Extinction Context Research Articles

Stress impairs retrieval of extinguished and unextinguished associations in a predictive learning task

Recovery effects which can frequently be observed after a seemingly successful extinction procedure indicate that extinction does not lead to an erasure of the memory trace. Investigating factors which modulate the retrieval of extinction memory is highly relevant for basic science and clinical applications alike. This study investigated the effect of stress on the retrieval of extinguished and unextinguished stimulus-outcome associations in a predictive learning task. In this task, participants had to imagine being the doctor of a patient who sometimes suffers from stomach trouble after meals in his favorite restaurants. They were presented with different food stimuli while having to predict the occurrence or non-occurrence of stomach trouble. As extinction memory is modulated by context, we manipulated contextual cues so that initial acquisition of critical associations occurred in context (restaurant frame) A on day one, whereas associations were reversed in context B (extinction, day two). On the third day, participants were either stressed (exposed to the socially evaluated cold pressor task (SECPT); n=21) or subjected to a control condition (n=21) shortly before extinction memory retrieval was tested (in contexts A and B). Salivary cortisol and blood pressure measures as well as subjective ratings indicated that stress induction was successful. When retrieval of extinguished associations was tested on day three, participants’ predictions reflected a renewal effect, as indicated by stronger recovery of responding in the acquisition context compared to the extinction context. Compared to controls, stressed participants showed impaired retrieval of extinguished and unextinguished associations. Contextual cues abolished the stress-induced memory impairment for unextinguished but not for extinguished associations. These findings might help to explain why stress leads to the reoccurrence of symptoms in affective disorders.

Extinction produces context inhibition and multiple-context extinction reduces response recovery in human predictive learning

Two experiments with human participants were used to investigate recovery of an extinguished learned response after a context change using ABC designs. In an ABC design, the context changes over the three successive stages of acquisition (context A), extinction (context B), and test (context C). In both experiments, we found reduced recovery in groups that had extinction in multiple contexts, and that the extinction contexts acquired inhibitory strength. These results confirm those of previous investigations, that multiple-context extinction can produce less response recovery than single-context extinction, and they also provide new evidence for the involvement of contextual inhibitory processes in extinction in humans. The foregoing results are broadly in line with a protection-from-extinction account of response recovery. Yet, despite the fact that we detected contextual inhibition, predictions based on protection-from-extinction were not fully reliable for the single- and multiple-context group differences that we observed in (1) rates of extinction and (2) the strength of context inhibition. Thus, although evidence was obtained for a protection-from-extinction account of response recovery, this account can not explain all of the data.

Mechanisms of renewal after the extinction of instrumental behavior.

Four experiments with rats examined renewal of extinguished instrumental behavior when the reinforcement histories of the contexts were equated by giving complementary training and extinction of a different response (lever press and chain pull) in each context. In Experiments 1 through 3, renewal occurred when the response was tested in the acquisition context (ABA) or outside the extinction context (AAB and ABC). Further, in Experiments 1 through 3, when both responses were simultaneously available, there was a clear preference for the response that was not in its extinction context. In Experiment 4, renewal was not reduced when testing occurred in a context that had been associated with extinction of the other instrumental response. The experimental designs rule out differential context-reinforcer associations being the only contributing mechanism of renewal, and also raise questions about configural and occasion-setting accounts. The results are consistent with the idea that during extinction an inhibitory association is formed between the context and the response.

Ensemble coding of context-dependent fear memory in the amygdala.

After fear conditioning, presenting the conditioned stimulus (CS) alone yields a context-specific extinction memory; fear is suppressed in the extinction context, but renews in any other context. The context-dependence of extinction is mediated by a brain circuit consisting of the hippocampus, prefrontal cortex (PFC) and amygdala. In the present work, we sought to determine at what level of this circuit context-dependent representations of the CS emerge. To explore this question, we used cellular compartment analysis of temporal activity by fluorescent in situ hybridization (catFISH). This method exploits the intracellular expression profile of the immediate early gene (IEG), Arc, to visualize neuronal activation patterns to two different behavioral experiences. Rats were fear conditioned in one context and extinguished in another; 24 h later, they were sequentially exposed to the CS in the extinction context and another context. Control rats were also tested in each context, but were never extinguished. We assessed Arc mRNA expression within the basal amygdala (BA), lateral amygdala (LA), ventral hippocampus (VH), prelimbic cortex (PL) and infralimbic cortex (IL). We observed that the sequential retention tests induced context-dependent patterns of Arc expression in the BA, LA, and IL of extinguished rats; this was not observed in non-extinguished controls. In general, non-extinguished animals had proportionately greater numbers of non-selective (double-labeled) neurons than extinguished animals. Collectively, these findings suggest that extinction learning results in pattern separation, particularly within the BA, in which unique neuronal ensembles represent fear memories after extinction.

