No impairment of contextual fear memory consolidation by oxytocin receptor antagonism in male rats.

Oxytocin is a peptide released into brain regions associated with the processing of aversive memory and threat responses. Given the expression of oxytocin receptors across this vigilance surveillance system of the brain, we investigated whether pharmacological antagonism of the receptor would impact contextual aversive conditioning and memory. Adult male rats were conditioned to form an aversive contextual memory. The effects of peripheral administration of either the competitive antagonist Atosiban or noncompetitive antagonist L-368,899 were compared to saline controls. Oxytocin receptor antagonism treatment did not significantly impact the consolidation of aversive contextual memory in any of the groups. We conclude that peripheral antagonism of oxytocin signalling did not impact the formation of aversive memory.

Comparing targeted memory reactivation during slow wave sleep and sleep stage 2.

Sleep facilitates declarative memory consolidation, which is assumed to rely on the reactivation of newly encoded memories orchestrated by the temporal interplay of slow oscillations (SO), fast spindles and ripples. SO as well as the number of spindles coupled to SO are more frequent during slow wave sleep (SWS) compared to lighter sleep stage 2 (S2). But, it is unclear whether memory reactivation is more effective during SWS than during S2. To test this question, we applied Targeted Memory Reactivation (TMR) in a declarative memory design by presenting learning-associated sound cues during SWS vs. S2 in a counterbalanced within-subject design. Contrary to our hypothesis, memory performance was not significantly better when cues were presented during SWS. Event-related potential (ERP) amplitudes were significantly higher for cues presented during SWS than S2, and the density of SO and SO-spindle complexes was generally higher during SWS than during S2. Whereas SO density increased during and after the TMR period, SO-spindle complexes decreased. None of the parameters were associated with memory performance. These findings suggest that the efficacy of TMR does not depend on whether it is administered during SWS or S2, despite differential processing of memory cues in these sleep stages.

Motor learning- and consolidation-related resting state fast and slow brain dynamics across wake and sleep.

Motor skills dynamically evolve during practice and after training. Using magnetoencephalography, we investigated the neural dynamics underpinning motor learning and its consolidation in relation to sleep during resting-state periods after the end of learning (boost window, within 30 min) and at delayed time scales (silent 4 h and next day 24 h windows) with intermediate daytime sleep or wakefulness. Resting-state neural dynamics were investigated at fast (sub-second) and slower (supra-second) timescales using Hidden Markov modelling (HMM) and functional connectivity (FC), respectively, and their relationship to motor performance. HMM results show that fast dynamic activities in a Temporal/Sensorimotor state network predict individual motor performance, suggesting a trait-like association between rapidly recurrent neural patterns and motor behaviour. Short, post-training task re-exposure modulated neural network characteristics during the boost but not the silent window. Re-exposure-related induction effects were observed on the next day, to a lesser extent than during the boost window. Daytime naps did not modulate memory consolidation at the behavioural and neural levels. These results emphasise the critical role of the transient boost window in motor learning and memory consolidation and provide further insights into the relationship between the multiscale neural dynamics of brain networks, motor learning, and consolidation.

Selection of experience for memory by hippocampal sharp wave ripples.

Experiences need to be tagged during learning for further consolidation. However, neurophysiological mechanisms that select experiences for lasting memory are not known. By combining large-scale neural recordings in mice with dimensionality reduction techniques, we observed that successive maze traversals were tracked by continuously drifting populations of neurons, providing neuronal signatures of both places visited and events encountered. When the brain state changed during reward consumption, sharp wave ripples (SPW-Rs) occurred on some trials, and their specific spike content decoded the trial blocks that surrounded them. During postexperience sleep, SPW-Rs continued to replay those trial blocks that were reactivated most frequently during waking SPW-Rs. Replay content of awake SPW-Rs may thus provide a neurophysiological tagging mechanism to select aspects of experience that are preserved and consolidated for future use.

Coupled sleep rhythms for memory consolidation.

