Prefrontal cortex VAMP1 gene network moderates the effect of the early environment on cognitive flexibility in children.

During development, genetic and environmental factors interact to modify specific phenotypes. Both in humans and in animal models, early adversities influence cognitive flexibility, an important brain function related to behavioral adaptation to variations in the environment. Abnormalities in cognitive functions are related to changes in synaptic connectivity in the prefrontal cortex (PFC), and altered levels of synaptic proteins. We investigated if individual variations in the expression of a network of genes co-expressed with the synaptic protein VAMP1 in the prefrontal cortex moderate the effect of early environmental quality on the performance of children in cognitive flexibility tasks. Genes overexpressed in early childhood and co-expressed with the VAMP1 gene in the PFC were selected for study. SNPs from these genes (post-clumping) were compiled in an expression-based polygenic score (PFC-ePRS-VAMP1). We evaluated cognitive performance of the 4 years-old children in two cohorts using similar cognitive flexibility tasks. In the first cohort (MAVAN) we utilized two CANTAB tasks: (a) the Intra-/Extra-dimensional Set Shift (IED) task, and (b) the Spatial Working Memory (SWM) task. In the second cohort, GUSTO, we used the Dimensional Change Card Sort (DCCS) task. The results show that in 4 years-old children, the PFC-ePRS-VAMP1 network moderates responsiveness to the effects of early adversities on the performance in attentional flexibility tests. The same result was observed for a spatial working memory task. Compared to attentional flexibility, reversal learning showed opposite effects of the environment, as moderated by the ePRS. A parallel ICA analysis was performed to identify relationships between whole-brain voxel based gray matter density and SNPs that comprise the PFC-ePRS-VAMP1. The early environment predicts differences in gray matter content in regions such as prefrontal and temporal cortices, significantly associated with a genetic component related to Wnt signaling pathways. Our data suggest that a network of genes co-expressed with VAMP1 in the PFC moderates the influence of early environment on cognitive function in children.

Synaptic consolidation as a temporally variable process: Uncovering the parameters modulating its time-course.

Memories are not instantly created in the brain, requiring a gradual stabilization process called consolidation to be stored and persist in a long-lasting manner. However, little is known whether this time-dependent process is dynamic or static, and the factors that might modulate it. Here, we hypothesized that the time-course of consolidation could be affected by specific learning parameters, changing the time window where memory is susceptible to retroactive interference. In the rodent contextual fear conditioning paradigm, we compared weak and strong training protocols and found that in the latter memory is susceptible to post-training hippocampal inactivation for a shorter period of time. The accelerated consolidation process triggered by the strong training was mediated by glucocorticoids, since this effect was blocked by pre-training administration of metyrapone. In addition, we found that pre-exposure to the training context also accelerates fear memory consolidation. Hence, our results demonstrate that the time window in which memory is susceptible to post-training interferences varies depending on fear conditioning intensity and contextual familiarity. We propose that the time-course of memory consolidation is dynamic, being directly affected by attributes of the learning experiences.

Sequential learning during contextual fear conditioning guides the rate of systems consolidation: Implications for consolidation of multiple memory traces.

Systems consolidation has been described as a time-dependent reorganization process involving the neocortical and hippocampal networks underlying memory storage and retrieval. Previous studies of our lab were able to demonstrate that systems consolidation is a dynamic process, rather than a merely passive, time-dependent phenomenon. Here, we studied the influence of sequential learning in contextual fear conditioning (CFC) with different training intensities in the time-course of hippocampal dependency and contextual specificity. We found that sequential learning with high-intensity shocks during CFC induces generalization of the first learning (context A) and maintains contextual specificity of the second learning (context B) 15 days after acquisition. Moreover, subsequent experiences reorganize brain structures involved in retrieval, accelerating the involvement of cortical structures and diminishing the hippocampal participation. Exposure to original context before novelty seems to only induce context specificity in hippocampal-dependent memories. We propose that systems consolidation could be considered a potential biological mechanism for reducing possible interferences between similar memory traces. © 2017 Wiley Periodicals, Inc.

Reconsolidation-induced rescue of a remote fear memory blocked by an early cortical inhibition: Involvement of the anterior cingulate cortex and the mediation by the thalamic nucleus reuniens.

