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PubMed2006

Associative and spatial learning and memory deficits in transgenic mice overexpressing the RNA-binding protein HuD.

HuD is a neuronal specific RNA-binding protein associated with the stabilization of short-lived mRNAs during brain development, nerve regeneration and synaptic plasticity. To investigate the functional significance of this protein in the mature brain, we generated transgenic mice overexpressing HuD in forebrain neurons under the control of the alphaCaMKinII promoter. We have previously shown that one of the targets of HuD, GAP-43 mRNA, was stabilized in neurons in the hippocampus, amygdala and cortex of transgenic mice. Animals from two independent lines expressing different levels of the transgene were subjected to a battery of behavioral tests including contextual fear conditioning and the Morris water maze. Our results show that although HuD is increased after learning and memory, constitutive HuD overexpression impaired the acquisition and retention of both cued and contextual fear and the ability to remember the position of a hidden platform in the Morris water maze. No motor-sensory abnormalities were observed in HuD transgenic mice, suggesting that the poor performance of the mice in these tests reflect a true cognitive impairment. We conclude that posttranscriptional regulation of gene expression by stabilization of specific mRNAs may have to be restricted temporally and spatially for proper acquisition and storage of memories.

Analysis of Variance↗
PubMed2002

Enhanced learning and memory and altered GABAergic synaptic transmission in mice lacking the alpha 5 subunit of the GABAA receptor.

The alpha5 subunit of the GABA(A) receptor is localized mainly to the hippocampus of the mammalian brain. The significance of this rather distinct localization and the function of alpha5-containing GABA(A) receptors has been explored by targeted disruption of the alpha5 gene in mice. The alpha5 -/- mice showed a significantly improved performance in a water maze model of spatial learning, whereas the performance in non-hippocampal-dependent learning and in anxiety tasks were unaltered in comparison with wild-type controls. In the CA1 region of hippocampal brain slices from alpha5 -/- mice, the amplitude of the IPSCs was decreased, and paired-pulse facilitation of field EPSP (fEPSP) amplitudes was enhanced. These data suggest that alpha5-containing GABA(A) receptors play a key role in cognitive processes by controlling a component of synaptic transmission in the CA1 region of the hippocampus.

Animals↗
PubMed2005

Arousal from hibernation alters contextual learning and memory.

Hibernation is a unique and highly regulated physiological state characterized by profound, albeit periodically reversible, depression in body temperature, metabolism, and consciousness. Hippocampal synapses undergo pronounced remodeling in concert with torpor and arousal. During hibernation, the number of postsynaptic densities, apical dendritic branches, and spine densities decreases substantially in the hippocampus. Upon arousal these parameters increase beyond pre-hibernation levels and peak within 2-3h. By 24h after arousal, dendritic parameters remain elevated but have started to subside, consistent with pruning and differentiation. The present study examined the functional consequences of these natural changes in synaptic structure. Wild-caught Arctic ground squirrels (AGS) were trained in a hippocampal-dependent contextual fear conditioning task at 3h, 24h, or 4 weeks after arousal (warm-adapted euthermic control group). All groups acquired the fear conditioned response similarly on the training day. During a subsequent retention test session, AGS in the 24h group exhibited enhanced expression of contextual fear compared to the other two groups. These data suggest that the morphological and biochemical changes occurring at 24h after arousal from hibernation affect hippocampal-dependent learning and memory. The natural change in synaptic structure during hibernation may provide a unique opportunity to assess the neural substrates underlying cognitive enhancement.

Analysis of Variance↗
PubMed1986

Effects of meclofenoxate on learning and memory--dependence on the experimental conditions.

In experiments on male albino rats, it was found that meclofenoxate at a dose of 100 mg/kg i. p. applied 7 days before and 5 days during shuttle-box training did not influence learning but significantly facilitated retention (retention test was given 7 days after the end of training). With the step-through method for passive avoidance meclofenoxate at the same dose applied for 7 days improved learning and retention. In the staircase maze training with alimentary reinforcement and in the step-down passive avoidance situation, meclofenoxate at a single dose (50 mg/kg i. p.) applied before or immediately after training only tended to facilitate learning and retention, while applied at the same dose twice daily for 5 days, it significantly improved learning and retention. When meclofenoxate at a dose of 50 mg/kg i. p. was administered twice daily for 5 days in parallel with the staircase maze training, learning reached its maximum on the 5th day and remained at this level till the 10th training day even after withdrawal of meclofenoxate. In the control animals the improvement of learning progressively increased till the 10th training day. The present results suggest that the learning- and memory-facilitating effect of meclofenoxate is influenced by the training method, motivation, dose used and treatment duration.

