The reach of reactivation: Effects of consciously triggered versus unconsciously triggered reactivation of associative memory.

Consolidating memories for long-term storage depends on reactivation. Reactivation occurs both consciously, during wakefulness, and unconsciously, during wakefulness and sleep. While considerable work has examined conscious awake and unconscious sleep reactivation, in this study, we directly compare the consequences of conscious and unconscious reactivation during wakefulness. Forty-one participants learned associations consisting of adjective-object-position triads. Objects were clustered into distinct semantic groups (e.g., fruits, vehicles) such that we could examine consequences of reactivation on semantically related memories. After an intensive learning protocol, we systematically reactivated some of the triads by presenting the adjective as a cue. Reactivation was done so that it was consciously experienced for some triads, and only unconsciously processed for others. Memory for spatial positions, the most distal part of the association, was affected by reactivation in a consciousness-dependent and memory-strength-dependent manner. Conscious reactivation resulted in weakening of semantically related memories that were strong initially, resonating with prior findings of retrieval-induced forgetting. Unconscious reactivation, on the other hand, selectively benefited weak reactivated memories, as previously shown for reactivation during sleep. Semantically linked memories were not impaired, but rather were integrated with the reactivated memory. These results taken together demonstrate that conscious and unconscious reactivation have qualitatively different consequences. Results support a consciousness-dependent inhibition account, whereby unconscious reactivation entails less inhibition than conscious reactivation, thus allowing more liberal spread of activation. Findings set the stage for additional exploration into the role of conscious experience in memory storage and structuring.

The reach of reactivation: Effects of consciously-triggered versus unconsciously-triggered reactivation of associative memory.

Newly formed memories are not passively stored for future retrieval; rather, they are reactivated offline and thereby strengthened and transformed. However, reactivation is not a uniform process: it occurs throughout different states of consciousness, including conscious rehearsal during wakefulness and unconscious processing during both wakefulness and sleep. In this study, we explore the consequences of reactivation during conscious and unconscious awake states. Forty-one participants learned associations consisting of adjective-object-position triads. Objects were clustered into distinct semantic groups (e.g., multiple fruits, vehicles, musical instruments) which allowed us to examine the consequences of reactivation on semantically-related memories. After an extensive learning phase, some triads were reactivated consciously, through cued retrieval, or unconsciously, through subliminal priming. In both conditions, the adjective was used as the cue. Reactivation impacted memory for the most distal association (i.e., the spatial position of associated objects) in a consciousness-dependent and memory-strength-dependent manner. First, conscious reactivation of a triad resulted in a weakening of other semantically related memories, but only those that were initially more accurate (i.e., memories with lower pre-reactivation spatial errors). This is similar to what has been previously demonstrated in studies employing retrieval-induced forgetting designs. Unconscious reactivation, on the other hand, benefited memory selectively for weak cued items. Semantically linked associations were not impaired, but rather integrated with the reactivated memory. Taken together, our results demonstrate that conscious and unconscious reactivation of memories during wakefulness have qualitatively different consequences on memory for distal associations. Effects are memory-strength-dependent, as has been shown for reactivation during sleep. Results support a consciousness-dependent inhibition account, according to which unconscious reactivation involves less inhibitory dynamics than conscious reactivation, thus allowing more liberal spread of activation. Our findings set the stage for additional exploration into the role of consciousness in memory structuring.

Memory consolidation during sleep involves context reinstatement in humans.

New memories are not quarantined from each other when first encoded; rather, they are interlinked with memories that were encoded in temporal proximity or that share semantic features. By selectively biasing memory processing during sleep, here we test whether context influences sleep consolidation. Participants first formed 18 idiosyncratic narratives, each linking four objects together. Before sleep, they also memorized an on-screen position for each object. During sleep, 12 object-specific sounds were unobtrusively presented, thereby cuing the corresponding spatial memories and impacting spatial recall as a function of initial memory strength. As hypothesized, we find that recall for non-cued objects contextually linked with cued objects also changed. Post-cue electrophysiological responses suggest that activity in the sigma band supports context reinstatement and predicts context-related memory benefits. Concurrently, context-specific electrophysiological activity patterns emerge during sleep. We conclude that reactivation of individual memories during sleep evokes reinstatement of their context, thereby impacting consolidation of associated knowledge.

