Brain oscillations: Hippocampal-prefrontal ripples unfolded.

Memory consolidation is the process of translating memory traces from the hippocampus to the cortex. Hippocampal ripples are key in driving this transfer. A new study now shows that independent cortical ripples can suppress this communication. What could be the underlying mechanisms?

The Role of Prefrontal Ensembles in Memory Across Time: Time-Dependent Transformations of Prefrontal Memory Ensembles.

The medial prefrontal cortex (mPFC) plays a critical role in recalling recent and remote fearful memories. Modern neuroscience techniques, such as projection-specific circuit manipulation and activity-dependent labeling, have illuminated how mPFC memory ensembles are reorganized over time. This chapter discusses the implications of new findings for traditional theories of memory, such as the systems consolidation theory and theories of memory engrams. It also examines the specific contributions of mPFC subregions, like the prelimbic and infralimbic cortices, in fear memory, highlighting how their distinct connections influence memory recall. Further, it elaborates on the cellular and molecular changes within the mPFC that support memory persistence and how these are influenced by interactions with the hippocampus. Ultimately, this chapter provides insights into how lasting memories are dynamically encoded in prefrontal circuits, arguing for a key role of memory ensembles that extend beyond strict definitions of the engram.

Engrams of Fear Memory Attenuation.

Fear attenuation is an etiologically relevant process for animal survival, since once acquired information needs to be continuously updated in the face of changing environmental contingencies. Thus, when situations are encountered that were originally perceived as fearful but are no longer so, fear must be attenuated, otherwise, it risks becoming maladaptive. But what happens to the original memory trace of fear during fear attenuation? In this chapter, we review the studies that have started to approach this question from an engram perspective. We find evidence pointing to both the original memory trace of fear being suppressed, as well as it being updated towards safety. These seemingly conflicting results reflect a well-established dichotomy in the field of fear memory attenuation, namely whether fear attenuation is mediated by an inhibitory mechanism that suppresses fear expression, called extinction, or by an updating mechanism that allows the fear memory to reconsolidate in a different form, called reconsolidation-updating. Which of these scenarios takes the upper hand is ultimately influenced by the behavioral paradigms used to induce fear attenuation, but is an important area for further study as the precise cell populations underlying fear attenuation and the molecular mechanisms therein can now be understood at unprecedented resolution.

Neurofeedback training can modulate task-relevant memory replay rate in rats.

Hippocampal replay - the time-compressed, sequential reactivation of ensembles of neurons related to past experience - is a key neural mechanism of memory consolidation. Replay typically coincides with a characteristic pattern of local field potential activity, the sharp-wave ripple (SWR). Reduced SWR rates are associated with cognitive impairment in multiple models of neurodegenerative disease, suggesting that a clinically viable intervention to promote SWRs and replay would prove beneficial. We therefore developed a neurofeedback paradigm for rat subjects in which SWR detection triggered rapid positive feedback in the context of a memory-dependent task. This training protocol increased the prevalence of task-relevant replay during the targeted neurofeedback period by changing the temporal dynamics of SWR occurrence. This increase was also associated with neural and behavioral forms of compensation after the targeted period. These findings reveal short-timescale regulation of SWR generation and demonstrate that neurofeedback is an effective strategy for modulating hippocampal replay.

Selective consolidation of learning and memory via recall-gated plasticity.

In a variety of species and behavioral contexts, learning and memory formation recruits two neural systems, with initial plasticity in one system being consolidated into the other over time. Moreover, consolidation is known to be selective; that is, some experiences are more likely to be consolidated into long-term memory than others. Here, we propose and analyze a model that captures common computational principles underlying such phenomena. The key component of this model is a mechanism by which a long-term learning and memory system prioritizes the storage of synaptic changes that are consistent with prior updates to the short-term system. This mechanism, which we refer to as recall-gated consolidation, has the effect of shielding long-term memory from spurious synaptic changes, enabling it to focus on reliable signals in the environment. We describe neural circuit implementations of this model for different types of learning problems, including supervised learning, reinforcement learning, and autoassociative memory storage. These implementations involve synaptic plasticity rules modulated by factors such as prediction accuracy, decision confidence, or familiarity. We then develop an analytical theory of the learning and memory performance of the model, in comparison to alternatives relying only on synapse-local consolidation mechanisms. We find that recall-gated consolidation provides significant advantages, substantially amplifying the signal-to-noise ratio with which memories can be stored in noisy environments. We show that recall-gated consolidation gives rise to a number of phenomena that are present in behavioral learning paradigms, including spaced learning effects, task-dependent rates of consolidation, and differing neural representations in short- and long-term pathways.

