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Lesions of the intermediate medial hyperstriatum ventrale impair sickness-conditioned learning in day-old chicks.

Lesion studies show that the intermediate medial hyperstriatum ventrale (IMHV), a forebrain visual association area in chicks, is involved in learning and memory for one-trial passive avoidance and imprinting. We examined the effects of IMHV lesions in a one-trial, nongustatory, sickness-conditioned learning task. This task is similar to passive avoidance and imprinting because all three tasks require the chick to remember visual cues in order to respond correctly. However, sickness-conditioned learning differs from imprinting and passive avoidance because it uses sickness as the aversive stimulus and there is a longer conditioned stimulus-unconditioned stimulus interval (30-min delay compared to seconds). Bilateral IMHV lesions given 24 h before training impaired the ability of the chicks to avoid a bead associated with sickness produced by lithium chloride injection, as did pretraining unilateral left or right IMHV lesions. Post-training IMHV lesions given 1 h after training did not impair avoidance of the test bead in the sickness-conditioned learning task. However, lesioned chicks showed generalized avoidance of all test beads. The pretraining lesion results are similar to those found in imprinting and passive avoidance learning; however, the effects of unilateral IMHV lesions differed. Post-training lesion effects are similar to those found in passive avoidance learning. We propose that both left and right IMHV are necessary for sickness-conditioned learning and that post-training IMHV lesions impair the ability of the chick to learn or remember the association between the color of the bead and the aversive consequences of LiCl injection.

Age Factors↗

Calcium channel antagonists enhance retention of passive avoidance and maze learning in mice.

Although a number of studies have shown that treatment with calcium channel antagonists (CCAs) can ameliorate impairments in learning and memory in aged animals, evidence for a general nootropic effect of CCAs in neurologically normal young adult animals is ambiguous. This study attempts to resolve some of this ambiguity by comparing the effects of several CCAs on retention of passive avoidance learning and acquisition and retention of appetitively motivated spatial discrimination learning in young adult mice. Animals were trained in a step through passive avoidance apparatus and, immediately after training, injected subcutaneously with different doses of nimodipine, nifedipine, amlodipine, flunarazine, diltiazem, or verapamil. Retention was tested 24 h after training. In the maze-learning task mice were treated with the same doses of the aforementioned CCAs immediately after a brief training session in a linear maze and retention was tested 24 h after training. The most effective dose of each agent in the maze-retention experiment was administered to additional groups of animals 1 h prior to training to determine the effects of CCAs on acquisition processes. The effects of central administration of CCAs were examined by intracerebroventricular injection of different doses of amlodipine immediately after passive avoidance training. Results showed (1) all peripherally administered drugs except verapamil facilitated retention of passive avoidance training in a dose-dependent manner, (2) all drugs dose dependently facilitated retention of linear maze learning, (3) all doses of the drugs (except verapamil) which facilitated maze retention also facilitated maze learning, and (4) central administration of the dihydropyridine amlodipine produced a dose-dependent facilitation of the retention of passive avoidance learning. These data indicate that drugs which block calcium channels can enhance retention of two different types of learning in mice.

Animals↗

Attentional control in learning to discriminate bars and gratings.

Transfer effects of learning a spatial-frequency and a bar-width discrimination task on the performance in three other discrimination tasks (relative bar position, local width, and global-size discrimination) have been investigated. In the spatial-frequency discrimination learning task, subjects were trained with grating stimuli which varied in spatial frequency, relative bar position, and grating patch size, but only spatial frequency was relevant for discrimination. The bar-width discrimination learners had to judge the width of single grating bars appearing at random positions distributed around a display center. During the course of 10 consecutive days, all subjects showed a significant reduction of discrimination thresholds. Regarding learning transfer, we find that practicing the spatial-frequency discrimination task yields quite strong improvement of bar-width discrimination and, vice versa, learning bar-width discrimination also leads to strong improvement of spatial-frequency discrimination performance, indicating involvement of coding pathways which are shared by both tasks. On the other hand, there is no performance improvement when subjects do different tasks (grating patch size and relative bar position discrimination) with the same stimulus material as the learning stimuli. The finding of task-driven selective learning for only one local stimulus attribute among other local and global attributes shows that feature-based attentional preselection of basic stimulus attributes is involved in learning. Moreover, differential learning effects for two different local stimulus features indicate that, governed by top-down control, different neural pathways starting from the same low-level code base may be formed in the course of discrimination training.

