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PubMed2006

Acute effects of the ampakine farampator on memory and information processing in healthy elderly volunteers.

Ampakines act as positive allosteric modulators of AMPA-type glutamate receptors and facilitate hippocampal long-term potentiation (LTP), a mechanism associated with memory storage and consolidation. The present study investigated the acute effects of farampator, 1-(benzofurazan-5-ylcarbonyl) piperidine, on memory and information processes in healthy elderly volunteers. A double-blind, placebo-controlled, randomized, cross-over study was performed in 16 healthy, elderly volunteers (eight male, eight female; mean age 66.1, SD 4.5 years). All subjects received farampator (500 mg) and placebo. Testing took place 1 h after drug intake, which was around Tmax for farampator. Subjects performed tasks assessing episodic memory (wordlist learning and picture memory), working and short-term memory (N-back, symbol recall) and motor learning (maze task, pursuit rotor). Information processing was assessed with a tangled lines task, the symbol digit substitution test (SDST) and the continuous trail making test (CTMT). Farampator (500 mg) unequivocally improved short-term memory but appeared to impair episodic memory. Furthermore, it tended to decrease the number of switching errors in the CTMT. Drug-induced side effects (SEs) included headache, somnolence and nausea. Subjects with SEs had significantly higher plasma levels of farampator than subjects without SEs. Additional analyses revealed that in the farampator condition the group without SEs showed a significantly superior memory performance relative to the group with SEs. The positive results on short-term memory and the favorable trends in the trail making test (CTMT) are interesting in view of the development of ampakines in the treatment of Alzheimer's disease and schizophrenia.

Adult↗
PubMedDate not supplied

Cerebrovascular permeability and cognition in the aging rat.

Regional cerebrovascular permeability-capillary surface area products (rPS) and brain vascular space (BVS) were measured in aging, conscious, unrestrained Sprague-Dawley rats. Three groups of animals were examined: young-mature (6 months), middle-aged (12-14 months), and old (24-26 months) rats. Complex maze learning had been previously characterized in these same animals. Maze learning declined with age. Brain vascular space did not differ significantly with age in any brain region. However, small, but significant age-dependent decreases in rPS (25-33%) were observed. These decreases occurred mainly in the old animals in the basal ganglia and parietal cortex, and in the middle-aged and old rats in the olfactory bulbs. Significant and unexpected positive average correlations between brain permeability-capillary surface area products (PS) and learning errors occurred primarily in young rats and were attributable mainly to changes in 5 of 14 brain regions; hypothalamus, hippocampus, parietal cortex, septal area and superior colliculus. The higher correlations between maze learning errors and PS in young animals may indicate dynamic regulation of this cerebrovascular parameter which is lessened with aging. Average correlations between PS and cerebral blood flow also were determined and found to be generally small and not significant for most brain regions and age groups.

Aging↗
PubMed2002

Dose-response effect of docosahexaenoic acid ethyl ester on maze behavior and brain fatty acid composition in adult mice.

The dose-response effect of dietary docosahexaenoic acid (DHA, 22:6 n-3) ethyl ester (EE) on maze-learning ability in mice was studied. Male Crj:CD-1 mice aged three months were fed a) a diet containing 5 g palm oil/100 g diet (control group); b) a diet containing 0.5 g DHA ethyl ester/100 g diet plus 4.5 g palm oil/100 g diet (DHA-EE 0.5% group); c) a diet containing 1 g DHA ethyl ester/100 g diet plus 4 g palm oil/100 g diet (DHA-EEE 1% group); d) a diet containing 2 g DHA ethyl ester/100 g diet plus 3 g palm oil/100 g diet (DHA-EE 2% group) for four months. Maze-learning ability was assessed three months after the start of the experiment. The time required to reach the maze exit and the number of times that a mouse strayed into blind alleys in the maze were measured in three trials, performed every four days. In trial 1, the DHA-EE 0.5%, 1% and 2% groups required less (p < 0.05) time to reach the maze exit, and the DHA-EE 2% group strayed (p < 0.05) into blind alleys fewer times than the control group. In trial 3 performed four days after the second trial, the DHA-EE 2% group needed less (p < 0.05) time to find the exit and spent a fewer (p < 0.05) number of times in blind alleys than did the control group. In the total lipids of plasma and brain of mice fed DHA, increasing intakes of DHA resulted in an increase in DHA levels, with a corresponding decrease in arachidonic acid (20:4 n-6). Improved maze-learning ability in mice fed DHA-EE 2% was associated with higher DHA levels in brain. Our resulted suggest that there are no linear dose-response effects of DHA on maze-learning ability, however, the intake of DHA-EE 2% diet improves learning ability in adult mice as demonstrated by maze performance.

