Microglial TNFα controls daily changes in synaptic GABAARs and sleep slow waves.

Microglia sense the changes in their environment. How microglia actively translate these changes into suitable cues to adapt brain physiology is unknown. We reveal an activity-dependent regulation of cortical inhibitory synapses by microglia, driven by purinergic signaling acting on P2RX7 and mediated by microglia-derived TNFα. We demonstrate that sleep induces microglia-dependent synaptic enrichment of GABAARs in a manner dependent on microglial TNFα and P2RX7. We further show that microglia-specific depletion of TNFα alters slow waves during NREM sleep and blunt memory consolidation in sleep-dependent learning tasks. Together, our results reveal that microglia orchestrate sleep-intrinsic plasticity of synaptic GABAARs, sculpt sleep slow waves, and support memory consolidation.

Delineating memory reactivation in sleep with verbal and non-verbal retrieval cues.

Sleep supports memory consolidation via the reactivation of newly formed memory traces. One way to investigate memory reactivation in sleep is by exposing the sleeping brain to auditory retrieval cues; a paradigm known as targeted memory reactivation. To what extent the acoustic properties of memory cues influence the effectiveness of targeted memory reactivation, however, has received limited attention. We addressed this question by exploring how verbal and non-verbal memory cues affect oscillatory activity linked to memory reactivation in sleep. Fifty-one healthy male adults learned to associate visual stimuli with spoken words (verbal cues) and environmental sounds (non-verbal cues). Subsets of the verbal and non-verbal memory cues were then replayed during sleep. The voice of the verbal cues was either matched or mismatched to learning. Memory cues (relative to unheard control cues) prompted an increase in theta/alpha and spindle power, which have been heavily implicated in sleep-associated memory processing. Moreover, verbal memory cues were associated with a stronger increase in spindle power than non-verbal memory cues. There were no significant differences between the matched and mismatched verbal cues. Our findings suggest that verbal memory cues may be most effective for triggering memory reactivation in sleep, as indicated by an amplified spindle response.

Infralimbic activity during REM sleep facilitates fear extinction memory.

Rapid eye movement (REM) sleep is known to facilitate fear extinction and play a protective role against fearful memories.1,2 Consequently, disruption of REM sleep after a traumatic event may increase the risk for developing PTSD.3,4 However, the underlying mechanisms by which REM sleep promotes extinction of aversive memories remain largely unknown. The infralimbic cortex (IL) is a key brain structure for the consolidation of extinction memory.5 Using calcium imaging, we found in mice that most IL pyramidal neurons are intensively activated during REM sleep. Optogenetically suppressing the IL specifically during REM sleep within a 4-h window after auditory-cued fear conditioning impaired extinction memory consolidation. In contrast, REM-specific IL inhibition after extinction learning did not affect the extinction memory. Whole-cell patch-clamp recordings demonstrated that inactivating IL neurons during REM sleep depresses their excitability. Together, our findings suggest that REM sleep after fear conditioning facilitates fear extinction by enhancing IL excitability and highlight the importance of REM sleep in the aftermath of traumatic events for protecting against traumatic memories.

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.

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.

The Intellectual Disability Risk Gene Kdm5b Regulates Long-Term Memory Consolidation in the Hippocampus.

The histone lysine demethylase KDM5B is implicated in recessive intellectual disability disorders, and heterozygous, protein-truncating variants in KDM5B are associated with reduced cognitive function in the population. The KDM5 family of lysine demethylases has developmental and homeostatic functions in the brain, some of which appear to be independent of lysine demethylase activity. To determine the functions of KDM5B in hippocampus-dependent learning and memory, we first studied male and female mice homozygous for a Kdm5b Δ ARID allele that lacks demethylase activity. Kdm5b Δ ARID/ Δ ARID mice exhibited hyperactivity and long-term memory deficits in hippocampus-dependent learning tasks. The expression of immediate early, activity-dependent genes was downregulated in these mice and hyperactivated upon a learning stimulus compared with wild-type (WT) mice. A number of other learning-associated genes were also significantly dysregulated in the Kdm5b Δ ARID/ Δ ARID hippocampus. Next, we knocked down Kdm5b specifically in the adult, WT mouse hippocampus with shRNA. Kdm5b knockdown resulted in spontaneous seizures, hyperactivity, and hippocampus-dependent long-term memory and long-term potentiation deficits. These findings identify KDM5B as a critical regulator of gene expression and synaptic plasticity in the adult hippocampus and suggest that at least some of the cognitive phenotypes associated with KDM5B gene variants are caused by direct effects on memory consolidation mechanisms.

