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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. [ABSTRACT FROM AUTHOR]

Memory consolidation is the process underlying the stabilization of labile short-term memory and the generation of long-term memory for persistent memory storage. The retrieval of contextual fear memory induces two distinct and opposite memory processes: reconsolidation and extinction. Reconsolidation re-stabilizes retrieved memory for re-storage, whereas memory extinction weakens fear memory and generates a new inhibitory memory. Importantly, the requirement for new gene expression is a critical biochemical feature of the consolidation, reconsolidation, and long-term extinction of memory. The locus coeruleus (LC) is a small nucleus in the brain stem that is composed predominantly of noradrenergic neurons that project to many brain regions. Recent studies have shown that the LC plays modulatory roles in the consolidation and extinction of auditory fear memory through its projections to brain regions contributing to memory storage. Here, we show that the LC is required for the consolidation, reconsolidation, and long-term extinction of contextual fear memory. We first observed that c-fos expression was induced in the LC following contextual fear conditioning to induce consolidation and following short and long re-exposure to the conditioning context to induce reconsolidation and long-term extinction, respectively. More importantly, inhibition of protein synthesis in the LC by a micro-infusion of anisomycin blocked the consolidation, reconsolidation, and long-term extinction of contextual fear memory. Our findings suggest that consolidation, reconsolidation, and long-term extinction occur in the LC and that the LC plays an essential role in memory storage and maintenance.

The classical fear conditioning is extensively used in preclinical studies as an animal model for post-traumatic stress disorder (PTSD). During the reconsolidation process, when memories are retrieved, the memory becomes susceptible to change and amenable to intervention. Interventions applied during the reconsolidation process triggered by exposure to a conditioned stimulus (CS) primarily lead to a decrease in fear responses triggered only by the exposed CS, without generalizing to other fear-related cues. However, in real-life scenarios, multiple CS's can be linked to fear-inducing events. Therefore, recent studies have focused on the reactivation procedure with an unconditioned stimulus (US), which is believed to result in the reconsolidation of the entire fear memory. Interventions applied during the reconsolidation process that are triggered by US-based retrieval are considered more effective. Grounding on the fear memory studies activated by either CS or US, this review study discussed how acquired fear can be extinguished through behavioral and pharmacological interventions. Additionally, the brain regions involved in fear memory and the impact of gender differences on fear memory were also addressed. The aim of this review was to contribute to the field by exploring more effective treatment approaches for fear disorders. [ABSTRACT FROM AUTHOR]

Various studies demonstrated that extinction training taking place shortly after the activation of the acquired fear could weaken the conditioned fear. The procedure is called post-retrieval extinction (PRE). However, from the time it emerged, it has suffered from inconsistencies in the ability of researchers to replicate the seemingly established effects. Extant literature implies that conditioned fear might be differentially sensitive to the nature of conditioned stimuli (CS) used. The aim of the present study, therefore, is threefold. First, we aimed to replicate Schiller et al. (Nature, 463, 49–53. 2010) procedure in which the PRE had produced positive results with arbitrary CSs only. Also, we examined the PRE as a function of CS type (ecological-fear-relevant (images of spider and snake) vs. arbitrary (images of yellow and blue circles)). Finally, we aimed to investigate the long-term effects of the PRE (i.e., 24 h, 15 d, and 3 mo). The study consisted of acquisition, re-activation and extinction, and re-extinction phases. Dependent measure was the recovery of fear responses as indexed by the skin conductance responses (SCRs) and arousal ratings of the participants at the last trial of the extinction and the first trial of the re-extinction. All groups showed significant acquisition and extinction patterns, compared to the other two groups (i.e., 6 h after the activating CS and without an activating stimulus) only the group that undertook extinction trials 10 min after the activating CS showed a sustained extinction. Thus, our findings provided further evidence for the robustness of the PRE paradigm in preventing the recovery of extinguished fears behaviorally, both with ecological and arbitrary stimuli. [ABSTRACT FROM AUTHOR]

Abstract Background Long-term memory formation is generally assumed to involve the permanent storage of recently acquired memories, making them relatively insensitive to disruption, a process referred to as memory consolidation. However, when retrieved under specific circumstances, consolidated fear memories are thought to return to a labile state, thereby opening a window for modification (e.g., attenuation) of the memory. Several interventions during a critical time frame after this destabilization seem to be able to alter the retrieved memory, for example by pharmacologically interfering with the restabilization process, either by direct protein synthesis inhibition or indirectly, using drugs that can be safely administered in patients (e.g., propranolol). Here, we find that, contrary to expectations, systemic pharmacological manipulations in auditory fear-conditioned rats do not lead to drug-induced post-retrieval amnesia. Results In a series of well-powered auditory fear conditioning experiments (four with propranolol, 10 mg/kg, two with rapamycin, 20–40 mg/kg, one with anisomycin, 150 mg/kg and cycloheximide, 1.5 mg/kg), we found no evidence for reduced cued fear memory expression during a drug-free test in adult male Sprague-Dawley rats that had previously received a systemic drug injection upon retrieval of the tone fear memory. All experiments used standard fear conditioning and reactivation procedures with freezing as the behavioral read-out (conceptual or exact replications of published reports) and common pharmacological agents. Additional tests confirmed that the applied drug doses and administration routes were effective in inducing their conventional effects on expression of fear (propranolol, acutely), body weight (rapamycin, anisomycin, cycloheximide), and consolidation of extinction memories (cycloheximide). Conclusions In contrast with previously published studies, we did not find evidence for drug-induced post-retrieval amnesia, underlining that this effect, as well as its clinical applicability, may be considerably more constrained and less readily reproduced than what the current literature would suggest.

