Consolidation Of Associative Memory Research Articles

The influence of encoding strategy on associative memory consolidation across wake and sleep.

Sleep benefits memory consolidation. However, factors present at initial encoding may moderate this effect. Here, we examined the role that encoding strategy plays in subsequent memory consolidation during sleep. Eighty-nine participants encoded pairs of words using two different strategies. Each participant encoded half of the word pairs using an integrative visualization technique, where the two items were imagined in an integrated scene. The other half were encoded nonintegratively, with each word pair item visualized separately. Memory was tested before and after a period of nocturnal sleep (N = 47) or daytime wake (N = 42) via cued recall tests. Immediate memory performance was significantly better for word pairs encoded using the integrative strategy compared with the nonintegrative strategy (P < 0.001). When looking at the change in recall across the delay, there was significantly less forgetting of integrated word pairs across a night of sleep compared with a day spent awake (P < 0.001), with no significant difference in the nonintegrated pairs (P = 0.19). This finding was driven by more forgetting of integrated compared with not-integrated pairs across the wake delay (P < 0.001), whereas forgetting was equivalent across the sleep delay (P = 0.26). Together, these results show that the strategy engaged in during encoding impacts both the immediate retention of memories and their subsequent consolidation across sleep and wake intervals.

The interconnection and function of associative memory neurons are upregulated for memory strengthening.

Memories associated to signals have been proven to rely on the recruitment of associative memory neurons that are featured by mutual synapse innervations among cross-modal cortices. Whether the consolidation of associative memory is endorsed by the upregulation of associative memory neurons in an intramodal cortex remains to be examined. The function and interconnection of associative memory neurons were investigated by in vivo electrophysiology and adeno-associated virus-mediated neural tracing in those mice that experienced associative learning by pairing the whisker tactile signal and the olfactory signal. Our results show that odorant-induced whisker motion as a type of associative memory is coupled with the enhancement of whisking-induced whisker motion. In addition to some barrel cortical neurons encoding both whisker and olfactory signals, i.e., their recruitment as associative memory neurons, the synapse interconnection and spike-encoding capacity of associative memory neurons within the barrel cortex are upregulated. These upregulated alternations were partially observed in the activity-induced sensitization. In summary, associative memory is mechanistically based on the recruitment of associative memory neurons and the upregulation of their interactions in intramodal cortices.

Functional MRI reveals brain-wide actions of thalamically-initiated oscillatory activities on associative memory consolidation

As a key oscillatory activity in the brain, thalamic spindle activities are long believed to support memory consolidation. However, their propagation characteristics and causal actions at systems level remain unclear. Using functional MRI (fMRI) and electrophysiology recordings in male rats, we found that optogenetically-evoked somatosensory thalamic spindle-like activities targeted numerous sensorimotor (cortex, thalamus, brainstem and basal ganglia) and non-sensorimotor limbic regions (cortex, amygdala, and hippocampus) in a stimulation frequency- and length-dependent manner. Thalamic stimulation at slow spindle frequency (8 Hz) and long spindle length (3 s) evoked the most robust brain-wide cross-modal activities. Behaviorally, evoking these global cross-modal activities during memory consolidation improved visual-somatosensory associative memory performance. More importantly, parallel visual fMRI experiments uncovered response potentiation in brain-wide sensorimotor and limbic integrative regions, especially superior colliculus, periaqueductal gray, and insular, retrosplenial and frontal cortices. Our study directly reveals that thalamic spindle activities propagate in a spatiotemporally specific manner and that they consolidate associative memory by strengthening multi-target memory representation.

Auditory Cortex Neurons Show Task-Related and Learning-Dependent Selectivity toward Sensory Input and Reward during the Learning Process of an Associative Memory Task.

