Search

Addiction can be conceptualised as a disorder of maladaptive learning and memory. Therefore, maladaptive drug memories supporting drug-seeking and relapse behaviours may present novel treatment targets for therapeutic approaches based upon reconsolidation-blockade. It is known that different structures within the limbic corticostriatal system contribute differentially to different types of maladaptive drug memories, including pavlovian associations between environmental cues and contexts with the drug high, and instrumental memories underlying drug-seeking. Here, we review the mechanisms underlying drug memory reconsolidation in the amygdala, striatum, and hippocampus, noting similarities and differences, and opportunities for future research., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Extinction within the reconsolidation window, or 'retrieval-extinction', has received much research interest as a possible technique for targeting the reconsolidation of maladaptive memories with a behavioural intervention. However, it remains to be determined whether the retrieval-extinction effect-a long-term reduction in fear behaviour, which appears resistant to spontaneous recovery, renewal and reinstatement-depends specifically on destabilisation of the original memory (the 'reconsolidation-update' account) or represents facilitation of an extinction memory (the 'extinction-facilitation' account). We propose that comparing the neurotransmitter systems, receptors and intracellular signalling pathways recruited by reconsolidation, extinction and retrieval-extinction will provide a way of distinguishing between these accounts.

Rationale: Animal models of alcohol-seeking are useful for understanding alcohol addiction and for treatment development, but throughput in these models is limited by the extensive pretraining required to overcome the aversive taste of ethanol. Work by Augier et al. (Psychopharmacology 231: 4561-4568, 2014) indicates that Wistar rats will self-administer alcohol without water deprivation, exposure to sweetened ethanol solutions or intermittent access to ethanol., Objectives and Methods: We sought to replicate and extend the work of Augier et al. by comparing the acquisition of instrumental self-administration of ethanol in Lister-Hooded rats that had been previously saccharin faded (SF group) or not (NSF group). We also aimed to determine whether NMDA receptor antagonism with MK-801, given at memory reactivation, reduced subsequent ethanol-seeking behaviour in both groups of animals. Finally, we assessed the ethanol preference of SF and NSF rats using the two-bottle choice procedure., Results: Both SF and NSF groups acquired instrumental self-administration of ethanol, though SF rats consumed fewer of the earned reinforcers. MK-801, given at memory reactivation, had different effects on NSF and SF rats: impairing the capacity of an ethanol-paired conditioned stimulus (CS) to support reinstatement in NSF rats, and enhancing it in SF rats. Finally, neither SF nor NSF rats showed a preference for ethanol., Conclusions: Our data support those of Augier et al. (Psychopharmacology 231: 4561-4568, 2014) that pretraining is unnecessary for rats to acquire instrumental self-administration of ethanol. Indeed, saccharin fading may produce a weaker memory that extinguishes more readily, thus accounting for the different effects of MK-801 on SF and NSF rats.

Fully consolidated fear memories can be maintained or inhibited by retrieval-dependent mechanisms depending on the degree of re-exposure to fear cues. Short exposures promote memory maintenance through reconsolidation, and long exposures promote inhibition through extinction. Little is known about the neural mechanisms by which increasing cue exposure overrides reconsolidation and instead triggers extinction. Using auditory fear conditioning in male rats, we analyzed the role of a molecular mechanism common to reconsolidation and extinction of fear, ERK1/2 activation within the basolateral amygdala (BLA), after intermediate conditioned stimulus (CS) exposure events. We show that an intermediate re-exposure (four CS presentations) failed to activate ERK1/2 in the BLA, suggesting the absence of reconsolidation or extinction mechanisms. Supporting this hypothesis, pharmacologically inhibiting the BLA ERK1/2-dependent signaling pathway in conjunction with four CS presentations had no effect on fear expression, and the NMDA receptor partial agonist d-cycloserine, which enhanced extinction and ERK1/2 activation in partial extinction protocols (seven CSs), had no behavioral or molecular effect when given in association with four CS presentations. These molecular and behavioral data reveal a novel retrieval-dependent memory phase occurring along the transition between conditioned fear maintenance and inhibition. CS-dependent molecular events in the BLA may arrest reconsolidation intracellular signaling mechanism in an extinction-independent manner. These findings are critical for understanding the molecular underpinnings of fear memory persistence after retrieval both in health and disease. SIGNIFICANCE STATEMENT Consolidated fear memories can be altered by retrieval-dependent mechanisms. Whereas a brief conditioned stimulus (CS) exposure promotes fear memory maintenance through reconsolidation, a prolonged exposure engages extinction and fear inhibition. The nature of this transition and whether an intermediate degree of CS exposure engages reconsolidation or extinction is unknown. We show that an intermediate cue exposure session (four CSs) produces the arrest of ERK1/2 activation in the basolateral amygdala, a common mechanism for reconsolidation and extinction. Amnestic or hypermnestic treatments given in association with four CSs had no behavioral or molecular effects, respectively. This evidence reveals a novel retrieval-dependent memory phase. Intermediate degrees of CS exposure fail to trigger reconsolidation or extinction, leaving the original memory in an insensitive state., (Copyright © 2018 the authors 0270-6474/18/383199-09$15.00/0.)

