©2010 Taipei Medical University
R E V I E W A R T I C L E
1. Introduction
Research over the last half century has demonstrated that memory is not unified but is instead composed of anatomically and mechanistically distinct processes.1 The greatest dissociation is between memories that depend on the hippocampus versus those that do not. Hippocampal-dependent memories, also called
declarative or explicit memories, are memories for peo-ple, places, or things; memories that we can consciously manipulate. In contrast, hippocampal-independent memories, also called non-declarative or implicit mem-ories, are memories to which we do not have conscious access, such as procedural and perceptual learning, hab-its, priming and conditioning. One strategy for gaining insight into this wide range of memory processes is to
The enhancement of normal cognition and breakthrough treatments in cognitive disorders require an improved understanding of memory consolidation. Insights into the mechanisms of memory consolidation have been advanced by the incorporation of a quantifiable variable: sleep. Over the past 20 years, a substantial number of studies have shown that memory performance is facilitated after a bout of sleep, compared with the same period of waking, implicating a slow, offline process during sleep that transforms the memory trace into a more robust form through a consolidation process. Until recently, the majority of these studies have examined cognitive tasks that utilize non-declarative, procedural memory (e.g., knowing “how”, learning actions, habits, perceptual and motor skills, and implicit learning) to show enhanced performance above baseline. Recent attention has turned to studying the relationship between sleep and declarative memory, which refers to con-sciously accessible memories of fact-based information (i.e., knowing “what”, in terms of events, places, and general knowledge) that are dependent on the hippocampus. Although the exact nature of the relationship between sleep and declarative memory consolidation is hotly debated, there is strong emerging evidence for the importance of slow wave sleep. In contrast with the “enhancement” model of procedural memory, there are two declarative memory models; first, the active model, in which memory depends on sleep specifically; and second, the permissive model, which posits a time-dependent, interference-sensitive process that opportunistically seizes any period of dampened hippocampal input to fur-ther process prior, learned information. We review the evidence for the active and permis-sive models and discuss areas of research that would benefit from future studies. Bridging these scientific fields will impact fundamental research in memory, sleep and pharmacol-ogy, as well as have relevance for treatment of memory impairments affecting people with mental illness and age-related cognitive decline.
Received: Mar 5, 2010 Revised: Apr 25, 2010 Accepted: May 2, 2010 KEY WORDS: declarative memory; GABA; hippocampus; implicit memory; memory; motor learning; nap; napping; perceptual learning; pharmacology; procedural memory; sleep
Comparing Models of Sleep-dependent Memory
Consolidation
Sara C. Mednick
1*, William A. Alaynick
21Department of Psychiatry, University of California, San Diego, San Diego, California, USA 2ScholarNexus, LLC, San Diego, California, USA
*Corresponding author. Department of Psychiatry 9116a, University of California, San Diego, 3350 La Jolla Village Drive, San Diego, CA 92116, USA.
study variables that seem to modulate memory, such as sleep and pharmacological agents. Studies of sleep and memory suggest that select types of memories are facilitated during sleep, with procedural and percep-tual learning2 typically exhibiting an absolute improve-ment in performance, and episodic memory typically exhibiting less forgetting.3 In addition, specific sleep stages are correlated with the consolidation of proce-dural and declarative memories. Furthermore, recent studies have shown that more experimentally tractable naps are as effective as nocturnal sleep in these mem-ory processes.4–8 Studies of procedural learning show that rapid eye movement (REM) sleep improves per-formance beyond the level attained at the end of train-ing through a slow, offline process.9 The role of sleep in declarative memory, on the other hand, has been more difficult to ascertain; however, studies indicate that slow wave sleep (SWS) may protect memories from interfer-ence, and, in so doing, lessen forgetting, perhaps by facilitating consolidation.10 The degree to which sleep, per se, is essential for declarative memory consolidation has not yet been established.
