Long-term memory formation for voices during sleep in three-month-old infants.

The ability to form long-term memories begins in early infancy. However, little is known about the specific mechanisms that guide memory formation during this developmental stage. We demonstrate the emergence of a long-term memory for a novel voice in three-month-old infants using the EEG mismatch response (MMR) to the word "baby". In an oddball-paradigm, a frequent standard, and two rare deviant voices (novel and mother) were presented before (baseline), and after (test) familiarizing the infants with the novel voice and a subsequent nap. Only the mother deviant but not the novel deviant elicited a late frontal MMR (∼850 ms) at baseline, possibly reflecting a long-term memory representation for the mother's voice. Yet, MMRs to the novel and mother deviant significantly increased in similarity after voice familiarization and sleep. Moreover, both MMRs showed an additional early (∼250 ms) frontal negative component that is potentially related to deviance processing in short-term memory. Enhanced spindle activity during the nap predicted an increase in late MMR amplitude to the novel deviant and increased MMR similarity between novel and mother deviant. Our findings indicate that the late positive MMR in infants might reflect emergent long-term memory that benefits from sleep spindles.

Slow-wave sleep drives sleep-dependent renormalization of synaptic AMPA receptor levels in the hypothalamus.

According to the synaptic homeostasis hypothesis (SHY), sleep serves to renormalize synaptic connections that have been potentiated during the prior wake phase due to ongoing encoding of information. SHY focuses on glutamatergic synaptic strength and has been supported by numerous studies examining synaptic structure and function in neocortical and hippocampal networks. However, it is unknown whether synaptic down-regulation during sleep occurs in the hypothalamus, i.e., a pivotal center of homeostatic regulation of bodily functions including sleep itself. We show that sleep, in parallel with the synaptic down-regulation in neocortical networks, down-regulates the levels of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) in the hypothalamus of rats. Most robust decreases after sleep were observed at both sites for AMPARs containing the GluA1 subunit. Comparing the effects of selective rapid eye movement (REM) sleep and total sleep deprivation, we moreover provide experimental evidence that slow-wave sleep (SWS) is the driving force of the down-regulation of AMPARs in hypothalamus and neocortex, with no additional contributions of REM sleep or the circadian rhythm. SWS-dependent synaptic down-regulation was not linked to EEG slow-wave activity. However, spindle density during SWS predicted relatively increased GluA1 subunit levels in hypothalamic synapses, which is consistent with the role of spindles in the consolidation of memory. Our findings identify SWS as the main driver of the renormalization of synaptic strength during sleep and suggest that SWS-dependent synaptic renormalization is also implicated in homeostatic control processes in the hypothalamus.

Sleep-dependent decorrelation of hippocampal spatial representations.

Neuronal ensembles are crucial for episodic memory and spatial mapping. Sleep, particularly non-REM (NREM), is vital for memory consolidation, as it triggers plasticity mechanisms through brain oscillations that reactivate neuronal ensembles. Here, we assessed their role in consolidating hippocampal spatial representations during sleep. We recorded hippocampus activity in rats performing a spatial object-place recognition (OPR) memory task, during encoding and retrieval periods, separated by intervening sleep. Successful OPR retrieval correlated with NREM duration, during which cortical oscillations decreased in power and density as well as neuronal spiking, suggesting global downregulation of network excitability. However, neurons encoding specific spatial locations (i.e., place cells) or objects during OPR showed stronger synchrony with brain oscillations compared to non-encoding neurons, and the stability of spatial representations decreased proportionally with NREM duration. Our findings suggest that NREM sleep may promote flexible remapping in hippocampal ensembles, potentially aiding memory consolidation and adaptation to novel spatial contexts.

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.

Sleep-slow oscillation-spindle coupling precedes spindle-ripple coupling during development.