Attention↗

High proline levels in the brains of mice as related to specific learning deficits.

Hyperprolinemic PRO/Re mice have been studied as potential models for hyperprolinemia in man. In addition to high proline levels, some heretofore unreported amino acid abnormalities in the brains of PRO/Re mice are described. The T-maze and shuttlebox learning abilities of PRO/Re mice were compared with those of CD-1 mice having normal proline levels. PRO/Re mice had a significant deficit for T-maze learning, but a significantly greater aptitude for shuttlebox learning when compared to CD-1 mice. By studying the F3 progency of the PRO/Re X CD-1 cross, these strain-specific differences in learning ability for different tasks were shown to be unrelated to the differences in brain proline levels. F3 mice could be subdivided into two distinct groups: those with high proline (HP+) and low proline (HP-) titers. Other amino acids in brain tissues were essentially identical in both groups. A comparison of learning abilities of these HP+ mice with their HP- littermates showed no meaningful differences. However, the slightly slower rate at which HP+ mice acquired shuttlebox learning was sufficiently consistent over the 8 day training period so that it became significant. These results do not support the hypothesis that high levels of proline in brain tissues and blood are necessarily accompanied by impaired learning and memory, but are in agreement with those studies of hyperprolinemia in man that suggest no consistent learning deficits in hyperprolinemic subjects. The results seem to validate the suitability of the PRO/Re mouse as a model for hyperprolinemia in man. The data suggest also that the altered amino acid pattern in brains of PRO/Re mice has multiple etiologies.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗

Electrical intracerebral stimulation of the area postrema on taste aversion learning.

The structural characteristics of the area postrema, its anatomical connections, participation in the detection of emesis-provoking substances and the effects of area postrema lesions on taste aversion learning acquisition, are all factors which speak in favor of a role as a chemoreceptor zone involved in the detection of aversive agents which act as effective inducers of taste aversion learning. The feasibility of substituting electrical intracerebral stimulation of the area postrema for the aversive stimulus was investigated in a taste aversion learning paradigm. In Expt. 1, 0.1-ms rectangular pulses of 50 Hz, delivered intermittently or continuously for 4 h after a 15-min delay following ingestion of the gustatory stimulus, produced reliable learning. Expt. 2 showed the learning thus induced to reflect all the characteristics features attributed to taste aversion learning: one-trial learning, long interstimulus delay and cue-consequence specificity. These results suggest that the area postrema could participate in the detection of the aversive consequences of particular taste aversion learning-inducing agents.

Animals↗

Neonatal exposure to triethyltin disrupts olfactory discrimination learning in preweanling rats.

Triethyltin is an organotin compound that is known to produce neurotoxicity in both adult and developing organisms. Although this neurotoxicity has been documented with a variety of behavioral and biological measures, the effects of this compound on learning during early development have been less extensively studied. The present study reports four experiments that examined this question with an odor aversion learning paradigm in which pups received presentations of one odor paired with footshock and an alternate odor without shock. In Experiment 1, Long-Evans rat pups were injected IP on postnatal day 5 (PND 5) with either 0, 3 or 5 mg/kg TET and then tested for olfactory discrimination learning on PND 18. Only the 5-mg/kg dose impaired discrimination learning. In Experiment 2, PND 5 exposure to TET (5 mg/kg) disrupted olfactory learning on PND 18 but not on PND 12, whereas exposure on PND 10 disrupted learning at both ages of testing. In Experiment 3, PND 16 exposure to TET (5 mg/kg) also disrupted acquisition of olfactory learning on PND 18 but had no effect on retention of an olfactory discrimination that was acquired prior to TET exposure (i.e., on PND 14 and PND 15). Unconditioned responses to footshock were also unaffected by TET (Experiment 4). These findings indicate that neonatal exposure to TET impairs associative learning in developing rats and are discussed in relation to other studies of the developmental neurotoxicity of this compound.

Aging↗

Novel peptides prevent alcohol-induced spatial learning deficits and proinflammatory cytokine release in a mouse model of fetal alcohol syndrome.

