Non-competitive NMDA antagonist MK-801 prevents memory reconsolidation impairment caused by protein synthesis inhibitors in young chicks.

Introduction: Reactivation of already consolidated memory can initiate its destabilization, making the memory trace labile. Normally, this destabilization is followed by reconsolidation of the memory trace, enriched by newly acquired experience. Disrupting the reconsolidation process, for example, by inhibiting protein synthesis, impairs subsequent memory retrieval, leading to reminder-related amnesia. Previous studies in various species have shown that this impairment can be prevented by using NMDA receptor antagonists, which interfere with memory destabilization. Methods: In the present study we examined this phenomenon using a one-trial passive avoidance learning model in newborn chicks, the hypothesis being that inactivation of the NMDA-mediated transmission during memory reactivation would inhibit the memory trace labilization and thus prevent the reminder-related amnesia. Results: We found that reminder-associated administration of the NMDA receptor antagonist MK-801 or one of the protein synthesis inhibitors (anisomycin, cycloheximide, 2-deoxygalactose) each alone produced amnesia. However, when combined, injection of MK-801 before the reminder prevented amnesia induced by protein synthesis inhibitors. Discussion: We suggest that the observed paradoxical effect implicates the involvement of NMDA receptors in both protein synthesis-independent engram destabilization upon its retrieval and protein synthesismediated engram stabilization after its updating. This puzzling dual role of NMDA receptors in memory destabilization/restabilization requires further investigation.

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.

Targeting fear memories: Examining pharmacological disruption in a generalized fear framework.

Labilization-reconsolidation, which relies on retrieval, has been considered an opportunity to attenuate the negative aspects of traumatic memories. A therapeutic strategy based on reconsolidation blockade is deemed more effective than current therapies relying on memory extinction. Nevertheless, extremely stressful memories frequently prove resistant to this process. Here, after inducing robust fear memory in mice through strong fear conditioning, we examined the possibility of rendering it susceptible to pharmacological modulation based on the degree of generalized fear (GF). To achieve this, we established an ordered gradient of GF, determined by the perceptual similarity between the associated context (CA) and non-associated contexts (CB, CC, CD, and CE) to the aversive event. We observed that as the exposure context became less similar to CA, the defensive pattern shifted from passive to active behaviors in both male and female mice. Subsequently, in conditioned animals, we administered propranolol after exposure to the different contexts (CA, CB, CC, CD or CE). In males, propranolol treatment resulted in reduced freezing time and enhanced risk assessment behaviors when administered following exposure to CA or CB, but not after CC, CD, or CE, compared to the control group. In females, a similar change in behavioral pattern was observed with propranolol administered after exposure to CC, but not after the other contexts. These results highlight the possibility of indirectly manipulating a robust contextual fear memory by controlling the level of generalization during recall. Additionally, it was demonstrated that the effect of propranolol on reconsolidation would not lead to a reduction in fear memory per se, but rather to its reorganization resulting in greater behavioral flexibility (from passive to active behaviors). Finally, from a clinical viewpoint, this would be of considerable relevance since following this strategy could make the treatment of psychiatric disorders associated with traumatic memory formation more effective and less stressful.

Pharmacological HDAC3 inhibition alters memory updating in young and old male mice.

Long-term memories are not stored in a stable state but must be flexible and dynamic to maintain relevance in response to new information. Existing memories are thought to be updated through the process of reconsolidation, in which memory retrieval initiates destabilization and updating to incorporate new information. Memory updating is impaired in old age, yet little is known about the mechanisms that go awry. One potential mechanism is the repressive histone deacetylase 3 (HDAC3), which is a powerful negative regulator of memory formation that contributes to age-related impairments in memory formation. Here, we tested whether HDAC3 also contributes to age-related impairments in memory updating using the Objects in Updated Locations (OUL) paradigm. We show that blocking HDAC3 immediately after updating with the pharmacological inhibitor RGFP966 ameliorated age-related impairments in memory updating in 18-m.o. male mice. Surprisingly, we found that post-update HDAC3 inhibition in young (3-m.o.) male mice had no effect on memory updating but instead impaired memory for the original information, suggesting that the original and updated information may compete for expression at test and HDAC3 helps regulate which information is expressed. To test this idea, we next assessed whether HDAC3 inhibition would improve memory updating in young male mice given a weak, subthreshold update. Consistent with our hypothesis, we found that HDAC3 blockade strengthened the subthreshold update without impairing memory for the original information, enabling balanced expression of the original and updated information. Together, this research suggests that HDAC3 may contribute to age-related impairments in memory updating and may regulate the strength of a memory update in young mice, shifting the balance between the original and updated information at test.

