Dynamics of a memory trace: effects of sleep on consolidation

BACKGROUND: There is evidence that sleep is important for memory consolidation, but the underlying neuronal changes are not well understood. We studied the effect of sleep modulation on memory and on neuronal activity in a memory system of the domestic chick brain after the learning process of imprinting. Neurons in this system become, through imprinting, selectively responsive to a training (imprinting) stimulus and so possess the properties of a memory trace. RESULTS: The proportion of neurons responsive to the training stimulus reaches a maximum the day after training. We demonstrate that sleep is necessary for this maximum to be achieved, that sleep stabilizes the initially unstable, selective responses of neurons to the imprinting stimulus, and that for sleep to be effective, it must occur during a particular period of time after training. During this period, there is a time-dependent increase in EEG activity in the 5-6 Hz band, that is, in the lower range of the theta bandwidth. The effects of sleep disturbance on consolidation cannot be attributed to fatigue or to stress. CONCLUSIONS: We establish that long-term trace consolidation requires sleep within a restricted period shortly after learning. Undisturbed sleep is necessary for the stabilization of long-term memory, measured at the behavioral and neuronal levels, and of long-term but not short-term neuronal responsiveness to the training stimulus.     

Does conditioned taste aversion learning in the pond snail Lymnaea stagnalis produce conditioned fear?

In conditioned taste aversion (CTA) training performed on the pond snail Lymnaea stagnalis, a stimulus (the conditional stimulus, CS; e.g., sucrose) that elicits a feeding response is paired with an aversive stimulus (the unconditional stimulus, US) that elicits the whole-body withdrawal response and inhibits feeding. After CTA training and memory formation, the CS no longer elicits feeding. We hypothesize that one reason for this result is that after CTA training the CS now elicits a fear response. Consistent with this hypothesis, we predict the CS will cause (1) the heart to skip a beat and (2) a significant change in the heart rate. Such changes are seen in mammalian preparations exposed to fearful stimuli. We found that in snails exhibiting long-term memory for one-trial CTA (i.e., good learners) the CS significantly increased the probability of a skipped heartbeat, but did not significantly change the heart rate. The probability of a skipped heartbeat was unaltered in control snails given backward conditioning (US followed by CS) or in snails that did not acquire associative learning (i.e., poor learners) after the one-trial CTA training. These results suggest that as a consequence of acquiring CTA, the CS evokes conditioned fear in the conditioned snails, as evidenced by a change in the nervous system control of cardiac activity.     

Critical Period of Memory Enhancement during Taste Avoidance Conditioning in Lymnaea stagnalis

The present study investigated the optimal training procedure leading to long-lasting taste avoidance behavior in Lymnaea. A training procedure comprising 5 repeated pairings of a conditional stimulus (CS, sucrose), with an unconditional stimulus (US, a tactile stimulation to the animal’s head), over a 4-day period resulted in an enhanced memory formation than 10 CS-US repeated pairings over a 2-day period or 20 CS-US repeated pairings on a single day. Backward conditioning (US-CS) pairings did not result in conditioning. Thus, this taste avoidance conditioning was CS-US pairing specific. Food avoidance behavior was not observed following training, however, if snails were immediately subjected to a cold-block (4°C for 10 min). It was critical that the cold-block be applied within 10 min to block long-term memory (LTM) formation. Further, exposure to the cold-block 180 min after training also blocked both STM and LTM formation. The effects of the cold-block on subsequent learning and memory formation were also examined. We found no long lasting effects of the cold-block on subsequent memory formation. If protein kinase C was activated before the conditioning paradigm, snails could still acquire STM despite exposure to the cold-block.     

