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.

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.

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.

Cellular mechanisms of contextual fear memory reconsolidation: Role of hippocampal SFKs, TrkB receptors and GluN2B-containing NMDA receptors.

Memories are stored into long-term representations through a process that depends on protein synthesis. However, a consolidated memory is not static and inflexible and can be reactivated under certain circumstances, the retrieval is able to reactivate memories and destabilize them engaging a process of restabilization known as reconsolidation. Although the molecular mechanisms that mediate fear memory reconsolidation are not entirely known, so here we investigated the molecular mechanisms in the hippocampus involved in contextual fear conditioning memory (CFC) reconsolidation in male Wistar rats. We demonstrated that the blockade of Src family kinases (SFKs), GluN2B-containing NMDA receptors and TrkB receptors (TrkBR) in the CA1 region of the hippocampus immediately after the reactivation session impaired contextual fear memory reconsolidation. These impairments were blocked by the neurotrophin BDNF and the NMDAR agonist, D-Serine. Considering that the study of the link between synaptic proteins is crucial for understanding memory processes, targeting the reconsolidation process may provide new ways of disrupting maladaptive memories, such as those seen in post-traumatic stress disorder. Here we provide new insights into the cellular mechanisms involved in contextual fear memory reconsolidation, demonstrating that SFKs, GluN2B-containing NMDAR, and TrkBR are necessary for the reconsolidation process. Our findings suggest a link between BDNF and SFKs and GluN2B-containing NMDAR as well as a link between NMDAR and SFKs and TrkBR in fear memory reconsolidation. These preliminary pharmacological findings provide new evidence of the mechanisms involved in the reconsolidation of fear memory and have the potential to contribute to the development of treatments for psychiatric disorders involving maladaptive memories.

The influence of electroconvulsive therapy on reconsolidation of autobiographical memories: A retrospective quasi-experimental study in patients with depression

Background/Objective: Electroconvulsive therapy (ECT) is effective for treatment-resistant and psychotic depression. One previously reported side effect of ECT is the disruption of memory reconsolidation. This study examines whether this disruption induced by ECT can be detected in routine neuropsychological assessments. Methods: In this retrospective study, the Autobiographical Memory Interview (AMI) was applied before and after ECT. Memories of the same events and facts were tested pre and post ECT treatments. 38 patients, receiving ECT for the treatment of unipolar or bipolar depression, were matched for age, sex, and stimulus intensity and divided into two groups: Group A was tested on the day before the first ECT treatment, whereas group B two or more days before. Results: Patients who were tested by AMI on the day before ECT and thus reactivated memorie shortly before the first ECT treatment deteriorated in AMI score. Patients who had at least two days between memory activation and treatment improved regarding the number of recalled memories. Memory impairment was not associated with depression severity. Conclusion: This finding suggests that ECT might be capable of impairing reconsolidation. The study demonstrates that memories of personal events can potentially be affected by ECT within a time interval of 24 h of memory vulnerability after reactivation. Implications for practice and future research are discussed. (AU)

Reminder-dependent alterations in long-term declarative memory expression.

The reminder of a previously-learned memory can render that memory vulnerable to disruption or change in expression. Such memory alterations have been viewed as supportive of the framework of memory reconsolidation. However, alternative interpretations and inconsistencies in the replication of fundamental findings have raised questions particularly in the domain of human declarative memory. Here we present a series of related experiments, all of which involve the learning of a declarative memory, followed 1-2 days later by memory reminder. Post-reminder learning of interfering material did result in modulation of subsequent recall at test, but the precise manifestation of that interference effect differed across experiments. With post-reminder performance of a visuospatial task, a quantitative impairment in test recall performance was observed within a visual list-learning paradigm, but not in a foreign vocabulary learning paradigm. These results support the existence of reminder-induced memory processes that can lead to the alteration of subsequent memory performance by interfering tasks. However, it remains unclear whether these effects are reflective of modulation or impairment of the putative memory reconsolidation process.

The influence of electroconvulsive therapy on reconsolidation of autobiographical memories: A retrospective quasi-experimental study in patients with depression.