The reduced deterioration of declarative memory traces by SWS has also been observed in some phar-macologically-induced brain states. Specifically, in the case of retrograde facilitation, memory for information learned just prior to administration of benzodiazepines or ethanol is enhanced, compared to placebo. These findings suggest that the brain state of sleep may be an ideal physiological state for declarative memory consoli-dation, which may be mimicked or enhanced by phar-macology. Thus, contrary to the sleep-dependence of procedural learning, declarative memory consolidation may be a time-dependent, interference-sensitive process that opportunistically seizes any period of dampened brain state, by sleep or pharmacology, to further process prior learned information. Future studies should aim to elucidate the underlying mechanisms of declarative memory consolidation, distinct from procedural learn-ing. In doing so, these studies would unify two distinct fields, psychopharmacology and sleep, in order to dis-cover common or separable mechanisms of learning.
2. Learning and Memory
With practice, humans generally show performance improvement on tasks. For example, practice leads to: (1) lower thresholds for detection or discrimination in a sensory task; (2) a greater number of words remem-bered in a declarative memory task; (3) more rapid lo-cation of a target on a spatial maze task; and (4) lower error rates on a motor task. Although these tasks differ considerably in their information content and their un-derlying neural mechanisms, they all represent facets of the large and unwieldy field of memory. A traditional clas-sification system for memory specifies that declarative
memory includes: episodic memory (comprising knowl-edge of personal events or episodes); and semantic memory (comprising knowledge of “facts” about the world). Non-declarative memory includes: information acquired during skill learning (including motor skills, perceptual skills, and cognitive skills); habit formation, simple classical conditioning; and priming and non-associative learning.11
The past decade of research into the underlying mechanisms of these different memory processes has shown that memory consolidation can be understood in terms of cortical plasticity—from the molecular to systems levels. The processes underlying plasticity occur both during and for some time following task perform-ance. Therefore, investigating the physiologic processes necessary for consolidation to occur may be a useful approach for understanding memory.
3. Mechanisms of Memory
With regard to declarative memory, two forms of con-solidation have been suggested. Synaptic concon-solidation refers to the stabilization of information storage at local nodes in the neuronal circuit that encodes the mem-ory. For example, long-term potentiation (LTP) spreads in the hippocampus, the major cellular model for syn-aptic plasticity that is thought to be associated with memory consolidation, in the hours (and perhaps, days) following the induction of LTP.12 LTP induction in hip-pocampal neurons involves the influx of calcium via postsynaptic N-methyl-D-aspartate (NMDA) receptors.13 When these receptors are blocked by an NMDA antag-onist, high-frequency stimulation fails to induce LTP. Consistent with these findings, NMDA antagonists have often been shown to impair the learning of hippocampal-dependent tasks in animals,14,15 suggesting that LTP-like processes play an important role in the formation of new episodic memories. A second form of consoli-dation associated with declarative memory is systems
consolidation, which refers to the time-limited role of
the hippocampus in explicit memory storage where learning-related changes occur first in the hippocam-pus followed by the gradual development of a more distributed memory trace in the neocortex. The mecha-nism that underlies systems consolidation is not known, but a leading candidate is neural replay, in which cells that are activated in sequence together during a learn-ing episode while awake are more likely to fire in a sim-ilar sequence during sleep16 and rest.17 For declarative memory consolidation, we hypothesize that both short-term synaptic consolidation (perhaps involving the sta-bilization of LTP in the hippocampus) and long-term systems consolidation (perhaps involving neural replay or reactivation) preferentially occur when the hippocam-pus is not encoding new information (i.e., when LTP or LTP-like processes are not being induced).
