The effects of life-long food restriction on spatial memory in young and aged Fischer 344 rats measured in the eight-arm radial and the Morris water mazes

The effect of life-long 60% ad lib food restriction on performance in two tasks involving spatial memory, the eight-arm radial maze and the Morris water maze, was studied in young and aged Fischer 344 rats. Restricted (R) and ad lib (AL) feeding groups were compared at 8, 16, and 24 months of age on both tasks. A 30-month-old R group was also tested in the Morris water maze. In the eight-arm maze, although 24-month-old animals performed more poorly than 8- and 16-month-old animals during the first week of testing, overall accuracy of performance did not vary significantly as a function of age. Twenty-four-month-old animals took longer to make 10 choices than did younger animals, and there was a significant interaction between feeding regimen and age, reflecting the fact that at the two younger ages, R groups performed more quickly than the AL groups. In the Morris water maze, both distance swum and time to find the platform increased with age. Life-long food restriction led to small but significant improvements in performance in the water maze in aged rats. R groups showed evidence for better retention over 24-hour intervals than did AL groups. By 30 months of age, however, R animals showed impaired performance relative to younger R groups. These differential findings on the two tasks, as they were used here, suggest that there was greater impairment with age on the spatial memory task requiring retention of information over long intervals than there was on the task primarily involving working memory within a trial. Life-long food restriction would appear to delay the impairments of age, but not prevent them.     

Portal hypertension in 18-month-old rats: Memory deficits and brain metabolic activity

Portal hypertension is a major complication of cirrhosis that frequently leads to a neuropsychiatric disorder that affects cognition. We compared the performance of 18-month-old prehepatic portal hypertensive rats (PH) and 18-month-old normal rats (CO) in spatial short-term and reference memory tasks in the Morris water maze and in active avoidance task. The PH group showed worse spatial short-term memory than the CO group. Also, the PH group tended to perform worse than the CO group in the reference memory task, but it presented a correct acquisition of the active avoidance task. We assessed the brain metabolic activity of the animals by means of cytochrome c-oxidase (COx) histochemistry. We found that the PH group developed prefrontal dysfunction characterized by increased COx activity in this region compared to the CO group. Similar results were found in the medial mammillary nucleus and dentate gyrus, whereas the CA1 area, bed nucleus of the stria terminalis, and supramammillary nucleus showed lower COx activity in the PH group as compared to the CO group. We conclude that the 18-month-old portal hypertensive rats present spatial memory impairment without alteration of implicit learning. This deficit could be related to the alteration of the metabolic activity of the brain regions involved in the processing of spatial memories.     

Application of a novel Active Allothetic Place Avoidance task (AAPA) in testing a pharmacological model of psychosis in rats: comparison with the Morris Water Maze

Administration of a non-competitive NMDA antagonist dizocilpine (MK-801) was proposed to be an animal model of psychosis. NMDA-receptor blockade is accompanied by increased locomotion, behavioral deficits, and other changes resembling psychotic symptoms. However, the role of NMDA-receptors in organizing brain representations is not understood yet. We tested the effect of NMDA-receptor blockade by systemic administration of dizocilpine at two different doses (0.1 or 0.2 mg/kg) in a recently designed Active Allothetic Place Avoidance (AAPA), a task which requires rats to separate spatial stimuli from two continuously dissociated subsets. The effect of dizocilpine on learning in the AAPA task was compared with its effect on acquisition of the reference memory version of the Morris Water Maze task. Both doses impaired performance in the Morris Water Maze task, whereas only the higher dose impaired performance in the AAPA task. The Morris Water Maze appears to be more sensitive to dizocilpine-induced behavioral deficit than the AAPA task. These findings support the notion that these two tasks are differentially dependent on the NMDA-receptor function.     

Analysis of sensitivity to MK-801 treatment in a novel active allothetic place avoidance task and in the working memory version of the Morris water maze reveals differences between Long-Evans and Wistar rats

The aims of the present study were to compare the effect of subchronic administration of MK-801 on performance in the active allothetic place avoidance (AAPA) task and in the working version of Morris water maze (MWM) in Long-Evans and Wistar rats. Animals were trained for four daily sessions either in the AAPA or in the working memory version of the MWM. Wistar rats treated by MK-801 (0.1 mg/kg) showed a cognitive deficit in the AAPA task without a significant hyperlocomotion, whereas they were not impaired in the working memory version of the MWM compared to controls. Long-Evans rats treated by MK-801 (0.1 mg/kg) were not impaired either in the AAPA task or in the MWM task. Higher doses of MK-801 (0.2 and 0.3 mg/kg) produced hyperlocomotion in both strains which corresponded to an inability to solve both spatial tasks. Long-Evans rats were superior in the MWM to the Wistar rats in the groups treated with the low dose of MK-801. In conclusion, intact Wistar rats can efficiently solve both spatial tasks; however, they are more sensitive to MK-801-induced behavioural deficit. This has relevance for modeling of the schizophrenia-related deficits and for screening substances for their therapeutic potential.     