OBJECTIVE: Previously, the novel peptides NAPVSIPQ and SALLRSIPA were shown to prevent alcohol-induced fetal death and growth abnormalities in a mouse model of fetal alcohol syndrome. This study evaluated whether these peptides could prevent long-term alcohol-induced learning abnormalities. In addition, because specific cytokines are known to effect long-term potentiation, a model of learning at the molecular level, we studied the effect of these novel peptides on tumor necrosis factor-alpha, interleukin-6, and interferon-gamma levels. STUDY DESIGN: We used a well-characterized mouse model of fetal alcohol syndrome. Pregnant mice were injected on day 8 with alcohol (0.03 mL/kg) or placebo. Pretreatment with NAPVSIPQ+SALLRSIPA (20 mug) or placebo was given 30 minutes before alcohol. Embryos were removed after 6 hours, at which time cytokine, tumor necrosis factor-alpha, interleukin-6, and interferon-gamma levels were measured with enzyme-linked immunoassays. To test spatial learning, adult offspring from litters that were treated with alcohol, control, NAPVSIPQ+SALLRSIPA then alcohol, or NAPVSIPQ+SALLRSIPA alone were evaluated for latency to find a hidden platform in the Morris water maze. RESULTS: Alcohol treatment increased tumor necrosis factor-alpha levels versus control levels (50.0 +/- 3.5 pg/mL vs 32.7 +/- 2.4 pg/mL; P < .001). NAPVSIPQ+SALLRSIPA pretreatment prevented this increase (39.9 9 +/- 2.8 pg/mL; P </= .01), with levels similar to control (P=.1). Similarly, alcohol increased interleukin-6 levels versus control levels (22.6 +/- 1.4 pg/mL vs 17.3 +/- 0.6 pg/mL; P < .001), and NAPVSIPQ+SALLRSIPA prevented this increase (19.1 +/- 1.0 pg/mL; P </= .02), with levels similar to control levels (P=.2). Interferon-gamma levels were not different among the 3 groups (alcohol, 14.6 +/- 4.9 pg/mL; control, 17.9 +/- 6.6 pg/mL; alcohol+NAPVSIPQ+SALLRSIPA, 13.6 +/- 4.9 pg/mL; P=.2). In the Morris water maze, alcohol-treated groups did not learn over the 7-day trial compared with the control group (P=.001). Groups that were pretreated with NAPVSIPQ+SALLRSIPA then alcohol learned significantly, which was similar to the control group. Groups that were treated with only NAPVSIPQ+SALLRSIPA learned significantly earlier, with the shortest latency once learning commenced. CONCLUSION: The peptides, NAPVSIPQ+SALLRSIPA, prevented the alcohol-induced spatial learning deficits and attenuated alcohol-induced proinflammatory cytokine increase in a model of fetal alcohol syndrome. This study demonstrates the peptides' significant in vivo efficacy with long-lasting effects obtained after prenatal administration.

Animals↗

Differential effects of M1 muscarinic receptor blockade and nicotinic receptor blockade in the dorsomedial striatum on response reversal learning.

The present studies determined whether blockade of M(1)-like muscarinic or nicotinic cholinergic receptors in the dorsomedial striatum affects acquisition or reversal learning of a response discrimination. Testing occurred in a modified cross-maze across two consecutive sessions. In the acquisition phase, a rat learned to turn to the left or to the right. In the reversal learning phase, a rat learned to turn in the opposite direction as required during acquisition. Experiment 1 investigated the effects of the M(1)-like muscarinic receptor antagonist, pirenzepine infused into the dorsomedial striatum on acquisition and reversal learning. Experiment 2 examined the effects of the nicotinic cholinergic antagonist, mecamylamine injected into the dorsomedial striatum on acquisition and reversal learning. Bilateral injections of pirenzepine at 10 microg, but not 1 microg, selectively impaired reversal learning. Analysis of the errors indicated that pirenzepine treatment did not impair the initial shift, but increased reversions back to the original response choice following the initial shift. Bilateral injections of mecamylamine, 6 or 18 microg, did not affect acquisition or reversal learning. The results suggest that activation of M(1) muscarinic cholinergic receptors, but not nicotinic cholinergic receptors, in the dorsomedial striatum is important for facilitating the flexible shifting of response patterns.