The activity of primary auditory cortex (A1) neurons is modulated not only by sensory inputs but also by other task-related variables in associative learning. However, it is unclear how A1 neural activity changes dynamically in response to these variables during the learning process of associative memory tasks. Therefore, we developed an associative memory task using auditory stimuli in rats. In this task, rats were required to associate tone frequencies (high and low) with a choice of ports (right or left) to obtain a reward. The activity of A1 neurons in the rats during the learning process of the task was recorded. A1 neurons increased their firing rates either when the rats were presented with a high or low tone (frequency-selective cells) before they chose either the left or right port (choice-direction cells), or when they received a reward after choosing either the left or right port (reward-direction cells). Furthermore, the proportion of frequency-selective cells and reward-direction cells increased with task acquisition and reached the maximum level in the last stage of learning. These results suggest that A1 neurons have task- and learning-dependent selectivity toward sensory input and reward when auditory tones and behavioral responses are gradually associated during task training. This selective activity of A1 neurons may facilitate the formation of associations, leading to the consolidation of associative memory.

No evidence for an effect of explicit relevance instruction on consolidation of associative memories

Newly encoded memories are stabilized over time through a process or a set of processes termed consolidation, which happens preferentially during sleep. However, not all memories profit equally from this offline stabilization. Previous research suggested that one factor, which determines whether a memory will benefit from sleep consolidation, is future relevance. The aim of our current study was to replicate these findings and expand them to investigate their neural underpinnings.In our experiment, 38 participants learned two sets of object-location associations. The two sets of stimuli were presented to each participant intermixed and in random order. After study, participants performed a baseline retention test and were thereafter instructed that, after a delay containing sleep, they would be tested and rewarded only on one of the two sets of stimuli. This relevance instruction was revoked, however, immediately before the test. Thus, this manipulation affected memory consolidation while having no influence on encoding and retrieval. This retention interval was monitored via actigraphy recordings.While the study session was purely behavioral, the test session was conducted in an MRI scanner, thus we collected neuroimaging data at retrieval of relevant compared with non-relevant items.Behaviorally, we found no effect of the relevance manipulation on memory retention, confidence rating, or reaction time. At a neural level, no effect of relevance on memory retrieval-related brain operations was observed. Contrary to our expectations, the relevance manipulation did not result in improved consolidation, nor in improved subsequent performance at retrieval. These findings challenge previously published results and suggest that future relevance as manipulated here may not be sufficient to produce enhanced memory consolidation.

Age-related emotional bias in associative memory consolidation: The role of sleep.

Sleep plays a crucial role in memory consolidation. However, the influence of sleep on emotional memory consolidation in older adults, especially in the context of associative memory, which is more cognitively demanding than item memory, remains elusive. For this study we recruited young and older adults, and randomly assigned them into the sleep or wake condition. They were administrated a visual-spatial associative memory task, which required them to remember a picture and its location. We measured memory performance for positive, neutral, and negative stimuli before and after a 12-h interval of being awake or asleep. An accuracy analysis indicated a beneficial effect of sleep on location memory regardless of age and valence. In addition, in a more fine-grained analysis, the drift rate from diffusion modeling showed that sleep facilitated the consolidation of negative stimuli in young adults, while this emotion bias shifted to positive stimuli in older adults. Moreover, negative correlations were observed between the change of memory performance and sleep characteristics in older adults, indicating that more sleep results in fewer negative memories. Our results provide a relatively weak support for an age-related emotional bias in the context of associative memory, manifested in the absence of an age-by-valence interaction in accuracy, whilst a modeling parameter in consideration of both accuracy and response time yielded evidence consistent with the predictions of the socioemotional selectivity theory.

Memory quality modulates the effect of aging on memory consolidation during sleep: Reduced maintenance but intact gain