Memory's gatekeeper: The role of PFC in the encoding of congruent events.

Theoretical models conventionally portray the consolidation of memories as a slow process that unfolds during sleep. According to the classical Complementary Learning Systems theory, the hippocampus (HPC) rapidly changes its connectivity during wakefulness to encode ongoing events and create memory ensembles that are later transferred to the prefrontal cortex (PFC) during sleep. However, recent experimental studies challenge this notion by showing that new information consistent with prior knowledge can be rapidly consolidated in PFC during wakefulness and that PFC lesions disrupt the encoding of congruent events in the HPC. The contributions of the PFC to memory encoding have therefore largely been overlooked. Moreover, most theoretical frameworks assume random and uncorrelated patterns representing memories, disregarding the correlations between our experiences. To address these shortcomings, we developed a HPC-PFC network model that simulates interactions between the HPC and PFC during the encoding of a memory (awake stage), and subsequent consolidation (sleeping stage) to examine the contributions of each region to the consolidation of novel and congruent memories. Our results show that the PFC network uses stored memory "schemas" consolidated during previous experiences to identify inputs that evoke congruent patterns of activity, quickly integrate it into its network, and gate which components are encoded in the HPC. More specifically, the PFC uses GABAergic long-range projections to inhibit HPC neurons representing input components correlated with a previously stored memory "schema," eliciting sparse hippocampal activity during exposure to congruent events, as it has been experimentally observed.

Intense training prevents the amnestic effect of inactivation of dorsomedial striatum and induces high resistance to extinction.

A large body of evidence has shown that treatments that interfere with memory consolidation become ineffective when animals are subjected to an intense learning experience; this effect has been observed after systemic and local administration of amnestic drugs into several brain areas, including the striatum. However, the effects of amnestic treatments on the process of extinction after intense training have not been studied. Previous research demonstrated increased spinogenesis in the dorsomedial striatum, but not in the dorsolateral striatum after intense training, indicating that the dorsomedial striatum is involved in the protective effect of intense training. To investigate this issue, male Wistar rats, previously trained with low, moderate, or high levels of foot shock, were used to study the effect of tetrodotoxin inactivation of dorsomedial striatum on memory consolidation and subsequent extinction of inhibitory avoidance. Performance of the task was evaluated during seven extinction sessions. Tetrodotoxin produced a marked deficit of memory consolidation of inhibitory avoidance trained with low and moderate intensities of foot shock, but normal consolidation occurred when a relatively high foot shock was used. The protective effect of intense training was long-lasting, as evidenced by the high resistance to extinction exhibited throughout the extinction sessions. We discuss the possibility that increased dendritic spinogenesis in dorsomedial striatum may underly this protective effect, and how this mechanism may be related to the resilient memory typical of post-traumatic stress disorder (PTSD).

Spindle-locked ripples mediate memory reactivation during human NREM sleep.

Memory consolidation relies in part on the reactivation of previous experiences during sleep. The precise interplay of sleep-related oscillations (slow oscillations, spindles and ripples) is thought to coordinate the information flow between relevant brain areas, with ripples mediating memory reactivation. However, in humans empirical evidence for a role of ripples in memory reactivation is lacking. Here, we investigated the relevance of sleep oscillations and specifically ripples for memory reactivation during human sleep using targeted memory reactivation. Intracranial electrophysiology in epilepsy patients and scalp EEG in healthy participants revealed that elevated levels of slow oscillation - spindle activity coincided with the read-out of experimentally induced memory reactivation. Importantly, spindle-locked ripples recorded intracranially from the medial temporal lobe were found to be correlated with the identification of memory reactivation during non-rapid eye movement sleep. Our findings establish ripples as key-oscillation for sleep-related memory reactivation in humans and emphasize the importance of the coordinated interplay of the cardinal sleep oscillations.

Social interaction-induced fear memory reduction: exploring the influence of dopamine and oxytocin receptors on memory updating.