Animals↗
PubMed2002

Animal learning and memory: an integration of cognition and ecology.

A wonderfully lucid framework for the ways to understand animal behaviour is that represented by the four 'whys' proposed by Tinbergen (1963). For much of the past three decades, however, these four avenues have been pursued more or less in parallel. Functional questions, for example, have been addressed by behavioural ecologists, mechanistic questions by psychologists and ethologists, ontogenetic questions by developmental biologists and neuroscientists and phylogenetic questions by evolutionary biologists. More recently, the value of integration between these differing views has become apparent. In this brief review, we concentrate especially on current attempts to integrate mechanistic and functional approaches. Most of our understanding of learning and memory in animals comes from the psychological literature, which tends to use only rats or pigeons, and more occasionally primates, as subjects. The underlying psychological assumption is of general processes that are similar across species and contexts rather than a range of specific abilities. However, this does not seem to be entirely true as several learned behaviours have been described that are specific to particular species or contexts. The first conspicuous exception to the generalist assumption was the demonstration of long delay taste aversion learning in rats (Garcia et al., 1955), in which it was shown that a stimulus need not be temporally contiguous with a response for the animal to make an association between food and illness. Subsequently, a number of other examples, such as imprinting and song learning in birds (e.g., Bolhuis and Honey, 1998; Catchpole and Slater, 1995; Horn, 1998), have been thoroughly researched. Even in these cases, however, it has been typical for only a few species to be studied (domestic chicks provide the 'model' imprinting species and canaries and zebra finches the song learning 'models'). As a result, a great deal is understood about the neural underpinnings and development of the behaviour, but substantially less is understood about interspecific variation and whether variation in behaviour is correlated with variation in neural processing (see review by Tramontin and Brenowitz, 2000 but see ten Cate and Vos, 1999).

Journal Article↗
PubMed2003

Associative learning and memory in Lymnaea stagnalis: how well do they remember?

The search for 'the how and the where' of memory formation in the brain, the engram, is still one of the unattained 'Holy Grails' of neuroscience. Over the years, various paths have been trodden in attempts to attain this goal, and while tantalizing glimpses appear now and then on the scientific horizon, the Grail still has not been grasped. One of the paths that investigators have walked is the invertebrate 'model system' approach. Some invertebrates possess relatively simple nervous systems that mediate relatively simple behaviours that are both interesting and trainable. In this commentary, we would like to shed light on a relatively new player, the pond snail Lymnaea stagnalis L., that is being used in the quest to illuminate 'the how and the where' the nervous systems encode and store memory. We will show that it is possible to demonstrate that a single neuron is a site of memory formation and storage for a form of associative learning in this lowly snail. It may be that the Grail is a little closer to being grasped.

Animals↗
PubMed2003

Suppression of adult neurogenesis impairs olfactory learning and memory in an adult insect.

Although adult neurogenesis has now been demonstrated in many different species, the functional role of newborn neurons still remains unclear. In the house cricket, a cluster of neuroblasts, located in the main associative center of the insect brain, keeps producing new interneurons throughout the animal's life. Here we address the functional significance of adult neurogenesis by specific suppression of neuroblast proliferation using gamma irradiation of the insect's head and by examining the impact on the insect's learning ability. Forty gray irradiation performed on the first day of adult life massively suppressed neuroblasts and their progeny without inducing any noticeable side effect. We developed a new operant conditioning paradigm especially designed for crickets: the "escape paradigm." Using olfactory cues, visual cues, or both, crickets had to choose between two holes, one allowing them to escape and the other leading to a trap. Crickets lacking adult neurogenesis exhibited delayed learning when olfactory cues alone were used. Furthermore, retention 24 hr after conditioning was strongly impaired in irradiated crickets. By contrast, when visual cues instead of olfactory ones were provided, performance of irradiated insects was only slightly affected; when both olfactory and visual cues were present, their performance was not different from that of controls. From these results, it can be postulated that newborn neurons participate in the processing of olfactory information required for complex operant conditioning.

Animals↗
PubMed2006

Disorders of learning and memory processes in a monkey model of Alzheimer's disease: the role of the associative area of the cerebral cortex.