STUDY OBJECTIVES: Sleep supports systems memory consolidation through the precise temporal coordination of specific oscillatory events during slow-wave sleep, i.e. the neocortical slow oscillations (SOs), thalamic spindles, and hippocampal ripples. Beneficial effects of sleep on memory are also observed in infants, although the contributing regions, especially hippocampus and frontal cortex, are immature. Here, we examined in rats the development of these oscillatory events and their coupling during early life. METHODS: EEG and hippocampal local field potentials were recorded during sleep in male rats at postnatal days (PD)26 and 32, roughly corresponding to early (1-2 years) and late (9-10 years) human childhood, and in a group of adult rats (14-18 weeks, corresponding to ~22-29 years in humans). RESULTS: SO and spindle amplitudes generally increased from PD26 to PD32. In parallel, frontocortical EEG spindles increased in density and frequency, while changes in hippocampal ripples remained nonsignificant. The proportion of SOs co-occurring with spindles also increased from PD26 to PD32. Whereas parietal cortical spindles were phase-locked to the depolarizing SO-upstate already at PD26, over frontal cortex SO-spindle phase-locking emerged not until PD32. Co-occurrence of hippocampal ripples with spindles was higher during childhood than in adult rats, but significant phase-locking of ripples to the excitable spindle troughs was observed only in adult rats. CONCLUSIONS: Results indicate a protracted development of synchronized thalamocortical processing specifically in frontocortical networks (i.e. frontal SO-spindle coupling). However, synchronization within thalamocortical networks generally precedes synchronization of thalamocortical with hippocampal processing as reflected by the delayed occurrence of spindle-ripple phase-coupling.

Context memory formed in medial prefrontal cortex during infancy enhances learning in adulthood.

Adult behavior is commonly thought to be shaped by early-life experience, although episodes experienced during infancy appear to be forgotten. Exposing male rats during infancy to discrete spatial experience we show that these rats in adulthood are significantly better at forming a spatial memory than control rats without such infantile experience. We moreover show that the adult rats' improved spatial memory capability is mainly based on memory for context information during the infantile experiences. Infantile spatial experience increased c-Fos activity at memory testing during adulthood in the prelimbic medial prefrontal cortex (mPFC), but not in the hippocampus. Inhibiting prelimbic mPFC at testing during adulthood abolished the enhancing effect of infantile spatial experience on learning. Adult spatial memory capability only benefitted from spatial experience occurring during the sensitive period of infancy, but not when occurring later during childhood, and when sleep followed the infantile experience. In conclusion, the infantile brain, by a sleep-dependent mechanism, favors consolidation of memory for the context in which episodes are experienced. These representations comprise mPFC regions and context-dependently facilitate learning in adulthood.

Sleep promotes T-cell migration towards CCL19 via growth hormone and prolactin signaling in humans.

Sleep strongly supports the formation of adaptive immunity, e.g., after vaccination. However, the underlying mechanisms remain largely obscure. Here we show in healthy humans that sleep compared to nocturnal wakefulness specifically promotes the migration of various T-cell subsets towards the chemokine CCL19, which is essential for lymph-node homing and, thus, for the initiation and maintenance of adaptive immune responses. Migration towards the inflammatory chemokine CCL5 remained unaffected. Incubating the cells with plasma from sleeping participants likewise increased CCL19-directed migration, an effect that was dependent on growth hormone and prolactin signaling. These findings show that sleep selectively promotes the lymph node homing potential of T cells by increasing hormonal release, and thus reveal a causal mechanism underlying the supporting effect of sleep on adaptive immunity in humans.

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.

Odor cueing of declarative memories during sleep enhances coordinated spindles and slow oscillations.

Long-term memories are formed by repeated reactivation of newly encoded information during sleep. This process can be enhanced by using memory-associated reminder cues like sounds and odors. While auditory cueing has been researched extensively, few electrophysiological studies have exploited the various benefits of olfactory cueing. We used high-density electroencephalography in an odor-cueing paradigm that was designed to isolate the neural responses specific to the cueing of declarative memories. We show widespread cueing-induced increases in the duration and rate of sleep spindles. Higher spindle rates were most prominent over centro-parietal areas and largely overlapping with a concurrent increase in the amplitude of slow oscillations (SOs). Interestingly, greater SO amplitudes were linked to a higher likelihood of coupling a spindle and coupled spindles expressed during cueing were more numerous in particular around SO up states. We thus identify temporally and spatially coordinated enhancements of sleep spindles and slow oscillations as a candidate mechanism behind cueing-induced memory processing. Our results further demonstrate the feasibility of studying neural activity patterns linked to such processing using olfactory cueing during sleep.

Reduced overnight memory consolidation and associated alterations in sleep spindles and slow oscillations in early Alzheimer's disease.

