Disrupting Memory Reconsolidation Research Articles

Demarcating the boundary conditions of memory reconsolidation: An unsuccessful replication

Disrupting memory reconsolidation provides an opportunity to abruptly reduce the behavioural expression of fear memories with long-lasting effects. The success of a reconsolidation intervention is, however, not guaranteed as it strongly depends on the destabilization of the memory. Identifying the necessary conditions to trigger destabilization remains one of the critical challenges in the field. We aimed to replicate a study from our lab, showing that the occurrence of a prediction error (PE) during reactivation is necessary but not sufficient for destabilization. We tested the effectiveness of a reactivation procedure consisting of a single PE, compared to two control groups receiving no or multiple PEs. All participants received propranolol immediately after reactivation and were tested for fear retention 24 h later. In contrast to the original results, we found no evidence for a reconsolidation effect in the single PE group, but a straightforward interpretation of these results is complicated by the lack of differential fear retention in the control groups. Our results corroborate other failed reconsolidation studies and exemplify the complexity of experimentally investigating this process in humans. Thorough investigation of the interaction between learning and memory reactivation is essential to understand the inconsistencies in the literature and to improve reconsolidation interventions.

Reducing Intrusive Memories of Childhood Trauma Using a Visuospatial Intervention: Case Study in Iceland.

BackgroundAdditional interventions are needed for survivors of psychological trauma because of several barriers to and limitations of existing treatment options (eg, need to talk about the trauma in detail). Case studies are an important step in exploring the development of novel interventions, allowing detailed examination of individual responses to treatment over time. Here, we present a case study that aims to test a novel intervention designed to disrupt memory reconsolidation, taking a single-symptom approach by focusing on intrusive memories of a traumatic event.ObjectiveThis study aims to examine a novel brief cognitive intervention to reduce the number of intrusive memories of trauma in an Icelandic setting and to extend previous studies by examining long-term effects for up to 3 months. The intervention was guided by a clinical psychologist and comprised a brief memory reminder, followed by Tetris gameplay with mental rotation, targeting one memory at a time in each session.MethodsThis was a single case study in Iceland with a woman in her 50s (drawn from an epidemiological study of trauma) with subthreshold posttraumatic stress disorder and a diagnosis of obsessive-compulsive disorder and social anxiety disorder. The participant had four different intrusive memories from a traumatic event that happened in her childhood. The primary outcome was the change in the number of intrusive memories from baseline to intervention phase and to follow-ups. The number of intrusions was monitored in a daily diary for 4 weeks preintervention, 8 weeks during the intervention, and 1 week at 1-month and 3-month follow-ups. Intrusions were targeted one by one over six intervention sessions, creating four repetitions of an AB design (ie, length of baseline A and intervention phase B varied for each memory). We examined changes in both the total number of intrusions (summed across all four memories) and individually for each memory. In addition, we explored whether having fewer intrusive memories would have an impact on functioning, posttraumatic stress, and depression or anxiety symptoms.ResultsThe total number of intrusions per week was 12.6 at baseline, 6.1 at the intervention phase (52% reduction from baseline), 3.0 at the 1-month follow-up (76% reduction), and 1.0 at the 3-month follow-up (92% reduction). Reductions in the symptoms of posttraumatic stress and depression were observed postintervention. Sleep, concentration, stress, and functioning improved. The participant considered the gameplay intervention acceptable and helpful in that she found that the memories disappeared while she was playing.ConclusionsThis guided brief cognitive intervention reduced the number of intrusive memories over the intervention phase and follow-ups. The brief memory reminder was well tolerated, removing the need to discuss trauma in detail. The next steps require an extension to more cases and exploring remote delivery of the intervention.

Stress-Potentiated Memory Updating as a Novel Intervention for Non-Treatment Seeking Smokers

Interventions to disrupt memory reconsolidation have held promise for the treatment of stress- and anxiety-related disorders. In the present study, we tested whether an intervention based on these principles, called memory updating, could be adapted for reward-seeking behaviors. Non-treatment seeking tobacco smokers were exposed to smoking cues and/or stress, two stimuli known to trigger smoking. It was predicted that exposure to a stress task would enhance the cues’ motivational salience and yield greater susceptibility to the memory updating procedure.