Systems consolidation is a time-dependent reorganization process involving neocortical and hippocampal networks underlying memory storage and retrieval. The involvement of the hippocampus during acquisition is well described; however we know much less about the concomitant contribution of cortical activity levels to the formation of stable remote memories. Here, after a reversible pharmacological inhibition of the anterior cingulate cortex (ACC) during the acquisition of a contextual fear conditioning, retrieval of both recent and remote memories were impaired, an effect that was reverted by a single memory reactivation session 48 h after training, through a destabilization-dependent mechanism interpreted as reconsolidation, that restored the normal course of systems consolidation in order to rescue a remote memory. Next we have shown that the integrity of both the anterior cingulate cortex and the thalamic nucleus reuniens (RE) were required for this reactivation-induced memory rescue. Because lidocaine infused into the RE inhibited LTP induction in the CA1-anterior cingulate cortex pathways, it seems that RE is a necessary component of the circuit underlying systems consolidation, mediating communication between dorsal hippocampus and cortical areas. To our notice, this is the first demonstration of the rescue of remote memories disrupted by ACC inhibition during acquisition, via a reconsolidation-driven mechanism. We have also shown the importance of RE to ensure the interconnection among brain areas that collectively seem to control the natural course of systems consolidation and allow the persistence of relevant emotional engrams. © 2017 Wiley Periodicals, Inc.

The dynamic nature of systems consolidation: Stress during learning as a switch guiding the rate of the hippocampal dependency and memory quality.

Memory fades over time, becoming more schematic or abstract. The loss of contextual detail in memory may reflect a time-dependent change in the brain structures supporting memory. It has been well established that contextual fear memory relies on the hippocampus for expression shortly after learning, but it becomes hippocampus-independent at a later time point, a process called systems consolidation. This time-dependent process correlates with the loss of memory precision. Here, we investigated whether training intensity predicts the gradual decay of hippocampal dependency to retrieve memory, and the quality of the contextual memory representation over time. We have found that training intensity modulates the progressive decay of hippocampal dependency and memory precision. Strong training intensity accelerates systems consolidation and memory generalization in a remarkable timeframe match. The mechanisms underpinning such process are triggered by glucocorticoid and noradrenaline released during training. These results suggest that the stress levels during emotional learning act as a switch, determining the fate of memory quality. Moderate stress will create a detailed memory, whereas a highly stressful training will develop a generic gist-like memory.

Involvement of the infralimbic cortex and CA1 hippocampal area in reconsolidation of a contextual fear memory through CB1 receptors: Effects of CP55,940.

The endocannabinoid system (ECS) has a pivotal role in different cognitive functions such as learning and memory. Recent evidence confirm the involvement of the hippocampal CB1 receptors in the modulation of both memory extinction and reconsolidation processes in different brain areas, but few studies focused on the infralimbic cortex, another important cognitive area. Here, we infused the cannabinoid agonist CP55,940 either into the infralimbic cortex (IL) or the CA1 area of the dorsal hippocampus (HPC) of adult male Wistar rats immediately after a short (3min) reactivation session, known to labilize a previously consolidated memory trace in order to allow its reconsolidation with some modification. In both structures, the treatment was able to disrupt reconsolidation in a relatively long lasting way, reducing the freezing response. To our notice, this is the first demonstration of ECS involvement in reconsolidation in the Infralimbic Cortex. Despite poorly discriminative between CB1 and CB2 receptors, CP55,940 is a potent agent, and these results suggest that a similar CB1-dependent circuitry is at work both in HPC and in the IL during memory reconsolidation.

Amnesia of inhibitory avoidance by scopolamine is overcome by previous open-field exposure.

The muscarinic cholinergic receptor (MAChR) blockade with scopolamine either extended or restricted to the hippocampus, before or after training in inhibitory avoidance (IA) caused anterograde or retrograde amnesia, respectively, in the rat, because there was no long-term memory (LTM) expression. Adult Wistar rats previously exposed to one or two open-field (OF) sessions of 3 min each (habituated), behaved as control animals after a weak though over-threshold training in IA. However, after OF exposure, IA LTM was formed and expressed in spite of an extensive or restricted to the hippocampus MAChR blockade. It was reported that during and after OF exposure and reexposure there was an increase in both hippocampal and cortical ACh release that would contribute to "prime the substrate," e.g., by lowering the synaptic threshold for plasticity, leading to LTM consolidation. In the frame of the "synaptic tagging and capture" hypothesis, plasticity-related proteins synthesized during/after the previous OF could facilitate synaptic plasticity for IA in the same structure. However, IA anterograde amnesia by hippocampal protein synthesis inhibition with anisomycin was also prevented by two OF exposures, strongly suggesting that there would be alternative interpretations for the role of protein synthesis in memory formation and that another structure could also be involved in this "OF effect."