Animals↗
PubMed1982

Learning ability of orphan foals, of normal foals and of their mothers.

The maze learning ability of six pony foals that had been weaned at birth was compared to that of six foals reared normally. The foals' learning ability was also compared to their mothers' learning ability at the same task; the correct turn in a single choice point maze. The maze learning test was conducted when the foals were 6 to 8 mo old and after the mothered foals had been weaned. There was no significant difference between the ability of orphaned (weaned at birth) and mothered foals in their ability to learn to turn left (6 +/- .7 and 5.1 +/- .1 trials, respectively) or to learn the reversal, to turn right (6.7 +/- .6 and 6.2 +/- .6 trials, respectively). The orphan foals spent significantly more time in the maze in their first exposure to it than the mothered foals (184 +/- 42 vs 55 +/- 15 s. Mann Whitney U = 7, P less than .05). The mothers of the foals (n = 11) learned to turn left as rapidly as the foals (5.9 +/- .7 trials), but they were slower to learn to turn right (9.8 +/- 1.4 vs 6.4 +/- .4 trials, Mann Whitney U = 33, P less than .05), indicating that the younger horses learned more rapidly. There was no correlation between the trials to criteria of the mare and those of her foal, but there was a significant negative correlation between rank in trials to criteria and age (r = -65, P less than .05) when data from the mare and foal trials were combined. The dominance hierarchy of the mares was determined using a paired feeding test in which two horses competed for one bucket of feed. Although there was no correlation between rank in the hierarchy and maze learning ability, there was a correlation between body weight and rank in the hierarchy (r = .7, P less than .05). This may indicate either that heavier horses are likely to be dominant or that horses high in dominance gain more weight. Maternal deprivation did not appear to seriously retard learning of a simple maze by foals, although the orphans moved more slowly initially. The lack of maternal influence on learning is also reflected in the lack of correlation between the mare's learning ability and that of her foal. Young horses appear to learn more rapidly than older horses.

Age Factors↗
PubMed1991

The NMDA receptor antagonists, CPP and gamma-L-glutamyl-L-aspartate, selectively block post-training improvement of performance in a Y-maze avoidance learning task.

Behavioral effects of CCP and gamma-L-glutamyl-L-aspartate (gamma-LGLA) were studied in a Y-maze avoidance learning task. Male Swiss mice had to leave the start alley of the maze within the first 5 s of a trial (temporal component) and to choose the left alley (spatial component) to avoid footshocks; they were trained to a criterion of 7 correct out of 8 consecutive trials. CPP and gamma-LGLA when administered immediately following the learning session (0.025-200 mumol/kg, i.p.) significantly impaired retention 48 h later at doses of 0.025-0.25 and 0.25-25 mumol/kg, respectively, but had no significant effect at higher doses. CPP, when administered 30 min before the learning session (0.025-25 mumol/kg) did not affect learning acquisition at any dose, whereas it significantly impaired retention 48 h later but only at the doses of 0.025-0.25 mumol/kg. CPP and gamma-LGLA did not erase all memory traces; posttraining performances on the temporal component, which significantly improved in control animals during the hours following acquisition, were much more affected by CPP and gamma-LGLA than posttraining performances on the spatial component which did not improve over time in controls. Moreover, CPP (0.025-25 mumol/kg) had no effect on spatial recognition memory in an alternation task in which no spontaneous improvement of posttraining performance was observed in controls. These results strongly suggest that CPP and gamma-LGLA interfere with mechanisms underlying posttraining organization of memory traces and that NMDA receptors are involved in this action.

Animals↗
PubMed2004

Neurofunctional deficits and potentiated apoptosis by neonatal NMDA antagonist administration.

