The influence of one memory retrieval on a subsequent memory retrieval

Ss produced an instance of a category and following zero or two intervening items produced a second instance of the same category. The second instance was produced more quickly than the initial instance. This finding, in conjunction with other data reported in the paper, indicate that the reduction in latency for the second instance is due mostly to a reduction in the rate with which the category is searched.     

Generalization of conditioned fear along a dimension of increasing fear intensity

The present study investigated the extent to which fear generalization in humans is determined by the amount of fear intensity in nonconditioned stimuli relative to a perceptually similar conditioned stimulus. Stimuli consisted of graded emotionally expressive faces of the same identity morphed between neutral and fearful endpoints. Two experimental groups underwent discriminative fear conditioning between a face stimulus of 55% fear intensity (conditioned stimulus, CS+), reinforced with an electric shock, and a second stimulus that was unreinforced (CS−). In Experiment 1 the CS− was a relatively neutral face stimulus, while in Experiment 2 the CS− was the most fear-intense stimulus. Before and following fear conditioning, skin conductance responses (SCR) were recorded to different morph values along the neutral-to-fear dimension. Both experimental groups showed gradients of generalization following fear conditioning that increased with the fear intensity of the stimulus. In Experiment 1 a peak shift in SCRs extended to the most fear-intense stimulus. In contrast, generalization to the most fear-intense stimulus was reduced in Experiment 2, suggesting that discriminative fear learning procedures can attenuate fear generalization. Together, the findings indicate that fear generalization is broadly tuned and sensitive to the amount of fear intensity in nonconditioned stimuli, but that fear generalization can come under stimulus control. These results reveal a novel form of fear generalization in humans that is not merely based on physical similarity to a conditioned exemplar, and may have implications for understanding generalization processes in anxiety disorders characterized by heightened sensitivity to nonthreatening stimuli.Fear generalization occurs when a fear response acquired to a particular stimulus transfers to another stimulus. Generalization is often an adaptive function that allows an organism to rapidly respond to novel stimuli that are related in some way to a previously learned stimulus. Fear generalization, however, can be maladaptive when nonthreatening stimuli are inappropriately treated as harmful, based on similarity to a known threat. For example, an individual may acquire fear of all dogs after an aversive experience with a single vicious dog. In this case, recognizing that a novel animal is related to a feared (or fear-conditioned) animal is made possible in part by shared physical features to the fear exemplar, such as four legs and a tail. On the other hand, fear generalization may be selective for those features that are associated with natural categories of threat; a harmless dog may not pose a threat, but possesses naturally threatening features common to other threatening animals, such as sharp teeth and claws. Moreover, the degree to which an individual fearful of dogs responds with fear may be related to either the physical similarity to the originally feared animal (e.g., from a threatening black dog to another black dog), or the intensity of those threatening features relative to the originally feared animal (e.g., sharp teeth from one animal to sharp teeth of another animal). Therefore, fear generalization based on perceptual information may occur via two routes—similarity to a learned fear exemplar along nonthreatening physical dimensions or along dimensions of fear relevance. Given that fear generalization often emerges as a consequence of conditioning or observational learning, it is important to determine which characteristics of novel stimuli facilitate fear generalization and the extent to which generalization processes can be controlled.Early explanations of stimulus generalization emphasized that an organism''s ability to generalize to nonconditioned stimuli is related to both the similarity and discriminability to a previously conditioned stimulus (CS) (Hull 1943; Lashley and Wade 1946). While Lashley and Wade (1946) argued that generalization was simply a failure of discriminating between a nonconditioned stimulus (CS−) and the reinforced CS (CS+), contemporary views contend that generalization enables learning to extend to stimuli that are readily perceptually distinguished from the CS (Pearce 1987; Shepard 1987; McLaren and Mackintosh 2002). This latter view has been supported by empirical studies of stimulus generalization in laboratory animals (Guttman and Kalish 1956; Honig and Urcuioli 1981). In these studies, animals were reinforced for responding to a CS of a specific physical quality such as color, and then tested with several different values along the same stimulus dimension as the CS (e.g., at various wavelengths along the color spectrum). Orderly gradients of responses are often reported that peak at or near the reinforced value and decrease as a function of physical similarity to the CS along the stimulus dimension (Honig and Urcuioli 1981). Further generalization was shown to extend from the CS+ to discriminable nonconditioned stimuli, suggesting that generalization is not bound to the organism''s ability to discriminate stimuli (Guttman and Kalish 1956, 1958; Shepard 1987).Interestingly, when animals learn to distinguish between a CS+ and a CS−, the peak of behavioral responses often shift to a new value along the dimension that is further away from the CS− (Hanson 1959). For instance, when being trained to discriminate a green CS+ and an orange CS−, pigeons will key peck more to a greenish-blue color than the actual CS+ hue. Intradimensional generalization of this sort is reduced when animals are trained to discriminate between two or more stimulus values that are relatively close during conditioning (e.g., discriminating a green-yellow CS+ from a green-blue CS−), suggesting that the extent of generalization can come under stimulus control through reinforcement learning (Jenkins and Harrison 1962). Spence (1937) described the transposition of response magnitude as an effect of interacting gradients of excitation and inhibition formed around the CS+ and CS−, respectively, which summate to shift responses to values further from the inhibitory CS− gradient. In all, early theoretical and empirical treatments of stimulus generalization in nonhuman animals revealed that behavior transfers to stimuli that are physically similar, but can be discriminated from a CS, and that differential reinforcement training can both sharpen the stimulus gradient and shift the peak of responses to a nonreinforced value.Although this rich literature