Differential effects of cholinergic blockade on performance of rats in the water tank navigation task and in a radial water maze

The disruptive effect of cholinergic blockade was tested under conditions in which either the working memory or the spatial mapping requirements of the behavioral task were emphasized. In Experiment 1, 13 rats were trained in an eight-arm radial water maze to asymptotic performance. When delays of 5, 10, 20, and 40 min were inserted between Choice 4 and Choice 5, incidence of errors in Choices 5-8 increased after pretrial (20 min) scopolamine injection (0.2 mg/kg, ip) faster than under control conditions and approached chance level with the 40-min delay. Scopolamine after Choice 4 or pretrial methylscopolamine was ineffective. In Experiment 2, 30 rats were trained in a Morris water tank. Acquisition was impaired by pretrial injection (20 min) of 0.1 and 0.2 mg/kg scopolamine, but a higher dose (1.0 mg/kg) was required to impair overtrained performance. In a working memory version of the navigation task, scopolamine administered 20 min before the first trial deteriorated retention tested 40 min later at a dose of 1.0 but not at 0.4 and 0.2 mg/kg. It is concluded that the disruptive effect of scopolamine is proportional to the demands on the working memory component of the task whereas the use of an overtrained mapping strategy is relatively resistant to cholinergic blockade.     

Working memory training decreases hippocampal neurogenesis

The relationship between adult hippocampal neurogenesis and cognition appears more complex than suggested by early reports. We aimed to determine if the duration and task demands of spatial memory training differentially affect hippocampal neurogenesis. Adult male rats were trained in the Morris water maze in a reference memory task for 4 days, or alternatively working memory for either 4 or 14 days. Four days of maze training did not impact neurogenesis regardless of whether reference or working memory paradigms were used. Interestingly, 2 weeks of working memory training using a hidden platform resulted in fewer newborn hippocampal neurons compared with controls that received either cue training or no maze exposure. Stress is a well-established negative regulator of hippocampal neurogenesis. We found that maze training in general, and a working memory task in particular, increased levels of circulating corticosterone after 4 days of training. Our study indicates that working memory training over a prolonged period of time reduces neurogenesis, and this reduction may partially be mediated by increased stress.     

Arachidonic acid improves aged rats' spatial cognition

To examine the effects of arachidonic acid (AA) on age-related cognitive deficits, F-344 rats were administered with an AA-supplemented powder diet from 79 weeks of age (OA group). For comparison, we also used an age-matched control group of animals (OC group) that were fed with a non AA-supplemented powder diet. When the subjects reached 87 weeks old, they were trained for Morris water maze place and cue tasks. Escape latencies of the OA group on the place task were significantly shorter than those of the OC group in the latter half of training. The probe test showed that OA rats remembered the trained platform position significantly better than OC rats. In the cue task training, the OC group was significantly slower than the OA group at the beginning of training, but their performance soon matched with that of the OA group. Fatty acids in the hippocampi were measured after the behavioral testing. There was no difference in AA composition in hippocampal phospholipids between the OA and OC groups. However, regression analysis conducted on AA composition and place task performance showed a significant correlation between these two parameters. The present study suggests that AA administration to aged animals can alleviate age-related deficits in spatial cognition.     

Effects of distraction and stress on delayed matching-to-place performance in aged rats

The performance of male Long-Evans rats on the delayed match-to-place (DMP) version of the Morris water maze was assessed in two separate experiments; the first compared young (4 months) with middle-aged (16 months) rats, whereas the second compared middle-aged (14 months) with old (26 months) rats. Old rats continued to use a short-term memory strategy on the DMP task, but their performance on both search and recall trials was impaired relative to that of middle-aged animals. Rats of all ages habituated rapidly to visual distraction and the performance of old rats was not affected by exposure to a mild predator stress in the form of cat urine. The performance of the middle-aged rats did not differ significantly from that of young rats, even when they were challenged on recall trials by visual distraction or by exposure to predator odour. These results do not provide strong support for the prediction that visual distraction and psychological stress would interact with age in affecting spatial short-term memory in Long-Evans rats.     