The processes of learning and storage of the results of learning were studied in a model of Alzheimer's disease in two groups of rhesus macaques (three individuals in each group). Studies were performed after injection of neurotoxins (group I) and physiological saline (group II, controls). Two months after injections (stage C1), learning parameters were studied in monkeys of both groups using a new stimulus discrimination test (filled geometrical figures versus outline figures). There were significant differences between the animals of the two groups. Learning was hindered in monkeys of group I, with significant increases in the learning time (the time to achieve a stable probability of correct responding of 0.85) and in the probability of refusals. Monkeys of group II showed no learning impairment. Animals were trained to discriminate new stimuli (images of two monkeys) six months after injections (stage C3). Learning was impaired in animals of group I, such that learning measures had the same levels as previously; monkeys of group II showed no learning impairment. Analysis of the characteristics of working memory, which is involved in storing the results of new learning, was performed at stage C1; monkeys of group I showed significant degradation of these measures, with a significant decrease in the probability of correct solutions at stage C1 (to a level of 0.5), with some increase at stages C2 (at four months) and C3, along with a significant increase in the probability of refusals, values being similar at all time points. For monkeys of group II, these characteristics showed no degradation. Motor response times at stages C1, C2, and C3 were not different for the two groups of monkeys. The structural-functional organization of interactions between sensory and cognitive processes during learning and the storage of information in working memory are discussed, as is the role of the associative areas of the cortex in these interactions.

Alzheimer Disease↗
PubMed2004

VEGF links hippocampal activity with neurogenesis, learning and memory.

An enriched environment is associated with hippocampal plasticity, including improved cognitive performance and increased neurogenesis. Here, we show that hippocampal expression of vascular endothelial growth factor (VEGF) is increased by both an enriched environment and performance in a spatial maze. Hippocampal gene transfer of VEGF in adult rats resulted in approximately 2 times more neurogenesis associated with improved cognition. In contrast, overexpression of placental growth factor, which signals through Flt1 but not kinase insert domain protein receptors (KDRs), had negative effects on neurogenesis and inhibited learning, although it similarly increased endothelial cell proliferation. Expression of a dominant-negative mutant KDR inhibited basal neurogenesis and impaired learning. Coexpression of mutant KDR antagonized VEGF-enhanced neurogenesis and learning without inhibiting endothelial cell proliferation. Furthermore, inhibition of VEGF expression by RNA interference completely blocked the environmental induction of neurogenesis. These data support a model in which VEGF, acting through KDR, mediates the effect of the environment on neurogenesis and cognition.

Animals↗
PubMed2001

Learning and memory in S100-beta transgenic mice: an analysis of impaired and preserved function.

S100-beta, a calcium-binding astrocytic protein from chromosome 21, has been implicated in CNS function generally and the hippocampus in particular. Elevated levels of S100-beta have been observed reliably in the brains of patients with Alzheimer's Disease and Down Syndrome. Groups of transgenic mice, carrying multiple S100-beta gene copies, and nontransgenic controls were administered a series of behavioral tests (delayed spatial and nonspatial non-matching-to-sample, radial arm maze, socially acquired food preference) that assessed a wide range of cognitive functions. Consistent with the widespread presence of S100-beta throughout the brain, transgenic mice exhibited learning or memory impairment on all tasks. The dementia-like cognitive profile of S100-beta mice represents a promising model for studying comparable cognitive deficits associated with neurodegenerative diseases.

Animals↗
PubMed2000

Effects of environmental enrichment on behavioral responses to novelty, learning, and memory, and the circadian rhythm in cortisol in growing pigs.

Previously we showed that pigs reared in an enriched environment had higher baseline salivary cortisol concentrations during the light period than pigs reared under barren conditions. In the present experiment, it was investigated whether these higher baseline salivary cortisol concentrations were a real difference in cortisol concentration or merely represented a phase difference in circadian rhythm. The effects of different cortisol concentrations on the behavioral responses to novelty and learning and long-term memory in a maze test were also studied in enriched and barren housed pigs. At 9 weeks of age enriched and barren housed pigs did not differ in baseline salivary cortisol concentrations nor in circadian rhythm, but at 22 weeks of age barren housed pigs had a blunted circadian rhythm in salivary cortisol as compared to enriched housed pigs. The differences in baseline salivary cortisol concentrations between enriched- and barren-housed pigs are age-dependent, and become visible after 15 weeks of age. Enriched- and barren-housed piglets did not differ in time spent on exploration in the novel environment test. Barren-housed pigs had an impaired long-term memory in the maze test compared to enriched-housed pigs; however, no differences in learning abilities between enriched- and barren-housed pigs were found. Because blunted circadian cortisol rhythms are often recorded during states of chronic stress in pigs and rats or during depression in humans, it is suggested that the blunted circadian rhythm in cortisol in barren-housed pigs similarily may reflect decreased welfare.

Aging↗
PubMed1996

Learning and memory in the autoimmune BXSB mouse: effects of neocortical ectopias and environmental enrichment.