Reconsolidation may incorporate state-dependency into previously consolidated memories.

Some memories enter into a labile state after retrieval, requiring reconsolidation in order to persist. One functional role of memory reconsolidation is the updating of existing memories. There are reports suggesting that reconsolidation can be modulated by a particular endogenous process taking place concomitantly to its natural course, such as water or sleep deprivation. Here, we investigated whether an endogenous process activated during a natural/physiological experience, or a pharmacological intervention, can also contribute to memory content updating. Using the contextual fear conditioning paradigm in rats, we found that the endogenous content of an aversive memory can be updated during its reconsolidation incorporating consequences of natural events such as water deprivation, transforming a previously stored memory into a state-dependent one. This updating seems to be mediated by the activation of angiotensin AT1 receptors in the dorsal hippocampus and local infusion of human angiotensin II (ANGII) was shown to mimic the water deprivation effects on memory reconsolidation. Systemic morphine injection was also able to turn a previously acquired experience into a state-dependent memory, reproducing the very same effects obtained by water deprivation or local angiotensin II infusion, and suggesting that other state-dependent-inducing protocols would also be able to contribute to memory updating. These findings trigger new insights about the influence of ordinary daily life events upon memory in its continuing reconstruction, adding the realm of reconsolidation to the classical view of endogenous modulation of consolidation.

Memory reconsolidation allows the consolidation of a concomitant weak learning through a synaptic tagging and capture mechanism.

Motivated by the synaptic tagging and capture (STC) hypothesis, it was recently shown that a weak learning, only able to produce short-term memory (STM), can succeed in establishing long-term memory (LTM) with a concomitant, stronger experience. This is consistent with the capture, by the first-tagged event, of the so-called plasticity-related proteins (PRPs) provided by the second one. Here, we describe how a concomitant session of reactivation/reconsolidation of a stronger, contextual fear conditioning (CFC) memory, allowed LTM to result from a weak spatial object recognition (wSOR) training. Consistent with an STC process, the effect was observed only during a critical time window and was dependent on the CFC reconsolidation-related protein synthesis. Retrieval by itself (without reconsolidation) did not have the same promoting effect. We also found that the inactivation of the NMDA receptor by AP5 prevented wSOR training to receive this support of CFC reconsolidation (supposedly through the production of PRPs), which may be the equivalent of blocking the setting of a learning tag in the dorsal CA1 region for that task. Furthermore, either a Water Maze reconsolidation, or a CFC extinction session, allowed the formation of wSOR-LTM. These results suggest for the first time that a reconsolidation session can promote the consolidation of a concomitant weak learning through a probable STC mechanism. These findings allow new insights concerning the influence of reconsolidation in the acquisition of memories of otherwise unrelated events during daily life situations.

Long-lasting effects of maternal separation on an animal model of post-traumatic stress disorder: effects on memory and hippocampal oxidative stress.

Adverse early life events, such as periodic maternal separation, may alter the normal pattern of brain development and subsequently the vulnerability to a variety of mental disorders in adulthood. Patients with a history of early adversities show higher frequency of post-traumatic stress disorder (PTSD). This study was undertaken to verify if repeated long-term separation of pups from dams would affect memory and oxidative stress parameters after exposure to an animal model of PTSD. Nests of Wistar rats were divided into intact and subjected to maternal separation (incubator at 32°C, 3 h/day) during post-natal days 1-10. When adults, the animals were subdivided into exposed or not to a PTSD model consisting of exposure to inescapable footshock, followed by situational reminders. One month after exposure to the shock, the animals were exposed to a memory task (Morris water maze) and another month later animals were sacrificed and DNA breaks and antioxidant enzymes activities were measured in the hippocampus. Rats exposed to shock or maternal separation plus shock showed long-lasting effects on spatial memory, spending more time in the opposite quadrant of the water maze. This effect was higher in animals subjected to both maternal separation and shock. Both shock and maternal separation induced a higher score of DNA breaks in the hippocampus. No differences were observed on antioxidant enzymes activities. In conclusion, periodic maternal separation may increase the susceptibility to the effects of a stressor applied in adulthood on performance in the water maze. Increased DNA breaks in hippocampus was induced by both, maternal separation and exposure to shock.

