place in a dedicated module or that cues compete for the control they acquire over behavior.

Animals↗
PubMed2002

Differential effects of haloperidol, risperidone, and clozapine exposure on cholinergic markers and spatial learning performance in rats.

Haloperidol (HAL), a potent typical antipsychotic, continues to be a frequently prescribed medication for behavioral disturbances associated particularly with schizophrenia despite well-documented adverse effects associated with its chronic use. Animal experiments have even indicated that HAL can damage cholinergic pathways and thus could be especially deleterious to those experiencing cognitive deficits. However, several recent clinical studies indicate that atypical antipsychotics may actually improve cognitive function in some patients, although this assertion requires further investigation. The purpose of this study was to compare the effects of prior chronic (45- or 90-day) oral exposure to HAL and the atypical antipsychotics risperidone (RISP) and clozapine (CLOZ) on cognitive performance and central cholinergic markers in rats. All analyses were done after 4 days of drug washout in order to minimize direct drug effects. Learning performance and choline acetyltransferase (ChAT) levels were assessed in a water maze task and with immunofluorescence staining, respectively. HAL significantly impaired learning performance after 90 but not after 45 days of treatment when compared to both vehicle controls and the atypical agents, while RISP slightly improved task performance. Both 45 and 90 days of previous HAL exposure reduced ChAT staining in several brain regions, including the cortex, caudate-putamen, and hippocampus. ChAT staining in the caudate-putamen and hippocampus was also decreased after 90 days of RISP exposure, raising the possibility of deleterious cognitive effects after exposure to this dosage for longer periods of time. The results suggest that antipsychotic drugs exert differential and temporally dependent effects on central cholinergic neurons and learning performance.

Animals↗
PubMed1997

Spatial learning activates neural cell adhesion molecule polysialylation in a corticohippocampal pathway within the medial temporal lobe.

Transient and time-dependent modulations of neural cell adhesion molecule (NCAM) polysialylation in the dentate gyrus of the rodent hippocampus are a feature of spatial and nonspatial forms of learning. In the hippocampal formation, polysialic acid immunoreactivity was localized to granule-like cells and their mossy fibre axons. We now demonstrate the latter to extend to the CA3 region where apparent recurrent and Schaffer collaterals were labelled. The axons of the CA1 pyramidal cell layer were immunopositive, as was the subiculum that they innervate. Layers I and III of the entorhinal cortex stained intensely for polysialic acid; however, these were not visible in the more lateral aspect of this region and were replaced by a single band of immunopositive neurons that extended to include the perirhinal and piriform cortices. After Morris water maze training, the number of polysialylated neurons within the entorhinal cortex exhibited a two- to threefold increase at the 10-12-h posttraining time with respect to that observed immediately after training. This increase was task specific, as no change was observed in freely swimming animals or those required to locate a visible platform. These results suggest the presence of a corticohippocampal pathway involved in the eventual consolidation of memory.

Age Factors↗
PubMed2001

Specific spatial learning deficits become severe with age in beta -amyloid precursor protein transgenic mice that harbor diffuse beta -amyloid deposits but do not form plaques.

Memory impairment progressing to dementia is the main clinical symptom of Alzheimer's disease (AD). AD is characterized histologically by the presence of beta-amyloid (Abeta) plaques and neurofibrillary tangles in specific brain regions. Although Abeta derived from the Abeta precursor protein (beta-APP) is believed to play a central etiological role in AD, it is not clear whether soluble and/or fibrillar forms are responsible for the memory deficit. We have generated and previously described mice expressing human wild-type beta-APP(751) isoform in neurons. These transgenic mice recapitulate early histopathological features of AD and form Abeta deposits but no plaques. Here we describe a specific and progressive learning and memory impairment in these animals. In the Morris water maze, a spatial memory task sensitive to hippocampal damage, one pedigree already showed significant differences in acquisition in 3-month-old mice that increased in severity with age and were expressed clearly in 6-month- and 2-year-old animals. The second transgenic pedigree displayed a milder impairment with a later age of onset. Performance deficits significantly decreased during the 6 days of training in young but not in aged transgenic animals. Both pedigrees of the transgenic mice differed from wild-type mice by less expressed increase of escape latencies after the platform position had been changed in the reversal experiment and by failure to prefer the goal quadrant in probe trials. Both pedigrees performed at wild-type level in a number of other tests (open field exploration and passive and active place avoidance). The results suggest that plaque formation is not a necessary condition for the neuronal beta-APP(751) transgene-induced memory impairment, which may be caused by beta-APP overexpression, isoform misexpression, or elevated soluble Abeta.

Aging↗
PubMed2005

Sensory preconditioning in spatial learning using a touch screen task in pigeons.

The authors used a touch screen-based visual-search task to investigate spatial integration in pigeons. First, pigeons were presented with a consistent spatial relationship between compound visual landmarks (LMs) A-X and B-Y, separately. Next, pigeons learned to find a hidden goal on the monitor in the presence of LMs A and B. The goal bore a consistent spatial relationship to LM A, but not to LM B. On nonreinforced probe tests, the peak and distribution of responses to LM X suggest that pigeons computed a novel X-goal spatial relationship on the basis of X-A and A-goal spatial vectors. Responses to LM Y, however, revealed no evidence of spatial integration. These results replicate and extend those of A. P. Blaisdell and R. G. Cook (2005) using an open-field task.

Animals↗