Erythropoietin improves spatial learning and memory in streptozotocin model of dementia

Alzheimer's disease is associated to impairments of learning and memory. Because studies demonstrated that erythropoietin has positive effects on central nervous system, the aim of this study was to evaluate the effect of erythropoietin on spatial learning and memory in a well defined model for Alzheimer's disease. Rat model of Alzheimer's was created by injecting streptozotocin in lateral ventricles of the brain. Two weeks later, the rats were assessed through passive avoidance learning test to confirm the induction of Alzheimer's. After that, they received erythropoietin (5000 IU/kg) every other day, for two weeks and then spatial learning and memory were assessed by a 5-day protocol of Morris water maze test in them. The results showed that streptozotocin severely damaged learning and memory in rats. Erythropoietin had no significant effect in the control rats; however, it significantly improved learning and memory in rats with Alzheimer's disease, as the task performance of the rats treated with erythropoietin was like the control group. The results suggest that erythropoietin can be considered as an effective treatment for neurodegenerative damages.     

Nerve growth factor improves spatial learning and restores hippocampal cholinergic fibers in rats withdrawn from chronic treatment with ethanol

The cholinergic septohippocampal pathway has long been known to be important for learning and memory. Prolonged intake of ethanol causes enduring memory deficits, which are paralleled by partial depletion of hippocampal cholinergic afferents. We hypothesized that exogenous supply of nerve growth factor (NGF), known to serve as a trophic substance for septal cholinergic neurons, can revert the ethanol-induced changes in the septohippocampal cholinergic system. Adult rats were given a 20% ethanol solution as their only source of fluid for 6 months. During the first 4 weeks after the animals were withdrawn from ethanol, they were intraventricularly infused with either NGF or vehicle alone via implanted osmotic minipumps. The vehicle-infused withdrawn animals showed impaired performance on a spatial reference memory version of the Morris water maze task, both during the task acquisition and on the retention test. In contrast, NGF-treated withdrawn rats were able to learn the task as well as controls, and significantly outperformed the vehicle-infused withdrawn rats. The histological analysis revealed that, in the latter group, the length density of fibers immunoreactive to choline acetyltransferase was reduced relative to control values by approximately 25%, as measured in the dentate gyrus and regio superior of the hippocampal formation. However, in NGF-treated withdrawn rats, the length density of these fibers was identical to that of control rats. These data provide support to the notion that NGF is capable of ameliorating memory deficits and restoring septohippocampal cholinergic projections following chronic treatment with ethanol. Electronic Publication     

Growth hormone replacement in hypophysectomized rats affects spatial performance and hippocampal levels of NMDA receptor subunit and PSD-95 gene transcript levels

Clinical studies have demonstrated that growth hormone (GH) promotes learning and memory processes in GH-deficient (GHD) patients. In animal studies, GH also influences the N-methyl-D-aspartate (NMDA) receptor system in the hippocampus, an essential component of long-term potentiation (LTP), which is highly involved in memory acquisition. This study was designed to examine the beneficial effects of recombinant human GH (rhGH) on cognitive function in male rats with multiple hormone deficiencies resulting from hypophysectomy (Hx). The performance of an rhGH-treated group and an untreated control group was appraised in the Morris water maze (MWM). The rhGH-treated group performed significantly better in the spatial memory task than the control animals on the second and third trial days. Further training eliminated this difference between the groups. Hippocampal mRNA expression of the NMDA subunits NR1, NR2A and NR2B, insulin-like growth factor type 1 receptor (IGF-1R), and postsynaptic density protein-95 (PSD-95) was then measured in the animals by Northern blot analysis. The results suggest that there may be a relationship between the NMDA receptor subunit mRNA expression levels and learning ability, and that learning is improved by rhGH in Hx rats. Furthermore, a link between MWM performance and PSD-95 was also suggested by this study.     