The early postnatal brain development, when many potentially sensitive processes occur, has been shown to be vulnerable to different pharmacological and environmental compounds. In the present investigation, four groups of neonatal NMRI male mice were administered the glutamate NMDA receptor antagonist ketamine (50 mg/kg, s.c.), or the GABA(A) receptor agonist diazepam (5 mg/kg, s.c.), or co-administered ketamine (50 mg/kg, s.c.) and diazepam (5 mg/kg, s.c.), or vehicle (0.9% saline, s.c.) on day 10 after birth. On day 11, mice from each treatment group were sacrificed and brains were taken for analysis of neuronal cell degeneration, using Fluoro-Jade staining technique. Ketamine, but not diazepam, induced a severe degeneration of cells in the parietal cortex. The opposite was observed for diazepam in the laterodorsal thalamus. The most pronounced cell degeneration was seen in parietal cortex of mice exposed to both ketamine and diazepam. At 2 months of age each treatment group was tested for motor activity and learning performance. Ketamine and ketamine + diazepam treated mice displayed severe deficits of habituation to the test chamber in the spontaneous motor activity test, marked deficits of acquisition learning and retention memory in the radial arm maze-learning task and less shift learning in the circular swim maze-learning task. This study indicates that the observed functional deficits can be related to cell degeneration induced during a critical stage of neonatal brain development. The potentiated apoptosis induced by ketamine and diazepam may have implications for the selection of drugs used in neonatal paediatric anaesthesia.

Animals↗
PubMedDate not supplied

Impact of hypericum (St.-John's-wort) given prenatally on cognition of mice offspring.

This study investigated the cognitive impact of prenatal exposure to the herbal antidepressant hypericum in CD-1 mice. Hypericum (182 mg/kg/day) or a placebo was consumed in food bars for 2 weeks before mating and throughout gestation. The hypericin content in our hypericum formulation was in the middle range of standardized hypericum products. One offspring per gender from each litter (hypericum 13, placebo 12) was tested on each of the following tasks: juvenile runway with adult memory, adult Morris maze, adult passive avoidance, or adult straight water runway followed by a dry Cincinnati maze. Learning occurred in both genders in all tasks (P<.003) with no significant differences between treatments at the final trial. Female offspring exposed to hypericum, rather than to a placebo, required more time to learn the Morris maze task (P<.05). Postlearning sessions did not show any significant differences. In conclusion, prenatal exposure to a therapeutic dose of hypericum did not have a major impact on certain cognitive tasks in mice offspring.

Animals↗
PubMed2001

Changes in maze behavior of mice occur after sufficient accumulation of docosahexaenoic acid in brain.

The relationship between the time of intake of docosahexaenoic acid [DHA, 22:6(n-3)] and maze behavior in mice was studied. Male Crj:CD-1 mice (3 mo old) were fed a diet containing 2 g DHA-ethyl ester/100 g diet plus 3 g palm oil/100 g diet (DHA-EE group) or a diet containing 5 g palm oil/100 g diet (control group) for different periods of time. Maze-learning ability was assessed at 1 and 2 wk and 1 and 3 mo after the start of the control and experimental diets. In each maze-learning test, the time required to reach the maze exit and the number of times that a mouse strayed into blind alleys in the maze were measured in three trials, one every 4 d. After the last learning test in each trial, all mice were killed and the fatty acid compositions of plasma and brain lipids were determined. There were no significant differences in the results of the maze-learning tests between mice fed the diets at 1 or 2 wk in any of the three trials. After 1 and 3 mo, the DHA-EE diet groups required less time (P < 0.05) to reach the maze exit and strayed into blind alleys fewer times (P< 0.05) than did the control diet groups during trial 3. Significantly greater DHA levels were observed in the plasma and brain total lipids of the mice fed the DHA-EE diet after 2 wk, compared with those fed the control diet (P < 0.05), which was compensated for by lower arachidonic acid [20:4 (n-6)] levels. There were no significant differences in brain DHA levels among mice fed the DHA-EE diet for 2 wk, 1 mo, or 3 mo. Improved maze-learning ability after DHA intake was evident at 1 mo after the start of feeding and were maintained up to 3 mo, whereas the increased DHA levels in brain were apparent after feeding for just 2 wk. These results suggest that it may take time after the incorporation of DHA into the brain for improvement in learning ability to occur.