has revealed principles of generalization in nonhuman animals, few studies of fear generalization have been conducted in humans (for review, see Honig and Urcuioli 1981; Ghirlanda and Enquist 2003). Moreover, the existing human studies have yet to consider the second route through which fear responses may generalize—via gradients of fear relevance. While a wide range of neutral stimuli, such as tones or geometric figures, can acquire fear relevance through conditioning processes, other stimuli, such as threatening faces or spiders, are biologically prepared to be fear relevant (Lanzetta and Orr 1980; Dimberg and Öhman 1996; Whalen et al. 1998; Öhman and Mineka 2001). Compared with fear-irrelevant CSs, biologically prepared stimuli capture attention (Öhman et al. 2001), are conditioned without awareness (Öhman et al. 1995; Öhman and Soares 1998), increase brain activity in visual and emotional processing regions (Sabatinelli et al. 2005), and become more resistant to extinction when paired with an aversive unconditioned stimulus (US) (Öhman et al. 1975). Although the qualitative nature of the CS influences acquisition and expression of conditioned fear, it is unknown how generalization proceeds along a gradient of natural threat. For instance, human studies to date have all tested variations of a CS along physically neutral stimulus dimensions, such as tone frequency (Hovland 1937), geometric shape (Vervliet et al. 2006), and physical size (Lissek et al. 2008). These investigations implicitly assume that the generalization gradient is independent of the conditioned value (equipotentiality principle). In other words, since the stimuli are all equally neutral prior to fear learning, fear generalization operates solely as a function of similarity along the reinforced physical dimension. However, since fear learning is predisposed toward fear-relevant stimuli, generalization may be selective to those shared features between a CS+ and CS− that are associated with natural categories of threat. Examining generalization using fear-relevant stimuli is thus important to gain better ecological validity and to develop a model system for studying maladaptive fear generalization in individuals who may express exaggerated fear responses to nonthreatening stimuli following a highly charged aversive experience (i.e., post-traumatic stress disorder or specific phobias).To address this issue, the present study examined generalization to fearful faces along an intradimensional gradient of fear intensity. A fearful face is considered a biologically prepared stimulus that recruits sensory systems automatically for rapid motor responses (Öhman and Mineka 2001), and detecting fearful faces may be evolutionarily selected as an adaptive response to social signals of impending danger (Lanzetta and Orr 1980; Dimberg and Öhman 1996). During conditioning, an ambiguous face containing 55% fear intensity (CS+) was paired with an electric shock US, while a relatively neutral face (11% fear intensity) was explicitly unreinforced (CS−) (Experiment 1). Skin conductance responses (SCR) were recorded as a dependent measure of fear conditioning. Before and following fear conditioning, SCRs were recorded in response to face morphs of the same actor expressing several values of increasing fear intensity (from 11% to 100%; see Fig. 1). A total of five values along the continuum were used: 11% fear/88% neutral, 33% fear/66% neutral, 55% fear/44% neutral, 77% fear/22% neutral, and 100% fear. For clarity, these stimuli are herein after labeled as S1, S2, S3, S4, and S5, respectively.Open in a separate windowFigure 1.Experimental design. (A) Pre-conditioning included six presentations of all five stimulus values without the US. (B) Fear conditioning involved discriminative fear learning between the S3, paired with the US (CS+), and either the unreinforced S1 (Experiment 1) or the unreinforced S5 (Experiment 2) (CS−). (C) The generalization test included nine presentations of all five stimuli (45 total), with three out of nine S3 trials reinforced with the US. Stimuli are not drawn to scale.Testing generalization along an intradimensional gradient of emotional expression intensity allows for an examination of the relative contributions of fear intensity and physical similarity on the magnitude of generalized fear responses. If fear generalization is determined purely by the perceptual overlap between the CS+ and other morph values, without regard to fear intensity, then we would expect a bell-shaped generalization function with the maximum SCR centered on the reinforced (intermediate) CS+ value (S3), less responding to the directly adjacent, but most perceptually similar values (S2 and S4), and the least amount of responding to the most distal and least perceptually similar morph values (S1 and S5). This finding would be in line with stimulus generalization reported along fear-irrelevant dimensions (Lissek et al. 2008) and in stimulus generalization studies using appetitive instrumental learning procedures (Guttman and Kalish 1956). If, however, fear generalization is biased toward nonconditioned stimuli of high fear intensity, then an asymmetric generalization function should result with maximal responding to the most fear-intense nonconditioned stimuli. This finding would suggest that fear generalization is selective to the degree of fear intensity in stimuli, similar to studies of physical intensity generalization gradients in nonhuman animals (Ghirlanda and Enquist 2003). We predicted that the latter effect would be observed, such that the magnitude of SCRs will disproportionately generalize to stimuli possessing a greater degree of fear intensity than the CS+ (Experiment 1). A secondary goal was to determine whether fear generalization to nonconditioned stimuli can be reduced through discriminative fear learning processes. Therefore, a second group of participants was run for whom the CS− was the 100% fearful face (Experiment 2). In this case, we predicted that discriminative fear conditioning between the CS+ (55% intensity) and the most fear-intense nonconditioned stimulus would sharpen the generalization gradient around the reinforced CS+ value, and that responses to the most fear-intense stimulus would decrease relative to Experiment 1. Moreover, this discriminative fear-learning process may provide evidence that fear generalization is influenced by associative learning processes and is not exclusively driven by selective sensitization to stimuli of high fear relevance (Lovibond et al. 1993). Finally, we were interested to discover whether generalization processes would yield subsequent false memory for the intensity of the CS+ in a post-experimental retrospective report. In sum, the present study has implications for understanding how fear generalization is related to the degree of fear intensity of a nonconditioned stimulus, the extent to which discrimination training efforts can thwart the generalization process, and how fear generalization affects stimulus recognition.     

