Hippocampus-dependent Declarative Memory Research Articles

Neurochemical mechanisms for memory processing during sleep: basic findings in humans and neuropsychiatric implications.

Sleep is essential for memory formation. Active systems consolidation maintains that memory traces that are initially stored in a transient store such as the hippocampus are gradually redistributed towards more permanent storage sites such as the cortex during sleep replay. The complementary synaptic homeostasis theory posits that weak memory traces are erased during sleep through a competitive down-selection mechanism, ensuring the brain's capability to learn new information. We discuss evidence from neuropharmacological experiments in humans to show how major neurotransmitters and neuromodulators are implicated in these memory processes. As to the major excitatory neurotransmitter glutamate that plays a prominent role in inducing synaptic consolidation, we show that these processes, while strengthening cortical memory traces during sleep, are insufficient to explain the consolidation of hippocampus-dependent declarative memories. In the inhibitory GABAergic system, we will offer insights how drugs may alter the intricate interplay of sleep oscillations that have been identified to be crucial for strengthening memories during sleep. Regarding the dopaminergic reward system, we will show how it is engaged during sleep replay, but that dopaminergic neuromodulation likely plays a side role for enhancing relevant memories during sleep. Also, we briefly go into basic evidence on acetylcholine and cortisol whose low tone during slow wave sleep (SWS) is crucial in supporting hippocampal-to-neocortical memory transmission. Finally, we will outline how these insights can be used to improve treatment of neuropsychiatric disorders focusing mainly on anxiety disorders, depression, and addiction that are strongly related to memory processing.

Neuroanatomical alterations and synaptic plasticity impairment in the perirhinal cortex of the Ts65Dn mouse model of Down syndrome

Down syndrome (DS), a genetic condition due to triplication of Chromosome 21, is characterized by numerous neurodevelopmental alterations and intellectual disability. Individuals with DS and DS mouse models are impaired in several memory domains, including hippocampus-dependent declarative (spatial, in rodents) memory and visual recognition memory, a form of memory in which the perirhinal cortex (PRC) plays a fundamental role. The anatomo-functional substrates of hippocampus-dependent memory impairment have been largely elucidated in the Ts65Dn mouse model of DS. In contrast, there is a lack of corresponding information regarding visual recognition memory. Therefore, we deemed it of interest to examine at both an anatomical and functional level the PRC of Ts65Dn mice. We found that the PRC of adult (1.5–3.5month-old) Ts65Dn mice exhibited diffused hypocellularity and neurons with a reduced spine density. No difference between Ts65Dn and euploid mice was detected in the abundance of glutamatergic and GABAergic terminals. We examined brain slices for long-term potentiation (LTP), a form of synaptic plasticity involved in long-term memory. Theta burst stimulation of intracortical fibers was used in order to elicit LTP in the superficial layers of the PRC. We found that in trisomic slices LTP had a similar time-course but a reduced magnitude in comparison with euploid slices. While exposure to the GABAA receptor antagonist picrotoxin had no effect on LTP magnitude, exposure to the GABAB receptor antagonist CGP55845 caused an increase in LTP magnitude that became even larger than in euploid slices. Western blot analysis showed increased levels of the G-protein-activated inwardly rectifying K+ channel 2 (GIRK2) in the PRC of Ts65Dn mice, consistent with triplication of the gene coding for GIRK2. This suggests that the reduced magnitude of LTP may be caused by GIRK2-dependent exaggerated GABAB receptor-mediated inhibition. Results provide novel evidence for anatomo-functional alterations in the PRC of Ts65Dn mice. These alterations may underlie trisomy-due impairment in visual recognition memory.

Involvement of sleep spindles in overnight declarative memory stabilization

Objective Numerous studies point to the involvement of sleep spindles and slow waves in memory processes, particularly in hippocampus-dependent declarative memory. We have shown previously that the overnight change in recall performance in a declarative word pair association task correlates significantly with increased spindle activity during the night after learning compared to a control night. The current study re-evaluates this relationship in detail and explores whether the observed positive correlation of two spindle parameters measured during stage 2 (S2) sleep with overnight stabilization depend on the time of night (early vs. late) and spindle type (fast vs. slow).