Successful consolidation of associative memories relies on the coordinated interplay of slow oscillations and sleep spindles during non-rapid eye movement (NREM) sleep. This enables the transfer of labile information from the hippocampus to permanent memory stores in the neocortex. During senescence, the decline of the structural and functional integrity of the hippocampus and neocortical regions is paralleled by changes of the physiological events that stabilize and enhance associative memories during NREM sleep. However, the currently available evidence is inconclusive as to whether and under which circumstances memory consolidation is impacted during aging. To approach this question, 30 younger adults (19–28 years) and 36 older adults (63–74 years) completed a memory task based on scene–word associations. By tracing the encoding quality of participants’ individual memory associations, we demonstrate that previous learning determines the extent of age-related impairments in memory consolidation. Specifically, the detrimental effects of aging on memory maintenance were greatest for mnemonic contents of intermediate encoding quality, whereas memory gain of poorly encoded memories did not differ by age. Ambulatory polysomnography (PSG) and structural magnetic resonance imaging (MRI) data were acquired to extract potential predictors of memory consolidation from each participant’s NREM sleep physiology and brain structure. Partial Least Squares Correlation was used to identify profiles of interdependent alterations in sleep physiology and brain structure that are characteristic for increasing age. Across age groups, both the ‘aged’ sleep profile, defined by decreased slow-wave activity (0.5–4.5 ​Hz), and a reduced presence of slow oscillations (0.5–1 ​Hz), slow, and fast spindles (9–12.5 ​Hz; 12.5–16 ​Hz), as well as the ‘aged’ brain structure profile, characterized by gray matter reductions in the medial prefrontal cortex, thalamus, entorhinal cortex, and hippocampus, were associated with reduced memory maintenance. However, inter-individual differences in neither sleep nor structural brain integrity alone qualified as the driving force behind age differences in sleep-dependent consolidation in the present study. Our results underscore the need for novel and age-fair analytic tools to provide a mechanistic understanding of age differences in memory consolidation.

Axon TRAP reveals learning-associated alterations in cortical axonal mRNAs in the lateral amgydala.

Local translation can support memory consolidation by supplying new proteins to synapses undergoing plasticity. Translation in adult forebrain dendrites is an established mechanism of synaptic plasticity and is regulated by learning, yet there is no evidence for learning-regulated protein synthesis in adult forebrain axons, which have traditionally been believed to be incapable of translation. Here, we show that axons in the adult rat amygdala contain translation machinery, and use translating ribosome affinity purification (TRAP) with RNASeq to identify mRNAs in cortical axons projecting to the amygdala, over 1200 of which were regulated during consolidation of associative memory. Mitochondrial and translation-related genes were upregulated, whereas synaptic, cytoskeletal, and myelin-related genes were downregulated; the opposite effects were observed in the cortex. Our results demonstrate that axonal translation occurs in the adult forebrain and is altered after learning, supporting the likelihood that local translation is more a rule than an exception in neuronal processes.

Proactive and retroactive interference with associative memory consolidation in the snail Lymnaea is time and circuit dependent

Interference-based forgetting occurs when new information acquired either before or after a learning event attenuates memory expression (proactive and retroactive interference, respectively). Multiple learning events often occur in rapid succession, leading to competition between consolidating memories. However, it is unknown what factors determine which memory is remembered or forgotten. Here, we challenge the snail, Lymnaea, to acquire two consecutive similar or different memories and identify learning-induced changes in neurons of its well-characterized motor circuits. We show that when new learning takes place during a stable period of the original memory, proactive interference only occurs if the two consolidating memories engage the same circuit mechanisms. If different circuits are used, both memories survive. However, any new learning during a labile period of consolidation promotes retroactive interference and the acquisition of the new memory. Therefore, the effect of interference depends both on the timing of new learning and the underlying neuronal mechanisms.

Effect of cerebral vasomotion during physical exercise on associative memory, a near-infrared spectroscopy study.

.Regular physical exercise has been shown to benefit neurocognitive functions, especially enhancing neurogenesis in the hippocampus. However, the effects of a single exercise session on cognitive functions are controversial. To address this issue, we measured hemodynamic changes in the brain during physical exercise using near-infrared spectroscopy (NIRS) and investigated related effects on memory consolidation processes. Healthy young participants underwent two experimental visits. During each visit, they performed an associative memory task in which they first encoded a series of pictures, then spent 30-min exercising or resting, and finally were asked to recall the picture associations. We used NIRS to track changes in oxygenated hemoglobin concentration over the prefrontal cortex during exercise and rest. To characterize local tissue oxygenation and perfusion, we focused on low frequency oscillations in NIRS, also called vasomotion. We report a significant increase in associative memory consolidation after exercise, as compared to after rest, along with an overall increase in vasomotion. Additionally, performance improvement after exercise correlated positively with power in the neurogenic component (0.02 to 0.04 Hz) and negatively with power in the endothelial component (0.003 to 0.02 Hz). Overall, these results suggest that changes in vasomotion over the prefrontal cortex during exercise may promote memory consolidation processes.