Background/Objective: Electroconvulsive therapy (ECT) is effective for treatment-resistant and psychotic depression. One previously reported side effect of ECT is the disruption of memory reconsolidation. This study examines whether this disruption induced by ECT can be detected in routine neuropsychological assessments. Methods: In this retrospective study, the Autobiographical Memory Interview (AMI) was applied before and after ECT. Memories of the same events and facts were tested pre and post ECT treatments. 38 patients, receiving ECT for the treatment of unipolar or bipolar depression, were matched for age, sex, and stimulus intensity and divided into two groups: Group A was tested on the day before the first ECT treatment, whereas group B two or more days before. Results: Patients who were tested by AMI on the day before ECT and thus reactivated memorie shortly before the first ECT treatment deteriorated in AMI score. Patients who had at least two days between memory activation and treatment improved regarding the number of recalled memories. Memory impairment was not associated with depression severity. Conclusion: This finding suggests that ECT might be capable of impairing reconsolidation. The study demonstrates that memories of personal events can potentially be affected by ECT within a time interval of 24 h of memory vulnerability after reactivation. Implications for practice and future research are discussed.

Epigenetic Processes of DNA Methylation Are Selectively Involved in the Mechanisms of Retrograde and Anteograde Amnesia.

The participation of DNA methylation processes in the mechanisms of anterograde and retrograde amnesia caused by impaired reconsolidation of conditioned food aversion memory by NMDA glutamate receptor antagonists or serotonin receptor antagonists, respectively, were studied on grape snails. Anterograde amnesia was characterized by impaired formation of long-term memory during repeated learning. Administration of a DNA methyltransferase (DNMT) inhibitor to amnestic animals resulted in accelerated formation of long-term memory during 1 day of repetitive training vs 3 days during initial training. In serotonin-dependent retrograde amnesia, repeated learning without DNMT inhibitor administration or after inhibitor injections led to the formation of long-term memory. The dynamics of memory formation was similar in both cases and did not differ from that during the initial training: the memory was formed within 3 days of training. Thus, epigenetic processes of DNA methylation are selectively involved in the mechanisms of anterograde amnesia, but do not participate in the mechanisms of retrograde amnesia.

Basolateral Amygdala Cannabinoid CB1 Receptor Controls Formation and Elimination of Social Fear Memory.

Patients with post-traumatic stress disorder (PTSD) usually manifest persistence of the traumatic memory for a long time after the event, also known as resistance to extinction learning. Numerous studies have shown that the endocannabinoid system, specifically the cannabinoid type-1 receptor (CB1R), plays an important role in traumatic memory. However, the effect of basolateral amygdala (BLA) CB1R in social fear memory formation and elimination is still unclear. Here, we built a mouse model of social avoidance induced by acute social defeat stress to investigate the role of BLA CB1R in social fear memory formation and anxiety- and depression-like behavior. Anterograde knockout of CB1R in BLA neurons facilitates social fear memory formation and manifests an anxiolytic effect but does not influence sociability and social novelty. Retrograde knockout of CB1R in BLA promotes social fear memory formation and shows an anxiogenic effect but does not affect sociability and social novelty. Moreover, intracerebral injection of the CB1R antagonist AM251 in BLA during the memory reconsolidation time window eliminates social fear memory. Our findings suggest the CB1R of BLA can be used as a novel molecular target in social fear memory formation and elimination and potential PTSD therapy with memory retrieval and AM251.

Manipulating critical memory periods to treat psychiatry disorders.

The persistence of pathological memory is the basis of several psychiatric disorders. Memory retrieval induces "reconsolidation", a time interval during which the original memory becomes labile and destabilized. Time- and retrieval-dependent processes and memory reconsolidation are critical periods for memory interference. Modulating memory reconsolidation has received considerable research attention as a treatment protocol for several psychiatric conditions such as posttraumatic stress disorder, addiction, anxiety, and trauma-related disorders. This specific time window provides an opportunity for intervention regarding mental diseases. This article reviews the effect of modulating memory reconsolidation using behavioral-, brain stimulation-, and pharmacological-based interventions, which may help bridge the gap between intervention in laboratories and application in clinical practice. The potential advantages, limitations, challenges, and opportunities for memory reconsolidation manipulations were discussed.

Traumatic memory retrieval followed by electroconvulsive therapy as a treatment for posttraumatic stress disorder: A pilot study.