Reap while you sleep: Consolidation of memories differs by how they were sown.

Newly formed memories are spontaneously reactivated during sleep, leading to their strengthening. This reactivation process can be manipulated by reinstating learning-related stimuli during sleep, a technique termed targeted memory reactivation. Numerous studies have found that delivering cues during sleep improves memory for simple associations, in which one cue reactivates one tested memory. However, real-life memories often live in rich, complex networks of associations. In this review, we will examine recent forays into investigating how targeted sleep reactivation affects memories within complex paradigms, in which one cue can reactivate multiple tested memories. A common theme across studies is that reactivation consequences do not merely depend on whether memories reside in complex arrangements, but on how memories interact with one another during acquisition. We therefore emphasize how intricate study design details that alter the nature of learning and/or participant intentions impact the outcomes of sleep reactivation. In some cases, complex networks of memories interact harmoniously to bring about mutual memory benefits; in other cases, memories interact antagonistically and produce selective impairments in retrieval. Ultimately, although this burgeoning area of research has yet to be systematically explored, results suggest that the fate of reactivated stimuli within complex arrangements depends on how they were learned.

Context matters: changes in memory over a period of sleep are driven by encoding context.

During sleep, recently acquired episodic memories (i.e., autobiographical memories for specific events) are strengthened and transformed, a process termed consolidation. These memories are contextual in nature, with details of specific features interwoven with more general properties such as the time and place of the event. In this study, we hypothesized that the context in which a memory is embedded would guide the process of consolidation during sleep. To test this idea, we used a spatial memory task and considered changes in memory over a 10-h period including either sleep or wake. In both conditions, participants (N = 62) formed stories that contextually bound four objects together and then encoded the on-screen spatial position of all objects. Results showed that the changes in memory over the sleep period were correlated among contextually linked objects, whereas no such effect was identified for the wake group. These results demonstrate that context-binding plays an important role in memory consolidation during sleep.

Sleep reactivation did not boost suppression-induced forgetting.

Sleep's role in memory consolidation is widely acknowledged, but its role in weakening memories is still debated. Memory weakening is evolutionary beneficial and makes an integral contribution to cognition. We sought evidence on whether sleep-based memory reactivation can facilitate memory suppression. Participants learned pairs of associable words (e.g., DIET-CREAM) and were then exposed to hint words (e.g., DIET) and instructed to either recall ("think") or suppress ("no-think") the corresponding target words (e.g., CREAM). As expected, suppression impaired retention when tested immediately after a 90-min nap. To test if reactivation could selectively enhance memory suppression during sleep, we unobtrusively presented one of two sounds conveying suppression instructions during sleep, followed by hint words. Results showed that targeted memory reactivation did not enhance suppression-induced forgetting. Although not predicted, post-hoc analyses revealed that sleep cues strengthened memory, but only for suppressed pairs that were weakly encoded before sleep. The results leave open the question of whether memory suppression can be augmented during sleep, but suggest strategies for future studies manipulating memory suppression during sleep. Additionally, our findings support the notion that sleep reactivation is particularly beneficial for weakly encoded information, which may be prioritized for consolidation.

Multiple memories can be simultaneously reactivated during sleep as effectively as a single memory.

Memory consolidation involves the reactivation of memory traces during sleep. If different memories are reactivated each night, how much do they interfere with one another? We examined whether reactivating multiple memories incurs a cost to sleep-related benefits by contrasting reactivation of multiple memories versus single memories during sleep. First, participants learned the on-screen location of different objects. Each object was part of a semantically coherent group comprised of either one, two, or six items (e.g., six different cats). During sleep, sounds were unobtrusively presented to reactivate memories for half of the groups (e.g., "meow"). Memory benefits for cued versus non-cued items were independent of the number of items in the group, suggesting that reactivation occurs in a simultaneous and promiscuous manner. Intriguingly, sleep spindles and delta-theta power modulations were sensitive to group size, reflecting the extent of previous learning. Our results demonstrate that multiple memories may be consolidated in parallel without compromising each memory's sleep-related benefit. These findings highlight alternative models for parallel consolidation that should be considered in future studies.

Memory and Sleep: How Sleep Cognition Can Change the Waking Mind for the Better.