Preventing Return of Fear in an Animal Model of Anxiety: Additive Effects of Massive Extinction and Extinction in Multiple Contexts

Fear conditioning and experimental extinction have been presented as models of anxiety disorders and exposure therapy, respectively. Moreover, the return of fear serves as a model of relapse after exposure therapy. Here we present two experiments, with rats as subjects in a lick suppression preparation, in which we assessed the additive effects of two different treatments to attenuate the return of fear. First, we evaluated whether two phenomena known to generate return of fear (i.e., spontaneous recovery and renewal) summate to produce a stronger reappearance of extinguished fear. At test, rats evaluated outside the extinction context following a long delay after extinction (i.e., a delayed context shift) exhibited greater return of extinguished fear than rats evaluated outside the extinction context alone, but return of extinguished fear following a delayed context shift did not significantly differ from the return of fear elicited in rats tested following a long delay after extinction alone. Additionally, extinction in multiple contexts and a massive extinction treatment each attenuated the strong return of fear produced by a delayed context shift. Moreover, the conjoint action of these treatments was significantly more successful in preventing the reappearance of extinguished fear, suggesting that extensive cue exposure administered in several different therapeutic settings has the potential to reduce relapse after therapy for anxiety disorders, more than either manipulation alone.

A model of amygdala–hippocampal–prefrontal interaction in fear conditioning and extinction in animals

Empirical research has shown that the amygdala, hippocampus, and ventromedial prefrontal cortex (vmPFC) are involved in fear conditioning. However, the functional contribution of each brain area and the nature of their interactions are not clearly understood. Here, we extend existing neural network models of the functional roles of the hippocampus in classical conditioning to include interactions with the amygdala and prefrontal cortex. We apply the model to fear conditioning, in which animals learn physiological (e.g. heart rate) and behavioral (e.g. freezing) responses to stimuli that have been paired with a highly aversive event (e.g. electrical shock). The key feature of our model is that learning of these conditioned responses in the central nucleus of the amygdala is modulated by two separate processes, one from basolateral amygdala and signaling a positive prediction error, and one from the vmPFC, via the intercalated cells of the amygdala, and signaling a negative prediction error. In addition, we propose that hippocampal input to both vmPFC and basolateral amygdala is essential for contextual modulation of fear acquisition and extinction. The model is sufficient to account for a body of data from various animal fear conditioning paradigms, including acquisition, extinction, reacquisition, and context specificity effects. Consistent with studies on lesioned animals, our model shows that damage to the vmPFC impairs extinction, while damage to the hippocampus impairs extinction in a different context (e.g., a different conditioning chamber from that used in initial training in animal experiments). We also discuss model limitations and predictions, including the effects of number of training trials on fear conditioning.

The role of medial prefrontal cortex in extinction and reinstatement of alcohol‐seeking in rats

The prelimbic (PL) and infralimbic (IL) medial prefrontal cortex (mPFC) are thought to play opposing roles in drug-seeking behaviour. Specifically, the PL promotes drug-seeking whereas the IL is necessary for the inhibition of drug-seeking during extinction. We studied the roles of the PL, IL and dorsal peduncular PFC (DP) in the expression of context-induced reinstatement, reacquisition and extinction of alcoholic beer-seeking. In context-induced reinstatement (renewal), animals were trained to nosepoke for alcoholic beer (context A), extinguished (context B) and then tested in context A and B. In reacquisition, animals received the same instrumental training and extinction without any contextual manipulation. On test, alcoholic beer was again available and responding was compared with naive controls. Just prior to the test, rats received bilateral infusion of baclofen/muscimol into the PL, IL or DP. Reversible inactivation of the PL attenuated ABA renewal but augmented reacquisition. Reversible inactivation of IL had no effect on the reinstatement or reacquisition of alcoholic beer-seeking and had no effect on extinction expression (ABB and AAA). IL inactivation did, however, increase the latencies with which animals responded on test but only when animals were tested in the extinction context. DP inactivation had no effect on reinstatement or reacquisition. These studies are inconsistent with the view that PL and IL exert opposing effects on drug-seeking. Rather, they support the view that PL is important for retrieval of drug-seeking contingency information and that the use of contextual information is enhanced with IL manipulation.