It has been well established that a consolidated memory can be updated during the plastic state induced by reactivation. This updating process opens the possibility to modify maladaptive memory. In the present study, we evaluated whether fear memory could be updated to less-aversive level by incorporating hedonic information during reactivation. Thus, male rats were fear conditioned and, during retrieval, a female was presented as a social rewarding stimulus. We found that memory reactivation with a female (but not a male) reduces fear expression within-session and in the test, without presenting reinstatement or spontaneous recovery. Interestingly, this intervention impaired extinction. Finally, we demonstrated that this emotional remodeling to eliminate fear expression requires the activation of dopamine and oxytocin receptors during retrieval. Hence, these results shed new lights on the memory updating process and suggests that the exposure to natural rewarding information such as a female during retrieval reduces a previously consolidated fear memory.

Prefrontal cortical ripples mediate top-down suppression of hippocampal reactivation during sleep memory consolidation.

Consolidation of initially encoded hippocampal representations in the neocortex through reactivation is crucial for long-term memory formation and is facilitated by the coordination of hippocampal sharp-wave ripples (SWRs) with cortical slow and spindle oscillations during non-REM sleep. Recent evidence suggests that high-frequency cortical ripples can also coordinate with hippocampal SWRs in support of consolidation; however, the contribution of cortical ripples to reactivation remains unclear. We used high-density, continuous recordings in the hippocampus (area CA1) and prefrontal cortex (PFC) over the course of spatial learning and show that independent PFC ripples dissociated from SWRs are prevalent in NREM sleep and predominantly suppress hippocampal activity. PFC ripples paradoxically mediate top-down suppression of hippocampal reactivation rather than coordination, and this suppression is stronger for assemblies that are reactivated during coordinated CA1-PFC ripples for consolidation of recent experiences. Further, we show non-canonical, serial coordination of independent cortical ripples with slow and spindle oscillations, which are known signatures of memory consolidation. These results establish a role for prefrontal cortical ripples in top-down regulation of behaviorally relevant hippocampal representations during consolidation.

Distributional Learning and Overnight Consolidation of Nonnative Tonal Contrasts by Tonal Language Speakers.

PURPOSE: Previous studies have reported the success of distributional learning for adult speakers across segmental and suprasegmental categories immediately after training. On the other hand, second language (L2) perception models posit that the ease with which learners perceive a nonnative speech contrast depends on the perceptual mapping between the contrast and learners' first language (L1) categories. This study examined whether a difference in perceptual mapping patterns for different L2-Mandarin tonal contrasts might result in a difference in distributional learning effectiveness for tonal speakers and whether an interval of sleep enhanced the knowledge through consolidation. METHOD: Following a pretest-training-posttest design, 66 L1-Cantonese participants with fewer than 9 years of Mandarin training were assigned to either the bimodal or unimodal distribution conditions. The participants of each group were asked to discriminate Mandarin level-falling (T1-T4) and level-rising (T1-T2) tone pairs on novel syllables in a within-subject design. All participants were trained in the evening, tested after training, and returned after 12 hr for overnight consolidation assessment. RESULTS: A significant distributional learning effect was observed for Mandarin T1-T4, but only after sleep. No significant distributional learning effect was observed for Mandarin T1-T2, either after training or after sleep. CONCLUSIONS: The findings may imply that distributional learning is contingent on perceptual mapping patterns of the target contrasts and that sleep may play a role in the consolidation of knowledge in an implicit statistical learning paradigm. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.25970008.

Differences in the consolidation by spontaneous and evoked ripples in the presence of active dendrites.

Ripples are a typical form of neural activity in hippocampal neural networks associated with the replay of episodic memories during sleep as well as sleep-related plasticity and memory consolidation. The emergence of ripples has been observed both dependent as well as independent of input from other brain areas and often coincides with dendritic spikes. Yet, it is unclear how input-evoked and spontaneous ripples as well as dendritic excitability affect plasticity and consolidation. Here, we use mathematical modeling to compare these cases. We find that consolidation as well as the emergence of spontaneous ripples depends on a reliable propagation of activity in feed-forward structures which constitute memory representations. This propagation is facilitated by excitable dendrites, which entail that a few strong synapses are sufficient to trigger neuronal firing. In this situation, stimulation-evoked ripples lead to the potentiation of weak synapses within the feed-forward structure and, thus, to a consolidation of a more general sequence memory. However, spontaneous ripples that occur without stimulation, only consolidate a sparse backbone of the existing strong feed-forward structure. Based on this, we test a recently hypothesized scenario in which the excitability of dendrites is transiently enhanced after learning, and show that such a transient increase can strengthen, restructure and consolidate even weak hippocampal memories, which would be forgotten otherwise. Hence, a transient increase in dendritic excitability would indeed provide a mechanism for stabilizing memories.

