Associative learning performance is impaired in zebrafish (Danio rerio) by the NMDA-R antagonist MK-801

The zebrafish is gaining popularity in behavioral neuroscience perhaps because of a promise of efficient large scale mutagenesis and drug screens that could identify a substantial number of yet undiscovered molecular players involved in complex traits. Learning and memory are complex functions of the brain and the analysis of their mechanisms may benefit from such large scale zebrafish screens. One bottleneck in this research is the paucity of appropriate behavioral screening paradigms, which may be due to the relatively uncharacterized nature of the behavior of this species. Here we show that zebrafish exhibit good learning performance in a task adapted from the mammalian literature, a plus maze in which zebrafish are required to associate a neutral visual stimulus with the presence of conspecifics, the rewarding unconditioned stimulus. Furthermore, we show that MK-801, a non-competitive NMDA-R antagonist, impairs memory performance in this maze when administered right after training or just before recall but not when given before training at a dose that does not impair motor function, perception or motivation. These results suggest that the plus maze associative learning paradigm has face and construct validity and that zebrafish may become an appropriate and translationally relevant study species for the analysis of the mechanisms of vertebrate, including mammalian, learning and memory.     

Sleep deprivation selectively impairs memory consolidation for contextual fear conditioning

Many behavioral and electrophysiological studies in animals and humans have suggested that sleep and circadian rhythms influence memory consolidation. In rodents, hippocampus-dependent memory may be particularly sensitive to sleep deprivation after training, as spatial memory in the Morris water maze is impaired by rapid eye movement sleep deprivation following training. Spatial learning in the Morris water maze, however, requires multiple training trials and performance, as measured by time to reach the hidden platform is influenced by not only spatial learning but also procedural learning. To determine if sleep is important for the consolidation of a single-trial, hippocampus-dependent task, we sleep deprived animals for 0–5 and 5–10 h after training for contextual and cued fear conditioning. We found that sleep deprivation from 0–5 h after training for this task impaired memory consolidation for contextual fear conditioning whereas sleep deprivation from 5–10 h after training had no effect. Sleep deprivation at either time point had no effect on cued fear conditioning, a hippocampus-independent task. Previous studies have determined that memory consolidation for fear conditioning is impaired when protein kinase A and protein synthesis inhibitors are administered at the same time as when sleep deprivation is effective, suggesting that sleep deprivation may act by modifying these molecular mechanisms of memory storage.     

Behavioral and neuronal attributes of short- and long-term habituation in the crab Chasmagnathus

Investigations using invertebrate species have led to a considerable progress in our understanding of the mechanisms underlying learning and memory. In this review we describe the main behavioral and neuronal findings obtained by studying the habituation of the escape response to a visual danger stimulus in the crab Chasmagnathus granulatus. Massed training with brief intertrial intervals lead to a rapid reduction of the escape response that recovers after a short term. Conversely, few trials of spaced training renders a slower escape reduction that endures for many days. As predicted by Wagner’s associative theory of habituation, long-term habituation in the crab proved to be determined by an association between the contextual environment of the training and the unconditioned stimulus. By performing intracellular recordings in the brain of the intact animal at the same time it was learning, we identified a group of neurons that remarkably reflects the short- and long-term behavioral changes. Thus, the visual memory abilities of crabs, their relatively simple and accessible nervous system, and the recording stability that can be achieved with their neurons provide an opportunity for uncovering neurophysiological and molecular events that occur in identifiable neurons during learning.     

A systems approach to the cellular analysis of associative learning in the pond snail Lymnaea

We show that appetitive and aversive conditioning can be analyzed at the cellular level in the well-described neural circuitries underlying rhythmic feeding and respiration in the pond snail, Lymnaea stagnalis. To relate electrical changes directly to behavior, the snails were first trained and the neural changes recorded at multiple sites in reduced preparations made from the same animals. Changes in neural activity following conditioning could be recorded at the level of motoneurons, central pattern generator interneurons and modulatory neurons. Of significant interest was recent work showing that neural correlates of long-term memory could be recorded in the feeding network following single-trial appetitive chemical conditioning. Available information on the synaptic connectivity and transmitter content of identified neurons within the Lymnaea circuits will allow further work on the synaptic and molecular mechanisms of learning and memory.     

