The amygdala and ventromedial prefrontal cortex in morality and psychopathy

Recent work has implicated the amygdala and ventromedial prefrontal cortex in morality and, when dysfunctional, psychopathy. This model proposes that the amygdala, through stimulus-reinforcement learning, enables the association of actions that harm others with the aversive reinforcement of the victims' distress. Consequent information on reinforcement expectancy, fed forward to the ventromedial prefrontal cortex, can guide the healthy individual away from moral transgressions. In psychopathy, dysfunction in these structures means that care-based moral reasoning is compromised and the risk that antisocial behavior is used instrumentally to achieve goals is increased.     

Differential involvement of the central amygdala in appetitive versus aversive learning

Understanding the function of the distinct amygdaloid nuclei in learning comprises a major challenge. In the two studies described herein, we used c-Fos immunolabeling to compare the engagement of various nuclei of the amygdala in appetitive and aversive instrumental training procedures. In the first experiment, rats that had already acquired a bar-pressing response to a partial food reinforcement were further trained to learn that an acoustic stimulus signaled either continuous food reinforcement (appetitive training) or a footshock (aversive training). The first training session of the presentation of the acoustic stimulus resulted in significant increases of c-Fos immunolabeling throughout the amygdala; however, the pattern of activation of the nuclei of the amygdala differed according to the valence of motivation. The medial part of the central amygdala (CE) responded, surprisingly, to the appetitive conditioning selectively. The second experiment was designed to extend the aversive versus appetitive conditioning to mice, trained either for place preference or place avoidance in an automated learning system (INTELLICAGE). Again, much more intense c-Fos expression was observed in the medial part of the CE after the appetitive training as compared to the aversive training. These data, obtained in two species and by means of novel experimental approaches balancing appetitive versus aversive conditioning, support the hypothesis that the central nucleus of the amygdala is particularly involved in appetitively motivated learning processes.     

Analysis of treatments to alleviate forgetting in rats

Two experiments with rats investigated the effectiveness of prior-cuing treatments for alleviating forgetting of aversive conditioning. The aim was to see which retrieval cues would be most effective within different contexts. Experiment 1 examined the contexts of classical fear conditioning and instrumental avoidance training. The results indicated that the response components were sufficient to reinstate avoidance training, whereas the unconditioned stimulus (US) was most effective for classical fear conditioning. In Experiment 1, the reinforcer per se was ineffective in reinstating instrumental avoidance training. Experiment 2 manipulated the training context and found that the US could be made an effective prior-cuing treatment for instrumental training if classical conditioning components were more prevalent during training. These results are interpreted to mean that a "critical context" must be reinstated by the cuing treatment if this treatment is to promote retrieval of the memory.     

Complex effects of NMDA receptor antagonist APV in the basolateral amygdala on acquisition of two-way avoidance reaction and long-term fear memory

Although much has been learned about the role of the amygdala in Pavlovian fear conditioning, relatively little is known about an involvement of this structure in more complex aversive learning, such as acquisition of an active avoidance reaction. In the present study, rats with a pretraining injection of the N-methyl-D-aspartate (NMDA) receptor antagonist, 2-amino-5-phosphonopentanoic acid (APV), into the basolateral amygdala (BLA) were found to be impaired in two-way active avoidance learning. During multitrial training in a shuttle box, the APV-injected rats were not different from the controls in sensitivity to shock or in acquisition of freezing to contextual cues. However, APV injection led to impaired retention of contextual fear when tested 48 h later, along with an attenuation of c-Fos expression in the amygdala. These results are consistent with the role of NMDA receptors of the BLA in long-term memory of fear, previously documented in Pavlovian conditioning paradigms. The APV-induced impairment in the active avoidance learning coincided with deficits in directionality of the escape reaction and in attention to conditioned stimuli. These data indicate that normal functioning of NMDA receptors in the basolateral amygdala is required during acquisition of adaptive instrumental responses in a shuttle box but is not necessary for acquisition of short-term contextual fear in this situation.     