Enhancement of synchronized activity between hippocampal CA1 neurons during initial storage of associative fear memory.

Learning and memory storage requires neuronal plasticity induced in the hippocampus and other related brain areas, and this process is thought to rely on synchronized activity in neural networks. We used paired whole-cell recording in vivo to examine the synchronized activity that was induced in hippocampal CA1 neurons by associative fear learning. We found that both membrane potential synchronization and spike synchronization of CA1 neurons could be transiently enhanced after task learning, as observed on day 1 but not day 5. On day 1 after learning, CA1 neurons showed a decrease in firing threshold and rise times of suprathreshold membrane potential changes as well as an increase in spontaneous firing rates, possibly contributing to the enhancement of spike synchronization. The transient enhancement of CA1 neuronal synchronization may play important roles in the induction of neuronal plasticity for initial storage and consolidation of associative memory. The hippocampus is critical for memory acquisition and consolidation. This function requires activity- and experience-induced neuronal plasticity. It is known that neuronal plasticity is largely dependent on synchronized activity. As has been well characterized, repetitive correlated activity of presynaptic and postsynaptic neurons can lead to long-term modifications at their synapses. Studies on network activity have also suggested that memory processing in the hippocampus may involve learning-induced changes of neuronal synchronization, as observed in vivo between hippocampal CA3 and CA1 networks as well as between the rhinal cortex and the hippocampus. However, further investigation of learning-induced synchronized activity in the hippocampus is needed for a full understanding of hippocampal memory processing. In this study, by performing paired whole-cell recording in vivo on CA1 pyramidal cells (PCs) in anaesthetized adult rats, we examined CA1 neuronal synchronization before and after associative fear learning. We first found in naive animals that there was a low level of membrane potential (MP) synchronization and spike synchronization of CA1 PCs. In conditioned animals, we found a significant enhancement of both MP synchronization and spike synchronization, as observed on day 1 after learning, and this enhancement was transient and not observed on day 5. Accompanying learning-induced synchronized activity was a decreased firing threshold and rise time of suprathreshold MP changes as well as an increased spontaneous firing rate, possibly contributing to the enhanced spike synchronization. The transiently enhanced CA1 neuronal synchronization may have important roles in generating neuronal plasticity for hippocampal storage and consolidation of associative memory traces.

Neuronal Oscillations Indicate Sleep-dependent Changes in the Cortical Memory Trace.

Sleep promotes the consolidation of newly acquired associative memories. Here we used neuronal oscillations in the human EEG to investigate sleep-dependent changes in the cortical memory trace. The retrieval activity for object-color associations was assessed immediately after encoding and after 3 hr of sleep or wakefulness. Sleep had beneficial effects on memory performance and led to reduced event-related theta and gamma power during the retrieval of associative memories. Furthermore, event-related alpha suppression was attenuated in the wake group for memorized and novel stimuli. There were no sleep-dependent changes in retrieval activity for missed items or items retrieved without color. Thus, the sleep-dependent reduction in theta and gamma oscillations was specific for the retrieval of associative memories. In line with theoretical accounts on sleep-dependent memory consolidation, decreased theta may indicate reduced mediotemporal activity because of a transfer of information into neocortical networks during sleep, whereas reduced parietal gamma may reflect effects of synaptic downscaling. Changes in alpha suppression in the wake group possibly index reduced attentional resources that may also contribute to a lower memory performance in this group. These findings indicate that the consolidation of associative memories during sleep is associated with profound changes in the cortical memory trace and relies on multiple neuronal processes working in concert.