Predatory Odor Exposure as a Potential Paradigm for Studying Emotional Modulation of Memory Consolidation-The Role of the Noradrenergic Transmission in the Basolateral Amygdala.

The pivotal role of the basolateral amygdala (BLA) in the emotional modulation of hippocampal plasticity and memory consolidation is well-established. Specifically, multiple studies have demonstrated that the activation of the noradrenergic (NA) system within the BLA governs these modulatory effects. However, most current evidence has been obtained by direct infusion of synthetic NA or beta-adrenergic agonists. In the present study, we aimed to investigate the effect of endogenous NA release in the BLA, induced by a natural aversive stimulus (coyote urine), on memory consolidation for a low-arousing, hippocampal-dependent task. Our experiments combined a weak object location task (OLT) version with subsequent mild predator odor exposure (POE). To investigate the role of endogenous NA in the BLA in memory modulation, a subset of the animals (Wistar rats) was treated with the non-selective beta-blocker propranolol at the end of the behavioral procedures. Hippocampal tissue was collected 90 min after drug infusion or after the OLT test, which was performed 24 h later. We used the obtained samples to estimate the levels of phosphorylated CREB (pCREB) and activity-regulated cytoskeleton-associated protein (Arc)-two molecular markers of experience-dependent changes in neuronal activity. The result suggests that POE has the potential to become a valuable behavioral paradigm for studying the interaction between BLA and the hippocampus in memory prioritization and selectivity.

Roles of feedback and feed-forward networks of dopamine subsystems: insights from Drosophila studies.

Across animal species, dopamine-operated memory systems comprise anatomically segregated, functionally diverse subsystems. Although individual subsystems could operate independently to support distinct types of memory, the logical interplay between subsystems is expected to enable more complex memory processing by allowing existing memory to influence future learning. Recent comprehensive ultrastructural analysis of the Drosophila mushroom body revealed intricate networks interconnecting the dopamine subsystems-the mushroom body compartments. Here, we review the functions of some of these connections that are beginning to be understood. Memory consolidation is mediated by two different forms of network: A recurrent feedback loop within a compartment maintains sustained dopamine activity required for consolidation, whereas feed-forward connections across compartments allow short-term memory formation in one compartment to open the gate for long-term memory formation in another compartment. Extinction and reversal of aversive memory rely on a similar feed-forward circuit motif that signals omission of punishment as a reward, which triggers plasticity that counteracts the original aversive memory trace. Finally, indirect feed-forward connections from a long-term memory compartment to short-term memory compartments mediate higher-order conditioning. Collectively, these emerging studies indicate that feedback control and hierarchical connectivity allow the dopamine subsystems to work cooperatively to support diverse and complex forms of learning.

Recalled through this day but forgotten next week?-retrieval activity predicts durability of partly consolidated memories.

Even partly consolidated memories can be forgotten given sufficient time, but the brain activity associated with durability of episodic memory at different time scales remains unclear. Here, we aimed to identify brain activity associated with retrieval of partly consolidated episodic memories that continued to be remembered in the future. Forty-nine younger (20 to 38 years; 25 females) and 43 older adults (60 to 80 years, 25 females) were scanned with functional magnetic resonance imaging during associative memory retrieval 12 h post-encoding. Twelve hours is sufficient to allow short-term synaptic consolidation as well as early post-encoding replay to initiate memory consolidation. Successful memory trials were classified into durable and transient source memories based on responses from a memory test ~6 d post-encoding. Results demonstrated that successful retrieval of future durable vs. transient memories was supported by increased activity in a medial prefrontal and ventral parietal area. Individual differences in activation as well as the subjective vividness of memories during encoding were positively related to individual differences in memory performance after 6 d. The results point to a unique and novel aspect of brain activity supporting long-term memory, in that activity during retrieval of memories even after 12 h of consolidation contains information about potential for long-term durability.

Perceptual encoding benefit of visual memorability on visual memory formation.