Spatial navigation critically underlies hippocampal-entorhinal circuit function that is early affected in Alzheimer's disease (AD). There is growing evidence that AD pathophysiology dynamically interacts with the sleep/wake cycle impairing hippocampal memory. To elucidate sleep-dependent consolidation in a cohort of symptomatic AD patients (n = 12, 71.25 ± 2.16 years), we tested hippocampal place learning by means of a virtual reality task and verbal memory by a word-pair association task before and after a night of sleep. Our results show an impaired overnight memory retention in AD compared with controls in the verbal task, together with a significant reduction of sleep spindle activity (i.e., lower amplitude of fast sleep spindles, p = 0.016) and increased duration of the slow oscillation (SO; p = 0.019). Higher spindle density, faster down-to-upstate transitions within SOs, and the time delay between SOs and nested spindles predicted better memory performance in healthy controls but not in AD patients. Our results show that mnemonic processing and memory consolidation in AD is slightly impaired as reflected by dysfunctional oscillatory dynamics and spindle-SO coupling during NonREM sleep. In this translational study based on experimental paradigms in animals and extending previous work in healthy aging and preclinical disease stages, our results in symptomatic AD further deepen the understanding of the memory decline within a bidirectional relationship of sleep and AD pathology.

Sleep consolidates stimulus-response learning.

Performing a motor response to a sensory stimulus creates a memory trace whose behavioral correlates are classically investigated in terms of repetition priming effects. Such stimulus-response learning entails two types of associations that are partly independent: (1) an association between the stimulus and the motor response and (2) an association between the stimulus and the classification task in which it is encountered. Here, we tested whether sleep supports long-lasting stimulus-response learning on a task requiring participants (1) for establishing stimulus-classification associations to classify presented objects along two different dimensions ("size" and "mechanical") and (2) as motor response (action) to respond with either the left or right index finger. Moreover, we examined whether strengthening of stimulus-classification associations is preferentially linked to nonrapid eye movement (non-REM) sleep and strengthening of stimulus-action associations to REM sleep. We tested 48 healthy volunteers in a between-subjects design comparing postlearning retention periods of nighttime sleep versus daytime wakefulness. At postretention testing, we found that sleep supports consolidation of both stimulus-action and stimulus-classification associations, as indicated by increased reaction times in "switch conditions"; that is, when, at test, the acutely instructed classification task and/or correct motor response for a given stimulus differed from that during original learning. Polysomnographic recordings revealed that both kinds of associations were correlated with non-REM spindle activity. Our results do not support the view of differential roles for non-REM and REM sleep in the consolidation of stimulus-classification and stimulus-action associations, respectively.

Human REM sleep recalibrates neural activity in support of memory formation.

The proposed mechanisms of sleep-dependent memory consolidation involve the overnight regulation of neural activity at both synaptic and whole-network levels. Now, there is a lack of in vivo data in humans elucidating if, and how, sleep and its varied stages balance neural activity, and if such recalibration benefits memory. We combined electrophysiology with in vivo two-photon calcium imaging in rodents as well as intracranial and scalp electroencephalography (EEG) in humans to reveal a key role for non-oscillatory brain activity during rapid eye movement (REM) sleep to mediate sleep-dependent recalibration of neural population dynamics. The extent of this REM sleep recalibration predicted the success of overnight memory consolidation, expressly the modulation of hippocampal-neocortical activity, favoring remembering rather than forgetting. The findings describe a non-oscillatory mechanism how human REM sleep modulates neural population activity to enhance long-term memory.

Rearing is critical for forming spatial representations in pre-weanling rats.

Rearing, i.e., standing on the hind limbs in an upright posture, is part of a rat's innate exploratory motor program. Here, we examined in developing rats whether rearing is critical for the pup's capability to form spatial representations based on distal environmental cues. Pups (male) were tested at PD18, i.e., the first day they typically exhibit stable rearing, on a spatial habituation paradigm comprising a Familiarization session (with the pup exposed to an arena with a specific configuration of distal cues) followed, 3 h later, by a Test session where the pups were either re-exposed to the identical distal cue configuration (NoChange) or a changed configuration (DistalChange). In Experiment 1, rearing activity (rearing events, duration) decreased from Familiarization to Test in the NoChange pups but, remained elevated in the DistalChange group indicating that these pups recognized the distal novelty. Recognition of distal novelty was associated with increased c-Fos expression in hippocampal and medial prefrontal cortex (mPFC) areas, compared with NoChange pups. Analysis of GAD67+ cells suggested a parallel increase in excitation and inhibition specifically in prelimbic mPFC networks in response to distal cue changes. In Experiment 2, the pups were mechanically prevented from rearing while still seeing the distal cues during Familiarization. Rearing activity in the Test session of these pups did not differ between groups that were or were not exposed to a changed distal cue configuration at Test. The findings evidence a critical role of rearing for the emergence of allocentric representations integrating distal space during early development.