Electroconvulsive Shock Does Not Impair the Reconsolidation of Cued and Contextual Pavlovian Threat Memory

Existing memories, when retrieved under certain circumstances, can undergo modification through the protein synthesis-dependent process of reconsolidation. Disruption of this process can lead to the weakening of a memory trace, an approach which is being examined as a potential treatment for disorders characterized by pathological memories, such as Post-Traumatic Stress Disorder. The success of this approach relies upon the ability to robustly attenuate reconsolidation; however, the available literature brings into question the reliability of the various drugs used to achieve such a blockade. The identification of a drug or intervention that can reliably disrupt reconsolidation without requiring intracranial access for administration would be extremely useful. Electroconvulsive shock (ECS) delivered after memory retrieval has been demonstrated in some studies to disrupt memory reconsolidation; however, there exists a paucity of literature characterizing its effects on Pavlovian fear memory. Considering this, we chose to examine ECS as an inexpensive and facile means to impair reconsolidation in rats. Here we show that electroconvulsive seizure induction, when administered after memory retrieval, (immediately, after 30 min, or after 1 h), does not impair the reconsolidation of cued or contextual Pavlovian fear memories. On the contrary, ECS administration immediately after extinction training may modestly impair the consolidation of fear extinction memory.

Alcohol inhibits morphine/cocaine reward memory acquisition and reconsolidation in rats.

Alcohol is a recreational substance that is generally socially acceptable and legal in most areas worldwide. An alcohol overdose will produce an inhibitory effect on the brain and impair cognition and memory. In this study, we examined the effect of alcohol on the acquisition, consolidation, and reconsolidation of drug reward memory induced by morphine and cocaine in rats. Rats were trained to acquire morphine sulfate (10mg/kg, s.c.) and cocaine (10mg/kg, i.p.) conditioned place preference (CPP) via an unbiased CPP paradigm. Vehicle or alcohol (0.25, 0.75, 1.5g/kg, i.p.) was administered at various time-points, including 30min before each CPP conditioning session (acquisition), immediately after each CPP conditioning session (consolidation), immediately after the reactivation of CPP (reconsolidation with re-exposure), or without reactivation to the drug-paired context (reconsolidation without re-exposure). Conditioning scores were recorded before or after each conditioning session or memory reactivation. Alcohol at a dose of 1.5g/kg but not 0.25g/kg or 0.75g/kg significantly inhibited the acquisition and reconsolidation of morphine- and cocaine-associated memory. In contrast, alcohol had no effect on the consolidation of morphine- or cocaine-induced CPP. The results suggested that pre-exposure alcohol dose-dependently attenuated morphine- or cocaine-induced place preference and prevented drug reinstatement in rats by disrupting memory reconsolidation, which may be explained by the inhibitory effect of alcohol on dopaminergic and glutamatergic neurotransmission.

Detrimental Effects of a Retrieval-Extinction Procedure on Nicotine Seeking, but Not Cocaine Seeking.

Retrieval-extinction memory reactivation procedures have been used to prevent the return of learned fear and drug seeking in preclinical models. These procedures first reactivate the original memory with a brief cue exposure (i.e., retrieval) session, and then disrupt memory reconsolidation by conducting extinction training within the reconsolidation window. The original memory is thought to be updated with the new information conveyed by extinction learning, resulting in a persistent therapeutic effect beyond that observed with extinction training alone (i.e., no retrieval). Here, we attempted to replicate the therapeutic effects on cocaine seeking reported by Xue et al. (2012), and extend these findings to nicotine seeking. Rats self-administered either cocaine or nicotine with contingent cues for weeks, and were then divided into two groups. The retrieval group underwent a 10-min retrieval session wherein drug cues were available, but drug was not. Ten minutes later, they were allowed to continue cue extinction training for an additional 60 min. The no retrieval group underwent a contiguous 70-min cue extinction session. These procedures continued for weeks, followed by a test for spontaneous recovery of drug seeking. No group differences were observed on any measure of cocaine seeking, although both groups exhibited extinction and spontaneous recovery. By contrast, for nicotine seeking, the retrieval group exhibited resistance to extinction, an effect that persisted on the spontaneous recovery test. These findings underscore the importance of drug type in the outcome of retrieval-extinction procedures and moreover indicate that retrieval-extinction procedures can be detrimental to nicotine seeking.

Inhibition of actin polymerization in the NAc shell inhibits morphine-induced CPP by disrupting its reconsolidation.

