Corticosterone effects on BDNF mRNA expression in the rat hippocampus during morris water maze training

Corticosterone and Brain-Derived Neurotrophic Factor (BDNF) have both been shown to be involved in spatial memory formation in rats. In the present study we have investigated the effect of corticosterone on hippocampal BDNF mRNA expression after training in the Morris water maze in young adult Wistar rats. Therefore, we first studied BDNF mRNA levels in the hippocampus in relation to corticosterone levels at several time points after 4 training trials in the Morris water maze. Corticosterone levels were significantly increased after this procedure, and hippocampal BDNF mRNA levels only displayed a minor change: an increase in CA1 at 1 hr after training. However, in a previous study we observed dramatically decreased hippocampal BDNF mRNA levels in dentate gyrus and CA1 at 3 hr after injection of corticosterone. In order to analyze this discrepancy, we subsequently investigated if hippocampal BDNF mRNA expression is affected by corticosterone at 3 hr after water maze training. Therefore, we incorporated ADX animals and ADX animals which were injected with corticosterone in our study. ADX animals which were subjected to water maze training displayed similar hippocampal BDNF mRNA levels 3 hr after training compared to control ADX animals. Furthermore, ADX animals which were injected with corticosterone showed decreased BDNF mRNA levels in all hippocampal regions compared to control ADX animals. Water maze training did not alter this effect. Thus, the increased corticosterone levels during water maze training do not affect hippocampal BDNF mRNA expression, although exogenous corticosterone is effective under these conditions. Hence, our results suggest that in this situation BDNF is resistant to regulation by endogenous corticosterone, which may be important for learning and memory processes.     

The effects of p-chloroamphetamine, a depletor of brain serotonin, on the performance of rats in two types of positively reinforced complex spatial discrimination tasks

Learning in male Sprague-Dawley rats was assessed in two types of positively reinforced complex spatial discrimination tasks (Stone 14-unit T-maze and eight-arm radial-arm maze) following cytotoxic lesions of central serotonergic terminal projection fields with p-chloroamphetamine (PCA). Learning, as expressed as mean number of errors per day and mean number of trails required to reach criterion, was significantly enhanced in the PCA-lesioned animals trained in the Stone maze. On the other hand, the performance of the PCA-lesioned animals trained in the eight-arm radial-arm maze was not found to differ significantly from that of saline-injected animals. The improved acquisition of the PCA-lesioned rats trained in the Stone maze was completely abolished following pretreatment with the selective serotonergic reuptake inhibitor norzimeldine. Neurochemical analyses of the brains of representative animals revealed that the levels of serotonin and its major metabolite, 5-hydroxy-3-indoleacetic acid, were both significantly reduced by PCA in all regions examined. While it is clear from these and other studies that the serotonergic nervous system plays an important role in the processes underlying learning and memory, these results further underscore the selective role of this neurotransmitter system in the way information is processed by the brain.     

The effects of aging and dorsal hippocampal lesions: performance on spatial and nonspatial comparable versions of the water maze

Aged intact and young hippocampal-lesioned rats show similar deficits on the spatial water maze. However, this does not necessitate that the source of these deficits in the aged animals is due to hippocampal damage. These water maze deficits may arise from other aging factors such as changes in thermoregulation, muscle fatigue, swim ability, and response to stress. Consequently, it is imperative to examine the performance of aged rats on a comparable nonhippocampal version of this task. Past attempts to develop a hippocampus-independent version of the water maze were confounded because these tasks were easier (i.e., the rats spent much less time swimming in the water) than the spatial versions of the task. The current study examined performance on a hippocampus-independent task comparable in difficulty to the spatial water one. Middle-aged (16-m) and old (25-m) male F344 rats were given sham or dorsal hippocampus lesions and tested on both a spatial and a nonspatial water maze. The middle-aged rats with hippocampal lesions were impaired on the spatial task but not on the nonspatial task. Conversely, aged animals showed a similar impairment on both types of water maze tasks. Additionally, hippocampal lesions exacerbated the age-related impairment on both tasks. These findings indicate that caution must be used when interpreting the results of water maze tasks for aged animals.     