A coupled neural field model for the standard consolidation theory.

The standard consolidation theory states that short-term memories located in the hippocampus enable the consolidation of long-term memories in the neocortex. In other words, the neocortex slowly learns long-term memories with a transient support of the hippocampus that quickly learns unstable memories. However, it is not clear yet what could be the neurobiological mechanisms underlying these differences in learning rates and memory time-scales. Here, we propose a novel modeling approach of the standard consolidation theory, that focuses on its potential neurobiological mechanisms. In addition to synaptic plasticity and spike frequency adaptation, our model incorporates adult neurogenesis in the dentate gyrus as well as the difference in size between the neocortex and the hippocampus, that we associate with distance-dependent synaptic plasticity. We also take into account the interconnected spatial structure of the involved brain areas, by incorporating the above neurobiological mechanisms in a coupled neural field framework, where each area is represented by a separate neural field with intra- and inter-area connections. To our knowledge, this is the first attempt to apply neural fields to this process. Using numerical simulations and mathematical analysis, we explore the short-term and long-term dynamics of the model upon alternance of phases of hippocampal replay and retrieval cue of an external input. This external input is encodable as a memory pattern in the form of a multiple bump attractor pattern in the individual neural fields. In the model, hippocampal memory patterns become encoded first, before neocortical ones, because of the smaller distances between the bumps of the hippocampal memory patterns. As a result, retrieval of the input pattern in the neocortex at short time-scales necessitates the additional input delivered by the memory pattern of the hippocampus. Neocortical memory patterns progressively consolidate at longer times, up to a point where their retrieval does not need the support of the hippocampus anymore. At longer times, perturbation of the hippocampal neural fields by neurogenesis erases the hippocampus pattern, leading to a final state where the memory pattern is exclusively evoked in the neocortex. Therefore, the dynamics of our model successfully reproduces the main features of the standard consolidation theory. This suggests that neurogenesis in the hippocampus and distance-dependent synaptic plasticity coupled to synaptic depression and spike frequency adaptation, are indeed critical neurobiological processes in memory consolidation.

Potential interactive effect of positive expectancy violation and sleep on memory consolidation in dogs.

In dogs, as in humans, both emotional and learning pretreatment affect subsequent behaviour and sleep. Although learning often occurs in an emotional-social context, the emotion-learning interplay in such context remain mainly unknown. Aims were to assess the effects of Controlling versus Permissive (emotional factors) training (learning factors) styles on dogs' behaviour, learning performance, and sleep. Family dogs (N = 24) participated in two command learning sessions employing the two training styles with each session followed by assessment of learning performance, a 2-h-long non-invasive sleep EEG measurement, and a retest of learning performance. Pre- to post-sleep improvement in learning performance was evident in dogs that received the Permissive training during the second learning session, indicating that dogs that experienced a more rewarding situation than expected (positive expectancy violation) during the second training session showed improved learning success after their afternoon sleep. These results possibly indicate an interactive effect of expectancy violation and sleep on enhancing learning.

Berberine and hesperidin prevent the memory consolidation impairment induced by pentylenetetrazole in zebrafish.