The memories that we retain can serve many functions. They guide our future actions, form a scaffold for constructing the self, and continue to shape both the self and the way we perceive the world. Although most memories we acquire each day are forgotten, those integrated within the structure of multiple prior memories tend to endure. A rapidly growing body of research is steadily elucidating how the consolidation of memories depends on their reactivation during sleep. Processing memories during sleep not only helps counteract their weakening but also supports problem solving, creativity, and emotional regulation. Yet, sleep-based processing might become maladaptive, such as when worries are excessively revisited. Advances in research on memory and sleep can thus shed light on how this processing influences our waking life, which can further inspire the development of novel strategies for decreasing detrimental rumination-like activity during sleep and for promoting beneficial sleep cognition.

Author Correction: Targeted memory reactivation during sleep boosts intentional forgetting of spatial locations.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Targeted memory reactivation during sleep boosts intentional forgetting of spatial locations.

Although we experience thousands of distinct events on a daily basis, relatively few are committed to memory. The human capacity to intentionally control which events will be remembered has been demonstrated using learning procedures with instructions to purposely avoid committing specific items to memory. In this study, we used a variant of the item-based directed-forgetting procedure and instructed participants to memorize the location of some images but not others on a grid. These instructions were conveyed using a set of auditory cues. Then, during an afternoon nap, we unobtrusively presented a cue that was used to instruct participant to avoid committing the locations of some images to memory. After sleep, memory was worse for to-be-forgotten image locations associated with the presented sound relative to those associated with a sound that was not presented during sleep. We conclude that memory processing during sleep can serve not only to secure memory storage but also to weaken it. Given that intentional suppression may be used to weaken unpleasant memories, such sleep-based strategies may help accelerate treatments for memory-related disorders such as post-traumatic stress disorder.

Targeted memory reactivation during sleep to strengthen memory for arbitrary pairings.

A powerful way to investigate memory consolidation during sleep utilizes acoustic stimulation to reactivate memories. In multiple studies, Targeted Memory Reactivation (TMR) using sounds associated with prior learning improved later memory, as in recalling locations where objects previously appeared. In the present experiment, we examined whether a variant of the same technique could strengthen memory for the locations of pairs of objects. Each sound was naturally connected to one object from each pair, but we hypothesized that both memories could be improved with TMR. We first asked participants to memorize each of 50 pairs of objects by associating the two objects with each other and with the sound of one of the objects (e.g., cat-meow). Next, objects were presented in unique locations on a grid. Participants learned these locations in an adaptive procedure. During an afternoon nap, 25 of the sounds were quietly presented. In memory tests given twice before and twice after the nap, participants heard the sound for each object pair and were asked to recall the name of the second object and the locations of both objects. Forgetting scores were calculated using the mean difference between pre-nap and post-nap spatial recall errors. We found less forgetting after the nap for cued compared to non-cued objects. Additionally, the extent of forgetting tended to be similar for the two members of each pair, but only for cued pairs. Results thus substantiate the potential for sounds to reactivate spatial memories during sleep and thereby improve subsequent recall performance, even for multiple objects associated with a single sound and when participants must learn a novel sound-object association.

Ketamine induced converged synchronous gamma oscillations in the cortico-basal ganglia network of nonhuman primates.

N-methyl-d-aspartate (NMDA) antagonists are widely used in anesthesia, pain management, and schizophrenia animal model studies, and recently as potential antidepressants. However, the mechanisms underlying their anesthetic, psychotic, cognitive, and emotional effects are still elusive. The basal ganglia (BG) integrate input from different cortical domains through their dopamine-modulated connections to achieve optimal behavior control. NMDA antagonists have been shown to induce gamma oscillations in human EEG recordings and in rodent cortical and BG networks. However, network relations and implications to the primate brain are still unclear. We recorded local field potentials (LFPs) simultaneously from the primary motor cortex (M1) and the external globus pallidus (GPe) of four vervet monkeys (26 sessions, 97 and 76 cortical and pallidal LFPs, respectively) before and after administration of ketamine (NMDA antagonist, 10 mg/kg im). Ketamine induced robust, spontaneous gamma (30-50 Hz) oscillations in M1 and GPe. These oscillations were initially modulated by ultraslow oscillations (~0.3 Hz) and were highly synchronized within and between M1 and the GPe (mean coherence magnitude = 0.76, 0.88, and 0.41 for M1-M1, GPe-GPe, and M1-GPe pairs). Phase differences were distributed evenly around zero with broad and very narrow distribution for the M1-M1 and GPe-GPe pairs (-3.5 ± 31.8° and -0.4 ± 6.0°), respectively. The distribution of M1-GPe phase shift was skewed to the left with a mean of -18.4 ± 20.9°. The increased gamma coherence between M1 and GPe, two central stages in the cortico-BG loops, suggests a global abnormal network phenomenon with a unique spectral signature, which is enabled by the BG funneling architecture.NEW & NOTEWORTHY This study is the first to show spontaneous gamma oscillations under NMDA antagonist in nonhuman primates. These oscillations appear in synchrony in the cortex and the basal ganglia. Phase analysis refutes the confounding effects of volume conduction and supports the funneling and amplifying architecture of the cortico-basal ganglia loops. These results suggest an abnormal network phenomenon with a unique spectral signature that could account for pathological mental and neurological states.