An important consideration for understanding the time-related effects of synaptic consolidation is that LTP is thought to have at least two stages: early-stage LTP, which does not involve protein synthesis (and dur-ing which time LTP is vulnerable to interference); and late-stage LTP, which does involve protein synthesis associated with morphological changes in dendritic spines and synapses (and after which LTP is less vulner-able to interference). Late-stage LTP, which begins ap-proximately 4–5 hours after the induction of LTP, can be prevented by protein synthesis inhibitors.18,19 Upon reaching the late stage, evidence suggests that LTP is less vulnerable to interference. For example, in experi-mental animals, memories formed in the hippocampus and LTP induced in the hippocampus both exhibit a similar temporal gradient with respect to retroactive interference (vulnerability to having memory traces corrupted by new memories).20,21 In humans, a similar timeline of vulnerability to interference has been shown for sleep-related memory.22,23 That is, sleep immediately after learning results in less forgetting than when sleep is delayed for 10 or more hours post-learning.
4. Sleep-dependent Memory Consolidation
4.1. Sleep structure
Sleep is a highly structured set of processes separated into five stages,24 each demonstrating: (1) stereotypic electrical activity; (2) neurochemical bases; (3) and both enhancement and depression of activities in specific brain regions. The five stages [Stages 1, 2, SWS (Stages 3 and 4) and REM (Stage 5)] progress in a 90–110-minute cycle from Stage 1 through SWS and then to REM sleep (Figure 1). Stages 3 and 4 are often collapsed and re-ferred to as SWS. Adults spend 60% of sleep in Stage 2, about 20% in REM, and the remaining 20% in the other stages, primarily SWS. Stage 1 is briefly observed at sleep onset. Stage 2 sleep is characterized by fast 12– 14-Hz EEG (termed spindles) and slower K-complex sig-nals. Early SWS consists of 0.5–3.0-Hz EEG (delta) and higher frequency signals, whereas later SWS has higher delta content. REM sleep, in contrast to SWS, is a lighter sleep accompanied by rapid irregular shallow breathing, rapid eye movements, increased heart rate, increased cortical blood flow, muscle paralysis, and a predomi-nance of 4–7-Hz EEG theta waves. Perhaps due to the focus of research on REM sleep, researchers commonly divide sleep into REM and non-REM (NREM), as illustrated in Figure 1. Sleep structure is circadian and, across noc-turnal sleep, the amount of SWS progresses from high to low and REM from low to high.
A significant difference between REM and SWS is the relationship to LTP.25–28 Generally, REM sleep has relatively normal synaptic plasticity (e.g., LTP can be in-duced), whereas SWS has reduced plasticity in that LTP
is more difficult to induce.27,28 Diekelmann and Born sug-gest that SWS and REM sleep support systems consoli-dation and synaptic consoliconsoli-dation, respectively. During SWS, slow oscillations, spindles and ripples (at mini-mum cholinergic activity) coordinate the reactivation and redistribution of hippocampus-dependent memo-ries to neocortical sites, whereas during REM sleep, local increases in plasticity-related immediate-early gene activity (at high cholinergic and theta activity) might favor the subsequent synaptic consolidation of memo-ries in the cortex.29
4.2. Procedural memory and sleep
Several studies have demonstrated that REM sleep contributes to perceptual learning. Karni and Sagi de-veloped a texture discrimination task with clear learn-ing results in regards to sleep.30 Specifically, they showed that post-training improvement is only evident several hours after training, and improvement can develop overnight that is REM-dependent.31 Extending these findings, Stickgold and colleagues demonstrated that firstly, improvement in performance on the texture dis-crimination task can only be achieved after 6 hours of nocturnal sleep;32,33 and secondly, additional nights of sleep appear to produce additional, incremental im-provements in performance.33 These improvements occurred without additional training33 and were SWS- and REM-dependent.32 Specifically, improvement was correlated with the product of the number of minutes in SWS in the first part of the night and the number of minutes in REM in the last part of the night. No correla-tion was seen between SWS and REM, indicating that each contributed independently to the improved per-formance. Other laboratories have corroborated these findings.34,35 Anatomically, a functional magnetic reso-nance imaging study showed that, along with improved performance, training could lead to enlarged regions of activation in the primary and secondary visual cortex.36 These results have been corroborated in subsequent studies.37–39
Stage 2 sleep has been shown to contribute to pro-cedural learning of motor skills. Walker and colleagues
Figure 1 Sleep cycle. Sleep consists of 90–100-minute
cycles composed of distinct sleep stages. At sleep onset, there is a brief period of Stage 1, followed by Stage 2 sleep charac-terized by spindles and k-complexes. Next is a period of slow wave sleep (SWS) with EEG signature of delta. These stages comprise non-rapid eye movement (NREM) sleep. Completing the cycle is a period of rapid eye movement (REM) or para-doxical sleep.