How do passing moments turn into lasting memories? Sheltered from external tasks and distractions, sleep constitutes an optimal state for the brain to reprocess and consolidate previous experiences. Recent work suggests that consolidation is governed by the intricate interaction of slow oscillations (SOs), spindles, and ripples - electrophysiological sleep rhythms that orchestrate neuronal processing and communication within and across memory circuits. This review describes how sequential SO-spindle-ripple coupling provides a temporally and spatially fine-tuned mechanism to selectively strengthen target memories across hippocampal and cortical networks. Coupled sleep rhythms might be harnessed not only to enhance overnight memory retention, but also to combat memory decline associated with healthy ageing and neurodegenerative diseases.

Long-term memory consolidation of new words in children with self-limited epilepsy with centro-temporal spikes.

Accelerated long-term forgetting has been studied and demonstrated in adults with epilepsy. In contrast, the question of long-term consolidation (delays > 1 day) in children with epilepsy shows conflicting results. However, childhood is a period of life in which the encoding and long-term storage of new words is essential for the development of knowledge and learning. The aim of this study was therefore to investigate long-term memory consolidation skills in children with self-limited epilepsy with centro-temporal spikes (SeLECTS), using a paradigm exploring new words encoding skills and their long-term consolidation over one-week delay. As lexical knowledge, working memory skills and executive/attentional skills has been shown to contribute to long-term memory/new word learning, we added standardized measures of oral language and executive/attentional functions to explore the involvement of these cognitive skills in new word encoding and consolidation. The results showed that children with SeLECTS needed more repetitions to encode new words, struggled to encode the phonological forms of words, and when they finally reached the level of the typically developing children, they retained what they had learned, but didn't show improved recall skills after a one-week delay, unlike the control participants. Lexical knowledge, verbal working memory skills and phonological skills contributed to encoding and/or recall abilities, and interference sensitivity appeared to be associated with the number of phonological errors during the pseudoword encoding phase. These results are consistent with the functional model linking working memory, phonology and vocabulary in a fronto-temporo-parietal network. As SeLECTS involves perisylvian dysfunction, the associations between impaired sequence storage (phonological working memory), phonological representation storage and new word learning are not surprising. This dual impairment in both encoding and long-term consolidation may result in large learning gap between children with and without epilepsy. Whether these results indicate differences in the sleep-induced benefits required for long-term consolidation or differences in the benefits of retrieval practice between the epilepsy group and healthy children remains open. As lexical development is associated with academic achievement and comprehension, the impact of such deficits in learning new words is certainly detrimental.

Neural and behavioural state switching during hippocampal dentate spikes.

Distinct brain and behavioural states are associated with organized neural population dynamics that are thought to serve specific cognitive functions1-3. Memory replay events, for example, occur during synchronous population events called sharp-wave ripples in the hippocampus while mice are in an 'offline' behavioural state, enabling cognitive mechanisms such as memory consolidation and planning4-11. But how does the brain re-engage with the external world during this behavioural state and permit access to current sensory information or promote new memory formation? Here we found that the hippocampal dentate spike, an understudied population event that frequently occurs between sharp-wave ripples12, may underlie such a mechanism. We show that dentate spikes are associated with distinctly elevated brain-wide firing rates, primarily observed in higher order networks, and couple to brief periods of arousal. Hippocampal place coding during dentate spikes aligns to the mouse's current spatial location, unlike the memory replay accompanying sharp-wave ripples. Furthermore, inhibiting neural activity during dentate spikes disrupts associative memory formation. Thus, dentate spikes represent a distinct brain state and support memory during non-locomotor behaviour, extending the repertoire of cognitive processes beyond the classical offline functions.

The importance of covert memory consolidation in schizophrenia: Dysfunctional network profiles of the hippocampus and the dorsolateral prefrontal cortex.

