An immediate-shock freezing deficit with discrete cues: A possible role for unconditioned stimulus processing mechanisms.

Five experiments with C57BL/6 mice (Mus musculus) investigated whether failures in shock processing might contribute to deficits in freezing that occur after an animal receives a shock immediately on exposure to a conditioning context. Experiment 1 found that more contextual freezing resulted from delayed shocks than from immediate shocks across 4 shock intensities. Experiment 2 extended the immediate-shock freezing deficit to discrete stimuli. Experiment 3 found that preexposure to the to-be-conditioned cue did not facilitate immediate cued conditioning. Experiment 4 found that context preexposure enhanced context-evoked fear after an immediate shock. Experiment 5 found that context preexposure also enhanced immediate cued conditioning. These findings are problematic for current theories of the immediate-shock freezing deficit that focus exclusively on processing of the conditioned stimulus, and they suggest that failures in shock processing may contribute to the deficit. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

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). (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Impaired trace and contextual fear conditioning in aged rats.

Trace and contextual fear conditioning were evaluated in adult (3-6 months), early middle-aged (8-12 months), late middle-aged (16-20 months), and aged (24-33 months) Sprague-Dawley rats. After trace conditioning, aged animals exhibited significantly less freezing to the tone conditioned stimulus and training context. Levels of trace-cue and context conditioning were negatively correlated with age (r = -0.56 and -0.59, respectively) and positively correlated with each other (r = +0.52). Aged rats showed robust conditioning in short- and long-delay fear paradigms, suggesting that the trace interval, rather than the use of a long interstimulus interval, is responsible for the aging-related deficits in trace fear conditioning. The authors suggest that these aging-related conditioning deficits furnish useful indices of functional changes within hippocampus or perirhinal cortex. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Impact of continuous versus intermittent CS-UCS pairing on human brain activation during Pavlovian fear conditioning.

During Pavlovian fear conditioning a conditioned stimulus (CS) is repeatedly paired with an aversive unconditioned stimulus (UCS). In many studies the CS and UCS are paired on every trial, whereas in others the CS and UCS are paired intermittently. To better understand the influence of the CS-UCS pairing rate on brain activity, the experimenters presented continuously, intermittently, and non-paired CSs during fear conditioning. Amygdala, anterior cingulate, and fusiform gyrus activity increased linearly with the CS-UCS pairing rate. In contrast, insula and left dorsolateral prefrontal cortex responses were larger during intermittently paired CS presentations relative to continuously and non-paired CSs. These results demonstrate two distinct patterns of activity in disparate brain regions. Amygdala, anterior cingulate, and fusiform gyrus activity paralleled the CS-UCS pairing rate, whereas the insula and dorsolateral prefrontal cortex appeared to respond to the uncertainty inherent in intermittent CS-UCS pairing procedures. These findings may further clarify the role of these brain regions in Pavlovian fear conditioning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Single neurons in the medial prefrontal cortex of the rat exhibit tonic and phasic coding during trace fear conditioning.

Trace fear conditioning is a learning task that requires the association of an auditory conditioned stimulus (CS) and a shock unconditioned stimulus (US) that are separated by a 20-s trace interval. Single neuron activity was recorded from the prelimbic and infralimbic areas of the medial prefrontal cortex in rats during trace fear conditioning or nonassociative unpaired training. Prelimbic neurons showed learning-related increases in activity to the CS and US, whereas infralimbic neurons showed learning-related decreases in activity to these stimuli. A subset of prelimbic neurons exhibited sustained increases in activity during the trace interval. These sustained prelimbic responses may provide a bridging code that allows for overlapping representations of CS and US information within the trace fear conditioning circuit. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Differential effects of training intertrial interval on acquisition of trace and long-delay fear conditioning in rats.