Genotype-dependent mice behavior in cognitive tasks. Effect of noopept

The interstrain differences in performance of C57BL/6J, BALB/c and DBA/2J male mice in two cognitive tasks were found. Mice C57BL/6J showed good learning ability and preservation of memory traces tested 10 days after performance in a simplified version of Morris water maze. Mice BALB/c learned the task but, virtually, no long-term memory traces were revealed, whereas DBA/2J demonstrated poor learning. The effect of nootropic drug Noopept (GVS-111, N-phenil-acetyl-L-prolylglycin ethyl ether) was shown to be genotype-dependent. Its administration (0.5 mg/kg i.p., 15 min before learning) improved the long-term memory in Morris test in BALB/c mice but failed to produce any improvement in C57BL/6J. The ability of mice for extrapolation of the direction of stimulus movement differently changed after Noopept injections: the proportion of correct task solutions increased in C57BL/6J and BALB/c mice, whereas the performance of DBA/2J did not change.     

Involvement of L1.1 in memory consolidation after active avoidance conditioning in zebrafish

To investigate the involvement of the cell adhesion molecules L1.1, L1.2, NCAM, and tenascin-C in memory formation, zebrafish (Brachydanio rerio) were trained in an active avoidance paradigm to cross a hurdle to avoid mild electric shocks after a light signal. Application of [(14)C]deoxyglucose prior to the training session revealed an increased energy demand in the optic tectum during acquisition of the active avoidance response compared with untrained fish and with fish not learning the task (nonlearners). In situ hybridization with digoxigenin-labeled cRNA probes directed against zebrafish L1.1, L1.2, NCAM, and tenascin-C revealed an enhanced expression of L1.1 and NCAM mRNA in the optic tectum of learners 3 h after acquisition of the task compared with untrained fish, nonlearners, overtrained fish, and learners decapitated 1 or 6 h after acquisition. Levels of L1.2 mRNA were not significantly increased in the tectum 3 h after learning. Tenascin-C was neither expressed in the optic tectum of untrained fish nor in the tectum of learners. To test for a possible involvement of L1.1 in memory consolidation, antibodies were injected intracerebroventricularly 1 h after the last training trial. Two days later, injected zebrafish were tested for recall and evaluated by a retention score (RS), ranging from 1.0 for immediate recall to 0.0 indicating no savings. The average retention score of L1.1 antibody-injected fish (RS = 0. 29) was different from that of tenascin-C antibody-injected (RS = 0. 71) or uninjected fish (RS = 0.78), indicating a pivotal function of L1.1 in long-term memory formation in zebrafish.     

Trace Fear Conditioning in Mice

In this experiment we present a technique to measure learning and memory. In the trace fear conditioning protocol presented here there are five pairings between a neutral stimulus and an unconditioned stimulus. There is a 20 sec trace period that separates each conditioning trial. On the following day freezing is measured during presentation of the conditioned stimulus (CS) and trace period. On the third day there is an 8 min test to measure contextual memory. The representative results are from mice that were presented with the aversive unconditioned stimulus (shock) compared to mice that received the tone presentations without the unconditioned stimulus. Trace fear conditioning has been successfully used to detect subtle learning and memory deficits and enhancements in mice that are not found with other fear conditioning methods. This type of fear conditioning is believed to be dependent upon connections between the medial prefrontal cortex and the hippocampus. One current controversy is whether this method is believed to be amygdala-independent. Therefore, other fear conditioning testing is needed to examine amygdala-dependent learning and memory effects, such as through the delay fear conditioning.     

Stable and unstable phase of memory in classically conditioned fly, Phormia regina: Effects of nitrogen gas anaesthesia and cycloheximide injection

This study examined the effects of nitrogen anaesthesia and cycloheximide injection on memory of the classically-conditioned fly, Phormia. 1 M NaCl solution was given to each fly as a conditioning stimulus and 0.5 M sucrose solution was the unconditioned stimulus that induced the proboscis extension response. The training period was as short as 2 min and testing was usually carried out 2 hr later. At varying times (0–60 min) between training and testing, flies were anaesthetized with nitrogen gas for 25 sec. When flies were anaesthetized immediately after training the effect of nitrogen gas was the greatest and few flies showed any conditioned response, but the sensitivity of memory to nitrogen gas declined as the interval between training and nitrogen treatment became longer, and such treatment had no effect on memory when the interval was longer than 30 min. The effect on memory of cycloheximide, an inhibitor of peptide bond synthesis, was also investigated. The injection of cycloheximide (0.37 μg) immediately after training diminished the memory, but when given 1 hr after training it had no effect on memory. These results show that the memory in Phormia has two phases, stable and an unstable phase, like long-term and short-term memory in vertebrates.     