Post-training administration of corticosterone enhances consolidation of contextual fear memory and hippocampal long-term potentiation in rats

This study was designed to examine the effect of corticosterone on consolidation of contextual fear memory and hippocampal long-term potentiation (LTP) in rats. In Experiment 1, dose–response effects of corticosterone on consolidation of contextual fear memory were determined. Immediately after training in contextual fear conditioning task, rats received different doses of corticosterone. Testing 24 h later, it revealed that corticosterone enhanced memory consolidation in an inverted U shape as evidenced in increased freezing behavior of corticosterone-treated animals. The most effective dose was 3 mg/kg. In Experiment 2, LTP was examined in rats whose memory consolidation has been enhanced with corticosterone. The rats were trained as the above and received corticosterone (3 mg/kg) immediately after training. Immediately or up to one day after retention test, rats were anesthetized with urethane for LTP experiments. For LTP induction, three episodes of high frequency stimuli, 30 s apart, were delivered to the perforant path, each consisting of 10 stimuli at 250 Hz. LTP was assessed by measuring the increase in the initial slope of the population excitatory post-synaptic potentials and the amplitude of the population spikes. Data indicated that animals whose memory has been enhanced by corticosterone, also displayed enhanced hippocampal LTP. The above findings suggest that glucocorticoids may enhance contextual fear memory consolidation via enhancing hippocampal LTP.     