On the participation of glycine receptors in the reconsolidation of spatial long-term memory in male rats.

The effects of intra-hippocampal manipulation of glycine receptors on the reconsolidation of recent and late long-term spatial memory were evaluated and assessed in the Morris water maze. The results obtained from the intra-hippocampal infusion of glycine and taurine demonstrated that taurine at a 100 nmol/side dose impaired the reconsolidation of recent and late long-term spatial memory. In comparison, at a dose of 10 nmol/side, it only affected the reconsolidation of late long-term spatial memory, reinforcing that there are differences between molecular mechanisms underlying recent and late long-term memory reconsolidation. On the other hand, glycine impaired the reconsolidation of early and late spatial memory when infused at a dose of 10 nmol/side, but not at a dose of 100 nmol/side, unless it is co-infused with an allosteric site antagonist of the NMDA receptor. Altogether these results show that glycine acting in situ in the hippocampal CA1 region exerts a pharmacological effect on U-curve, which can be explained by its concomitant action on its ionotropic receptor GlyR and on its NMDA receptor co-agonist site.

Inhibition of ERK1/2 or CRMP2 Disrupts Alcohol Memory Reconsolidation and Prevents Relapse in Rats.

Relapse to alcohol abuse, often caused by cue-induced alcohol craving, is a major challenge in alcohol addiction treatment. Therefore, disrupting the cue-alcohol memories can suppress relapse. Upon retrieval, memories transiently destabilize before they reconsolidate in a process that requires protein synthesis. Evidence suggests that the mammalian target of rapamycin complex 1 (mTORC1), governing the translation of a subset of dendritic proteins, is crucial for memory reconsolidation. Here, we explored the involvement of two regulatory pathways of mTORC1, phosphoinositide 3-kinase (PI3K)-AKT and extracellular regulated kinase 1/2 (ERK1/2), in the reconsolidation process in a rat (Wistar) model of alcohol self-administration. We found that retrieval of alcohol memories using an odor-taste cue increased ERK1/2 activation in the amygdala, while the PI3K-AKT pathway remained unaffected. Importantly, ERK1/2 inhibition after alcohol memory retrieval impaired alcohol-memory reconsolidation and led to long-lasting relapse suppression. Attenuation of relapse was also induced by post-retrieval administration of lacosamide, an inhibitor of collapsin response mediator protein-2 (CRMP2)-a translational product of mTORC1. Together, our findings indicate the crucial role of ERK1/2 and CRMP2 in the reconsolidation of alcohol memories, with their inhibition as potential treatment targets for relapse prevention.

Virtual realities, real recoveries: exploring the efficacy of 3MDR therapy for treatment-resistant PTSD.

Exposure-based therapies have shown promise in treating post-traumatic stress disorder (PTSD), but challenges exist in maintaining patient engagement and finding appropriate stimuli for graded exposure. Virtual reality (VR) technology has been used to enhance exposure therapy, but current software lacks customization and some patients remain treatment-resistant. A novel approach called multimodular motion-assisted memory desensitization and reconsolidation (3MDR) has the potential to solve some of the current limitations of VR-assisted exposure therapy. This study examines the efficacy of 3MDR treatment for individuals with treatment-resistant PTSD through a systematic review of relevant literature and clinical studies. Preliminary findings indicate promise for 3MDR in reducing PTSD symptoms, including emotional regulation and moral injury. However, further research with larger samples and controlled studies is needed to understand underlying mechanisms and validate these results. Moreover, this study highlights the importance of health-economic evaluations to assess costs and resource utilization associated with implementing 3MDR treatment in clinical services.

