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Shift in the performance of 24-month-old Wistar rats in the Morris water escape task: a comparison across 36 experiments.

Spatial discrimination learning in aged rats serves as an animal model of cognitive aging. We assessed the replicability of spatial discrimination performance in the standard Morris water escape task. To this end the learning curves and the performance in a probe trial of 24-month-old outbred Wistar (HsdWin:Wu) control rats from 36 experiments were compared. These experiments had been performed at our laboratory under strictly controlled conditions over a period of 71 weeks. There was a very high variability in the learning curves between experiments. The initial performance level, i.e. the performance during the first session, did not change systematically across the 36 experiments. In contrast, the final performance level, i.e. the level reached in the fifth training session, decreased over the 71 week period, when the platform escape latency and the distance swam to reach the platform, measured as number of line crossings, were considered. In the last experiments of the series, learning curves were no longer seen: the rats did not improve their performance across the acquisition sessions. By contrast, the swimming speed and, in the probe trial, the bias for the quadrant where the platform had been positioned during training, did not change. This indicates that a decrease across experiments occurred predominantly with respect to spatial orientation performance, whereas the motor performance appeared to be unchanged. Explanations for this observation, such as differences in viability between shipments and the possible occurrence of genetic drift, are discussed.

Aging↗

GM1 ganglioside improves spatial learning and memory of aged rats.

GM1 ganglioside, 30 mg/kg, i.p., was administered to cognitively impaired aged rats for 30 days, and spatial learning and memory evaluated in a Morris water maze paradigm. During treatment with GM1, aged animals improved both the acquisition and retention of place navigation, as reflected by reduced escape latencies and swim distances to a hidden platform, and persistently performed better than the aged control animals. Furthermore, the GM1-treated animals showed improved spatial acuity in a spatial probe test when the hidden platform was removed. The improved performance in place navigation was not lost if GM1 treatment was discontinued and the animals tested up to 15 days later. GM1 treatment had no effect on the performance of young rats in the water maze. These results indicate that memory deficits associated with aging can be attenuated by treatment with GM1 ganglioside.

Aging↗

Differential modulation of lateral septal vasopressin receptor blockade in spatial learning, social recognition, and anxiety-related behaviors in rats.

The role of lateral septal vasopressin (VP) in the modulation of spatial memory, social memory, and anxiety-related behavior was studied in adult, male Wistar rats. Animals were equipped with osmotic minipumps delivering the VP-antagonist d(CH2)5-D-Tyr(Et)VAVP (1 ng/0.5 microl per h) bilaterally into the lateral septum (LS). Subsequently, all rats were subjected to four behavioral tests. First, animals were tested in a spatial learning paradigm (Morris water maze; 12 trials), followed by the social recognition test. A possible role for VP in anxiety-related behavior was then studied in the shock-probe burying test and the elevated plus-maze, respectively. The results showed that VP receptor antagonism impaired social recognition and reduced open-arm activity in the plus-maze, while it had no effect on spatial learning (Morris maze) and shock-probe burying behavior. The results indicate a strong task-dependent specificity of lateral septal VP functioning.

Animals↗

Effects of hippocampal lesions on spatial operant discrimination in pigeons.

In experiment 1, pigeons were trained on spatial or color autodiscrimination. Presentation of one of two keys or one of two colors was followed by food presentation. However, the other side of the keys or the other color was not. The hippocampal lesions disturbed the acquisition of spatial discrimination but not of color discrimination. In experiment 2, pigeons were preoperatively trained the spatial autodiscrimination, then received the hippocampal lesions. The subjects maintained the discrimination. These results suggest that the avian hippocampus plays a crucial role in acquisition of spatial discrimination.

Animals↗

Functional role of rat prelimbic-infralimbic cortices in spatial memory: evidence for their involvement in attention and behavioural flexibility.