Animals↗
PubMed1998

Age-associated memory impairment. Assessing the role of nitric oxide.

Several neurotransmitter systems have been investigated to assess hypothesized mechanisms underlying the decline in recent memory abilities in normal aging and in Alzheimer's disease. Examining the performance of F344 rats in a 14-unit T-maze (Stone maze), we have focused on the muscarinic cholinergic (mACh) and the N-methyl-D-aspartate (NMDA) glutamate (Glu) systems and their interactions. Maze learning is impaired by antagonists to mACh or NMDA receptors. We have also shown that stimulation of mACh receptors can overcome a maze learning deficit induced by NMDA blockade, and stimulation of the NMDA receptor can overcome a similar blockade of mACh receptors. No consistent evidence in rats has been produced from our laboratory to reveal significant age-related declines in mACh or NMDA receptor binding in the hippocampus (HC), a brain region that is greatly involved in processing of recent memory. Thus, we have directed attention to the possibility of a common signal transduction pathway, the nitric oxide (NO) system. Activated by calcium influx through the NMDA receptor, NO is hypothesized to be a retrograde messenger that enhances presynaptic Glu release. Maze learning can be impaired by inhibiting the synthetic enzyme for NO, nitric oxide synthase (NOS), or enhanced by stimulating NO release. However, we have found no age-related loss of NOS-containing HC neurons or fibers in rats. Additionally, other laboratories have reported no evidence of an age-related loss of HC NOS activity. In a microdialysis study we have found preliminary evidence of reduced NO production following NMDA stimulation. We are currently working to identify the parameters of this phenomenon as well as testing various strategies for safely stimulating the NO system to improve memory function in aged rats.

Aging↗
PubMed1997

Peripheral and cerebral asymmetries in the rat.

Rats learn a novel foraging pattern better with their right-side whiskers than with their left-side whiskers. They also learn better with the left cerebral hemisphere than with the right hemisphere. Rotating an already learned maze relative to the external environment most strongly reduces right-whisker performance; starting an already learned maze at a different location most strongly reduces left-whisker performance. These results suggest that the right-periphery-left-hemisphere system accesses a map-like representation of the foraging problem, whereas the left-periphery-right-hemisphere system accesses a rote path. Thus, as in humans, functional asymmetries in rats can be elicited by both peripheral and cortical manipulation, and each hemisphere makes qualitatively distinct contributions to a complex natural behavior.

Animals↗
PubMed1988

Constraints on water maze spatial learning in rats: implications for behavioral studies of brain damage and recovery of function.

In an effort to develop spatial learning tasks not requiring food or water deprivation for use in studies of recovery of function after brain damage, T-maze spatial alternation learning was examined in intact rats using water maze swim-escape procedures. Consistent with previous studies, rewarded spatial alternation involving food or water deprivation was readily learned by intact rats. However, none of the groups of rats trained in the swim-escape tasks learned to alternate goal arm choices in the water maze at reliable rates. This was true regardless of whether non-correction or correction procedures were used, and regardless of intertrial delay intervals. Although average alternation rates over sessions did increase from chance levels, the majority of the rats did not reach criterion levels, even with as many as 38 consecutive days of testing. In contrast, a conditional spatial alternation task in the water maze, using a win-shift procedure, was readily learned. Surprisingly, a win-stay version of this conditional spatial task was not learned over 21 days of testing. These unexpected constraints on spatial learning and memory processes in rats cannot be attributed simply to failure of spatial information processing, nor to strict limitations on working memory in swim-escape tasks, since excellent spatial navigation abilities have been documented, and mastery of at least some working-memory tasks have now been demonstrated in swim-escape tasks.

Animals↗
PubMed2001

Varieties of human spatial memory: a meta-analysis on the effects of hippocampal lesions.

The current meta-analysis included 27 studies on spatial-memory dysfunction in patients with hippocampal damage. Each study was classified on the basis of the task that was used, i.e., maze learning, working memory, object-location memory, or positional memory. The overall results demonstrated impairments on all spatial-memory tasks. Clear differences in effect size were found between positional memory on the one hand and maze learning, object-location memory, and working memory on the other hand. Lateralization was found only on maze learning and object-location memory. These findings clearly indicate that specific aspects of spatial memory can be affected in various degrees in patients with hippocampal lesions. Moreover, these results strongly support the notion that the hippocampus is important in the processing of metric positional information, probably in the form of an allocentric cognitive map.