Cocaine- and amphetamine-regulated transcript in the nucleus accumbens shell attenuates context-induced reinstatement of alcohol seeking.

We investigated the impact of cocaine- and amphetamine-regulated transcript (CART) in the nucleus accumbens shell (AcbSh) on context-induced reinstatement of alcoholic beer-seeking. Rats were trained to respond for 4% (vol/vol) alcoholic beer in one context (A) followed by extinction in a second context (B). Rats were subsequently tested for renewal of extinguished responding in the training context (A). Return to the training context elicited responding (reinstatement), whereas intra-AcbSh injections of CART (55-102) attenuated reinstatement without affecting general behavioral activity (Experiment 1). CART (55-102) attenuated reinstatement dose-dependently across the 0.025 - 2.5 μg range (Experiment 2), and no effect was observed with the inactive CART (1-27) fragment (Experiment 3). Together, these findings suggest that intra-AcbSh CART (55-102) modulates the impact of drug-associated environments on reward seeking behavior.

D-cycloserine does not facilitate fear extinction by reducing conditioned stimulus processing or promoting conditioned inhibition to contextual cues

The NMDA receptor partial agonist d-cycloserine (DCS) enhances the extinction of learned fear in rats and exposure therapy in humans with anxiety disorders. Despite these benefits, little is known about the mechanisms by which DCS promotes the loss of fear. The present study examined whether DCS augments extinction retention (1) through reductions in conditioned stimulus (CS) processing or (2) by promoting the development of conditioned inhibition to contextual cues. Rats administered DCS prior to extinction showed enhanced long-term extinction retention (Experiments 3 and 4). The same nonreinforced CS procedure used in extinction also reduced freezing at test when presented as pre-exposure before conditioning, demonstrating latent inhibition (Experiment 1). DCS administered shortly prior to pre-exposure had no effect on latent inhibition using parameters which produced weak (Experiment 2) or strong (Experiment 3) expression of latent inhibition. Therefore, DCS facilitated learning involving CS-alone exposures, but only when these exposures occurred after (extinction) and not before (latent inhibition) conditioning. We also used a retardation test procedure to examine whether the extinction context gained inhibitory properties for rats given DCS prior to extinction. With three different footshock intensities, there was no evidence that DCS promoted accrual of associative inhibition to the extinction context (Experiment 4). The present findings demonstrate that DCS does not facilitate extinction by reducing CS processing or causing the extinction context to become a conditioned inhibitor. Investigations into the mechanisms underlying the augmentation of extinction by DCS are valuable for understanding how fear can be inhibited.

Cholinergic Blockade Frees Fear Extinction from Its Contextual Dependency

Fears that are maladaptive or inappropriate can be reduced through extinction training. However, extinction is highly context-sensitive, resulting in the renewal of fear after shifts in context and limiting the clinical efficacy of extinction training. Lesion and inactivation studies have shown that the contextualization of extinction depends on the hippocampus. Parallel studies have found that intrahippocampal scopolamine (Scop) blocks contextual fear conditioning. Importantly, this effect was replicated with a noninvasive technique in which a low dose of Scop was administered systemically. We aimed to transfer the effects of this noninvasive approach to block the contextualization of fear extinction. Rats were tone fear conditioned and extinguished under various systemic doses of Scop or the saline vehicle. They were subsequently tested (off drug) for tone fear in a context that was the same (control subjects) or shifted (renewal group) with respect to the extinction context. The lowest dose of Scop produced a significant attenuation of fear renewal when renewal was tested either in the original training context or a novel context. The drug also slowed the rate of long-term extinction memory formation, which was readily overcome by extending extinction training. Scopolamine only gave this effect when it was administered during but not after extinction training. Higher doses of Scop severely disrupted extinction learning. We discovered that disrupting contextual processing during extinction with the cholinergic antagonist Scop blocked subsequent fear renewal. Low doses of Scop might be a clinically promising adjunct to exposure therapy by making extinction more relapse-resistant.