Stage 1 Stage 2 SWS REM NREM
studied performance on a motor task (finger-tapping, in which subjects are asked to enter a specific sequence of keys on a key pad as quickly and accurately as pos-sible) and found improvement after an episode of sleep relative to being awake.40 Overnight improve-ment was specific to both the motor sequence learned and the hand used to perform the task.41,42 While per-ceptual learning correlated with the product of SWS and REM, motor learning improvement correlated with the amount of Stage 2 sleep.40,43 Rickard and colleagues, however, have argued that some of this sleep effect may be due to a release from motor fatigue.44 Fogel and Smith reported that following an intense period of sim-ple motor procedural learning, the duration of Stage 2 sleep and spindle density increased. There were no changes observed in the duration of any other sleep stage.45 Similarly, improvement on a visuomotor pur-suit task (in which optimal performance required de-veloping an implicit model of the motion of the learned trajectory) was dependent on a post-training night of sleep.46 In one sleep-deprivation study, half of the subjects were sleep-deprived on the night after train-ing. After all subjects slept on night 2, only the sleep-deprived group demonstrated a lack of improvement.22 Although making comparisons between well-rested and sleep-deprived subjects has been criticized, these re-sults indicate that, first, sleep may also improve visuo-motor learning, and second, there is a critical window for sleep to occur, without which information can be lost.
Interestingly, daytime sleep is equivalent to noctur-nal sleep for procedural learning. Mednick et al showed that: (1) perceptual learning occurred only after naps containing REM sleep;4 (2) naps of either 60 or 90 min-utes produced the same levels of learning as a full night’s sleep; (3) naps promoted the same levels of learning on a motor learning task as nocturnal sleep;47 (4) sleep spindles and sigma power increases were cor-related with improved motor memory in habitual nap-pers compared with non-habitual napnap-pers;48 and (5) REM sleep during naps, compared with NREM and be-ing awake, enhances access to implicitly primed infor-mation for solutions in a creative problem-solving task (Figure 2).5 These studies suggest that nocturnal sleep and naps enhance procedural memories during an offline process in a sleep-stage-dependent manner.
4.3. Declarative memory and sleep
Until recently, the relationship between sleep and de-clarative memory had not been well examined. Neural models of declarative memory formation emphasize the critical importance of structures in the medial tem-poral lobe.49 In contrast with “enhancement” models of procedural memory, traditional declarative memory models involve stabilization and protection of memo-ries from interference and decay. A newer hypothesis put forward by Wixted combines the psychological
concept of interference with the physiological concept of consolidation.50 He proposes that memories are formed and maintained by LTP in the hippocampus, but are also temporarily vulnerable to interference which occurs by subsequent induction of additional LTP associated with the formation of newer memories.50 Importantly, the Wixted hypothesis has never been experimentally studied. We next summarize the competing theories for the role of sleep in declarative memory.
In their review, Ellenbogen and colleagues51 sum-marized the major findings of sleep and declarative memory and categorized four theoretical relationships for the role of sleep: (1) no relationship; (2) passive; (3) permissive; and (4) active.
