Procedures between training and reactivation influence the destabilization of instrumental sucrose memory.

Memory destabilization and reconsolidation is hypothesized to be a fundamental mnemonic process that can underpin memory updating. Instrumental memories have been shown recently to be destabilized following a reactivation session that involves a change in instrumental reward contingency. However, the acquisition and performance of an instrumental response occurs in the presence of the learning of other reward-related memories. This may influence the ability of a given reactivation session to destabilize the previously learned instrumental memory. Here we present a series of experiments in male rats involving an instrumental memory trained on an FR1 schedule over 10 days, and then reactivated in a session that imposed a VR5 schedule of reinforcement. When MK-801 was injected prior to the VR5 reactivation session, it reliably impaired subsequent instrumental performance at test only when the reactivation session occurred 48 h, and not 24 h, after the end of training. The interposition between the end of training and the reactivation session of a context extinction session, an additional VR5 reactivation session, or indeed the simple experience of being handled and injected with vehicle, resulted in MK-801 no longer having an amnestic effect on test performance. While we do not have a clear account for the process and mechanism underpinning this apparent selectivity of the effect of the VR5 session to destabilize the instrumental memory, it does additionally highlight the need for greater understanding of the conditions that facilitate reactivation-induced memory destabilization.

Memory destabilization during reconsolidation: a consequence of homeostatic plasticity?

Remembering is not a static process: When retrieved, a memory can be destabilized and become prone to modifications. This phenomenon has been demonstrated in a number of brain regions, but the neuronal mechanisms that rule memory destabilization and its boundary conditions remain elusive. Using two distinct computational models that combine Hebbian plasticity and synaptic downscaling, we show that homeostatic plasticity can function as a destabilization mechanism, accounting for behavioral results of protein synthesis inhibition upon reactivation with different re-exposure times. Furthermore, by performing systematic reviews, we identify a series of overlapping molecular mechanisms between memory destabilization and synaptic downscaling, although direct experimental links between both phenomena remain scarce. In light of these results, we propose a theoretical framework where memory destabilization can emerge as an epiphenomenon of homeostatic adaptations prompted by memory retrieval.

Postreactivation mifepristone impairs generalization of strongly conditioned contextual fear memories.

The efficacy of pharmacological disruption of fear memory reconsolidation depends on several factors, including memory strength and age. We built on previous observations that systemic treatment with the nootropic nefiracetam potentiates cued fear memory destabilization to facilitate mifepristone-induced reconsolidation impairment. Here, we applied nefiratecam and mifepristone to strongly conditioned, 1-wk-old contextual fear memories in male rats. Unexpectedly, the combined treatment did not result in impairment of contextual fear expression. However, mifepristone did reduce freezing to a novel context. These observations suggest that strong and established contextual fear memories do undergo destabilization without the need for pharmacological facilitation, and that impairments in strong context fear memory reconsolidation can manifest as a reduction in generalization.

Memory reconsolidation impairments in sign-tracking to an audiovisual compound stimulus.

Studies of memory reconsolidation of pavlovian memories have typically employed unimodal conditioned stimuli, despite the use of multimodal compound stimuli in other settings. Here we studied sign-tracking behaviour to a compound audiovisual stimulus. First, we observed not unexpectedly that sign-tracking was poorer to the audiovisual compound than to unimodal visual stimuli. Then, we showed that, depending on the parameters of compound stimulus re-exposure at memory reactivation, systemic MK-801 treatment either impaired extinction to improve sign-tracking at test, or disrupted reconsolidation to impair test behaviour. When memory reactivation consisted of re-exposure to only the auditory component of the compound stimulus, we observed sign-tracking impairments following MK-801 treatment, but only under certain test conditions. This was in contrast to the consistent impairment following reactivation with the full audiovisual compound. Moreover, the parameters of auditory stimulus presentation to enable MK-801-induced impairment at test varied depending on whether the stimulus was presented within or outside the training context. These findings suggest that behaviour under the control of appetitive pavlovian compound stimuli can be modulated by targeting both extinction and reconsolidation, and that it is not necessary to re-expose to the full compound stimulus in order to achieve a degree of modulation of behaviour.