Pallidal spiking activity reflects learning dynamics and predicts performance.

The basal ganglia (BG) network has been divided into interacting actor and critic components, modulating the probabilities of different state-action combinations through learning. Most models of learning and decision making in the BG focus on the roles of the striatum and its dopaminergic inputs, commonly overlooking the complexities and interactions of BG downstream nuclei. In this study, we aimed to reveal the learning-related activity of the external segment of the globus pallidus (GPe), a downstream structure whose computational role has remained relatively unexplored. Recording from monkeys engaged in a deterministic three-choice reversal learning task, we found that changes in GPe discharge rates predicted subsequent behavioral shifts on a trial-by-trial basis. Furthermore, the activity following the shift encoded whether it resulted in reward or not. The frequent changes in stimulus-outcome contingencies (i.e., reversals) allowed us to examine the learning-related neural activity and show that GPe discharge rates closely matched across-trial learning dynamics. Additionally, firing rates exhibited a linear decrease in sequences of correct responses, possibly reflecting a gradual shift from goal-directed execution to automaticity. Thus, modulations in GPe spiking activity are highest for attention-demanding aspects of behavior (i.e., switching choices) and decrease as attentional demands decline (i.e., as performance becomes automatic). These findings are contrasted with results from striatal tonically active neurons, which show none of these task-related modulations. Our results demonstrate that GPe, commonly studied in motor contexts, takes part in cognitive functions, in which movement plays a marginal role.

Hold your pauses: external globus pallidus neurons respond to behavioural events by decreasing pause activity.

Awareness of its rich structural pathways has earned the external segment of the globus pallidus (GPe) recognition as a central figure within the basal ganglia circuitry. Interestingly, GPe neurons are uniquely identified by the presence of prominent pauses interspersed among a high-frequency discharge rate of 50-80 spikes/s. These pauses have an average pause duration of 620 ms with a frequency of 13/min, yielding an average pause activity (probability of a GPe neuron being in a pause) of (620 × 13)/(60 × 1000) = 0.13. Spontaneous pause activity has been found to be inversely related to arousal state. The relationship of pause activity with behavioural events remains to be elucidated. In the present study, we analysed the electrophysiological activity of 200 well-isolated GPe pauser cells recorded from four non-human primates (Macaque fascicularis) while they were engaged in similar classical conditioning tasks. The isolation quality of the recorded activity and the pauses were determined with objective automatic methods. The results showed that the pause probability decreased by 9.09 and 10.0%, and the discharge rate increased by 2.96 and 1.95%, around cue and outcome presentation, respectively. Analysis of the linear relationship between the changes in pause activity and discharge rate showed r(2)  = 0.46 and r(2)  = 0.66 upon cue onset and outcome presentation, respectively. Thus, pause activity is a pertinent element in short-term encoding of relevant behavioural events, and has a significant, but not exclusive, role in the modulation of GPe discharge rate around these events.

Coinciding decreases in discharge rate suggest that spontaneous pauses in firing of external pallidum neurons are network driven.