Psychopathy,frustration, and reactive aggression: The role of ventromedial prefrontal cortex

Psychopathy is a developmental disorder marked by emotional hyporesponsiveness and an increased risk for instrumental and reactive aggression. The increased risk for reactive aggression is the focus of the current paper. It will be argued that the increased risk for reactive aggression does not relate to an increased sensitivity to threatening stimuli since psychopathy is associated with a reduced sensitivity to threat. Instead, it is argued that the increased risk for reactive aggression relates to an increased risk for frustration; i.e., the emotional state following the performance of an action in the expectation of a particular reward and not receiving this reward. Two impairments seen in psychopathy would increase the risk for frustration and consequent potential reactive aggression; impairments in stimulus‐reinforcement learning and reversal learning. It is argued that both are known consequences of impairment in ventromedial prefrontal cortex, one of the regions principally implicated in psychopathy.     

Autonomic conditioning to monetary and social stimuli and aggression in children

Poor conditioning to punishment, such as loud tones or electric shock, has been proposed as an important factor involved in the etiology of aggressive and psychopathic behavior. However, it is not known whether the association holds when monetary or social stimulus is used as the unconditioned stimulus, and if aggressive individuals also have impaired conditioning to rewards. In this study, skin conductance responses in a conditioning task involving both monetary/social reward and punishment as unconditioned stimuli were assessed in 340 male and female 8‐ to 9‐year‐old children from the community. Children reported their reactive and proactive aggression using the Reactive and Proactive Aggression Questionnaire (RPQ; Raine et al., 2006). Results showed that monetary/social reward and punishment were effective in eliciting physiological classical conditioning in children, and that reduced reward conditioning was associated with high levels of proactive aggression in particular. Findings highlight the importance of distinguishing between reactive and proactive aggression when examining antisocial behavior in children, and suggest that reward‐oriented treatment programs may not be effective for children with more proactive, instrumental aggressive behavior.

     

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.     

Is there a mutual relationship between opposite attentional biases underlying anxiety?

Current models that account for attentional processes in anxiety have proposed that high-trait anxious individuals are characterized by a hypervigilant-avoidant pattern of attentional biases to threat. We adopted a laboratory conditioning procedure to induce concomitant hypervigilance and avoidance to threat, emphasizing a putative relationship between lower-level reactive and upper-level controlled attentional mechanisms as the core account of attentional processes involved in the development and maintenance of anxiety. Eighty high- and low-trait anxious participants underwent Pavlovian conditioning to a human face. Eye tracking was used to monitor attentional changes to the conditioned stimulus (CS+) face and the neutral stimulus (CS-) face, presented at 200, 500, and 800 ms durations. The high-anxious participants developed the expected attentional bias toward the CS+ at 200 ms presentation time and attentional avoidance at 500 and 800 ms durations. Hypervigilance to aversive stimuli at 200 ms and later avoidance to the same stimuli at 500 and 800 ms were associated with higher levels of galvanic skin conductance to the CS+. The low-anxious individuals developed the opposite attentional pattern with an initial tendency to orient attention away from the aversive stimuli in the 200 ms condition and to orient attention toward aversive stimuli in the remaining time. The differential modulation between hypervigilance and avoidance elicited in the two groups by the conditioning procedure suggests that vulnerability to anxiety is characterized by a latent relationship between diverse attentional mechanisms. Within this relationship, hypervigilance and avoidance to threat operate at different stages of information processing suggesting fuzzy boundaries between early reactive and later-strategic processing of threat.     

Effects of partial avoidance and punishment contingencies on shuttlebox-avoidance learning in Fischer 344 rats

An unsignaled, escapable shock was presented contingent on an avoidance response. Fischer 344 rats responded less to the warning signal in proportion to its temporal distance from the avoidance response. Partial contingency effects were further obtained by variation in the instrumental conditioning space for an aversive stimulus. However, the arbitrary omission of an imminent shock on half the trial in which the rats failed to avoid a shock, led to little avoidance acquisition, and shock-frequency reduction was thus not sufficient to produce the acquisition of the avoidance response. Because early avoidance responses were initiated by escape from shock, a stimulus contingency may be essential for response initiation, and an explicit response contingency is important in maintaining successful avoidance responses.     

