Competing Roles of Slow Oscillations and Delta Waves in Memory Consolidation versus Forgetting.

Sleep has been implicated in both memory consolidation and forgetting of experiences. However, it is unclear what governs the balance between consolidation and forgetting. Here, we tested how activity-dependent processing during sleep might differentially regulate these two processes. We specifically examined how neural reactivations during non-rapid eye movement (NREM) sleep were causally linked to consolidation versus weakening of the neural correlates of neuroprosthetic skill. Strikingly, we found that slow oscillations (SOs) and delta (δ) waves have dissociable and competing roles in consolidation versus forgetting. By modulating cortical spiking linked to SOs or δ waves using closed-loop optogenetic methods, we could, respectively, weaken or strengthen consolidation and thereby bidirectionally modulate sleep-dependent performance gains. We further found that changes in the temporal coupling of spindles to SOs relative to δ waves could account for such effects. Thus, our results indicate that neural activity driven by SOs and δ waves have competing roles in sleep-dependent memory consolidation.

Differential second messenger signaling via dopamine neurons bidirectionally regulates memory retention.

Memory formation and forgetting unnecessary memory must be balanced for adaptive animal behavior. While cyclic AMP (cAMP) signaling via dopamine neurons induces memory formation, here we report that cyclic guanine monophosphate (cGMP) signaling via dopamine neurons launches forgetting of unconsolidated memory in Drosophila. Genetic screening and proteomic analyses showed that neural activation induces the complex formation of a histone H3K9 demethylase, Kdm4B, and a GMP synthetase, Bur, which is necessary and sufficient for forgetting unconsolidated memory. Kdm4B/Bur is activated by phosphorylation through NO-dependent cGMP signaling via dopamine neurons, inducing gene expression, including kek2 encoding a presynaptic protein. Accordingly, Kdm4B/Bur activation induced presynaptic changes. Our data demonstrate a link between cGMP signaling and synapses via gene expression in forgetting, suggesting that the opposing functions of memory are orchestrated by distinct signaling via dopamine neurons, which affects synaptic integrity and thus balances animal behavior.

Novel Electrophysiological Signatures of Learning and Forgetting in Human Rapid Eye Movement Sleep.

Despite the known behavioral benefits of rapid eye movement (REM) sleep, discrete neural oscillatory events in human scalp electroencephalography (EEG) linked with behavior have not been discovered. This knowledge gap hinders mechanistic understanding of the function of sleep, as well as the development of biophysical models and REM-based causal interventions. We designed a detection algorithm to identify bursts of activity in high-density, scalp EEG within theta (4-8 Hz) and alpha (8-13 Hz) bands during REM sleep. Across 38 nights of sleep, we characterized the burst events (i.e., count, duration, density, peak frequency, amplitude) in healthy, young male and female human participants (38; 21F) and investigated burst activity in relation to sleep-dependent memory tasks: hippocampal-dependent episodic verbal memory and nonhippocampal visual perceptual learning. We found greater burst count during the more REM-intensive second half of the night (p < 0.05), longer burst duration during the first half of the night (p < 0.05), but no differences across the night in density or power (p > 0.05). Moreover, increased alpha burst power was associated with increased overnight forgetting for episodic memory (p < 0.05). Furthermore, we show that increased REM theta burst activity in retinotopically specific regions was associated with better visual perceptual performance. Our work provides a critical bridge between discrete REM sleep events in human scalp EEG that support cognitive processes and the identification of similar activity patterns in animal models that allow for further mechanistic characterization.

Medial Prefrontal Cortex Stimulation Reduces Retrieval-Induced Forgetting via Fronto-parietal Beta Desynchronization.

The act of recalling memories can paradoxically lead to the forgetting of other associated memories, a phenomenon known as retrieval-induced forgetting (RIF). Inhibitory control mechanisms, primarily mediated by the prefrontal cortex, are thought to contribute to RIF. In this study, we examined whether stimulating the medial prefrontal cortex (mPFC) with transcranial direct current stimulation modulates RIF and investigated the associated electrophysiological correlates. In a randomized study, 50 participants (27 males and 23 females) received either real or sham stimulation before performing retrieval practice on target memories. After retrieval practice, a final memory test to assess RIF was administered. We found that stimulation selectively increased the retrieval accuracy of competing memories, thereby decreasing RIF, while the retrieval accuracy of target memories remained unchanged. The reduction in RIF was associated with a more pronounced beta desynchronization within the left dorsolateral prefrontal cortex (left-DLPFC), in an early time window (<500 ms) after cue onset during retrieval practice. This led to a stronger beta desynchronization within the parietal cortex in a later time window, an established marker for successful memory retrieval. Together, our results establish the causal involvement of the mPFC in actively suppressing competing memories and demonstrate that while forgetting arises as a consequence of retrieving specific memories, these two processes are functionally independent. Our findings suggest that stimulation potentially disrupted inhibitory control processes, as evidenced by reduced RIF and stronger beta desynchronization in fronto-parietal brain regions during memory retrieval, although further research is needed to elucidate the specific mechanisms underlying this effect.