Antagonizing the different stages of kappa opioid receptor activation selectively and independently attenuates acquisition and consolidation of associative memories

Previous work from our laboratory has shown that nonspecific kappa opioid receptor (KOR) antagonism in primary somatosensory cortex (S1) can inhibit acquisition for the forebrain-dependent associative task, Whisker-Trace Eyeblink conditioning (WTEB). Although studies have demonstrated that KOR activation can alter stimuli salience, our studies controlled for these factors, demonstrating that KOR also plays a role in facilitating learning. KOR has two distinct phases of activation followed by internalization/downregulation, that each independently activate kinases and transcription factors known to mediate task acquisition and memory consolidation respectively. The current study demonstrated that antagonism of the initial phase of KOR activation in S1 via local injections of the g-protein inhibitor, pertussis toxin (PTX), blocked initial WTEB acquisition without affecting retention of the association. In contrast, KOR late phase antagonism in S1 via local injections of the GRK3-specific antagonist, guanidinonaltrindole (GNTI), blocked retention of the WTEB association without affecting task acquisition. Consistent with the known mechanism for KOR activation, KOR protein expression in S1 was found to be decreased following WTEB training, further supporting the involvement of neocortical KOR activation with learning. Prior studies have shown that task acquisition and memory consolidation are mediated by distinct molecular processes; however, little is known regarding a potential mechanism driving these processes. The current study suggests that neocortical KOR activation mediates activation of these processes with learning. This study provides the first evidence for a time- and learning-dependent property of neocortical KOR in facilitating acquisition and consolidation of associative memories, while elucidating an unexplored neocortical learning mechanism.

Kappa-opioid antagonism impairs forebrain-dependent associative learning: A trace eyeblink conditioning study.

The opioid receptor system is well known for its relationship to painful stimuli but has also been discovered to have a role in acquisition and consolidation of associative memories. Most opioid receptor specific studies have focused on, and attributed these findings to, modulation of the mu-opioid receptor (MOR); however, some studies have suggested that the kappa-opioid receptor (KOR) also plays in role in memory modulation. The following study set out to determine KOR involvement in acquisition for forebrain-dependent associations. Using the forebrain-dependent associative task whisker-trace eyeblink conditioning (WTEB), the current study demonstrated that KOR inhibition via NorBNI (10 mg/kg) significantly delayed acquisition. To explore the brain region mediating these NorBNI-induced learning impairments, subsequent experiments focused on primary somatosensory cortex (S1). S1 plays a pivotal role in the acquisition of WTEB with lesions either before or after conditioning inhibiting acquisition or retrieval respectively. NorBNI (10 μg or 20 μg) in S1 was found to significantly delay acquisition, similar to that observed following systemic injections. In support of these findings, studies have suggested a role for dynorphin (KOR's endogenous ligand) expressing GABAergic interneurons in cortical processing of whisker information. Although, additional studies will be required to determine the specific mechanism for KOR and these GABAergic interneurons; these findings strongly support previous studies suggesting KOR involvement in learning mechanisms, while elucidating an unexplored neocortical learning mechanism.

Inhibitory effects of modafinil on emotional memory in mice

Modafinil (MOD), a psychostimulant used to treat narcolepsy, excessive daytime sleepiness, and sleepiness due to obstructive sleep apnea, appears to promote a possible facilitatory effect on cognitive function. In the present study, we investigated the effects of the acute administration of MOD on the different steps of emotional memory formation and usage (acquisition, consolidation and retrieval) as well as the possible participation of the state-dependency phenomenon on the cognitive effects of this compound. Mice were acutely treated with 32, 64 or 128 mg/kg MOD before training or testing or immediately after training and were subjected to the plus-maze discriminative avoidance task. The results showed that although pre-training MOD administration did not exert any effects on learning, the doses of 32 or 64 mg/kg induced emotional memory deficits during testing. Still, the post-training acute administration of the higher doses of MOD (64 and 128 mg/kg) impaired associative memory consolidation. When the drug was administered pre-test, only the 32 mg/kg dose impaired the task retrieval. Importantly, the cognitive impairing effects induced by 32 mg/kg MOD were not related to the phenomenon of state-dependency. In all, our findings provide pre-clinical evidence of potential emotional memory amnesia induced by MOD.This article is part of a Special Issue entitled ‘Cognitive Enhancers’.