Spatial and non-spatial visual discrimination learning in zebrafish (Danio rerio)

Zebrafish (Danio rerio) provide an excellent model for assessment of molecular processes of neurodevelopment. To determine the functional importance of molecular events during neurodevelopment, we have developed methods for assessing learning in zebrafish in a three-chambered fish tank. In the first study, simple escape response was assessed. Zebrafish tested with a moving net learned to escape to another chamber more rapidly over the six sessions of training than the fish with the still net which did not learn. Upon reversal of the contingencies, the fish switched to the inactive net rapidly learned to suppress the escape response and fish formerly in the inactive net condition learned to avoid the moving net. In the second study, spatial discrimination learning was assessed. Zebrafish were trained on a right-left position discrimination to avoid the active net. Zebrafish showed significant improvement in escape responses over six sessions of training with three trials per session. In the third study, red-blue non-spatial discrimination learning was assessed. There was a significant improvement over the first six training sessions. With the reversal of contingencies, there was a significant decline of performance. With continued training, the fish again significantly improved avoidance. These studies found an effective motivational stimulus and procedure for studying escape behavior in zebrafish; a procedure whereby zebrafish would learn both spatial and non-spatial discrimination. These methods are being developed to help determine the functional importance of molecular events during zebrafish neurodevelopment. Accepted after revision: 20 August 2001 Electronic Publication     

Latent memory for sensitization in Aplysia

In the analysis of memory it is commonly observed that, even after a memory is apparently forgotten, its latent presence can still be revealed in a subsequent learning task. Although well established on a behavioral level, the mechanisms underlying latent memory are not well understood. To begin to explore these mechanisms, we have used Aplysia, a model system that permits the simultaneous study of memory at the behavioral, cellular, and molecular levels. We first demonstrate that robust latent memory is induced by long-term sensitization training of the tail-elicited siphon withdrawal reflex. It is revealed by its ability to facilitate the subsequent induction of three mechanistically distinct temporal domains of sensitization memory: short-term, intermediate-term, and long-term memory. Under our training conditions, the latent memory persists for at least 2 d following the decay of original memory expression but appears to be gone by 4 d. Interestingly, we also find that latent memory is induced even in the absence of overt memory for the original training. These findings now permit the analysis of the cellular and molecular architecture of a common feature of learning and memory.     

Measuring memory monitoring with judgements of retention (JORs)

Most prior research has examined predictions of future memory performance by eliciting judgements of learning (JOLs). In six experiments, we explored monitoring with an alternative prospective measure. Specifically, participants made judgements of retention (JORs) predicting how long (in min) they would be able to remember information. Results revealed that participants provided relatively short predictions of how long they would remember information. Further, participants' JORs were sensitive to recall performance as well as manipulations that influenced memory performance indicating that they were able to effectively monitor learning using JORs. JORs influenced study decisions as well, with participants selecting more items for restudy following JORs than following JOLs or no monitoring judgement. However, restudy selection did not vary between a JOR and a JOL condition framed in terms of forgetting. Thus, we suggest that, much like forget-framed JOLs, JORs may bring different information—such as memory failure—to mind. In all, the inferential mechanisms underlying metacognitive monitoring with JOLs extends to monitoring when measured with JORs. Assessing monitoring with JORs provides information not available with JOLs (i.e., memory duration estimates) and a different basis for study decisions from remember-framed JOLs.     

Active avoidance conditioning in zebrafish (Danio rerio)