Sleep-A brain-state serving systems memory consolidation.

Although long-term memory consolidation is supported by sleep, it is unclear how it differs from that during wakefulness. Our review, focusing on recent advances in the field, identifies the repeated replay of neuronal firing patterns as a basic mechanism triggering consolidation during sleep and wakefulness. During sleep, memory replay occurs during slow-wave sleep (SWS) in hippocampal assemblies together with ripples, thalamic spindles, neocortical slow oscillations, and noradrenergic activity. Here, hippocampal replay likely favors the transformation of hippocampus-dependent episodic memory into schema-like neocortical memory. REM sleep following SWS might balance local synaptic rescaling accompanying memory transformation with a sleep-dependent homeostatic process of global synaptic renormalization. Sleep-dependent memory transformation is intensified during early development despite the immaturity of the hippocampus. Overall, beyond its greater efficacy, sleep consolidation differs from wake consolidation mainly in that it is supported, rather than impaired, by spontaneous hippocampal replay activity possibly gating memory formation in neocortex.

Accelerating Maturation of Spatial Memory Systems by Experience: Evidence from Sleep Oscillation Signatures of Memory Processing.

During early development, memory systems gradually mature over time, in parallel with the gradual accumulation of knowledge. Yet, it is unknown whether and to what extent maturation is driven by discrete experience. Sleep is thought to contribute to the formation of long-term memory and knowledge through a systems consolidation process that is driven by specific sleep oscillations (i.e., ripples, spindles, and slow oscillations) in cortical and hippocampal networks. Based on these oscillatory signatures, we show here in rats that discrete spatial experience speeds the functional maturation of spatial memory systems during development. Juvenile male rats were exposed for 5 min periods to changes in the spatial configuration of two identical objects on postnatal day (PD)25, PD27, and PD29 (Spatial experience group), while a Control group was exposed on these occasions to the same two objects without changing their positions. On PD31, both groups were tested on a classical Object Place Recognition (OPR) task with a 3 h retention interval during which the sleep-associated EEG and hippocampal local field potentials were recorded. On PD31, consistent with forgoing studies, Control rats still did not express OPR memory. By contrast, rats with Spatial experience formed significant OPR memory and, in parallel, displayed an increased percentage of hippocampal ripples coupled to parietal slow oscillation-spindle complexes, and a stronger ripple-spindle phase-locking during the retention sleep. Our findings support the idea that experience promotes the maturation of memory systems during development by enhancing cortico-hippocampal information exchange and the formation of integrated knowledge representations during sleep.SIGNIFICANCE STATEMENT Cognitive and memory capabilities mature early in life. We show here that and how discrete spatial experience contributes to this process. Using a simple recognition paradigm in developing rats, we found that exposure of the rat pups to three short-lasting experiences enhances spatial memory capabilities to adult-like levels. The adult-like capability of building spatial memory was connected to a more precise coupling of ripples in the hippocampus with slow oscillation-spindle complexes in the thalamo-cortical system when the memory was formed during sleep. Our findings support the view that discrete experience accelerates maturation of cognitive and memory capabilities by enhancing the dialogue between hippocampus and cortex when these experiences are reprocessed during sleep.

Sleep electroencephalogram (EEG) oscillations and associated memory processing during childhood and early adolescence.

The architecture of sleep undergoes distinct changes during childhood and early adolescence. Slow wave sleep is involved in memory processing and may support active consolidation of newly encoded representations to support the formation of abstracted "gist" memories. Here, we examined sleep and overnight memory formation in German school children (n = 33) between 7 and 15 years of age, after the encoding phase of a verbal Deese-Roediger-McDermott (DRM) task. Effects of age were analyzed on sleep electroencephalogram (EEG) signatures of memory processing during nonrapid eye movement (NonREM) sleep, and the overnight formation of veridical and gist-based memories. Increasing age decreases time spent in slow wave sleep, and slow wave activity, whereas density and amplitude of fast sleep spindles in NonREM sleep were increased. Moreover, fast spindles were more consistently and more closely coupled to the upstate of the slow oscillation in the older children. Also, veridical and gist-based recall of words after sleep increased with age. Notably, a closer slow oscillation upstate-fast spindle coupling predicted veridical recall of words, and this relationship was found independent of age. Memory performance in the sleeping children did not differ from that of an age-matched control group (n = 32) tested over a daytime wake retention interval, with adolescents even showing superior veridical recall after wake. Our findings suggest that slow oscillation-spindle coupling as a mechanism of sleep-dependent memory formation becomes increasingly relevant during childhood and early adolescence. However, wake-associated mechanisms similarly effective in forming medium-term memory exist in this age as well. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Memory for nonadjacent dependencies in the first year of life and its relation to sleep.

