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Latent learning in a radial arm maze following neonatal dopamine depletion.

Animals neonatally depleted of dopamine show decreases in exploratory behaviour. As latent learning may depend on exploratory behaviour the present study was undertaken to examine the effects of neonatal dopamine depletion on latent learning. In two experiments dopamine was depleted neonatally, using 6-hydroxydopamine injected intracisternally on day 1 after birth. In both experiments, exploratory behaviour, measured as rearing and head-dip responses in a modified openfield/holeboard, was reduced in the dopamine depleted rats whereas ambulatory behaviour was elevated. In a modified radial arm maze also, rearing responses were decreased while ambulation was increased for the 6-hydroxydopamine treated rats. Latent learning was tested in each experiment following preexposure to the maze for either a single trial or four trials. 6-Hydroxydopamine treated rats demonstrated a comparable latent learning effect to vehicle treated rats after four maze exposures but showed a greatly attenuated latent learning effect following only a single exposure. It is suggested that the effects of neonatal dopamine upon maze and latent learning are secondary to the effects on hyperactivity, reduced exploration and/or increased neophobia shown by these rats.

Journal Article↗

Fatty acid mixture counters stress changes in cortisol, cholesterol, and impair learning.

A mixture of linoleic and alpha-linolenic acids (free non-esterified unsaturated fatty acids) administered for 3 weeks prior to injection of cortisol (10 mg/kg), or prior to immersion of rats in a 10 degree C saline bath, prevented elevation of blood levels of cortisol and cholesterol and deficits in Morris water maze spatial learning that usually accompany such stressful conditions. Differences from controls on all behavioural and biochemical measures were statistically significant (P < .05). It is proposed that induction of intense stress, and the associated increase in cortisol, cholesterol and other corticosteroids may damage hippocampal structures and help account for the cognitive decline witnessed in Alzheimer's disease and other age-related conditions. The modulation of these consequences by the fatty acid mixture may provide an alternative strategy for the study of stress markers and for the development of other intervention options in humans.

Animals↗

[Strain differences of mice in learning of swimming behavior and effect of hemicholinium and vasopressin. Observation by a simple water maze apparatus].

In order to determine the strain differences in learning of swimming behavior and to study the influence of vasopressin or its derivatives on hemicholinium-3-induced impairment of water maze learning in mice, we designed a new apparatus using water maze which has three panels in small fish breeding water bath (L60 x W30 x H36 cm). In the first swimming, six strains of adult male mice, ICR, ddY, ddN, C3H/He, BALB/C and C57BL were subjected to learn swimming behavior twice a day for 6 d in a straight course. Only ICR, ddN, C57BL and BALB/C strain mice were chosen for the next experiment. In the second swimming, mice (ICR, ddN, C57BL, BALB/C) were swum in the water maze apparatus. Scopolamine-induced impairment of water maze learning was produced only in ICR, BALB/C mice, but not in C57BL and ddN strain, which was recovered by physostigmine. Amnesia was not obtained by intracerebroventricular injection (i.c.v.) of cycloheximide and AlCl3 in mice (ICR). Hemicholinium-induced amnesia was improved by vasopressin and desmopressin. Lysine-vasopressin and oxytocin were without affecting hemicholinium-induced amnesia. Pretreatment with a vasopressin antagonist, ([1-(beta-mercapto-beta,beta-cyclopenta-methylene propionic acid), 2-(o-methyl)tyrosine arginine]-vasopressin) resulted in a reversible effect on the improvement of hemicholinium-induced amnesia by vasopressin. Of four different strain mice, ICR mice were the most preferable to the presently used test. They were also more responsive to hemicholinium and vasopressin than the other strains. These results suggest that the simple water maze apparatus may be useful for a pre-examination of nootropics or a study of learning of swimming behavior in mice.

Animals↗

Differential rearing experience, gender, and radial maze performance.

Since both differential rearing and gender have been known to affect maze abilities, the present study examines the performance of male and female hooded rats raised from weaning in either a complex environment (EC) or isolated environment (IC) on the 17-arm radial maze. In two separate replications, EC rats learned the maze more quickly and accurately than IC rats, as assessed by total errors, the number of correct choices to the first error, and the number correct in the first 17 choices. However, EC rats were more likely than IC rats to employ an adjacent-arm strategy which may have contributed to their superior performance. There were no gender differences or environment by gender interaction effects on any measure of accuracy or adjacent arm strategy in either replication. It appears that the performance of both male and female rats on the 17-arm radial maze is similarly influenced by the rearing environment.