• Erasing the emotional memories is crucial for the emerging of psychiatric disorders. • Brain stimulation techniques represent a crucial tool to modulate fear memories. • State-dependent TMS during reconsolidation is critical to manipulate fear memories. • Optogenetic stimulation to reveal causal relationship between neural firing and fear processing. The acquisition of fear associative memory requires brain processes of coordinated neural activity within the amygdala, prefrontal cortex (PFC), hippocampus, thalamus and brainstem. After fear consolidation, a suppression of fear memory in the absence of danger is crucial to permit adaptive coping behavior. Acquisition and maintenance of fear extinction critically depend on amygdala-PFC projections. The robust correspondence between the brain networks encompassed cortical and subcortical hubs involved into fear processing in humans and in other species underscores the potential utility of comparing the modulation of brain circuitry in humans and animals, as a crucial step to inform the comprehension of fear mechanisms and the development of treatments for fear-related disorders. The present review is aimed at providing a comprehensive description of the literature on recent clinical and experimental researches regarding the noninvasive brain stimulation and optogenetics. These innovative manipulations applied over specific hubs of fear matrix during fear acquisition, consolidation, reconsolidation and extinction allow an accurate characterization of specific brain circuits and their peculiar interaction within the specific fear processing. [ABSTRACT FROM AUTHOR]

Reactivation of consolidated memories can induce a labile period, in which these reactivated memories might be susceptible to change and need reconsolidation. Prediction error (PE) has been recognized as a necessary boundary condition for memory destabilization. Moreover, memory strength is also widely accepted as an essential boundary condition to destabilize fear memory. This study investigated whether different strengths of conditioned fear memories require different degrees of PE during memory reactivation in order for the memories to become destabilized. Here, we assessed the fear-potentiated startle and skin conductance response, using the post-retrieval extinction procedure. A violation of expectancy (PE) was induced during retrieval to reactivate enhanced (unpredictable-shock) or ordinary (predictable-shock) fear memories that were established the day before. Results showed that a PE retrieval before extinction can prevent the return of predictable-shock fear memory but cannot prevent the return of unpredictable-shock fear memory, indicating that a single PE is insufficient to destabilize enhanced fear memory. Therefore, we further investigated whether increasing the degree of PE could destabilize enhanced fear memory using different retrieval strategies (multiple PE retrieval and unreinforced CS retrieval). We found that spontaneous recovery of enhanced fear memory was prevented in both retrieval strategies, but reinstatement was only prevented in the multiple PE retrieval group, suggesting that a larger amount of PE is needed to destabilize enhanced fear memory. The findings suggest that behavioral updating during destabilization requires PE, and the degree of PE needed to induce memory destabilization during memory retrieval depends on the strength of fear memory. The study indicates that memory reconsolidation inference can be used to destabilize stronger memories, and the findings shed lights on the treatment of posttraumatic stress disorders and anxiety disorders.

A host of learning, memory, and decision-making processes form the individual's response to threat and may be disrupted in anxiety and post-trauma psychopathology. Here we review the neural computations of threat, from the first encounter with a dangerous situation, through learning, storing, and updating cues that predict it, to making decisions about the optimal course of action. The overview highlights the interconnected nature of these processes and their reliance on shared neural and computational mechanisms. We propose an integrative approach to the study of threat-related processes, in which specific computations are studied across the various stages of threat experience rather than in isolation. This approach can generate new insights about the evolution, diagnosis, and treatment of threat-related psychopathology. The response to threat comprises multiple learning, memory, and decision-making processes. These processes may be disrupted in anxiety and trauma-related disorders. We describe five stages of processing: experience of imminent threat; formation of threat associations; post-association learning; storing and updating of these associations; and decision-making under threat. These stages rely on overlapping computations and shared neural circuits. We propose that, to reach a fundamental understanding of anxiety and trauma-related disorders, these processes should be studied together rather than in isolation. [ABSTRACT FROM AUTHOR]

Background: Long-term memory formation is generally assumed to involve the permanent storage of recently acquired memories, making them relatively insensitive to disruption, a process referred to as memory consolidation. However, when retrieved under specific circumstances, consolidated fear memories are thought to return to a labile state, thereby opening a window for modification (e.g., attenuation) of the memory. Several interventions during a critical time frame after this destabilization seem to be able to alter the retrieved memory, for example by pharmacologically interfering with the restabilization process, either by direct protein synthesis inhibition or indirectly, using drugs that can be safely administered in patients (e.g., propranolol). Here, we find that, contrary to expectations, systemic pharmacological manipulations in auditory fear-conditioned rats do not lead to drug-induced post-retrieval amnesia. Results: In a series of well-powered auditory fear conditioning experiments (four with propranolol, 10 mg/kg, two with rapamycin, 20–40 mg/kg, one with anisomycin, 150 mg/kg and cycloheximide, 1.5 mg/kg), we found no evidence for reduced cued fear memory expression during a drug-free test in adult male Sprague-Dawley rats that had previously received a systemic drug injection upon retrieval of the tone fear memory. All experiments used standard fear conditioning and reactivation procedures with freezing as the behavioral read-out (conceptual or exact replications of published reports) and common pharmacological agents. Additional tests confirmed that the applied drug doses and administration routes were effective in inducing their conventional effects on expression of fear (propranolol, acutely), body weight (rapamycin, anisomycin, cycloheximide), and consolidation of extinction memories (cycloheximide). Conclusions: In contrast with previously published studies, we did not find evidence for drug-induced post-retrieval amnesia, underlining that this effect, as well as its clinical applicability, may be considerably more constrained and less readily reproduced than what the current literature would suggest. [ABSTRACT FROM AUTHOR]

Reactivation of consolidated memories can induce a labile period, in which these reactivated memories might be susceptible to change and need reconsolidation. Prediction error (PE) has been recognized as a necessary boundary condition for memory destabilization. Moreover, memory strength is also widely accepted as an essential boundary condition to destabilize fear memory. This study investigated whether different strengths of conditioned fear memories require different degrees of PE during memory reactivation in order for the memories to become destabilized. Here, we assessed the fear-potentiated startle and skin conductance response, using the post-retrieval extinction procedure. A violation of expectancy (PE) was induced during retrieval to reactivate enhanced (unpredictable-shock) or ordinary (predictable-shock) fear memories that were established the day before. Results showed that a PE retrieval before extinction can prevent the return of predictable-shock fear memory but cannot prevent the return of unpredictable-shock fear memory, indicating that a single PE is insufficient to destabilize enhanced fear memory. Therefore, we further investigated whether increasing the degree of PE could destabilize enhanced fear memory using different retrieval strategies (multiple PE retrieval and unreinforced CS retrieval). We found that spontaneous recovery of enhanced fear memory was prevented in both retrieval strategies, but reinstatement was only prevented in the multiple PE retrieval group, suggesting that a larger amount of PE is needed to destabilize enhanced fear memory. The findings suggest that behavioral updating during destabilization requires PE, and the degree of PE needed to induce memory destabilization during memory retrieval depends on the strength of fear memory. The study indicates that memory reconsolidation inference can be used to destabilize stronger memories, and the findings shed lights on the treatment of posttraumatic stress disorders and anxiety disorders. [ABSTRACT FROM AUTHOR]