Persistent impairments in hippocampal, dorsal striatal, and prefrontal cortical function following repeated photoperiod shifts in rats

Cognitive impairments are observed when learned associations are being acquired or retrieved during a period of circadian disruption. However, the extent of the functional impacts on previously acquired associations following circadian rhythm re-entrainment is unknown. The impacts of repeated photoperiod shifts on learning and memory in male and female rats were examined. For these experiments, rats were trained on a spatial version of the Morris water task (MWT) and a visual discrimination task designed for the 8-arm radial maze. Following asymptotic performance on these tasks, rats experienced a repeating photoperiod shift procedure and were then re-entrained. Following circadian re-entrainment, retention of pre-photoperiod-shift-acquired associations was tested. In addition, an extra-dimensional set shift was performed using the 8-arm radial maze. Impaired retention of the MWT platform location was observed in photoperiod-shifted subjects relative to subjects with stable, unmanipulated photoperiods. Repeated photoperiod shifts negatively impacted retention in males and females compared with subjects with stable photoperiods. Retention and the ability to detect extra-dimensional shifts on the visual discrimination task were also impaired, though not consistently by sex or photoperiod condition. Running wheel availability was also included in the analyses to determine whether exercise influenced the effects of photoperiod shifting. The absence of a running wheel produced significant declines in memory retention on both MWT and the visual discrimination task, but only for male rats. The observed impairments indicate that multiple neural systems supporting different learning and memory functions are susceptible to circadian disruption, even if the association is acquired prior to rhythm fragmentation and tested following rhythm re-entrainment.     

DAU 6215, a novel 5-HT3 receptor antagonist, improves performance in the aged rat in the Morris water maze task

The effects of the new 5-HT3 receptor antagonist, DAU 6215, on aged rats' cognition were assessed in the Morris water maze task. Task performance of aged animals that received acutely the dose of 10 μg/kg IP was not different than that of their aged controls treated with the vehicle. Conversely, a repeated IP administration of 10 μg/kg DAU 6215 for 3 weeks significantly improved task performance of the aged animals as compared to that displayed by the old rats treated with the vehicle.     

Persistence of spatial memory in the Morris water tank task

Persistence of the spatial memory record was examined in 30 rats overtrained in the working memory version of the Morris water tank task. In Experiment 1, the animal had to find during the acquisition trial an invisible underwater platform randomly located at one of 4 possible sites in the pool. Retention test was performed 1 min, 60 min, 4 h or 24 h later with the same position of the platform and same or changed position of the start. Whereas in the acquisition trials the rats reached the goal after 12 s on average, the latency in the retrieval trials increased with the acquisition-retrieval interval. It was 5 s with the 1-min delay and exponentially approached, but did not quite reach the acquisition trial latency with the 24-h delay. In Experiment 2 the rats were started from the same position of the tank to goal positions changing from trial to trial in a prearranged sequence. There were either 1-h or alternating 1-min and 2-h intervals between the 6 daily trials. The latencies were long during the first trial and whenever the goal changed and short when the goal remained the same as on the previous trial. The latencies were not significantly influenced by intertrial interval in the 1 min to 2 h range. It is concluded that the decay of spatial memory in the water tank task is slow and is little affected by proactive interference.     

Spatial reference and working memory across the lifespan of male Fischer 344 rats

Loss of mnemonic function is among the earliest and most disconcerting consequences of the aging process. This study was designed to provide a comprehensive profile of spatial mnemonic abilities in male Fischer 344 (F344) rats across the lifespan. Young, middle-aged, and aged F344 rats were trained in spatial reference and working memory versions of the water maze task. There was a progressive age-related decline in spatial reference memory across the lifespan. Reliable individual differences were observed among aged rats, with some aged rats performing as well as young cohorts and others performing outside this range. An age-related delay-dependent decline was observed on a working memory version of the water maze task although no relationship between performance on reference and working memory tasks was present. Notably, middle-aged rats were impaired relative to young on both tasks. Together these data demonstrate that individual differences in spatial reference memory exist among aged F344 rats and provide novel data demonstrating an unrelated decline in working memory across the lifespan, suggesting that age-related mnemonic dysfunction may occur across multiple brain systems.     

Deficit in the water-maze after lesions in the anteromedial extrastriate cortex in rats.