Short forms of the "reference-" and "working-memory" Morris water maze for assessing age-related deficits.

Short forms of the reference- and working-memory versions of the Morris water maze, each limited to 10 trials, were examined for their reliability and sensitivity to age-related deficits in 16- and 24-month F-344 rats, relative to 2- to 2.5-month young controls. The reference-memory task used long intertrial intervals of 23 h, but required learning only one target location, while the working-memory task used shorter intertrial intervals of 60 min but required learning many different target locations. The reference-memory task was very reliable, revealed large age-related deficits, and correctly identified almost all aged rats as impaired relative to young controls. The working-memory task was less reliable, revealed smaller deficits than the reference memory task at 24 months, and did not discriminate as well between 2.5- and 24-month rats. Furthermore, in the working-memory task 16- and 24-month rats had longer swim paths than 2- to 2.5-month rats on the first trial of each trial pair, which is suggestive of a deficit in processing spatial information and raises questions about the validity of this test as a specific test of working memory. Although the working-memory procedures may be preferable under certain conditions, perhaps as a measure specific to hippocampal dysfunction, the reference-memory task seems more sensitive to age-related deficits and more accurately identifies older rats as impaired. These results are consistent with previous reports that age-related deficits in acquiring spatial learning tasks are common and that the magnitude of the deficit increases as the length of the retention interval increases.     

Individual differences in anxiety trait are related to spatial learning abilities and hippocampal expression of mineralocorticoid receptors

Although high levels of anxiety might be expected to negatively influence learning and memory, it remains to be shown whether individual differences in anxiety may influence spatial learning and memory in outbred rat populations. We have studied this possibility in male Wistar rats whose levels of anxiety were first characterized as either high (HA) or low (LA) according to their behavior in the elevated plus maze or in the open field test. Subsequently, their performance in the Morris water maze was studied, a task dependent on hippocampal activity. Interestingly, LA rats showed a faster acquisition and better memory in the water maze when compared to HA rats. Indeed, this difference in performance could mainly be attributed to the increase in thigmotactic behavior (swimming in circles close to the maze walls) displayed by HA rats during spatial navigation. Glucocorticoids are known to affect the state of anxiety and the hippocampus is the main target of glucocorticoids in the brain. Hence, we investigated whether the hippocampal expression of the two classical corticosteroid receptors, mineralocorticoid (MR) and glucocorticoid (GR) differed in the two groups of rats. We found that LA rats displayed higher hippocampal expression of MR but not GR than HA rats. Indeed, the expression levels for these receptors were positively correlated with the amount of time spent by the animals in the open arms of the elevated plus maze. Moreover, we present evidence that the levels of anxiety quantified in the first stages of our study constitute a trait rather than a state. Taken together, this study has generated evidence of a close interaction between the anxiety trait, hippocampal MR expression and the learning abilities of individuals in stressful spatial orientation tasks.     

Working memory deficits in transgenic rats overexpressing human adenosine A2A receptors in the brain

Adenosine receptors in the central nervous system have been implicated in the modulation of different behavioural patterns and cognitive functions although the specific role of A(2A) receptor (A(2A)R) subtype in learning and memory is still unclear. In the present work we establish a novel transgenic rat strain, TGR(NSEhA2A), overexpressing adenosine A(2A)Rs mainly in the cerebral cortex, the hippocampal formation, and the cerebellum. Thereafter, we explore the relevance of this A(2A)Rs overexpression for learning and memory function. Animals were behaviourally assessed in several learning and memory tasks (6-arms radial tunnel maze, T-maze, object recognition, and several Morris water maze paradigms) and other tests for spontaneous motor activity (open field, hexagonal tunnel maze) and anxiety (plus maze) as modification of these behaviours may interfere with the assessment of cognitive function. Neither motor performance and emotional/anxious-like behaviours were altered by overexpression of A(2A)Rs. TGR(NSEhA2A) showed normal hippocampal-dependent learning of spatial reference memory. However, they presented working memory deficits as detected by performance of constant errors in the blind arms of the 6 arm radial tunnel maze, reduced recognition of a novel object and a lack of learning improvement over four trials on the same day which was not observed over consecutive days in a repeated acquisition paradigm in the Morris water maze. Given the interdependence between adenosinic and dopaminergic function, the present results render the novel TGR(NSEhA2A) as a putative animal model for the working memory deficits and cognitive disruptions related to overstimulation of cortical A(2A)Rs or to dopaminergic prefrontal dysfunction as seen in schizophrenic or Parkinson's disease patients.     