The search for a hippocampal engram

Understanding the molecular and cellular changes that underlie memory, the engram, requires the identification, isolation and manipulation of the neurons involved. This presents a major difficulty for complex forms of memory, for example hippocampus-dependent declarative memory, where the participating neurons are likely to be sparse, anatomically distributed and unique to each individual brain and learning event. In this paper, I discuss several new approaches to this problem. In vivo calcium imaging techniques provide a means of assessing the activity patterns of large numbers of neurons over long periods of time with precise anatomical identification. This provides important insight into how the brain represents complex information and how this is altered with learning. The development of techniques for the genetic modification of neural ensembles based on their natural, sensory-evoked, activity along with optogenetics allows direct tests of the coding function of these ensembles. These approaches provide a new methodological framework in which to examine the mechanisms of complex forms of learning at the level of the neurons involved in a specific memory.

Sex differences in stress effects on response and spatial memory formation

Stress and stress hormones are known to affect learning and memory processes. However, although effects of stress on hippocampus-dependent declarative learning and memory are well-documented, relatively little attention has been paid to the impact of stress on striatum-dependent stimulus–response (S–R) learning and memory. Recent evidence indicates that glucocorticoid stress hormones shortly after learning enhance S–R memory consolidation, whereas stress prior to retention testing impairs S–R memory retrieval. Whether stress affects also the acquisition of S–R memories in humans remains unclear. For this reason, we examined here the effects of acute stress on S–R memory formation and contrasted these stress effects with those on hippocampus-dependent spatial memory. Healthy men and women underwent a stressor (socially evaluated cold pressor test, SECPT) or a control manipulation before they completed an S–R task and two spatial learning tasks. Memory was assessed one week later. Our data showed that stress impaired S–R memory performance in men but not in women. Conversely, spatial memory was impaired by stress in women but not in men. These findings provide further evidence that stress may alter learning and memory processes beyond the hippocampus. Moreover, our data underline that participants’ sex may play a critical role in the impact of stress on multiple memory systems.

Differential contribution of mineralocorticoid and glucocorticoid receptors to memory formation during sleep

Corticosteroids are known to modulate the consolidation of memories during sleep, specifically in the hippocampus-dependent declarative memory system. However, effects of the major human corticosteroid cortisol are conveyed via two different receptors, i.e., mineralocorticoid (MRs) and glucocorticoid receptors (GRs) whose specific contributions to memory consolidation are unclear. Whereas a shift in the balance between MR and GR activation toward predominant GR activation has been found to impair sleep-dependent consolidation of declarative memories, the effect of predominant MR activation is not well characterized. Here, we examined differential corticosteroid receptor contributions to memory consolidation during post-learning sleep in two placebo-controlled double-blind studies in humans, by comparing the effects of the selective MR agonist fludrocortisone (0.2 mg, orally, Study 1) and of hydrocortisone (22 mg, intravenously, Study 2) with strong binding affinity to both MR and GR. We hypothesized increased activation of MRs during sleep to enhance declarative memory consolidation, but the joint MR/GR activation to impair it. Participants (16 men in each study) learned a declarative (word pair associates) and a procedural task (mirror tracing) before a 7-h period of nocturnal retention sleep, with the substances administered before sleep (Study 1) and during sleep (Study 2), respectively. As hypothesized, retention of word pairs, but not of mirror tracing skill, was selectively enhanced by the MR agonist fludrocortisone. An impairing effect of hydrocortisone on word pair retention remained non-significant possibly reflecting that hydrocortisone administration failed to establish robust predominance of GR activation. Our results show that predominant MR activation benefits declarative memory consolidation presumably by enhancing the sleep-dependent reactivation of hippocampal memories and resultant synaptic plastic processes. The effect is counteracted by additional GR activation. Insufficient MR activation, like GR overactivation, might be a factor contributing to memory impairment in pathological conditions.

Sleep-Dependent Declarative Memory Consolidation—Unaffected after Blocking NMDA or AMPA Receptors but Enhanced by NMDA Coagonist D-Cycloserine