Delivering electroconvulsive therapy (ECT) during the reconsolidation of traumatic memories may enhance the treatment efficacy in posttraumatic stress disorder (PTSD). To test this, 14 patients with severe and refractory PTSD were randomly allocated to receive ECT sessions either after retrieving the traumatic (n=8) or a neutral (n=6) memory. We found that delivering ECT after retrieving the traumatic memory enhanced the improvement of PTSD symptoms and the reduction of subjective reactivity to the traumatic memory. Reduction in anxiety and mood symptoms and physiological reactivity to the traumatic memory were observed in the sample as a whole regardless of memory retrieval.

Role of Hippocampal Wnt Signaling Pathways on Contextual Fear Memory Reconsolidation.

Memories already consolidated when reactivated return to a labile state and can be modified, this process is known as reconsolidation. It is known the Wnt signaling pathways can modulate hippocampal synaptic plasticity as well as learning and memory. Yet, Wnt signaling pathways interact with NMDA (N-methyl-D-aspartate) receptors. However, whether canonical Wnt/ß-catenin and non-canonical Wnt/Ca2 + signaling pathways are required in the CA1 region of hippocampus for contextual fear memory reconsolidation remains unclear. So, here we verified that the inhibition of canonical Wnt/ß-catenin pathway with DKK1 (Dickkopf-1) into CA1 impaired the reconsolidation of contextual fear conditioning (CFC) memory when administered immediately and 2 h after reactivation session but not 6 h later, while the inhibition of non-canonical Wnt/Ca2+ signaling pathway with SFRP1 (Secreted frizzled-related protein-1) into CA1 immediately after reactivation session had no effect. Moreover, the impairment induced by DKK1 was blocked by the administration of the agonist of the NMDA receptors glycine site, D-Serine, immediately and 2 h after reactivation session. We found that hippocampal canonical Wnt/ß-catenin is necessary to the reconsolidation of CFC memory at least two hours after reactivation, while non-canonical Wnt/Ca2+ signaling pathway is not involved in this process and, that there is a link between Wnt/ß-catenin signaling pathway and NMDA receptors. In view of this, this study provides new evidence regarding the neural mechanisms underlying contextual fear memory reconsolidation and contributes to provide a new possible target for the treatment of fear related disorders.

Systemic corticosterone administration impairs the late fear memory reconsolidation via basolateral amygdala glucocorticoid receptors: Dependence on the time window and memory age.

Glucocorticoid receptors (GRs) of the basolateral amygdala (BLA) play an important role in memory reconsolidation. The present study investigated the role of the BLA GRs in the late reconsolidation of fear memory using an inhibitory avoidance (IA) task in male Wistar rats. Stainless steel cannulae were implanted bilaterally into the BLA of the rats. After 7 days of recovery, the animals were trained in a one-trial IA task (1 mA, 3 s). In Experiment One, 48 h after the training session, the animals received 3 systemic doses of corticosterone (CORT; 1, 3, or 10 mg/kg, i.p.) followed by an intra-BLA microinjection of the vehicle (0.3 µl/side) at different time points (immediately, 12, or 24 h) after memory reactivation. Memory reactivation was performed by returning the animals to the light compartment while the sliding door was open. No shock was delivered during memory reactivation. CORT (10 mg/kg) injection 12 h after memory reactivation most effectively impaired the late memory reconsolidation (LMR). In the second part of Experiment One, immediately, 12, or 24 h after memory reactivation, GR antagonist RU38486 (RU; 1 ng/0.3 µl/side) was injected into BLA following a systemic injection of CORT (10 mg/kg) to examine whether it would block the CORT effect. RU inhibited the impairing effects of CORT on LMR. In Experiment Two, the animals received CORT (10 mg/kg) with time windows immediately, 3, 6, 12, and 24 h after memory reactivation. Again, CORT (10 mg/kg) injection 12 h after memory reactivation impaired LMR. Memory reactivation was performed in the third Experiment, 7, 14, 28, or 56 days after the training session. Injection of CORT (10 mg/kg) 12 h later had no significant effect on the LMR. The impairing effect of CORT was seen only in 2-day-old but not 7, 14, 28, and 56-day-old memories. GRs located in BLA seem to play an important role in the LMR of young memory, as with increasing the age of memories, they become less sensitive to manipulation.

A critical perspective on updating drug memories through the integration of memory editing and brain stimulation.