The involvement of the medial prefrontal cortex (mPFC), and more particularly the prelimbic and infralimbic cortices (PL-IL area), in spatial memory remains controversial. The present study investigates the effects of neurotoxic lesions restricted to the PL-IL area of the mPFC in rats trained in two different spatial tasks. In experiment 1, PL-IL lesioned rats showed normal acquisition of a delayed non-matching to position task. They were also able to plan their responses for a prospective strategy but were transiently disrupted when the initial delay was extended. In experiment 2, rats were trained to locate one baited box among 13 identical boxes distributed on a circular arena. Lesioned rats performed normally when trained from a single start position but were severely disrupted when four start positions were used. A probe trial showed this deficit was not due to failure to learn the goal location. The addition of a proximal cue signalling the goal box helped lesioned rats to directly open the goal box, but did not compensate for greater distances that they travelled to reach it. Results from both experiments indicate that the PL-IL area is directly involved neither in allocentric spatial representations nor prospective memory and is not specifically involved in working memory. This area seems more likely to be involved in both attentional processes and behavioural flexibility that may be important for processing information for working memory as well as for spatial memory.

Animals↗

Perinatal exposure to polychlorinated biphenyls Aroclor 1016 or 1254 did not alter brain catecholamines nor delayed alternation performance in Long-Evans rats.

Several reports have indicated that polychlorinated biphenyls (PCB) altered development of biogenic amine systems in the brain, impaired behavioral performances, and disrupted maturation of the thyroid axis. The current study examines whether these developmental effects of PCB are correlated. Timed-pregnant Long-Evans rats were gavaged with the PCB mixture Aroclor 1016 (A-1016, 10 mg/kg) from gestation day (GD) 6 to parturition. Some pups continued to receive daily oral administration of PCB (10 mg/kg) until weaning at postnatal day (PD) 21. Another group of pregnant rats was given Aroclor 1254 (A-1254, 8 mg/kg) daily from GD 6 to weaning. At various age intervals, rats were sacrificed and six brain regions (prefrontal cortex, striatum, hippocampus, diencephalon, cerebellum, midbrain + brain stem) were removed and analyzed for dopamine (DA) and norepinephrine (NE) levels by high-performance liquid chromatography. In addition, transmitter turnover rates were determined after an acute treatment of alpha-methyl-p-tyrosine. Serum samples were collected and analyzed for triiodothyronine (T(3)) and thyroxine (T(4)) by radioimmunoassay. Behaviorally, rats were evaluated for spatial learning and memory by means of T-maze delayed alternation and Morris maze tasks on PD 23 and PD 70, respectively. A-1016 treatment produced only small and transient reductions in body weight gain, and generally did not alter the thyroid status of the developing rats. It did not cause any significant changes in DA or NE level, or turnover rate in any of the brain regions examined, nor did it affect behavioral measures of cognitive development. In contrast, perinatal exposure to A-1254 led to marked deficits of growth, and sharply reduced serum T(4), although T(3) remained largely unaffected. Accompanying this hormonal imbalance, brain NE contents in the A-1254-exposed pups were reduced, although brain DA was not significantly affected; no demonstrable neurobehavioral deficits were seen in the T-maze or Morris maze tests. These results indicated that development of central noradrenergic neurons was compromised by perinatal exposure to A-1254 but not A-1016, and both PCB mixtures failed to alter behavioral performances.

Animals↗

Behavioural specificity of neocortical grafts of fetal basal forebrain tissue after unilateral lesion of the nucleus basalis with alpha-amino-3-OH-4-isoxozole propionic acid (AMPA).

The previous articles in this series [4,9] have shown that unilateral AMPA lesions of the nucleus basalis magnocellularis (nbm) produced widespread morphological and functional changes to the forebrain cholinergic projection system that could be reversed by transplants of fetal cholinergic tissue. At earlier postgraft time points, the effects of cholinergic grafts were specific to the neocortical region (frontal or parietal cortex) into which the grafts were targeted. Here we report that nbm lesion-induced spatial learning and memory deficits in the Morris water maze were reversed at 6-8 weeks postsurgery only by cholinergic grafts placed in the frontal cortex or frontal and parietal cortices combined. Similar grafts to parietal cortex only and noncholinergic fetal transplants to any cortical site were ineffective. In contrast, using separate groups of animals, deficits in sensorimotor function could be reversed in only one measure (open field turning) by cholinergic transplants targeted to the parietal (somatosensory) cortex or frontal and parietal cortex combined. These behavioural dissociations demonstrate that the frontal cortical cholinergic innervation from the nbm is necessary for effective spatial cognitive performance.

Animals↗

Beneficial effects of aged garlic extract on learning and memory impairment in the senescence-accelerated mouse.