Under certain conditions pavlovian memories undergo reconsolidation, whereby the reactivated memory can be disrupted by manipulations such as knockdown of zif268. For instrumental memories, reconsolidation disruption is less well established. Our previous, preliminary data identified that there was an increase in Zif268 in the posterior dorsolateral striatum (pDLS) after expression of an instrumental habit-like 'response' memory, but not an instrumental goal-directed 'place' memory on a T-maze task. Here, the requirement for Zif268 in the reconsolidation of a response memory was tested by knockdown of Zif268, using antisense oligodeoxynucleotide infusion into the pDLS, at memory reactivation. Zif268 knockdown reduced response memory expression 72H, but not 7d later. Western blotting revealed a non-significant increase in Zif268 in the pDLS in rats using response memories, but there was no change in Zif268 expression in the hippocampus following retrieval of a place memory. Zif268 expression increased in the basolateral amygdala after memory reactivation whether a response or place strategy was used during reactivation. We propose that Zif268 expression in the basolateral amygdala may be linked to prediction error, generated by the absence of reward at reactivation. Taken together, these results suggest a complex role for Zif268 in the maintenance of instrumental memories., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

We have investigated the requirement for signaling at CB1 receptors in the reconsolidation of a previously consolidated auditory fear memory, by infusing the CB1 receptor antagonist AM251, or the FAAH inhibitor URB597, directly into the basolateral amygdala (BLA) in conjunction with memory reactivation. AM251 disrupted memory restabilization, but only when administered after reactivation. URB597 produced a small, transient enhancement of memory restabilization when administered after reactivation. The amnestic effect of AM251 was rescued by coadministration of the GABAA receptor antagonist bicuculline at reactivation, indicating that the disruption of reconsolidation was mediated by altered GABAergic transmission in the BLA. These data show that the endocannabinoid system in the BLA is an important modulator of fear memory reconsolidation and that its effects on memory are mediated by an interaction with the GABAergic system. Thus, targeting the endocannabinoid system may have therapeutic potential to reduce the impact of maladaptive memories in neuropsychiatric disorders such as posttraumatic stress disorder.

Memory persistence is critically influenced by retrieval. In rats, a single presentation of a conditioned fear stimulus induces memory reconsolidation and fear memory persistence, while repeated fear cue presentations result in loss of fear through extinction. These two opposite behavioral outcomes are operationally linked by the number of cue presentations at memory retrieval. However, the behavioral properties and mechanistic determinants of the transition have not yet been explored; in particular, whether reconsolidation and extinction processes coexist or are mutually exclusive, depending on the exposure to non-reinforced retrieval events. We characterized both behaviorally and molecularly the transition from reconsolidation to extinction of conditioned fear and showed that an increase in calcineurin (CaN) in the basolateral amygdala (BLA) supports the shift from fear maintenance to fear inhibition. Gradually increasing the extent of retrieval induces a gradual decrease in freezing responses to the conditioned stimulus and a gradual increase in amygdala CaN level. This newly synthesized CaN is required for the extinction, but not the reconsolidation, of conditioned fear. During the transition from reconsolidation to extinction, we have revealed an insensitive state of the fear memory where NMDA-type glutamate receptor agonist and antagonist drugs are unable either to modulate CaN levels in the BLA or alter the reconsolidation or extinction processes. Together, our data indicate both that reconsolidation and extinction are mutually exclusive processes and also reveal the presence of a transitional, or "limbo," state of the original memory between these two alternative outcomes of fear memory retrieval, when neither process is engaged.