The zebrafish represents a potentially useful organism for studying genes involved in learning and memory function in vertebrates, because a number of genetic techniques in zebrafish have been developed to produce a wide variety of genetic mutants. While zebrafish mutants are being developed, behavioral studies on learning and memory function in zebrafish are in urgent need. The present study investigated active avoidance conditioning in normal zebrafish. Zebrafish were trained to swim from a lighted (CS) compartment to a dark compartment to avoid an electrical body shock (US) in a shuttle-box that consisted of a water-filled tank separated by an opaque barrier into two equal compartments. By varying the number of trials per training session and the duration of the intertrial interval, Experiments 1 and 2 showed that, with the CS, US, and intertrial interval being 12s, zebrafish learned avoidance responses within a training session consisting of 30 trials and retained the avoidance responses. Experiment 3 showed that zebrafish learned avoidance responses following the association between the CS of light and the US of shock in the avoidance conditioning paradigm. Using the avoidance conditioning paradigm, Experiment 4 investigated the amnestic effects of N-methyl-D-aspartate receptor antagonist MK-801 and nitric oxide synthase inhibitor L-NAME in zebrafish. Experiment 4 showed that post-training injection of L-NAME significantly impaired retention of avoidance responses while MK-801 did not, confirming previous results with other vertebrates. The results of the present study suggest the similar involvements of neurochemicals in learning and memory among vertebrates. Thus, future studies with zebrafish mutants may identify genes involved in learning and memory in vertebrates.     

Reconsolidation of a context long-term memory in the terrestrial snail requires protein synthesis

We investigated the influence of the protein synthesis blocker anisomycin on contextual memory in the terrestrial snail Helix. Prior to the training session, the behavioral responses in two contexts were similar. Two days after a session of electric shocks (5 d) in one context only, the context conditioning was observed as the significant difference of behavioral response amplitudes in two contexts. On the day following testing of context learning, a session of "reminding" was performed, immediately after which the snails were injected with anisomycin or vehicle. Testing of long-term context memory has shown that only anisomycin injections impaired the context conditioning. In control series, the snails were injected after the training session with anisomycin/saline without reminding, and no impairment of the long-term context memory was observed, while injection of anisomycin during the training session completely abolished the long-term memory. No effects of anisomycin on the short-term memory were observed. Surprisingly, injection of anisomycin after the reminding combined with reinforcing stimuli elicited no effect on the context memory. Differences between single-trial and multisession learning are discussed.     

Adaptive training leads to sustained enhancement of poor working memory in children

Working memory plays a crucial role in supporting learning, with poor progress in reading and mathematics characterizing children with low memory skills. This study investigated whether these problems can be overcome by a training program designed to boost working memory. Children with low working memory skills were assessed on measures of working memory, IQ and academic attainment before and after training on either adaptive or non‐adaptive versions of the program. Adaptive training that taxed working memory to its limits was associated with substantial and sustained gains in working memory, with age‐appropriate levels achieved by the majority of children. Mathematical ability also improved significantly 6 months following adaptive training. These findings indicate that common impairments in working memory and associated learning difficulties may be overcome with this behavioral treatment.     

Testing the Idea of Distinct Storage Mechanisms in Memory

This paper sets out quantitative foundations for testing the idea that memory is served by two distinct storage mechanisms, a short-term and a separate long-term store, using data from the single-trial free-recall experiment by Murdock and Okada (1970). In single-trial free recall one can observe which word is recalled next and how long that recall takes, but that is all. So justification for two separate stores must turn either on the probabilities of recall, or on the latencies, for particular serial positions in the stimulus list. (a) Nearly one-third of all recalls after the first are successors (Word n+1 immediately following recall of Word n). So recall is dominated, not by absolute serial position (as a short-term store would require), but by position relative to the preceding recall. (b) To a first approximation, all first recalls have the same latency distribution except for Word 1. A common latency distribution is compatible with a single store. An explanation is offered why Word 1 should take longer, in which Word 1 is the second retrieval from a common store. The idea of two separate stores appears to lack experimental support.     

Behavioral and genetic characterization of habituation using Caenorhabditis elegans

This review surveys the literature that investigates the behavioral characterization and cellular and molecular mechanisms of habituation using the model organism Caenorhabditis elegans. In 1990, C. elegans was first observed to show habituation to a non-localized mechanical tap. The parameters that govern this behavioral plasticity in C. elegans were subsequently characterized, which lead to the important hypothesis that habituation is mediated by multiple mechanisms. Many tools are available to C. elegans researchers that allow for relatively easy genetic manipulation. This has lead to a number of recent genetic studies that have begun to identify key genes and molecules that play a role in the mechanisms of habituation. Some of these genes include a vesicular glutamate transporter, a glutamate receptor subunit, a dopamine receptor and downstream intracellular signaling molecules, such as G proteins and kinases. Some of these genes only affect certain parameters of habituation, but not others supporting the hypothesis that multiple mechanisms mediate habituation. The field of research has also led to the dissection of different phases of memory (short-term vs. long-term memory for habituation), which are triggered by different training paradigms. The differences in mechanism between these various forms of memory are also beginning to be revealed.     