Evidence for an expectancy-based theory of avoidance behaviour

In most studies on avoidance learning, participants receive an aversive unconditioned stimulus after a warning signal is presented, unless the participant performs a particular response. Lovibond (2006) recently proposed a cognitive theory of avoidance learning, according to which avoidance behaviour is a function of both Pavlovian and instrumental conditioning. In line with this theory, we found that avoidance behaviour was based on an integration of acquired knowledge about, on the one hand, the relation between stimuli and, on the other hand, the relation between behaviour and stimuli.     

Evidence for an expectancy-based theory of avoidance behaviour

In most studies on avoidance learning, participants receive an aversive unconditioned stimulus after a warning signal is presented, unless the participant performs a particular response. Lovibond (2006) recently proposed a cognitive theory of avoidance learning, according to which avoidance behaviour is a function of both Pavlovian and instrumental conditioning. In line with this theory, we found that avoidance behaviour was based on an integration of acquired knowledge about, on the one hand, the relation between stimuli and, on the other hand, the relation between behaviour and stimuli.     

伤害回避的脑机制及其生物基础

伤害回避是指个体对厌恶刺激信号做出强烈的反应,并学会被动地回避惩罚的一种倾向,这一倾向使得个体反复思考未来的结局,并谨慎小心地对待不确定情景中的事件,进而更有可能诱发情感障碍。伤害回避涉及的神经网络包括三个子网络,即额顶叶-前扣带皮层的连接、皮层-杏仁核的连接和白质通道的结构性连接,这三个子网络分别与羞怯感-易疲劳性、预期担心以及不确定环境中的害怕情绪有关。而其生物基础则包括单一基因多态性和基因多态间的交互作用。今后的研究应该集中在深化伤害回避神经网络与生物基础间的联合机制、研究三种及以上基因多态间的交互作用、考察其他因素对基因效应的调节作用、注重伤害回避四种亚型相关神经网络之间的连接、探讨5-HT4等其他几种5-羟色胺受体多态性与伤害回避的关系以及分析伤害回避内部机制在抗抑郁治疗中的作用等方面。     

Opioid modulation of Fos protein expression and olfactory circuitry plays a pivotal role in what neonates remember

Paradoxically, fear conditioning (odor-0.5 mA shock) yields a learned odor preference in the neonate, presumably due to a unique learning and memory circuit that does not include apparent amygdala participation. Post-training opioid antagonism with naltrexone (NTX) blocks consolidation of this odor preference and instead yields memory of a learned odor aversion. Here we characterize the neural circuitry underlying this switch during memory consolidation. Experiment 1 assessed post-training opioid modulation of Fos protein expression within olfactory circuitry (olfactory bulb, piriform cortex, amygdala). Odor-shock conditioning with no post-training treatment (odor preference) induced significant changes in Fos protein expression in the granule cell layer of the olfactory bulb and anterior piriform cortex. Post-training opioid receptor antagonism (odor aversion) prevented the learning-induced changes in the anterior piriform cortex and also induced significant changes in Fos protein expression in the central nucleus of the amygdala. Experiment 2 assessed intra-amygdala opioid modulation of neonate memory consolidation. Post-training infusion of NTX within the amygdala permitted consolidation of an odor aversion, while vehicle-infused pups continued to demonstrate an odor preference. Overall, results demonstrate that opioids modulate memory consolidation in the neonate via modulating Fos protein expression in olfactory circuitry. Furthermore, these results suggest that opioids are instrumental in suppressing neonate fear behavior via modulating the amygdala.     

Flavor-illness aversions: potentiation of odor by taste is disrupted by application of novocaine into amygdala

Taste and odor have different properties in toxiphobic conditioning. When each is used alone, taste becomes aversive when followed by immediate or delayed poison, while odor becomes aversive only if followed by immediate poison. However, if odor and taste are presented as a compound and followed by delayed poison, then odor does become aversive when tested alone. It is as if taste has potentiated the odor signal. Several experiments assessed the role of the amygdala in this potentiation effect by anesthetizing the amygdala with 10% novocaine. Novocaine applied 30 min before presentation (Pre-CS) of an odor-taste compound disrupted the potentiated odor aversion but not the taste aversion. In contrast, novocaine applied 1 min after the compound odor-taste or 1 min prior to LiCl poison did not dissociate odor and taste aversions; both odor and taste aversions were facilitated. Novocaine applied 30 min before an odor alone also disrupted an odor aversion induced by immediate LiCl. But identical treatment did not disrupt odor avoidance conditioned by immediate foot-shock, suggesting that amygdala anesthesia does not simply produce anosmia. Pre-CS novocaine treatment also disrupted flavor neophobia prior to conditioning. The results suggest that novocaine applied to the amygdala disrupts the integration of odor with taste and illness during toxiphobic conditioning.     