Delusions are the persistent and often bizarre beliefs that characterise psychosis. Previous studies have suggested that their emergence may be explained by disturbances in prediction error-dependent learning. Here we set up complementary studies in order to examine whether such a disturbance also modulates memory reconsolidation and hence explains their remarkable persistence. First, we quantified individual brain responses to prediction error in a causal learning task in 18 human subjects (8 female). Next, a placebo-controlled within-subjects study of the impact of ketamine was set up on the same individuals. We determined the influence of this NMDA receptor antagonist (previously shown to induce aberrant prediction error signal and lead to transient alterations in perception and belief) on the evolution of a fear memory over a 72 hour period: they initially underwent Pavlovian fear conditioning; 24 hours later, during ketamine or placebo administration, the conditioned stimulus (CS) was presented once, without reinforcement; memory strength was then tested again 24 hours later. Re-presentation of the CS under ketamine led to a stronger subsequent memory than under placebo. Moreover, the degree of strengthening correlated with individual vulnerability to ketamine's psychotogenic effects and with prediction error brain signal. This finding was partially replicated in an independent sample with an appetitive learning procedure (in 8 human subjects, 4 female). These results suggest a link between altered prediction error, memory strength and psychosis. They point to a core disruption that may explain not only the emergence of delusional beliefs but also their persistence.

Signaling at NMDA receptors (NMDARs) is known to be important for memory reconsolidation, but while most studies show that NMDAR antagonists prevent memory restabilization and produce amnesia, others have shown that GluN2B-selective NMDAR antagonists prevent memory destabilization, protecting the memory. These apparently paradoxical, conflicting data provide an opportunity to define more precisely the requirement for different NMDAR subtypes in the mechanisms underlying memory reconsolidation and to further understand the contribution of glutamatergic signaling to this process. Here, using rats with fully consolidated pavlovian auditory fear memories, we demonstrate a double dissociation in the requirement for GluN2B-containing and GluN2A-containing NMDARs within the basolateral amygdala in the memory destabilization and restabilization processes, respectively. We further show a double dissociation in the mechanisms underlying memory retrieval and memory destabilization, since AMPAR antagonism prevented memory retrieval while still allowing the destabilization process to occur. These data demonstrate that glutamatergic signaling mechanisms within the basolateral amygdala differentially and dissociably mediate the retrieval, destabilization, and restabilization of previously consolidated fear memories.

Addiction is a chronic, relapsing disorder, characterised by the long-term propensity of addicted individuals to relapse. A major factor that obstructs the attainment of abstinence is the persistence of maladaptive drug-associated memories, which can maintain drug-seeking and taking behaviour and promote unconscious relapse of these habits. Thus, addiction can be conceptualised as a disorder of aberrant learning of the formation of strong instrumental memories linking actions to drug-seeking and taking outcomes that ultimately are expressed as persistent stimulus-response habits; of previously neutral environmental stimuli that become associated with drug highs (and/or withdrawal states) through pavlovian conditioning, and of the subsequent interactions between pavlovian and instrumental memories to influence relapse behaviour. Understanding the psychological, neurobiological and molecular basis of these drug memories may produce new methods of pro-abstinence, anti-relapse treatments for addiction., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Memory reconsolidation is the process by which memories, destabilised at retrieval, require restabilisation to persist in the brain. It has been demonstrated that even old, well-established memories require reconsolidation following retrieval; therefore, memory reconsolidation could potentially be exploited to disrupt, or even erase, aberrant memories that underlie psychiatric disorders, thereby providing a novel therapeutic target. Drug addiction is one such disorder; it is both chronic and relapsing, and one prominent risk factor for a relapse episode is the presentation of environmental cues that have previously been associated with drugs of abuse. This 'cue-induced relapse' can be accounted for in psychological terms by reinforcing memories of the pavlovian association between the cue and the drug, which can thus influence behaviour through at least three psychologically and neurobiologically dissociable mechanisms: conditioned reinforcement, conditioned approach and conditioned motivation. As each of these psychological processes could contribute to the resumption of drug-seeking following abstinence, it is important to develop treatments that can reduce drug-seeking re-established via influences on each or all of these pavlovian processes, in order to minimise the risk of a subsequent relapse. Investigation of the memory reconsolidation mechanisms of the memories underlying conditioned reinforcement, conditioned approach and conditioned motivation indicate that they depend upon different neurochemical systems, including the glutamatergic and adrenergic systems within limbic corticostriatal circuitry. We also discuss here the subsequent translation to the clinic of this preclinical work.