• Association formation models dominate fear conditioning research. • Alternative theoretical approaches may inspire new avenues of treatment research. • A goal-directed account of conditioned fear is introduced and evaluated. For decades already, the human fear conditioning paradigm has been used to study and develop treatments for anxiety disorders. This research is guided by theoretical assumptions that, in some cases indirectly, stem from the tradition of association formation models (e.g., the Rescorla-Wagner model). We argue that one of these assumptions – fear responding as a monotonic function of the associative activation of aversive memory representations – restricts the types of treatment that the research community currently considers. We discuss the importance of this assumption in the context of research on extinction-enhancing and reconsolidation interference techniques. While acknowledging the merit of this research, we argue that unstrapping the straitjacket of this assumption can lead to exploring new directions for utilizing fear conditioning procedures in treatment research. We discuss two determinants of fear responding other than associative memory activation. First, fear responding might also depend on relational information. Second, a recent goal-directed emotion theory suggests that goals might be the primary determinant of the response pattern characterized as fear. [ABSTRACT FROM AUTHOR]

Reconsolidation is the post-retrieval stabilization of memories, a time-limited process during which reactivated (i.e., retrieved) memories can be updated with new information, become stronger or weaker, depending on the specific treatment. We have previously shown that the stress hormone cortisol has an enhancing effect on the reconsolidation of fear memories in men. This effect was specific, i.e., limited to the conditioned stimulus (CS) that was reactivated, and did not generalize to other previously reinforced, but not reactivated CS. Based on these results, we suggested that cortisol plays a critical role in the continuous strengthening of reactivated emotional memories, contributing to their persistence and robustness. In the current study, we aimed to achieve a more generalized reconsolidation enhancement using an alternative reactivation method, i.e., by a low-intensity unconditioned stimulus (UCS) presentation instead of the more common unreinforced CS presentation. In previous studies, UCS reactivation was shown to lead to a more generalized reconsolidation effect. Therefore, we hypothesized that the combination of cortisol treatment and UCS reactivation would lead to an enhanced fear memory reconsolidation, which would generalize from previously reinforced CS to stimuli that resemble it. We tested 75 men in a 3-day fear conditioning paradigm: fear acquisition training on day 1; UCS reactivation/no reactivation and pharmacological treatment (20 mg hydrocortisone/placebo) on day 2; extinction training, reinstatement and test (of original and modified stimuli) on day 3. In contrast to our hypothesis, UCS reactivation prevented the return of fear [observed in skin conductance responses (SCR)] regardless of the pharmacological manipulation: while reinstatement to the original CS was found in the no-reactivation group, both reactivation groups (cortisol and placebo) showed no reinstatement. As the only methodological difference between our previous study and the current one was the reactivation method, we focus on UCS reactivation as the main explanation for these unexpected findings. We suggest that the robust prediction error generated by the UCS reactivation method (as opposed to CS reactivation), combined with the lower UCS intensity, has by itself weakened the emotional value of the UCS, thus preventing the return of fear to the CS that was associated with it. We call for future research to support these findings and to examine the potential of this reactivation method, or variations thereof, as a tool for therapeutic use.

Experimental evidence in humans and non-human animals suggests that the administration of propranolol shortly after the retrieval of an emotional memory can lead to an attenuation of its later expression, a phenomenon known as post-reactivation amnesia. Using more potent amnestic drugs, post-reactivation amnesia has been shown in animals to be reversible by re-administration of the drug prior to memory retention testing. The latter finding suggests that, at least under some circumstances, post-reactivation amnesia may not reflect a disruption of reconsolidation (i.e., a memory storage deficit) but an acquired state-dependency of memory expression (i.e., a memory retrieval deficit that is relieved when the drug state is recreated during testing). We conducted a double-blind, placebo-controlled study to investigate whether the previously established amnestic effects of post-reactivation propranolol administration on memory retention in humans may similarly reflect a retrieval deficit. In four groups of participants, fear memories were first established through differential fear conditioning. One day later, a single presentation of the CS+ without shock was used to reactivate the memory in three of the four groups, followed by the administration of 40 mg Propranolol HCl (Groups PrPl and PrPr) or placebo (Group PlPl). Memory was not reactivated in the fourth group (Group NR). Another 24 h later, Propranolol HCl (Group PrPr) or placebo (Groups PrPl, PlPl, and NR) was again administered, followed by a test of memory retention (extinction testing) and recovery (reinstatement testing). We did not observe any effects of post-reactivation propranolol on memory retention; conditioned responding was similar for all groups at the start of retention testing and similarly sensitive to recovery through reinstatement. We did observe an acute effect of propranolol administration on fear-potentiated startle responding during retention testing in Group PrPr, where participants exhibited attenuated startle responses during extinction testing but similar sensitivity to reinstatement as participants in the other groups. While our findings fail to corroborate previous reports of propranolol-induced post-reactivation amnesia in humans, they do point to acute effects of propranolol administration on extinction performance.

Reconsolidation is the post-retrieval stabilization of memories, a time-limited process during which reactivated (i.e., retrieved) memories can be updated with new information, become stronger or weaker, depending on the specific treatment. We have previously shown that the stress hormone cortisol has an enhancing effect on the reconsolidation of fear memories in men. This effect was specific, i.e., limited to the conditioned stimulus (CS) that was reactivated, and did not generalize to other previously reinforced, but not reactivated CS. Based on these results, we suggested that cortisol plays a critical role in the continuous strengthening of reactivated emotional memories, contributing to their persistence and robustness. In the current study, we aimed to achieve a more generalized reconsolidation enhancement using an alternative reactivation method, i.e., by a low-intensity unconditioned stimulus (UCS) presentation instead of the more common unreinforced CS presentation. In previous studies, UCS reactivation was shown to lead to a more generalized reconsolidation effect. Therefore, we hypothesized that the combination of cortisol treatment and UCS reactivation would lead to an enhanced fear memory reconsolidation, which would generalize from previously reinforced CS to stimuli that resemble it. We tested 75 men in a 3-day fear conditioning paradigm: fear acquisition training on day 1; UCS reactivation/no reactivation and pharmacological treatment (20 mg hydrocortisone/placebo) on day 2; extinction training, reinstatement and test (of original and modified stimuli) on day 3. In contrast to our hypothesis, UCS reactivation prevented the return of fear [observed in skin conductance responses (SCR)] regardless of the pharmacological manipulation: while reinstatement to the original CS was found in the no-reactivation group, both reactivation groups (cortisol and placebo) showed no reinstatement. As the only methodological difference between our previous study and the current one was the reactivation method, we focus on UCS reactivation as the main explanation for these unexpected findings. We suggest that the robust prediction error generated by the UCS reactivation method (as opposed to CS reactivation), combined with the lower UCS intensity, has by itself weakened the emotional value of the UCS, thus preventing the return of fear to the CS that was associated with it. We call for future research to support these findings and to examine the potential of this reactivation method, or variations thereof, as a tool for therapeutic use. [ABSTRACT FROM AUTHOR]