On the Resistance to Relapse to Cocaine-Seeking Following Impairment of Instrumental Cocaine Memory Reconsolidation.

Reconsolidation normally functions to update and maintain memories in the long-term. However, this process can be disrupted pharmacologically to weaken memories. Exploiting such experimental amnesia to disrupt the maladaptive reward memories underpinning addiction may provide a novel therapeutic avenue to prevent relapse. Here, we tested whether targeted disruption of the reconsolidation of instrumental (operant) lever pressing for cocaine resulted in protection against different forms of relapse in a rat self-administration model. We first confirmed that systemic injection of the non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist MK-801 did impair reconsolidation to reduce spontaneous instrumental drug-seeking memory at test. This deficit was not rescued by pharmacological induction of stress with the anxiogenic α2-noradrenergic receptor antagonist yohimbine. In contrast, cocaine-seeking was restored to control levels following priming with cocaine itself, or presentation of a cocaine-associated cue. These results suggest that while stress-induced relapse can be reduced by disruption of instrumental memory reconsolidation, the apparent sparing of the pavlovian cue-drug memory permitted other routes to relapse. Therefore, future reconsolidation-based therapeutic strategies for addictive drug-seeking may need to target both instrumental and pavlovian memories.

Dopaminergic D1 receptor signalling is necessary, but not sufficient for cued fear memory destabilisation.

RATIONALE: Pharmacological targeting of memory reconsolidation is a promising therapeutic strategy for the treatment of fear memory-related disorders. However, the success of reconsolidation-based approaches depends upon the effective destabilisation of the fear memory by memory reactivation. OBJECTIVES: Here, we aimed to determine the functional involvement of dopamine D1 receptors in cued fear memory destabilisation, using systemic drug administration. RESULTS: We observed that direct D1 receptor agonism was not sufficient to stimulate tone fear memory destabilisation to facilitate reconsolidation disruption by the glucocorticoid receptor antagonist mifepristone. Instead, administration of the nootropic nefiracetam did facilitate mifepristone-induced amnesia, in a manner that was dependent upon dopamine D1 receptor activation. Finally, while the combined treatment with nefiracetam and mifepristone did not confer fear-reducing effects under conditions of extinction learning, there was some evidence that mifepristone reduces fear expression irrespective of memory reactivation parameters. CONCLUSIONS: The use of combination pharmacological treatment to stimulate memory destabilisation and impair reconsolidation has potential therapeutic benefits, without risking a maladaptive increase of fear.

Different temporal windows for CB1 receptor involvement in contextual fear memory destabilisation in the amygdala and hippocampus.

Reconsolidation is a process in which re-exposure to a reminder causes a previously acquired memory to undergo a process of destabilisation followed by subsequent restabilisation. Different molecular mechanisms have been postulated for destabilisation in the amygdala and hippocampus, including CB1 receptor activation, protein degradation and AMPA receptor exchange; however, most of the amygdala studies have used pre-reexposure interventions, while those in the hippocampus have usually performed them after reexposure. To test whether the temporal window for destabilisation is similar across both structures, we trained Lister Hooded rats in a contextual fear conditioning task, and 1 day later performed memory reexposure followed by injection of either the NMDA antagonist MK-801 (0.1 mg/kg) or saline in order to block reconsolidation. In parallel, we also performed local injections of either the CB1 antagonist SR141716A or its vehicle in the hippocampus or in the amygdala, either immediately before or immediately after reactivation. Infusion of SR141716A in the hippocampus prevented the reconsolidation-blocking effect of MK-801 when performed after reexposure, but not before it. In the amygdala, meanwhile, pre-reexposure infusions of SR141716A impaired reconsolidation blockade by MK-801, although the time-dependency of this effect was not as clear as in the hippocampus. Our results suggest the temporal windows for CB1-receptor-mediated memory destabilisation during reconsolidation vary between brain structures. Whether this reflects different time windows for engagement of these structures or different roles played by CB1 receptors in destabilisation across structures remains an open question for future studies.

Postretrieval Relearning Strengthens Hippocampal Memories via Destabilization and Reconsolidation.