Adolescent female rats undergo full systems consolidation of an aversive memory, while males of the same age fail to discriminate contexts.

Generalization is an adaptive process that allows animals to deal with threatening circumstances similar to prior experiences. Systems consolidation is a time-dependent process in which memory loses it precision concomitantly with reorganizational changes in the brain structures that support memory retrieval. In this, memory becomes progressively independent from the hippocampus and more reliant on cortical structures. Generalization, however, may take place much faster in adult animals depending on the presence of sex hormones. Notwithstanding its relevance, there are few studies on sex differences in memory modulation. Here, a contextual fear discrimination task was used to investigate the onset of memory generalization and hippocampus-independence in adolescent male and female rats (P42-49). Subjects were tested 2, 7, 14, 21, or 28 days after training, with females showing memory generalization from day 21 on, whereas males surprisingly unable to discriminate contexts at any time. Ovariectomized (OVX) females, however, displayed an early onset of generalization. Consistently, pretest pharmacological blocking of dorsal hippocampus was able to impair memory retrieval in females, but not in males, which indicate that precise memory is dependent on the hippocampus. To our notice, this is the first report of a memory systems consolidation process-expressed in its two dimensions, neuroanatomical and qualitative-in adolescent female rats, and one that can also be accelerated by the reduction of sex hormones through ovariectomy. It is also unprecedented that despite adolescent male rats being able to remember fear learning, they did not discriminate contexts with any precision. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Conflict Test Battery for Studying the Act of Facing Threats in Pursuit of Rewards.

Survival depends on the ability of animals to avoid threats and approach rewards. Traditionally, these two opposing motivational systems have been studied separately. In nature, however, they regularly compete for the control of behavior. When threat- and reward-eliciting stimuli (learned or unlearned) occur simultaneously, a motivational conflict emerges that challenges individuals to weigh available options and execute a single behavioral response (avoid or approach). Most previous animal models using approach/avoidance conflicts have often focused on the ability to avoid threats by forgoing or delaying the opportunity to obtain rewards. In contrast, behavioral tasks designed to capitalize on the ability to actively choose to execute approach behaviors despite threats are scarce. Thus, we developed a behavioral test battery composed of three conflict tasks to directly study rats confronting threats to obtain rewards guided by innate and conditioned cues. One conflict task involves crossing a potentially electrified grid to obtain food on the opposite end of a straight alley, the second task is based on the step-down threat avoidance paradigm, and the third one is a modified version of the open field test. We used diazepam to pharmacologically validate conflict behaviors in our tasks. We found that, regardless of whether competing stimuli were conditioned or innate, a low diazepam dose decreased risk assessment and facilitated taking action to obtain rewards in the face of threats during conflict, without affecting choice behavior when there was no conflict involved. Using this pharmacologically validated test battery of ethologically designed innate/learned conflict tasks could help understand the fundamental brain mechanisms underlying the ability to confront threats to achieve goals.

Muscarinic inhibition of hippocampal and striatal adenylyl cyclase is mainly due to the M(4) receptor.

The five muscarinic acetylcholine receptors (M(1)-M(5)) are differentially expressed in the brain. M(2) and M(4) are coupled to inhibition of stimulated adenylyl cyclase, while M(1), M(3) and M(5) are mainly coupled to the phosphoinositide pathway. We studied the muscarinic receptor regulation of adenylyl cyclase activity in the rat hippocampus, compared to the striatum and amygdala. Basal and forskolin-stimulated adenylyl cyclase activity was higher in the striatum but the muscarinic inhibition was much lower. Highly selective muscarinic toxins MT1 and MT2-affinity order M(1) > or = M(4) >> others-and MT3-highly selective M(4) antagonist-did not show significant effects on basal or forskolin-stimulated cyclic AMP production but, like scopolamine, counteracted oxotremorine inhibition. Since MTs have negligible affinity for M(2), M(4) would be the main subtype responsible for muscarinic inhibition of forskolin-stimulated enzyme. Dopamine stimulated a small fraction of the enzyme (3.1% in striatum, 1.3% in the hippocampus). Since MT3 fully blocked muscarinic inhibition of dopamine-stimulated enzyme, M(4) receptor would be responsible for this regulation.