(1) No relationship: This argument is countered by a mul-titude of findings showing that performance is usu-ally better with sleep than without, and while this is a formal possibility that must be experimentally con-trolled for, we spend no more time on this category. (2) Passive: Classical memory research by Jenkins and
Dallenbach in 1924 consisted of presenting a set of nonsense syllables before a sleep or wake epi-sode and found better retention after the sleep episode.52 The authors concluded, “The results of our study as a whole indicate that forgetting is not so much a matter of the decay of old impressions and associations as it is a matter of interference, inhibition, or obliteration of the old by the new.” Thus, memory traces are not enhanced by processes occurring during sleep, per se, but rather sleep may be a period of reduced interference.
(3) Permissive: This hypothesis considers declarative memory consolidation to be a time-dependent, interference-sensitive process that utilizes any 60 50 40 30 20 10 Rest Impr o v ement (%) NREM REM 0 −10 −20
Figure 2 Rapid eye movement (REM) sleep facilitates the use
of prior information for creative problem solving. Subjects who had REM sleep displayed a significant improvement above non-REM and quiet rest groups. Strikingly, although the quiet rest and NREM nap groups received the same prim-ing, they displayed no improvement on the primed remote associates task items, whereas the REM group improved by almost 40% above the morning performance. Reprinted with permission from Reference 5.
permissive brain state of reduced LTP to consoli-date memory.50 This model predicts that permissive states of reduced LTP, such as SWS28 or pharmaco-logically-reduced LTP, will improve declarative memory for information studied within a time be-fore sleep or drugs: the phenomenon of retrograde
facilitation. Retrograde facilitation is the observation
that a post-learning intervention (e.g., a period of sleep or the administration of a benzodiazepine or ethanol after learning) can improve performance relative to a control intervention (e.g., no sleep or placebo post-learning).
(4) Active: This theory is similar to the permissive the-ory except that it specifies that sleep is a critical component of consolidation, and no other brain state will serve the same function.
4.3.1. Passive vs. permissive hypothesis
An important difference between passive and permis-sive hypotheses is that the paspermis-sive hypothesis does not incorporate a critical period for consolidation. For example, if one considers a 6-hour training-to-test in-terval, both models agree that interference will occur. With an intervention, such as 2 hours of sleep, improve-ment would occur by reducing interference to 4 hours, compared to 6 hours in awake controls. The passive theory would predict that it does not matter when in the subsequent 6 hours the sleep occurs (ignoring fa-tigue effects for the moment), only that total time of interference is reduced. Consolidation plays no part in the passive hypothesis. In contrast, the permissive hy-pothesis predicts that memories need time to consoli-date in order to become resilient to the interference of new memory formation, and sleep provides a window of time for such consolidation to unfold in the absence of interference. Thus, sleep soon after learning should confer more protection than sleep that is delayed.
The permissive account hypothesizes that memori-zation involves a period of LTP induction and mainte-nance directly following learning, without which the memory would be lost. This initial “critical period” pro-duces experimentally tractable hypotheses about the temporal gradient of declarative memory consolida-tion. Specifically, sleep, or a similar pharmacologically-induced brain state, needs to occur within a temporal window soon after learning in order to protect LTP when it is vulnerable to interference. SWS (or other pe-riod of LTP inhibition) shortly after training allows a cascade of gene expression, protein synthesis and syn-aptic changes associated with LTP formation for mem-ory consolidation. A period of new LTP formation, such as occurs during waking or REM sleep, would interfere with the fragile memory trace. This model predicts that studies comparing periods of SWS to equivalent peri-ods of wake or REM (both periperi-ods of high LTP-like activ-ity in the brain) will find retrograde facilitation of prior
experiences.50 In other words, SWS sleep may produce improved performance compared to an active wake or REM group due to an absence of LTP-induced interfer-ence. Although sleep and pharmacology researchers do not use the same nomenclature (e.g., retroactive facilitation), their results show the same pattern. These results are described in more detail below. This theo-retical framework comparing the memory benefits of sleep and pharmacologically-induced LTP inhibition has never been tested.
