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The reconsolidation process is the mechanism by which strength and/or content of consolidated memories are updated. Prediction error (PE) is the difference between the prediction made and current events. It is proposed as a necessary condition to trigger the reconsolidation process. Here we analyzed deeply the role of the PE in the associative memory reconsolidation in the crab Neohelice granulata . An incongruence between the learned temporal relationship between conditioned and unconditioned stimuli (CS-US) was enough to trigger the reconsolidation process. Moreover, after a partial reinforced training, a PE of 50% opened the possibility to labilize the consolidated memory with a reminder which included or not the US. Further, during an extinction training a small PE in the first interval between CSs was enough to trigger reconsolidation. Overall, we highlighted the relation between training history and different reactivation possibilities to recruit the process responsible of memory updating. [ABSTRACT FROM AUTHOR]

Pituitary adenylate cyclase-activating polypeptide (PACAP) has a broad spectrum of biological functions including neurotransmitter, neurotrophic and neuroprotective. Moreover, it has been suggested that PACAP plays a role in the modulation of learning and memory as well as on the modulation of glutamate signaling. Thus, in the current study we investigated in the CA1 region of hippocampus and in the basolateral amygdala (BLA) the role of PACAP in the consolidation and extinction of contextual fear conditioning (CFC) and the interaction between PACAP and NMDA receptors. Male rats with cannulae implanted in the CA1 region of the hippocampus or in the BLA received immediately after the training or extinction training of the CFC infusions of the Vehicle, PACAP-38 (40 pg/side), PACAP 6-38 (40 pg/side) or PACAP 6-38 plus D-serine (50 μg/side). After 24 h, the animals were subjected to a 3-min retention test. The results indicated that in the CA1 region of hippocampus, PACAP participates in the consolidation and extinction of the CFC, and in the BLA, PACAP participates only in the consolidation of the CFC. Additionally, the results suggest that the action of PACAP on the consolidation and extinction of the CFC is mediated by the glutamate NMDA receptors. [ABSTRACT FROM AUTHOR]

Abstract: Disruption of the reconsolidation of conditioned fear memories has been suggested as a non-pharmacological means of preventing the return of learned fear in human populations. A reconsolidation update paradigm was developed in which a reconsolidation window is opened by a single isolated retrieval trial of a previously reinforced CS+ which is then followed by Extinction Training within that window. However, follow-up studies in humans using multi-methods fear conditioning indices (e.g., fear-potentiated startle, skin conductance, US-expectancy) have failed to replicate the retrieval+extinction effects. In the present study, we further investigated the retrieval+extinction reconsolidation update paradigm by directly comparing the acquisition, extinction, and return of fear-potentiated startle in the absence or presence of US-expectancy measures (using a trial-by-trial response keypad) with and without retrieval of a previously acquired CS-US association. Participants were fear conditioned to two visual cue CS+’s, one of which was presented as a single, isolated retrieval trial before Extinction Training and one that was extinguished as usual. The results show that the inclusion of US-expectancy measures strengthens the CS–US association to provide enhanced fear conditioning and maintenance of fear memories over the experimental sessions. In addition, in the groups that used on-line US-expectancy measures, the retrieval+extinction procedure reduced reinstatement of fear-potentiated startle to both previously reinforced CS+’s, as compared to the extinction as usual group. [Copyright &y& Elsevier]

Abstract: Although conditioned fear can be effectively extinguished by unreinforced exposure to a threat cue, fear responses tend to return when the cue is encountered some time after extinction (spontaneous recovery), in a novel environment (renewal), or following presentation of an aversive stimulus (reinstatement). As extinction represents a context-dependent form of new learning, one possible strategy to circumvent the return of fear is to conduct extinction across several environments. Here, we tested the effectiveness of multiple context extinction in a two-day fear conditioning experiment using 3-D virtual reality technology to create immersive, ecologically-valid context changes. Fear-potentiated startle served as the dependent measure. All three experimental groups initially acquired fear in a single context. A multiple extinction group then underwent extinction in three contexts, while a second group underwent extinction in the acquisition context and a third group underwent extinction in a single different context. All groups returned 24h later to test for return of fear in the extinction context (spontaneous recovery) and a novel context (renewal and reinstatement/test). Extinction in multiple contexts attenuated reinstatement of fear but did not reduce spontaneous recovery. Results from fear renewal were tendential. Our findings suggest that multi-context extinction can reduce fear relapse following an aversive event – an event that often induces return of fear in real-world settings – and provides empirical support for conducting exposure-based clinical treatments across a variety of environments. [Copyright &y& Elsevier]