Purpose Of Review: Anxiety- and trauma-related disorders are prevalent and debilitating mental illnesses associated with a significant socioeconomic burden. Current treatment approaches often have inadequate therapeutic responses, leading to symptom relapse. Here we review recent preclinical and clinical findings on the potential of cannabinoids as novel therapeutics for regulating fear and anxiety.Recent Findings: Evidence from preclinical studies has shown that the non-psychotropic phytocannabinoid cannabidiol and the endocannabinoid anandamide have acute anxiolytic effects and also regulate learned fear by dampening its expression, enhancing its extinction and disrupting its reconsolidation. The findings from the relevant clinical literature are still very preliminary but are nonetheless encouraging. Based on this preclinical evidence, larger-scale placebo-controlled clinical studies are warranted to investigate the effects of cannabidiol in particular as an adjunct to psychological therapy or medication to determine its potential utility for treating anxiety-related disorders in the future. [ABSTRACT FROM AUTHOR]

Experimental evidence in humans and non-human animals suggests that the administration of propranolol shortly after the retrieval of an emotional memory can lead to an attenuation of its later expression, a phenomenon known as post-reactivation amnesia. Using more potent amnestic drugs, post-reactivation amnesia has been shown in animals to be reversible by re-administration of the drug prior to memory retention testing. The latter finding suggests that, at least under some circumstances, post-reactivation amnesia may not reflect a disruption of reconsolidation (i.e., a memory storage deficit) but an acquired state-dependency of memory expression (i.e., a memory retrieval deficit that is relieved when the drug state is recreated during testing). We conducted a double-blind, placebo-controlled study to investigate whether the previously established amnestic effects of post-reactivation propranolol administration on memory retention in humans may similarly reflect a retrieval deficit. In four groups of participants, fear memories were first established through differential fear conditioning. One day later, a single presentation of the CS+ without shock was used to reactivate the memory in three of the four groups, followed by the administration of 40 mg Propranolol HCl (Groups PrPl and PrPr) or placebo (Group PlPl). Memory was not reactivated in the fourth group (Group NR). Another 24 h later, Propranolol HCl (Group PrPr) or placebo (Groups PrPl, PlPl, and NR) was again administered, followed by a test of memory retention (extinction testing) and recovery (reinstatement testing). We did not observe any effects of post-reactivation propranolol on memory retention; conditioned responding was similar for all groups at the start of retention testing and similarly sensitive to recovery through reinstatement. We did observe an acute effect of propranolol administration on fear-potentiated startle responding during retention testing in Group PrPr, where participants exhibited attenuated startle responses during extinction testing but similar sensitivity to reinstatement as participants in the other groups. While our findings fail to corroborate previous reports of propranolol-induced post-reactivation amnesia in humans, they do point to acute effects of propranolol administration on extinction performance. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract Clinical trials have demonstrated that 3,4-methylenedioxymethamphetamine (MDMA) paired with psychotherapy is more effective at reducing symptoms of post-traumatic stress disorder (PTSD) than psychotherapy or pharmacotherapy, alone or in combination. The processes through which MDMA acts to enhance psychotherapy are not well understood. Given that fear memories contribute to PTSD symptomology, MDMA could augment psychotherapy by targeting fear memories. The current studies investigated the effects of a single administration of MDMA on extinction and reconsolidation of cued and contextual fear memory in adult, male Long-Evans rats. Rats were exposed to contextual or auditory fear conditioning followed by systemic administration of saline or varying doses of MDMA (between 1 and 10 mg/kg) either 30 min before fear extinction training or immediately after brief fear memory retrieval (i.e. during the reconsolidation phase). MDMA administered prior to fear extinction training failed to enhance fear extinction memory, and in fact impaired drug-free cued fear extinction recall without impacting later fear relapse. MDMA administered during the reconsolidation phase, but not outside of the reconsolidation phase, produced a delayed and persistent reduction in conditioned fear. These findings are consistent with a general memory-disrupting effect of MDMA and suggest that MDMA could augment psychotherapy by modifying fear memories during reconsolidation without necessarily enhancing their extinction. Highlights • MDMA impairs cued fear extinction recall without impacting relapse. • Post-retrieval MDMA interferes with reconsolidation of fear memories. • The effects of MDMA on reconsolidation are delayed and persistent. • Clinical efficacy of MDMA could be attributed to modification of fear memory during reconsolidation. [ABSTRACT FROM AUTHOR]

Rationale: Memories can return to a labile state and become amenable to modification by pharmacological and behavioral manipulations after retrieval. This process may reduce the impact of aversive memories and provide a promising therapeutic technique for the treatment of anxiety disorders. A growing body of evidence suggests that the mammalian neuropeptide oxytocin (OT) plays a role in the regulation of emotional memories in animals. However, the effects of OT on threat memory in humans remain largely unknown.Objectives: This study aimed to investigate the effects of OT administration following threat memory retrieval on subsequent memory expression in human participants.Methods: In a double-blind, randomized, placebo-controlled, between-subject design, 61 healthy human individuals completed a 3-day experiment. All the participants underwent threat conditioning on day 1. On day 2, the participants were randomized to receive an intranasal dose of OT (40 IU) or placebo after memory retrieval, or an intranasal dose of OT (40 IU) without retrieval. On day 3, the participants were tested for extinction and reinstatement.Results: On day 3, all groups showed equivalent stimulus discrimination during the early phase of extinction. However, the group that received OT following a memory reminder showed a greater decline in stimulus discrimination by the late phase of extinction relative to the two other groups.Conclusions: The results indicate that OT did not block reconsolidation to prevent the return of threat memory but rather interacted with post-retrieval processes to facilitate next day extinction. The study provides novel preliminary evidence for the role of OT in human threat memory. [ABSTRACT FROM AUTHOR]