Sleep has a pivotal role in the consolidation of declarative memory. The coordinated neuronal replay of information encoded before sleep has been identified as a key process. It is assumed that the repeated reactivation of firing patterns in glutamatergic neuron assemblies translates into plastic synaptic changes underlying the formation of longer-term neuronal representations. Here, we tested the effects of blocking and enhancing glutamatergic neurotransmission during sleep on declarative memory consolidation in humans. We conducted three placebo-controlled, crossover, double-blind studies in which participants learned a word-pair association task. Afterwards, they slept in a sleep laboratory and received glutamatergic modulators. Our first two studies aimed at impairing consolidation by administering the NMDA receptor blocker ketamine and the AMPA receptor blocker caroverine during retention sleep, which, paradoxically, remained unsuccessful, inasmuch as declarative memory performance was unaffected by the treatment. However, in the third study, administration of the NMDA receptor coagonist D-cycloserine (DCS) during retention sleep facilitated consolidation of declarative memory (word pairs) but not consolidation of a procedural control task (finger sequence tapping). Administration of DCS during a wake interval remained without effect on retention of word pairs but improved encoding of numbers. From the overall pattern, we conclude that the consolidation of hippocampus-dependent declarative memory during sleep relies on NMDA-related plastic processes that differ from those processes leading to wake encoding. We speculate that glutamatergic activation during sleep is not only involved in consolidation but also in forgetting of hippocampal memory with both processes being differentially sensitive to DCS and unselective blockade of NMDA and AMPA receptors.

Mineralocorticoid Receptor Blockade Prevents Stress-Induced Modulation of Multiple Memory Systems in the Human Brain

Accumulating evidence suggests that stress may orchestrate the engagement of multiple memory systems in the brain. In particular, stress is thought to favor dorsal striatum-dependent procedural over hippocampus-dependent declarative memory. However, the neuroendocrine mechanisms underlying these modulatory effects of stress remain elusive, especially in humans. Here, we targeted the role of the mineralocorticoid receptor (MR) in the stress-induced modulation of dorsal striatal and hippocampal memory systems in the human brain using a combination of event-related functional magnetic resonance imaging and pharmacologic blockade of the MR. Eighty healthy participants received the MR antagonist spironolactone (300 mg) or a placebo and underwent a stressor or control manipulation before they performed, in the scanner, a classification task that can be supported by the hippocampus and the dorsal striatum. Stress after placebo did not affect learning performance but reduced explicit task knowledge and led to a relative increase in the use of more procedural learning strategies. At the neural level, stress promoted striatum-based learning at the expense of hippocampus-based learning. Functional connectivity analyses showed that this shift was associated with altered coupling of the amygdala with the hippocampus and dorsal striatum. Mineralocorticoid receptor blockade before stress prevented the stress-induced shift toward dorsal striatal procedural learning, same as the stress-induced alterations of amygdala connectivity with hippocampus and dorsal striatum, but resulted in significantly impaired performance. Our findings indicate that the stress-induced shift from hippocampal to dorsal striatal memory systems is mediated by the amygdala, required to preserve performance after stress, and dependent on the MR.

Partial loss in septo-hippocampal cholinergic neurons alters memory-dependent measures of brain connectivity without overt memory deficits

The functional relevance of septo-hippocampal cholinergic (SHC) degeneration to the degradation of hippocampus-dependent declarative memory (DM) in aging and Alzheimer's disease (AD) remains ill-defined. Specifically, selective SHC lesions often fail to induce overt memory impairments in animal models. In spite of apparent normal performance, however, neuronal activity within relevant brain structures might be altered by SHC disruption. We hypothesized that partial SHC degeneration may contribute to functional alterations within memory circuits occurring in aging before DM decline. In young adult mice, we studied the effects of behaviorally ineffective (saporin-induced) SHC lesions – similar in extent to that seen in aged animals – on activity patterns and functional connectivity between three main neural memory systems: the septo-hippocampal system, the striatum and the amygdala that sustain declarative, procedural and emotional memory, respectively. Animals were trained in a radial maze procedure dissociating the human equivalents of relational/DM and non-R/DM expressions in animals. Test-induced Fos activation pattern revealed that the partial SHC lesion significantly altered the brain's functional activities and connectivity (co-activation pattern) despite the absence of overt behavioral deficit. Specifically, hippocampal CA3 hyperactivity and abnormal septo-hippocampo-amygdalar inter-connectivity resemble those observed in aging and prodromal AD. Hence, SHC neurons critically coordinate hippocampal function in concert with extra-hippocampal structures in accordance with specific mnemonic demand. Although partial SHC degeneration is not sufficient to impact DM performance by itself, the connectivity change might predispose the emergence of subsequent DM loss when, due to additional age-related insults, the brain can no longer compensate the holistic imbalance caused by cholinergic loss.