Animals↗

Assessment of a cholinergic contribution to chlordiazepoxide-induced deficits of place learning in the Morris water maze.

This investigation sought to characterize the interaction between benzodiazepine and cholinergic systems in place learning in the Morris water maze. In the first experiment, rats were treated with scopolamine (1 mg/kg) alone or concomitantly with one of two doses of flumazenil (15 and 30 mg/kg) or with chlordiazepoxide (5 mg/kg) alone or concomitantly with flumazenil (15 mg/kg). Chlordiazepoxide and scopolamine severely impaired place learning but not cue learning. The low dose of flumazenil completely reversed the impairment produced by chlordiazepoxide and both high and low doses of flumazenil attenuated the place learning deficit produced by scopolamine. Neither dose of flumazenil affected place learning when administered alone. In the second experiment, rats were administered chlordiazepoxide (5 mg/kg) or scopolamine (1 mg/kg) alone or concomitantly with one of four doses of physostigmine (0.05, 0.10, 0.25, and 0.5 mg/kg). Once again, both chlordiazepoxide and scopolamine impaired place but not cue learning. Physostigmine reversed the impairment produced by scopolamine in a dose-dependent manner but failed at every dose to attenuate the impairment produced by chlordiazepoxide. The higher doses of physostigmine impaired place learning when administered alone. None of the drug treatments impaired cue learning. Together, these results suggest that the scopolamine-induced impairment of place learning is due to an increase in benzodiazepine/GABA activity, and contradict the notion that benzodiazepines impair memory by cholinergic mechanisms.

Acetylcholine↗

Diazepam impairs place learning in native but not in maze-experienced rats in the Morris water maze.

Anxiolytic benzodiazepines have been shown to impair place learning in the Morris water maze. However, a clear-cut demonstration of a direct and specific effect on mnemonic processes has not yet been offered. In the present study, the effects of diazepam on place navigation in the Morris water maze were studied in rats. Three conditions were examined: learning, reversal learning and learning after familiarisation of animals with the maze. In view of the anxiolytic and sedative properties of diazepam, appropriate doses of the drug, i.e. those that produced an anxiolytic effect but no major motor impairment, were initially selected in the water-lick conflict and rotarod tests, respectively. Doses of 2.5 and 5 mg/kg PO increased punished drinking in the water-lick conflict test without significantly decreasing rotarod performance. These doses were then used to assess the effects of diazepam on spatial behaviour. Diazepam, at both doses, impaired place learning in behaviourally naive rats. Such an effect appeared to be transient: diazepam-treated rats eventually reached control performance. Moreover, analysis of the probe trial at the end of training revealed adoption of a spatial strategy to locate the submerged platform. Neither reversal learning nor learning after familiarisation was affected. These results do not replicate previous findings in the Morris water maze and provide some evidence that the diazepam-induced place learning deficit may be primarily anxiolytic in nature.

Animals↗

Learning deficits after unilateral AF64A lesions in the rat basal forebrain: role of cholinergic and noncholinergic systems.

Rats were given unilateral infusions of ethylcholine aziridinium ion (AF64A) into the basal forebrain (BF). BF-lesioned rats had significant acquisition and retention deficits in two different types of learning tasks (water maze and active avoidance). Choline acetyltransferase activity was lower than control in the frontal cortex but not in the hippocampus or striatum. AF64A markedly reduced the levels of norepinephrine, dopamine, and serotonin in all brain regions studied. However, L-glutamic acid decarboxylase activity was not altered by AF64A injection. Cholinergic agents (physostigmine and arecoline) ameliorated the AF64A-induced learning deficits in the water maze task but not in the active avoidance task. Noncholinergic agents (desipramine and L-dopa) ameliorated the AF64A-induced avoidance deficits in the active avoidance task but not in the water maze task. 5-Methoxy-N,N-dimethyltryptamine did not improve either active avoidance or water maze learning. These results suggest that intra-BF injection of AF64A produces extensive brain dysfunction and that different neuronal systems are involved in associative and spatial learning.

Animals↗

[The participation of the cholinergic systems of the dorsal and ventral striatum in the active avoidance learning of rats in a T maze].