Active forgetting requires Sickie function in a dedicated dopamine circuit in Drosophila.

Forgetting is an essential component of the brain's memory management system, providing a balance to memory formation processes by removing unused or unwanted memories, or by suppressing their expression. However, the molecular, cellular, and circuit mechanisms underlying forgetting are poorly understood. Here we show that the memory suppressor gene, sickie, functions in a single dopamine neuron (DAn) by supporting the process of active forgetting in Drosophila. RNAi knockdown (KD) of sickie impairs forgetting by reducing the Ca2+ influx and DA release from the DAn that promotes forgetting. Coimmunoprecipitation/mass spectrometry analyses identified cytoskeletal and presynaptic active zone (AZ) proteins as candidates that physically interact with Sickie, and a focused RNAi screen of the candidates showed that Bruchpilot (Brp)-a presynaptic AZ protein that regulates calcium channel clustering and neurotransmitter release-impairs active forgetting like sickie KD. In addition, overexpression of brp rescued the impaired forgetting of sickie KD, providing evidence that they function in the same process. Moreover, we show that sickie KD in the DAn reduces the abundance and size of AZ markers but increases their number, suggesting that Sickie controls DAn activity for forgetting by modulating the presynaptic AZ structure. Our results identify a molecular and circuit mechanism for normal levels of active forgetting and reveal a surprising role of Sickie in maintaining presynaptic AZ structure for neurotransmitter release.

Loss aversion, the endowment effect, and gain-loss framing shape preferences for noninstrumental information.

We often talk about interacting with information as we would with a physical good (e.g., "consuming content") and describe our attachment to personal beliefs in the same way as our attachment to personal belongings (e.g., "holding on to" or "letting go of" our beliefs). But do we in fact value information the way we do objects? The valuation of money and material goods has been extensively researched, but surprisingly few insights from this literature have been applied to the study of information valuation. This paper demonstrates that two fundamental features of how we value money and material goods embodied in Prospect Theory-loss aversion and different risk preferences for gains versus losses-also hold true for information, even when it has no material value. Study 1 establishes loss aversion for noninstrumental information by showing that people are less likely to choose a gamble when the same outcome is framed as a loss (rather than gain) of information. Study 2 shows that people exhibit the endowment effect for noninstrumental information, and so value information more, simply by virtue of "owning" it. Study 3 provides a conceptual replication of the classic "Asian Disease" gain-loss pattern of risk preferences, but with facts instead of human lives, thereby also documenting a gain-loss framing effect for noninstrumental information. These findings represent a critical step in building a theoretical analogy between information and objects, and provide a useful perspective on why we often resist changing (or losing) our beliefs.

Selective memory retrieval can revive forgotten memories.

Humans remember less and less of what was encoded as more and more time passes. Selective retrieval can interrupt such time-dependent forgetting, enhancing recall not only of the retrieved but also of the nonretrieved information. The recall enhancement has been attributed to context retrieval and the idea that selective retrieval reactivates the retrieved item's temporal context during study, which can facilitate recall of other items that had a similar context at study. However, it is unclear whether context retrieval induces a transient discontinuity in the stream of temporal context only, or a more permanent updating of context that would entail a lasting interruption of time-dependent forgetting. In three experiments, we analyzed time-dependent forgetting of encoded information right after study and after time-lagged selective retrieval. Selective retrieval boosted recall of the nonretrieved information up to the levels observed directly after study. Intriguingly, it also created a restart of time-dependent forgetting that made forgetting after retrieval indistinguishable from forgetting after study and thus induced a reset of the recall process. The results suggest that selective retrieval can revive forgotten memories and cause lasting recall enhancement, effects likely mediated by context retrieval and a permanent updating of temporal context.

Social experiences switch states of memory engrams through regulating hippocampal Rac1 activity.