Sleep Microstructure and Memory Function

Several studies investigated the effect of sleep on memory. In humans, arguably the first experimental description of a ben-eficial role of sleep for memory stabiliza-tion was provided in 1924 (1), indicating a protective benefit of sleep in prevent-ing the normal decay-curve of forgetting that develops across time spent awake. Specific stages of sleep appear to be criti-cal for memory consolidation. Memory is commonly divided into a declarative and a non-declarative memory system (2). Declarative memory is defined by memo-ries accessible to conscious recollection, i.e., memories for events in a spatio-tem-poral context (episodic memory) and fact-based information (semantic memory). Procedural memory for skills is the type of non-declarative memory most thoroughly studied with regard to the effects of sleep. Sleep is characterized by the cyclic occur-rence of REM and NREM sleep comprising SWS (sleep stages 3 and 4) and lighter sleep stages 1 and 2. Two hypotheses were pro-posed regarding sleep stages and memory consolidation (3). The dual process the-ory assumes that the specific sleep stages support consolidation of different types of memories. SWS supports declarative memory consolidation whereas REM sleep does so for procedural memories ( 4). The sequential hypothesis, on the other hand, proposes that sleep benefits memory opti-mally through the cyclic succession of both SWS and REM sleep. The original version of this hypothesis assumed that SWS func-tions to weaken non-adaptive memory traces whereas REM sleep re-stores the remaining traces (5). The dual process hypothesis received support mainly based on the early late sleep comparison, i.e., an approach comparing effects of retention intervals covering the first (SWS-rich) or the second (REM sleep-rich) half of nocturnal sleep. SWS-rich early sleep con-sistently found to support consolidation of hippocampus-dependent declarative memories, whereas REM sleep benefited non-declarative types of memory like priming, and memories for visuo-motor skills ( 6, 7). However, this dichotomy does not fit all results. Several non-declarative tasks, like visual texture discrimination, are also supported by SWS whereas REM sleep in some instances seems to benefit aspects of declarative memory (8).More recently, Genzel and colleagues (9) tried to clarify the link between spe-cific sleep stages and different types of memory consolidation by suppressing sleep stages. They deprived subjects once each of REM sleep and SWS, and once let them sleep undisturbed through the night. After each night, the authors tested declarative and procedural memory con-solidation. Although REM sleep and SWS awakenings led to a significant reduction of the respective sleep stages, memory con-solidation remained unaffected. According to the authors, there are two possible explanations for REM deprivation and SWS deprivation not influencing sleep-dependent consolidation of motor tasks: (1) the diminished amount of REM sleep in the REM deprivation condition was still sufficient for sleep-dependent memory consolidation or (2) the memory con-solidation is dependent on stage 2 sleep. Another explanation of the results is that sleep-associated processes contributing to memory consolidation requires analyses of polysomnographic phenomena, like sleep spindles and slow-wave activity (SWA). This aspect is very important also for the implications for the cognitive decline by increasing age (10, 11). Other factors that change with age, such as hormones and neurotransmitters, or hypoxia related to sleep-disordered breathing (12, 13), may also play an important role.

Memory for Semantically Related and Unrelated Declarative Information: The Benefit of Sleep, the Cost of Wake

Numerous studies have examined sleep's influence on a range of hippocampus-dependent declarative memory tasks, from text learning to spatial navigation. In this study, we examined the impact of sleep, wake, and time-of-day influences on the processing of declarative information with strong semantic links (semantically related word pairs) and information requiring the formation of novel associations (unrelated word pairs). Participants encoded a set of related or unrelated word pairs at either 9am or 9pm, and were then tested after an interval of 30 min, 12 hr, or 24 hr. The time of day at which subjects were trained had no effect on training performance or initial memory of either word pair type. At 12 hr retest, memory overall was superior following a night of sleep compared to a day of wakefulness. However, this performance difference was a result of a pronounced deterioration in memory for unrelated word pairs across wake; there was no sleep-wake difference for related word pairs. At 24 hr retest, with all subjects having received both a full night of sleep and a full day of wakefulness, we found that memory was superior when sleep occurred shortly after learning rather than following a full day of wakefulness. Lastly, we present evidence that the rate of deterioration across wakefulness was significantly diminished when a night of sleep preceded the wake period compared to when no sleep preceded wake, suggesting that sleep served to stabilize the memories against the deleterious effects of subsequent wakefulness. Overall, our results demonstrate that 1) the impact of 12 hr of waking interference on memory retention is strongly determined by word-pair type, 2) sleep is most beneficial to memory 24 hr later if it occurs shortly after learning, and 3) sleep does in fact stabilize declarative memories, diminishing the negative impact of subsequent wakefulness.