Addiction is a persistent, recurring condition characterized by repeated relapses despite the desire to control drug use or maintain sobriety. The attainment of abstinence is hindered by persistent maladaptive drug-associated memories, which drive drug-seeking and use behavior. This article examines the preliminary evidence supporting the combination of non-invasive brain stimulation (NIBS) techniques and memory editing (or reconsolidation) interventions as add-on forms of treatment for individuals with substance-related disorders (SUD). Studies have shown that NIBS can modestly reduce drug use and craving through improved cognitive control or other undetermined reasons. Memory reconsolidation, a process by which a previously consolidated memory trace can be made labile again, can potentially erase or significantly weaken SUD memories underpinning craving and the propensity for relapse. This approach conveys enthusiasm while also emphasizing the importance of managing boundary conditions and null results for interventions found on fear memory reconsolidation. Recent studies, which align with the state-dependency and activity-selectivity hypotheses, have shown that the combination of NIBS and behavioral interventions holds promise for treating SUD by reducing self-reported and physiological aspects of craving. Effective long-term outcomes for this procedure require better identification of critical memories, a deeper understanding of the brain mechanisms underlying SUD and memory reconsolidation and overcoming any boundary conditions of destabilized memories. This will enable the procedure to be personalized to the unique needs of individual patients.

Corticosterone injection into the dorsal and ventral hippocampus impairs fear memory reconsolidation in a time-dependent manner in rats.

Reconsolidation is an active process induced following the reactivation of previously consolidated memories. Recent studies suggest brain corticosteroid receptors may participate in the modulation of fear memory reconsolidation. Glucocorticoid receptors (GRs), with 10-fold lower affinity than mineralocorticoid receptors (MRs), are mainly occupied during the peak of the circadian rhythm, and after stress, so they probably have a more critical role than MRs in memory phases during stressful situations. This study investigated the role of dorsal and ventral hippocampal (DH and VH) GRs and MRs on fear memory reconsolidation in rats. Male Wistar rats with surgically implanted bilaterally cannulae at the DH and VH were trained and tested in an inhibitory avoidance task. The animals received bilateral microinjections of vehicle (0.3 µl/side), corticosterone (3 ng/0.3 µl/side), the GRs antagonist RU38486 (3 ng/0.3 µl/side), or the MRs antagonist spironolactone (3 ng/0.3 µl/side) immediately after memory reactivation. Moreover, drugs were injected into VH 90 min after memory reactivation. Memory tests were performed 2, 9, 11, and 13 days after memory reactivation. Results indicated that injection of corticosterone into the DH but not VH immediately after memory reactivation significantly impaired fear memory reconsolidation. Moreover, corticosterone injection into VH 90 min after memory reactivation impaired fear memory reconsolidation. RU38486, but not spironolactone reversed these effects. These findings indicate that corticosterone injection into the DH and VH via GRs activation impairs the reconsolidation of fear memory in a time-dependent manner.

[25 Years of TraumaTherapy with Children and Adolescents ‒ a Personal-Professional Review]. / 25 Jahre Traumatherapie mit Kindern und Jugendlichen ­ ein persönlich-fachlicher Rückblick.

The author was fortunate to experience and help shape the development of the trauma approach with children and adolescents from the very beginning. This brought a great joy for and in the therapeutic work, an intense impulse for one's own inner work, an intellectual pleasure in working out new concepts andmany wonderful encounters in all the workshops with people who had the welfare of children so much at heart. He is deeply convinced that the future belongs to this approach because it is effective and counteracts the "privatization of stress" (Fisher, 2013).

[Resource-Oriented Narrative TraumaTherapy (Resonat): Treating Complex Trauma Disorders in Children and Adolescents Gently and Specifically]. / Ressourcenorientierte narrative Traumatherapie (ResonaT): Komplexe Traumafolgestörungen bei Kindern und Jugendlichen schonend und spezifisch behandeln.

Resource-oriented narrative trauma therapy (ResonaT; Hiller u. Hensel, 2019) is an innovative and creative approach within existing narrative trauma procedures. It is based on the three core elements of modern trauma therapy (actualisation, resource activation, dual attention) and invokes the neurobiological self-healing mechanism of memory reconsolidation. Due to its low demands on the children, its resourceful and gentle actualisation of the traumatic material, the distance-creating use of animal protagonists and a supportive therapeutic relationship, it is particularly suitable for children and adolescents with complex trauma sequelae. Through specific structuring (orientation to the leading symptoms, elaboration of central basic emotions, allocation of current triggers to earlier traumatic events), the narratives can be formulated precisely for each child.The workload for the therapists is made considerably easier by the availability of around 100 elaborated, topic-specific narratives.