Differences in learning between hyperprolinemic mice and their congenic controls

These experiments expanded earlier work on hyperprolinemic mice which showed learning deficits. The following behavioral tasks were used: step-through, passive avoidance; T-maze acquisition; shuttlebox acquisition, and radial-arm maze. Mouse species included PRO/Re-bb (genetically hyperprolinemic mice) and PRO/Re-aa (congenic nonhyperprolinemic controls) obtained from the Jackson Breeding Laboratories. Hyperprolinemic mice were impaired in acquiring T-maze and shuttlebox footshock avoidance behavior. One-trial passive avoidance behavior did not clearly differentiate between the groups. Radial maze performance was poor in both groups due possibly to observed acrophobia and lack of exploratory behavior. The results of this study combined with previously published work suggest that high-brain proline in conjunction with other amino acid changes account for the learning deficits.     

Effects of arachidonic acid on the spatial cognition of aged rats

Abstract:  To examine the effects of arachidonic acid (AA) on age-related cognitive deficits, Fischer 344 rats were given an AA-supplemented powder diet for 12 weeks from 18.6 months old as part of the old AA (OA) group. Other age-matched rats were fed a non-AA-supplemented powder diet as part of the old control (OC) group, and young rats were fed lab pellets as part of the young control (YC) group. When the aged rats reached 20.0 months old, all animals were tested for spontaneous activity in an open field, followed by the Morris water maze place and cue tasks. Escape latencies for the place task showed that the YC rats were fastest, and there was no difference between the OA and OC groups. However, the probe test and the first block of the cue task indicated that the OA rats remembered the location of an invisible platform better than the OC rats. Although the amount of hippocampal AA was larger in the OA rats than in the OC rats, the difference was not significant. The results showed that AA administration to aged animals may alleviate age-related deficits in spatial cognition.     

Cognitive performances and locomotor activity following dentate granule cell damage in rats: role of lesion extent and type of memory tested

Intradentate injection of colchicine is one of the techniques used to destroy granule cells. This study compared the behavioral effects of various amounts of colchicine (1.0, 3.0, and 6.0 microg; Col 1, Col 3, and Col 6, respectively) injected into the dentate gyrus of adult Long-Evans male rats. Starting 10 days after lesion surgery, behavioral testing assessed home-cage and open-field locomotion, alternation in a T-maze, water-maze, and radial-maze learning according to protocols placing emphasis on reference, and working memory. All of these tasks are sensitive to hippocampal disruption. Histological verifications showed that the extent of the lesions depends on the dose of colchicine (index of dentate gyrus shrinkage: -33% in Col 1, -54% in Col 3, and -67% in Col 6 rats). Colchicine dose-dependently increased nocturnal home cage activity (an effect found 10 days but not 5 months after surgery), but had no significant effect on open-field locomotion or T-maze alternation. A dose-dependent reference memory impairment was found during the acquisition of spatial navigation in the water maze; Col 3 and Col 6 rats were more impaired than Col 1 rats. During the probe trial (platform removed), control rats spent a longer distance swimming over the platform area than all rats with colchicine lesions. In the working memory version of the test, all rats with colchicine lesions showed significant deficits. The deficits were larger in Col 3 and Col 6 rats compared to Col 1 rats. The lesions had no effect on swimming speed. In the radial-maze test, there was also a dose-dependent working memory impairment. However, reference memory was disrupted in a manner that did not differ among the three groups of lesioned rats. Our data are in line with the view that the dentate gyrus plays an important role in the acquisition of new information and is an integral neural substrate for spatial reference and spatial working memory. They also suggest that damage to granule cells might have more pronounced effects on reference than on working memory in the radial maze. Finally, they demonstrate that part of the variability in the conclusions from previous experiments concerning the role of granule cells in cognitive processes, particularly in spatial learning and memory, may be due to the type of tests used and/or the extent of the damage produced.     

