Stages Of Memory Consolidation Research Articles

Behavioural interference at event boundaries reduces long-term memory performance in the virtual water maze task without affecting working memory performance

Narrative episodic memory of movie clips can be retroactively impaired by presenting unrelated stimuli coinciding with event boundaries. This effect has been linked with rapid hippocampal processes triggered by the offset of the event, that are alternatively related either to memory consolidation or with working memory processes. Here we tested whether this effect extended to spatial memory, the temporal specificity and extent of the interference, and its effect on working- vs long-term memory. In three computerized adaptations of the Morris Water Maze, participants learned the location of an invisible target over three trials each. A second spatial navigation task was presented either immediately after finding the target, after a 10-s delay, or no second task was presented (control condition). A recall session, in which participants indicated the learned target location with 10 ‘pin-drop’ trials for each condition, was performed after a 1-h or a 24-h break. Spatial memory was measured by the mean distance between pins and the true location. Results indicated that the immediate presentation of the second task led to worse memory performance, for both break durations, compared to the delayed condition. There was no difference in performance between the delayed presentation and the control condition. Despite this long-term memory effect, we found no difference in the rate of performance improvement during the learning session, indicating no effect of the second task on working memory. Our findings are in line with a rapid process, linked to the offset of an event, that is involved in the early stages of memory consolidation.

Neuroplasicity and the developmental dyslexia intervention

A growing body of literature suggests that timing plays a critical role in neuroplasticity processes and the molecular mechanisms necessary for learning and memory [1, 2]. Of particular significance to remedial education is identifying the time parameters for primary stimulation that are necessary and sufficient, the time frame relevant for transitioning to long-term memory, and the appropriate periods for restimulation. The translation of short-term stimulation into long-term memory is regulated by diverse processes that are mechanistically distinct and activated by synaptic activity [1], while also relying on protein and glycoprotein synthesis [3] and myelination processes. The current research explores the potential benefits of incorporating neuroscience research on the timing of neuroplasticity mechanisms in designing intervention programs for individuals with developmental dyslexia, specifically focusing on enhancing cognitive functions and skills crucial for reading. Based on available evidence, we have determined optimal training and break time periods for a 10-year-old child with developmental dyslexia resulting from multiple deficits. During the 21-day intervention program, 12 training sessions were conducted each day, commencing at 8 or 9 am and held hourly thereafter. Each session comprised a brief, targeted training exercise ranging from 3 to 7 minutes, depending on the child’s aptitude, followed by a playing session or computer game lasting up to 15 minutes. A 40-minute break followed each session. Brief training sessions were required due to the swift exhaustion of the subject child. The sessions were selected based on the evidence that brief stimulation can still result in a high level of CERB phosphorylation, even if it lasts only a few minutes [4]. Playing sessions were necessary for supporting the child’s motivation throughout the lengthy and intensive intervention program, and the activities performed during these sessions were pertinent to developing specific skills. The duration of the breaks was determined by evidence indicating the time required for primary memory consolidation processes and protein synthesis necessary for long-lasting synaptic plasticity. We have made an effort to eliminate any potential sources of emotional engagement or significant new information during breaks, allowing the initial stage of memory consolidation to occur without any unnecessary disruption. During the training sessions, various tasks were used to target specific types of processing such as phonological, visual, speech, and multimodal processing (e.g., visual-motor, audio-visual, or reading). Each session exclusively focused on one type of exercise. In our prior study [5], we discussed the linguistic aspects of the program and the exercises employed. Significant progress was achieved as a result of the 21-day intervention, surpassing the progress achieved in three years of schooling and during traditional remediation programs with speech therapists that lasted 1–3 sessions per week for 40–120 minutes. Following the intensive intervention, supportive training was continued for one year while considering the crucial timing for neuroplasticity. Afterward, the child reached a normative level of reading, and the effect was maintained throughout their entire period of school education. Based on the timing of neuroplasticity processes, this is the first intensive intervention program experience for dyslexia that we are aware of. Intensive remediation programs, based on relevant findings regarding the mechanisms of memory consolidation, may enhance neural memory trace reinforcement. However, further research is necessary to optimize the timing and length of sessions and identify the most effective combination of linguistic and neurophysiological aspects for intervention.