Electric field modulation of long-term plastic effects

Event Abstract Back to Event Electric field modulation of long-term plastic effects Belen Lafon1*, Davide Reato1, Asif Rahman1, Marom Bikson1 and Lucas C. Parra1 1 City College of the City University of New York, United States Transcranial electrical stimulation in humans can lead to electric fields of at most 1V/m on the cortical surface. This may polarize cell membranes by a fraction of a milivolt. While these intensities seem very small, there are a number of in vitro experiments explaining the basic mechanisms by which such low-amplitude electric fields may nevertheless acutely alter neuronal activity, both at the single cell and at the network level . However, the long-term plastic effects which have been repeatedly observed clinically are less understood. Here we are particularly interested in the effects of slow-oscillating stimulation during sleep which were shown to boost the consolidation of hippocampus-dependent declarative memory. How synaptic connections are modified resulting in a memory improvement is still unknown. Currently, two main complementary hypotheses exist regarding consolidation of memory during sleep. The synaptic homeostasis hypothesis conjunctures that consolidation is in part a result of synaptic downscaling that improves the signal-to-noise ratio for all synapses that were potentiated during prior waking experiences. The active system consolidation hypothesis proposes an active consolidation process where learning-specific synaptic connections are strengthened by means of increased plasticity-related immediate early gene transcription and induction of LTP. Slow-oscillating stimulation might be improving memory consolidation by means of modulating synaptic downscaling and/or learning-specific synaptic connections. Current results of our group show that this low-amplitude fields induced an effect on the homeostatic downscaling of endogenous slow-waves during sleep. However, the modulation LTP processes related to the potentiation of learning related synapses has not yet been studied for such fields. Previous studies show that electrical stimulation coupled with ongoing activity in the brain induces plasticity, here we will focus on the modulation of LTP processes while applying acutely several low-amplitude field configurations. Thus linking the long-term behavioral effects with acute electrical stimulation. References Nature. 2006 Nov 30;444(7119):610-3. Epub 2006 Nov 5. Boosting slow oscillations during sleep potentiates memory. Marshall L, Helgadóttir H, Mölle M, Born J. Sleep Med Rev. 2006 Feb;10(1):49-62. Epub 2005 Dec 22. Sleep function and synaptic homeostasis. Tononi G, Cirelli C. Nat Rev Neurosci. 2010 Feb;11(2):114-26. Epub 2010 Jan 4. The memory function of sleep. Diekelmann S, Born J. Keywords: plasticity, Electrical Stimulation, Sleep, long term potentiation, HIPPOCAMPUS AND MEMORY Conference: Bernstein Conference 2012, Munich, Germany, 12 Sep - 14 Sep, 2012. Presentation Type: Poster Topic: Learning, plasticity, memory Citation: Lafon B, Reato D, Rahman A, Bikson M and Parra LC (2012). Electric field modulation of long-term plastic effects. Front. Comput. Neurosci. Conference Abstract: Bernstein Conference 2012. doi: 10.3389/conf.fncom.2012.55.00035 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 18 Jun 2012; Published Online: 12 Sep 2012. * Correspondence: Miss. Belen Lafon, City College of the City University of New York, New York, United States, belulafon@gmail.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Belen Lafon Davide Reato Asif Rahman Marom Bikson Lucas C Parra Google Belen Lafon Davide Reato Asif Rahman Marom Bikson Lucas C Parra Google Scholar Belen Lafon Davide Reato Asif Rahman Marom Bikson Lucas C Parra PubMed Belen Lafon Davide Reato Asif Rahman Marom Bikson Lucas C Parra Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Working Memory Performance Is Associated with Common Glucocorticoid Receptor Gene Polymorphisms