Simplifying environmental cues in a Morris-type water maze improves place learning in old NMRI mice.

Old virgin female NMRI mice aged 17 months were compared with mice aged 3 months for their spatial learning abilities in two versions of the Morris water maze. The first one was a simplified version with a salient configuration of cues comparable to a black/white discrimination and the second one was the classical version of the Morris test with many distal cues surrounding the maze. In the simplified version, old mice presented a slower rate of acquisition and a transient poorer retention compared to young mice. However, old mice achieved a final level of performance statistically comparable to their young counterparts as assessed by latencies to escape onto the concealed platform and by the spatial bias measured in probe trials at intervals during testing. When subsequently subjected to classical Morris maze learning, the same old animals showed marked learning deficits and were persistently impaired in their latencies to escape onto the platform. They presented no spatial bias for the location of the platform in the different probe trials. When the goal was cued at the end of the experiment, the performances of old mice rapidly improved, showing that motivation, motor disabilities, or fatigue and ability to use proximal cues cannot explain the place learning deficit. Our results were discussed in terms of cognitive versus sensory/perceptual disabilities in aged rats and mice.     

Acute Ethanol Administration Impairs Spatial Performance While Facilitating Nonspatial Performance in Rats

Acute ethanol administration produces learning and memory impairments similar to those found following lesions to the hippocampal system in rats. For example, both ethanol and hippocampal lesions impair performance on spatial learning and memory tasks while sparing performance on many nonspatial learning and memory tasks. Lesions to the hippocampal system can also alter the nature of the information that the animal uses to guide its behavior, from using spatial information to using individual cues. In the present experiment, rats were trained, while sober, to navigate on an eight-arm radial arm maze to a specific arm for food reward. During training, the rewarded arm was always in the same specific location and contained well-defined cues. After the rat learned the task, a memory test was conducted under different doses of ethanol (0.0 g/kg [saline control], 1.0, 1.5, or 2.0 g/kg, intraperitoneal). On the test day the maze was rotated so that the cued arm was 90 degrees to the right of its original position. During testing, intact rats showed a significant bias to approach the place where they had been previously rewarded, even though the cue was no longer located there. Acute ethanol administration dose dependently reduced approaches to the rewarded place. However, ethanol administration did not result in increases in random choices; rather, it resulted in a dose-dependent increase in approaches to the cued arm, now in a new location. These results extend previous research showing that acute ethanol administration and lesions to the hippocampal system produce similar effects on learning and memory in rats.     

Effects of opiate antagonists on spatial memory in young and aged rats

The effects of post-training opiate antagonist administration on spatial memory were assessed in young and aged male Long Evans rats. In Experiment I rats were trained to visit each arm of an eight-arm radial maze once in a session to obtain a food reward placed at the end of each arm. During training aged rats required significantly more trials to achieve criterion performance when compared to young mature rats. However, administration of the opiate antagonist naloxone (2.0 mg/kg) immediately after each training trial did not significantly alter the rate of achieving accurate performance in either age group. In Experiment II young and aged rats that were previously trained to a comparable criterion on the radial maze were tested on the same maze apparatus in novel spatial environments. When animals were exposed to novel spatial information, the effects of post-trial opiate antagonists were examined using a within-subjects counter-balanced design. In Experiment IIa naloxone (2 mg/kg) enhanced the performance of both young and aged rats. In Experiment IIB naltrexone (1.0 mg/kg) was found to have a comparable effect of enhancing the performance of both age groups. In addition, in Experiment IIb a significant age-related deficit was found in rats tested in novel spatial environments. These results indicate that opiate antagonists are capable of improving memory for new spatial information in both young and aged rats on a task that is sensitive to behavioral deficits during normal aging.     