Nimodipine-Induced Hypotension but Not Nitroglycerin-Induced Hypotension Preserves Long- and Short-Term Memory in Adult Mice

Acute hypotension may be implicated in cognitive dysfunction. L-type calcium channel blockers in the setting of hypoxia are protective of learning and memory. We tested the hypothesis that hypotension induced by nimodipine (NIMO) and nicardipine (NICA) would be protective of long- and short-term memory compared to hypotension induced by nitroglycerin (NTG). Forty Swiss-Webster mice (30 to 35 g, 6 to 8 weeks) were randomized into 4 groups for i.p. injection immediately after passive avoidance (PA) learning on day 0: (1) NTG (30 mg/kg); (2) NICA (40 mg/kg); (3) NIMO (40 mg/kg); and (4) saline. PA training latencies (seconds) were recorded for entry from a suspended platform into a Plexiglas tube where a shock (0.3 mA; 2-second duration) was automatically delivered. On day 2 latencies were recorded during a testing trial during which no shock was delivered. Latencies >900 seconds were assigned this value. Lower testing latency is indicative of an impairment of long-term associative memory. Forty-nine additional mice were randomized into similar groups for object recognition testing (ORT) and given i.p. injections on day 0. ORT measures short-term memory by exploiting the tendency of mice to prefer novel objects where a familiar object is present. On day 5 during training, 2 identical objects were placed in a circular arena and mice explored both for 15 minutes. A testing trial was conducted 1 hour later for 3 minutes after a novel object replaced a familiar one. Mice with intact memory spend about 65% of the time exploring the novel object. Mice with impaired memory devote equal time to each object. Recognition index (RI) is defined as the ratio of time spent exploring the novel object to time spent exploring both objects was the measure of memory. Mean arterial blood pressure (MAP), cerebral bloodflow, and body and brain oxygenation (PO(2)) studies were done in separate groups of mice to determine the dosages for matched degrees of hypotension and the physiological profile of each treatment. The median PA latencies for the different conditions were as follows: NTG (219.5 ± 93.5 second semi-interquartile range [SIQR]), NICA (372.5 ± 75.5 second SIQR), NIMO (540 ± 200 second SIQR) and saline (804 ± 257.5 second SIQR). Rank methods were used to analyze the PA latencies for significant differences. NTG latency was significantly shorter than NIMO latency (P = 0.012) and saline latency (P = 0.006), but not NICA latency (P = 0.126). ORT RI values showed a similar pattern. We found that NTG RI (47.2 ± 5.9% SEM) was different from NIMO RI (60.2 ± 4.6% SEM, P = 0.031) and different from saline RI (66.9 + 3.7% SEM, P = 0.006). Physiological experiments showed that MAP decreased to 45 to 50 mm Hg in all animals who became minimally responsive to external stimuli within 10 to 15 minutes of injection. Intergroup differences for MAP, body and brain oxygenation, and cerebral bloodflow were not statistically significant. Acute hypotension induced by NIMO was protective of 2 categories of memory formation relevant to the clinical posttreatment period. Both immediate long-term associative memory consolidation as measured by the PA learning paradigm and delayed short-term working memory function as measured by the ORT paradigm were significantly improved compared to matched levels of hypotension induced by NTG. These results indicate the utility of further investigation of l-type calcium channel blockers as a potential means of preserving cognition in the setting of hypotensive and low flow states.