Memory reconsolidation is hypothesized to be a mechanism by which memories can be updated with new information. Such updating has previously been shown to weaken memory expression or change the nature of the memory. Here we demonstrate that retrieval-induced memory destabilization also allows that memory to be strengthened by additional learning. We show that for rodent contextual fear memories, this retrieval conditioning effect is observed only when conditioning occurs within a specific temporal window opened by retrieval. Moreover, it necessitates hippocampal protein degradation at the proteasome and engages hippocampal Zif268 protein expression, both of which are established mechanisms of memory destabilization-reconsolidation. We also demonstrate a conceptually analogous pattern of results in human visual paired-associate learning. Retrieval-relearning strengthens memory performance, again only when relearning occurs within the temporal window of memory reconsolidation. These findings link retrieval-mediated learning in humans to the reconsolidation literature, and have potential implications both for the understanding of endogenous memory gains and strategies to boost weakly learned memories.SIGNIFICANCE STATEMENT Memory reconsolidation allows existing memories to be updated with new information. Previous research has demonstrated that reconsolidation can be manipulated pharmacologically and behaviorally to impair problematic memories. In this article, we show that reconsolidation can also be exploited to strengthen memory. This is shown both in rats, in a fear memory setting, and in a human declarative memory setting. For both, the behavioral conditions necessary to observe the memory strengthening match those that are required to trigger memory reconsolidation. There are several behavioral approaches that have previously been shown convincingly to strengthen memory. The present demonstration that reconsolidation can underpin long-lasting memory improvements may both provide an underlying mechanism for such approaches and provide new strategies to boost memories.

On the transition from reconsolidation to extinction of contextual fear memories.

Retrieval of an associative memory can lead to different phenomena. Brief reexposure sessions tend to trigger reconsolidation, whereas more extended ones trigger extinction. In appetitive and fear cued Pavlovian memories, an intermediate "null point" period has been observed where neither process seems to be engaged. Here we investigated whether this phenomenon extends to contextual fear memory. Adult rats were subjected to a contextual fear conditioning paradigm, reexposed to the context 2 d later for 3, 5, 10, 20, or 30 min, with immediate injections of MK-801 or saline following reexposure, and tested on the following day. We observed a significant effect of MK-801 with the 3- and 30-min sessions, impairing reconsolidation and extinction, respectively. However, it did not have significant effects with 5-, 10-, or 20-min sessions, even though freezing decreased from reexposure to test. Further analyses indicated that this is not likely to be due to a variable transition point at the population level. In conclusion, the results show that in contextual fear memories there is a genuine "null point" between the parameters that induce reconsolidation and extinction, as defined by the effects of MK-801, although NMDA receptor-independent decreases in freezing can still occur in these conditions.

An Update on Memory Reconsolidation Updating.

The reactivation of a stored memory in the brain can make the memory transiently labile. During the time it takes for the memory to restabilize (reconsolidate) the memory can either be reduced by an amnesic agent or enhanced by memory enhancers. The change in memory expression is related to changes in the brain correlates of long-term memory. Many have suggested that such retrieval-induced plasticity is ideally placed to enable memories to be updated with new information. This hypothesis has been tested experimentally, with a translational perspective, by attempts to update maladaptive memories to reduce their problematic impact. We review here progress on reconsolidation updating studies, highlighting their translational exploitation and addressing recent challenges to the reconsolidation field.

Cannabidiol regulation of emotion and emotional memory processing: relevance for treating anxiety-related and substance abuse disorders.