Infusion of lidocaine into the dorsal hippocampus before or after the shock training phase impaired conditioned freezing in a two-phase training task of contextual fear conditioning

Learning in a contextual fear conditioning task involves forming a context representation and associating it with a shock. The dorsal hippocampus (DH) is implicated in representing the context, but whether it also has a role in associating the context and shock is unclear. To address this issue, male Wistar rats were trained on the task by a two-phase training paradigm, in which rats learned the context representation on day 1 and then reactivated it to associate with the shock on day 2; conditioned freezing was tested on day 3. Lidocaine was infused into the DH at various times in each of the two training sessions. Results showed that intra-DH infusion of lidocaine shortly before or after the context training session on day 1 impaired conditioned freezing, attesting to the DH involvement in context representation. Intra-DH infusion of lidocaine shortly before or after the shock training session on day 2 also impaired conditioned freezing. This deficit was reproduced by infusing lidocaine or APV (alpha-amino-5-phosphonovaleric acid) into the DH after activation of the context memory but before shock administration. The deficit was not due to drug-induced state-dependency, decreased shock sensitivity or reconsolidation failure of the contextual memory. These results suggest that in contextual fear conditioning integrity of the DH is required for memory processing of not only context representation but also context-shock association.     

Learning and memory in conditioned fear extinction: effects of D-cycloserine

This review addresses the effects of the cognitive enhancer D-cycloserine (DCS) on the memory processes that occur in conditioned fear extinction, which is the experimental model for exposure techniques to reduce clinical anxiety. All reported rat studies show an enhanced fear extinction effect when DCS is administered acutely before or shortly after extinction training. DCS also promotes the generalization of this fear extinction effect. In addition, DCS reduces some forms of relapse (reduced reinstatement, reduced spontaneous recovery), but not others (contextual renewal, rapid reacquisition). It is argued that this pattern of results is best explained by assuming that DCS promotes extinction learning to the background context, resulting in enhanced contextual inhibition. Four human studies have produced mixed results, but some methodological issues complicate the reported failures. It is concluded that DCS is a promising tool as an adjunct to extinction techniques in exposure treatment, but that more pre-clinical and clinical research is needed to fully characterize its behavioral consequences.     

Contributions of the medial temporal lobe to declarative memory retrieval: manipulating the amount of contextual retrieval

We investigated how the hippocampus and its adjacent mediotemporal structures contribute to contextual and noncontextual declarative memory retrieval by manipulating the amount of contextual information across two levels of the same contextual dimension in a source memory task. A first analysis identified medial temporal lobe (MTL) substructures mediating either contextual or noncontextual retrieval. A linearly weighted analysis elucidated which MTL substructures show a gradually increasing neural activity, depending on the amount of contextual information retrieved. A hippocampal engagement was found during both levels of source memory but not during item memory retrieval. The anterior MTL including the perirhinal cortex was only engaged during item memory retrieval by an activity decrease. Only the posterior parahippocampal cortex showed an activation increasing with the amount of contextual information retrieved. If one assumes a roughly linear relationship between the blood-oxygenation level-dependent (BOLD) signal and the associated cognitive process, our results suggest that the posterior parahippocampal cortex is involved in contextual retrieval on the basis of memory strength while the hippocampus processes representations of item-context binding. The anterior MTL including perirhinal cortex seems to be particularly engaged in familiarity-based item recognition. If one assumes departure from linearity, however, our results can also be explained by one-dimensional modulation of memory strength.     

Inhibition of matrix metalloproteinase activity disrupts reconsolidation but not consolidation of a fear memory