Increased Entorhinal–Prefrontal Theta Synchronization Parallels Decreased Entorhinal–Hippocampal Theta Synchronization during Learning and Consolidation of Associative Memory

Memories are thought to be encoded as a distributed representation in the neocortex. The medial prefrontal cortex (mPFC) has been shown to support the expression of memories that initially depend on the hippocampus (HPC), yet the mechanisms by which the HPC and mPFC access the distributed representations in the neocortex are unknown. By measuring phase synchronization of local field potential (LFP) oscillations, we found that learning initiated changes in neuronal communication of the HPC and mPFC with the lateral entorhinal cortex (LEC), an area that is connected with many other neocortical regions. LFPs were recorded simultaneously from the three brain regions while rats formed an association between an auditory stimulus (CS) and eyelid stimulation (US) in a trace eyeblink conditioning paradigm, as well as during retention 1 month following learning. Over the course of learning, theta oscillations in the LEC and mPFC became strongly synchronized following presentation of the CS on trials in which rats exhibited a conditioned response (CR), and this strengthened synchronization was also observed during remote retention. In contrast, CS-evoked theta synchronization between the LEC and HPC decreased with learning. Our results suggest that communication between the LEC and mPFC are strengthened with learning whereas the communication between the LEC and HPC are concomitantly weakened, suggesting that enhanced LEC–mPFC communication may be a neuronal correlate for theoretically proposed neocortical reorganization accompanying encoding and consolidation of a memory.

Inhibition of the interactions between eukaryotic initiation factors 4E and 4G impairs long-term associative memory consolidation but not reconsolidation

Considerable evidence indicates that the general blockade of protein synthesis prevents both the initial consolidation and the postretrieval reconsolidation of long-term memories. These findings come largely from studies of drugs that block ribosomal function, so as to globally interfere with both cap-dependent and -independent forms of translation. Here we show that intra-amygdala microinfusions of 4EGI-1, a small molecule inhibitor of cap-dependent translation that selectively disrupts the interaction between eukaryotic initiation factors (eIF) 4E and 4G, attenuates fear memory consolidation but not reconsolidation. Using a combination of behavioral and biochemical techniques, we provide both in vitro and in vivo evidence that the eIF4E-eIF4G complex is more stringently required for plasticity induced by initial learning than for that triggered by reactivation of an existing memory.

Hippocampal Sharp Wave/Ripples during Sleep for Consolidation of Associative Memory

The beneficial effect of sleep on memory has been well-established by extensive research on humans, but the neurophysiological mechanisms remain a matter of speculation. This study addresses the hypothesis that the fast oscillations known as ripples recorded in the CA1 region of the hippocampus during slow wave sleep (SWS) may provide a physiological substrate for long term memory consolidation. We trained rats in a spatial discrimination task to retrieve palatable reward in three fixed locations. Hippocampal local field potentials and cortical EEG were recorded for 2 h after each daily training session. There was an increase in ripple density during SWS after early training sessions, in both trained rats and in rats randomly rewarded for exploring the maze. In rats learning the place -reward association, there was a striking further significant increase in ripple density correlated with subsequent improvements in behavioral performance as the rat learned the spatial discrimination aspect of the task. The results corroborate others showing an experience-dependent increase in ripple activity and associated ensemble replay after exploratory activity, but in addition, for the first time, reveal a clear further increase in ripple activity related to associative learning based on spatial discrimination.

Improvement in Fear Memory by Histamine-Elicited ERK2 Activation in Hippocampal CA3 Cells

Consolidation of associative memories appears to require extracellular signal-related kinase2 (ERK2) activation, which is modulated by several factors, including neurotransmitter receptor stimulation. Here we show that in vitro stimulation of either H2 or H3 histaminergic receptors activates ERK2 in hippocampal CA3 pyramidal cells. In behaving animals, bilateral posttraining injections into the dorsal hippocampus of histamine H2 or H3 receptor agonists improve memory consolidation after contextual fear conditioning. Local administration of U0126, a selective inhibitor of ERK kinase, prevents memory improvements exerted by the agonists, without causing any behavioral effect per se. This is the first evidence of a positive correlation between ERK phosphorylation and memory improvement. Moreover, we demonstrate that the brain histaminergic system regulates hippocampal ERK cascade. Finally, our data indicate that early ERK2 hippocampal activation is not required for the expression of long-term fear memories.