Impaired appetitively as well as aversively motivated behaviors and learning in PDE10A-deficient mice suggest a role for striatal signaling in evaluative salience attribution

Phosphodiesterase 10A (PDE10A) hydrolyzes both cAMP and cGMP, and is a key element in the regulation of medium spiny neuron (MSN) activity in the striatum. In the present report, we investigated the effects of targeted disruption of PDE10A on spatial learning and memory as well as aversive and appetitive conditioning in C57BL/6 J mice. Because of its putative role in motivational processes and reward learning, we also determined the expression of the immediate early gene zif268 in striatum and anterior cingulate cortex. Animals showed decreased response rates in scheduled appetitive operant conditioning, as well as impaired aversive conditioning in a passive avoidance task. Morris water maze performance revealed not-motor related spatial learning and memory deficits. Anxiety and social explorative behavior was not affected in PDE10A-deficient mice. Expression of zif268 was increased in striatum and anterior cingulate cortex, which suggests alterations in the neural connections between striatum and anterior cingulate cortex in PDE10A-deficient mice. The changes in behavior and plasticity in these PDE10A-deficient mice were in accordance with the proposed role of striatal MSNs and corticostriatal connections in evaluative salience attribution.     

Social anxiety and cognitive expectancy of aversive outcome in avoidance conditioning

Fear conditioning studies have shown that social anxiety is associated with enhanced expectancy of aversive outcome. However, the relation between cognitive expectancy and social anxiety has never been tested in avoidance conditioning paradigms. We compared 48 low (LSA) and high socially anxious individuals (HSA) on subjective expectancy of aversive outcome during an avoidance conditioning task. Displays of neutral faces were coupled with an aversive outcome (US): a shout and a shock. Participants could avoid the US by pressing a correct button from a button box. First, HSA showed higher US expectancy than LSA during the initial phase of avoidance conditioning, supporting the view that socially anxious individuals have an expectancy bias when social situations are ambiguous. Second, when the avoidance response became unavailable, LSA showed lower US expectancy than HSA, suggesting that low socially anxious individuals are prone to a positive bias when perceived threat is high. A lack of such positive bias in socially anxious individuals may lead to higher susceptibility to safety behavior interpretations. Together, these findings support the role of cognitive processes in avoidance conditioning and underscore the relevance to encounter avoidance learning when studying social anxiety.     

Toxicosis affects instrumental behaviour in rats

Three experiments examined the effect of toxicosis on instrumental responding. These studies were prompted by Morrison and Collyer's (1974, Experiment 1) finding that the induction of toxicosis after an instrumental conditioning session produces greater response suppression if the response is reinforced by a novel saccharin solution rather than familiar water during conditioning. Experiments 1 and 2 investigated whether this suppression was mediated by the Pavlovian contingency between the contextual cues and the saccharin solution or the instrumental relationship between the response and the reward. A role for the instrumental contingency was indicated by the greater suppression of the response producing novel saccharin rather than water when the context of both responses was equally associated with the saccharin and illness. Experiment 3 found that extinction of the aversion to a novel reinforcer following aversive conditioning would re-establish an action previously associated with that reinforcer, in contrast to an action whose reinforcer remained aversive. This result was a further indication that the instrumental contingency between the response and reward contributes to response suppression.     