Cortisol has a modulatory influence on cognitive functions in humans. Both impairing and enhancing effects of cortisol administration have been shown for hippocampus-dependent declarative memory, and impairing effects have been shown for prefrontal-cortex-dependent working memory function. Given the high density of glucocorticoid (GC) receptors in the prefrontal cortex, we investigated whether common polymorphisms of the GC receptor (GR) gene (ER22/23EK, N363S, BclI, 9β A3669G) modulate the influence of cortisol administration on working memory. Working memory performance was investigated in 169 subjects on 10 mg hydrocortisone (cortisol) and placebo using an item recognition task. No impairing effect of hydrocortisone treatment became evident. However, a sex × genotype interaction on general working memory performance was revealed (p = 0.02). While female heterozygous carriers of the 9β G allele displayed faster reaction times than the other genotype groups, 9β G heterozygous men were relatively slower. Heritability estimates for memory are roughly 50%, indicating that common genetic polymorphisms have an important impact on cognitive performance. Our results suggest that variants of the GR gene might explain some of the variance attributable to genetic factors. Furthermore, it can be speculated that they modulate the individual vulnerability for memory impairments related to stress-related psychiatric disorders.

Still Missing Some Significant Ingredients

Still Missing Some Significant Ingredients

Protein synthesis is essential not only for consolidation but also for maintenance and post-retrieval reconsolidation of acrobatic motor skill in rats

It has been reported that consolidation of motor skill, a type of non-declarative memories, requires protein synthesis, as hippocampus-dependent declarative memory does. However, little is known about the importance of protein synthesis in maintenance and especially post-retrieval reconsolidation of acrobatic motor skill. Here, we show that protein synthesis is essential not only for the consolidation but also for the maintenance and reconsolidation of a rotarod-running skill. Intra-ventricle infusion of the protein synthesis inhibitor anisomycin 0 h but not 2 h post-training caused a severe deficit in the acquisition of the rotarod-running skill. Protein synthesis inhibition (PSI) also caused a deficit in the maintenance of the rotarod-running skill, as well-trained rats demonstrated a deficit in the rotarod-running performance upon treatment with anisomycin. Similarly, PSI impaired the post-retrieval reconsolidation of the rotarod-running skill: well-trained rats treated with anisomycin 0 h but not 0.5, 2 and 4 h after the task performance exhibited amnesia for the running skill later on. Interestingly, rats treated with anisomycin 6 and 12 h post-retrieval exhibited amnesia for the running skill. Thus, protein synthesis is essential not only for the consolidation but also for the maintenance and post-retrieval reconsolidation of rotarod-running acrobatic motor skill.

Memory consolidation during sleep: Interactive effects of sleep stages and HPA regulation

Sleep is critically involved in the consolidation of previously acquired memory traces. However, nocturnal sleep is not uniform but is subject to distinct changes in electrophysiological and neuroendocrine activity. Specifically, the first half of the night is dominated by slow wave sleep (SWS), whereas rapid eye movement (REM) sleep prevails in the second half. Concomitantly, hypothalamo-pituitary–adrenal (HPA) activity as indicated by cortisol release is suppressed to a minimum during early sleep, while drastically increasing during late sleep. We have shown that the different sleep stages and the concomitant glucocorticoid release are interactively involved in the consolidation of different types of memories. SWS-rich early sleep has been demonstrated to benefit mainly the consolidation of hippocampus-dependent declarative memories (i.e. facts and episodes). In contrast, REM sleep-rich late sleep was shown to improve in particular emotional memories involving amygdalar function, as well as procedural memories (for skills) not depending on hippocampal or amygdalar function. Enhancing plasma glucocorticoid concentrations during SWS-rich early sleep counteracted hippocampus-dependent declarative memory consolidation, but did not affect hippocampus-independent procedural memory. Preventing the increase in cortisol during late REM sleep-rich sleep by administration of metyrapone impaired hippocampus-dependent declarative memory but enhanced amygdala-dependent emotional aspects of memory. The data underscore the importance of pituitary–adrenal inhibition during early SWS-rich sleep for efficient consolidation of declarative memory. The increase in cortisol release during late REM sleep-rich sleep may counteract an overshooting consolidation of emotional memories.