Learning to associate cues or contexts with potential threats or rewards is adaptive and enhances survival. Both aversive and appetitive memories are therefore powerful drivers of behaviour, but the inappropriate expression of conditioned responding to fear- and drug-related stimuli can develop into anxiety-related and substance abuse disorders respectively. These disorders are associated with abnormally persistent emotional memories and inadequate treatment, often leading to symptom relapse. Studies show that cannabidiol, the main non-psychotomimetic phytocannabinoid found in Cannabis sativa, reduces anxiety via 5-HT1A and (indirect) cannabinoid receptor activation in paradigms assessing innate responses to threat. There is also accumulating evidence from animal studies investigating the effects of cannabidiol on fear memory processing indicating that it reduces learned fear in paradigms that are translationally relevant to phobias and post-traumatic stress disorder. Cannabidiol does so by reducing fear expression acutely and by disrupting fear memory reconsolidation and enhancing fear extinction, both of which can result in a lasting reduction of learned fear. Recent studies have also begun to elucidate the effects of cannabidiol on drug memory expression using paradigms with translational relevance to addiction. The findings suggest that cannabidiol reduces the expression of drug memories acutely and by disrupting their reconsolidation. Here, we review the literature demonstrating the anxiolytic effects of cannabidiol before focusing on studies investigating its effects on various fear and drug memory processes. Understanding how cannabidiol regulates emotion and emotional memory processing may eventually lead to its use as a treatment for anxiety-related and substance abuse disorders. Linked Articles This article is part of a themed section on Pharmacology of Cognition: a Panacea for Neuropsychiatric Disease? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.19/issuetoc.

Bidirectional Effects of Cannabidiol on Contextual Fear Memory Extinction.

Cannabidiol (CBD) has been established to have both acute and long-lasting effects to reduce fear memory expression. The long-lasting impact might be mediated by an enhancement of memory extinction or an impairment of memory reconsolidation. Here, we directly compared the effects of i.p. injections of cannabidiol (10 mg/kg) with those of the NMDA receptor antagonist MK-801 (0.1 mg/kg) and partial agonist D-cycloserine (DCS; 15 mg/kg) in order to determine the mnemonic basis of long-term fear reduction. We showed that under conditions of strong fear conditioning, CBD reduced contextual fear memory expression both acutely during the extinction session as well as later at a fear retention test. The latter test reduction was replicated by DCS, but MK-801 instead elevated test freezing. In contrast, when initial conditioning was weaker, CBD and MK-801 had similar effects to increase freezing at the fear retention test relative to vehicle controls, whereas DCS had no observable impact. This pattern of results is consistent with CBD enhancing contextual fear memory extinction when the initial conditioning is strong, but impairing extinction when conditioning is weak. This bidirectional effect of CBD may be related to stress levels induced by conditioning and evoked at retrieval during extinction, rather than the strength of the memory per se.

Cannabidiol Regulation of Learned Fear: Implications for Treating Anxiety-Related Disorders.

Anxiety and trauma-related disorders are psychiatric diseases with a lifetime prevalence of up to 25%. Phobias and post-traumatic stress disorder (PTSD) are characterized by abnormal and persistent memories of fear-related contexts and cues. The effects of psychological treatments such as exposure therapy are often only temporary and medications can be ineffective and have adverse side effects. Growing evidence from human and animal studies indicates that cannabidiol, the main non-psychotomimetic phytocannabinoid present in Cannabis sativa, alleviates anxiety in paradigms assessing innate fear. More recently, the effects of cannabidiol on learned fear have been investigated in preclinical studies with translational relevance for phobias and PTSD. Here we review the findings from these studies, with an emphasis on cannabidiol regulation of contextual fear. The evidence indicates that cannabidiol reduces learned fear in different ways: (1) cannabidiol decreases fear expression acutely, (2) cannabidiol disrupts memory reconsolidation, leading to sustained fear attenuation upon memory retrieval, and (3) cannabidiol enhances extinction, the psychological process by which exposure therapy inhibits learned fear. We also present novel data on cannabidiol regulation of learned fear related to explicit cues, which indicates that auditory fear expression is also reduced acutely by cannabidiol. We conclude by outlining future directions for research to elucidate the neural circuit, psychological, cellular, and molecular mechanisms underlying the regulation of fear memory processing by cannabidiol. This line of investigation may lead to the development of cannabidiol as a novel therapeutic approach for treating anxiety and trauma-related disorders such as phobias and PTSD in the future.