The reconsolidation hypothesis posits that memories that have been reactivated can be either enhanced or disrupted by pharmacological manipulation. Synaptic plasticity is presumed to underlie the reconsolidation process. Matrix metalloproteinases are proteins that regulate the extracellular matrix involved in plasticity events, and these proteins have recently been shown to influence learning and memory. However, all studies on the role of matrix metalloproteinases in learning and memory have employed tasks that rely on contextual cues. The goal of this study was to determine the extent to which FN-439 would disrupt the consolidation and/or reconsolidation of a fear memory associated with a conditioned stimulus that signaled tone-shock pairings and that was independent of contextual cues. Male Sprague-Dawley rats were given infusions of FN-439 (35 microg intracerebroventricular) 30 min prior to conditioning (tone-shock paired association) or 30 min prior to a single reactivation session given 24h after conditioning. Administration of FN-439 did not disrupt consolidation of the freezing response when the tone (conditioned stimulus) was presented. In contrast, FN-439 infusion disrupted reconsolidation of the fear memory in a reactivation-dependent manner. The reduced freezing behavior was not due to a decrease in general anxiety levels, since FN-439 had no effect on the percent of open-arm time or open-arm entries in an elevated-plus maze task. Thus, we demonstrated for the first time that matrix metalloproteinase inhibition in the brain is capable of disrupting the reconsolidation of a tone-shock association memory that does not depend on contextual cues. The finding that a fear response to a previously paired conditioned stimulus can be disrupted by treatment with an MMP inhibitor during a single reactivation session suggests that this class of compounds may have therapeutic potential for posttraumatic stress disorder and/or simple phobias.     

d-Cycloserine: effects on long-term retention of a conditioned response and on memory for contextual attributes.

d-Cycloserine (DCS), a partial agonist of the glycine recognition site of the N-methyl d-aspartate receptor, has beneficial effects on learning and memory. In order to investigate its potential to influence learning and memory of both the response and the stimulus attributes of training, male Sprague-Dawley albino rats were trained in a one-trial inhibitory avoidance task following an acute intraperitoneal injection of DCS (3 mg/kg) or an equal volume of saline. In order to measure memory for stimulus attributes, testing involved a context shift paradigm, in which subjects are tested in either the environment of training or a different one. Good memory for the contextual attributes of training is indicated by poor performance in the alternate context. Retention was assessed either 1, 7, or 14 days after training. At 1 day, Saline subjects were affected by a change in context, while DCS subjects were not. In subjects tested 1 week following training, Saline subjects were no longer affected by a change in context, in that they performed the avoidance response in both contexts. This indicates the forgetting of stimulus attributes in Saline subjects. DCS subjects did show the context shift effect at 1 week, indicating the retention of stimulus attributes. Finally, Saline subjects demonstrated the context shift rebound at 14 days, while DCS subjects performed equivalently in both contexts. Taken together, these data suggest that DCS may enhance retention of fear and slow the forgetting of stimulus attributes.     

Post-training ethanol disrupts trace conditioned fear in rats: effects of timing of ethanol, dose and trace interval duration

Ethanol has complex effects on memory performance, although hippocampus-dependent memory may be especially vulnerable to disruption by acute ethanol intoxication occurring during or shortly after a training episode. In the present experiments, the effects of post-training ethanol on delay and trace fear conditioning were examined in adolescent rats. In Experiment 1, 30-day-old Sprague-Dawley rats were given delay or trace conditioning trials in which a 10s flashing light CS was paired with a 0.5 mA shock US. For trace groups, the trace interval was 10 s. On days 31-33, animals were administered ethanol once daily (0.0 or 2.5 g/kg via intragastric intubation), and on day 34 animals were tested for CS-elicited freezing. Results showed that post-training ethanol affected the expression of trace, but had no effect on delay conditioned fear. Experiment 2 revealed that this effect was dose-dependent; doses lower than 2.5 g/kg were without effect. Experiment 3 evaluated whether proximity of ethanol to the time of training or testing was critical. Results show that ethanol administration beginning 24h after training was more detrimental to trace conditioned freezing than administration that was delayed by 48 h. Finally, in Experiment 4 animals were trained with one of three different trace intervals: 1, 3 or 10s. Results indicate that post-training administration of 2.5 g/kg ethanol disrupted trace conditioned fear in subjects trained with a 10s, but not with a 1 or 3s, trace interval. Collectively the results suggest that ethanol administration impairs post-acquisition memory processing of hippocampus-dependent trace fear conditioning.     

Context preexposure prevents forgetting of a contextual fear memory: implication for regional changes in brain activation patterns associated with recent and remote memory tests

Contextual fear conditioning was maintained over a 15-day retention interval suggesting no forgetting of the conditioning experience. However, a more subtle generalization test revealed that, as the retention interval increased, rats showed enhanced generalized fear to an altered context. Preexposure to the training context prior to conditioning, however, prevented this enhanced generalized fear from developing. These results support the hypothesis that the memory representation of the context degrades as the memory ages and is responsible for enhanced generalization. The implications of these results for systems consolidation versus forgetting interpretations of regional changes in neural activation patterns that occur as memories age are discussed.     