Many factors govern conditioning effectiveness, including the intertrial interval (ITI) used during training. The present study systematically varied the training ITI during both trace and long-delay fear conditioning. Rats were trained using one of six different ITIs and subsequently tested for conditioning to the white noise conditioned stimulus (CS) and the training context. After trace conditioning, percent freezing to the CS was positively correlated with training ITI, whereas percent freezing to the context was negatively correlated with training ITI. In contrast, when rats were trained using a long-delay paradigm, freezing during the CS test session did not vary as a function of training ITI; rats exhibited robust freezing at all ITIs. The long-delay conditioned rats exhibited relatively low levels of freezing during the context test. Thus, trace is more sensitive than long-delay fear conditioning to variations in the training ITI. These data suggest that training ITI is an important variable to consider when evaluating age or treatment effects, where the optimal ITI may vary with advancing age or pharmacological treatment. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Anterograde amnesia for Pavlovian fear conditioning and the role of one trial overshadowing: Effects of preconditioning exposures to morphine in rat.

Four experiments studied anterograde deficits in Pavlovian fear conditioning following prolonged exposure to the μ-opioid receptor agonist morphine. Injections of morphine produced temporally graded anterograde amnesia characterized by deficits in contextual and conditioned-stimulus (CS) conditioning 1 or 7 days and selective impairment in CS conditioning 21 days after last injection. This anterograde deficit in conditioning did not recover across a retention interval, was absent when rats were tested immediately after conditioning, and required the presence of an auditory CS. These results suggest that anterograde deficits in Pavlovian fear conditioning emerged from differences in susceptibility to 1-trial overshadowing of context by CS. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Factors governing single-trial contextual fear conditioning in the weanling rat.

Although contextual fear conditioning emerges later in development than explicit-cue fear conditioning, little is known about the stimulus parameters and biological substrates required at early ages. The authors adapted methods for investigating hippocampus function in adult rodents to identify determinants of contextual fear conditioning in developing rats. Experiment 1 examined the duration of exposure required by weanling rats at postnatal day (PND) 23 to demonstrate contextual fear conditioning. This experiment demonstrated that 30 s of context exposure is sufficient to support conditioning. Furthermore, preexposure enhanced conditioning to an immediate footshock, the context preexposure facilitation effect (CPFE), but had no effect on contextual conditioning to a delayed shock. Experiment 2 demonstrated that N-methyl-D-aspartate (NMDA) receptor inactivation during preexposure impairs contextual learning at PND 23. Thus, the conjuctive representations underlying the CPFE are NMDA-dependent as early as PND23 in the rat. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Amygdalar unit activity during three learning tasks: Eyeblink classical conditioning, Pavlovian fear conditioning, and signaled avoidance conditioning.

Neural activity in central and basolateral amygdala nuclei (CeA and BLA, respectively) was recorded during delay eyeblink conditioning, Pavlovian fear conditioning, and signaled barpress avoidance. During paired training, the CeA exhibited robust learning-related excitatory activity during all 3 tasks. By contrast, the BLA exhibited minimal activity during eyeblink conditioning, while demonstrating pronounced increases in learning-related excitatory responsiveness during fear conditioning and barpress avoidance. In addition, the relative amount of amygdalar activation observed appeared to be related to the relative intensity of the unconditioned stimulus and somatic requirements of the task. Results suggest the CeA mediates the Pavlovian association between sensory stimuli and the BLA mediates the modulation of instrumental responding through the assignment of motivational value to the unconditioned stimulus. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

CS-US preexposure effects on trace eyeblink conditioning in young rats: Potential implications for functional brain development.

Recent studies of delay eyeblink conditioning (EBC) in young rats have demonstrated different effects of various conditioned and unconditioned stimulus (CS-US) preexposure conditions on learning at different ages. The present study extends this research to trace EBC. Subjects experienced 1 of 3 preexposure conditions (paired CS-US, unpaired CS-US, or no stimuli) at either 20 or 24 days of age. Four days later, they were conditioned using either trace (Experiment 1) or delay (Experiment 2) EBC parameters. Results were similar at both ages tested. Paired preexposure facilitated acquisition of delay but not trace relative to context preexposure. Unpaired preexposure impaired acquisition of both delay and trace. These behavioral findings provide a foundation for hypotheses about the functional maturation of cerebellar, hippocampal, and entorhinal learning circuits. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Potentiation and overshadowing in Pavlovian fear conditioning.