Sleep Enforces the Temporal Order in Memory

BackgroundTemporal sequence represents the main principle underlying episodic memory. The storage of temporal sequence information is thought to involve hippocampus-dependent memory systems, preserving temporal structure possibly via chaining of sequence elements in heteroassociative networks. Converging evidence indicates that sleep enhances the consolidation of recently acquired representations in the hippocampus-dependent declarative memory system. Yet, it is unknown if this consolidation process comprises strengthening of the temporal sequence structure of the representation as well, or is restricted to sequence elements independent of their temporal order. To address this issue we tested the influence of sleep on the strength of forward and backward associations in word-triplets.Methodology/Principal FindingsSubjects learned a list of 32 triplets of unrelated words, presented successively (A-B-C) in the center of a screen, and either slept normally or stayed awake in the subsequent night. After two days, retrieval was assessed for the triplets sequentially either in a forward direction (cueing with A and B and asking for B and C, respectively) or in a backward direction (cueing with C and B and asking for B and A, respectively). Memory was better for forward than backward associations (p<0.01). Sleep did not affect backward associations, but enhanced forward associations, specifically for the first (AB) transitions (p<0.01), which were generally more difficult to retrieve than the second transitions.Conclusions/SignificanceOur data demonstrate that consolidation during sleep strengthens the original temporal sequence structure in memory, presumably as a result of a replay of new representations during sleep in forward direction. Our finding suggests that the temporally directed replay of memory during sleep, apart from strengthening those traces, could be the key mechanism that explains how temporal order is integrated and maintained in the trace of an episodic memory.

Odor Cues During Slow-Wave Sleep Prompt Declarative Memory Consolidation

Sleep facilitates memory consolidation. A widely held model assumes that this is because newly encoded memories undergo covert reactivation during sleep. We cued new memories in humans during sleep by presenting an odor that had been presented as context during prior learning, and so showed that reactivation indeed causes memory consolidation during sleep. Re-exposure to the odor during slow-wave sleep (SWS) improved the retention of hippocampus-dependent declarative memories but not of hippocampus-independent procedural memories. Odor re-exposure was ineffective during rapid eye movement sleep or wakefulness or when the odor had been omitted during prior learning. Concurring with these findings, functional magnetic resonance imaging revealed significant hippocampal activation in response to odor re-exposure during SWS.

Transcranial slow Oscillatory Stimulation Drives Consolidation of Declarative Memory by Synchronization of the Neocortex

Evaluation of: Marshall L, Helgadottir H, Molle M, Born J: Boosting slow oscillations during sleep potentiates memory. Nature 444, 610–613 (2006). Slow-wave sleep plays a crucial role in the consolidation of declarative memory. During this sleep stage the electroencephalogram predominantly shows slow oscillatory activity and slow sleep spindles. The latter are likely to be linked to hippocampal fast ripples and subsequent neuronal firing, presumably supporting the transformation of memory. Anodal transcranial direct-current stimulation generates a temporary negativity of the extracellular space in the underlying tissue, secondarily causing a shift of the neuronal membrane potential towards depolarization. A novel type of transcranial ‘intermittent’ slow oscillatory stimulation was applied over the frontal cortex during early stage-two sleep with the purpose of inducing endogenous slow oscillations and slow spindle activity. It is argued that this form of stimulation elicited a specific enhancement of the hippocampus-dependent declarative memory, while the nondeclarative memory remained unaffected. It is proposed that transcranial slow oscillatory stimulation, capable of modulating a wide thalamo–cortico–hippocampal network, could contribute to the treatment of memory and sleep disorders.

Boosting slow oscillations during sleep potentiates memory

There is compelling evidence that sleep contributes to the long-term consolidation of new memories. This function of sleep has been linked to slow (<1 Hz) potential oscillations, which predominantly arise from the prefrontal neocortex and characterize slow wave sleep. However, oscillations in brain potentials are commonly considered to be mere epiphenomena that reflect synchronized activity arising from neuronal networks, which links the membrane and synaptic processes of these neurons in time. Whether brain potentials and their extracellular equivalent have any physiological meaning per se is unclear, but can easily be investigated by inducing the extracellular oscillating potential fields of interest. Here we show that inducing slow oscillation-like potential fields by transcranial application of oscillating potentials (0.75 Hz) during early nocturnal non-rapid-eye-movement sleep, that is, a period of emerging slow wave sleep, enhances the retention of hippocampus-dependent declarative memories in healthy humans. The slowly oscillating potential stimulation induced an immediate increase in slow wave sleep, endogenous cortical slow oscillations and slow spindle activity in the frontal cortex. Brain stimulation with oscillations at 5 Hz--another frequency band that normally predominates during rapid-eye-movement sleep--decreased slow oscillations and left declarative memory unchanged. Our findings indicate that endogenous slow potential oscillations have a causal role in the sleep-associated consolidation of memory, and that this role is enhanced by field effects in cortical extracellular space.