In pathological or artificial conditions, memory can be formed as silenced engrams that are unavailable for retrieval by presenting conditioned stimuli but can be artificially switched into the latent state so that natural recall is allowed. However, it remains unclear whether such different states of engrams bear any physiological significance and can be switched through physiological mechanisms. Here, we show that an acute social reward experience switches the silent memory engram into the latent state. Conversely, an acute social stress causes transient forgetting via turning a latent memory engram into a silent state. Such emotion-driven bidirectional switching between latent and silent states of engrams is mediated through regulation of Rac1 activity­dependent reversible forgetting in the hippocampus, as stress-activated Rac1 suppresses retrieval, while reward recovers silenced memory under amnesia by inhibiting Rac1. Thus, data presented reveal hippocampal Rac1 activity as the basis for emotion-mediated switching between latent and silent engrams to achieve emotion-driven behavioral flexibility.

Digital computing through randomness and order in neural networks.

We propose that coding and decoding in the brain are achieved through digital computation using three principles: relative ordinal coding of inputs, random connections between neurons, and belief voting. Due to randomization and despite the coarseness of the relative codes, we show that these principles are sufficient for coding and decoding sequences with error-free reconstruction. In particular, the number of neurons needed grows linearly with the size of the input repertoire growing exponentially. We illustrate our model by reconstructing sequences with repertoires on the order of a billion items. From this, we derive the Shannon equations for the capacity limit to learn and transfer information in the neural population, which is then generalized to any type of neural network. Following the maximum entropy principle of efficient coding, we show that random connections serve to decorrelate redundant information in incoming signals, creating more compact codes for neurons and therefore, conveying a larger amount of information. Henceforth, despite the unreliability of the relative codes, few neurons become necessary to discriminate the original signal without error. Finally, we discuss the significance of this digital computation model regarding neurobiological findings in the brain and more generally with artificial intelligence algorithms, with a view toward a neural information theory and the design of digital neural networks.

Differential Recruitment of Inhibitory Control Processes by Directed Forgetting and Thought Substitution.

Humans have the ability to intentionally forget information via different strategies, included suppression of encoding (directed forgetting) and mental replacement of the item to encode (thought substitution). These strategies may rely on different neural mechanisms; namely, encoding suppression may induce prefrontally mediated inhibition, whereas thought substitution is potentially accomplished through modulating contextual representations. Yet, few studies have directly related inhibitory processing to encoding suppression, or tested its involvement in thought substitution. Here, we directly tested whether encoding suppression recruits inhibitory mechanisms with a cross-task design, relating the behavioral and neural data from male and female participants in a Stop Signal task (a task specifically testing inhibitory processing) to a directed forgetting task with both encoding suppression (Forget) and thought substitution (Imagine) cues. Behaviorally, Stop Signal task performance (stop signal reaction times) was related to the magnitude of encoding suppression, but not thought substitution. Two complementary neural analyses corroborated the behavioral result. Namely, brain-behavior analysis demonstrated that the magnitude of right-frontal beta activity following stop signals was related to stop signal reaction times and successful encoding suppression, but not thought substitution; and classifiers trained to discriminate successful and unsuccessful stopping in the Stop Signal task could also classify successful and unsuccessful forgetting following Forget cues, but not Imagine cues. Importantly, inhibitory neural mechanisms were engaged following Forget cues at a later time than motor stopping. These findings not only support an inhibitory account of directed forgetting, and that thought substitution engages separate mechanisms, but also potentially identify a specific time in which inhibition occurs when suppressing encoding.SIGNIFICANCE STATEMENT Forgetting often seems like an unintended experience, but forgetting can be intentional, and can be accomplished with multiple strategies. These strategies, including encoding suppression and thought substitution, may rely on different neural mechanisms. Here, we test the hypothesis that encoding suppression engages domain-general prefrontally driven inhibitory control mechanisms, while thought substitution does not. Using cross-task analyses, we provide evidence that encoding suppression engages the same inhibitory mechanisms used for stopping motor actions, but these mechanisms are not engaged by thought substitution. These findings not only support the notion that mnemonic encoding processes can be directly inhibited, but also have broad relevance, as certain populations with disrupted inhibitory processing may be more successful accomplishing intentional forgetting through thought substitution strategies.

Task Termination Triggers Spontaneous Removal of Information From Visual Working Memory.

Working memory (WM) is a goal-directed memory system that actively maintains a limited amount of task-relevant information to serve the current goal. By this definition, WM maintenance should be terminated after the goal is accomplished, spontaneously removing no-longer-relevant information from WM. Past studies have failed to provide direct evidence of spontaneous removal of WM content by allowing participants to engage in a strategic reallocation of WM resources to competing information within WM. By contrast, we provide direct neural and behavioral evidence that visual WM content can be largely removed less than 1 s after it becomes obsolete, in the absence of a strategic allocation of resources (total N = 442 adults). These results demonstrate that visual WM is intrinsically a goal-directed system, and spontaneous removal provides a means for capacity-limited WM to keep up with ever-changing demands in a dynamic environment.