The amygdala has long been considered a primary locus in mediating the effects of previously drug-associated stimuli on subsequent drug-seeking behavior, and the NMDA subtype of glutamate receptor within the amygdala is important for the consolidation of associations between environmental conditioned stimuli and the effects of addictive drugs. Here we demonstrate that amygdala NMDA receptors are also necessary for the reconsolidation of drug-associated memories. Using a behavioral task that specifically measures the conditioned reinforcing properties of a previously drug-paired stimulus, we show that infusion of the NMDA receptor antagonist D(-)-2-amino-5-phosphonopentanoic acid (D-APV) into the basolateral amygdala before a memory reactivation session disrupted the drug-associated memory and abolished subsequent instrumental responding for conditioned reinforcement. This effect was memory reactivation dependent, and the memory deficit persisted for at least 4 weeks. In contrast, infusion of d-APV immediately after the memory reactivation session had no effect on subsequent responding for conditioned reinforcement, indicating that NMDA receptors have a temporally limited role in the reconsolidation process. Furthermore, in molecular studies, we show that the reconsolidation-impairing effect of D-APV is correlated with downstream reductions in expression of the plasticity-related immediate early gene, zif268. We also demonstrate that systemic antagonism of NMDA receptors with MK-801 [(+)-5-methyl-10,11-dihydro-SH-dibenzo[a,d]cyclohepten-5,10-imine maleate] before memory reactivation subsequently reduced previously acquired instrumental drug-seeking behavior that depends on drug-associated cues acting as conditioned reinforcers. These data suggest that drugs modulating glutamatergic transmission at the NMDA receptor may be useful in the future treatment of relapse prevention in drug addiction through memory reconsolidation blockade.

We have investigated the neurochemical mechanisms of memory reconsolidation and, in particular, the functional requirement for intracellular mechanisms initiated by beta-adrenergic signaling. We show that propranolol, given in conjunction with a memory reactivation session, can specifically disrupt the conditioned reinforcing properties of a previously appetitively reinforced conditioned stimulus (CS), whether the stimulus had been associated with self-administered cocaine or with sucrose. These data show that memories for both drug and nondrug CS-US associations are dependent on beta-adrenergic receptor-mediated signaling for their reconsolidation, with implications for the potential development of a novel treatment for drug addiction and some forms of obesity.

NMDA receptors are important for the acquisition, reconsolidation, and extinction of memories. NMDA receptor antagonists impair these memory processes, whereas the partial agonist D-cycloserine (DCS) potentiates both learning and extinction. Here, we used DCS and the noncompetitive NMDA receptor antagonist (+)-5-methyl-10,11-dihydro-SH-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) to investigate the effects of enhancing and blocking NMDA receptor-mediated glutamatergic transmission on the reconsolidation and extinction of a conditioned fear memory. Either long extinction training or short memory reactivation sessions were used to preferentially engage extinction and reconsolidation processes, respectively. MK-801 blocked extinction to maintain high levels of conditioned freezing, and DCS potentiated extinction to reduce freezing, when they were administered before a long extinction training session. However, the opposite behavioral outcome was observed when the brief memory reactivation session was used: MK-801 administration impaired, whereas DCS increased, freezing, likely reflecting impairment and enhancement of reconsolidation, respectively. Finally, by using localized intracerebral infusions, we showed that the basolateral amygdala is a primary locus of action of systemically administered DCS. Thus, intrabasolateral amygdala DCS potentiated both the extinction and the reconsolidation of fear conditioning, depending on the length of the extinction/memory reactivation session. Therefore, memory reconsolidation can be both disrupted and enhanced, and extinction can be both potentiated and impaired, either to reduce or increase conditioned fear. These results have important implications for the use of reconsolidation blockade and potentiation of extinction as treatment strategies for maladaptive memory disorders.