This study verified the effects of the natural compounds berberine and hesperidin on seizure development and cognitive impairment triggered by pentylenetetrazole (PTZ) in zebrafish. Adult animals were submitted to a training session in the inhibitory avoidance test and, after 10 minutes, they received an intraperitoneal injection of 25, 50, or 100 mg/kg berberine or 100 or 200 mg/kg hesperidin. After 30 minutes, the animals were exposed to 7.5 mM PTZ for 10 minutes. Animals were submitted to the test session 24 h after the training session to verify their cognitive performance. Zebrafish larvae were exposed to 100 µM or 500 µM berberine or 10 µM or 50 µM hesperidin for 30 minutes. After, larvae were exposed to PTZ and had the seizure development evaluated by latency to reach the seizure stages I, II, and III. Adult zebrafish pretreated with 50 mg/kg berberine showed a longer latency to reach stage III. Zebrafish larvae pretreated with 500 µM berberine showed a longer latency to reach stages II and III. Hesperidin did not show any effect on seizure development both in larvae and adult zebrafish. Berberine and hesperidin pretreatments prevented the memory consolidation impairment provoked by PTZ-induced seizures. There were no changes in the distance traveled in adult zebrafish pretreated with berberine or hesperidin. In larval stage, berberine caused no changes in the distance traveled; however, hesperidin increased the locomotion. Our results reinforce the need for investigating new therapeutic alternatives for epilepsy and its comorbidities.

Distinct Hippocampal Oscillation Dynamics in Trace Eyeblink Conditioning Task for Retrieval and Consolidation of Associations.

Trace eyeblink conditioning (TEBC) has been widely used to study associative learning in both animals and humans. In this paradigm, conditioned responses (CRs) to conditioned stimuli (CS) serve as a measure for retrieving learned associations between the CS and the unconditioned stimuli (US) within a trial. Memory consolidation, that is, learning over time, can be quantified as an increase in the proportion of CRs across training sessions. However, how hippocampal oscillations differentiate between successful memory retrieval within a session and consolidation across TEBC training sessions remains unknown. To address this question, we recorded local field potentials (LFPs) from the rat dorsal hippocampus during TEBC and investigated hippocampal oscillation dynamics associated with these two functions. We show that transient broadband responses to the CS were correlated with memory consolidation, as indexed by an increase in CRs across TEBC sessions. In contrast, induced alpha (8-10 Hz) and beta (16-20 Hz) band responses were correlated with the successful retrieval of the CS-US association within a session, as indexed by the difference in trials with and without CR.

Acute physical exercise prevents memory amnesia caused by protein synthesis inhibition in rats' hippocampus.

The benefits of physical exercise (PE) on memory consolidation have been well-documented in both healthy and memory-impaired animals. However, the underlying mechanisms through which PE exerts these effects are still unclear. In this study, we aimed to investigate the role of hippocampal protein synthesis in memory modulation by acute PE in rats. After novel object recognition (NOR) training, rats were subjected to a 30-min moderate-intensity acute PE on the treadmill, while control animals did not undergo any procedures. Using anisomycin (ANI) and rapamycin (RAPA), compounds that inhibit protein synthesis through different mechanisms, we manipulated protein synthesis in the CA1 region of the hippocampus to examine its contribution to memory consolidation. Memory was assessed on days 1, 7, and 14 post-training. Our results showed that inhibiting protein synthesis by ANI or RAPA impaired NOR memory consolidation in control animals. However, acute PE prevented this impairment without affecting memory persistence. We also evaluated brain-derived neurotrophic factor (BDNF) levels after acute PE at 0.5h, 2h, and 12h afterward and found no differences in levels compared to animals that did not engage in acute PE or were only habituated to the treadmill. Therefore, our findings suggest that acute PE could serve as a non-pharmacological intervention to enhance memory consolidation and prevent memory loss in conditions associated with hippocampal protein synthesis inhibition. This mechanism appears not to depend on BDNF synthesis in the early hours after exercise.

Short- and long-delay consolidation of memory accessibility and precision across childhood and young adulthood.