Slow wave sleep is associated with forgetting in patients with temporal lobe epilepsy.

While time spent in slow wave sleep (SWS) after learning promotes memory consolidation in the healthy brain, it is unclear if the same benefit is obtained in patients with temporal lobe epilepsy (TLE). Interictal epileptiform discharges (IEDs) are potentiated during SWS and thus may disrupt memory consolidation processes thought to depend on hippocampal-neocortical interactions. Here, we explored the relationship between SWS, IEDs, and overnight forgetting in patients with TLE. Nineteen patients with TLE studied object-scene pairs and memory was tested across a day of wakefulness (6 hrs) and across a night of sleep (16 hrs) while undergoing continuous scalp EEG monitoring. We found that time spent in SWS after learning was related to greater forgetting overnight. Longer duration in SWS and number of IEDs were each associated with greater forgetting, although the number of IEDs did not mediate the relationship between SWS and memory. Further research, particularly with intracranial recordings, is required to identify the mechanisms by which SWS and IEDs can be pathological to sleep-dependent memory consolidation in patients with TLE.

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

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

Overexpression of the limk1 Gene in Drosophila melanogaster Can Lead to Suppression of Courtship Memory in Males.

Courtship suppression is a behavioral adaptation of the fruit fly. When majority of the females in a fly population are fertilized and non-receptive for mating, a male, after a series of failed attempts, decreases its courtship activity towards all females, saving its energy and reproductive resources. The time of courtship decrease depends on both duration of unsuccessful courtship and genetically determined features of the male nervous system. Thereby, courtship suppression paradigm can be used for studying molecular mechanisms of learning and memory. p-Cofilin, a component of the actin remodeling signaling cascade and product of LIM-kinase 1 (LIMK1), regulates Drosophila melanogaster forgetting in olfactory learning paradigm. Previously, we have shown that limk1 suppression in the specific types of nervous cells differently affects fly courtship memory. Here, we used Gal4 > UAS system to induce limk1 overexpression in the same types of neurons. limk1 activation in the mushroom body, glia, and fruitless neurons decreased learning index compared to the control strain or the strain with limk1 knockdown. In cholinergic and dopaminergic/serotoninergic neurons, both overexpression and knockdown of limk1 impaired Drosophila short-term memory. Thus, proper balance of the limk1 activity is crucial for normal cognitive activity of the fruit fly.

Drinking the waters of Lethe: Bringing voluntary choice into the study of voluntary forgetting.

The directed forgetting paradigm has long been used to test whether humans can voluntarily choose to forget learned information. However, to date, nearly all directed forgetting paradigms have involved a forced-choice paradigm, in which the participants are instructed about which learned information they should forget. While studies have repeatedly shown that this directed forgetting does lead to a decreased ability to later remember the information, it is still unclear whether these effects would be present if participants were allowed to, of their own accord, choose which information they wanted to forget. In two experiments here, we introduce a free-choice variety of the item method directed forgetting paradigm and show that directed forgetting effects are robust, both for instructed and voluntary forgetting. We discuss the implications of our findings for notions of voluntary forgetting and for the self-choice effect in memory.

Durability of retrieval-induced forgetting: Effects of different practice schedules.

If retrieval-induced forgetting (RIF) is to play a role in the formation of collective memories, it should be long lasting. Although several studies have found that RIF is short-lived, there is other evidence to suggest that repeated selective practice schedules with a temporal gap between each practice trial may increase the durability of RIF. We tested this possibility in three experiments, focusing on socially shared retrieval-induced forgetting (SSRIF). In two experiments, participants studied scientific or story materials, then listened to someone selectively recall the material repeatedly, either in rapid succession or over an extended time period, and finally recalled the original materials either immediately, after a 1-week delay, or after a 3-week delay. A third experiment examined selective practice in free-flowing conversations. In each instance, RIF was found with repeated selective practice with a temporal gap between trials. The results are discussed in terms of the role RIF might play in the formation of collective memory.

Short-term retention of words as a function of encoding depth.