The present experiments addressed a fundamental discrepancy in the Pavlovian conditioning literature concerning responding to a target cue following compound reinforced training with another cue of higher salience. Experiment 1 identified one determinant of whether the target cue will be overshadowed or potentiated by the more salient cue, namely contiguity between compound CS termination and US presentation. Overshadowing and potentiation were observed with delay and trace procedures, respectively. Experiments 2 and 3 contrasted elemental and configural explanations of potentiation. Both experiments supported a configural account. Experiments 3 and 4, by manipulating prior learning experiences to bias subjects to encode the same compound elementally or configurally, demonstrated decreased potentiation and overshadowing, respectively. Overall, these experiments demonstrate potentiation with nontaste stimuli and identify one variable that determines whether overshadowing or potentiation will occur. Moreover, they show that prior experiences can determine how a compound is encoded and are compatible with the idea of flexible encoding as a principle of information processing. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Opioid Receptors Regulate the Extinction of Pavlovian Fear Conditioning.

Rats received a single pairing of an auditory conditioned stimulus (CS) with a footshock unconditioned stimulus (US). The fear (freezing) that had accrued to the CS was then extinguished. Injection of naloxone prior to this extinction significantly impaired the development of extinction. This impairment was mediated by opioid receptors in the brain and was not observed when naloxone was injected after extinction training. Finally, an injection of naloxone on test failed to reinstate extinguished responding that had already accrued to the CS. These experiments show that opioid receptors regulate the development, but not the expression, of fear extinction and are discussed with reference to the roles of opioid receptors in US processing, memory, and appetitive motivation. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Opioid regulation of Pavlovian overshadowing in fear conditioning.

In Pavlovian overshadowing, a stimulus that predicts a biologically important event reduces conditioning to another, equally predictive stimulus. We tested the effects of an opioid antagonist and dopamine agonist on the ability of a salient white noise to overshadow a less salient light. Rats were conditioned to fear a light or a noise–light compound using a mild footshock. Compound-conditioned rats trained under the saline vehicle revealed significant overshadowing of the light by the noise. This overshadowing effect was significantly attenuated in rats trained under the opioid antagonist naltrexone, consistent with an opioid-mediated negative feedback model of conditioning. In line with predictions made by negative feedback-type models, we failed to obtain overshadowing with few trials, suggesting that the processes underlying conditioning during initial trials do not contribute to the opioid-dependent Pavlovian overshadowing obtained in our preparation. Lastly, we compared the involvement of dopamine-mediated and opioid-mediated processes in overshadowing by conditioning rats under the partial dopamine D1 receptor agonist SKF 38393 or the opioid antagonist naltrexone. Both naltrexone and SKF 38393 were found to attenuate overshadowing; however, the behavioral profiles produced by each pharmacological manipulation were distinct. Collectively, these studies demonstrate an important role for both opioid- and dopamine-mediated processes in multiple-trial overshadowing. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Neurophysiological theory of Kamin blocking in fear conditioning.

Kamin blocking in fear conditioning is thought to reflect diminished processing of the unconditional stimulus (US) in the presence of a conditional stimulus (CS+) that was previously paired with this US. According to Fanselow's (1998) hypothesis, the CS+ drives output from the amygdala that ultimately produces analgesia by causing opiate release onto afferent pain circuits. This hypothesis was explored quantitatively through neurophysiological simulations. The results suggest that opiate-mediated, negative-feedback control of US processing is too slow for efficient blocking of cue conditioning. The reason is that conditioning-produced synaptic modifications can be induced before the opiate-mediated inhibition has any substantial effect on US processing. The results suggest the existence of an additional, faster-acting, inhibitory neurotransmitter in the blocking circuit. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Opioid receptors regulate retrieval of infant fear memories: Effects of naloxone on infantile amnesia.

The authors examined the role of the endogenous opioid system in infantile amnesia for contextual fear conditioning. Rats that were 18 days of age received an aversive footshock in a novel context. Rats displayed conditioned fear when tested 1 min after training but not 24 hr after training. Systemic injection of the opioid receptor antagonist naloxone prior to test, but not immediately after training, alleviated infantile amnesia. Naloxone also alleviated infantile amnesia when injected prior to test 7 days after training. These effects of naloxone were due to actions on central rather than peripheral opioid receptors and were not due to any tendency of the drug to produce fear or freezing. These results show that central opioid receptors regulate retrieval of fear memories in infant rats. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of bed nucleus of the stria terminalis lesions on conditioned anxiety: Aversive conditioning with long-duration conditional stimuli and reinstatement of extinguished fear.