Variation in working memory capacity and episodic recall: The contributions of strategic encoding and contextual retrieval

The present study examined the extent to which differences in strategic encoding and contextual retrieval account for the relation between individual differences in working memory capacity (WMC) and variation in episodic recall. Participants performed a continual distractor task under either incidental- or intentional-encoding conditions. High-WMC individuals outperformed low-WMC individuals across both encoding conditions and, notably, to a greater degree in the intentional-encoding condition. These results suggest that WMC differences in episodic recall are likely due to a combination of differences in both contextual-retrieval and strategic-encoding processes. These findings are consistent with prior work showing that high-WMC individuals are better at engaging in strategic-encoding processes during the presentation of items than are low-WMC individuals and are better at using contextual cues to focus the search on correct items during retrieval.     

The effect of a conditioned fear inhibitor (CS-) during response prevention upon extinction of an avoidance response

Pairing a Pavlovian safety signal (CS—) with a response prevention period was contrasted with other response prevention procedures to determine relative effectiveness for the elimination of learned avoidance behavior. After acquiring a one-way avoidance response, five groups of ten rats received various blocking or control treatments and were then compared on extinction performance. The four blocking treatments included blocking paired with a safety signal; blocking only; blocking paired with a novel stimulus; and blocking paired with a preexposed noncontingent tone. The fifth group served as a handling control. Compared to the handling control, all four blocking groups reached extinction criterion in fewer trials. Further, the safety signal group extinguished faster than the blocking only group or the blocking with noncontingent tone group. Results were viewed as an indication of the potential efficacy of pairing-conditioned fear-inhibiting cues with response prevention procedures for the elimination of fear-motivated behavior. Implications for behavioral therapy techniques were discussed.     

Automaticity without extensive training: The role of memory retrieval in implementation of task-defined rules

Although the concept of automaticity is closely associated with extensive rote training, previous studies have shown that task-defined stimulus-response (S-R) mappings can be implemented in parallel and involuntarily, without much training, as if they are automatically processed. An irrelevant task context may trigger a task-defined rule because the rule is actively maintained in working memory, resulting in erroneous implementation of that rule. However, the present study demonstrated that active maintenance of task rules is not necessary for their automatic implementation. Instead, the results are consistent with the memory view of automaticity, according to which task-defined S-R rules are implemented via automatic retrieval of S-R episodes.     

Biphasic ERK1/2 activation in both the hippocampus and amygdala may reveal a system consolidation of contextual fear memory

There is accumulating evidences to suggest that memory consolidation in some conditions involves two waves of neuronal plastic change. Using two fear conditioning procedures in male C57BL/6J mice, we have recently shown that consolidation of the foreground contextual fear memory required two waves of ERK1/2 activation in hippocampal CA1, while consolidation of cue conditioning was only associated with the early phase of activation. The present experiment further showed that this bi-phasic pattern of ERK1/2 activation was not restricted to hippocampal CA1, but could also be observed in other fear memory-related brain areas. The unpaired conditioning procedure (context in foreground) induced two waves of ERK1/2 activation in hippocampal CA1 and CA3, as well as in the LA and BLA nuclei of the amygdala. In contrast, the paired conditioning procedure (context in background) led to a transient early phase only in hippocampal CA1 and LA. In addition, ERK1/2 phosphorylation in the hippocampus was found to correlate with that in the amygdala nuclei specifically after the unpaired procedure. Taken together, our data suggest that the observed biphasic pattern of neuronal plastic events may reflect the interplay between hippocampal and amygdala activity-dependent plasticity critical for the system consolidation of contextual fear memory.     

Exposure to a novel context after extinction causes a renewal of extinguished conditioned responses: Implications for the treatment of fear

Renewal gives an experimental model for the relapse of fear symptoms following exposure therapy. While renewal of extinguished fear in humans has been observed following a return to the original context in which fear was acquired (ABA design), it has been more difficult to show upon presentation of a novel context (ABC design). The present experiment used a particularly strong context manipulation in a fear conditioning procedure. Context was manipulated by using large photographs of real environments taken from various angles and was present throughout the entire experiment. A renewal of cognitive expectancy was found in both ABA and ABC renewal designs, although it was larger in the former than in the latter. Response times in making the expectancy judgments increased when there was a change to a new context. The results demonstrate consistency in fear renewal effects between human and animal studies and suggest that relapse following exposure therapy via renewal remains a danger when people encounter a previously feared object in a novel context.     