Failure of Neural Responses to Safety Cues in Schizophrenia

CONTEXT Abnormalities in associative memory processes, such as Pavlovian fear conditioning and extinction, have been observed in schizophrenia. The retrieval of fear extinction memories (safety signals) may be particularly affected; although schizophrenic patients can extinguish conditioned fear, they show a deficit in retrieving fear extinction memories after a delay. The neurobiological basis of this abnormality is unknown, but clues have emerged from studies in rodents and humans demonstrating that the ventromedial prefrontal cortex (vmPFC) is a key mediator of extinction memory retrieval. OBJECTIVE To measure autonomic and neural responses during the acquisition and extinction of conditioned fear and the delayed recall of fear and extinction memories in patients with schizophrenia and healthy control participants. DESIGN Cross-sectional case control, functional magnetic resonance imaging study. SETTING Academic medical center. PARTICIPANTS Twenty schizophrenic patients and 17 healthy control participants demographically matched to the patient group. MAIN OUTCOME MEASURES Skin conductance and blood oxygen level-dependent responses. RESULTS During fear conditioning, schizophrenic patients showed blunted autonomic responses and abnormal blood oxygen level-dependent responses, relative to control participants, within the posterior cingulate gyrus, hippocampus, and other regions. Several of these abnormalities were linked to negative symptoms. During extinction learning, patients with schizophrenia and control participants showed comparable autonomic and neural responses. Twenty-four hours after the learning phases, the control subjects exhibited decreased fear and increased vmPFC responses in the extinction (safe) context as expected, indicating successful retention of the extinction memory. In contrast, the schizophrenic patients showed inappropriately elevated fear and poor vmPFC responses in the safe context. CONCLUSION Failure of extinction memory retrieval in schizophrenia is associated with vmPFC dysfunction. In future studies, abnormalities in fear learning and extinction recall may serve as quantitative phenotypes that can be linked to genetic, symptom, or outcome profiles in schizophrenia and those at risk for the disorder.

P300/CBP-Associated Factor Selectively Regulates the Extinction of Conditioned Fear

It is well established that the activity of chromatin-modifying enzymes is crucial for regulating gene expression associated with hippocampal-dependent memories. However, very little is known about how these epigenetic mechanisms influence the formation of cortically dependent memory, particularly when there is competition between opposing memory traces, such as that which occurs during the acquisition and extinction of conditioned fear. Here we demonstrate, in C57BL/6 mice, that the activity of p300/CBP-associated factor (PCAF) within the infralimbic prefrontal cortex is required for long-term potentiation and is necessary for the formation of memory associated with fear extinction, but not for fear acquisition. Further, systemic administration of the PCAF activator SPV106 enhances memory for fear extinction and prevents fear renewal. The selective influence of PCAF on fear extinction is mediated, in part, by a transient recruitment of the repressive transcription factor ATF4 to the promoter of the immediate early gene zif268, which competitively inhibits its expression. Thus, within the context of fear extinction, PCAF functions as a transcriptional coactivator, which may facilitate the formation of memory for fear extinction by interfering with reconsolidation of the original memory trace.

Conditioned suppression is an inverted-U function of footshock intensity

Most theories of associative learning assert that conditioned responding to a target cue is a monotonically increasing function of unconditioned-stimulus (US) intensity. In a lick suppression preparation with rats, a cue was paired with a 0.4-, 0.6-, 0.8-, 1.0-, 1.2-, or 1.4-mA footshock in Experiment 1a, and with a 0.3-, 0.8-, 1.3-, or 1.8-mA footshock in Experiment 1b. Subsequent suppression in response to the cue was an inverted-U function of the US intensity. In Experiment 2, we demonstrated that massive extinction of the training context and compound conditioning can each attenuate the response decrement caused by training with a high-intensity US. The sometimes-competing-retrieval model (Stout & Miller, Psychological Review 114:759-783, 2007) provides a better fit to these data than do several other models of associative learning.