Role of amygdala astrocytes in different phases of contextual fear memory.

Growing evidence indicates a critical role of astrocytes in learning and memory. However, little is known about the role of basolateral amygdala complex (BLA-C) astrocytes in contextual fear conditioning (CFC), a paradigm relevant to understand and generate treatments for fear- and anxiety-related disorders. To get insights on the involvement of BLA-C astrocytes in fear memory, fluorocitrate (FLC), a reversible astroglial metabolic inhibitor, was applied at critical moments of the memory processing in order to target the acquisition, consolidation, retrieval and reconsolidation process of the fear memory. Adult Wistar male rats were bilaterally cannulated in BLA-C. Ten days later they were infused with different doses of FLC (0.5 or 1 nmol/0.5 µl) or saline before or after CFC and before or after retrieval. FLC impaired fear memory expression when administered before and shortly after CFC, but not one hour later. Infusion of FLC prior and after retrieval did not affect the memory. Our findings suggest that BLA-C astrocytes are critically involved in the acquisition/early consolidation of fear memory but not in the retrieval and reconsolidation. Furthermore, the extinction process was presumably not affected (considering that peri-retrieval administration could also affect this process).

Can neutral episodic memories become emotional? Evidence from facial expressions and subjective feelings.

Maladaptive emotional memories are a transdiagnostic feature of mental health problems. Therefore, understanding whether and how emotional memories can change might help to prevent and treat mental disorders. We tested whether neutral memories of naturalistic events can retroactively acquire positive or negative affect, in a preregistered three-day Modification of Valence in Episodes (MOVIE) paradigm. On Day 1, participants (N = 41) encoded memories of neutral movie scenes, representing lifelike naturalistic experiences. On Day 2, they retrieved each episode before viewing a happy, sad, or neutral scene from the same movie (yielding a within-subjects design with a neutral-negative, neutral-positive, and neutral-neutral condition). On Day 3, participants again retrieved each memory from Day 1. We assessed the affective tone of episodes through facial expressions of positive and negative affect (using facial electromyography, fEMG) and through self-reported feelings. Positive updating of neutral episodes led to increased expressions of positive affect, whereas negative updating led to increased self-reported negative feelings. These results suggest that complex neutral episodic memories can retroactively acquire an affective tone, but the effects were modest and inconsistent across affect readouts. Future research should investigate alternative approaches to updating emotional memories that produce more profound changes in the valence of memories.

Interfering with reconsolidation by rimonabant results in blockade of heroin-associated memory.

Drug-associated pathological memory remains a critical factor contributing to the persistence of substance use disorder. Pharmacological amnestic manipulation to interfere with drug memory reconsolidation has shown promise for the prevention of relapse. In a rat heroin self-administration model, we examined the impact of rimonabant, a selective cannabinoid receptor indirect agonist, on the reconsolidation process of heroin-associated memory. The study showed that immediately administering rimonabant after conditioned stimuli (CS) exposure reduced the cue- and herion + cue-induced heroin-seeking behavior. The inhibitory effects lasted for a minimum of 28 days. The effect of Rimonabant on reduced drug-seeking was not shown when treated without CS exposure or 6 hours after CS exposure. These results demonstrate a disruptive role of rimonabant on the reconsolidation of heroin-associated memory and the therapeutic potential in relapse control concerning substance use disorder.

Conflict Dynamics of Post-Retrieval Extinction: A Comparative Analysis of Unconditional and Conditional Reminders Using Skin Conductance Responses and EEG.