Learning to Attend to Threat Accelerates and Enhances Memory Consolidation

Practice on a procedural task involves within-session learning and between-session consolidation of learning, with the latter requiring a minimum of about four hours to evolve due to involvement of slower cellular processes. Learning to attend to threats is vital for survival and thus may involve faster memory consolidation than simple procedural learning. Here, we tested whether attention to threat modulates the time-course and magnitude of learning and memory consolidation effects associated with skill practice. All participants (N = 90) practiced in two sessions on a dot-probe task featuring pairs of neutral and angry faces followed by target probes which were to be discriminated as rapidly as possible. In the attend-threat training condition, targets always appeared at the angry face location, forming an association between threat and target location; target location was unrelated to valence in a control training condition. Within each attention training condition, duration of the between-session rest interval was varied to establish the time-course for emergence of consolidation effects. During the first practice session, we observed robust improvement in task performance (online, within-session gains), followed by saturation of learning. Both training conditions exhibited similar overall learning capacities, but performance in the attend-threat condition was characterized by a faster learning rate relative to control. Consistent with the memory consolidation hypothesis, between-session performance gains (delayed gains) were observed only following a rest interval. However, rest intervals of 1 and 24 hours yielded similar delayed gains, suggesting accelerated consolidation processes. Moreover, attend-threat training resulted in greater delayed gains compared to the control condition. Auxiliary analyses revealed that enhanced performance was retained over several months, and that training to attend to neutral faces resulted in effects similar to control. These results provide a novel demonstration of how attention to threat can accelerate and enhance memory consolidation effects associated with skill acquisition.     

Rapid and Transient Learning-Associated Increase in NMDA NR1 Subunit in the Rat Hippocampus

Several lines of evidence indicate that glutamate NMDA receptors are critically involved in long-term potentiation (LTP) and in certain forms of learning. It was previously demonstrated that memory formation of an inhibitory avoidance task in chick is specifically associated with an increase in the density of NMDA receptor in selected brain regions. Here we report on the effect of a one trial inhibitory avoidance training in rats, a hippocampal-dependent learning task, on the levels of different subunits of the glutamate NMDA receptor in synaptic plasma membranes (SPM) isolated from the hippocampus. Training rats on a one trial inhibitory avoidance task results in a rapid, transient and selective increase (+33 %, p < 0.05) in NMDA NR1 subunit expression in hippocampal SPM of rats sacrificed 30 min posttraining. No changes were observed at 0 or 120 min after training or in shocked animals in comparison to naive control rats. In addition, no training-associated increase in the levels of NMDA NR2A and NR2B or AMPA GluR 2/3 subunits was observed at any timepoint tested. In conclusion, the present findings support the hypothesis that alterations in expression of synaptic NMDA NR1 subunits in the hippocampus are specifically associated with memory formation of an inhibitory avoidance task and strongly suggest that hippocampal NMDA receptors are crucially involved in the neural mechanisms underlying certain forms of learning.These authors contributed equally to this work     

Effects of Acute Methamphetamine on Emotional Memory Formation in Humans: Encoding vs Consolidation

Understanding how stimulant drugs affect memory is important for understanding their addictive potential. Here we examined the effects of acute d-methamphetamine (METH), administered either before (encoding phase) or immediately after (consolidation phase) study on memory for emotional and neutral images in healthy humans. Young adult volunteers (N = 60) were randomly assigned to either an encoding group (N = 29) or a consolidation group (N = 31). Across three experimental sessions, they received placebo and two doses of METH (10, 20 mg) either 45 min before (encoding) or immediately after (consolidation) viewing pictures of emotionally positive, neutral, and negative scenes. Memory for the pictures was tested two days later, under drug-free conditions. Half of the sample reported sleep disturbances following the high dose of METH, which affected their memory performance. Therefore, participants were classified as poor sleepers (less than 6 hours; n = 29) or adequate sleepers (6 or more hours; n = 31) prior to analyses. For adequate sleepers, METH (20 mg) administered before encoding significantly improved memory accuracy relative to placebo, especially for emotional (positive and negative), compared to neutral, stimuli. For poor sleepers in the encoding group, METH impaired memory. METH did not affect memory in the consolidation group regardless of sleep quality. These results extend previous findings showing that METH can enhance memory for salient emotional stimuli but only if it is present at the time of study, where it can affect both encoding and consolidation. METH does not appear to facilitate consolidation if administered after encoding. The study also demonstrates the important role of sleep in memory studies.     