Memory Consolidation during Ultra-short Offline States.

Traditionally, neuroscience and psychology have studied the human brain during periods of "online" attention to the environment, while participants actively engage in processing sensory stimuli. However, emerging evidence shows that the waking brain also intermittently enters an "offline" state, during which sensory processing is inhibited and our attention shifts inward. In fact, humans may spend up to half of their waking hours offline [Wamsley, E. J., & Summer, T. Spontaneous entry into an "offline" state during wakefulness: A mechanism of memory consolidation? Journal of Cognitive Neuroscience, 32, 1714-1734, 2020; Killingsworth, M. A., & Gilbert, D. T. A wandering mind is an unhappy mind. Science, 330, 932, 2010]. The function of alternating between online and offline forms of wakefulness remains unknown. We hypothesized that rapidly switching between online and offline states enables the brain to alternate between the competing demands of encoding new information and consolidating already-encoded information. A total of 46 participants (34 female) trained on a memory task just before a 30-min retention interval, during which they completed a simple attention task while undergoing simultaneous high-density EEG and pupillometry recording. We used a data-driven method to parse this retention interval into a sequence of discrete online and offline states, with a 5-sec temporal resolution. We found evidence for three distinct states, one of which was an offline state with features well-suited to support memory consolidation, including increased EEG slow oscillation power, reduced attention to the external environment, and increased pupil diameter (a proxy for increased norepinephrine). Participants who spent more time in this offline state following encoding showed improved memory at delayed test. These observations are consistent with the hypothesis that even brief, seconds-long entry into an offline state may support the early stages of memory consolidation.

HOW THE HUMAN BRAIN LEARNS AND MEMORIES AND HOW IT SHOWS SIMILAR NEURAL PATTERNS TO ITS SOCIAL NETWORK

We are continuously faced with a stream of information, which the brain needs to encode and integrate into existing knowledge. Numerous factors affect this process, such as emotions, neurogenesis, and neuroplasticity. To explain how memory and learning are encoded in the brain, Semon's proposed the existence of engrams cells distributed across the cortex forming a network supporting a given memory, which are activated both during encoding and during recall. It appears that engrams can be either active or silent depending on the stage of memory consolidation. This would be in accordance with the system consolidation theory; however, incongruences in the literature still make it impossible to exclude other alternatives, like the multiple trace theory, as possible explanations. Moreover, it has been found that both learning and memory processes are socially affected. In fact, friendship status, social network features, and hierarchy position have an influence on how people encode information and store them.

The G protein-coupled estrogen receptor (GPER) regulates recognition and aversively–motivated memory in male rats

Estrogens, particularly 17β-estradiol (estradiol, E2), regulate memory formation. E2 acts through its intracellular receptors, estrogen receptors (ER) ERα and ERβ, as well as a recently identified G protein-coupled estrogen receptor (GPER). Although the effects of E2 on memory have been investigated, studies examining the effects of GPER stimulation are scarce. Selective GPER agonism improves memory in ovariectomized female rats, but little information is available regarding the effects of GPER stimulation in male rodents. The aim of the present study was to investigate the effects of the GPER agonist, G1, on consolidation and reconsolidation of inhibitory avoidance (IA) and object recognition (OR) memory in male rats. Animals received vehicle, G1 (15, 75, 150 µg/kg; i.p.), or the GPER antagonist G15 (100 µg/kg; i.p.) immediately after training, or G1 (150 µg/kg; i.p.) 3 or 6 h after training. To investigate reconsolidation, G1 was administered immediately after IA retention Test 1. Results indicated that G1 administered immediately after training at the highest dose enhanced both OR and IA memory consolidation, while GPER blockade immediately after training impaired OR. No effects of GPER stimulation were observed when G1 was given 3 or 6 h after training or after Test 1. The present findings provide evidence that GPER is involved in the early stages of memory consolidation in both neutral and emotional memory tasks in male adult rats.