Animals↗
PubMed1999

Strain distribution of mice in discriminated Y-maze avoidance learning: genetic and procedural differences.

The current study was conducted to characterize discriminated avoidance learning in mice by using a Y-maze task. In Experiment 1, the task parameters were manipulated, including the amount of time spent in the start arm, the amount of time to make the avoidance response, and the intertrial interval (ITI) using C57 x SJL F1 hybrid mice. Avoidance performance was significantly improved with longer times to avoid the shock and longer ITIs. In Experiment 2, mice from 4 inbred strains (BALB/cByJ, DBA/2J, C57BL/6J, and SJL/J), an F1 hybrid (C57 x SJL), and 1 outbred strain (CD1) were tested with various ITIs. Strain differences were observed in avoidance learning, with BALB, DBA, C57 x SJL and CD1 mice showing significantly better avoidance learning than C57 mice, which were better than SJL mice. These data demonstrate that Y-maze performance is significantly influenced by the genetic background of the mouse and the parameters of the task.

Animals↗
PubMed2004

Impaired performance of children exposed in utero to cocaine on a novel test of visuospatial working memory.

The present study examines the potentially harmful effects of prenatal cocaine exposure on later visuospatial memory functions. A novel neuropsychological measure of immediate- and short-term memory for visuospatial information was administered to 40 children, who were identified as cocaine-exposed, and 11 age and socioeconomic status matched controls (all children were 8-9 years old). The Groton Maze Learning Test is a computer-based hidden maze learning test that consists of a 'timed chase test' (a simple measure of visuomotor speed), 5 learning trials on a hidden maze, followed by a delayed recall trial after an 8 min delay. The specific test parameters are chosen based on the age cohort of the subjects. The cocaine-exposed group performed significantly slower on the 'timed chase test,' the last 3 learning trials, and the delayed recall trial (p < or = .05 for all comparisons). Although there was a modest trend for the cocaine-exposed group to make more errors throughout the learning trials, there were no significant group differences. These results suggest that children who were exposed in utero to cocaine exhibit slowed visuomotor speed, a possible impairment in procedural learning, and diminished efficiency in accessing and using the internal spatial map that subjects create to master the maze.

Child↗
PubMed2003

Longitudinal axis of the hippocampus: both septal and temporal poles of the hippocampus support water maze spatial learning depending on the training protocol.

It has been suggested previously that 30% sparing of the hippocampus is enough to support spatial learning of a reference memory task in a water maze provided the spared tissue is located septally (Moser et al. 1995, Proc Natl Acad Sci USA 92:9697-9701). Therefore, the temporal hippocampus may not be involved in spatial memory. Place cells are also found in this part of the structure, and it has been suggested that these place cells have larger, less well-tuned place fields than are found in the septal hippocampus. We tested the possibility that the temporal hippocampus might be involved in spatial learning when the animals are required to distinguish between different contexts. Experiment 1 was a replication of the findings reported by Moser et al., using their protocol (8 trials/day, 6 days) and the groups with 20-40% hippocampus spared septally or temporally (volume assessed by quantitative volumetric techniques). In experiment 2, rats with also 20-40% sparing of the hippocampus either septally or temporally were trained in two water maze concurrently (four trials/day/water maze, 8 days). Rats with 20-40% hippocampus spared temporally were able to learn the two water maze tasks normally, and no difference was observed between rats with septal and temporal hippocampus spared across different measures of performance. In experiment 3, rats with 20-40% hippocampus spared septally or temporally were trained in one water maze as in experiment 1, but using a spaced training protocol similar to that of experiment 2 (four trials/day, 8 days). Rats with temporal hippocampus spared developed a preference for the training quadrant and acquired levels of performance indistinguishable from those of rats with septal hippocampus spared. The results suggest that the temporal hippocampus can support the learning of two, but also one, spatial water maze reference memory task, provided the training protocol is adequate.