Long-lasting vulnerability to drug cue-induced relapse to a drug-taking habit is a major challenge to the treatment of drug addiction. Here we show that blockade of drug memory reconsolidation, through infusion of Zif268 antisense oligodeoxynucleotides into the basolateral amygdala shortly before reexposure to a cocaine-associated stimulus but not simply to the training context, severely impaired subsequently cue-maintained cocaine seeking under a second-order schedule of reinforcement and abolished cue-induced reinstatement of and relapse to cocaine seeking. This reduction in relapse after disrupted memory reconsolidation was not only seen after several hundred pairings of the stimulus with self-administered cocaine, but older, as well as recent, memories were also disrupted. Reconsolidation blockade may thus provide a potential therapeutic strategy for the prevention of relapse in drug addiction.

A distributed limbic-corticostriatal circuitry is implicated in cue-induced drug craving and relapse. Exposure to drug-paired cues not only precipitates relapse, but also triggers the reactivation and reconsolidation of the cue-drug memory. However, the limbic cortical-striatal circuitry underlying drug memory reconsolidation is unclear. The aim of this study was to investigate the involvement of the nucleus accumbens core and the basolateral amygdala in the reconsolidation of a cocaine-conditioned stimulus-evoked memory. Antisense oligodeoxynucleotides (ASO) were infused into each structure to knock down the expression of the immediate-early gene "zif268," which is known to be required for memory reconsolidation. Control infusions used missense oligodeoxynucleotides (MSO). The effects of zif268 knockdown were measured in two complementary paradigms widely used to assess the impact of drug-paired CSs upon drug seeking: the acquisition of a new instrumental response with conditioned reinforcement and conditioned place preference. The results show that both intranucleus accumbens core and intrabasolateral amygdala zif268 ASO infusions at memory reactivation impaired the reconsolidation of the memory underlying a cocaine-conditioned place preference. However, knockdown of zif268 in the nucleus accumbens at memory reactivation had no effect on the memory underlying the conditioned reinforcing properties of the cocaine-paired CS measured subsequently, and this is in contrast to the marked impairment observed previously following intrabasolateral amygdala zif268 ASO infusions. These results suggest that both the basolateral amygdala and nucleus accumbens core are key structures within limbic cortical-striatal circuitry where reconsolidation of a cue-drug memory occurs. However reconsolidation of memory representations formed during Pavlovian conditioning are differentially localized in each site.

We have investigated the neurochemical mechanisms of memory reconsolidation and, in particular, the functional requirement for intracellular mechanisms initiated by [beta]-adrenergic signaling. We show that propranolol, given in conjunction with a memory reactivation session, can specifically disrupt the conditioned reinforcing properties of a previously appetitively reinforced conditioned stimulus (CS), whether the stimulus had been associated with self-administered cocaine or with sucrose. These data show that memories for both drug and nondrug CS-US associations are dependent on [beta]-adrenergic receptor-mediated signaling for their reconsolidation, with implications for the potential development of a novel treatment for drug addiction and some forms of obesity.

This document is an editorial published in the journal Frontiers in Behavioral Neuroscience. It discusses the destabilization of maladaptive memory and provides updates and future perspectives on this topic. The editorial highlights the importance of understanding the molecular and physiological signatures of memory destabilization and the potential for therapies based on the modulation of this process. It also presents original research articles that explore the boundary conditions and mechanisms underlying memory destabilization, with a focus on fear and anxiety disorders and drug addiction. The editorial concludes by emphasizing the contributions of this research to the theoretical framework and future studies on the modulation of maladaptive memories. [Extracted from the article]

• Disrupting reconsolidation may allow new treatments for mental health disorders. • There are challenges in translating reconsolidation-based approaches to the clinic. • Understanding boundary conditions should facilitate clinical translation. Reconsolidation results in the restabilisation, and thus persistence, of a memory made labile by retrieval, and interfering with this process is thought to enable modification or weakening of the original trace. As such, reconsolidation-blockade has been a focus of research aiming to target the maladaptive memories underlying mental health disorders, including post-traumatic stress disorder and drug addiction. Current first-line therapies are not effective for all patients, and a substantial proportion of those for whom therapies are effective later relapse. A reconsolidation-based intervention would be invaluable as an alternative treatment for these conditions. However, the translation of reconsolidation-based therapies to the clinic presents a number of challenges, with arguably the greatest being the overcoming of the boundary conditions governing the opening of the reconsolidation window. These include factors such as the age and strength of memory, and can broadly be divided into two categories: intrinsic features of the targeted memory itself, and parameters of the reactivation procedure used. With maladaptive memory characteristics inevitably varying amongst individuals, manipulation of the other limitations imposed by procedural variables have been explored to circumvent the boundary conditions on reconsolidation. Although several apparently discrepant results remain to be reconciled and these limitations yet to be truly defined, many studies have produced successful results which encouragingly demonstrate that boundary conditions may be overcome using various proposed strategies to enable translation of a reconsolidation-based intervention to clinical use. [ABSTRACT FROM AUTHOR]