Metaplasticity contributes to memory formation in the hippocampus.

Prior learning can modify the plasticity mechanisms that are used to encode new information. For example, NMDA receptor (NMDAR) activation is typically required for new spatial and contextual learning in the hippocampus. However, once animals have acquired this information, they can learn new tasks even if NMDARs are blocked. This finding suggests that behavioral training alters cellular plasticity mechanisms such that NMDARs are not required for subsequent learning. The mechanisms that mediate this change are currently unknown. To address this issue, we tested the idea that changes in intrinsic excitability (induced by learning) facilitate the encoding of new memories via metabotropic glutamate receptor (mGluR) activation. Consistent with this hypothesis, hippocampal neurons exhibited increases in intrinsic excitability after learning that lasted for several days. This increase was selective and only observed in neurons that were activated by the learning event. When animals were trained on a new task during this period, excitable neurons were reactivated and memory formation required the activation of mGluRs instead of NMDARs. These data suggest that increases in intrinsic excitability may serve as a metaplastic mechanism for memory formation.

Differential role of the hippocampal endocannabinoid system in the memory consolidation and retrieval mechanisms.

CB1 cannabinoid receptors are abundantly expressed in the brain, with large concentrations present in the hippocampus, a brain structure essential for memory processing. In the present study, we have investigated the possible modulatory role of the endocannabinoid system in the dorsal hippocampus upon the different phases of memory processing of an aversive task. AM251, a selective antagonist of CB1 receptors, and anandamide, an endogenous agonist of cannabinoid receptors, were bilaterally infused into the dorsal hippocampus of male Wistar rats either before training, immediately after training, or before test in the step-down inhibitory avoidance (IA) task. Results showed that pre-training infusion of CB1 drugs did not influence the acquisition of the task. In contrast, post-training infusion of the CB1 antagonist disrupted while the antagonist facilitated memory consolidation of IA. The post-training results demonstrate that memory consolidation depends on the integrity of the endocannabinoid system in the CA1 region of the dorsal hippocampus. While we still have no direct proof of endocannabinoids released there after an aversive task such as IA, these results suggests that (a) AM251 acts blocking the binding of endogenously released cannabinoids and (b) exogenously supplemented anandamide may be adding its contribution to the action of the endogenously released pool. Considering our data and the higher density of CB1 receptors present in the GABAergic interneurons, we propose them as the putative target of the endocannabinoid modulation of memory, a hypothesis that needs to be proven. In addition, pre-test infusion of the CB1 receptor antagonist facilitated while infusion of the agonist did not affect memory retrieval of IA. The completely opposite action of the same drug upon memory at the post-training (consolidation) and pre-test (recall) contexts suggests that some durable change took place in the CA1 region during the consolidation process that modified the logical attributes of the pharmacological response, i.e., the drug response changed from memory disruption to memory facilitation. A similar phenomenon was previously described by us in the M4 cholinergic muscarinic subsystem in the hippocampus for the same task (Diehl, F., Fürstenau, L. O., Sanchez, G., Camboim, C., de Oliveira Alvares, L., Lanziotti, V. B., et al. (2007). Facilitatory effect of the intra-hippocampal pretest administration of MT3 in the inhibitory avoidance task. Behavioral Brain Research, 177(2), 227-231), but the biological nature of such change in the local neural circuitry remains to be investigated.

Glial alterations in the hippocampus of rats submitted to ibotenic-induced lesion of the nucleus basalis magnocellularis.

Lesion of the nucleus basalis magnocellularis (nbm) is a suitable approach to study cognitive deficit and behavior alterations involving cholinergic dysfunction, which is associated with the major types of dementia. Cortical astrogliosis also has been described in this model, but it is not clear whether hippocampal astrocytes are activated. In this study, we investigated possible specific astrocyte alterations in the hippocampi of Wistar rats submitted to nbm damage with ibotenic acid, investigating the content and immunohistochemistry of glial fibrillary acidic protein (GFAP), as well as S100B protein content, glutamate uptake and glutamine synthetase activity on the 7th and 28th post-lesion days. Cognitive deficit was confirmed by the step-down inhibitory avoidance task. Interestingly, we found a decrease in GFAP content, S100B content and glutamate uptake activity in the hippocampus on the 28th day after nbm lesion. No alterations were observed in glutamine synthetase activity or in the cerebrospinal fluid S100B content. Although our data suggest caution in the use of nbm lesion with ibotenic acid as a dementia model, it is possible that these alterations could contribute to the cognitive deficit observed in these rats.