Drug-associated contextual cues contribute to drug craving and relapse after abstinence, which is a major challenge to drug addiction treatment. Previous studies showed that disrupting memory reconsolidation impairs drug reward memory. However, the underlying mechanisms remain elusive. Although actin polymerization is involved in memory formation, its role in the reconsolidation of drug reward memory is unknown. In addition, the specific brain areas responsible for drug memory have not been fully identified. In the present study, we found that inhibiting actin polymerization in the nucleus accumbens (NAc) shell, but not the NAc core, abolishes morphine-induced conditioned place preference (CPP) by disrupting its reconsolidation in rats. Moreover, this effect persists for more than 2 weeks by a single injection of the actin polymerization inhibitor, which is not reversed by a morphine-priming injection. Furthermore, the application of actin polymerization inhibitor outside the reconsolidation window has no effect on morphine-associated contextual memory. Taken together, our findings first demonstrate that inhibiting actin polymerization erases morphine-induced CPP by disrupting its reconsolidation. Our study suggests that inhibition of actin polymerization during drug memory reconsolidation may be a potential approach to prevent drug relapse.

Stress-induced increases in depression-like and cocaine place-conditioned behaviors are reversed by disruption of memories during reconsolidation.

Maladaptive behavioral responses characteristic of post-traumatic stress disorders are notably resistant to treatment. We hypothesized that the pharmacological disruption of memories activated during reconsolidation might reverse established stress-induced increases in depression-like behaviors and cocaine reward. C57BL/6J mice were subjected to repeated social defeat stress (SDS), and examined for time spent immobile in a subsequent forced swim test (FST). An additional set of SDS-exposed mice were place-conditioned with cocaine, and tested for cocaine-conditioned place preference (CPP). All stress-exposed mice were then subjected to a single additional trial of SDS while under the influence of propranolol or cycloheximide to disrupt memory reconsolidation, then given one additional FST or CPP test the next day. Mice subjected to repeated SDS subsequently demonstrated increases in time spent immobile in the FST or in the cocaine-paired chamber. Vehicle-treatment followed by additional SDS exposure did not alter these behaviors, but propranolol or cycloheximide treatment reversed each of the potentiated responses in a dose-dependent manner. Overall, these results demonstrate that while repeated exposure to a social defeat stressor subsequently increased depression-like behavior and cocaine-CPP, disruption of traumatic memories made labile by re-exposure to SDS during reconsolidation may have therapeutic value in the treatment of established post-traumatic stress disorder-related behaviors.

High Trait Anxiety: A Challenge for Disrupting Fear Memory Reconsolidation

Disrupting reconsolidation may be promising in the treatment of anxiety disorders but the fear-reducing effects are thus far solely demonstrated in the average organism. A relevant question is whether disrupting fear memory reconsolidation is less effective in individuals who are vulnerable to develop an anxiety disorder. By collapsing data from six previous human fear conditioning studies we tested whether trait anxiety was related to the fear-reducing effects of a pharmacological agent targeting the process of memory reconsolidation - n = 107. Testing included different phases across three consecutive days each separated by 24 h. Fear responding was measured by the eye-blink startle reflex. Disrupting the process of fear memory reconsolidation was manipulated by administering the β-adrenergic receptor antagonist propranolol HCl either before or after memory retrieval. Trait anxiety uniquely predicted the fear-reducing effects of disrupting memory reconsolidation: the higher the trait anxiety, the less fear reduction. Vulnerable individuals with the propensity to develop anxiety disorders may need higher dosages of propranolol HCl or more retrieval trials for targeting and changing fear memory. Our finding clearly demonstrates that we cannot simply translate observations from fundamental research on fear reduction in the average organism to clinical practice.

Cognitive Enhancement: Promises and Perils

The potential use of drugs to enhance cognition, emotion, and executive function has engendered controversy despite the fact that few such agents exist today. Here, I provide a context for discussions based on medical, regulatory, and ethical concerns that have been raised by the possibility that enhancers will emerge from current efforts to discover drugs for neuropsychiatric disorders.

Repeated treatment with the NMDA antagonist MK-801 disrupts reconsolidation of memory for amphetamine-conditioned place preference

Long-lasting drug-associated memories can contribute to relapse; therefore these memories must be inactivated to enable sustainable success in addiction therapy. As drug associations are usually acquired over several conditioning events, we assume that an effective treatment should be repeatedly applied to achieve persistent effects. In this study, we examine whether 10 repeated memory reactivation tests followed by systemic N-methyl-D-aspartate receptor antagonist MK-801 (0.1 mg/kg) administrations can disrupt memory reconsolidation in rats, leading to a reduction of well-established amphetamine-conditioned place preference (CPP). We found that immediate (but not 60-min delayed) administration of MK-801 after the tests reduced amphetamine-CPP expression after at least four treatments. These effects were specific to CPP expression as no MK-801-induced change in locomotion was observed during all tests. We discuss these results as being caused by MK-801 disrupting memory reconsolidation and we propose the applied repeated-treatment regimen as a new therapeutic research strategy to persistently disrupt drug-associated memories.