Influence of cholinergic activation of dorsal (caudo-putamen) and ventral (accumbens) striatum on active avoidance learning was studied in chronic experiments in Sprague-Dawley male rats. The results obtained on the same behavioural model testify to specific roles of dorsal and ventral cholinergic systems in the control of motor behaviour. Single carbacholine microinjection into the right Accumbens increased the level of correct responses on the first and subsequent learning days. Similar microinjection into the left accumbens on the first training day improved the level of correct responses on the second and the third learning days. Microinjections into the dorsal striatum did not change active avoidance learning in T maze. Changes in locomotor activity of the animals of different experimental groups were principally of the same nature, i.e., the level of locomotor activity in the open field decreased from trial to trial in all the groups. Carbacholine microinjection did not change spontaneous locomotion in rats. However, there were variations in modifications of locomotor activity induced by microinjections into accumbens depending on localization of the cannula. Injection into the lateral accumbens induced the most pronounced changes. This fact testifies to the functional heterogeneity of this small nucleus.

Animals↗

Bilateral knife cuts to the perforant path disrupt spatial learning in the Morris water maze.

Both the hippocampus and the entorhinal cortex are known to be crucial for spatial learning, but the contribution of the pathway linking the two structures, the perforant path (PP), has never been tested in a spatial learning paradigm. The present study examined the role of the PP in spatial learning using the Morris water maze. Seven days after bilateral transection of the PP with a fine-bladed knife, rats were habituated to the pool, then trained to swim from varying start locations to a platform submerged in a fixed location. After 28 training trials over 5 days, probe trials (without any platform present) were given to assess spatial memory for the location. Compared to sham-operated controls, lesioned rats showed slower learning and poorer asymptotic performance in terms of both swim path distance and escape latency, and less preference for the correct quadrant during probe trials. When the platform location was "reversed" to the opposite quadrant, the lesioned rats again showed poorer learning, poorer asymptotic performance, and reduced preference for the correct quadrant on the probe trial. When tested with a visible platform whose position varied from trial to trial, lesioned rats performed as well as controls. These results are congruent with previous analyses of the contributions of the entorhinal cortex and hippocampus to spatial learning and suggest that for spatial learning, the PP is a critical functional link between these two structures.

Animals↗

The olfactory tubing maze: a new apparatus for studying learning and memory processes in mice.

In order to have an ethologically relevant behavioral task, we developed the olfactory tubing maze to study learning and memory processes in mice. Mice have to make two olfactory-reward associations across three training sessions. The maze is made up of four identical testing chambers connected to each other by semicircular cylinders. After having chosen one of two odors presented on each side of a testing chamber, the mice have to run to the next testing chamber. From one testing chamber to the next, the side for presentating each odor is randomly assigned. The mouse must run through the entire circular maze to make a response at the four testing chambers. A complete session consists of 20 trials made by running five times clockwise through the maze with 4 trials per run. The training and data recording are fully automated by a custom-made software program. Three different experiments were performed. The results indicated that mice can easily make the olfactory discriminative associations in this new apparatus. Analysis of the data suggests that it would be possible using this olfactory tubing maze to study sub-categories of memory similar in some respects to those observed in humans. Consequently, possible effects on learning and memory of classical treatments (i.e. pharmacological or lesions) or genetic modifications in transgenic or gene-targeting mice could be tested.

Animals↗

N-methyl-D-aspartate receptor subunit changes are associated with lead-induced deficits of long-term potentiation and spatial learning.

The present study demonstrates that impairments of spatial learning and hippocampal long-term potentiation in rats chronically exposed to lead are associated with changes in gene and protein expression of N-methyl-D-aspartate receptor subunits. Rats exposed to 750 and 1500 ppm lead acetate were found to exhibit deficits in acquisition of a water maze spatial learning task. Furthermore, lead-exposed rats show dose-dependent reductions in the maintenance of in vivo hippocampal long-term potentiation induced in entorhinal cortex-dentate gyrus synapses. We found an unexpected, but significant (P<0.05), correlation between spatial learning and long-term potentiation when control and lead-exposed rats were analysed as a single, combined population. Dentate gyrus NR1 subunit messenger RNA was reduced 18% and 28% by exposure to 750 and 1500 ppm lead acetate, respectively. NR2A subunit messenger RNA was reduced 18% but only in the dentate gyrus of rats exposed to 1500 ppm lead acetate. No significant changes in dentate NR2B messenger RNA expression were measured in either of the lead-exposed groups. NR1 subunit protein was reduced 24% and 58% in hippocampal homogenates from rats exposed to 750 and 1500 ppm lead acetate. In contrast, no changes in NR2A or NR2B subunit protein were observed in the same hippocampal homogenates. These data show that reductions of specific N-methyl-D-aspartate receptor subunits are associated with deficits of both hippocampal long-term potentiation and spatial learning, induced in rats by chronic exposure to environmentally relevant levels of lead. These findings strongly suggest that the effects of lead on N-methyl-D-aspartate receptors may be the mechanistic basis for lead-induced deficits in cognitive function.