HSP70 Facilitates Memory Consolidation of Fear Conditioning through MAPK Pathway in the Hippocampus.

Heat shock proteins of the 70-kDa (HSP70) family are cytoprotective molecular chaperones that are present in neuronal cells and can be induced by a variety of homeostatically stressful situations (not only proteostatic insults), but also by synaptic activity, including learning tasks. Physiological stimuli that induce long-term memory formation are also capable of stimulating the synthesis of HSP70 through the activation of heat shock transcription factor-1 (HSF1). In this study, we investigated the influence of HSP70 on fear memory consolidation and MAPK activity. Male rats were trained in contextual fear conditioning task and HSP70 content was analyzed by western blot in the hippocampus at different time points. We observed rapid and transient elevations in HSP70 60 min following training. Double immunofluorescence with GFAP and HSP72 revealed that astrocytes were not the site for HSP72 induction by CFC training. HSP72 distribution markedly surrounded synapses between Shaffer collateral and CA1 pyramidal cells. Infusion of recombinant HSP70 (hspa1a) into the dorsal hippocampus immediately after training facilitated memory consolidation and enhanced ERK activity while decreasing the activated forms of JNK and p38 in the hippocampus. Blocking endogenous extracellular HSP70 through the administration of specific antibody did not produce any further effect on memory consolidation when applied immediately after training, suggesting that it is indeed acting intracellularly. Induction of HSP70 after fear conditioning is fast and can act as a signaling molecule, modulating MAPK downstream signaling during memory consolidation in the hippocampus, which is crucial for fear memory formation.

Enhancement of extinction memory by pharmacological and behavioral interventions targeted to its reactivation.

Extinction is a process that involves new learning that inhibits the expression of previously acquired memories. Although temporarily effective, extinction does not erase an original fear association. Since the extinction trace tends to fade over time, the original memory can resurge. On the other hand, strengthening effects have been described in several reconsolidation studies using different behavioral and pharmacological manipulations. In order to know whether an extinction memory can be strengthened by reactivation-based interventions in the contextual fear conditioning task, we began by replicating the classic phenomenon of spontaneous recovery to show that brief reexposure sessions can prevent the decay of the extinction trace over time in a long-lasting way. This fear attenuation was shown to depend both on L-type calcium channels and protein synthesis, which suggests a reconsolidation process behind the reactivation-induced strengthening effect. The extinction trace was also susceptible to enhancement by a post-reactivation infusion of a memory-enhancing drug (NaB), which was also able to prevent rapid fear reacquisition (savings). These findings point to new reactivation-based approaches able to strengthen an extinction memory to promote its persistence. The constructive interactions between extinction and reconsolidation may represent a promising novel approach in the realm of fear-related disorder treatments.

Reconsolidation allows fear memory to be updated to a less aversive level through the incorporation of appetitive information.

The capacity to adapt to new situations is one of the most important features of memory. When retrieved, memories may undergo a labile state that is sensitive to modification. This process, called reconsolidation, can lead to memory updating through the integration of new information into a previously consolidated memory background. Thus reconsolidation provides the opportunity to modify an undesired fear memory by updating its emotional valence to a less aversive level. Here we evaluated whether a fear memory can be reinterpreted by the concomitant presentation of an appetitive stimulus during its reactivation, hindering fear expression. We found that memory reactivation in the presence of appetitive stimuli resulted in the suppression of a fear response. In addition, fear expression was not amenable to reinstatement, spontaneous recovery, or rapid reacquisition. Such effect was prevented by either systemic injection of nimodipine or intra-hippocampal infusion of ifenprodil, indicating that memory updating was mediated by a reconsolidation mechanism relying on hippocampal neuronal plasticity. Taken together, this study shows that reconsolidation allows for a 're-signification' of unwanted fear memories through the incorporation of appetitive information. It brings a new promising cognitive approach to treat fear-related disorders.