Memory consolidation is the process underlying the stabilization of labile short-term memory and the generation of long-term memory for persistent memory storage. The retrieval of contextual fear memory induces two distinct and opposite memory processes: reconsolidation and extinction. Reconsolidation re-stabilizes retrieved memory for re-storage, whereas memory extinction weakens fear memory and generates a new inhibitory memory. Importantly, the requirement for new gene expression is a critical biochemical feature of the consolidation, reconsolidation, and long-term extinction of memory. The locus coeruleus (LC) is a small nucleus in the brain stem that is composed predominantly of noradrenergic neurons that project to many brain regions. Recent studies have shown that the LC plays modulatory roles in the consolidation and extinction of auditory fear memory through its projections to brain regions contributing to memory storage. Here, we show that the LC is required for the consolidation, reconsolidation, and long-term extinction of contextual fear memory. We first observed that c-fos expression was induced in the LC following contextual fear conditioning to induce consolidation and following short and long re-exposure to the conditioning context to induce reconsolidation and long-term extinction, respectively. More importantly, inhibition of protein synthesis in the LC by a micro-infusion of anisomycin blocked the consolidation, reconsolidation, and long-term extinction of contextual fear memory. Our findings suggest that consolidation, reconsolidation, and long-term extinction occur in the LC and that the LC plays an essential role in memory storage and maintenance. • LC induces c-fos when fear memory is consolidated, reconsolidated, and extinguished. • Contextual fear memory consolidation requires protein synthesis in the LC. • Contextual fear memory reconsolidation requires protein synthesis in the LC. • Long-term contextual fear memory extinction requires protein synthesis in the LC. • LC is suggested to play an essential role in memory storage and maintenance. [ABSTRACT FROM AUTHOR]

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.

Pairing a previously neutral conditioned stimulus (CS; e.g., a tone) to an aversive unconditioned stimulus (US; e.g., a footshock) leads to associative learning such that the tone alone comes to elicit a conditioned response (e.g., freezing). We have previously shown that an extinction session that occurs within the reconsolidation window (termed retrieval+extinction) attenuates fear responding and prevents the return of fear in Pavlovian fear conditioning (Monfils et al., 2009). To date, the mechanisms that explain the different behavioral outcomes between standard extinction and retrieval+extinction remain poorly understood. Here we sought to examine the differential temporal engagement of specific neural systems by these 2 approaches using Arc catFISH (cellular compartment analysis of temporal activity using fluorescence in situ hybridization). Our results demonstrate that extinction and retrieval+extinction lead to differential patterns of expression, suggesting that they engage different networks. These findings provide insight into the neural mechanisms that allow extinction during reconsolidation to prevent the return of fear in rats.

Reactivated fear memories may enter an unstable state that could be interrupted by behavioral interventions such as the retrieval-extinction procedure. Studies of pharmacological interventions have shown that retrieval cues are not necessarily an exact reduplication of initial conditioned stimuli (CSs); they can instead be abstract word cues. However, the effectiveness of using abstract reminder cues in behavioral intervention procedures remains unknown, as do the conditions under which they are effective. The typicality of CS and the abstraction level of reminders are also likely to be important in the paradigm but have not been investigated to date. Here, in three experiments (n = 107), we manipulate the fear conditioning process, including single CS–unconditioned stimulus (US) and multiple CS–US connections, as well as the CS typicality and abstraction level of reminder cues, to explore the conditions for adopting retrieval-extinction with abstract reminders. The results of Experiments 1 and 2 show that the abstract cue is ineffective for use as a reminder in the procedure; this is the case for single exemplar category learning and perceptual discriminative learning, independent of the typicality of CS+ or the abstraction level of reminder cues. Only the outcome of Experiment 3, which contains multiple CS–US connections, shows no indication of fear return. The limitations of the study and possible interpretations of the results are discussed. • Little evidence showed that abstract cues can be used as a reminder in the retrieval-extinction procedure. • The effect is independent of the typicality of CS+ or the abstraction level of reminders. • Multi-exemplar learning during fear conditioning may play a role in the process. • Limitations of this study make it difficult to draw firm conclusions from the findings. [ABSTRACT FROM AUTHOR]

Freezing has become the predominant measure used in rodent studies of conditioned fear, but conditioned suppression of reward-seeking behavior may provide a measure that is more relevant to human anxiety disorders; that is, a measure of how fear interferes with the enjoyment of pleasurable activities. Previous work has found that an isolated presentation of a fear conditioned stimulus prior to extinction training (retrieval + extinction) results in a more robust and longer-lasting reduction in fear. The objective of this study was to assess whether the retrieval + extinction effect is evident using conditioned suppression of reward seeking, operationalized as a reduction in baseline licking (without prior water deprivation) for a 10% sucrose solution. We found that, compared to freezing, conditioned suppression of reward seeking was much more sensitive to fear conditioning and far less responsive to extinction training. As in previous work, we found that retrieval + extinction reduced post-extinction fear reinstatement when measured as freezing, but it did not reduce fear reinstatement when measured as conditioned suppression. This suggests that there is still residual fear following retrieval + extinction, or that this procedure only modifies memory traces in neural circuits relevant to the expression of freezing, but not to the suppression of reward seeking.

Careaga MBL, Girardi CEN, Suchecki D. Understanding posttraumatic stress disorder through fear conditioning, extinction and reconsolidation. NEUROSCI BIOBEHAV REV −Posttraumatic stress disorder (PTSD) is a psychopathology characterized by exacerbation of fear response. A dysregulated fear response may be explained by dysfunctional learning and memory, a hypothesis that was proposed decades ago. A key component of PTSD is fear conditioning and the study of this phenomenon in laboratory has expanded the understanding of the underlying neurobiological changes in PTSD. Furthermore, traumatic memories are strongly present even years after the trauma and maintenance of this memory is usually related to behavioral and physiological maladaptive responses. Persistence of traumatic memory may be explained by a dysregulation of two memory processes: extinction and reconsolidation. The former may explain the over-expression of fear responses as an imbalance between traumatic and extinction memory. The latter, in turn, explains the maintenance of fear responses as a result of enhancing trauma-related memories. Thus, this review will discuss the importance of fear conditioning for the establishment of PTSD and how failure in extinction or abnormal reconsolidation may contribute to the maintenance of fear response overtime. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