Aversive CS control of instrumental avoidance as a function of selected parameters and method of Pavlovian conditioning

Effects of aversive CSs upon dogs' instrumental avoidance responding were assessed as a function of the Pavlovian conditioning parameters using off-baseline (Experiment 1) and on-baseline (Experiment 2) conditioning procedures. In each experiment, three UCS intensitites (2, 6, and 10 mA) were crossed factorially with two CS-UCS intervals (10 and 90 sec) yielding six groups. After 4 days of conditioning, the CS-produced effects on avoidance were determined primarily by an interaction between Pavlovian procedure (off- versus on-baseline) and UCS intensity. With off-baseline conditioning, CS-produced facilitation of avoidance was an increasing function of the UCS intensity. However, with on-baseline conditioning, only the CS paired with weak UCS facilitated avoidance, and the CS paired with the strong UCS suppressed responding. This reversing parametric function poses problems for two-process motivational theories of avoidance.     

The role of amygdala nuclei in the expression of auditory signaled two-way active avoidance in rats

Using a two-way signaled active avoidance (2-AA) learning procedure, where rats were trained in a shuttle box to avoid a footshock signaled by an auditory stimulus, we tested the contributions of the lateral (LA), basal (B), and central (CE) nuclei of the amygdala to the expression of instrumental active avoidance conditioned responses (CRs). Discrete or combined lesions of the LA and B, performed after the rats had reached an asymptotic level of avoidance performance, produced deficits in the CR, whereas CE lesions had minimal effect. Fiber-sparing excitotoxic lesions of the LA/B produced by infusions of N-methyl-d-aspartate (NMDA) also impaired avoidance performance, confirming that neurons in the LA/B are involved in mediating avoidance CRs. In a final series of experiments, bilateral electrolytic lesions of the CE were performed on a subgroup of animals that failed to acquire the avoidance CR after 3 d of training. CE lesions led to an immediate rescue of avoidance learning, suggesting that activity in CE was inhibiting the instrumental CR. Taken together, these results indicate that the LA and B are essential for the performance of a 2-AA response. The CE is not required, and may in fact constrain the instrumental avoidance response by mediating the generation of competing Pavlovian responses, such as freezing.Early studies of the neural basis of fear often employed avoidance conditioning procedures where fear was assessed by measuring instrumental responses that reduced exposure to aversive stimuli (e.g., Weiskrantz 1956; Goddard 1964; Sarter and Markowitsch 1985; Gabriel and Sparenborg 1986). Despite much research, studies of avoidance failed to yield a coherent view of the brain mechanisms of fear. In some studies, a region such as the amygdala would be found to be essential and in other studies would not. In contrast, rapid progress in understanding the neural basis of fear and fear learning was made when researchers turned to the use of Pavlovian fear conditioning (Kapp et al. 1984, 1992; LeDoux et al. 1984; Davis 1992; LeDoux 1992; Cain and Ledoux 2008a). It is now well established from such studies that specific nuclei and subnuclei of the amygdala are essential for the acquisition and storage of Pavlovian associative memories about threatening situations (LeDoux 2000; Fanselow and Gale 2003; Maren 2003; Maren and Quirk 2004; Schafe et al. 2005; Davis 2006).Several factors probably contributed to the fact that Pavlovian conditioning succeeded where avoidance conditioning struggled. First, avoidance conditioning has long been viewed as a two-stage learning process (Mowrer and Lamoreaux 1946; Miller 1948b; McAllister and McAllister 1971; Levis 1989; Cain and LeDoux 2008b). In avoidance learning, the subject initially undergoes Pavlovian conditioning and forms an association between the shock and cues in the apparatus. The shock is an unconditioned stimulus (US) and the cues are conditioned stimuli (CS). Subsequently, the subject learns the instrumental response to avoid the shock. Further, the “fear” aroused by the presence of the CS motivates learning of the instrumental response. Fear reduction associated with successful avoidance has even been proposed to be the event that reinforces avoidance learning (e.g., Miller 1948b; McAllister and McAllister 1971; Cain and LeDoux 2007). Given that Pavlovian conditioning is the initial stage of avoidance conditioning, as well as the source of the “fear” in this paradigm, it would be more constructive to study the brain mechanisms of fear through studies of Pavlovian conditioning rather than through paradigms where Pavlovian and instrumental conditioning are intermixed. Second, avoidance conditioning was studied in a