Reduction in Responding for Sucrose and Cocaine Reinforcement by Disruption of Memory Reconsolidation

Stored memories are dynamic and, when reactivated, can undergo a process of destabilization and reconsolidation to update them with new information. Reconsolidation has been shown for a variety of experimental settings; most recently for well-learned instrumental memories, a class of memory previously thought not to undergo reconsolidation. Here we tested, in rats, whether a weakly-trained lever-pressing memory destabilized following a shift in reinforcement contingency. We show that lever-pressing memory for both sucrose and cocaine reinforcement destabilized under appropriate conditions, and that the reconsolidation of this memory was impaired by systemic administration of the NMDA receptor (NMDAR) antagonist [5R,10S]-[+]-5-methyl-10,1-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801). We went on to investigate the potential role of the nucleus accumbens (NAc) in the reconsolidation of sucrose-reinforced instrumental memories, showing that co-infusion of the NMDAR antagonist 2-amino-5-phosphonopentanoic acid (AP-5) and the dopamine-1 receptor (D1R) antagonist 7-chloro-3-methyl-1-phenyl-1,2,4,5-tetrahydro-3-benzazepin-8-ol (SCH23390) into the NAc prior to memory reactivation impaired reconsolidation; however, there was no effect when these drugs were infused alone. Further investigation of this effect suggests the combined infusion disrupted the reconsolidation of pavlovian components of memory, and we hypothesize that coactivation of accumbal D1Rs and NMDARs may contribute to both the destabilization and reconsolidation of appetitive memory. Our work demonstrates that weakly-trained instrumental memories undergo reconsolidation under similar parameters to well-trained ones, and also suggests that receptor coactivation in the NAc may contribute to memory destabilization. Furthermore, it provides an important demonstration of the therapeutic potential of reconsolidation-based treatments that target the instrumental components of memory in maladaptive drug seeking.

The retrosplenial cortex is involved in the formation of memory for context and trace fear conditioning.

The retrosplenial cortex (RSC) is known to play a role in the retrieval of context memory, but its involvement in memory formation and consolidation is unclear. To better characterize the role of the RSC, we tested its involvement in the formation and retrieval of memory for trace fear conditioning, a task that requires the association of two cues separated by an empty period of time. We have previously shown that trace fear extinction requires the RSC (Kwapis, Jarome, Lee, Gilmartin, & Helmstetter, 2014) and have hypothesized that trace memory may be stored in a distributed cortical network that includes prelimbic and retrosplenial cortices (Kwapis, Jarome, & Helmstetter, 2015). Whether the RSC participates in acquiring and storing cued trace fear, however, is currently unknown. Here, we demonstrate that blocking protein synthesis in the RSC before, but not after acquisition impairs rats' memory for trace CS and context fear without affecting memory for the CS in standard delay fear conditioning. We also show that NMDA receptor blockade in the RSC transiently impairs memory retrieval for trace, but not delay memory. The RSC therefore appears to critically contribute to formation of trace and context fear memory in addition to its previously recognized role in context memory retrieval.

Dopamine D1-like receptor signalling in the hippocampus and amygdala modulates the acquisition of contextual fear conditioning.

RATIONALE: Dopamine D1-like receptor signalling is involved in contextual fear conditioning, but the brain regions involved and its role in other contextual fear memory processes remain unclear. OBJECTIVES: The objective of this study was to investigate (1) the effects of SCH 23390, a dopamine D1/D5 receptor antagonist, on contextual fear memory encoding, retrieval and reconsolidation, and (2) if the effects of SCH 23390 on conditioning involve the dorsal hippocampus (DH) and/or basolateral amygdala (BLA). METHODS: Rats were used to examine the effects of systemically administering SCH 23390 on the acquisition, consolidation, retrieval and reconsolidation of contextual fear memory, and on locomotor activity and shock sensitivity. We also determined the effects of MK-801, an NMDA receptor antagonist, on contextual fear memory reconsolidation. The effects of infusing SCH 23390 locally into DH or BLA on contextual fear conditioning and locomotor activity were also examined. RESULTS: Systemic administration of SCH 23390 impaired contextual fear conditioning but had no effects on fear memory consolidation, retrieval or reconsolidation. MK-801 was found to impair reconsolidation, suggesting that the behavioural parameters used allowed for the pharmacological disruption of memory reconsolidation. The effects of SCH 23390 on conditioning were unlikely the result of any lasting drug effects on locomotor activity at memory test or any acute drug effects on shock sensitivity during conditioning. SCH 23390 infused into either DH or BLA impaired contextual fear conditioning and decreased locomotor activity. CONCLUSIONS: These findings suggest that dopamine D1-like receptor signalling in DH and BLA contributes to the acquisition of contextual fear memory.