A brief 10-min time delay between an initial and subsequent exposure to extinction trials has been found to impair memory reconsolidation in fear-conditioned rodents and humans, providing a potential means to reduce fearfulness in anxiety disorders and posttraumatic stress disorder (PTSD). The present study used videos of biologically prepared, conditioned stimuli (tarantulas) to test the efficacy of delayed extinction in blocking reconsolidation of conditioned fear in healthy young adults. Strong differential conditioning, measured by skin conductance, was observed among a screened subset of participants during acquisition. However, the delayed-extinction intervention failed to reduce reactivity to the conditioned stimulus paired with the extinction delay. These results are partially consistent with other recent, mixed findings and point to a need for testing other candidate interventions designed to interfere with the reconsolidation process. [ABSTRACT FROM AUTHOR]

Background: Memory reconsolidation is the direct effect of memory reactivation followed by stabilization of newly synthesized proteins. It has been well proven that neural encoding of both newly and reactivated memories requires synaptic plasticity. Brain derived neurotrophic factor (BDNF) has been extensively investigated regarding its role in the formation of synaptic plasticity and in the alteration of fear memories. However, its role in fear reconsolidation is still unclear; hence, the current study has been designed to investigate the role of the BDNF val66met polymorphism (rs6265) in fear memory reconsolidation in humans. Methods: An auditory fear-conditioning paradigm was conducted, which comprised of three stages (acquisition, reactivation, and spontaneous recovery). One day after fear acquisition, the experimental group underwent reactivation of fear memory followed by the extinction training (reminder group), whereas the control group (non-reminder group) underwent only extinction training. On day 3, both groups were subjected to spontaneous recovery of earlier learned fearful memories. The treat-elicited defensive response due to conditioned threat was measured by assessing the skin conductance response to the conditioned stimulus. All participants were genotyped for rs6265. Results: The results indicate a diminishing effect of reminder on the persistence of fear memory only in the Met-allele carriers, suggesting a moderating effect of the BDNF polymorphism in fear memory reconsolidation. Conclusions: Our findings suggest a new role for BDNF gene variation in fear memory reconsolidation in humans. [ABSTRACT FROM AUTHOR]

Pairing a previously neutral conditioned stimulus (CS; e.g., a tone) to an aversive unconditioned stimulus (US; e.g., a footshock) leads to associative learning such that the tone alone comes to elicit a conditioned response (e.g., freezing). We have previously shown that an extinction session that occurs within the reconsolidation window (termed retrieval + extinction) attenuates fear responding and prevents the return of fear in Pavlovian fear conditioning (Monfils et al., 2009). To date, the mechanisms that explain the different behavioral outcomes between standard extinction and retrieval + extinction remain poorly understood. Here we sought to examine the differential temporal engagement of specific neural systems by these two approaches using Arc catFISH (cellular compartment analysis of temporal activity using fluorescence in situ hybridization (FISH)). Our results demonstrate that extinction and retrieval + extinction lead to differential patterns of expression, suggesting that they engage different networks. These findings provide insight into the neural mechanisms that allow extinction during reconsolidation to prevent the return of fear in rodents. [ABSTRACT FROM AUTHOR]

Upon recall, a memory can enter a labile state in which it requires new protein synthesis to restabilize. This two-phased reconsolidation process raises the prospect to directly target excessive fear memory as opposed to the formation of inhibitory memory following extinction training. In our previous studies, we convincingly demonstrated that 40 mg propranolol HCl administration before or after memory reactivation eliminated the emotional expression of fear memory indexed by the fear-potentiated startle reflex. To apply this procedure in clinical practice it is important to understand the optimal and boundary conditions of this procedure. As part of a large project aimed at unraveling putative boundary conditions of disrupting reconsolidation of associative fear memory with propranolol HCl, we again tested our memory reconsolidation procedure. Participants (N = 44) underwent a three-day differential fear conditioning procedure. Twenty-four hours after fear acquisition, participants received 40 mg propranolol HCl prior to memory reactivation. The next day, participants were subjected to extinction training and reinstatement testing. In sharp contrast to our previous findings, propranolol HCl before memory reactivation did not attenuate the startle fear response. Remarkably, the startle fear response even persisted during extinction training and did not show the usually observed gradual decline in conditioned physiological responding (startle potentiation and skin conductance) upon repeated unreinforced trials. We discuss these unexpected findings and propose some potential explanations. It remains however unclear why we observed a resistance to reduce conditioned fear responding by either disrupting reconsolidation or extinction training. The present results underscore that the success of human fear conditioning research may depend on subtle manipulations and instructions.

Freezing has become the predominant measure used in rodent studies of conditioned fear, but conditioned suppression of reward-seeking behavior may provide a measure that is more relevant to human anxiety disorders; that is, a measure of how fear interferes with the enjoyment of pleasurable activities. Previous work has found that an isolated presentation of a fear conditioned stimulus (CS) prior to extinction training (retrieval + extinction) results in a more robust and longer-lasting reduction in fear. The objective of this study was to assess whether the retrieval + extinction effect is evident using conditioned suppression of reward seeking, operationalized as a reduction in baseline licking (without prior water deprivation) for a 10% sucrose solution. We found that, compared to freezing, conditioned suppression of reward seeking was much more sensitive to fear conditioning and far less responsive to extinction training. As in previous work, we found that retrieval + extinction reduced post-extinction fear reinstatement when measured as freezing, but it did not reduce fear reinstatement when measured as conditioned suppression. This suggests that there is still residual fear following retrieval + extinction, or that this procedure only modifies memory traces in neural circuits relevant to the expression of freezing, but not to the suppression of reward seeking. [ABSTRACT FROM AUTHOR]

At the present, effective treatments are available to reduce anxiety symptoms and their associated distress. Nevertheless, it is frequently observed that anxiety responses are recovered after extinction, without being clear the responsible mechanism of such phenomenon. For decades, it has been presumed the existence of a reconsolidation mechanism. Such mechanism is thought to participate in the re-storage of memories that have been evoked. Recent research apparently reveals that intervention on reconsolidation mechanisms prevents the recovery of anxiety responses that have been previously extinguished. Intervention on these mechanisms could represent an alternative to current psychological treatments for anxiety disorders based on exposure procedures. The objective of the present work is to review the evidence on reconsolidation mechanisms and its effects on the reduction of anxiety responses. Finally some clinical implications will be discussed. [ABSTRACT FROM AUTHOR]