Abstract: Little is known about the role of discrete stimulus features in the regulation of fear. This study examined the effects of feature learning on the acquisition and extinction of fear conditioning. Human participants were fear conditioned to a yellow triangle (CS+) using an electrical shock. We manipulated feature learning through differential conditioning. The nonconditioned control stimulus (CS−) was a red triangle in one group (Color-Relevant), but a yellow circle in the other group (Shape-Relevant). Next, two generalization stimuli were tested that shared the shape- or color-feature with the CS+ (a blue triangle and a yellow square). Online shock-expectancy ratings and skin conductance responding showed that the CS− determined the pattern of fear generalization: the same-color stimulus elicited more fear in Group Color-Relevant, versus the same-shape stimulus in group Shape-Relevant. Furthermore, extinguishing these two generalization stimuli had no detectable effect on fear of the CS+. These results show that fear generalization is influenced by feature learning through differential conditioning, and that exposures to different features of a stimulus are not sufficient to extinguish fear of that stimulus as a whole. [Copyright &y& Elsevier]

Highlights: [•] Amygdala gamma oscillations are enhanced following auditory fear conditioning. [•] Amygdala gamma oscillations during extinction learning are associated with spontaneous fear recovery. [•] Amygdala gamma oscillations are locally generated. [•] Maintenance of amygdala gamma oscillations during extinction learning linearly predicts spontaneous fear recovery. [Copyright &y& Elsevier]

Abstract: A number of studies have reported that d-cycloserine (DCS), a partial agonist of the N-methyl-d-aspartate glutamate receptor, can facilitate the loss of conditioned fear if it is administered during an extinction trial. Here we examine the effects of DCS injected into the hippocampus or amygdala on extinction of context-evoked freezing after contextual fear conditioning in C57BL/6 mice. We find that DCS administered prior to an extinction session decreased freezing from the outset of the session regardless of which brain region was targeted. Retention tests revealed opposite effects on fear expression despite identical behavioral treatments: intra-hippocampal DCS inhibited fear expression while intra-amygdala DCS potentiated fear expression. Following post-extinction session injections of DCS, we found a similar though less pronounced effect. Closer inspection of the data revealed that the effects of DCS interacted with the behavior of the subjects during extinction. Intra-hippocampal injections of DCS enhanced extinction in those mice that showed the greatest amount of within-session extinction, but had less pronounced effects on mice that showed the least within-session extinction. Intra-amygdala injections of DCS impaired extinction in those mice that showed the least within-session extinction, but there was some evidence that the effect in the amygdala did not depend on behavior during extinction. These findings demonstrate that even with identical extinction trial durations, the effects of DCS administered into the hippocampus and amygdala can heavily depend on the organism’s behavior during the extinction session. The broader implication of these findings is that the effects of pharmacological treatments designed to enhance extinction by targeting hippocampal or amygdalar processes may depend on the responsivity of the subject to the behavioral treatment. [Copyright &y& Elsevier]

Abstract: Post-extinction exposure of rats to a sub-conditioning procedure can evoke conditioned fear, which may correspond to fear return and/or fear learning potentiation. The aim of the present study was to clarify this issue and examine the effects of tetanic stimulation of the hippocampus (HPC) and medial prefrontal cortex (mPFC), two brain regions implicated in post-extinction modulation of conditioned fear. Rats were initially submitted to five tone-shock pairings with either a 0.7-mA or 0.1-mA shock. Tone-evoked freezing was observed only with the higher shock intensity, indicating that the 0.1-mA shock corresponded to a sub-conditioning procedure. All conditioned rats underwent fear extinction with 20 tone-alone trials. When retrained with the sub-conditioning procedure, they displayed again tone-evoked freezing, except when the initial tone was unpaired or a new tone was paired with the 0.1-mA shock, demonstrating fear return rather than fear learning potentiation. We also found that HPC and mPFC tetanic stimulations, applied 24h after the sub-conditioning procedure, similarly reduced this fear return. However, mPFC inactivation abolished temporary HPC tetanus effect, whereas HPC inactivation did not interfere with mPFC tetanus effect. These data confirm our previous findings and reveal the nature of HPC-mPFC interactions in post-extinction modulation of conditioned fear. [Copyright &y& Elsevier]

