Postextinction infusion of a mitogen-activated protein kinase inhibitor into the medial prefrontal cortex impairs memory of the extinction of conditioned fear

We investigated whether postextinction training infusion of PD098059, a selective inhibitor of mitogen-activated protein kinase (MAPK) activation, into the medial prefrontal cortex, would impair retention of extinction learning in rats. We found that immediate, but not late (2 or 4 h), postextinction infusion of PD098059 provoked a full return of conditioned freezing. These results suggest that activation of prefrontal MAPK in early stages of postextinction training participates in processes that protect against spontaneous recovery of aversive responses.     

Reinstatement of fear to an extinguished conditioned stimulus: two roles for context

The authors studied the role of context in reinstatement. Freezing was reinstated when the conditioned stimulus (CS) was extinguished in 1 context and rats moved to another context for reexposure to the shock unconditioned stimulus (US) and test. It was also reinstated (rather than renewed) when rats were shocked in the extinction context and moved to another context for test. This reinstatement was CS specific and reduced by nonreinforced exposures to the extinction context. Rats shocked in the context in which a stimulus had been preexposed froze when tested in another context. These findings suggest 2 roles for context in reinstatement: conditioning of the test context (M. E. Bouton, 1993) and mediated conditioning by the extinction context (P. C. Holland, 1990).     

Compounds of conditioned fear stimuli

A differential conditioning procedure was used with rats to establish different levels of suppression to two different stimuli. One stimulus was paired with shock every time it was presented, while the other stimulus cued shock on only 25% of its presentations. When these two component stimuli were subsequently tested as a simultaneous compound, two different types of component-compound relationships were observed. Some subjects showed greater suppression to the compound than they did to either component stimulus, while other subjects showed an intermediate level of suppression to the compound. The difference in type of component-compound relationship appeared to be related to the degree of stability (over trials) of each subject's reaction to the probabilistic (25%) cue.When a similar discrimination was established based on the intensity of the shock, rather than its probability of occurrence, all subjects showed more suppression to the compound than to its individual component stimuli. These results are discussed in terms of their implications for choice of model for characterizing the interaction of conditioned states.     

Forgetting of conditioned fear inhibition

Three experiments assessed retention of conditioned fear and of fear inhibition over long-term retention intervals (35 days in two experiments, 25 days in the third). Although excitatory conditioning was retained well, conditioned inhibition was not. This effect occurred when inhibition was assessed by compounding stimuli on an appetitive baseline and when it was assessed by testing cues on a baseline of unsignalled avoidance responding. Inhibition was also forgotten when the initial conditioning treatment was designed to reduce the role of possible proactive interference processes.     

Timing behavior and conditioned fear

Rats were trained on a two-response timing procedure which required that response B follow response A by at least a minimum specified interval in order to be reinforced with food. Repeated presentation (5 min on, 5 min off) of an auditory warning stimulus terminated by a brief electric shock to the feet (conditioned fear) produced a marked suppression in the frequency of A-to-B response sequences during the warning stimulus. The distribution of A-to-B interresponse times (timing behavior), however, did not change during the warning stimulus.     

Face your fears: attenuating remote fear memories by reconsolidation-updating

Traumatic events generate some of the most enduring memories, yet little is known about how long-lasting fear memories can be attenuated. In this review, we collect the surprisingly sparse evidence on remote fear memory attenuation from both animal and human research. What is becoming apparent is twofold: although remote fear memories are more resistant to change compared with recent ones, they can nevertheless be attenuated when interventions are targeted toward the period of memory malleability instigated by memory recall, the reconsolidation window. We describe the physiological mechanisms underlying remote reconsolidation-updating approaches and highlight how they can be enhanced through interventions promoting synaptic plasticity. By capitalizing on an intrinsically relevant phase of memory, reconsolidation-updating harbors the potential to permanently alter remote fear memories.     

Effects of contingency violations on the extinction of a conditioned fear inhibitor and a conditioned fear excitor

Rats were used in a conditioned-suppression paradigm to assess the effects of contingency variations on responding to a conditioned inhibitor (CS-) and a conditioned excitor (CS+). In Experiment 1, various unconditioned stimulus (US) frequencies were equated across the presence and absence of a CS- in the context of either background cues (continuous-trial procedure) or an explicit neutral event (discrete-trial procedure). With both procedures, a CS-alone treatment enhanced inhibition, whereas treatments involving 50% or 100% reinforcement for the CS- eliminated inhibition without conditioning excitation to that CS. The latter outcome also occurred in Experiment 2, with discrete-trial training equating considerably reduced US frequencies for the presence and absence of the CS-. In further evidence that inhibition was eliminated without conditioning excitation to the CS-, Experiment 3 showed that a novel CS did not acquire excitation when 25%, 50%, or 100% reinforcement was equated across the presence and absence of that CS in the context of a discrete-trial event. Using the procedures of Experiment 1, Experiment 4 showed that a CS+ was extinguished by a CS-alone treatment but was substantially maintained by treatments involving 50% or 100% uncorrelated reinforcement. These effects for a CS+ and a CS- implicate CS-US contiguity, rather than contingency, as the factor determining the extinction of a CS.     

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.     