High-fat diets impair spatial learning in the radial-arm maze in mice

It has been suggested that hyperglycemia and insulin resistance triggered by energy-dense diets can account for hippocampal damage and deficits of cognitive behaviour. We wonder if the impairment of learning and memory processes detected in diet-induced obese (DIO) mice is linked to diet composition itself. With this purpose we have evaluated learning performance in mice undergoing a short-term high-fat (HF) treatment, which leads to a pre-obese state characterized by increased adiposity without significant changes of glucose and insulin plasma levels. C57BL/6J mice were fed either a HF (45 kcal% from fat) or control diet (10 kcal% from fat) during 8 weeks. Learning performance was evaluated by using the four-arm baited version of the eight-arm radial maze test (RAM). Mice were trained to learn the RAM protocol and then memory was tested at different time-points. Time spent to consume food placed in baited arms and errors committed to find them were measured in all sessions. DIO mice significantly spent more time in learning the task and made a greater number of errors than controls. Moreover, retention tests revealed that both working and total memory errors were also more numerous in DIO mice. The current results show that short-term DIO impairs spatial learning and suggest that impairment of hippocampal learning elicited by HF diets might be perceptible before metabolic alterations linked to obesity develop.     

Intrahippocampal muscimol shifts learning strategy in gonadally intact young adult female rats

Learning strategy preferences depend upon circulating estrogen levels, with enhanced hippocampus-sensitive place learning coinciding with elevated estrogen levels. The effects of estrogen on strategy may be mediated by fluctuations in GABAergic function, given that inhibitory tone in the hippocampus is low when estrogen is high. We investigated the effects on learning strategy of intrahippocampal injections of a GABA(A) agonist in gonadally intact female rats. On the day of training, rats received 0.3 microL intrahippocampal infusions of muscimol (0.26 nmol or 2.6 nmol) or saline 20 min prior to training on a T-maze in which place (hippocampus-sensitive) or response (striatum-sensitive) strategies offer effective solutions. Muscimol treatment increased the use of the response strategy in a dose-dependent manner without influencing learning speed, indicating that muscimol modulated strategy and not learning ability. Furthermore, the muscimol-related shift to response strategies varied across the estrous cycle. The results indicate that increasing inhibition in the hippocampus biases rats away from hippocampus-sensitive place learning strategies and toward hippocampus-insensitive response learning strategies without a learning deficit. Furthermore, rats at proestrus demonstrated the most dramatic shift in learning strategy following muscimol treatment compared with control conditions, while rats at estrus demonstrated the most complete bias toward response strategies. The enhanced use of hippocampus-sensitive strategies at proestrus likely results from reduced hippocampal inhibition.     

Effects of chronic cocaine administration on spatial learning and hippocampal spine density in two genetically different strains of rats

Lewis and Fischer-344 rats have been proposed as an addiction model because of their differences in addiction behaviour. It has been suggested that drug addiction is related to learning and memory processes and depends on individual genetic background. We have evaluated learning performance using the eight-arm radial maze (RAM) in Lewis and Fischer-344 adult rats undergoing a chronic treatment with cocaine. In order to study whether morphological alterations were involved in the possible changes in learning after chronic cocaine treatment, we counted the spine density in hippocampal CA1 neurons from animals after the RAM protocol. Our results showed that Fischer-344 rats significantly took more time to carry out test acquisition and made a greater number of errors than Lewis animals. Nevertheless, cocaine treatment did not induce changes in learning and memory processes in both strains of rats. These facts indicate that there are genetic differences in spatial learning and memory that are not modified by the chronic treatment with cocaine. Moreover, hippocampal spine density is cocaine-modulated in both strains of rats. In conclusion, cocaine induces similar changes in hippocampal neurons morphology that are not related to genetic differences in spatial learning in the RAM protocol used here.