The Morris water-maze task was used to evaluate the role of the anteromedial extrastriate visual cortex in the processing of visuospatial information in rats. Six gray male rats received bilateral ibotenic acid injections targeted stereotactically to the rostral part of the anteromedial extrastriate visual cortex. These operated subjects and six other unoperated control rats were tested in the maze. Histological analysis confirmed the localization, symmetry, and depth of lesions in the rostral part of anteromedial area (AMa) in the operated subjects. In these animals, a significantly greater latency to reach the submerged platform was found (U = 0, p = 0.004). The Morris water-maze may be considered as a reference memory task. It presents a stronger demand on the use of allocentric spatial visual cues than on the use of egocentric cues for navigation. Therefore, the present data lend support to the participation of area AMa in the integration of allocentric visuospatial cues or as a link in the memory system involved in the acquisition of this task.     

Some features of learning in the Morris water test in rats selected for responses to humans

The characteristics of learning in the Morris water test were studied in gray rats subjected to prolonged selection for elimination (the tame strain) and enhanced (the aggressive strain) aggressivity towards humans. Blood corticosterone levels at different stages of learning were also estimated. Tame rats learned to locate the invisible platform better than aggressive rats. The time spent seeking the platform by aggressive rats increased because they spent more time at the periphery of the basin. The duration of vertical investigative activity while on the platform was greater in tame rats than in aggressive rats. Fixation of the memory trace was demonstrated by the observation that rats of both strains spent more time in the sector in which the platform had been located during the training period. Rats of the two strains showed essentially no difference in terms of the time spent seeking the platform when it was placed in the opposite sector. After one day of training, blood corticosterone was significantly lower in tame than in aggressive rats. On subsequent training days, hormone levels in tame animals increased and were no different from those in aggressive rats. It is suggested that decreased emotionality and stress reactivity facilitated the learning process in tame rats in the Morris water test.     

Effects of morphine dependence on the performance of rats in reference and working versions of the water maze

Numerous studies have dealt with the role of opiate system in tasks aimed at measurement of cognitive behavior, but the role of morphine dependence on learning and memory is still controversial. In this study chronic exposure to morphine was employed to evaluate learning ability and spatial short-term memory (working memory) and long-term memory (reference memory) in the water maze task. Male albino rats were made dependent by chronic administration of morphine in drinking water that lasted at least 21 days. In Experiment 1, the performance of animals was evaluated in reference memory version of the water maze. Rats were submitted to a session of 6 trials for 6 consecutive days to find the submerged platform that was located in the center of a quadrant. Latency and traveled distance to find the platform were measured as indexes of learning. Memory retention was tested 24 h after the last training session in a probe trial (60 s) in which there was no platform and the time spent in each quadrant of the water maze was recorded. Results indicated that latency and traveled distance to find the platform were same in control and dependent rats during training days, but during the probe test morphine-dependent group spent significantly less time in the target quadrant. In Experiment 2, training on working memory version of the water maze task was started. Only two trials per day were given until the performance of animals was stabilized (at least 5 days). Final test was done at day 6. Acquisition-retention interval was 75 min. No significant differences were found on acquisition and retention trials between morphine and control groups. Our findings indicate that chronic exposure to morphine did not impair learning ability, but partially impaired retention of spatial long-term (reference) memory. Moreover, dependence on morphine did not affect either acquisition or retention of spatial short (working) memory.     

Intracranial self-stimulation facilitates a spatial learning and memory task in the Morris water maze

Learning and memory improvement by post-training intracranial self-stimulation has been observed mostly in implicit tasks, such as active avoidance, which are acquired with multiple trials and originate rigid behavioral responses, in rats. Here we wanted to know whether post-training self-stimulation is also able to facilitate a spatial task which requires a flexible behavioral response in the Morris water maze. Three experiments were run with Wistar rats. In each of them subjects were given at least five acquisition sessions, one daily, consisting of 2-min trials. Starting from a random variable position, rats had to swim in a pool until they located a hidden platform with a cue located on its opposite site. Each daily session was followed by an immediate treatment of intracranial self-stimulation. Control subjects did not receive the self-stimulation treatment but were instead placed in the self-stimulation box for 45 min after each training session. In the three successive experiments, independent groups of rats were given five, three and one trial per session, respectively. Temporal latencies and trajectories to locate the platform were measured for each subject. Three days after the last acquisition session, the animals were placed again in the pool for 60 s but without the platform and the time spent in each quadrant and the swim trajectories were registered for each subject. A strong and consistent improvement of performance was observed in the self-stimulated rats when they were given only one trial per session, i.e. when learning was more difficult. These findings agree with our previous data showing the capacity of post-training self-stimulation to improve memory especially in rats with little training or low conditioning levels, and clearly prove that post-training self-stimulation can also improve spatial learning and memory.