4.3.2. Active hypothesis
In the spirit of findings in procedural learning of absolute performance enhancement (not merely less forgetting), proponents of the active role hypothesis argue that de-clarative memory consolidation crucially depends on a brain property unique to sleep. Research cited as sup-port for this model includes studies that show that NREM sleep facilitates declarative memory compared with being awake and REM sleep.53–58 We argue that these results essentially show retrograde facilitation, in that memory for information learned prior to sleep ex-hibits less forgetting relative to awake controls. More-over, a temporal gradient is observed (i.e., sleep soon after learning is more protective than sleep after a delay), implicating a critical period for consolidation to occur after training. Whereas these findings are con-sistent with the permissive theory, other findings sup-port the active theory for sleep-related consolidation. For example, changes in memory consolidation due to pharmacologic manipulations have been cited as evi-dence for the essential role of sleep in consolidation.59,60 Gais and Born increased cholinergic tone (via physostig-mine) during early sleep, a period rich in SWS activity,61 which blocked declarative memory in a paired word association task, but did not alter performance in a procedural memory task. Thus, low cholinergic tone is necessary for SWS-dependent declarative memory to occur. These studies show that specific pharmacologi-cal alterations during SWS can have discrete effects on specific memory processes.
4.3.3. Reactivation and consolidation
Recent neurophysiology data show intriguing possi-bilities for what might be the active neural mechanism of sleep-dependent memory processing. Specifically, strong evidence for a relationship between spatial memory and sleep comes from animal studies report-ing post-acquisition neuronal reactivation durreport-ing sleep that recapitulates the firing pattern of neurons in the hippocampus during alert exploratory behavior in a memory task.62–64 These data and others suggest that hippocampal and neocortical parietal regions cooper-atively participate in the processing of spatial memo-ries,65 and perform off-line activity during NREM sleep
involved in consolidation of these memories into long-term memory stores.66 This is thought by some to be the mechanism that underlies systems consolidation (i.e., the process that results in a declarative memory trace even-tually becoming independent of the hippocampus).
One recent study linked reactivation processes dur-ing sleep with performance improvement in humans.67 Peigneux and colleagues showed that following train-ing on a virtual spatial maze task, activation of hippoc-ampal and parahippochippoc-ampal navigation-related neural populations occurs during SWS sleep.67 They used pos-itron emission tomography to show that the amount of post-training reactivation of hippocampal formation during SWS correlates with the amount of next-day learning on the task. Another functional magnetic res-onance imaging study showed that odor could be as-sociated with declarative memory on a spatial task, and that if the odor was presented during SWS, but not REM sleep, subjects would perform better at the test the following day.68 Interestingly, they found that odor cues that were previously associated with learning stim-uli were capable of activating the hippocampus during post-learning SWS. Direct comparisons between awake and sleep conditions revealed an even stronger activa-tion in response to odor presentaactiva-tion during SWS than during wakefulness in both the anterior and posterior part of the left hippocampus. Beyond showing that memory-associated odors have access to the hippo-campus during SWS, this observation points to a par-ticular sensitivity of hippocampal networks during SWS to stimuli that are capable of reactivation. Returning to our active/permissive distinction, would a pattern of reactivation of previously learned material be reflected similarly in SWS sleep and pharmacologically-induced brain states? Be cause no other brain state (except being awake) has been compared with sleep, it is impossible to be certain as to whether or not sleep is essential for this process, or simply convenient. More generally, it is important to note that all of the abovementioned results are consistent with both the permissive and active models.