Background Sub-anesthetic doses of the NMDA antagonist ketamine have been shown to model the formation and stability of delusion in human subjects. The latter has been predicted to be due to aberrant prediction error resulting in enhanced destabilization of beliefs. To extend the scope of this model, we investigated the effect of administration of low dose systemic ketamine on memory in a rodent model of memory reconsolidation. Methods Systemic ketamine was administered either prior to or immediately following auditory fear memory reactivation in rats. Memory strength was assessed by measuring freezing behavior 24 h later. Follow up experiments were designed to investigate an effect of pre-reactivation ketamine on short-term memory (STM), closely related memories, and basolateral amygdala (BLA) specific destabilization mechanisms. Results Rats given pre-reactivation, but not post-reactivation, ketamine showed larger freezing responses 24 h later compared to vehicle. This enhancement was not observed 3 h after the memory reactivation, nor was it seen in a closely related contextual memory. Prior inhibition of a known destabilization mechanism in the BLA blocked the effect of pre-reactivation ketamine. Conclusions Pre- but not post-reactivation ketamine enhances fear memory. These data together with recent data in human subjects supports a model of delusion fixity that proposes that aberrant prediction errors result in enhanced destabilization and strengthening of delusional belief. [ABSTRACT FROM AUTHOR]

The chronically stressed brain may present a vulnerability to develop maladaptive fear-related behaviors in response to a traumatic event. In rodents, chronic stress leads to amygdala hyperresponsivity and dendritic hypertrophy and produces a post traumatic stress disorder (PTSD)-like phenotype that includes exaggerated fear learning following Pavlovian fear conditioning and resistance to extinction. It is unknown whether chronic stress-induced enhanced fear memories are vulnerable to disruption via reconsolidation blockade, as a novel therapeutic approach for attenuating exaggerated fear memories. We used a chronic stress procedure in a rat model (wire mesh restraint for 6 h/d/21 d) to create a vulnerable brain that leads to a PTSD-like phenotype. We then examined freezing behavior during acquisition, reactivation and after post-reactivation rapamycin administration (i.p., 40 mg/kg) in a Pavlovian fear conditioning paradigm to determine its effects on reconsolidation as well as the subsequent functional activation of limbic structures using zif268 mRNA. Chronic stress increased amygdala zif268 mRNA during fear memory retrieval at reactivation. Moreover, these enhanced fear memories were unaffected by post reactivation rapamycin to disrupt long-term fear memory. Also, post-reactivation long term memory processing was also associated with increased amygdala (LA and BA), and decreased hippocampal CA1 zif268 mRNA expression. These results suggest potential challenges for reconsolidation blockade as an effective approach in treating exaggerated fear memories, as in PTSD. Our findings also support chronic stress manipulations combined with fear conditioning as a useful preclinical approach to study a PTSD-like phenotype. [ABSTRACT FROM AUTHOR]

Pharmacologic blockade of memory reconsolidation has been demonstrated in fear-conditioned rodents and humans and may provide a means to reduce fearfulness in anxiety disorders and posttraumatic stress disorder. Studying the efficacy of potential interventions in clinical populations is challenging, creating a need for paradigms within which candidate reconsolidation-blocking interventions can be readily tested. We used videos of biologically prepared conditioned stimuli (tarantulas) to test the efficacy of propranolol in blocking reconsolidation of conditioned fear in healthy young adults. Strong differential conditioning, measured by skin conductance, was observed among a screened subset of participants during acquisition. However, subsequent propranolol failed to reduce reactivity to the reactivated conditioned stimulus. These results are consistent with other recent findings and point to a need for testing other candidate drugs. [ABSTRACT FROM AUTHOR]

ABSTRACT Protein phosphatases are important regulators of neural plasticity and memory. Some studies support that the Ca2+/calmodulin-dependent phosphatase calcineurin (CaN) is, on the one hand, a negative regulator of memory formation and, on the other hand, a positive regulator of memory extinction and reversal learning. However, the signaling mechanisms by which CaN exerts its action in such processes are not well understood. Previous findings support that CaN negatively regulate the nuclear factor kappaB (NF-κB) signaling pathway during extinction. Here, we have studied the role of CaN in contextual fear memory consolidation and reconsolidation in the hippocampus. We investigated the CaN control on the NF-κB signaling pathway, a key mechanism that regulates gene expression in memory processes. We found that post-training intrahippocampal administration of the CaN inhibitor FK506 enhanced memory retention one day but not two weeks after training. Accordingly, the inhibition of CaN by FK506 increased NF-κB activity in dorsal hippocampus. The administration of the NF-κB signaling pathway inhibitor sulfasalazine (SSZ) impeded the enhancing effect of FK506. In line with our findings in consolidation, FK506 administration before memory reactivation enhanced memory reconsolidation when tested one day after re-exposure to the training context. Strikingly, memory was also enhanced two weeks after training, suggesting that reinforcement during reconsolidation is more persistent than during consolidation. The coadministration of SSZ and FK506 blocked the enhancement effect in reconsolidation, suggesting that this facilitation is also dependent on the NF-κB signaling pathway. In summary, our results support a novel mechanism by which memory formation and reprocessing can be controlled by CaN regulation on NF-κB activity. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Retrieval of consolidated memories induces a labile phase during which memory can be disrupted or updated through a reconsolidation process. A central component of behavioral updating during reconsolidation using a retrieval–extinction manipulation (Ret + Ext) is the synaptic removal of a calcium-permeable-α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor (CP-AMPARs) in the lateral amygdala—a metabotropic GluR1 receptor (mGluR1) dependent mechanism. In the present study, we investigate the effect of Ret + Ext on the expression of molecular markers that could play a role in the reconsolidation process. Specifically, we tested the effects of Ret + Ext on the global expression of zinc-finger 268 protein (Zif268), a marker previously found to be implicated in memory reconsolidation, to confirm its occurrence after retrieval (Ret) and Ret + Ext. We also evaluated the global expression of phosphorylated ribosomal protein S6 (rpS6P), here proposed as a marker of the mGluR1-mediated memory process induced by Ret + Ext. The expression of both markers (zif268, rpS6P) was assessed by immunolocalization in prelimbic cortex (PRL), infralimbic cortex (IL), ventral subdivision of the lateral amygdala (LA) and hippocampus CA1 (CA1) in fear-conditioned rats. Our results showed that retrieval and Ret + Ext, but not extinction alone, increased Zif268 expression in prefrontal cortex and lateral amygdala. Ret + Ext, but not retrieval, retrieval followed by context exposure or extinction alone, increased the expression of rpS6P in prefrontal cortex and LA. In summary, (i) Zif268 increased after retrieval confirming that reconsolidation is engaged in our conditions, (ii) Zif268 increased after Ret + Ext confirming that it does not simply reflect an extinction or reconsolidation disruption (Zif268 level of expression should be lower in both cases) and (iii) rpS6P increased after Ret + Ext, but not after extinction, suggesting, as expected, a potential mGluR1 mediated molecular mechanism specific for Ret + Ext. Together with the Zif268 increase, our results suggest that the Ret + Ext induced memory process is more similar to reconsolidation updating than extinction facilitation. [ABSTRACT FROM AUTHOR]