We first investigated the effect of aged garlic extract (AGE) on the longevity and learning performance in the Senescence-Accelerated Mouse (SAM). A solid diet containing AGE was fed after two months of age. An AGE treatment increased the survival ratio of the SAMP8. Moreover, the preparation ameliorated the memory acquisition deficit and the memory retention impairment of the SAMP8 at 10 months old. The learning improvement was also confirmed in a spatial cognition test. We next studied the effect of AGE on another strain of the SAM, SAMP10. Although the life span prolongation was not observed in the AGE-treated SAMP10, the preparation improved the grading score, an index of aging. A surprising result was obtained by measuring the brain size. The degree of shrinkage in the frontal cerebrum was 2-9% in the SAMP10. Chronic ingestion of AGE prevented this atrophy and kept the brain size at the control level. These results suggest that AGE has an antiaging effect on the SAM.

Aging↗

Prenatal exposure to anti-HIV drugs. long-term neurobehavioral effects of lamivudine (3TC) in CD-1 mice.

The present study was aimed at investigating the long-term effects of prenatal exposure to lamivudine (3TC), an antiretroviral drug used in clinical practice alone or in combination with zidovudine (AZT) to prevent mother-to-child transmission of the HIV virus. Pregnant CD-1 mice were given per os twice daily either 3TC at different doses (125, 250, or 500 mg/kg) or vehicle solution (NaCl 0. 9%) from pregnancy day 10 to delivery. Offspring behavior was examined on postnatal day 35 in a 20-min social interaction test. At adulthood different behavioral endpoints were analyzed, including locomotor activity and exploration in an open field following administration of the muscarinic antagonist scopolamine (2 mg/kg), spatial learning in either radial arm or Morris water maze, virgin female behavior in a maternal induction test, and pain sensitivity in a hot-plate test (52 +/- 0.1 degrees C). Our findings confirm the low neurotoxicity of 3TC in comparison to AZT. However some significant behavioral alterations were found, namely (1) a decrease in immobility in the open field test, (2) an increase in the responsiveness to scopolamine shown by the 500-mg/kg 3TC mice (sniffing behavior) in the open field, and (3) a longer escape latency in the first day of the reversal phase in the Morris task (particularly marked in the 250-mg/kg treatment group). No significant changes in either pain sensitivity, social/affiliative, or maternal behavior were found, although a higher occurrence of aggressive behavior toward foster pups was noted in both 125- and 500-mg/kg 3TC females.

Animals↗

Specificity of cognitive impairment from Pfiesteria piscicida exposure in rats: attention and visual function versus behavioral plasticity.

Pfiesteria piscicida is a toxic dinoflagellate that has caused massive fish kills in estuaries along the East Coast of the United States, and exposure of humans to toxic Pfiesteria has been associated with cognitive impairment. A visual signal detection task was used to determine the possible importance of attentional and visual processes in Pfiesteria effects on cognitive function. Adult female rats were trained to perform the signal detection task. After training, the rats were injected subcutaneously with fish culture water containing toxic Pfiesteria (35,600 or 106,800 cells of Pfiesteria/kg of rat body weight) or with (control) fish culture water containing no Pfiesteria. Effects of toxic Pfiesteria on maintenance of signal detection behavior were assessed for 2 weeks after treatment. Then, the signal-response contingencies were reversed. After the discrimination was reestablished on the reversed levers, the rats received a second dose of toxic Pfiesteria. The rats were again tested for 2 weeks, after which a second reversal was imposed. Pfiesteria did not affect behavior in the signal detection task during 2 weeks of prereversal testing after either exposure. However, a significant Pfiesteria-induced deficit emerged when the signal-response contingencies were reversed. These findings suggest that Pfiesteria-induced deficits emerge during periods of behavioral transition and not during performance of previously learned tasks.

Animals↗

Effects of chronic, low-level organophosphate exposure on delayed recall, discrimination, and spatial learning in monkeys and rats.