Maladaptive emotional memories contribute to the persistence of many mental health disorders, and therefore the prospect of disrupting these memories to produce long-term reductions in relapse is of great clinical appeal. Reducing the impact of maladaptive emotional memories on behaviour could be achieved by two retrieval-dependent manipulations that engage separate mnemonic processes: "reconsolidation disruption" and "extinction enhancement." Extinction occurs during a prolonged re-exposure session in the absence of the expected emotional outcome and is widely accepted as reflecting the formation of a new, inhibitory memory that prevents behavioural expression of the original trace. Reconsolidation, by contrast, involves the destabilisation of the original memory, allowing for subsequent updating and restabilisation in specific brain regions, unless the re-stabilization process is prevented through specific pharmacological or behavioural interventions. Both destabilisation of the original memory and memory extinction require that re-exposure induces prediction error—a mismatch between what is expected and what actually occurs—but the parameters that allow reconsolidation and extinction to occur, and control the transition between them, have not been well-characterised. Here, we review what is known about the induction of memory destabilisation and extinction, and the transition period that separates these mnemonic processes, drawing on preclinical and clinical examples. A deeper understanding of the processes that determine the alternative routes to memory persistence or inhibition is critical for designing new and more reliable clinical treatments targeting maladaptive emotional memories. [ABSTRACT FROM AUTHOR]

Addicted individuals are highly susceptible to relapse when exposed to drug-associated conditioned stimuli (CSs; "drug cues") even after extensive periods of abstinence. Until recently, these maladaptive emotional drug memories were believed to be permanent and resistant to change. The rediscovery of the phenomenon of memory reconsolidation—by which retrieval of the memory can, under certain conditions, destabilize the previously stable memory before it restabilizes in its new, updated form—has led to the hypothesis that it may be possible to disrupt the strong maladaptive drug-memories that trigger a relapse. Furthermore, recent work has suggested that extinction training "within the reconsolidation window" may lead to a long-term reduction in relapse without the requirement for pharmacological amnestic agents. However, this so-called "retrieval-extinction" effect has been inconsistently observed in the literature, leading some to speculate that rather than reflecting memory updating, it may be the product of facilitation of extinction. In this mini review article, we will focus on factors that might be responsible for the retrieval-extinction effects on preventing drug-seeking relapse and how inter-individual differences may influence this therapeutically promising effect. A better understanding of the psychological and neurobiological mechanisms underpinning the "retrieval-extinction" paradigm, and individual differences in boundary conditions, should provide insights with the potential to optimize the translation of "retrieval-extinction" to clinical populations. [ABSTRACT FROM AUTHOR]

The amygdala has traditionally been associated with fear, mediating the impact of negative emotions on memory. However, this view does not fully encapsulate the function of the amygdala, nor the impact that processing in this structure has on the motivational limbic corticostriatal circuitry of which it is an important structure. Here we discuss the interactions between different amygdala nuclei with cortical and striatal regions involved in motivation; interconnections and parallel circuitries that have become increasingly understood in recent years. We review the evidence that the amygdala stores memories that allow initially motivationally neutral stimuli to become associated through pavlovian conditioning with motivationally relevant outcomes which, importantly, can be either appetitive (e.g. food) or aversive (e.g. electric shock). We also consider how different psychological processes supported by the amygdala such as conditioned reinforcement and punishment, conditioned motivation and suppression, and conditioned approach and avoidance behavior, are not only psychologically but also neurobiologically dissociable, being mediated by distinct yet overlapping neural circuits within the limbic corticostriatal circuitry. Clearly the role of the amygdala goes beyond encoding aversive stimuli to also encode the appetitive, requiring an appreciation of the amygdala's mediation of both appetitive and fearful behavior through diverse psychological processes. [ABSTRACT FROM AUTHOR]