Animals↗

Effects of injections of glucose into the dorsal striatum on learning of place and response mazes.

The present experiment tested the hypothesis that facilitation of striatal function with intra-striatal glucose injections would facilitate learning a striatum-dependent response maze and impair learning a hippocampus-dependent place maze. Food-deprived Sprague-Dawley male rats were trained to find food in a Y-maze. In the place version of the maze, rats were rewarded for learning to go to an arm located in a fixed location while in the response task rats were rewarded for consistently turning in the same direction at the choice point. Artificial cerebrospinal fluid (1 microL) containing either 0.7 nmol of glucose (control) or 20 nmol of glucose was injected bilaterally into the dorsal striatum immediately before training. The animals were trained to a criterion of 9/10 correct choices. In the place maze, glucose injections impaired learning, as measured by number of trials required to reach 9/10 correct. However, in the response task, glucose injections did not enhance learning. A subsequent experiment examined the effects of intra-striatal glucose injections on acquisition of the response task under two different visual cue conditions, addition of an intra-maze light cue that predicted the correct arm or with removal of most visual extramaze cues. Glucose again failed to facilitate acquisition of the response task under these conditions. These findings suggest that facilitation of striatal function via intra-striatal glucose injections is sufficient to impair place learning but not to enhance response learning, perhaps separating the neurochemical mechanisms for striatal involvement in impairment of place and enhancement of response learning.

Animals↗

NMDA receptor activity in learning spatial procedural strategies I. The influence of hippocampal lesions.

To acquire knowledge about the environment two types of learning are necessary: declarative localizatory learning about where environmental cues and the subject are, and procedural learning about how to explore and move around the environment. Experimental data indicate that hippocampal regions are involved in spatial learning, playing a key role in building spatial cognitive maps. The contribution of hippocampal NMDA receptors to spatial functions is indicated by the disruption of place learning when NMDA long-term potentiation is blocked. Conversely, the hippocampal contribution to the acquisition of procedural strategies is still controversial. Inactivation of the hippocampus by antagonizing the activity of AMPA/kainate receptors results in impaired spatial procedural learning. However, in the presence of a blockade of NMDA long-term potentiation in hippocampal areas it is still possible to learn explorative strategies. To investigate the involvement of the hippocampal NMDA receptors in spatial procedural learning, an NMDA receptor antagonist (CGS 19755) was administered i.p. to unlesioned animals or to animals with total ablation of hippocampal structures that had been tested in the Morris water maze. The CGS administration induced peripheral circling in both unlesioned control animals and in rats with bilateral hippocampal ablation. Conversely, circling was not observed if the drug-treated animals (either unlesioned or lesioned) had been spatially trained before drug administration. These findings indicate that even in the absence of the hippocampal formation the NMDA receptor antagonist found a site of action to influence the acquisition of spatial procedures to search for the platform.

Analysis of Variance↗

The effect of N-methyl-D-aspartate receptor blockade on acetylcholine efflux in the dorsomedial striatum during response reversal learning.

Separate experiments found that activation of N-methyl-d-aspartate (NMDA) receptors or increased acetylcholine (ACh) efflux in the rat dorsomedial striatum is critical for learning when conditions require a shift in strategies. Increasing evidence indicates that NMDA receptor activity affects cholinergic efflux in the basal ganglia. The present studies determined whether NMDA receptor blockade in the dorsomedial striatum with dl-2-amino-5-phosphonopentanoic acid (AP-5) affects dorsomedial striatal ACh output in a resting condition, as well as during response reversal learning. Experiment 1 investigated the effects of AP-5 (12.5, 25 or 50 muM) infused into the dorsomedial striatum on ACh output in a resting condition. AP-5 infusion at 25 and 50 muM led to a 20% and 40% decrease in dorsomedial striatal ACh output, respectively. AP-5 (12.5 muM) infusion did not change dorsomedial striatal ACh output from basal levels. Experiment 2 determined whether dorsomedial striatal ACh efflux increases during response reversal learning and whether AP-5, at a dose that does not affect basal levels, modifies response reversal learning and ACh efflux. Following acquisition of a response discrimination, rats had microdialysis probes bilaterally inserted into the dorsomedial striatum prior to the reversal learning test. After baseline samples, rats received a response reversal learning test for 30 min. Control rats rapidly improved in the reversal learning session while simultaneously exhibiting an approximately 40% increase in ACh output compared with baseline levels. AP-5 (12.5 muM) treatment during testing significantly impaired response reversal learning while concomitantly blocking an increase in ACh output. These findings suggest that NMDA receptor activation in the dorsomedial striatum may facilitate a shift in response patterns, in part, by increasing ACh efflux.