Altered brain network profiles in schizophrenia (SCZ) during memory consolidation are typically observed during task-active periods such as encoding or retrieval. However active processes are also sub served by covert periods of memory consolidation. These periods are active in that they allow memories to be recapitulated even in the absence of overt sensorimotor processing. It is plausible that regions central to memory formation like the dlPFC and the hippocampus, exert network signatures during covert periods. Are these signatures altered in patients? The question is clinically relevant because real world learning and memory is facilitated by covert processing, and may be impaired in schizophrenia. Here, we compared network signatures of the dlPFC and the hippocampus during covert periods of a learning and memory task. Because behavioral proficiency increased non-linearly, functional connectivity of the dlPFC and hippocampus [psychophysiological interaction (PPI)] was estimated for each of the Early (linear increases in performance) and Late (asymptotic performance) covert periods. During Early periods, we observed hypo-modulation by the hippocampus but hyper-modulation by dlPFC. Conversely, during Late periods, we observed hypo-modulation by both the dlPFC and the hippocampus. We stitch these results into a conceptual model of network deficits during covert periods of memory consolidation.

[Research progress on the relationship between neural synchronization activity and memory consolidation during non-rapid eye movement sleep].

Neural synchronization activity is considered a key aspect of information processing in the nervous system. Local synchronization within different frequency ranges and inter-regional synchronization are ubiquitous and related to various behavioral and cognitive functions. As memory is a higher cognitive function of the brain, the formation and consolidation of memory are closely related to neural synchronization activity. This article provides an overview of the research progress on the relationship between neural synchronization activity and memory consolidation, focusing primarily on the neuro-oscillatory activities across multiple brain regions during non-rapid eye movement (NREM) sleep in vivo, as well as the synchronous burst activity in cultured neural networks in vitro. Finally, we analyzed the existing issues in current research and provided a perspective on future relevant studies.

Recurring memory reactivation: The offline component of learning.

One can be aware of the effort needed to memorize a new fact or to recall the name of a new acquaintance. Because of experiences like this, learning can seem to have only two components, encoding information and, after some delay, retrieving information. To the contrary, learning entails additional, intervening steps that sometimes are hidden from the learner. For firmly acquiring fact and event knowledge in particular, learners are generally not cognizant of the necessity of offline consolidation. The memories that persist to be available reliably at a later time, according to the present conceptualization, are the ones we repeatedly rehearse and integrate with other knowledge, whether we do this intentionally or unknowingly, awake or asleep. This article examines the notion that learning is not a function of waking brain activity alone. What happens in the brain while we sleep also impacts memory storage, and consequently is a critical component of learning. The idea that memories can change over time and become enduring has long been present in memory research and is foundational for the concept of memory consolidation. Nevertheless, the notion that memory consolidation happens during sleep faced much resistance before eventually being firmly established. Research is still needed to elucidate the operation and repercussions of repeated reactivation during sleep. Comprehensively understanding how offline memory reactivation contributes to learning is vital for both theoretical and practical considerations.

Acute pain impairs retention of locomotor learning.

Despite abundant evidence that pain alters movement performance, considerably less is known about the potential effects of pain on motor learning. Some of the brain regions involved in pain processing are also responsible for specific aspects of motor learning, indicating that the two functions have the potential to interact, yet it is unclear if they do. In experiment 1, we compared the acquisition and retention of a novel locomotor pattern in young, healthy individuals randomized to either experience pain via capsaicin and heat applied to the lower leg during learning or no stimulus. On day 1, participants learned a new asymmetric walking pattern using distorted visual feedback, a paradigm known to involve mostly explicit re-aiming processes. Retention was tested 24 h later. Although there were no differences in day 1 acquisition between groups, individuals who experienced pain on day 1 demonstrated reduced retention on day 2. Furthermore, the degree of forgetting between days correlated with pain ratings during learning. In experiment 2, we examined the effects of a heat stimulus alone, which served as a control for (nonpainful) cutaneous stimulation, and found no effects on either acquisition or retention of learning. Thus, pain experienced during explicit, strategic locomotor learning interferes with motor memory consolidation processes and does so most likely through a pain mechanism and not an effect of distraction. These findings have important implications for understanding basic motor learning processes and for clinical rehabilitation, in which painful conditions are often treated through motor learning-based interventions.NEW & NOTEWORTHY Pain is a highly prevalent and burdensome experience that rehabilitation practitioners often treat using motor learning-based interventions. Here, we showed that experimental acute pain, but not a heat stimulus, during locomotor learning impaired 24-h retention of the newly learned walking pattern. The degree of retention loss was related to the perceived pain level during learning. These findings suggest important links between pain and motor learning that have significant implications for clinical rehabilitation.