Changes in corticospinal excitability during consolidation predict acute exercise-induced off-line gains in procedural memory

A single bout of cardiovascular exercise performed immediately after practicing a motor task improves the long-term retention of the skill through an optimization of memory consolidation. However, the specific brain mechanisms underlying the effects of acute cardiovascular exercise on procedural memory are poorly understood. We sought to determine if a single bout of exercise modifies corticospinal excitability (CSE) during the early stages of memory consolidation. In addition, we investigated if changes in CSE are associated with exercise-induced off-line gains in procedural memory. Participants practiced a serial reaction time task followed by either a short bout of acute exercise or a similar rest period. To monitor changes in CSE we used transcranial magnetic stimulation applied to the primary motor cortex (M1) at baseline, 15, 35, 65 and 125min after exercise or rest. Participants in the exercise condition showed larger (∼24%) improvements in procedural memory through consolidation although differences between groups did not reach statistical significance. Exercise promoted an increase in CSE, which remained elevated 2h after exercise. More importantly, global increases in CSE following exercise correlated with the magnitude of off-line gains in skill level assessed in a retention test performed 8h after motor practice. A single bout of exercise modulates short-term neuroplasticity mechanisms subserving consolidation processes that predict off-line gains in procedural memory.

Neuron Activity in the Retrosplenial Cortex of the Rat at the Early and Late Stages of Memory Consolidation

Activity was recorded from single neurons in the retrosplenial cortex during performance of an operant food-procuring behavior in two groups of rats; in the first six days after training to this behavior (group 1) and one week later, during which the animal did not perform the learned skill (group 2). At the same time, these groups showed no significant difference in the percentages of neurons specialized with respect to the learned behavior; in group 1, 40% of the cells of this category showed activation occurring in 80–90% of performances of the specific act, and not in all (100%), which was significantly different from the proportion of such cells (4%) in animals of group 2. All neurons with less than 100% activation at the early post-training stage were specialized with respect to the most recent act in the training history: approach to and pressing of the pedal. It is suggested that at the first stages of consolidation of the operant skill, its realization may occur by means of a variable set of cells in the retrosplenial cortex specialized with relative to the system of new behavioral acts.

Acute Exercise and Motor Memory Consolidation: The Role of Exercise Timing.

High intensity aerobic exercise amplifies offline gains in procedural memory acquired during motor practice. This effect seems to be evident when exercise is placed immediately after acquisition, during the first stages of memory consolidation, but the importance of temporal proximity of the exercise bout used to stimulate improvements in procedural memory is unknown. The effects of three different temporal placements of high intensity exercise were investigated following visuomotor skill acquisition on the retention of motor memory in 48 young (24.0 ± 2.5 yrs), healthy male subjects randomly assigned to one of four groups either performing a high intensity (90% Maximal Power Output) exercise bout at 20 min (EX90), 1 h (EX90+1), 2 h (EX90+2) after acquisition or rested (CON). Retention tests were performed at 1 d (R1) and 7 d (R7). At R1 changes in performance scores after acquisition were greater for EX90 than CON (p < 0.001) and EX90+2 (p = 0.001). At R7 changes in performance scores for EX90, EX90+1, and EX90+2 were higher than CON (p < 0.001, p = 0.008, and p = 0.008, resp.). Changes for EX90 at R7 were greater than EX90+2 (p = 0.049). Exercise-induced improvements in procedural memory diminish as the temporal proximity of exercise from acquisition is increased. Timing of exercise following motor practice is important for motor memory consolidation.

Encoding and Retrieval of Artificial Visuoauditory Memory Traces in the Auditory Cortex Requires the Entorhinal Cortex

Damage to the medial temporal lobe impairs the encoding of new memories and the retrieval of memories acquired immediately before the damage in human. In this study, we demonstrated that artificial visuoauditory memory traces can be established in the rat auditory cortex and that their encoding and retrieval depend on the entorhinal cortex of the medial temporal lobe in the rat. We trained rats to associate a visual stimulus with electrical stimulation of the auditory cortex using a classical conditioning protocol. After conditioning, we examined the associative memory traces electrophysiologically (i.e., visual stimulus-evoked responses of auditory cortical neurons) and behaviorally (i.e., visual stimulus-induced freezing and visual stimulus-guided reward retrieval). The establishment of a visuoauditory memory trace in the auditory cortex, which was detectable by electrophysiological recordings, was achieved over 20-30 conditioning trials and was blocked by unilateral, temporary inactivation of the entorhinal cortex. Retrieval of a previously established visuoauditory memory was also affected by unilateral entorhinal cortex inactivation. These findings suggest that the entorhinal cortex is necessary for the encoding and involved in the retrieval of artificial visuoauditory memory in the auditory cortex, at least during the early stages of memory consolidation.