Grammar learning requires memory for dependencies between nonadjacent elements in speech. Immediate learning of nonadjacent dependencies has been observed in very young infants, but their memory of such dependencies has remained unexplored. Here we used event-related potentials to investigate whether 6- to 8-month-olds retain nonadjacent dependencies and if sleep after learning affects this memory. Infants were familiarised with two rule-based morphosyntactic dependencies, presented in sentences of an unknown language. Brain responses after a retention period reveal memory of the nonadjacent dependencies, independent of whether infants napped or stayed awake. Napping, however, altered a specific processing stage, suggesting that memory evolves during sleep. Infants with high left frontal spindle activity show an additional brain response indicating memory of individual speech phrases. Results imply that infants as young as 6 months are equipped with memory mechanisms relevant to grammar learning. They also suggest that during sleep, consolidation of highly specific information can co-occur with changes in the nature of generalised memory.

Protocol for spike-triggered closed-loop auditory stimulation during sleep in patients with epilepsy.

Several epilepsies are characterized by interictal spikes in the electroencephalogram occurring preferentially during sleep. We present a closed-loop auditory stimulation protocol with potential for treating sleep epilepsies. We describe the pre-sleep preparations, sleep recordings, the auditory stimulation, in which tones are triggered upon spike detection, and post-sleep procedures. This protocol has been shown to decrease likelihood and amplitude of subsequent spikes in patients with BECTS (Benign epilepsy with centrotemporal spikes) and can be applied to study non-pharmacological treatments of sleep epilepsies. For complete details on the use and execution of this protocol, please refer to Klinzing et al. (2021).

Two distinct ways to form long-term object recognition memory during sleep and wakefulness.

Memory consolidation is promoted by sleep. However, there is also evidence for consolidation into long-term memory during wakefulness via processes that preferentially affect nonhippocampal representations. We compared, in rats, the effects of 2-h postencoding periods of sleep and wakefulness on the formation of long-term memory for objects and their associated environmental contexts. We employed a novel-object recognition (NOR) task, using object exploration and exploratory rearing as behavioral indicators of these memories. Remote recall testing (after 1 wk) confirmed significant long-term NOR memory under both conditions, with NOR memory after sleep predicted by the occurrence of EEG spindle-slow oscillation coupling. Rats in the sleep group decreased their exploratory rearing at recall testing, revealing successful recall of the environmental context. By contrast, rats that stayed awake after encoding showed equally high levels of rearing upon remote testing as during encoding, indicating that context memory was lost. Disruption of hippocampal function during the postencoding interval (by muscimol administration) suppressed long-term NOR memory together with context memory formation when animals slept, but enhanced NOR memory when they were awake during this interval. Testing remote recall in a context different from that during encoding impaired NOR memory in the sleep condition, while exploratory rearing was increased. By contrast, NOR memory in the wake rats was preserved and actually superior to that after sleep. Our findings indicate two distinct modes of long-term memory formation: Sleep consolidation is hippocampus dependent and implicates event-context binding, whereas wake consolidation is impaired by hippocampal activation and strengthens context-independent representations.

Effects of Information Load on Schema and Episodic Memory Formation.

The formation of semantic memories is assumed to result from the abstraction of general, schema-like knowledge across multiple experiences, while at the same time, episodic details from individual experiences are forgotten. Against this backdrop, our study examined the effects of information load (high vs. low) during encoding on the formation of episodic and schema memory using an elaborated version of an object-place recognition (OPR) task in rats. The task allowed for the abstraction of a spatial rule across four (low information load) or eight (high information load) encoding episodes (spaced apart by a 20 min interval) in which the rats could freely explore two objects in an open field arena. After this encoding phase, animals were left undisturbed for 24 h and then tested either for the expression of schema memory, i.e., for the spatial rule, or memory for an individual encoding episode. Rats in the high information load condition exhibited a more robust schema memory for the spatial rule than in the low information load condition. In contrast, rats in the low load condition showed more robust memory for individual learning episodes than in the high information load condition. Our findings of opposing effects might point to an information-load-dependent competitive relationship between processes of schema and episodic memory formation, although other explanations are possible.