The reach of reactivation: Effects of consciously triggered versus unconsciously triggered reactivation of associative memory.

Consolidating memories for long-term storage depends on reactivation. Reactivation occurs both consciously, during wakefulness, and unconsciously, during wakefulness and sleep. While considerable work has examined conscious awake and unconscious sleep reactivation, in this study, we directly compare the consequences of conscious and unconscious reactivation during wakefulness. Forty-one participants learned associations consisting of adjective-object-position triads. Objects were clustered into distinct semantic groups (e.g., fruits, vehicles) such that we could examine consequences of reactivation on semantically related memories. After an intensive learning protocol, we systematically reactivated some of the triads by presenting the adjective as a cue. Reactivation was done so that it was consciously experienced for some triads, and only unconsciously processed for others. Memory for spatial positions, the most distal part of the association, was affected by reactivation in a consciousness-dependent and memory-strength-dependent manner. Conscious reactivation resulted in weakening of semantically related memories that were strong initially, resonating with prior findings of retrieval-induced forgetting. Unconscious reactivation, on the other hand, selectively benefited weak reactivated memories, as previously shown for reactivation during sleep. Semantically linked memories were not impaired, but rather were integrated with the reactivated memory. These results taken together demonstrate that conscious and unconscious reactivation have qualitatively different consequences. Results support a consciousness-dependent inhibition account, whereby unconscious reactivation entails less inhibition than conscious reactivation, thus allowing more liberal spread of activation. Findings set the stage for additional exploration into the role of conscious experience in memory storage and structuring.

Waveform-based classification of dentate spikes.

Synchronous excitatory discharges from the entorhinal cortex (EC) to the dentate gyrus (DG) generate fast and prominent patterns in the hilar local field potential (LFP), called dentate spikes (DSs). As sharp-wave ripples in CA1, DSs are more likely to occur in quiet behavioral states, when memory consolidation is thought to take place. However, their functions in mnemonic processes are yet to be elucidated. The classification of DSs into types 1 or 2 is determined by their origin in the lateral or medial EC, as revealed by current source density (CSD) analysis, which requires recordings from linear probes with multiple electrodes spanning the DG layers. To allow the investigation of the functional role of each DS type in recordings obtained from single electrodes and tetrodes, which are abundant in the field, we developed an unsupervised method using Gaussian mixture models to classify such events based on their waveforms. Our classification approach achieved high accuracies (> 80%) when validated in 8 mice with DG laminar profiles. The average CSDs, waveforms, rates, and widths of the DS types obtained through our method closely resembled those derived from the CSD-based classification. As an example of application, we used the technique to analyze single-electrode LFPs from apolipoprotein (apo) E3 and apoE4 knock-in mice. We observed that the latter group, which is a model for Alzheimer's disease, exhibited wider DSs of both types from a young age, with a larger effect size for DS type 2, likely reflecting early pathophysiological alterations in the EC-DG network, such as hyperactivity. In addition to the applicability of the method in expanding the study of DS types, our results show that their waveforms carry information about their origins, suggesting different underlying network dynamics and roles in memory processing.

Distinct engrams control fear and extinction memory.

Memories are stored in engram cells, which are necessary and sufficient for memory recall. Recalling a memory might undergo reconsolidation or extinction. It has been suggested that the original memory engram is reactivated during reconsolidation so that memory can be updated. Conversely, during extinction training, a new memory is formed that suppresses the original engram. Nonetheless, it is unknown whether extinction creates a new engram or modifies the original fear engram. In this study, we utilized the Daun02 procedure, which uses c-Fos-lacZ rats to induce apoptosis of strongly activated neurons and examine whether a new memory trace emerges as a result of a short or long reactivation, or if these processes rely on modifications within the original engram located in the basolateral amygdala (BLA) and infralimbic (IL) cortex. By eliminating neurons activated during consolidation and reactivation, we observed significant impacts on fear memory, highlighting the importance of the BLA engram in these processes. Although we were unable to show any impact when removing the neurons activated after the test of a previously extinguished memory in the BLA, disrupting the IL extinction engram reactivated the aversive memory that was suppressed by the extinction memory. Thus, we demonstrated that the IL cortex plays a crucial role in the network involved in extinction, and disrupting this specific node alone is sufficient to impair extinction behavior. Additionally, our findings indicate that extinction memories rely on the formation of a new memory, supporting the theory that extinction memories rely on the formation of a new memory, whereas the reconsolidation process reactivates the same original memory trace.