2-Amino-5-phosphonovalerate↗

Differential effects of estrogen on hippocampal- and striatal-dependent learning.

Estrogen's role in learning and memory may be to predispose animals to use specific cognitive strategies (Korol & Kolo, 2002). Specifically, estrogen may facilitate hippocampal-dependent learning, while at the same time attenuate striatal-dependent learning. As a stringent test of this hypothesis, place or response learning on an eight-arm radial maze was compared between ovariectomized (OVX) female Long-Evans rats and rats with chronic estrogen replacement (OVX+E; 5mg 17-beta estradiol 60-day release tablet). Reference and working memory errors were monitored separately for both place and response learning tasks. OVX+E rats learned the place task significantly faster than the response task, and faster than OVX rats. OVX rats required fewer days to reach criterion on the response task than OVX+E rats. Estrogen selectively enhanced reference memory performance, but only during place learning. The specific pattern of estrogen effects on learning suggests that future studies include verification of cognitive strategies used by animals.

Animals↗

Behavioral LTP during learning in rat hippocampal CA3.

Behavioral long-term potentiation (LTP) of the potentials with the advance of learning were investigated in hippocampal mossy fiber (MF)-CA3 synapses. In both acute and chronic experiments, control and test groups of rats were used. Daily learning tasks in the radial arm maze were given to animals in the test groups. Complete acquisition of learning was observed on day 5. In acute experiments, when MF stimulation-induced population spikes (PS) were examined on day 7 of learning task, relatively higher PS were observed in the test group than those in the control group, and tetanic stimulation (TS)-induced LTP was still observed from the increased PS before TS in the test groups. In chronic experiments, in which the MF stimulation-induced PS were recorded daily after the learning tasks with implanted electrodes, amplitude of PS of the test groups, but not the control, increased concomitantly with the progress in learning. The PS potentiation persisted steadily from day 4 to day 7 of training. The fact that LTP in the MF-CA3 system coincided well with the advance of learning suggests that the MF-CA3 system is involved in the acquisition of learning and/or memory storage.

Anesthesia↗

Associative and perceptual learning and the concept of memory systems.

An introductory review is followed by some new experimental data and a final discussion. The primate temporal lobe contains multiple qualitatively distinct memory systems. The functional properties of these memory systems can be explained by reference to the nature of the afferent information which they process, rather than by reference to any putative specialization in memory processing. In this way, the plasticity of 'memory systems' in associative memory is probably similar in principle to the plasticity of 'perceptual systems' in perceptual learning. Therefore, it is important to consider the relationship between perceptual and associative learning. Two experiments investigated perceptual learning in the Rhesus monkey (Macaca mulatta). Substantial perceptual learning was observed both with complex scenes and with simple colours. Two hypotheses as to the basis of perceptual learning are discussed. A physiological hypothesis is that training with a particular set of stimuli expands the cortical representation of those stimuli. This can explain the effects in both experiments. A psychological hypothesis is that perceptual learning is produced by learned associations among multiple features of complex stimuli. This can explain the effects in Expt. 1 but not in Expt. 2. The psychological associative hypothesis is therefore redundant. Furthermore, associative learning can itself be viewed as an expansion of the cortical representation of a complex event. Thus, the distinction between perceptual and memory systems will need to be abandoned as deeper understanding of cortical plasticity is achieved.

Animals↗

Implicit learning of new verbal associations.