The NMDA antagonist MK-801 disrupts reconsolidation of a cocaine-associated memory for conditioned place preference but not for self-administration in rats

Recent research suggests that drug-related memories are reactivated after exposure to environmental cues and may undergo reconsolidation, a process that can strengthen memories. Conversely, reconsolidation may be disrupted by certain pharmacological agents such that the drug-associated memory is weakened. Several studies have demonstrated disruption of memory reconsolidation using a drug-induced conditioned place preference (CPP) task, but no studies have explored whether cocaine-associated memories can be similarly disrupted in cocaine self-administering animals after a cocaine priming injection, which powerfully reinstates drug-seeking behavior. Here we used cocaine-induced CPP and cocaine self-administration to investigate whether the N-methyl-D-aspartate receptor antagonist (+)-5methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) given just prior to reactivation sessions would suppress subsequent cocaine-primed reinstatement (disruption of reconsolidation). Systemic injection of MK-801 (0.05 or 0.20 mg/kg administered intraperitoneally) in rats just prior to reactivation of the cocaine-associated memory in the CPP context attenuated subsequent cocaine-primed reinstatement, while no disruption occurred in rats that did not receive reactivation in the CPP context. However, in rats trained to self-administer cocaine, systemic administration of MK-801 just prior to either of two different types of reactivation sessions had no effect on subsequent cocaine-primed reinstatement of lever-pressing behavior. Thus, systemic administration of MK-801 disrupted the reconsolidation of a cocaine-associated memory for CPP but not for self-administration. These findings suggest that cocaine-CPP and self-administration do not use similar neurochemical processes to disrupt reconsolidation or that cocaine-associated memories in self-administering rats do not undergo reconsolidation, as assessed by lever-pressing behavior under cocaine reinstatement conditions.The ability to disrupt previously consolidated memories in a reactivation-dependent manner is thought to be due to the disruption of a memory reconsolidation process. This disruption of reconsolidation has been observed in a wide variety of tasks and species (Nader et al. 2000b; Sara 2000; Alberini 2005; Riccio et al. 2006). Early reconsolidation experiments primarily focused on aversive learning paradigms, with an emphasis on disruption of reconsolidation as a potential treatment for posttraumatic stress disorder (Misanin et al. 1968; Nader et al. 2000a; Debiec and Ledoux 2004; Brunet et al. 2008). Only more recently have investigators demonstrated that appetitive memories also undergo reconsolidation; most, but not all (Yim et al. 2006), studies found a disruption of expression for the drug-associated memory, suggesting the potential to target the reconsolidation process as a treatment for drug addiction (Lee et al. 2005; Miller and Marshall 2005; Milekic et al. 2006; Valjent et al. 2006; Brown et al. 2007; Kelley et al. 2007; Sadler et al. 2007; Fricks-Gleason and Marshall 2008; Milton et al. 2008a, b).Miller and Marshall (2005) showed that reconsolidation of cocaine conditioned place preference (CPP) in the rat could be disrupted by either pre- or post-treatment of a phosphorylation inhibitor of extracellular signal-regulated kinase (1/2) (ERK) in a reactivation-dependent manner. Other studies have shown that protein synthesis inhibitors (Milekic et al. 2006), a matrix metalloproteinase (MMP) inhibitor (Brown et al. 2007), a β-noradrenergic receptor antagonist (Bernardi et al. 2006; Robinson and Franklin 2007a; Fricks-Gleason and Marshall 2008), and an N-methyl-D-aspartate (NMDA) receptor antagonist (Kelley et al. 2007; Sadler et al. 2007) can also disrupt the reconsolidation of drug-associated CPP memories. Studies by Lee and colleagues have shown that Zif268 antisense oligodeoxynucleotide infused into the basolateral amygdala prior to reactivation of memory for a cocaine-associated cue (the conditioned stimulus or CS) disrupts the ability of cocaine-associated cues to establish subsequent acquisition of a new instrumental response (Lee et al. 2005), and the ability of a drug-associated cue to induce relapse under a second-order schedule (Lee et al. 2006a). Thus, cocaine-associated memories appear to undergo reconsolidation in both Pavlovian and operant conditioning paradigms.Relapse to drug-seeking or drug-taking behavior can occur after re-exposure to three types of stimuli: the drug itself, drug-associated contextual and discrete cues, and stress; and all of these may promote relapse in humans (for review, see Epstein et al. 2006). Only a few CPP studies (Valjent et al. 2006; Brown et al. 2007) and no self-administration studies to our knowledge have tested whether the drug-associated memory can be rendered susceptible to disruption by pharmacological agents such that subsequent cocaine-primed reinstatement is suppressed. This drug-primed effect is observed in humans, producing relapse (Ludwig et al. 1974; Jaffe et al. 1989), and in rats, producing robust reinstatement of drug-seeking behavior in both CPP and self-administration tasks (McFarland and Ettenberg 1997; McFarland and Kalivas 2001; Sanchez and Sorg 2001; Kalivas and McFarland 2003). The development of a treatment strategy that makes use of the reconsolidation process will ultimately need to be powerful enough to diminish drug-seeking behavior in the presence of sizable doses of the drug itself. Therefore, the primary goal of this study was to determine whether drug-primed reinstatement could be suppressed in rats that have the memory reactivated in the presence of a pharmacological agent in cocaine self-administering rats. Since we previously have demonstrated the ability to disrupt cocaine-primed reinstatement only in animals in which the memory was reactivated using cocaine-induced CPP, we also tested the extent to which the same parameters used to disrupt reconsolidation in a cocaine-induced CPP task would disrupt reconsolidation in a cocaine self-administration task under conditions of drug-induced reinstatement.To examine this question, we chose the noncompetitive NMDA receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801). MK-801 has been shown to disrupt reconsolidation of spatial tasks (Przybyslawski and Sara 1997), fear tasks (Lee et al. 2006b), amphetamine-induced CPP (Sadler et al. 2007), cocaine-induced CPP (Kelley et al. 2007), and sucrose self-administration (Lee and Everitt 2008). Importantly, the two studies examining CPP using MK-801 did not explore whether MK-801 suppressed drug-seeking behavior in a manner that was dependent on whether the memory was reactivated, leaving open the possibility that it was not a reconsolidation process that was disrupted by MK-801.Here we demonstrate that MK-801 injected prior to cocaine-primed reinstatement of CPP disrupted subsequent cocaine-primed reinstatement of CPP, and this disruption was dependent on CPP contextual reactivation since injection of MK-801 and cocaine in the home cage did not disrupt subsequent cocaine-primed reinstatement of CPP. However, drug-seeking behavior in animals trained for cocaine self-administration was not disrupted when rats were reactivated under the same parameters that disrupted cocaine-induced CPP or when rats were given a reactivation session identical to their self-administration sessions. We thus demonstrate for the first time that memories associated with cocaine-induced CPP and cocaine self-administration are not similarly susceptible to disruption by MK-801.     