The traditional short- and long-term storage view of information processing and the levels-of-processing view both discuss the forgetting of information over time. In the traditional stage view, there is loss of at least poorly encoded information across several seconds when the information cannot be rehearsed (e.g., Ricker et al., 2020, Learning, Memory, and Cognition, 46, 60-76). In the levels-of-processing approach, information that is encoded in a shallow manner is lost more quickly over time than deeply-encoded information (Craik & Lockhart, 1972, Journal of Verbal Learning and Verbal Behavior, 11, 671-684.). Previous studies of the depth of encoding, however, have mostly been conducted using delayed tests, so there are few studies directly comparing the rate of forgetting over time for information as a function of different depths of encoding. We manipulated the level of processing with immediate recall in a modified Brown-Peterson task. An effect of the level of processing was robust, but evidence of forgetting across retention intervals was not always observed. When encoding time was curtailed (in Experiments 3 and 4), we found main effects of both the level of processing and the retention interval, but no interaction between the two variables. The results suggest that the depth-of-encoding effect may occur during the initial encoding of items, but without differential forgetting within the range of retention intervals that we examined (0-18 s), in contrast to the suggestion by Craik and Lockhart. Further work is needed to determine whether the depth-of-processing effect would grow over longer intervals.

Influence of degree of learning on rate of forgetting of tonal sequences.

Initial performance is frequently equated in studies that compare forgetting rates across groups. However, since the encoding capacity of different groups can be different, some procedures to match initial degree of learning need to be implemented, adding confounding variables such as longer exposures to the material, which would create memories of a different age. Slamecka and McElree Journal of Experimental Psychology: Learning, Memory, and Cognition, 9, 384-397, (1983) and our previous work found that the rate of forgetting was independent from initial degree of learning using verbal material. The present study seeks to determine whether this pattern holds true when undertaken with nonverbal material. In two experiments, we manipulate initial degree of learning by varying the number of presentations of the material and studying the effect on the forgetting rates. A set of 30 tonal sequences were presented to young, healthy participants either once or three times. Forgetting was evaluated in a yes/no recognition paradigm immediately and 1 hour or 24 hours after the study phase. A different subset of 10 sequences was tested along with 10 nontargets at each retention interval. The results of these experiments showed that initial acquisition was modulated by the number of repetitions. However, the forgetting rates were independent of initial degree of learning. These results are in keeping with the pattern found by Slamecka and McElree, and in our own previous studies. They suggest that the pattern of parallel forgetting after different levels of initial learning is not limited to verbal material.

Effect of levels-of-processing on rates of forgetting.

The levels-of-processing (LOP) framework, proposing that deep processing yields superior retention, has provided an important paradigm for memory research and a practical means of improving learning. However, the available levels-of-processing literature focuses on immediate memory performance. It is assumed within the LOP framework that deep processing will lead to slower forgetting than will shallow processing. However, it is unclear whether, or how, the initial level of processing affects the forgetting slopes over longer retention intervals. The present three experiments were designed to explore whether items encoded at qualitatively different LOP are forgotten at different rates. In the first two experiments, depth of processing was manipulated within-participants at encoding under deep and shallow conditions (semantic vs. rhyme judgement in Experiment 1; semantic vs. consonant-vowel pattern decision in Experiment 2). Recognition accuracy (d prime) was measured between-participants immediately after learning and at 30-min, 2-h, and 24-h delays. The third experiment employed a between-participants design, contrasting the rates of forgetting following semantic and phonological (rhyme) processing at immediate, 30-min, 2-h, and 6-h delays. Results from the three experiments consistently demonstrated a large effect size of levels of processing on immediate performance and a medium-to-large level effect size on delayed recognition, but crucially no LOP × delay group interaction. Analysis of the retention curves revealed no significant differences between the slopes of forgetting for deep and shallow processing. These results suggest that the rates of forgetting are independent of the qualitatively distinct encoding operations manipulated by levels of processing.

How varying cue duration influences item-method directed forgetting: A novel selective retrieval interpretation.

A series of four experiments tested the assumptions of the most prominent and longstanding account of item-method directed forgetting: the selective rehearsal account. In the item-method directed forgetting paradigm, each presented item is followed by its own instructional cue during the study phase - either to-be-forgotten (F) or to-be-remembered (R). On a subsequent test, memory is poorer for F items than for R items. To clarify the mechanism underlying memory performance, we manipulated the time available for rehearsal, examining instructional cue durations of 1 s, 5 s, and 10 s. Experiments 1a and 1b, where the order of cue durations was randomized, showed no effect of cue duration on item recognition of unrelated single words, for either R or F items. Experiment 2, using unrelated word pairs, again showed no effect of randomized cue duration, this time on associative recognition. Experiments 3 and 4 blocked cue duration and showed equivalent increases in recognition of both R and F single words and word pairs with increasing cue duration. We suggest that any post-cue rehearsal is carried out only when cue duration is predictable, and that such limited rehearsal is equally likely for F items and R items. The consistently better memory for R items than for F items across cue duration depends on selective retrieval involving (1) a rapid retrieval check engaged for R items only and (2) a rapid removal process implemented for F items only.