Maintenance of Procedural Motor Memory across Brief Rest Periods Requires the Hippocampus.

Research on the role of the hippocampus in memory acquisition has generally focused on active learning. But to understand memory, it is at least as important to understand processes that happen offline, during both wake and sleep. In a study of patients with amnesia, we previously demonstrated that although a functional hippocampus is not necessary for the acquisition of procedural motor memory during training session, it is required for its offline consolidation during sleep. Here, we investigated whether an intact hippocampus is also required for the offline consolidation of procedural motor memory while awake. Patients with amnesia due to hippocampal damage (n = 4, all male) and demographically matched controls (n = 10, 8 males) trained on the finger tapping motor sequence task. Learning was measured as gains in typing speed and was divided into online (during task execution) and offline (during interleaved 30 s breaks) components. Amnesic patients and controls showed comparable total learning, but differed in the pattern of performance improvement. Unlike younger adults, who gain speed across breaks, both groups gained speed only while typing. Only controls retained these gains over the breaks; amnesic patients slowed down and compensated for these losses during subsequent typing. In summary, unlike their peers, whose motor performance remained stable across brief breaks in typing, amnesic patients showed evidence of impaired access to motor procedural memory. We conclude that in addition to being necessary for the offline consolidation of motor memories during sleep, the hippocampus maintains access to motor memory across brief offline periods during wake.

Post-encoding task engagement not attentional load is detrimental to awake consolidation.

The fate of new memories depends partly on the cognitive state experienced immediately following encoding. Wakeful rest, relative to task engagement, benefits retention and this effect is typically explained through a consolidation account: rest is theorised to provide a state of minimal interference, which would otherwise disrupt consolidation. Yet, the determinants of consolidation interference, notably the contribution of attention, remain poorly characterised. Through a repeated measures design, we investigated attention load's impact on consolidation. In three phases, participants encountered a set of nonwords and underwent immediate recognition testing, experienced a 5-min delay condition, and completed a delayed recognition test for the nonwords. This cycle repeated for each phase before proceeding to the next. Delay conditions comprised of wakeful rest and two sustained attention to response tasks (SART) that were of low (SART-fixed) and high (SART-random) attention load. Immediate memory was matched across conditions, but delayed recognition was poorer after completing the SART-fixed and SART-random conditions, relative to rest. There was no difference between the two SART conditions. These data provide insights into the factors that contribute to the success of consolidation and indicate that the attention load of a task does not determine the magnitude of consolidation interference and associated forgetting.

Sleep-wake dependent hippocampal regulation of fear memory.

The hippocampus (HPC) plays a pivotal role in fear learning and memory. Our two recent studies suggest that rapid eye movement (REM) sleep via the HPC downregulates fear memory consolidation and promotes fear extinction. However, it is not clear whether and how the dorsal and the ventral HPC regulates fear memory differently; and how the HPC in wake regulates fear memory. By chemogenetic stimulating in the HPC directly and its afferent entorhinal cortex that selectively activated the HPC in REM sleep for 3-6 h post-fear-acquisition, we found that HPC activation in REM sleep consolidated fear extinction memory. In particular, dorsal HPC (dHPC) stimulation in REM sleep virtually eliminated fear memory by enhancing fear extinction and reducing fear memory consolidation. By contrast, chemogenetic stimulating HPC afferent the supramammillary nucleus (SUM) induced 3-hr wake with HPC activation impaired fear extinction. Finally, desipramine (DMI) injection that selectively eliminated REM sleep for >6 h impaired fear extinction. Our results demonstrate that the HPC is critical for fear memory regulation; and wake HPC and REM sleep HPC have an opposite role in fear extinction of respective impairment and consolidation.

