Noradrenergic enhancement of associative fear memory in humans

Ample evidence in animals and humans supports the noradrenergic modulation in the formation of emotional memory. However, in humans the effects of stress on emotional memory are traditionally investigated by declarative memory tests (e.g., recall, recognition) for non-associative emotional stimuli (e.g., stories, pictures). Given that anxiety disorders are thought to originate from associative learning processes and are characterized by distressing emotional responses, the existing literature seems to be inconclusive for the understanding of these disorders. Here, we tested whether noradrenaline strengthens the emotional expression of associative fear memory by using a differential fear conditioning procedure in humans. Stimulation of the noradrenergic system by the administration of yohimbine HCl (20 mg) during memory formation did not directly augment the differential startle fear response 48 h later. Yet, the other retention tests uncovered that the administration of yohimbine HCl contrary to placebo pill extensively delayed the process of extinction learning and generated a superior recovery of fear (i.e., reinstatement and reacquisition). Conversely, the yohimbine HCl manipulation did not affect the skin conductance responding and the US expectancy ratings, emphasizing the concept of multiple memory systems. To our knowledge this is the first demonstration in humans that increased noradrenaline release during or shortly after a stressful event strengthens the formation of associative fear memory traces. The present findings suggest that noradrenaline may play an important role in the etiology and maintenance of anxiety disorders.     

Sensitivity to spacing changes in faces and nonface objects in preschool-aged children and adults

Sensitivity to variations in the spacing of features in faces and a class of nonface objects (i.e., frontal images of cars) was tested in 3- and 4-year-old children and adults using a delayed or simultaneous two-alternative forced choice matching-to-sample task. In the adults, detection of spacing information was robust against exemplar differences for faces but varied across exemplars for cars (Experiment 1A). The 4-year-olds performed above chance in both face and car discrimination even when differences in spacing were very small (within ±1.6 standard deviations [SDs]) and the task involved memory components (Experiment 1B), and the same was true for the 3-year-olds when tested with larger spacing changes (within ±2.5 SDs) in a task that posed no memory demands (Experiment 2). An advantage in the discrimination of faces over cars was found at 4 years of age, but only when spacing cues were made more readily available (within ±2.5 SDs). Results demonstrate that the ability to discriminate objects based on feature spacing (i.e., sensitivity to second-order information) is present at 3 years of age and becomes more pronounced for faces than cars by 4 years of age.     

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.     

Delayed backward conditioning of place preference induced by wheel running in rats

Backward conditioning of place preference has been obtained in hungry rats when wheel running (the rewarding US) is followed immediately by exposure to a distinctive chamber (the CS). We tested whether such backward conditioning would occur with a 10-min delay. In each of four paired exposures, a period of wheel running (2 or 22 h, in separate experiments) was followed by 10 min in the home cage and then 30 min in the CS chamber. Control rats were put in the CS chamber without wheel running. In other similar experiments, a 0-, 10-, or 30-min delay separated wheel running from exposure to the CS chamber. Reliable conditioned place preference (CPP) occurred when the delay was 0 or 10 but not 30 min. The strength of CPP decreased as the delay increased. These findings imply that the reward process initiated by wheel running remains active for some time after running stops. They support the view that the suppression of feeding produced by wheel running in hungry rats (activity anorexia) is mediated by this reward process.     

Social reinforcement of somatic versus psychological description of depressive events

The cultural construction of illness model explains the clinical observation that psychological correlates of depression such as sadness and worthlessness are frequently reported in Western cultures, whereas somatic or vegetative complaints are often associated with depression in non-Western cultures. This study employed Portnoy and Salzinger's (J. Gen. Psychol. 70 (1964) 311) verbal conditioning paradigm to determine whether social contingencies, in the form of verbal and non-verbal reinforcement contingent upon verbal responses, affect the reporting of experiences related to depressive events. Using an ABA design, this experimental study (N=36) demonstrated that one's reporting of experiences of hypothetical depressive events, via psychological, somatic, or neutral verbal response classes, can be conditioned by verbal and non-verbal positive social reinforcement, and therefore socially constructed through environmental contingencies. This suggests one pathway by which culture can shape symptom presentation. Implications for clinical interviewing and behavioral assessment, especially in the cross-cultural context, are discussed.     

Classical fear conditioning in the anxiety disorders: a meta-analysis

Fear conditioning represents the process by which a neutral stimulus comes to evoke fear following its repeated pairing with an aversive stimulus. Although fear conditioning has long been considered a central pathogenic mechanism in anxiety disorders, studies employing lab-based conditioning paradigms provide inconsistent support for this idea. A quantitative review of 20 such studies, representing fear-learning scores for 453 anxiety patients and 455 healthy controls, was conducted to verify the aggregated result of this literature and to assess the moderating influences of study characteristics. Results point to modest increases in both acquisition of fear learning and conditioned responding during extinction among anxiety patients. Importantly, these patient-control differences are not apparent when looking at discrimination studies alone and primarily emerge from studies employing simple, single-cue paradigms where only danger cues are presented and no inhibition of fear to safety cues is required.     