Boosting Long-Term Memory via Wakeful Rest: Intentional Rehearsal Is Not Necessary,Consolidation Is Sufficient

People perform better on tests of delayed free recall if learning is followed immediately by a short wakeful rest than by a short period of sensory stimulation. Animal and human work suggests that wakeful resting provides optimal conditions for the consolidation of recently acquired memories. However, an alternative account cannot be ruled out, namely that wakeful resting provides optimal conditions for intentional rehearsal of recently acquired memories, thus driving superior memory. Here we utilised non-recallable words to examine whether wakeful rest boosts long-term memory, even when new memories could not be rehearsed intentionally during the wakeful rest delay. The probing of non-recallable words requires a recognition paradigm. Therefore, we first established, via Experiment 1, that the rest-induced boost in memory observed via free recall can be replicated in a recognition paradigm, using concrete nouns. In Experiment 2, participants heard 30 non-recallable non-words, presented as ‘foreign names in a bridge club abroad’ and then either rested wakefully or played a visual spot-the-difference game for 10 minutes. Retention was probed via recognition at two time points, 15 minutes and 7 days after presentation. As in Experiment 1, wakeful rest boosted recognition significantly, and this boost was maintained for at least 7 days. Our results indicate that the enhancement of memory via wakeful rest is not dependent upon intentional rehearsal of learned material during the rest period. We thus conclude that consolidation is sufficient for this rest-induced memory boost to emerge. We propose that wakeful resting allows for superior memory consolidation, resulting in stronger and/or more veridical representations of experienced events which can be detected via tests of free recall and recognition.     

Age-related deficits of long-term memory in the crab Chasmagnathus

Short and long-term memory in adult crabs Chasmagnathus granulatus of different age are evaluated in two learning paradigms: habituation to a visual danger stimulus and appetitive conditioning. No difference between young, middle-aged and aged animals is found in short-term habituation with 15 training trials. A good level of retention of the habituated response at 24 h is exhibited by young and middle-aged crabs but a poor one by aged crabs. When the training-to-testing interval is lengthened to 48 h or the training session reduced to 7 trials, young and middle-aged crabs continue to show long-term habituation but aged individuals exhibit no retention at all. As regards appetitive conditioning, young, middle-aged and aged crabs present similar short-term memory with 5 training trials and similar long-term memory when tested at 24 h, but an age-related deficit in long-term retention is exhibited when the intersession interval is lengthened to 48 h or the training reduced to 3 trials. Thus, a reduction of long-term memory related to age is demonstrated in the crab Chasmagnathus. Since it is shown in two different learning paradigms, the possibility of explaining the deficit in terms of a failure in memory mechanisms due to aging rather than as a consequence of ontogenetic shift in the crab's behavior is discussed.     

Memory of a choice direction in a T maze as measured by spontaneous alternation in mice: Effects of intertrial interval and reward

Spontaneous alternation in a T maze was studied as a one trial learning paradigm in mice of the BALB/c strain. In the first experiment the combined effects of time interval between the first and second trial (intertrial interval: ITI), food deprivation and feeding given during the first trial, were shown to affect performance. Thus, on the one hand, the percentage of spontaneous alternation decreased as ITI increased; on the other hand, food reward dramatically improved spontaneous alternation for the 24-h ITI, but had no significant effect for 30-sec and 1-h ITI. Since the effect of feeding might be due either to an increase of arousal, thus favoring input of informations associated with the first choice, or to an improvement in memory consolidation, a second experiment was aimed at testing the effect of food given after the first trial. It was shown that, as in the first experiment, post-trial feeding improved spontaneous alternation on the second trial given 24 hours later with a temporal gradient of effect less than 30 min. These results clearly showed that the reinforcement of run to one side (first trial) increased the tendency to go to the other side 24 hours later. It is concluded that reinforcement might have two distinct effects: (i) according to SR theory, reinforcement increases conditioned responses and (ii), as shown here, acts on memory processes by preventing memory traces from fading. The fact that this last effect was only observed for long ITI suggests that short-term or transient memory and long-term memory are two relatively independent processes.     