New Approaches for Alcohol Use Disorder Treatment via Memory Retrieval and Reconsolidation Manipulations.

Relapse to alcohol seeking and drinking is a major clinical challenge in alcohol use disorder and is frequently brought about by cue-induced craving, caused by exposure to cues that evoke alcohol-related memories. It has been postulated that memories become labile for manipulation shortly after their retrieval and then restabilize in a "memory reconsolidation" process. Disruption or interference with the reconsolidation of drug-associated memories has been suggested as a possible strategy to reduce or even prevent cue-induced craving and relapse. Here, we review literature demonstrating the capacity of behavioral or pharmacological manipulations to reduce relapse in animal models and humans when applied after a short retrieval of memories associated with alcohol, suggestively disrupting the reconsolidation of such memories. We suggest that while there is a clear potential of using post-retrieval manipulations to target specific relapse-evoking memories, future research should be more systematic, standardized, and translational. Specifically, we discuss several critical limitations and boundary conditions, which should be addressed to improve consistency and replicability in the field and lead to the development of an efficient reconsolidation-based relapse prevention therapy.

A paradigm shift in the treatment of emotional memory disorders: Lessons from basic science.

Experiments demonstrating post-reactivation amnesia for learned fear in animals have generated a novel and influential hypothesis on the plasticity of memory, usually referred to as memory reconsolidation. The clinical potential of pharmacologically disrupting the process of memory reconsolidation has sparked a wave of interest into whether this phenomenon can also be demonstrated in humans, and ultimately harnessed for therapeutic purposes. In this essay we outline how the work of Karim Nader and colleagues has moved the field forward from a focus on extinction learning to the prospect of disrupting memory reconsolidation. We then review some promising findings on the necessary conditions, as well as potential boundary conditions, of pharmacologically disrupting the process of memory reconsolidation obtained in our laboratory. Even though laboratory experiments in animals and humans suggest that we may be at the brink of a breakthrough in fundamentally changing emotional memories, the necessary and sufficient conditions for targeting and disrupting memory reconsolidation in clinical practice are largely unknown. There is likely no universally effective reactivation procedure for triggering the reconsolidation of clinically significant emotional memories, and the impact of subtle boundary conditions observed in basic experiments compounds this issue. Notwithstanding these challenges, the discovery of changing emotional memory through disrupting the process of memory reconsolidation has unquestionably invigorated the field.

DNA methylation inhibition participates in the anterograde amnesia key mechanism through the suppression of the transcription of genes involved in memory formation in grape snails.

The study of the amnesia mechanisms is of both theoretical and practical importance. The mechanisms of anterograde amnesia are the least studied, due to the lack of an experimental model that allows studying this amnesia type molecular and cellular mechanisms. Previously, we found that conditional food aversion memory reconsolidation impairment in snails by NMDA glutamate receptor antagonists led to the amnesia induction, in the late stages of which (>10 days) repeated training did not cause long-term memory formation. In the same animals, long-term memory aversion to a new food type was formed. We characterized this amnesia as specific anterograde amnesia. In the present work we studied the role of epigenetic DNA methylation processes as well as protein and mRNA synthesis in the mechanisms of anterograde amnesia and memory recovery. DNMT methyltransferase inhibitors (iDNMT: zebularine, RG108 (N-Phthalyl-1-tryptophan), and 5-AZA (5-Aza-2'-deoxycytidine)) were used to alter DNA methylation. It was found that in amnesic animals the iDNMT administration before or after shortened repeated training led to the rapid long-term conditional food aversion formation (Ebbinghaus saving effect). This result suggests that amnestic animals retain a latent memory, which is the basis for accelerated memory formation during repeated training. Protein synthesis inhibitors administration (cycloheximide) before or immediately after repeated training or administration of RNA synthesis inhibitor (actinomycin D) after repeated training prevented memory formation under iDNMT action. The earlier protein synthesis inhibitor effect suggests that the proteins required for memory formation are translated from the pre-existing, translationally repressed mRNAs. Thus, we have shown for the first time that the anterograde amnesia key mechanism is DNMT-dependent suppression of the transcription of genes involved in memory mechanisms. Inhibition of DNMT during repeated training reversed these genes expression blockade, opening access to them by transcription factors synthesized during training from the pre-existing mRNAs.