The external segment of the globus pallidus (GPe) is one of the core nuclei of the basal ganglia, playing a major role in normal control of behavior and in the pathophysiology of basal ganglia-related disorders such as Parkinson's disease. In vivo, most neurons in the GPe are characterized by high firing rates (50-100 spikes/s), interspersed with long periods (∼0.6 s) of complete silence, which are termed GPe pauses. Previous physiological studies of single and pairs of GPe neurons have failed to fully disclose the physiological process by which these pauses originate. We examined 1001 simultaneously recorded pairs of high-frequency discharge GPe cells recorded from four monkeys during task-irrelevant periods, considering the activity in one cell while the other is pausing. We found that pauses (n = 137,278 pauses) coincide with a small yet significant reduction in firing rate (0.78 ± 0.136 spikes/s) in other GPe cells. Additionally, we found an increase in the probability of the simultaneously recorded cell to pause during the pause period of the "trigger" cell. Importantly, this increase in the probability to pause at the same time does not account for the reduction in firing rate by itself. Modeling of GPe cells as class 2 excitability neurons (Hodgkin, 1948) with common external inputs can explain our results. We suggest that common inputs decrease the GPe discharge rate and lead to a bifurcation phenomenon (pause) in some of the GPe neurons.

Spatial localization of auditory stimuli in human auditory cortex is based on both head-independent and head-centered coordinate systems.

In humans, whose ears are fixed on the head, auditory stimuli are initially registered in space relative to the head. Eventually, locations of sound sources need to be encoded also relative to the body, or in absolute allocentric space, to allow orientation toward the sounds sources and consequent action. We can therefore distinguish between two spatial representation systems: a basic head-centered coordinate system and a more complex head-independent system. In an ERP experiment, we attempted to reveal which of these two coordinate systems is represented in the human auditory cortex. We dissociated the two systems using the mismatch negativity (MMN), a well studied EEG effect evoked by acoustic deviations. Contrary to previous findings suggesting that only primary head-related information is present at this early stage of processing, we observed significant MMN effects for both head-independent and head-centered deviant stimuli. Our findings thus reveal that both primary head-related and secondary body- or world-related reference frames are represented at this stage of auditory processing.

Enhanced synaptic integration of adult-born neurons in the olfactory bulb of lactating mothers.

One of the most dramatic events during the life of adult mammals is the transition into motherhood. This transition is accompanied by specific maternal behaviors, displayed by the mother, that ensure the survival and the well-being of her offspring. The execution of these behaviors is most likely accompanied by plastic changes in specific neuronal circuits, but these are still poorly defined. In this work, we studied the mammalian olfactory bulb (OB), which has been shown to be an essential brain region for maternal behaviors in mice. In the OB, we focused on adult-born neurons, which are continuously incorporated into the circuit during adulthood, thus providing a potential substrate for heightened plasticity after parturition. We analyzed the dynamics and morphological characteristics of adult-born granule cells (abGCs), innervating the OB of primiparous lactating mothers, shortly after parturition as well as in naive females. In vivo time-lapse imaging of abGCs revealed that dendritic spines were significantly more stable in lactating mothers compared with naive virgins. In contrast, spine stability of resident GCs remained unchanged after parturition. In addition, while spine size distribution of abGCs was approximately similar between mothers and naive virgins, the spine density of abGCs was lower in lactating mothers and the density of their presynaptic components was higher. These structural features are indicative of enhanced integration of adult-born neurons into the bulbar circuitry of lactating mothers. This enhanced integration may serve as a cellular mechanism, supporting changes in olfactory coding of new mothers during their first days following parturition.

Negative valence widens generalization of learning.

Learning includes the ability to generalize to new situations and respond to similar, yet not identical stimuli. We use stimulus generalization in humans to show that tones that were negatively reinforced induce wider generalization curves than tones that were positively reinforced, and these in turn induce wider curves than neutral memory. Importantly, these wider generalization curves persist even if outcomes for all tones are made identical, indicating that the learning induced a perceptual change, and not merely a decision bias. Moreover, it persists after taking into account loss-aversion, suggesting it is a result of valence per se, and not intensity that reflects overweighting of the aversive stimuli. This effect of emotional valence on learning suggests different locations of plasticity and network mechanisms in the brain. Particularly, it suggests that brain areas that mediate reinforcement and emotions are involved during the learning process to induce a neural representation that can support this broader behavioral generalization. In addition, these findings highlight a model for anxiety and trauma disorders in which aversive experiences affect more than they should, sometimes even in seemingly irrational situations.