Upon recall, a memory can enter a labile state in which it requires new protein synthesis to restabilize. This two-phased reconsolidation process raises the prospect to directly target excessive fear memory as opposed to the formation of inhibitory memory following extinction training. In our previous studies, we convincingly demonstrated that 40mg propranolol HCl administration before or after memory reactivation eliminated the emotional expression of fear memory indexed by the fear potentiated startle reflex. To apply this procedure in clinical practice it is important to understand the optimal and boundary conditions of this procedure. As part of a large project aimed at unraveling putative boundary conditions of disrupting reconsolidation of associative fear memory with propranolol HCl, we again tested our memory reconsolidation procedure. Participants (N D44) underwent a three-day differential fear conditioning procedure. Twenty-four hours after fear acquisition, participants received 40mg propranolol HCl prior to memory reactivation. The next day, participants were subjected to extinction training and reinstatement testing. In sharp contrast to our previous findings, propranolol HCl before memory reactivation did not attenuate the startle fear response. Remarkably, the startle fear response even persisted during extinction training and did not show the usually observed gradual decline in conditioned physiological responding (startle potentiation and skin conductance) upon repeated unreinforced trials. We discuss these unexpected findings and propose some potential explanations. It remains, however, unclear why we observed a resistance to reduce conditioned fear responding by either disrupting reconsolidation or extinction training. The present results underscore that the success of human fear conditioning research may depend on subtle manipulations and instructions. [ABSTRACT FROM AUTHOR]

Rational: Memories return to a labile state following their retrieval and must undergo a process of reconsolidation to be maintained. Thus, disruption of cocaine reward memories by interference with reconsolidation may be therapeutically beneficial in the treatment of cocaine addiction. Objective: The objectives were to elucidate the signaling pathway involved in reconsolidation of cocaine reward memory and to test whether targeting this pathway could disrupt cocaine-associated contextual memory. Methods: Using a mouse model of conditioned place preference, regulation of the activity of glycogen synthase kinase-3 (GSK3), mammalian target of Rapamycin complex 1 (mTORC1), P70S6K, β-catenin, and the upstream signaling molecule Akt, was studied in cortico-limbic-striatal circuitry after re-exposure to an environment previously paired with cocaine. Result: Levels of phosporylated Akt-Thr308, GSK3α-Ser21, GSK3β-Ser9, mTORC1, and P70S6K were reduced in the nucleus accumbens and hippocampus 10 min after the reactivation of cocaine cue memories. Levels of pAkt and pGSK3 were also reduced in the prefrontal cortex. Since reduced phosphorylation of GSK3 indicates heightened enzyme activity, the effect of a selective GSK3 inhibitor, SB216763, on reconsolidation was tested. Administration of SB216763 immediately after exposure to an environment previously paired with cocaine abrogated a previously established place preference, suggesting that GSK3 inhibition interfered with reconsolidation of cocaine-associated reward memories. Conclusions: These findings suggest that the Akt/GSK3/mTORC1 signaling pathway in the nucleus accumbens, hippocampus, and/or prefrontal cortex is critically involved in the reconsolidation of cocaine contextual reward memory. Inhibition of GSK3 activity during memory retrieval can erase an established cocaine place preference. [ABSTRACT FROM AUTHOR]

Memory retrieval, often termed reconsolidation, can render previously consolidated memories susceptible to manipulation that can lead to alterations in memory strength. Although it is known that reconsolidation requires mammalian target of rapamycin complex 1 (mTORC1)-dependent translation, the specific contributions of its downstream effectors in reconsolidation are unclear. Using auditory fear conditioning in mice, we investigated the role of eukaryotic translation initiation factor 4E (eIF4E)- eIF4G interactions and p70 S6 kinase polypeptide 1 (S6K1) in reconsolidation. We found that neither 4EGI-1 (2-[(4-(3,4-dichlorophenyl)-thiazol-2-ylhydrazono)-3-(2- nitrophenyl)]propionic acid), an inhibitor of eFI4E-eIF4G interactions, nor PF-4708671 [2-((4-(5-ethylpyrimidin-4-yl)piperazin-1- yl)methyl)-5-(trifluoromethyl)-1H-benzo[d]imidazole], an inhibitor of S6K1, alone blocked the reconsolidation of auditory fear memory. In contrast, using these drugs in concert to simultaneously block eIF4E- eIF4G interactions and S6K1 immediately after memory reactivation significantly attenuated fear memory reconsolidation. Moreover, the combination of 4EGI-1 and PF-4708671 further destabilized fear memory 10 d after memory reactivation, which was consistent with experiments using rapamycin, an mTORC1 inhibitor. Furthermore, inhibition of S6K1 immediately after retrieval resulted in memory destabilization 10 d after reactivation, whereas inhibition of eIF4E- eIF4G interactions did not. These results indicate that the reconsolidation of fear memory requires concomitant association of eIF4E to eIF4G as well as S6K1 activity and that the persistence of memory at longer intervals after memory reactivation also requires mTORC1-dependent processes that involve S6K1. These findings suggest a potential mechanism for how mTORC1-dependent translation is fine tuned to alter memory persistence. [ABSTRACT FROM AUTHOR]

Highlights: [•] The literature on human reconsolidation is reviewed and discussed. [•] Methods of memory reactivation to induce reconsolidation are discussed. [•] The rationale behind the clinical interest of reconsolidation studies is discussed. [Copyright &y& Elsevier]

Highlights: [•] Newly developed methods allow manipulation of hippocampus-dependent memories. [•] Cued reactivation during sleep and transcranial stimulation can enhance memories. [•] Pharmacological agents can delete memories. [•] Optogenetics and DREADDs can be used to incept memories. [•] Electrophysiology and fMRI have been used to investigate the underlying mechanisms. [Copyright &y& Elsevier]

Highlights: [•] DNMT inhibition impairs fear memory consolidation. [•] DNMT inhibition impairs the consolidation of neural plasticity in the LA. [•] DNMT inhibition impairs fear memory reconsolidation. [•] DNMT inhibition impairs the reconsolidation of neural plasticity in the LA. [Copyright &y& Elsevier]