The post-retrieval extinction paradigm, rooted in reconsolidation theory, holds promise for enhancing extinction learning and addressing anxiety and trauma-related disorders. This study investigates the impact of two reminder types, mild US-reminder (US-R) and CS-reminder (CS-R), along with a no-reminder extinction, on fear recovery prevention in a categorical fear conditioning paradigm. Scalp EEG recordings during reminder and extinction processes were conducted in a three-day design. Results show that the US-R group exhibits a distinctive extinction learning pattern, characterized by a slowed-down yet successful process and pronounced theta-alpha desynchronization (source-located in the prefrontal cortex) during CS processing, followed by enhanced synchronization (source-located in the anterior cingulate) after shock cancellation in extinction trials. These neural dynamics correlate with the subtle advantage of US-R in the Day 3 recovery test, presenting faster spontaneous recovery fading and generally lower fear reinstatement responses. Conversely, the CS reminder elicits CS-specific effects in later episodic tests. The unique neural features of the US-R group suggest a larger prediction error and subsequent effortful conflict learning processes, warranting further exploration.

Combining brief recall and ketamine treatment prevents stress-primed methamphetamine memory reinstatement via heightening mPFC GABA activity.

This study aimed to assess whether brief recall of methamphetamine (MA) memory, when combined with ketamine (KE) treatment, may prevent stress-primed MA memory reinstatement. Combining 3-min recall and KE facilitated MA memory extinction and resistance to subsequent stress-primed reinstatement. Such combination also produced glutamate metabotropic receptor 5 (mGluR5) upregulation in animals' medial prefrontal cortex (mPFC) γ-amino-butyric acid (GABA) neuron. Accordingly, chemogenetic methods were employed to bi-directionally modulate mPFC GABA activity. Following brief recall and KE-produced MA memory extinction, intra-mPFC mDlx-Gi-coupled-human-muscarinic-receptor 4 (hM4Di)-infused mice receiving compound 21 (C21) treatment showed eminent stress-primed reinstatement, while their GABA mGluR5 expression seemed to be unaltered. Intra-mPFC mDlx-Gq-coupled-human-muscarinic-receptor 3 (hM3Dq)-infused mice undergoing C21 treatment displayed MA memory extinction and resistance to stress-provoked reinstatement. These results suggest that combining a brief recall and KE treatment and exciting mPFC GABA neuron may facilitate MA memory extinction and resistance to stress-primed recall. mPFC GABA neuronal activity plays a role in mediating brief recall/KE-produced effects on curbing the stress-provoked MA seeking.

Knowledge of Memory Reconsolidation Can Improve Psychodynamic Technique.

The gold standard of scientific medicine is using knowledge of underlying processes to shape treatment. This has previously not been possible for psychotherapy, but with the science of memory reconsolidation, requirements for change can be more precisely defined and can improve psychotherapeutic technique by focusing on three areas: the activation of maladaptive implicit learning, the provision of disconfirming information, and attention to transmission between consciousness and limbic memory. Overall, better understanding of processes helps liberate psychotherapy from rigidities dictated by set methods.

Novelty-retrieval-extinction paradigm to decrease high-intensity fear memory recurrence.

BACKGROUND: The retrieval-extinction paradigm based on memory reconsolidation can prevent fear memory recurrence more effectively than the extinction paradigm. High-intensity fear memories tend to resist reconsolidation. Novelty-retrieval-extinction can promote the reconsolidation of fear memory lacking neuroplasticity in rodents; however, whether it could effectively promote high-intensity fear memory reconsolidation in humans remains unclear. METHODS: Using 120 human participants, we implemented the use of the environment (novel vs. familiar) with the help of virtual reality technology. Novelty environment exploration was combined with retrieval-extinction in fear memory of two intensity levels (normal vs. high) to examine whether novelty facilitates the reconsolidation of high-intensity fear memory and prevents recurrence. Skin conductance responses were used to clarify novelty-retrieval-extinction effects at the behavioral level across three experiments. RESULTS: Retrieval-extinction could prevent the reinstatement of normal-intensity fear memory; however, for high-intensity fear memory, only the novelty-retrieval-extinction could prevent recurrence; we further validated that novelty-retrieval-extinction may be effective only when the environment is novel. LIMITATIONS: Although the high-intensity fear memory is higher than normal-intensity in this study, it may be insufficient relative to fear experienced in real-world contexts or by individuals with mental disorders. CONCLUSIONS: To some extent, these findings indicate that the novelty-retrieval-extinction paradigm could prevent the recurrence of high-intensity fear memory, and we infer that novelty of environment may play an important role in novelty-retrieval-extinction paradigm. The results of this study have positive implications for the existing retrieval extinction paradigm and the clinical treatment of phobia.