Context and the renewal of conditioned taste aversion: the role of rat dorsal hippocampus examined by electrolytic lesion

An extinguished conditioned response can sometimes be restored. Previous research has shown that this renewal effect depends on the context in which conditioning versus extinction takes place. Here we provide evidence that the dorsal hippocampus is critically involved in the representation of context that underscores the renewal effect. We performed electrolytic lesions in dorsal hippocampus, before or after extinction, in a conditioned taste aversion paradigm with rats. Rats that underwent all conditioning, extinction and testing procedures in the same experimental context showed no renewal during testing in the original context. In contrast, rats that underwent extinction procedures in a different experimental context than the one in which they had acquired the conditioned response, showed a reliable renewal effect during testing in the original context. When electrolytic lesion was performed prior to extinction, the context-dependent renewal effect was disrupted. When electrolytic lesion was undertaken after extinction, we observed a complex pattern of data including the blockage of the conventional renewal effect, and the appearance of an unconventional renewal effect. The implications of these results are discussed with respect to current views on the role of the dorsal hippocampus in processing context information.

The extinction context enables extinction performance after a change in context

One experiment with human participants determined the extent to which recovery of extinguished responding with a context switch was due to a failure to retrieve contextually controlled learning, or some other process such as participants learning that context changes signal reversals in the meaning of stimulus-outcome relationships. In a video game, participants learned to suppress mouse clicking in the presence of a stimulus that predicted an attack. Then, that stimulus underwent extinction in a different context (environment within the game). Following extinction, suppression was recovered and then extinguished again during testing in the conditioning context. In a final test, participants that were tested in the context where extinction first took place showed less of a recovery than those tested in a neutral context, but they showed a recovery of suppression nevertheless. A change in context tended to cause a change in the meaning of the stimulus, leading to recovery in both the neutral and extinction contexts. The extinction context attenuated that recovery, perhaps by enabling retrieval of the learning that took place in extinction. Recovery outside an extinction context is due to a failure of the context to enable the learning acquired during extinction, but only in part.

The dual role of the context in postpeak performance decrements resulting from extended training

The context's role in Pavlovian conditioning depends on the trial spacing during training, with massed trials revealing a function akin to that of discrete stimuli, and spaced trials revealing a modulatory function (Urcelay & Miller, Journal of Experimental Psychology. Animal Behavior Processes, 36, 268-280, 2010). Here we examined the contextual determinants of a common but largely ignored effect: attenuated conditioned responding with extended reinforced training (i.e., a postpeak performance deficit [PPD]). Contextual sources of PPDs were investigated in four fear-conditioning experiments with rats. In Experiment 1, as the number of reinforced trials increased, conditioned responding decreased, even when testing occurred outside the training context. Experiment 2 revealed opposing influences of context on the PPD based on trial spacing, which interacted with whether testing occurred in the training context. This finding reconciles Experiment 1's results with previous data (Bouton, Frohardt, Sunsay, Waddell, & Morris, Journal of Experimental Psychology. Animal Behavior Processes, 34, 223-236, 2008). Experiment 3 suggested that extended training with these parameters did not lead to habituation to conditioned or unconditioned stimuli. In Experiment 4, few or many massed training trials were followed orthogonally by context extinction or no context extinction. After many pairings, context extinction reduced the PPD (i.e., enhanced responding), suggesting a competitive role of the context. These results, together with prior data suggesting that context modulates expressions of the PPD, are consistent with the view that contexts can play two distinctly different roles.

Genetic Strain Differences in Learned Fear Inhibition Associated with Variation in Neuroendocrine, Autonomic, and Amygdala Dendritic Phenotypes

Mood and anxiety disorders develop in some but not all individuals following exposure to stress and psychological trauma. However, the factors underlying individual differences in risk and resilience for these disorders, including genetic variation, remain to be determined. Isogenic inbred mouse strains provide a valuable approach to elucidating these factors. Here, we performed a comprehensive examination of the extinction-impaired 129S1/SvImJ (S1) inbred mouse strain for multiple behavioral, autonomic, neuroendocrine, and corticolimbic neuronal morphology phenotypes. We found that S1 exhibited fear overgeneralization to ambiguous contexts and cues, impaired context extinction and impaired safety learning, relative to the (good-extinguishing) C57BL/6J (B6) strain. Fear overgeneralization and impaired extinction was rescued by treatment with the front-line anxiety medication fluoxetine. Telemetric measurement of electrocardiogram signals demonstrated autonomic disturbances in S1 including poor recovery of fear-induced suppression of heart rate variability. S1 with a history of chronic restraint stress displayed an attenuated corticosterone (CORT) response to a novel, swim stressor. Conversely, previously stress-naive S1 showed exaggerated CORT responses to acute restraint stress or extinction training, insensitivity to dexamethasone challenge, and reduced hippocampal CA3 glucocorticoid receptor mRNA, suggesting downregulation of negative feedback control of the hypothalamic-pituitary-adrenal axis. Analysis of neuronal morphology in key neural nodes within the fear and extinction circuit revealed enlarged dendritic arbors in basolateral amygdala neurons in S1, but normal infralimbic cortex and prelimbic cortex dendritic arborization. Collectively, these data provide convergent support for the utility of the S1 strain as a tractable model for elucidating the neural, molecular and genetic basis of persistent, excessive fear.