Animals↗

Pretraining or previous non-spatial experience improves spatial learning in the Morris water maze of nucleus basalis lesioned rats.

Previous experiments have shown that infusions of ibotenic acid in the nucleus basalis magnocellularis (NBM) induce a strong impairment in spatial navigation for a hidden platform in the Morris water maze. This effect was initially attributed to a cholinergic deficit, but later studies showed that performance level did not correlate with the degree of cholinergic denervation. Therefore, this impairment is due to a combined cholinergic and non-cholinergic deficit. However, it is not clear in which particular processes the NBM is involved. In this study we have evaluated the origin of behavioural impairment in spatial navigation in the water maze after an ibotenic acid-induced lesion of NBM. In the first experiment, Wistar rats were trained preoperatively in an allocentric navigation task. Postoperatively, they were tested in the same task. All lesioned animals showed a performance level similar to controls. Lesions did not impede the acquisition of new positions in the water maze, nor did affect the ability of animals to remember new platform positions after an intertrial interval of 20s, even if animals had received only allocentric experience with the platform position, or allocentric and path integration information concurrently. Lesions also failed to affect the ability to locate a hidden platform in a new environment. However, hippocampal infusions of scopolamine (5 microg) produced a severe impairment in NBM-damaged animals, without impairing performance of controls. In the second experiment Wistar rats with the same lesion were first trained in a visual-guided task in the water maze, and subsequently evaluated in the spatial task. In both tasks lesioned animals were not different from controls. These results suggest that the NBM played an important role during acquisition phases but not in the execution of spatial navigation. Moreover, the excessive emotional response displayed by lesioned animals is postulated as a relevant cause for the impairment observed in spatial navigation after NBM damage.

Animals↗

T-maze discrimination and reversal learning after unilateral temporal or frontal lobe lesions in man.

The interpretation of conditional discrimination and reversal learning as acquisition of declarative knowledge suggests that subjects with temporal lobe/hippocampal lesions are likely to be impaired on such tasks. Patients with unilateral left or right temporal lobectomy (and small hippocampal excisions) and patients with unilateral frontal lobe resections were compared with healthy controls on a discrimination reversal task, embedded in a computer game modelled on T-maze tasks traditionally used in animal experiments. The right temporal group showed a deficit in acquiring an initial conditional discrimination, and the frontal group tended to display a marginal impairment in discrimination reversal. These findings are compared with results from animal studies in terms of the mechanisms underlying reversal learning.

Adult↗

The use of the Morris Water Maze in the study of memory and learning.

Although the Morris Water Maze (MWM) was introduced only a few years ago, this technique has gained wide popularity, as the large number of publications in which it is employed, testifies. A review of the literature reveals that a wide variety of technical variables were used by the various research groups employing the MWM. This review describes the major changes in research variables, i.e., environmental variables, various manipulations, and the effects of diet or age on performance. The general principles of learning as demonstrated by the MWM are discussed.

Animals↗

Threshold relationship between lesion extent of the cholinergic basal forebrain in the rat and working memory impairment in the radial maze.

The cholinergic basal forebrain (CBF) degenerates in Alzheimer's Disease (AD), and the degree of this degeneration correlates with the degree of dementia. In the present study we have modeled this degeneration in the rat by injecting various doses of the highly selective immunotoxin 192 IgG-saporin (192-sap) into the ventricular system. The ability of 192-sap-treated rats to perform in a previously learned radial maze working memory task was then tested. We report here that 192-sap created lesions of the CBF and, to a lesser extent, cerebellar Purkinje cells in a dose-dependent fashion. Furthermore, we found that rats harboring lesions of the entire CBF greater than 75% had impaired spatial working memory in the radial maze. Correlational analysis of working memory impairment and lesion extent of the component parts of the CBF revealed that high-grade lesions of the hippocampal-projecting neurons of the CBF were not sufficient to impair working memory. Only rats with high-grade lesions of the hippocampal and cortical projecting neurons of the CBF had impaired working memory. These data are consistent with other 192-sap reports that found behavioral deficits only with high-grade CBF lesions and indicate that the relationship between CBF lesion extent and working memory impairment is a threshold relationship in which a high degree of neuronal loss can be tolerated without detectable consequences. Additionally, the data suggest that the CBF modulates spatial working memory via its connections to both the hippocampus and cortex.