Animals↗
PubMed2005

Effects of laterality and sex on cognitive strategy in a water maze place learning task and modification by nicotine and nitric oxide synthase inhibition in rats.

The aim of the present study was to investigate sex differences in learning strategies and to elucidate the mechanisms, which may underlie these differences. In two separate experiments, rats were presented with different strategies that could be employed to learn the position of a platform in a water maze (WM); furthermore, rats received treatments that could influence these strategies. In the first experiment, we demonstrated that the response-learning paradigm can be applied to the WM and can be compared with visually cued learning and reversal learning. Naïve rats of either sex could acquire this protocol relatively easily. On the probe trial, where the rats are presented with a choice between using response versus visually cued learning, initially response learning was preferred, however, during these experiments, laterality emerged as a significant factor and rats trained to turn right had difficulty in reversing the learned pattern to find the platform. The second part of our study evaluated the effects of nicotine and nitric oxide synthase (NOS) inhibition on the aforementioned parameters. Drug treatments impaired acquisition compared to saline treatments and the effect was more pronounced with NOS inhibition. During the probe trial, while NOS inhibition enhanced the right-side bias in both sexes, nicotine treatment had the same effect only in males. In conclusion, naïve rats can acquire place learning using visible cues or response learning; however, there is a right side bias in both sexes and the laterality effect is more pronounced in male rats. In drug-treated animals, while NOS inhibition enhances laterality (right bias) in both sexes similarly, nicotine modifies the cognitive strategy in a sexually dimorphic manner by augmenting the right bias only in male rats.

Animals↗
PubMed1990

Task-dependent memory loss and recovery following unilateral nucleus basalis lesion: behavioral and neurochemical correlation.

We found that rats with unilateral AF64A lesions of the nucleus basalis of Meynert (nbM) showed significant impairment of active avoidance and Morris water maze learning. Impairment of active avoidance learning almost subsided within one month but impairment of Morris water maze learning persisted 5 months later. Two weeks after production of the lesion, choline acetyltransferase (ChAT) activity was reduced by 45% in the frontal cortex (FC), but not in the hippocampus or corpus striatum. The decreased ChAT activity in the FC gradually recovered, but it was still reduced by 20% even after 20 weeks. In contrast, ChAT activity on the contralateral side of the FC began to increase from 5 weeks onwards. Histological examination also indicated that loss of cholinergic fibers in the FC gradually recovered with time after induction of the lesion. The results from the present study suggest that specific learning (Morris water maze) tasks involve the cholinergic system and that recovery of cholinergic function (ChAT) may be related to plasticity of the contralateral FC.

Acetylcholine↗
PubMed2000

Cognitive impairment and synaptosomal choline uptake in rats following impact acceleration injury.

Traumatic brain injury is well known to cause deficits in learning and memory, which typically improve with time. Animal studies with fluid percussion or controlled cortical impact injury have identified transient disturbances in forebrain cholinergic innervation which may contribute to such cognitive problems. This study examines the extent to which water maze performance and forebrain synaptosomal choline uptake are affected one week after injury using the newly developed impact acceleration injury model. Injury or sham injury was delivered to adult male Sprague-Dawley rats under halothane anesthesia using a 500-g 2.1-m weight drop. Based on righting reflex, injured rats were divided into moderate (< or = 12 min) or severe (>12 min) groups. Water maze testing was performed on days 5-7 postinjury. On day 7, choline uptake was determined in synaptosomes from hippocampus, a parietal cortex, and entorhinal cortex. Maze learning was severely impaired in the severe injury group but not in the moderate injury group. Learning retention was slightly impaired in the moderate injury group and severely affected in the severe injury group. There was a very strong correlation between the severity of injury as determined by prolongation of righting times and disruption of maze learning at 1 week postinjury. There was no change in synaptosomal choline uptake in any of the forebrain regions in the severe injury group, but a slight (14%) decrease in the hippocampus and parietal cortex of the moderate injury group. Correlation analysis showed no relationship between synaptosomal choline uptake in any brain region and performance in either water maze learning or retention. This study shows that the impact acceleration model produces cognitive impairments equivalent to those seen with fluid percussion injury and controlled cortical impact. Compared with those models, the impact acceleration model does not produce a similar disruption of forebrain cholinergic nerve terminals.

Acceleration↗