Implicit learning of a series of new verbal associations was studied in four experiments. The first two experiments demonstrated that learning of a repeating sequence of verbal stimuli may occur without awareness, but only when the stimulus-response mapping requires an attention-demanding activity: Subjects who were unaware of the sequence learned when instructed to categorize the stimuli, but not when instructed simply to read them. However, in both situations, unaware subjects performed no better than untrained control subjects in expressing their knowledge of the sequence explicitly. In Experiments 3 and 4, subjects showed implicit learning when the task involved either motor responses to verbal stimuli or verbal responses to spatially arranged stimuli. These findings are discussed in terms of the conditions under which implicit learning can be obtained. First, they demonstrate implicit learning of a set of new associations in the verbal domain. Second, the data suggest that attention is important in implicit learning. Finally, the degree of interitem organization that is familiar preexperimentally seems to partially determine the amount of implicit learning.

Adult↗

Failure to replicate visceral learning in the acute curarized rat preparation.

An attempt was made to replicate a series of experiments reported to demonstrate robust visceral learning (autonomic instrumental learning) in rats during acute (2-4 hr) pharmacological paralysis. The results of exploratory procedures involving more than 2,000 animals are described, and six complete experiments, representing systematic observations on an additional 500 animals, are presented. In the first three experiments, which closely followed the original procedures, the characteristics of the preparation were reproduced with the exception of initial heart rhythm and visceral learning. In the second three, the respiration procedure was modified to satisfactorily reproduce the heart rhythm, and the PaO2, PaCO2, and pH were verified to be within the range of freely moving, normally behaving animals; nevertheless, visceral learning was not observed in these experiments either. After more than 2,500 rats were studied, it is concluded that the original visceral learning experiments are not replicable and that the existence of visceral learning remains unproven; however, neither the original experiments nor the replication attempt included the necessary controls to support a general negative conclusion about visceral learning. Because continuing and extensive citation of the original experiments indicates their widely perceived significance, specific requirements for critically testing the visceral learning hypothesis are given, and the limited theoretical implications and practical value of neuromuscular blockade are discussed.

Animals↗

Visual discrimination learning and strategy behavior in the fat-tailed dunnart (Sminthopsis crassicaudata).

Fat-tailed dunnarts (Sminthopsis crassicaudata) were trained on visual discrimination learning-set, reversal-set, and spatial delayed-alternation tasks. The learning set involved 36 2-way black-and-white pattern discriminations and 5 probe reversals. Ten reversals of a black-and-white pattern discrimination were followed by 5 novel tasks. Spatial alternation was tested at delays up to 20 s. Learning-set and reversal-set formation, including 1-trial learning and spontaneous transfer from learning set to reversals and vice versa, was found. Learning-set-experienced dunnarts showed no retention of previously learned tasks 1 week after testing but demonstrated consistently high Trial 2 performance, indicating the retention of a response strategy. Delayed-alternation tasks were learned up to 10-s delays. These results provide the first evidence of a visually guided "win-stay, lose-shift" strategy in a marsupial.

Analysis of Variance↗

A mouse model for the learning and memory deficits associated with neurofibromatosis type I.

Neurofibromatosis type I (NF1) is one of the most commonly inherited neurological disorders in humans, affecting approximately one in 4,000 individuals. NF1 results in a complex cluster of developmental and tumour syndromes that include benign neurofibromas, hyperpigmentation of melanocytes and hamartomas of the iris. Some NF1 patients may also show neurologic lesions, such as optic pathway gliomas, dural ectasia and aqueduct stenosis. Importantly, learning disabilities occur in 30% to 45% of patients with NF1, even in the absence of any apparent neural pathology. The learning disabilities may include a depression in mean IQ scores, visuoperceptual problems and impairments in spatial cognitive abilities. Spatial learning has been assessed with a variety of cognitive tasks and the most consistent spatial learning deficits have been observed with the Judgement of Line Orientation test. It is important to note that some of these deficits could be secondary to developmental abnormalities and other neurological problems, such as poor motor coordination and attentional deficits. Previous studies have suggested a role for neurofibromin in brain function. First, the expression of the Nf1 gene is largely restricted to neuronal tissues in the adult. Second, this GTPase activating protein may act as a negative regulator of neurotrophin-mediated signalling. Third, immunohistochemical studies suggest that activation of astrocytes may be common in the brain of NF1 patients. Here, we show that the Nf1+/- mutation also affects learning and memory in mice. As in humans, the learning and memory deficits of the Nf1+/- mice are restricted to specific types of learning, they are not fully penetrant, they can be compensated for with extended training, and they do not involve deficits in simple associative learning.

Acoustic Stimulation↗