Abstract: In this study, we investigated how midazolam and d-cycloserine regulate the tonic activity and/or phasic reactivity of brain neurotransmitter systems to fear-evoking stimuli in rats with varying intensities of a fear response. We used a new animal model composed of high (HR) and low (LR) anxiety rats, selected according to their behaviour in the contextual fear test (i.e., the duration of a freezing response was used as a discriminating variable). In these rats, we examined the effects of both drugs on the release of glutamate and GABA in the basolateral amygdala (BLA) during the first extinction trial of a conditioned fear test. The results showed that administration of d-cycloserine (15mg/kg, i.p.) significantly enhanced the inhibition of an aversive context-induced freezing response observed during the extinction session in HR and LR rats. In contrast, midazolam (0.75mg/kg, i.p.) accelerated the attenuation of fear responses only in HR rats. The less anxious behaviour of LR animals given saline was accompanied by elevated basal levels of glutamate in the BLA, in comparison with HR rats, and a stronger elevation of GABA in response to contextual fear. In HR animals, the pretreatment of rats with d-cycloserine and midazolam significantly increased the local concentration of GABA and inhibited the expression of contextual fear. These findings suggest that animals more vulnerable to stress have innate deficits in brain systems that control the activity of the BLA mediating the central effect of stress. These results contribute to our understanding of observed individual differences in the effects of anxiolytic drugs among patients with anxiety disorders. [Copyright &y& Elsevier]

Abstract: Fear conditioning is accepted as a useful experimental paradigm to investigate anxious disorders following stress. In this field it is important to understand the mechanisms underlying the extinction of conditioned fear. In the rat it has been shown that the amygdalar basolateral nucleus plays a crucial role in all memorization phases of this type of memory (acquisition, consolidation, retrieval, and also reconsolidation and extinction). Recent results show that both the substantia nigra and nucleus basalis magnocellularis, two sites strongly connected with the basolateral amygdala are also involved in the consolidation of contextual fear conditioning. The aim of the present work is to investigate if latter two sites, besides the basolateral amygdala, are also involved in the extinction of the conditioned fear response. The results show that tetrodotoxin-induced inactivation of post-extinction training of either site does not impair the extinction process, which instead is impaired by inactivation of the basolateral amygdala. Thus, the present results confirm previous ones which show that diverse memorization phases (post-acquisition consolidation, extinction, reconsolidation) may be sustained by different neural sites and circuits. [ABSTRACT FROM AUTHOR]

Abstract: Chronic stress produces dendritic retraction in medial prefrontal cortex and impairs retrieval of extinction of conditioned fear, a behavior mediated by the infralimbic region (IL) of medial prefrontal cortex. To test the hypothesis that stress-induced changes in IL contribute to the stress-induced impairment in extinction retrieval, we performed an occlusion experiment in which we assessed the effects of stress alone, lesion of IL alone, and the combined effects of stress and lesion on extinction retrieval. If IL is the substrate upon which stress acts to produce deficits in extinction retrieval, then prior removal of IL should prevent the effect of stress on extinction retrieval. Rats received either sham or ibotenic acid lesions of IL. Rats in each group then remained unstressed or underwent daily restraint stress for 1week. Following the final day of restraint, rats received five habituation trials to a 30-s tone, followed by seven pairings of the tone with a 500-ms coterminating footshock. One hour later, rats received tone-alone extinction trials. On the following day, rats were given two extinction trials to test for extinction retrieval. Percent freezing was assessed throughout. Stress increased freezing during conditioning, and IL lesion did not block this effect. Either IL lesion alone or stress alone increased freezing on initial extinction trials. IL lesion did not attenuate the effect of stress during initial extinction. Similarly, IL lesion alone and stress alone produced deficits in extinction retrieval. However, stressed rats with IL lesions showed extinction retrieval comparable to that seen in unstressed, sham-lesioned rats. Thus, lesion of IL occluded the stress-induced impairment of extinction retrieval but failed to prevent the stress-induced facilitation of fear conditioning. This dissociation suggests that the effects of stress on these two aspects of emotion regulation are mediated at least in part by independent mechanisms, and that stress-induced changes in IL contribute to stress-induced deficits in extinction retrieval. [Copyright &y& Elsevier]