Lack of phenotype for LTP and fear conditioning learning in calpain 1 knock-out mice

We previously proposed the hypothesis that calpain activation played an important role in long-term potentiation (LTP) of synaptic transmission in hippocampus. Two forms of calpain are predominant in brain tissues, calpain 1 (mu-calpain), activated by micromolar calcium concentration and calpain 2 (m-calpain), activated by millimolar calcium concentration in vitro. In the present study, we tested the role of calpain 1 in LTP and in learning and memory using calpain 1 knock-out mice. Changes in learning and memory were assessed using both context and tone fear conditioning. No differences in freezing responses were observed between the knock-out and the wild-type animals during the acquisition phase of the training, eliminating the possibility that the knock-out animals could be differentially affected by the foot shock. Likewise, no differences in freezing responses elicited by either the context or the tone were observed during the retention phase. No differences in short-term potentiation (STP) or LTP were observed in hippocampal slices from the knock-out and matched wild-type mice. Several interpretations might explain these negative results. First, it is conceivable that calpain 2 plays a more dominant role in neurons, and that calpain 1 makes a minor contribution as opposed to its suspected predominant role in the hematopoietic system. Alternatively, it is conceivable that some as yet unknown compensatory mechanisms take effect, and that calpain 2 or another calpain isoform substitutes for the missing calpain 1.     

Chronic stress impairs recall of extinction of conditioned fear

Chronic restraint stress produces retraction of apical dendrites of pyramidal neurons in medial prefrontal cortex. To begin to examine the functional significance of this dendritic reorganization, we assessed the effects of chronic restraint stress on a prefrontally mediated behavior, extinction of conditioned fear. After bar press training to obtain a baseline of activity against which to measure freezing, rats were either unstressed or stressed via placement in a plastic restrainer (3 h/day for 1 week). After an additional day of bar press training, rats underwent fear conditioning and extinction. Rats received five habituation trials to a 30-s tone (4.5 kHz, 80 db) followed by seven pairings of tone and footshock (500 ms, 0.5 mA). One hour later, rats received tone-alone extinction trials to criterion. The next day, rats received 15 additional extinction trials. Percent freezing was assessed during all phases of training. Stress did not significantly affect unconditioned responding to tone, acquisition of conditioned fear, or initial extinction, but significantly increased freezing on extinction day 2. Thus, consistent with the regressive dendritic changes seen in medial prefrontal cortex, one week of restraint stress specifically impaired recall of extinction, a pattern of deficits typical of animals with impaired medial prefrontal function.     

Some determinants of changes in preference over time

Results of longitudinal studies suggest that the stability of preferences varies across individuals, although it is unclear what variables account for these differences. We extended this work by conducting periodic assessments of preference for leisure activities over 3 to 6 months with 10 adults with developmental disabilities. Although previous research has collectively shown that preferences identified via repeated assessment are highly variable, our results showed that preferences were relatively stable for the majority (80%) of participants. In an attempt to identify some environmental determinants of shifts in preference, we provided extended daily access to high-preference items (preference-weakening manipulation) and paired access to low-preference items with social and edible putative reinforcers during brief sessions (preference-strengthening manipulation). Preference assessments continued over the course of these manipulations with 2 participants. Results showed that changes in preference across time could be produced systematically and suggest that naturally occurring changes in establishing operations or conditioning histories contribute to temporal shifts in preference. Implications for preference assessments, reinforcer usage, and planned attempts to change preferences are discussed.     

Expectancy-learning and evaluative learning in human classical conditioning: affective priming as an indirect and unobtrusive measure of conditioned stimulus valence

It has been argued that in classical conditioning two processes might be operative. First, one may learn that the conditioned stimulus (CS+) is a valid predictor for the occurrence of the biologically negative or positive event (US; expectancy-learning). Second, one may learn to perceive the conditioned stimulus itself as a negative or positive stimulus, depending on the valence of the event it has been associated with (evaluative learning). Until the present, however, both forms of learning have been investigated using rather different conditioning procedures. Using a differential aversive conditioning preparation with pictures of human faces as CSs and an electrocutaneous stimulus as US, we were able to demonstrate that both forms of learning can co-occur. Moreover, the extent of evaluative learning in this aversive conditioning procedure did not significantly differ from the amount of evaluative learning in an evaluative conditioning procedure with positive and negative adjectives as USs, which was administered to the same participants. In the present study evaluative learning was not only indexed by direct evaluative ratings, but we introduced affective priming as an indirect and unobtrusive, reaction time based measure of stimulus valence. Finally, imagery instructions during acquisition did not facilitate expectancy-learning nor evaluative learning.