Effects of Lanthanum Chloride Administration in Prenatal Stage on One-Trial Passive Avoidance Learning in Chicks

Lanthanum cations (La 3+) are well known for their inhibitory actions on calcium channels. Prenatal lanthanum exposure may affect the development of embryo and alter the capacity for learning and memory in adults, and the one-trial passive avoidance learning paradigm with day-old chicks is an excellent model to study several mechanisms of memory formation. In the present study, we examined the effects of prenatal lanthanum chloride exposure on memory consolidation using one-trial passive avoidance learning task in day-old chicks. The data suggest that chicks injected with lanthanum chloride (2 mg/kg) daily from E9 to E16 had significantly impaired long-term memory at 120 min after training (p < 0.05) but not the chicks injected with lanthanum chloride (0.1 mg/kg) daily from E9 to E16.     

Consolidation of an Olfactory Memory Trace in the Olfactory Bulb Is Required for Learning-Induced Survival of Adult-Born Neurons and Long-Term Memory

Background

It has recently been proposed that adult-born neurons in the olfactory bulb, whose survival is modulated by learning, support long-term olfactory memory. However, the mechanism used to select which adult-born neurons following learning will participate in the long-term retention of olfactory information is unknown. We addressed this question by investigating the effect of bulbar consolidation of olfactory learning on memory and neurogenesis.

Methodology/Principal Findings

Initially, we used a behavioral ecological approach using adult mice to assess the impact of consolidation on neurogenesis. Using learning paradigms in which consolidation time was varied, we showed that a spaced (across days), but not a massed (within day), learning paradigm increased survival of adult-born neurons and allowed long-term retention of the task. Subsequently, we used a pharmacological approach to block consolidation in the olfactory bulb, consisting in intrabulbar infusion of the protein synthesis inhibitor anisomycin, and found impaired learning and no increase in neurogenesis, while basic olfactory processing and the basal rate of adult-born neuron survival remained unaffected. Taken together these data indicate that survival of adult-born neurons during learning depends on consolidation processes taking place in the olfactory bulb.

Conclusion/Significance

We can thus propose a model in which consolidation processes in the olfactory bulb determine both survival of adult-born neurons and long-term olfactory memory. The finding that adult-born neuron survival during olfactory learning is governed by consolidation in the olfactory bulb strongly argues in favor of a role for bulbar adult-born neurons in supporting olfactory memory.     

Is it possible to replace stimulus animals by scent-filled cups in the social discrimination test?

A study in which the rat social discrimination test was refined is described. This test measures social memory by using, in general, juvenile rats as stimulus animals. Rats are offered a first juvenile to investigate (learning trial), and after a specified interval, the rats are offered the same rat and a second juvenile rat to investigate again (retrieval trial). When the rats sniff the second juvenile in the retrieval trial more than the first, social memory for the second juvenile is said to be present. This test is mainly based on scents from the juvenile. Attempts were made to refine the test to reduce the number of animals used, to enhance the scope of the test, and to improve its validity. Firstly, the stimulus animals were replaced by the scent of juveniles, in the form of cups filled with sawdust taken from cages of juvenile rats. Similar results to those in the original test were obtained when using these scents. Furthermore, male and female scents were tested, and showed the same results as for the juvenile scents. Secondly, rats were also given two cups (one scent-filled and one filled with plain sawdust) in the learning trial, to determine which allowed a more-precise delineation of motivational, discriminatory and memory components. Overall, it is possible to replace stimulus animals by scent-filled cups in the social discrimination test, to enhance the scope of the test, and to draw more-valid conclusions with respect to social memory.     