variety of ways, but it was not as well appreciated at the time as it is today; that subtle differences in the way tasks are structured can have dramatic effects on the brain mechanisms required to perform the task. There was also less of an appreciation for the detailed organization of circuits in areas such as the amygdala. Thus, some avoidance studies examined the effects of removal of the entire amygdala or multiple subdivisions (for review, see Sarter and Markowitsch 1985). Finally, fear conditioning studies typically involved a discrete CS, usually a tone, which could be tracked from sensory processing areas of the auditory system to specific amygdala nuclei that process the CS, form the CS–US association, and control the expression of defense responses mediated by specific motor outputs. In contrast, studies of avoidance conditioning often involved diffuse cues, and the instrumental responses used to indirectly measure fear were complex and not easily mapped onto neural circuits.Despite the lack of progress in understanding the neural basis of avoidance responses, this behavioral paradigm has clinical relevance. For example, avoidance behaviors provide an effective means of dealing with fear in anticipation of a harmful event. When information is successfully used to avoid harm, not only is the harmful event prevented, but also the fear arousal, anxiety, and stress associated with such events; (Solomon and Wynne 1954; Kamin et al. 1963). Because avoidance is such a successful strategy to cope with danger, it is used extensively by patients with fear-related disorders to reduce their exposure to fear- or anxiety-provoking situations. Pathological avoidance is, in fact, a hallmark of anxiety disorders: In avoiding fear and anxiety, patients often fail to perform normal daily activities (Mineka and Zinbarg 2006).We are revisiting the circuits of avoidance conditioning from the perspective of having detailed knowledge of the circuit of the first stage of avoidance, Pavlovian conditioning. To most effectively take advantage of Pavlovian conditioning findings, we have designed an avoidance task that uses a tone and a shock. Rats were trained to shuttle back and forth in a runway in order to avoid shock under the direction of a tone. That is, the subjects could avoid a shock if they performed a shuttle response when the tone was on, but received a shock if they stayed in the same place (two-way signaled active avoidance, 2-AA). While the amygdala has been implicated in 2-AA (for review, see Sarter and Markowitsch 1985), the exact amygdala nuclei and their interrelation in a circuit are poorly understood.We focused on the role of amygdala areas that have been studied extensively in fear conditioning: the lateral (LA), basal (B), and central (CE) nuclei. The LA is widely thought to be the locus of plasticity and storage of the CS–US association, and is an essential part of the fear conditioning circuitry. The basal amygdala, which receives inputs from the LA (Pitkänen 2000), is not normally required for the acquisition and expression of fear conditioning (Amorapanth et al. 2000; Nader et al. 2001), although it may contribute under some circumstances (Goosens and Maren 2001; Anglada-Figueroa and Quirk 2005). The B is also required for the use of the CS in the motivation and reinforcement of responses in other aversive instrumental tasks (Killcross et al. 1997; Amorapanth et al. 2000). The CE, through connections to hypothalamic and brainstem areas (Pitkänen 2000), is required for the expression of Pavlovian fear responses (Kapp et al. 1979, 1992; LeDoux et al. 1988; Hitchcock and Davis 1991) but not for the motivation or reinforcement of aversive instrumental responses (Amorapanth et al. 2000; LeDoux et al. 2009). We thus hypothesized that damage to the LA or B, but not to the CE, would interfere with the performance of signaled active avoidance.     

Escape from fear: a detailed behavioral analysis of two atypical responses reinforced by CS termination

Escape from fear (EFF) is a controversial paradigm according to which animals learn to actively escape a fear-eliciting conditioned stimulus (CS) if the escape response (R-sub(e)) is paired with CS termination. Some theories posit that EFF learning is responsible for instrumental avoidance conditioning. However, EFF learning has typically been weaker than avoidance learning and difficult to reproduce. The authors examined EFF learning and memory with 2 atypical R-sub(e)s: rearing and nose-poking. The data suggest that rearing, but not nose-poking, can be learned as an instrumental EFF response. Further, EFF memory was response specific, aversively motivated, and controlled by the CS. Successful EFF learning also resulted in better long-term elimination of a passive fear reaction (freezing). Factors important for EFF experiments and theoretical considerations are discussed.