Abstract: Past research has shown that the N-methyl-d-aspartate receptor (NMDAr) is critically involved in the extinction of learned fear in adult rats with NMDAr antagonists impairing extinction retention and NMDAr agonists enhancing it. In the present study we examined the effects of the NMDAr antagonist MK-801 on extinction in the developing rat. In Experiment 1, rats were given pairings of a white-noise conditioned stimulus (CS) and a shock unconditioned stimulus (US) on postnatal day (P)16. An extinction session, where the CS was presented without the US, occurred on P17 or P24. Prior to extinction rats were injected with MK-801 or saline. All rats were tested for fear of the CS on P25, while drug free. Saline-treated rats exhibited good retention of extinction whether they were extinguished at P17 or P25. Rats treated with MK-801 exhibited impaired extinction retention but only if extinction occurred on P24. These findings show that extinction is NMDAr-dependent at P24 but NMDAr-independent at P17. Experiment 2 further examined the involvement of NMDA receptors in extinction at different stages of development by taking advantage of a finding from several recent studies on re-extinction. These studies have shown, in adult rats, a transition from NMDAr-dependent extinction to NMDAr-independent re-extinction. That is, if rats are trained, extinguished, re-trained to the same CS, and then extinguished again (i.e., re-extinction), then NMDA receptors are not required for extinction the second time. In Experiment 2, rats were trained to fear the CS at P16; this fear was extinguished at either P17 or P24. All rats were then re-trained to fear the CS at P25, re-extinguished at P26, and tested at P27. Prior to re-extinction, rats were injected with MK-801 or saline. Rats initially extinguished at P24, an age where NMDA receptors are involved in extinction, exhibited the transition to an NMDAr-independent re-extinction process. In contrast, rats initially extinguished at P17, an age where NMDA receptors are not involved in extinction, did not (i.e., these rats still exhibited an impairment in extinction retention if given MK-801 prior to re-extinction). Taken together, these findings demonstrate that a qualitatively different system mediates extinction early in life. [Copyright &y& Elsevier]

Abstract: Just as fear can be learned, it can also be inhibited. The most common way of reducing learned fear is through extinction, where the conditioned stimulus (CS) previously paired with an aversive unconditioned stimulus (US) is repeatedly presented on its own. Another, much less commonly studied, way to inhibit learned fear is by habituating, or devaluing, the US. In this procedure, fear responding to a CS is reduced by repeatedly presenting the US in the absence of the CS following the conditioning phase. The purpose of the present study was to directly compare the effects of US habituation and CS extinction on a learned fear response (freezing). Experiment 1 demonstrated that US habituation given either after (Experiment 1A) or before (Experiment 1B) fear conditioning reduced freezing to the CS at test. We then showed that the reduction in freezing resulting from either US habituation or CS extinction was context-specific (i.e., a change in context led to a renewal of the learned fear response; Experiment 2) and, furthermore, was attenuated when a pre-test shock was given (i.e., reinstatement of fear was observed in both cases; Experiment 3). Finally, Experiment 4 demonstrated that an injection of the NMDA antagonist MK-801 prior to US habituation impaired long-term retention of the learning that takes place during this procedure. Together, these results suggest that the decrement in conditioned fear responses produced by US habituation and CS extinction could rely on overlapping processes. [Copyright &y& Elsevier]

Abstract: Recent studies suggest that extinction may involve different processes across development. The present study attempted to further clarify the nature of the processes involved in extinction of Pavlovian conditioned fear across development by employing a compound test procedure in rats. In this procedure, a comparison is made between the responding elicited by individual versus compound presentations of two extinguished CSs. The first two experiments showed that PND25 rats exhibit reliable compound summation (i.e., greater responding to the compound than to the individual CSs), at least when a between-subjects design is employed, but that PND18 rats do not exhibit such an effect. Experiment 3 demonstrated that this developmental difference in compound summation was not simply due to PND 25 rats acquiring a stronger CS–US association in the conditioning phase, and Experiment 4 showed that the results cannot be explained in terms of developmental differences in how the compound stimulus is processed at a perceptual level at test. Taken together, these results suggest that there are developmental differences in the amount of associative change that occurs to CSs during extinction training. [Copyright &y& Elsevier]

Abstract: Extinction has mostly been studied in conditioning paradigms, more sparsely in spatial tasks, and never as a function of the age of a spatial memory. Using rats, we compared the time-course of extinction of a recent (5 days) vs. remote (25 days) spatial memory in a water maze, over three probe trials. When the trials were set 24h apart, performance in the remote memory group was significantly worse on the first probe trial and significantly better on the third probe trial, as compared to the recent memory group, thereby showing differences between cognitive operations underlying recent vs. remote memory extinction. In contrast, when trials were given consecutively, both groups showed a similar profile of extinction. Furthermore, in a room with overly-salient cues providing a strong remote memory trace, no difference between groups was observed when the spaced extinction paradigm was used. These results might be related to a balance between reconsolidation and extinction processes occurring after a first retrieval experience, of which the outcome may depend on the extinction protocol, and on the age and strength of a memory. [Copyright &y& Elsevier]