Reciprocal inhibition of a laboratory conditioned fear

Electric shock was used to establish a conditioned fear in 48 college Ss, who then received either deep muscle relaxation training, cognitive relaxation training or anxiety relief conditioning. Relaxation was conditioned to a slide of the word NOW and the aversive stimulus was a pure red slide. The compound stimulus NOW on a red background was presented to generate counterconditioning, followed by a re-presentation of pure red as a measure of transfer. GSR and Blood Volume Pulse were recorded for evaluation of the fear reduction generated by each training procedure. All group differences were non-significant. The two relaxation procedures were equally effective, while the Anxiety Relief group manifested consistently smaller response-reduction. Implications and the usefulness of the paradigm were discussed.     

Counteraction between two kinds of conditioned inhibition training

In a Pavlovian fear-conditioning preparation, we investigated the effects of combining Pavlovian and explicitly unpaired inhibition treatments. A summation test for inhibition suggested a strong tendency toward unpaired inhibition when that treatment was administered alone and found robust Pavlovian inhibition when that treatment was administered alone, but detected little behavior indicative of inhibition in subjects that experienced both treatments during training. The retardation test showed reliable unpaired and Pavlovian inhibition when these treatments were administered alone but no indication of inhibition in subjects that experienced both treatments. These counterintuitive results suggest that in some circumstances the effects of two inhibitory treatments are not additive but rather counteractive. The present results provide some information about the nature of conditioned inhibition and, more generally, cue interaction.     

Contextual control of the extinction of conditioned fear

Rats received 15 pairings of a CS and shock in one context, and then a series of CS-alone trials in a second context. Even though this extinction procedure produced a complete loss of conditioned suppression, when the animals were returned to the site of original conditioning, suppression was renewed to a level comparable to that of animals that had not undergone extinction. Controls indicated that the renewed suppression was not due solely to pseudoconditioning, suggesting that the CS-US association had survived extinction. Renewed suppression was also demonstrated in a third context that was never associated with shock. Loss of suppression did not necessarily depend upon inhibitory conditioning of the extinction context. The data suggest that extinction of conditioned fear is specific to the context in which it occurs. They also suggest the possibility that animals might discriminate episodes in which a CS is reinforced and nonreinforced independently of the excitatory or inhibitory status of cues, like contextual stimuli, that are coincidentally present during those episodes.     

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.     

条件性恐惧提取消退的性别差异

基于记忆再巩固理论的提取消退范式能够有效地削弱非适应性恐惧记忆。性别差异是个体差异性研究的关键变量, 但在提取消退范式的研究中仍然比较少见关于性别差异的探索。因此本研究以立体几何图形作为条件刺激, 腕部电击作为非条件刺激, 皮肤电反应为恐惧反应指标, 探究提取消退范式在恐惧消退效果上是否存在性别差异。结果表明, 在恐惧自发恢复测试中, 提取消退范式的所有被试都成功抑制了恐惧复发, 但恐惧重建测试中只有女性被试抑制了恐惧复发。这说明, 提取消退范式在抑制恐惧自发恢复方面效果显著, 在恐惧重建上女性的消退效果显著优于男性。     

Post-training unilateral amygdala lesions selectively impair contextual fear memories

The basolateral amygdala (BLA) and the dorsal hippocampus (dHPC) are both structures with key roles in contextual fear conditioning. During fear conditioning, it is postulated that contextual representations of the environment are formed in the hippocampus, which are then associated with foot shock in the amygdala. However, it is not known to what extent a functional connection between these two structures is required. This study investigated the effect on contextual and cued fear conditioning of disconnecting the BLA and dHPC, using asymmetrically placed, excitotoxic unilateral lesions. Post-training lesions selectively impaired contextual, but not cued, fear, while pretraining lesions resulted in a similar but nonsignificant pattern of results. This effect was unexpectedly observed in both the contralateral disconnection group and the anticipated ipsilateral control, which prompted further examination of individual unilateral lesions of BLA and dHPC. Post-training unilateral dHPC lesions had no effect on contextual fear memories while bilateral dHPC lesions and unilateral BLA lesions resulted in a near total abolition of contextual fear but not cued conditioned fear. Again, pretraining unilateral BLA lesions resulted in a strong but nonsignificant trend to the impairment of contextual fear. Furthermore, an analysis of context test-induced Fos protein expression in the BLA contralateral to the lesion site revealed no differences between post-training SHAM and unilateral BLA lesioned animals. Therefore, post-training unilateral lesions of the BLA are sufficient to severely impair contextual, but not cued, fear memories.     

远期恐惧记忆再巩固更新机制的线索选择性特点

已有动物和人类研究均表明, 通过记忆的再巩固更新机制能有效削弱新形成的条件性恐惧记忆(1天), 并且存在线索选择性特点。然而创伤后应激障碍(PTSD)往往在形成相当一段时间后才能得到治疗, 且现实生活中人们通常一次习得对多个线索的恐惧。因此找到针对多线索创伤记忆的有效治疗方法显得尤为重要。目前未有人研究远期恐惧记忆的再巩固更新机制是否存在线索选择性特点。为探究远期恐惧记忆(>7天)的再巩固更新机制是否同样存在线索选择性特点, 本研究采用被试内实验设计, 以皮肤电作为恐惧反应指标, 多个线索作为条件刺激进行恐惧习得, 习得14天后给被试单独呈现一个线索进行恐惧记忆提取, 10分钟后进行消退训练, 24小时后对不同线索进行自发恢复测试。结果显示：未提取线索的自发恢复程度显著高于提取线索。说明远期记忆(14天)的再巩固更新机制同样存在线索选择性特点, 并确认了提取消退作为一种行为手段对远期恐惧记忆再巩固进行干预的有效性, 对临床干预具有一定指导意义。