Chronic exposure to low levels of organophosphate (OP) compounds impairs acetylcholine (ACh) degradation by acetylcholinesterase (AChE) and, in humans, may produce lasting neurotoxicity affecting cognitive function. The present studies examined the ability of such exposure to impair performance of well-learned cognitive tasks in two species, nonhuman primates and rats. During 25 days of exposure to a 0.01 mg/kg dose of the OP diisopropylfluorophosphate (DFP), mature adult monkeys were not impaired in their performance of a well-learned delayed matching-to-sample task (DMTS). However, erythrocyte AChE activity was reduced from predrug levels by 76.26 +/- 3.33% by 14 days after the initiation of DFP administration. Following titration of DFP to a 0.015 mg/kg dose for 15 days, DMTS performance remained at or above baseline levels. DMTS accuracy was moderately, but not significantly, reduced after titration to a dose of 0.02 mg/kg. However, decrements were associated with mild, overt symptoms of OP toxicity and performance returned to baseline levels after withdrawal from OP exposure. In rats, chronic exposure to a low-dose regimen of DFP (0.25 mg/kg/day for 14 days) impaired the ability to initially learn a spatial navigation task, but did not impair performance of previously learned stimulus discrimination and spatial navigation tasks. These data indicate that performance of memory tasks dependent upon reference concepts is not impaired by OP exposure regimens that impair acquisition of novel cognitive tasks prior to the onset of overt toxicity.

Animals↗

Memory for objects and their locations: the role of the hippocampus in retention of object-place associations.

Computational models of hippocampal function have suggested that the hippocampus is involved in the formation and storage of arbitrary associations. Previous studies have shown that rats with hippocampal lesions are impaired in object-place associative learning. However, few studies have examined the role of the hippocampus in the retention of previously learned arbitrary associations. In the present study, male Long-Evans rats with either cortical control or hippocampal lesions were tested on a task measuring the retention of previously learned arbitrary associations using an object-place paired-associate task. To assess retention, each animal was trained on the paired-associate task for 360 trials, then received a lesion, and was retested to examine retention of the previously learned associations. The results indicate that all rats learned the task prior to surgery. Following surgery, rats with cortical control lesions were not impaired in the retention of object-place associations. In contrast, hippocampal lesions resulted in an initial deficit in retention of the paired-associate task followed by recovery. Therefore, the hippocampus may play a role in the retrieval of previously learned arbitrary association.

Animals↗

Working memory, response selection, and effortful processing in rats with medial prefrontal lesions.

This study examined the effects of lesions of the prelimbic area of the rat prefrontal cortex on acquisition and retention of nonmatching (NMTS) and matching-to-sample (MTS) tasks. Both tasks involved a reference and a working memory component, but only working memory was impaired by the lesions. A comparison of the 2 tasks revealed quantitatively similar deficits in postoperatively trained rats. In preoperatively trained rats, however, the deficits were more important in the MTS task than in the NMTS task. In addition, an effect of interference between successive trials was observed in the NMTS task but not in the MTS task. Perseverative tendencies were observed in the MTS task only. These results suggest that prefrontal lesions induce working memory deficits as a result of poor temporal encoding and increased susceptibility to interference and impair effortful processing, such as that engaged in response selection mechanisms.

Animals↗

Role of the dorsomedial striatum in behavioral flexibility for response and visual cue discrimination learning.

These experiments examined the effects of dorsomedial striatal inactivation on the acquisition of a response and visual cue discrimination task, as well as a shift from a response to a visual cue discrimination, and vice versa. In Experiment 1, rats were tested on the response discrimination task followed by the visual cue discrimination task. In Experiment 2, the testing order was reversed. Infusions of 2% tetracaine did not impair acquisition of the response or visual cue discrimination but impaired performance when shifting from a response to a visual cue discrimination, and vice versa. Analysis of the errors revealed that the deficit was not due to perseveration of the previously learned strategy, but to an inability to maintain the new strategy. These results contrast with findings indicating that prelimbic inactivation impairs behavioral flexibility due to perseveration of a previously learned strategy. Thus, specific circuits in the prefrontal cortex and striatum may interact to enable behavioral flexibility, but each region may contribute to distinct processes that facilitate strategy switching.

Animals↗

Preserved spatial memory after hippocampal lesions: effects of extensive experience in a complex environment.

Damage to the hippocampus typically impairs spatial learning and memory in animals, but humans with hippocampal lesions retain spatial memories of premorbidly familiar environments. We showed that, like humans, normal rats reared in a complex environment and then given hippocampal lesions retained allocentric spatial memory for that environment. These results, which ruled out dependency on single cues, landmarks or specific routes, suggest that extensive premorbid experience leads to spatial representations that are independent of the hippocampus.