Childhood is a period when memory consolidation and knowledge base undergo rapid changes. The present study examined short-delay (overnight) and long-delay (after a 2-week period) consolidation of new information either congruent or incongruent with prior knowledge in typically developing 6- to 8-year-old children (n = 32), 9- to 11-year-old children (n = 33), and 18- to 30-year-old young adults (YA; n = 39). Both memory accessibility (cued recall of objects) and precision (precision of object placement) of initially well-learned object-scene pairs were measured. Our results showed that overnight, memory accessibility declined similarly in all age groups; memory precision improved more in younger children (YC) compared to older children (OC) and even declined in YA. After a 2-week period, both memory accessibility and precision became worse. Specifically, while age groups showed similar decline in memory accessibility, precision decline was less in YC than in OC and YA. The accessibility and precision of congruent and incongruent information changed similarly with consolidation in all age groups. Taken together, our results showed that, for initially well-learned information, YC have robust memory consolidation, despite their overall lower mnemonic performance compared to OC and YA, which is potentially crucial for stable and precise knowledge accumulation early on in development. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

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.

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.

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.

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.

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.

An Enduring Role for Hippocampal Pattern Completion in Addition to an Emergent Nonhippocampal Contribution to Holistic Episodic Retrieval after a 24†h Delay.

Episodic memory retrieval is associated with the holistic neocortical reinstatement of all event information, an effect driven by hippocampal pattern completion. However, whether holistic reinstatement occurs, and whether hippocampal pattern completion continues to drive reinstatement, after a period of consolidation is unclear. Theories of systems consolidation predict either a time-variant or time-invariant role of the hippocampus in the holistic retrieval of episodic events. Here, we assessed whether episodic events continue to be reinstated holistically and whether hippocampal pattern completion continues to facilitate holistic reinstatement following a period of consolidation. Female and male human participants learned "events" that comprised multiple overlapping pairs of event elements (e.g., person-location, object-location, location-person). Importantly, encoding occurred either immediately before or 24 h before retrieval. Using fMRI during the retrieval of events, we show evidence for holistic reinstatement, as well as a correlation between reinstatement and hippocampal pattern completion, regardless of whether retrieval occurred immediately or 24 h after encoding. Thus, hippocampal pattern completion continues to contribute to holistic reinstatement after a delay. However, our results also revealed that some holistic reinstatement can occur without evidence for a corresponding signature of hippocampal pattern completion after a delay (but not immediately after encoding). We therefore show that hippocampal pattern completion, in addition to a nonhippocampal process, has a role in holistic reinstatement following a period of consolidation. Our results point to a consolidation process where the hippocampus and neocortex may work in an additive, rather than compensatory, manner to support episodic memory retrieval.

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.

G protein-coupled estrogen receptor (GPER) in the dorsal hippocampus regulates memory consolidation in gonadectomized male mice, likely via different signaling mechanisms than in female mice.

Studies in ovariectomized (OVX) female rodents suggest that G protein-coupled estrogen receptor (GPER) is a key regulator of memory, yet little is known about its importance to memory in males or the cellular mechanisms underlying its mnemonic effects in either sex. In OVX mice, bilateral infusion of the GPER agonist G-1 into the dorsal hippocampus (DH) enhances object recognition and spatial memory consolidation in a manner dependent on rapid activation of c-Jun N-terminal kinase (JNK) signaling, cofilin phosphorylation, and actin polymerization in the DH. However, the effects of GPER on memory consolidation and DH cell signaling in males are unknown. Thus, the present study first assessed effects of DH infusion of G-1 or the GPER antagonist G-15 on object recognition and spatial memory consolidation in gonadectomized (GDX) male mice. As in OVX mice, immediate post-training bilateral DH infusion of G-1 enhanced, whereas G-15 impaired, memory consolidation in the object recognition and object placement tasks. However, G-1 did not increase levels of phosphorylated JNK (p46, p54) or cofilin in the DH 5, 15, or 30 min after infusion, nor did it affect phosphorylation of ERK (p42, p44), PI3K, or Akt. Levels of phospho-cAMP-responsive element binding protein (CREB) were elevated in the DH 30 min following G-1 infusion, indicating that GPER in males activates a yet unknown signaling mechanism that triggers CREB-mediated gene transcription. Our findings show for the first time that GPER in the DH regulates memory consolidation in males and suggests sex differences in underlying signaling mechanisms.