Regulation of histone acetylation by garcinol blocks the reconsolidation of heroin-associated memory.

Drug-associated long-term memories underlie substance use disorders, including heroin use disorder (HUD), which are difficult to eliminate through existing therapies. Addictive memories may become unstable when reexposed to drug-related cues and need to be stabilized again through protein resynthesis. Studies have shown the involvement of histone acetylation in the formation and reconsolidation of long-term drug-associated memory. However, it remains unknown whether and how histone acetyltransferases (HAT), the essential regulators of histone acetylation, contribute to the reconsolidation of heroin-associated memories. Herein, we investigated the function of HAT in the reconsolidation concerning heroin-conditioned memory by using a rat self-administration model. Systemic administration of the HAT inhibitor garcinol inhibited cue and heroin-priming induced reinstatement of heroin seeking, indicating the treatment potential of garcinol for relapse prevention.

Elevated fear states facilitate ventral hippocampal engagement of basolateral amygdala neuronal activity.

Fear memory formation and retention rely on the activation of distributed neural circuits. The basolateral amygdala (BLA) and ventral hippocampus (VH) in particular are two regions that support contextual fear memory processes and share reciprocal connections. The VH → BLA pathway is critical for increases in fear after initial learning, in both fear renewal following extinction learning and during fear generalization. This raises the possibility that functional changes in VH projections to the BLA support increases in learned fear. In line with this, fear can also be increased with alterations to the original content of the memory via reconsolidation, as in fear elevation procedures. However, very little is known about the functional changes in the VH → BLA pathway supporting reconsolidation-related increases in fear. In this study, we used in vivo extracellular electrophysiology to examine the functional neuronal changes within the BLA and in the VH → BLA pathway as a result of fear elevation and standard fear retrieval procedures. Elevated fear expression was accompanied by higher BLA spontaneous firing compared to a standard fear retrieval condition. Across a range of stimulation frequencies, we also found that VH stimulation evoked higher BLA firing following fear elevation compared to standard retrieval. These results suggest that fear elevation is associated with an increased capacity of the VH to drive neuronal activity in the BLA, highlighting a potential circuit involved in strengthening existing fear memories.

Rapamycin attenuates reconsolidation of a backwards-conditioned aversive stimuli in female mice.

RATIONALE: The mammalian target of rapamycin (mTOR) kinase is known to mediate consolidation and reconsolidation of aversive memories. Most studies in this area use a forward conditioning paradigm in which the conditioned stimulus (CS) precedes the unconditioned stimulus (US). Little is known, however, about the neurobiological underpinnings of backwards (BW) conditioning paradigms, particularly in female mice. In BW conditioning, the CS does not become directly associated with the US; it instead evokes conditioned fear by reactivating a memory of the conditioning context and indirectly retrieving a memory of the aversive US. OBJECTIVES: We sought to examine BW conditioned fear memory processes in female mice. First, we examined whether freezing to a BW CS is mediated by fear to the conditioning context. Second, we tested whether blocking consolidation of a BW CS attenuated memory of the CS and conditioning context. Finally, we tested whether blocking reconsolidation of a BW CS attenuated memory of the conditioning context. RESULTS: We show that conditioned freezing to a BW CS is mediated by fear to the conditioning context. Furthermore, rapamycin-an mTOR inhibitor, when given immediately following BW conditioning, impairs consolidation of both cued and contextual fear memory. Similarly, rapamycin given following retrieval of a BW CS blocks context recall. Rapamycin is acting on reconsolidation as CS retrieval is necessary to see the effects of rapamycin on context memory recall. CONCLUSIONS: Our study provides novel evidence that indirect retrieval cues are sensitive to rapamycin in female mice. The capacity to indirectly reactivate memories and render them susceptible to disruption is critical in the translation of reconsolidation-based approaches to the clinic.

Evaluating the effects of single, multiple, and delayed systemic rapamycin injections to contextual fear reconsolidation: Implications for the neurobiology of memory and the treatment of PTSD-like re-experiencing.