Updating memories--the role of prediction errors in memory reconsolidation.

Memories are not static imprints of past experience, but rather are dynamic entities which enable us to predict outcomes of future situations and inform appropriate behaviours. In order to maintain the relevance of existing memories to our daily lives, memories can be updated with new information via a process of reconsolidation. In this review we describe recent experimental advances in the reconsolidation of both appetitive and aversive memory, and explore the neuronal mechanisms that underpin the conditions under which reconsolidation will occur. We propose that a prediction error signal, originating from dopaminergic midbrain neurons, is necessary for destabilisation and subsequent reconsolidation of a memory.

Reconsolidation of a well-learned instrumental memory.

Once consolidated, memories are dynamic entities that go through phases of instability in order to be updated with new information, via a process of reconsolidation. The phenomenon of reconsolidation has been demonstrated in a wide variety of experimental paradigms. However, the memories underpinning instrumental behaviors are currently not believed to reconsolidate. We show that well-learned lever pressing in rats does undergo reconsolidation, which can be disrupted by systemic administration of the noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist (+)-5-methyl-10,11-dihydro-SH-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) when administered prior to a switch to a variable, but not fixed, ratio schedule. Disruption of reconsolidation resulted in a reduction in long-term lever pressing performance and diminished the sensitivity of behavior to contingency change. Further investigation demonstrated that expression of the reconsolidation impairment was not affected by outcome value, implying a deficit in a stimulus-response (S-R) process. The ability to disrupt the performance of well-learned instrumental behaviors is potentially of great importance in the development of reconsolidation-based clinical treatments for conditions that involve compulsive seeking behaviors.

Inhibition and enhancement of contextual fear memory destabilization.

The reactivation of a memory can result in its destabilization, necessitating a process of memory reconsolidation to maintain its persistence. Here we show that the destabilization of a contextual fear memory is potentiated by the cannabinoid CB1 receptor agonist Arachidonyl-2-chloroethylamide (ACEA). Co-infusion of ACEA and the IkappaB kinase (IKK) inhibitor sulfasalazine (Sulf) into the dorsal hippocampus impaired contextual fear memory reconsolidation. This observation was achieved under behavioral conditions that, by themselves, did not result in a reconsolidation impairment by Sulf alone. Moreover, we show that the destabilization of a contextual fear memory is dependent upon neuronal activity in the dorsal hippocampus, but not memory expression per se. The effect on contextual fear memory destabilization of intra-hippocampal ACEA was replicated by systemic injections, allowing an amnestic effect of MK-801. These results indicate that memory expression and destabilization, while being independent from one another, are both dependent upon memory reactivation. Moreover, memory destabilization can be enhanced pharmacologically, which may be of therapeutic potential.

Extinguishing trace fear engages the retrosplenial cortex rather than the amygdala.

Extinction learning underlies the treatment for a variety of anxiety disorders. Most of what is known about the neurobiology of extinction is based on standard "delay" fear conditioning, in which awareness is not required for learning. Little is known about how complex, explicit associations extinguish, however. "Trace" conditioning is considered to be a rodent model of explicit fear because it relies on both the cortex and hippocampus and requires explicit contingency awareness in humans. Here, we explore the neural circuit supporting trace fear extinction in order to better understand how complex memories extinguish. We first show that the amygdala is selectively involved in delay fear extinction; blocking intra-amygdala glutamate receptors disrupted delay, but not trace extinction. Further, ERK phosphorylation was increased in the amygdala after delay, but not trace extinction. We then identify the retrosplenial cortex (RSC) as a key structure supporting trace extinction. ERK phosphorylation was selectively increased in the RSC following trace extinction and blocking intra-RSC NMDA receptors impaired trace, but not delay extinction. These findings indicate that delay and trace extinction require different neural circuits; delay extinction requires plasticity in the amygdala whereas trace extinction requires the RSC. Anxiety disorders linked to explicit memory may therefore depend on cortical processes that have not been traditionally targeted by extinction studies based on delay fear.