Memory rehabilitation for older adults: preserving independent living / Rehabilitación de la memoria para adultos mayores: preservación de la autonomía de vida

Abstract

Episodic memory problems are the hallmark of cognitive ageing in normal elderly people. Learning of new material is worse in pathological cognitive ageing, such as dementia and its preliminary states (mild cognitive impairment). Because episodic learning is crucial to preserve independent living in the elderly, rehabilitation programmes for everyday memory problems are welcomed. The scope of scientific interest has switched from treatment to prevention. We claim that lifestyle interventions are the most direct way to preserve cognition. We summarize evidence for changes in nutrition and exercise. In addition, psychological interventions for elderly people with normal or pathological cognitive ageing are available. Recent meta-analyses found lacking evidence of transfer to everyday life and long-term effects. We critically assess these meta-analyses. We propose theoretically derived experimental interventions relying on spared learning mechanisms. As an example we report visual-imagery training showing positive effects in a randomized control trial, using individual memory diaries on memory improvement.     

Applying cognitive training to target executive functions during early development

Developmental psychopathology is increasingly recognizing the importance of distinguishing causal processes (i.e., the mechanisms that cause a disease) from developmental outcomes (i.e., the symptoms of the disorder as it is eventually diagnosed). Targeting causal processes early in disordered development may be more effective than waiting until outcomes are established and then trying to reverse the pathogenic process. In this review, I evaluate evidence suggesting that neural and behavioral plasticity may be greatest at very early stages of development. I also describe correlational evidence suggesting that, across a number of conditions, early emerging individual differences in attentional control and working memory may play a role in mediating later-developing differences in academic and other forms of learning. I review the currently small number of studies that applied direct and indirect cognitive training targeted at young individuals and discuss methodological challenges associated with targeting this age group. I also discuss a number of ways in which early, targeted cognitive training may be used to help us understand the developmental mechanisms subserving typical and atypical cognitive development.     

Operant conditioning in Lymnaea: evidence for intermediate- and long-term memory

Aerial respiration of the pond snail, Lymnaea stagnalis, can be operantly conditioned; however, the parameters necessary to produce long-term (LTM) or intermediate term memory (ITM) have not previously been investigated. We conducted training using procedures that varied in the duration of the training session, the number of training sessions per day or the amount of time between subsequent training sessions (SI). We found that by varying the duration and frequency of the training session learning could be differentially produced. Furthermore, the ability to form LTM was dependent not only on the duration of the training session was also the interval between training sessions, the SI. Thus it was possible to produce ITM, which persists for up to 3 hr, and not form LTM, which persists at least 18 hr. Learning, ITM, and LTM can be differentially produced by altering the SI, the duration of the training session, or the number of training sessions per day. These findings may allow us to begin to elucidate the underlying neural mechanisms of learning, ITM, and LTM.     

Training and transfer effects of executive functions in preschool children

Executive functions, including working memory and inhibition, are of central importance to much of human behavior. Interventions intended to improve executive functions might therefore serve an important purpose. Previous studies show that working memory can be improved by training, but it is unknown if this also holds for inhibition, and whether it is possible to train executive functions in preschoolers. In the present study, preschool children received computerized training of either visuo‐spatial working memory or inhibition for 5 weeks. An active control group played commercially available computer games, and a passive control group took part in only pre‐ and posttesting. Children trained on working memory improved significantly on trained tasks; they showed training effects on non‐trained tests of spatial and verbal working memory, as well as transfer effects to attention. Children trained on inhibition showed a significant improvement over time on two out of three trained task paradigms, but no significant improvements relative to the control groups on tasks measuring working memory or attention. In neither of the two interventions were there effects on non‐trained inhibitory tasks. The results suggest that working memory training can have significant effects also among preschool children. The finding that inhibition could not be improved by either one of the two training programs might be due to the particular training program used in the present study or possibly indicate that executive functions differ in how easily they can be improved by training, which in turn might relate to differences in their underlying psychological and neural processes.     