A Single Bout of Exercise Improves Motor Memory

Regular physical activity has a positive impact on cognition and brain function. Here we investigated if a single bout of exercise can improve motor memory and motor skill learning. We also explored if the timing of the exercise bout in relation to the timing of practice has any impact on the acquisition and retention of a motor skill. Forty-eight young subjects were randomly allocated into three groups, which practiced a visuomotor accuracy-tracking task either before or after a bout of intense cycling or after rest. Motor skill acquisition was assessed during practice and retention was measured 1 hour, 24 hours and 7 days after practice. Differences among groups in the rate of motor skill acquisition were not significant. In contrast, both exercise groups showed a significantly better retention of the motor skill 24 hours and 7 days after practice. Furthermore, compared to the subjects that exercised before practice, the subjects that exercised after practice showed a better retention of the motor skill 7 days after practice. These findings indicate that one bout of intense exercise performed immediately before or after practicing a motor task is sufficient to improve the long-term retention of a motor skill. The positive effects of acute exercise on motor memory are maximized when exercise is performed immediately after practice, during the early stages of memory consolidation. Thus, the timing of exercise in relation to practice is possibly an important factor regulating the effects of acute exercise on long-term motor memory.

Glutamate Receptor Modulator Dimebon Stimulates Consolidation and Reconsolidation of Weak Memory in Chicks

Effects of glutamate receptor modulator dimebon on memory consolidation and reconsolidation were investigated in passive avoidance paradigm in newborn chicks. Systemic administration of 0.1 mg/kg dimebon 5 min before or 4 h after "weak" training resulted in formation of long-term memory. Dimebon administration in combination with memory reactivation 24 h after "weak" training recovered the memory decayed by the time of reminder and ensured its subsequent long-term maintenance over 24 h. Thus, we showed the possibility for dimebon-induced recovery of the memory that decayed and had no manifestations in behavior. Dimebon administration potentiated early and late stages of memory consolidation in learning as well as in memory reconsolidation following its reactivation.

Memantine ameliorates scopolamine-induced amnesia in chicks trained on taste-avoidance learning

In day-old chicks trained on the one-trial taste-avoidance task, activation of NMDA receptors by glutamate is particularly important in the initial stages of memory consolidation. In addition, acetylcholine receptor activation has been shown to be a necessary component of memory formation for this task because injection of scopolamine produces amnesia. Memantine, a non-competitive NMDA receptor antagonist, improves memory formation under certain impairing circumstances, despite inhibiting the activation of NMDA receptors. The present experiments tested the hypothesis that memantine can ameliorate scopolamine-induced amnesia in day-old chicks ( Gallus gallus domesticus) trained on the one-trial taste-avoidance task. Three experiments assessed the effects of scopolamine, memantine, and glutamate in this task. The results of Experiment 1 demonstrated that 50.0 mM scopolamine produces significant amnesia. In Experiment 2, 1.0 mM memantine reversed the scopolamine-induced amnesia, while other doses were ineffective. In Experiment 3, injection of 50.0 mM glutamate in combination with scopolamine reversed the memantine amelioration. These results indicate a relationship between glutamate and acetylcholine in memory formation in the day-old chick.