Encoding, consolidation, and retrieval of contextual memory: differential involvement of dorsal CA3 and CA1 hippocampal subregions

Studies on human and animals shed light on the unique hippocampus contributions to relational memory. However, the particular role of each hippocampal subregion in memory processing is still not clear. Hippocampal computational models and theories have emphasized a unique function in memory for each hippocampal subregion, with the CA3 area acting as an autoassociative memory network and the CA1 area as a critical output structure. In order to understand the respective roles of the CA3- and CA1-hippocampal areas in the formation of contextual memory, we studied the effects of the reversible inactivation by lidocaine of the CA3 or CA1 areas of the dorsal hippocampus on acquisition, consolidation, and retrieval of a contextual fear conditioning. Whereas infusions of lidocaine never impaired elementary tone conditioning, their effects on contextual conditioning provided interesting clues about the role of these two hippocampal regions. They demonstrated first that the CA3 area is necessary for the rapid elaboration of a unified representation of the context. Secondly, they suggested that the CA1 area is rather involved in the consolidation process of contextual memory. Third, they showed that CA1 or CA3 inactivation during retention test has no effect on contextual fear retrieval when a recognition memory procedure is used. In conclusion, our findings point as evidence that CA1 and CA3 subregions of the dorsal hippocampus play important and different roles in the acquisition and consolidation of contextual fear memory, whereas they are not required for context recognition.