Human observers often exhibit remarkable consistency in remembering specific visual details, such as certain face images. This phenomenon is commonly attributed to visual memorability, a collection of stimulus attributes that enhance the long-term retention of visual information. However, the exact contributions of visual memorability to visual memory formation remain elusive as these effects could emerge anywhere from early perceptual encoding to post-perceptual memory consolidation processes. To clarify this, we tested three key predictions from the hypothesis that visual memorability facilitates early perceptual encoding that supports the formation of visual short-term memory (VSTM) and the retention of visual long-term memory (VLTM). First, we examined whether memorability benefits in VSTM encoding manifest early, even within the constraints of a brief stimulus presentation (100-200 ms; Experiment 1). We achieved this by manipulating stimulus presentation duration in a VSTM change detection task using face images with high- or low-memorability while ensuring they were equally familiar to the participants. Second, we assessed whether this early memorability benefit increases the likelihood of VSTM retention, even with post-stimulus masking designed to interrupt post-perceptual VSTM consolidation processes (Experiment 2). Last, we investigated the durability of memorability benefits by manipulating memory retention intervals from seconds to 24 h (Experiment 3). Across experiments, our data suggest that visual memorability has an early impact on VSTM formation, persisting across variable retention intervals and predicting subsequent VLTM overnight. Combined, these findings highlight that visual memorability enhances visual memory within 100-200 ms following stimulus onset, resulting in robust memory traces resistant to post-perceptual interruption and long-term forgetting.

Infralimbic activity during REM sleep facilitates fear extinction memory.

Rapid eye movement (REM) sleep is known to facilitate fear extinction and play a protective role against fearful memories.1,2 Consequently, disruption of REM sleep after a traumatic event may increase the risk for developing PTSD.3,4 However, the underlying mechanisms by which REM sleep promotes extinction of aversive memories remain largely unknown. The infralimbic cortex (IL) is a key brain structure for the consolidation of extinction memory.5 Using calcium imaging, we found in mice that most IL pyramidal neurons are intensively activated during REM sleep. Optogenetically suppressing the IL specifically during REM sleep within a 4-h window after auditory-cued fear conditioning impaired extinction memory consolidation. In contrast, REM-specific IL inhibition after extinction learning did not affect the extinction memory. Whole-cell patch-clamp recordings demonstrated that inactivating IL neurons during REM sleep depresses their excitability. Together, our findings suggest that REM sleep after fear conditioning facilitates fear extinction by enhancing IL excitability and highlight the importance of REM sleep in the aftermath of traumatic events for protecting against traumatic memories.

Recognizing the opponent: The consolidation of long-term social memory in zebrafish males.

Recognizing and remembering another individual in a social context could be beneficial for individual fitness. Especially in agonistic encounters, remembering an opponent and the previous fight could allow for avoiding new conflicts. Considering this, we hypothesized that this type of social interaction forms a long-term recognition memory lasting several days. It has been shown that a second encounter 24 h later between the same pair of zebrafish males is resolved with lower levels of aggression. Here, we evaluated if this behavioral change could last for longer intervals and a putative mechanism associated with memory storage: the recruitment of NMDA receptors. We found that if a pair of zebrafish males fight and fight again 48 or 72 h later, they resolve the second encounter with lower levels of aggression. However, if opponents were exposed to MK-801 (NMDA receptor antagonist) immediately after the first encounter, they solved the second one with the same levels of aggression: that is, no reduction in aggressive behaviors was observed. These amnesic effect suggest the formation of a long-term social memory related to recognizing a particular opponent and/or the outcome and features of a previous fight.

Consolidation of emotional memory during waking rest depends on trait anxiety.

A short period of eyes-closed waking rest improves long-term memory for recently learned information, including declarative, spatial, and procedural memory. However, the effect of rest on emotional memory consolidation remains unknown. This preregistered study aimed to establish whether post-encoding rest affects emotional memory and how anxiety levels might modulate this effect. Participants completed a modified version of the dot-probe attention task that involved reacting to and encoding word stimuli appearing underneath emotionally negative or neutral photos. We tested the effect of waking rest on memory for these words and pictures by manipulating the state that participants entered just after this task (rest vs. active wake). Trait anxiety levels were measured using the State-Trait Anxiety Inventory and examined as a covariate. Waking rest improved emotional memory consolidation for individuals high in trait anxiety. These results suggest that the beneficial effect of waking rest on memory extends into the emotional memory domain but depends on individual characteristics such as anxiety.