Four experiments investigated the effects of lesions of the bed nucleus of the stria terminalis (BNST) on conditioned fear and anxiety. Though BNST lesions did not disrupt fear conditioning with a short-duration conditional stimulus (CS; Experiments 1 and 3), the lesion attenuated conditioning with a longer duration CS (Experiments 1 and 2). Experiment 3 found that lesions attenuated reinstatement of extinguished fear, which relies on contextual conditioning. Experiment 4 confirmed that the lesion reduced unconditioned anxiety in an elevated zero maze. The authors suggest that long-duration CSs, whether explicit cues or contexts, evoke anxiety conditioned responses, which are dissociable from fear responses to shorter CSs. Results are consistent with behavioral and anatomical distinctions between fear and anxiety and with a behavior-systems view of defensive conditioning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Two roles of the context in Pavlovian fear conditioning.

At both empirical and theoretical levels, multiple functional roles of contextual information upon memory performance have been proposed without a clear dissociation of these roles. Some theories have assumed that contexts are functionally similar to cues, whereas other views emphasize the retrieval facilitating properties of contextual information. In Experiment 1, we observed that one critical parameter, the spacing of trials, could determine whether the context would function as a conditioned stimulus or as a retrieval cue for memories trained in different phases. Experiments 2 and 3 doubly dissociated these functions by selectively disrupting one role but not the other, and vice versa. Overall, these observations identify one determinant of different functions of contextual information and pose a major challenge to theories of learning that assume exclusively one or the other function of the context. Moreover, these data emphasize the importance of parametric variations on behavioral control, which has critical implications for studies designed to understand the role of the hippocampus in processing of contextual attributes. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Unblocking in Pavlovian fear conditioning.

Six experiments used rats to study blocking and unblocking of fear learning. An excitatory stimulus (A) blocked fear learning to a neutral stimulus (B). Unblocking of B occurred if the AB compound signaled an increase in unconditioned stimulus (US) intensity or number. Assessments of associative change during blocking showed that more was learned about B than A. Such assessments during unblocking revealed that more was learned about B than A following an increase in US intensity but not US number. These US manipulations had no differential effects on single-cue learning. The results show that variations in US intensity or number produce unblocking of fear learning, but for each there is a different profile of associative change and a potentially different mechanism. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Impaired trace fear conditioning following neonatal ethanol: Reversal by choline.

Neonatal ethanol exposure in animals results in performance deficits on tests of hippocampus-dependent spatial memory, and recent studies have shown that extra dietary choline can ameliorate some of these impairments. In this experiment, rats were administered 5.25 g/kg ig ethanol per day or sham intubations on Postnatal Days (PD) 4-9 and choline (0.1 ml of an 18.8 mg/ml solution) or saline subcutaneously on PD 4-20. On PD 30, rats were given delay or trace fear conditioning trials and were tested for conditioned stimulus-elicited freezing 24 hr later. Neonatal ethanol produced a profound impairment in trace conditioning that was reversed by choline. Groups did not differ in delay conditioned responding, indicating that neonatal ethanol produces a relatively selective cognitive deficit that can be alleviated with supplemental choline. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Topography of spatially directed conditioned responding: Effects of context and trial duration.

Domesticated quail (Coturnix japonica) received a discrete conditioned stimulus (CS) at one end of the experimental chamber paired with the opportunity to copulate with a female quail (the unconditioned stimulus) in a goal box located 112 cm away. Approach to the CS (sign tracking) and approach to the goal area (goal tracking) were measured. The duration of exposure to the experimental context (C) was varied in Experiment 1, and the duration of the conditioning trials (T) was varied in Experiment 2 for independent groups, creating C/T ratios of 1.0, 1.5, 4.5, 45, and 180. Contrary to previous reports of a direct relation between the C/T ratio and conditioned responding, in the present experiments, a shift in the topography and stimulus control of conditioned behavior occurred. Low C/T ratios (1.0–4.5) produced goal tracking controlled by contextual cues, whereas high C/T ratios (45 and 180) produced sign tracking controlled by the discrete CS. (PsycINFO Database Record (c) 2010 APA, all rights reserved)