学习记忆对脑内c-fos基因表达的影响

学习记忆是人和动物重要的脑功能，大量事实表明，学习记忆过程与脑内ｃ－ｆｏｓ基因的表达密切相关。由学习记忆所诱导的ｃ－ｆｏｓ基因表达在脑内广泛分布，以皮层、海马和边缘系统为多，依学习记忆训练模型的不同，其表达时程有所差异，但一般于训练后立即或３０分钟左右出现，１～２小时左右达峰值。被动和主动回避训练、光辨别训练及味觉厌恶性条件反射训练等多种学习记忆模型均可诱导脑内ｃ－ｆｏｓ基因的表达。其他影响学习记     

The Consolidation of Implicit Sequence Memory in Obstructive Sleep Apnea

Obstructive Sleep Apnea (OSA) Syndrome is a relatively frequent sleep disorder characterized by disrupted sleep patterns. It is a well-established fact that sleep has beneficial effect on memory consolidation by enhancing neural plasticity. Implicit sequence learning is a prominent component of skill learning. However, the formation and consolidation of this fundamental learning mechanism remains poorly understood in OSA. In the present study we examined the consolidation of different aspects of implicit sequence learning in patients with OSA. We used the Alternating Serial Reaction Time task to measure general skill learning and sequence-specific learning. There were two sessions: a learning phase and a testing phase, separated by a 10-hour offline period with sleep. Our data showed differences in offline changes of general skill learning between the OSA and control group. The control group demonstrated offline improvement from evening to morning, while the OSA group did not. In contrast, we did not observe differences between the groups in offline changes in sequence-specific learning. Our findings suggest that disrupted sleep in OSA differently affects neural circuits involved in the consolidation of sequence learning.     

Repeated post trial administration of vasopressin impairs subsequent Differential Reinforcement of Low rates (DRL) performance

Twenty-six male rats, maintained on a 23-h food deprivation regime, were trained on a DRL learning schedule. During pretraining (CRF) rats were placed in two groups according to speed in obtaining the criterion (good and poor learners). The performance of good and poor learners, injected with lysine vasopressin (LVP) immediately after each training session, was compared with that of control good and poor learners injected with saline. During the first DRL 20 stage, injected rats had fewer reinforcements than control rats. Fifty-five days later, during reacquisition of DRL 20, LVP rats again had fewer reinforcements, especially those which were formerly good learners in the CRF stage. Nonetheless, treated rats were able to shift their rate of responding from high to low frequency. A reduction of the minimal interresponse time to 16 s showed that LVP rats were able to adapt to this condition and that, in a further DRL 20 stage, the difference between the two groups was no longer significant.The results are discussed in terms of a modification of the behavioral expression of a learned response, without a specific action on memory processes.     

Classical reward conditioning in Drosophila melanogaster

Negatively reinforced olfactory conditioning has been widely employed to identify learning and memory genes, signal transduction pathways and neural circuitry in Drosophila. To delineate the molecular and cellular processes underlying reward-mediated learning and memory, we developed a novel assay system for positively reinforced olfactory conditioning. In this assay, flies were involuntarily exposed to the appetitive unconditioned stimulus sucrose along with a conditioned stimulus odour during training and their preference for the odour previously associated with sucrose was measured to assess learning and memory capacities. After one training session, wild-type Canton S flies displayed reliable performance, which was enhanced after two training cycles with 1-min or 15-min inter-training intervals. Higher performance scores were also obtained with increasing sucrose concentration. Memory in Canton S flies decayed slowly when measured at 30 min, 1 h and 3 h after training; whereas, it had declined significantly at 6 h and 12 h post-training. When learning mutant t beta h flies, which are deficient in octopamine, were challenged, they exhibited poor performance, validating the utility of this assay. As the Drosophila model offers vast genetic and transgenic resources, the new appetitive conditioning described here provides a useful tool with which to elucidate the molecular and cellular underpinnings of reward learning and memory. Similar to negatively reinforced conditioning, this reward conditioning represents classical olfactory conditioning. Thus, comparative analyses of learning and memory mutants in two assays may help identify the molecular and cellular components that are specific to the unconditioned stimulus information used in conditioning.