The mechanistic target of rapamycin (mTOR) kinase is known to mediate the formation and persistence of aversive memories. Rapamycin, an mTOR inhibitor, administered around the time of reactivation blocks retrieval-induced mTOR activity and de novo protein synthesis in the brains of rodents, while correspondingly diminishing subsequent fear memory. The goal of the current experiments was to further explore rapamycin's effects on fear memory persistence. First, we examined whether mTOR blockade at different time-points after reactivation attenuates subsequent contextual fear memory. We show that rapamycin treatment 3 or 12 h post-reactivation disrupts memory persistence. Second, we examined whether consecutive days of reactivation paired with rapamycin had additive effects over a single pairing at disrupting a contextual fear memory. We show that additional reactivation-rapamycin pairings exacerbates the reconsolidation impairment. Finally, we examined if impaired reconsolidation of a contextual fear memory from rapamycin treatment had any after-effects on learning and recalling a new fear association. We show that rapamycin-impaired reconsolidation does not affect new learning or recall and protects against fear generalization. Our findings improve our understanding of mTOR- dependent fear memory processes, as well as provide insight into potentially novel treatment options for stress-related psychopathologies such as posttraumatic stress disorder.

Esketamine enhances memory reconsolidation in the novel object recognition task.

Esketamine, the right-handed optical isomer of racemic ketamine, is a rapidly acting antidepressant approved by the FDA for treatment-resistant depression in 2019. However, few studies have investigated esketamine's role in learning and memory, particularly in the context of memory reconsolidation. Herein, we evaluated esketamine's role in memory reconsolidation in 7-week-old male Institute of Cancer Research mice subjected to the novel object recognition (NOR) memory task. The NOR reconsolidation procedure comprised three phases: sampling, reactivation, and testing. Esketamine-enhanced NOR memory performance when injected into mice 0 h after reactivation rather than following a 6 h delay. Conversely, administering esketamine 24 h after sampling without reactivation did not enhance NOR memory performance. Notably, esketamine exhibited no discernible effects on nonspecific responses, such as locomotor activity and exploratory behavior. Furthermore, the α-amino-3­hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type receptor antagonist NBQX effectively blocked the esketamine-induced enhancement of memory reconsolidation. In conclusion, esketamine treatment markedly improves memory reconsolidation in NOR tasks, and this effect is linked to AMPA receptor activity.

Requisite role of dorsal raphé in contextual cocaine-memory reconsolidation.

Memory reconsolidation is a process by which labile drug memories are restabilized in long-term memory stores, permitting their enduring control over drug-seeking behaviors. In the present study, we investigated the involvement of the dorsal raphé nuclei (DRN) in cocaine-memory reconsolidation. Sprague-Dawley rats (male, female) were trained to self-administer cocaine in a distinct environmental context to establish contextual drug memories. They then received extinction training in a different context. Next, the rats were re-exposed to the cocaine-predictive context for 15 min to reactivate their cocaine memories or remained in their home cages (no-reactivation control). Memory reactivation was sufficient to increase c-Fos expression, an index of neuronal activation, in the DRN, but not in the median raphé nuclei, during reconsolidation, compared to no reactivation. To determine whether DRN neuronal activity was necessary for cocaine-memory reconsolidation, rats received intra-DRN baclofen plus muscimol (BM; GABAB/A agonists) or vehicle microinfusions immediately after or 6 h after a memory reactivation session conducted with or without lever access. The effects of DRN functional inactivation on long-term memory strength, as indicated by the magnitude of context-induced cocaine seeking, were assessed 72 h later. Intra-DRN BM treatment immediately after memory reactivation with or without lever access attenuated subsequent context-induced cocaine-seeking behavior, independent of sex. Conversely, BM treatment in the adjacent periaqueductal gray (PAG) immediately after memory reactivation, or BM treatment in the DRN 6 h after memory reactivation, did not alter responding. Together, these findings indicate that the DRN plays a requisite role in maintaining cocaine-memory strength during reconsolidation.