Memantine improves memory for taste-avoidance learning in day-old chicks exposed to isolation stress

Activation of NMDA receptors by glutamate is particularly important in the initial stages of memory consolidation. Memantine, a noncompetitive NMDA receptor antagonist, ameliorates memory impairment under certain circumstances, despite blocking the activation of NMDA receptors. The present experiments tested the hypothesis that memantine can improve memory deficits induced by isolation stress in day-old chicks ( Gallus gallus domesticus) trained in a one-trial taste-avoidance task. Three experiments assessed the effects of memantine at different concentrations and in combination with isolation stress. The results of Experiment 1 indicate that, under normal, non-stressed conditions, memory in control animals is strong and 15.0 mM memantine impairs memory, similar to that seen in many studies of the effects of NMDA receptor antagonists on learning. However, the results of Experiments 2 and 3 showed that, when chicks were exposed to isolation stress during the pre-training period, memory formation for saline-injected control animals was impaired and 5.0 mM memantine significantly improved memory in an inverted U-shaped dose response function. The current results extend the findings that memantine can ameliorate memory impairment and supports the hypothesis that memantine, despite its action to reduce NMDA receptor activity, can facilitate normalized memory acquisition.

Long-lasting second stage of recognition memory consolidation in mice

We investigated the effects of anisomycin (ANI) treatment (150 mg/kg s.c.) during late stages of memory consolidation in a juvenile recognition task in mice. ANI treatment blocked 24 h recognition memory if administered 9 h, 12 h or 15 h after learning. As shown by a significantly reduced incorporation of radioactively labelled amino acids into newly synthesized proteins, translational arrest by ANI treatment lasted for 3–4 h, thus covering the complete time period between 9 h and 18 h after memory acquisition. Together with previous findings [Richter K, Wolf G, Engelmann M. Social recognition memory requires two stages of protein synthesis in mice. Learn Mem 2005;12(4):407–13], our data suggest two distinct stages of protein synthesis to occur during the first 24 h after learning: an early, relatively short-stage, starting immediately after learning and lasting for approximately 3 h, and a second stage starting 6 h after learning lasting for approximately 12 h. This is the first report of such a long-lasting protein synthesis-dependent second consolidation phase in mice and suggests that long-term consolidation of juvenile recognition memory comprises multiple waves of protein synthesis and complex cascades of inter- and intra-cellular signaling processes.

Memory Replay and Memory Consolidation

The replay of behaviorally induced multi-neuronal activity patterns during subsequent sleep or quiet waking is conjectured to play an important role in the consolidation process of certain types of memory. During the early stages of memory consolidation, the hippocampus appears to be critical; however, over time the involvement of the hippocampus decreases as the memories become gradually consolidated in the neocortex. In this article, we review how temporal spike patterns are replayed during sleep and the possible interactions of the hippocampus and neocortex through these patterns.

Time-dependent involvement of cAMP and cGMP in consolidation of object memory: Studies using selective phosphodiesterase type 2, 4 and 5 inhibitors

The present study investigated the time-dependent memory enhancing properties of three selective phosphodiesterase inhibitors (PDE-I) vardenafil (PDE5-I), rolipram (PDE4-I) and BAY 60-7550 (PDE2-I) in the object recognition task. In particular, the time-dependent involvement of cAMP and cGMP in memory consolidation was assessed by altering the time points of drug administration. Vardenafil (1 mg/kg, p.o.), rolipram (0.03 mg/kg, i.p.), and BAY 60-7550 (3 mg/kg, p.o.) were tested in rats with a 24 h delay between the learning and the test trial. The PDE-Is were administered at different time points, i.e. directly after, 1 h, 3 h and 6 h after the first trial. Using a 24 h interval, vardenafil only showed an effect on object memory when injected directly after trial 1, rolipram only showed an improvement when injected 3 h after trial 1 and BAY 60-7550 improved memory when injected either directly after or 3 h after trial 1. No treatment effects were found when the compounds were administered 1 h or 6 h after the first trial. Our results extend our previous data that different types of PDE-Is affect different stages of memory consolidation. Moreover, the present study provides further support that selective PDE-Is can influence memory consolidation in a time-dependent manner, assumingly by elevating central cAMP and cGMP levels.