Approximately 40-60% of BXSB mice have ectopic cell clusters in layer 1 of neocortex. Prior studies have shown distinct behavioral differences between those with ectopias and their non-ectopic littermates. In this study, female BXSB mice were reared after weaning in either enriched environments or standard cages. Following an initial round of behavioral testing, all mice were housed in standard cages and retested. Enriched cage mice (both ectopic and non-ectopic) showed increased activity, greater speed, and enhanced learning scores across a variety of tests. Additionally, prior test experience itself had significant positive effects on Hebb-Williams maze learning. The presence of ectopias resulted in better Morris maze learning for standard cage reared mice. Further, ectopic mice, regardless of their housing condition, showed better long-term retention in the Morris maze than did their non-ectopic counterparts. These findings show that abnormalities in corticogenesis need not always result in functional deficit.

Analysis of Variance↗
PubMed1991

Effects of an extract of Ginkgo biloba on learning and memory in mice.

The effects of an extract of Ginkgo biloba (EGb 761) on acquisition, performance, and retention of mice in an appetitive operant conditioning were investigated. The animals were trained for 30 consecutive days to acquire a two-lever response sequence followed by food reward. EGb 761 was administered daily at a dose level of 100 mg/kg PO. Drug treatment started four and eight weeks before the training and was maintained until a retention test 10 weeks after it. The results indicated that EGb 761 facilitated memory processes. EGb 761 quickened the acquisition and improved the performance of the two-response sequence: The number of correct responses was increased and correct responses were performed more frequently in the most effective manner. Besides, incorrect responses were reduced sooner and faster and to a lower level in EGb 761-treated mice. With regard to the retention EGb 761 improved the retrieval of the learned response.

Animals↗
PubMed2004

Incidental learning and memory for three basic tastes in food.

Forty three subjects were invited under the pretence that they would take part in an experiment on hunger feelings. They came without having eaten anything that morning and received a standard breakfast containing orange juice, cream cheese on crackers and yoghurt. These products were later (when subjects returned after scoring hunger feelings during the day) used as targets amidst a set of distractors varied by adding or subtracting different amounts of two basic tastes. Orange juice was varied in sweetness and bitterness, cream cheese in sourness and bitterness and yoghurt in sweetness and sourness. The changes were made comparable by using just noticeable differences, determined in preliminary experiments with other subjects, as units of change. Two measurements of memory were compared, an absolute (indicating which were the targets) and a relative one (indicating whether the targets and distractors were more, less or equally pleasant, sweet, sour, bitter or salty as the item eaten at breakfast). Both methods showed incidental learning, but relative memory was superior. Memory differed between tastes and was partly product dependent. These experiments suggest that taste memory is tuned to detect novel and potentially dangerous stimuli rather than to remember features of earlier experienced stimuli with great precision.

Adult↗
PubMed2004

When development and learning decrease memory. Evidence against category-based induction in children.

Inductive inference is crucial for learning: If one learns that a cat has a particular biological property, one could expand this knowledge to other cats. We argue that young children perform induction on the basis of similarity of compared entities, whereas adults may induce on the basis of category information. If different processes underlie induction at different points in development, young children and adults would form different memory traces during induction, and would subsequently have different memory accuracy. Experiment 1 demonstrates that after performing an induction task, 5-year-olds exhibit more accurate memory than adults. Experiment 2 indicates that after 5-year-olds are trained to perform induction in an adultlike manner, their memory accuracy drops to the level of adults. These results, indicating that sometimes 5-year-olds exhibit better memory than adults, support the claim that, unlike adults, young children perform similarity-based rather than category-based induction.

Child Development↗
PubMed2001

Effect of batroxobin on expression of neural cell adhesion molecule in temporal infarction rats and spatial learning and memory disorder.

The effect of Batroxobin expression of neural cell adhesion molecule (NCAM) in left temporal ischemic rats with spatial memory disorder was investigated by means of Morri's water maze and immunohistochemical methods. The results showed that the mean reaction time and distance of temporal ischemic rats for searching a goal were significantly longer than those of sham-operated rats and at the same time NCAM expression of left temporal ischemic region was significantly increased. However, the mean reaction time and distance of Batroxobin-treated rats were shorter and they used normal strategies more often and earlier than those of ischemic rats. The number of NCAM immune reactive cells of Batroxobin-treated rats was more than that of ischemic group. In conclusion, Batroxobin can improve spatial memory disorder of temporal ischemic rats and the regulation of the expression of NCAM is probably related to the neuroprotective mechanism.

Animals↗