Sleep shapes the associative structure underlying pattern completion in multielement event memory.

Sleep supports the consolidation of episodic memory. It is, however, a matter of ongoing debate how this effect is established, because, so far, it has been demonstrated almost exclusively for simple associations, which lack the complex associative structure of real-life events, typically comprising multiple elements with different association strengths. Because of this associative structure interlinking the individual elements, a partial cue (e.g., a single element) can recover an entire multielement event. This process, referred to as pattern completion, is a fundamental property of episodic memory. Yet, it is currently unknown how sleep affects the associative structure within multielement events and subsequent processes of pattern completion. Here, we investigated the effects of post-encoding sleep, compared with a period of nocturnal wakefulness (followed by a recovery night), on multielement associative structures in healthy humans using a verbal associative learning task including strongly, weakly, and not directly encoded associations. We demonstrate that sleep selectively benefits memory for weakly associated elements as well as for associations that were not directly encoded but not for strongly associated elements within a multielement event structure. Crucially, these effects were accompanied by a beneficial effect of sleep on the ability to recall multiple elements of an event based on a single common cue. In addition, retrieval performance was predicted by sleep spindle activity during post-encoding sleep. Together, these results indicate that sleep plays a fundamental role in shaping associative structures, thereby supporting pattern completion in complex multielement events.

Context and Time Regulate Fear Memory Consolidation and Reconsolidation in the Basolateral Amygdala Complex.

It is widely accepted that fear memories are consolidated through protein synthesis-dependent changes in the basolateral amygdala complex (BLA). However, recent studies show that protein synthesis is not required to consolidate the memory of a new dangerous experience when it is similar to a prior experience. Here, we examined whether the protein synthesis requirement for consolidating the new experience varies with its spatial and temporal distance from the prior experience. Female and male rats were conditioned to fear a stimulus (S1, e.g., light) paired with shock in stage 1 and a second stimulus (S2, e.g., tone) that preceded additional S1-shock pairings (S2-S1-shock) in stage 2. The latter stage was followed by a BLA infusion of a protein synthesis inhibitor, cycloheximide, or vehicle. Subsequent testing with S2 revealed that protein synthesis in the BLA was not required to consolidate fear to S2 when the training stages occurred 48 h apart in the same context; was required when they were separated by 14 d or occurred in different contexts; but was again not required if S1 was re-presented after the delay or in the different context. Similarly, protein synthesis in the BLA was not required to reconsolidate fear to S2 when the training stages occurred 48 h apart but was required when they occurred 14 d apart. Thus, the protein synthesis requirement for consolidating/reconsolidating fear memories in the BLA is determined by similarity between present and past experiences, the time and place in which they occur, and reminders of the past experiences.

Memory consolidation of sequence learning and dynamic adaptation during wakefulness.

Motor learning involves acquiring new movement sequences and adapting motor commands to novel conditions. Labile motor memories, acquired through sequence learning and dynamic adaptation, undergo a consolidation process during wakefulness after initial training. This process stabilizes the new memories, leading to long-term memory formation. However, it remains unclear if the consolidation processes underlying sequence learning and dynamic adaptation are independent and if distinct neural regions underpin memory consolidation associated with sequence learning and dynamic adaptation. Here, we first demonstrated that the initially labile memories formed during sequence learning and dynamic adaptation were stabilized against interference through time-dependent consolidation processes occurring during wakefulness. Furthermore, we found that sequence learning memory was not disrupted when immediately followed by dynamic adaptation and vice versa, indicating distinct mechanisms for sequence learning and dynamic adaptation consolidation. Finally, by applying patterned transcranial magnetic stimulation to selectively disrupt the activity in the primary motor (M1) or sensory (S1) cortices immediately after sequence learning or dynamic adaptation, we found that sequence learning consolidation depended on M1 but not S1, while dynamic adaptation consolidation relied on S1 but not M1. For the first time in a single experimental framework, this study revealed distinct neural underpinnings for sequence learning and dynamic adaptation consolidation during wakefulness, with significant implications for motor skill enhancement and rehabilitation.