An endogenous inhibitor of calcium/calmodulin‐dependent kinase II is up‐regulated during consolidation of fear memory

CaMKIINalpha and CaMKIINbeta are endogenous inhibitors of the abundant synaptic protein, calcium/calmodulin-dependent protein kinase II (CaMKII). CaMKII exerts a prominent function in memory formation and the endogenous inhibitors might be important regulators of CaMKII activity during this process. Here we investigated whether or not CaMKIINalpha and CaMKIINbeta gene expressions are regulated in the mouse hippocampus and amygdala after background contextual fear conditioning. Quantitative real-time PCR revealed that the hippocampal expression of CaMKIINalpha mRNA was up-regulated 30 and 60 min after conditioning. In contrast, CaMKIINbeta mRNA expression did not change. The up-regulation of CaMKIINalpha expression was specific for the fear memory because the context alone and a shock control did not induce any variation of transcription level. Quantification of in situ hybridization signals showed that CaMKIINalpha expression increased in hippocampal area CA1, in the dentate gyrus (DG) and in the lateral amygdala (LA) 30 min after training. Our findings show an up-regulation in the expression of the endogenous inhibitor gene CaMKIINalpha during consolidation of fear memory. The early onset and the amplitude of the up-regulation are similar to those of immediate-early genes. Taken together, our results suggest that the CaMKIINalpha inhibitor has a physiological role in controlling CaMKII activity from an early stage of memory consolidation.

What is consolidated during sleep-dependent motor skill learning?

Learning procedural skills involves improvement in speed and accuracy. Walker proposes two stages of memory consolidation: enhancement, which requires sleep, and stabilization, which does not require sleep. Speed improvement for a motor learning task but not accuracy occurs after sleep-dependent enhancement. We discuss this finding in the context of computational models and underlying sleep mechanisms.

Effects of long-term estrogen replacement on social investigation and social memory in ovariectomized C57BL/6 mice

Estrogen has been shown to play a role in modulating social recognition memory. However, the literature regarding the influence of estrogen on social memory is sparse and only covers two experimental manipulations: acute injections and receptor knockout. Long-term effects of estrogen replacement on social investigation and social recognition are unknown. Furthermore, existing social recognition protocols focus on memory of very short durations (<2 h). In the present study, we examined long-term effects of estrogen replacement on both short- (<30 min) and long-term (24 h) social recognition in ovariectomized female C57BL/6 mice by implanting 60-day time-release pellets containing physiological doses of estradiol (0, 0.18, or 0.72 mg of 17β-estradiol). After 55 days of treatment, evidence of social recognition memory, measured by 24-h habituation, was found only in mice receiving the 0.72-mg pellet. This result is remarkable as previous reports indicate that individually-housed untreated rats and mice do not show habituation beyond 2 h. Our study further revealed that estrogen also increased frequencies of baseline social investigation without affecting general activity levels and decreased delayed post-swim-stress serum corticosterone concentration. Thus, these results suggest that long-term estrogen replacement increased the interest in social interaction as well as decreased stress responses. It is likely that the 24-h habituation observed in the estrogen replacement group is mediated jointly by the non-mnemonic effects of estrogen on the behavior displayed during the stage of memory encoding as well as mnemonic effects during the stage of memory consolidation.

Blockade of NMDA Receptors in Prelimbic Cortex Induces an Enduring Amnesia for Odor–Reward Associative Learning

The competitive antagonist 2-amino-5-phosphonoeptanoic acid (APV) was injected intracerebroventricularly to determine the involvement of NMDA receptors in different stages of memory consolidation. Subsequent experiments used local injections to determine possible sites of drug action. Rats were trained in a rapidly learned olfactory task to find palatable food in a hole in a sponge impregnated with the target odor in the presence of two other sponges with nonrewarded odors. APV injections were made intracerebroventricularly 5 min or 2 hr after the end of the training, and a retention test was given 48 hr later. The results showed that blockade of NMDA receptors immediately after training induces a profound and enduring amnesia with no effect when the treatment is delayed at 2 hr after training. To address the question of the effective sites of action of the intracerebroventricular treatment, APV injections into the hippocampus and into the prelimblic region of the frontal cortex (PLC) were made. Blockade of NMDA receptors into the PLC but not into the hippocampus impaired memory formation of the odor-reward association. The amnesia is not transient, because the retention tests were made 48 hr after training. These results underlie the role of NMDA receptors in the early stage of consolidation of a simple odor-reward associative memory and confirm the role of the PLC in the consolidation of long-term memory.