Animals↗

Neurobehavior effects in four strains of mice offspring exposed prenatally to alprazolam.

OBJECTIVE: This study was performed to determine whether prenatal exposure to alprazolam affects offspring behavior in different strains of mice. STUDY DESIGN: Eight to 11 gravid mice of the C3H/He, C57BL/6, A/J, and DBA/2 strains were given either an anxiolytic dose of alprazolam (0.32 mg/kg) or a placebo by gavage on day 18 of an anticipated 19- to 21-day gestation. Neurobehavior tasks were conducted to assess anxiety, learning and memory, and social interaction. Data were analyzed by analysis of variance or a Fisher exact probability test. RESULTS: Anxiety in alprazolam-exposed offspring was reduced in C3H/He (P <.05) and A/J (P <.05) newborn infants by separation vocalization but may be increased in the C3H/He adult strain on the plus maze task. Learning was slower among C57BL/6 mice exposed to alprazolam (P <.01), whereas memory was reduced in exposed A/J and DBA/2 offspring (P <.05). Alprazolam exposure was associated with more aggression among C3H/He and C57BL/6 male offspring (P <.01) and with less group activity by C57BL/6 offspring (P <.05). CONCLUSION: Altered behaviors in several mouse strains after prenatal exposure to alprazolam suggests a vulnerability of GABA-benozdiazepine receptor formation in fetal brain development.

Aggression↗

Multiple kainic acid seizures in the immature and adult brain: ictal manifestations and long-term effects on learning and memory.

PURPOSE: While there is increasing evidence that the adverse effects of prolonged seizures are less pronounced in the immature than in the mature brain, there have been few investigations of the long-term effects of recurrent seizures during development. This study examined the effects of multiple administrations of the convulsant kainic acid (KA) on seizure characteristics and spatial learning as a function of brain development. METHODS: To determine the long-term effects of serial KA seizures during ontogeny, saline or convulsant doses of KA were given intraperitoneally 4 times, at 2-day intervals. Immature rats were given KA on P20, P22, P24 and P26; adult rats got KA on P60, P62, P64 and P66. Ictal characteristics and EEGs were recorded. To examine the effects of multiple KA seizures on the retention of spatial learning, water maze testing was performed before (immature group: from P16-19, adult group: from P56-P59) and after (immature: from P60-P63, adult: from P100-P103) KA injections. Finally, histology was performed to compare KA-induced damage at each age. RESULTS: In immature animals, serial KA administration resulted in seizures with a progressively longer onset latency and decreased severity. In contrast, KA serially administered to adult rats caused severe seizures after each of the 4 injections. In immature rats, epileptiform EEG changes were most prominent after the first KA injection, whereas in adults, prolonged paroxysmal EEG patterns were seen after all 4 KA injections. Before KA, both rat pups and adults acquired place learning in the water maze. One month after the final KA injection, there was no deficit in spatial learning retention in the immature group, whereas the adult group had profound impairment compared to age-matched, saline-injected controls. Histology revealed no lesions in immature rats treated multiple times with KA but profound cell loss in hippocampal fields CA4, CA3 and CA1 in rats treated serially with KA as adults. CONCLUSIONS: Previous studies have shown that a single KA injection causes prolonged status epilepticus (which persists for several hours), leading to severe histologic and behavioral sequelae in adult rats but not in pups. Our study extends those findings, demonstrating that immature rats are spared the cognitive and pathological sequelae of multiple injections of convulsant doses of KA as well.

Animals↗

Galanin and learning.

A number of studies indicate that galanin (GAL) is a potent modulator of basal acetylcholine release in the rat forebrain e.g. in the cholinergic neurons of the septo-hippocampal projections. Thus, GAL perfused through the microdialysis probe decreased basal acetylcholine release in the ventral hippocampus, while it enhanced acetylcholine release in the dorsal hippocampus. This finding indicates that GAL may act via different mechanisms within the subsystems of the hippocampus. This hypothesis has received support from studies using the Morris swim maze, a learning task dependent on hippocampal mechanisms. GAL (3 nmol/rat) infused into the ventral hippocampus impaired spatial learning acquisition, while it tended to facilitate when injected into the dorsal hippocampus. However, the effects of GAL on acetylcholine release and on spatial learning, which are due to activation of GAL-receptors, appear to be indirectly mediated possibly via noradrenaline transmission. GAL is also a potent inhibitor of mesencephalic 5-HT neurotransmission in vivo. These findings are discussed in relation to the role of acetylcholine and serotonin in cognition.

Acetylcholine↗