Flexible cue use in food-caching birds

An animal’s memory may be limited in capacity, which may result in competition among available memory cues. If such competition exists, natural selection may favor prioritization of different memory cues based on cue reliability and on associated differences in the environment and life history. Food-caching birds store numerous food items and appear to rely on memory to retrieve caches. Previous studies suggested that caching species should always prioritize spatial cues over non-spatial cues when both are available, because non-spatial cues may be unreliable in a changing environment; however, it remains unclear whether non-spatial cues should always be ignored when spatial cues are available. We tested whether mountain chickadees (Poecile gambeli), a food-caching species, prioritize memory for spatial cues over color cues when relocating previously found food in an associative learning task. In training trials, birds were exposed to food in a feeder where both spatial location and color were associated. During subsequent unrewarded test trials, color was dissociated from spatial location. Chickadees showed a significant pattern of inspecting feeders associated with correct color first, prior to visiting correct spatial locations. Our findings argue against the hypothesis that the memory of spatial cues should always take priority over any non-spatial cues, including color cues, in food-caching species, because in our experiment mountain chickadees chose color over spatial cues. Our results thus suggest that caching species may be more flexible in cue use than previously thought, possibly dependent upon the environment and complexity of available cues.     

Prospective memory training in older adults and its relevance for successful aging

In research on cognitive plasticity, two training approaches have been established: (1) training of strategies to improve performance in a given task (e.g., encoding strategies to improve episodic memory performance) and (2) training of basic cognitive processes (e.g., working memory, inhibition) that underlie a range of more complex cognitive tasks (e.g., planning) to improve both the training target and the complex transfer tasks. Strategy training aims to compensate or circumvent limitations in underlying processes, while process training attempts to augment or to restore these processes. Although research on both approaches has produced some promising findings, results are still heterogeneous and the impact of most training regimes for everyday life is unknown. We, therefore, discuss recent proposals of training regimes aiming to improve prospective memory (i.e., forming and realizing delayed intentions) as this type of complex cognition is highly relevant for independent living. Furthermore, prospective memory is associated with working memory and executive functions and age-related decline is widely reported. We review initial evidence suggesting that both training regimes (i.e., strategy and/or process training) can successfully be applied to improve prospective memory. Conceptual and methodological implications of the findings for research on age-related prospective memory and for training research in general are discussed.     

Learning-induced axonal remodeling: evolutionary divergence and conservation of two components of the mossy fiber system within Rodentia

Damage to the hippocampal formation results in profound impairments in spatial navigation in rats and mice leading to the widely accepted assumption that the hippocampal cellular and molecular memory mechanisms of both genera are conserved. Recently our group has shown in two rat strains that hippocampal-dependent training in the water maze specifically induces robust 'sprouting' of granule cell suprapyramidal mossy fiber axon terminal fields. Here we sought to investigate whether the pronounced remodeling of adult hippocampal circuitry observed in the rat is also present in the mouse motivated by the thought that subsequent studies using genetically-engineered mice could then be implemented to explore the molecular mechanisms underlying training-dependent axonal growth in adult rodents. However, in contrast to Wistar rats, no changes in the Timm's-stained area of mossy fiber terminal fields (MFTFs) were observed in C57BL/6J or 129Sv/EmsJ inbred wild-type mice after water maze training. Neither extending the duration of training nor scaling down the size of the apparatus was able to induce sprouting in mouse mossy fiber pathways. Though there may be similarities in the ultimate output of the hippocampus of rats and mice as inferred from lesion studies, the current results, as well as differences in learning and memory characteristics between the two genera, suggest that the way in which the component circuitry functions is likely to be different; a not too surprising conclusion given the substantial evolutionary distance between them (>20 million years). The present findings afford an opportunity for uncovering linkages between evolutionarily significant alterations in hippocampal circuitry in relation to genera-specific information storage requirements.