5. Pharmacological Manipulations of
Memory Consolidation
Ethanol has been shown to block acquisition of new information and, surprisingly, to enhance memory for previously acquired information.69–72 Parker et al found that when normal subjects ingested alcohol (1 mL/kg) after they had encoded some material, they remembered the material better than subjects who had ingested placebo drinks.73 But they showed no consolidation of material trained post-ethanol ingestion. Further, in a dose-response study,74 subjects ingested 0, 0.25, 0.50, and 1.00 mL/kg ethanol after studying a group of pictures. After 7 hours, retesting showed significant increases in
memory in the subjects who had ingested 0.5 and 1.00 mL/kg ethanol. A similar finding has been re-ported in animals.75
The mechanisms by which ethanol may retroac-tively facilitate memory while suppressing new learn-ing are hypothesized to involve the suppression of LTP in brain areas required for normal memory processing, i.e., the hippocampus and prefrontal cortex. Ethanol produces a dose-dependent suppression on the mag-nitude of LTP following high-frequency stimulation.
In vitro, low concentrations of ethanol (5 mM) in a
hip-pocampal slice preparation inhibited LTP and correlated with an inhibited NMDA response.76 The NMDA receptor is critical for LTP induction as well as for hippocampus-dependent cognitive functions. The NMDA receptor antagonist aminophosphonovaleric acid blocks the in-duction but not the expression of LTP, indicating that induction and expression involve different physiologi-cal mechanisms.77 This is an important point, as the permissive hypothesis predicts that sleep and drugs should inhibit new LTP formation, not the expression and maintenance of previously induced LTP. Ethanol inhibits NMDA-mediated currents in hippocampal neu-rons,78 suggesting that the effects of ethanol on LTP may be specific to induction. Indeed, Givens and McMahon demonstrated that ethanol specifically blocked the induction but not expression or maintenance of LTP.79 Thus, no new LTP induction occurs during expression and maintenance of LTP associated with memories formed in the recent past. It is unclear, however, whether the mechanism of action to block LTP is due to a direct interaction with the NMDA receptor or with the γ-aminobutyric acid (GABA) A receptor.80
Similar to ethanol, benzodiazepines have been shown repeatedly to improve memory for material learned prior to drug administration.81–83 Weingartner et al randomized subjects to three drug conditions (placebo, 4.5 μg/kg or 6.0 μg/kg).81 Subjects studied a list of words just prior to oral drug administration and then were given a new list of words while on the drug. Recall was tested for both study lists. Triazolam increased the probability of remembering studied words at both doses compared with placebo (Figure 3).81 Although anterograde amnesia for words studied on the drug was not significant, the trend was in the expected di-rection. Furthermore, other studies have found both retrograde facilitation and anterograde amnesia for triazolam at equivalent doses.82–84
Similar to other benzodiazepines, triazolam has been reported to disrupt LTP induction via potentiation of GABAergic activity and a concomitant attenuation of excitatory synaptic transmission in the mammalian hip-pocampus.85,86 It is this property that is thought to un-derlie the ability to produce anterograde amnesia in humans. We hypothesize that this same suppression of LTP induction underlies the phenomenon of retrograde facilitation.
6. Conclusion
The relatively recent addition of sleep to studies of the neural basis and underlying mechanisms of memory has generated an extensive literature for both proce-dural and declarative memory. Although behavioral profiles of the effects of sleep on declarative memory appear similar to findings from an older literature on the effects of pharmacological interventions, there is a need for studies to directly compare the effects of sleep and pharmacology on memory consolidation. Impor-tantly, there is evidence to support the hypothesis that learning is similarly benefited by SWS and benzodiaze-pines. Future studies should focus on understanding the behavioral outcomes, temporal dynamics and neural representations underlying declarative memory consoli-dation produced by SWS and other pharmacologically-induced, dampened brain states that reduce LTP. In addition to laying groundwork to improve normal cog-nition, this knowledge will impact basic research in mem-ory, sleep and pharmacology. Furthermore, there is the applied relevance for improving memory impairments associated with psychiatric disorders, neurodegenerative diseases and normal aging.
Acknowledgments
This research was supported by a grant (K01 MH080992) to Sara C. Mednick.
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