The role of contextual associations in producing the partial reinforcement acquisition deficit.

Three conditioned suppression experiments with rats as subjects assessed the contributions of the conditioned stimulus (CS)-context and context-unconditioned stimulus (US) associations to the degraded stimulus control by the CS that is observed following partial reinforcement relative to continuous reinforcement training. In Experiment 1, posttraining associative deflation (i.e., extinction) of the training context after partial reinforcement restored responding to a level comparable to the one produced by continuous reinforcement. In Experiment 2, posttraining associative inflation of the context (achieved by administering unsignaled outcome presentations in the context) enhanced the detrimental effect of partial reinforcement. Experiment 3 found that the training context must be an effective competitor to produce the partial reinforcement acquisition deficit. When the context was down-modulated, the target regained behavioral control thereby demonstrating higher-order retrospective revaluation. The results are discussed in terms of retrospective revaluation, and are used to contrast the predictions of a performance-focused model with those of an acquisition-focused model.

Hippocampal and Prefrontal Projections to the Basal Amygdala Mediate Contextual Regulation of Fear after Extinction

Knowing when and where to express fear is essential to survival. Recent work in fear extinction paradigms reveals that the contextual regulation of fear involves a neural network involving the hippocampus, medial prefrontal cortex, and amygdala. The amygdaloid basal nuclei (BA) receive convergent input from the ventral hippocampus (VH) and prelimbic (PL) prefrontal cortex and may integrate VH and PL input to regulate fear expression. To examine the functional organization of this neural circuit, we used cellular imaging of c-fos expression in anatomically defined neuronal populations and circuit disconnections to identify the pathways involved in the contextual control of extinguished fear. Before behavioral testing, we infused a retrograde tracer into the amygdala to label BA-projecting neurons in VH and PL. Rats then underwent fear conditioning and extinction and were tested for their fear to the extinguished conditioned stimulus (CS) in either the extinction context or in another context; freezing behavior served as the index of conditional fear. CS presentation outside the extinction context renewed conditional freezing and was associated with significantly more c-fos expression in BA-projecting neurons in the VH and PL than that induced by CS presentation in the extinction context. We next examined whether direct or indirect projections of VH to BA mediate fear renewal. Interestingly, disconnections of the VH from either the BA or PL eliminated renewal. These findings suggest that convergent inputs from both the VH and PL in the BA mediate the contextual control of fear after extinction.

The chemotherapy agent oxaliplatin impairs the renewal of fear to an extinguished conditioned stimulus in rats

Recent evidence has shown that diverse chemotherapy agents can induce cognitive impairments and neurotoxic damage to the central nervous system. Oxaliplatin (OXP), a platinum compound, has been linked with acute and chronic peripheral neuropathies. This study explored the cognitive impacts of OXP in the rat with a fear conditioning procedure. 10 days prior to conditioning and testing, rats received an intraperitoneal injection of OXP (12 mg/kg). On the first day of conditioning, the rats were conditioned to two CSs (CS-ren and CS-ext) in one set of chambers (context A). They then received three tests on separate days. First, the rats were assessed for contextual fear conditioning in context A. Next, the CSs were presented 20 times in a new context (B) until fear conditioning had extinguished. Finally, one of the CSs (CS-ext) was tested again in the extinction context (B), and the other (CS-ren) presented in a new context (C). Results showed that OXP had no effect on the ability of rats to express fear to the conditioning context (A), or on the expression and extinction of conditioned fear to either CS when presented in a second context (B). However, the administration of OXP did impair the ability of rats to renew levels of conditioned fear to CS-ren when this CS was presented in a novel context (C) following extinction. This profile of impairment is consistent with hippocampal damage, and may also involve frontal cortical, amygdalar and thalamic regions important for context discrimination and the contextual modulation of behaviour.