Animals↗

Inhibition of fatty-acid amide hydrolase accelerates acquisition and extinction rates in a spatial memory task.

Recent reports have demonstrated that disruption of CB(1) receptor signaling impairs extinction of learned responses in conditioned fear and Morris water maze paradigms. Here, we test the hypothesis that elevating brain levels of the endogenous cannabinoid anandamide through either genetic deletion or pharmacological inhibition of its primary catabolic enzyme fatty-acid amide hydrolase (FAAH) will potentiate extinction in a fixed platform water maze task. FAAH (-/-) mice and mice treated with the FAAH inhibitor OL-135, did not display any memory impairment or motor disruption, but did exhibit a significant increase in the rate of extinction. Unexpectedly, FAAH-compromised mice also exhibited a significant increase in acquisition rate. The CB(1) receptor antagonist SR141716 (rimonabant) when given alone had no effects on acquisition, but disrupted extinction. Additionally, SR141716 blocked the effects of OL-135 on both acquisition and extinction. Collectively, these results indicate that endogenous anandamide plays a facilitatory role in extinction through a CB(1) receptor mechanism of action. In contrast, the primary psychoactive constituent of marijuana, Delta(9)-tetrahydrocannabinol, failed to affect extinction rates, suggesting that FAAH is a more effective target than a direct acting CB(1) receptor agonist in facilitating extinction. More generally, these findings suggest that FAAH inhibition represents a promising pharmacological approach to treat psychopathologies hallmarked by an inability to extinguish maladaptive behaviors, such as post-traumatic stress syndrome and obsessive-compulsive disorder.

Amidohydrolases↗

REM sleep enhancement induced by different procedures improves memory retention in rats.

Growing evidence supports the idea that sleep following learning is critically involved in memory formation. Recent studies suggest that information acquired during waking is reactivated and possibly consolidated during subsequent sleep, especially during rapid-eye movement (REM) or paradoxical sleep (PS). Critical reviews, however, have questioned PS and memory relationships, particularly because of shortcomings of the PS deprivation paradigm applied in many studies. Therefore, in the present study we used an opposite strategy, i.e. we investigated the effects of PS enhancement on memory retention. In three experiments, we found that selective PS enhancement, induced by different procedures after discrimination training in rats, results in increased retention tested 24 h later. Moreover, calculated in all animals (n = 61), there was a highly significant correlation between post-training PS values and retention scores. Our results suggest that an experimentally induced increase of PS after learning facilitates memory consolidation.

Adrenocorticotropic Hormone↗

Neprilysin-sensitive synapse-associated amyloid-beta peptide oligomers impair neuronal plasticity and cognitive function.

A subtle but chronic alteration in metabolic balance between amyloid-beta peptide (Abeta) anabolic and catabolic activities is thought to cause Abeta accumulation, leading to a decade-long pathological cascade of Alzheimer disease. However, it is still unclear whether a reduction of the catabolic activity of Abeta in the brain causes neuronal dysfunction in vivo. In the present study, to clarify a possible connection between a reduction in neprilysin activity and impairment of synaptic and cognitive functions, we cross-bred amyloid precursor protein (APP) transgenic mice (APP23) with neprilysin-deficient mice and biochemically and immunoelectron-microscopically analyzed Abeta accumulation in the brain. We also examined hippocampal synaptic plasticity using an in vivo recording technique and cognitive function using a battery of learning and memory behavior tests, including Y-maze, novel-object recognition, Morris water maze, and contextual fear conditioning tests at the age of 13-16 weeks. We present direct experimental evidence that reduced activity of neprilysin, the major Abeta-degrading enzyme, in the brain elevates oligomeric forms of Abeta at the synapses and leads to impaired hippocampal synaptic plasticity and cognitive function before the appearance of amyloid plaque load. Thus, reduced neprilysin activity appears to be a causative event that is at least partly responsible for the memory-associated symptoms of Alzheimer disease. This supports the idea that a strategy to reduce Abeta oligomers in the brain by up-regulating neprilysin activity would contribute to alleviation of these symptoms.

Alzheimer Disease↗