Pavlovian heart rate and jaw movement conditioning in the rabbit: effects of medial prefrontal lesions

An experiment was conducted in which jaw movements (JM) and heart rate (HR) were concomitantly assessed in rabbits during simple Pavlovian conditioning. A 2-s 1200-Hz tone was the conditioned stimulus (CS) and an intraoral 1-cc pulse of 0.5 M sucrose-water solution was the unconditioned stimulus (US). Sham and medial prefrontal (mPFC)-lesioned animals received paired CS/US training with a 70- to 75-dB CS and were compared with sham- and mPFC-lesioned animals that received explicitly unpaired CS/US presentations. The percentages of JM CRs were significantly greater in the paired than the unpaired groups, but mPFC lesions had no effect on this measure. Conditioned HR decelerations occurred only in the paired groups and then only during the first session of training. Moreover, these CS-evoked cardiac decelerations were somewhat attenuated by the mPFC lesion. CS-evoked HR accelerations, which were significantly greater in unpaired than in paired animals, occurred during the four subsequent sessions. These results suggest that a CS-evoked cardioinhibitory process, mediated by the mPFC, is engendered by Pavlovian appetitive conditioning, as has been previously demonstrated for aversive conditioning. However, during JM conditioning these inhibitory changes are quickly replaced by tachycardia, possibly related to increased nonspecific somatomotor activity, since the tachycardia was somewhat greater in the unpaired animals.     

Posttraining prefrontal lesions impair jaw movement conditioning performance,but have no effect on accompanying heart rate changes

This experiment examined the role of the medial prefrontal cortex (mPFC) in regulating learned autonomic and somatomotor responses in rabbits using appetitive Pavlovian conditioning. Interstimulus interval (ISI) duration [i.e., the time between the onset of the conditioned stimulus (CS) and unconditioned stimulus (US)] was manipulated in order to determine whether ISI duration was related to the heart rate (HR) responses obtained during conditioning. Two groups received either a 1- or a 4-s ISI, with a tone as the CS and an intraoral pulse of water as the US. Another two groups received explicitly unpaired presentations of either the 1- or 4-s tone CS and water US. Few conditioned jaw movement (JM) or HR conditioned responses (CRs) were observed in the unpaired conditions. Significant JM conditioning was, however, elicited by the paired conditions, especially to the 4-s ISI. Consistent CS-evoked HR accelerations were observed in both ISI conditions. After five sessions of training, the mPFC was lesioned in half the animals. A separate group of paired animals received sham lesions. After surgical recovery, all animals received 3 days of postoperative training. During the first postoperative training session, JM CRs significantly declined in both groups with mPFC lesions in comparison to the groups with sham lesions. The mPFC lesions, however, did not affect the CS-evoked cardiac accelerations, which again occurred during postoperative training.     

Classically conditioned cardiac responses in "old" and "young" Fischer 344 rats

Male and female Fischer 344 rats, 12 or 26-28 months of age, received two sessions of Pavlovian heart rate conditioning, and were compared with same-sex and same-age controls receiving unpaired presentations of the tone conditional stimulus (CS) and the shock unconditional stimulus (US). Older rats of both sexes demonstrated slower acquisition of the heart rate (HR) conditioned response (CR), and smaller magnitude changes than did the younger animals. Control experiments in 6-, 12-, 24-, and 30-month-old animals indicated that these differences were not due to an impaired sensitivity to the CS or US in the older animals. Results are discussed in terms of their implications for use of this animal model in investigations of age-related deficits in associative learning.     

The incubation theory of fear/anxiety: experimental investigation in a human laboratory model of Pavlovian conditioning

The aim of this work was to test Eysenck's incubation theory of fear/anxiety in human Pavlovian B conditioning of heart rate (HR) responses. The conditioned stimuli (CSs) were phobia-relevant slides (snakes and spiders) and the unconditioned stimuli (UCSs) were aversive noises. The subjects were presented with two levels of noise intensity during acquisition and three levels of nonreinforced CS presentation (CS-only) in a delay differential (CS+/CS-) conditioning paradigm (2 x 3 x 2). Consistent with the incubation theory, conditioned HR acceleratory responses were sustained (resistance to extinction) for high-noise intensity and short-presentations of CS-only subjects. During the extinction phase, HR acceleratory responses quickly extinguished in low-noise intensity groups after the first presentations of CS-only. These findings were interpreted as support for the incubation theory of phobic fear.     

Learning-dependent potentiation in the vibrissal motor cortex is closely related to the acquisition of conditioned whisker responses in behaving mice

The role of the primary motor cortex in the acquisition of new motor skills was evaluated during classical conditioning of vibrissal protraction responses in behaving mice, using a trace paradigm. Conditioned stimulus (CS) presentation elicited a characteristic field potential in the vibrissal motor cortex, which was dependent on the synchronized firing of layer V pyramidal cells. CS-evoked and other event-related potentials were particular cases of a motor cortex oscillatory state related to the increased firing of pyramidal neurons and to vibrissal activities. Along conditioning sessions, but not during pseudoconditioning, CS-evoked field potentials and unitary pyramidal cell responses grew with a time-course similar to the percentage of vibrissal conditioned responses (CRs), and correlated significantly with CR parameters. High-frequency stimulation of barrel cortex afferents to the vibrissal motor cortex mimicked CS-related potentials growth, suggesting that the latter process was due to a learning-dependent potentiation of cortico-cortical synaptic inputs. This potentiation seemed to enhance the efficiency of cortical commands to whisker-pad intrinsic muscles, enabling the generation of acquired motor responses.     

In vitro analog of classical conditioning of feeding behavior in aplysia

The feeding behavior of Aplysia californica can be classically conditioned using tactile stimulation of the lips as a conditioned stimulus (CS) and food as an unconditioned stimulus (US). Moreover, several neural correlates of classical conditioning have been identified. The present study extended previous work by developing an in vitro analog of classical conditioning and by investigating pairing-specific changes in neuronal and synaptic properties. The preparation consisted of the isolated cerebral and buccal ganglia. Electrical stimulation of a lip nerve (AT4) and a branch of the esophageal nerve (En2) served as the CS and US, respectively. Three protocols were used: paired, unpaired, and US alone. Only the paired protocol produced a significant increase in CS-evoked fictive feeding. At the cellular level, classical conditioning enhanced the magnitude of the CS-evoked synaptic input to pattern-initiating neuron B31/32. In addition, paired training enhanced both the magnitude of the CS-evoked synaptic input and the CS-evoked spike activity in command-like neuron CBI-2. The in vitro analog of classical conditioning reproduced all of the cellular changes that previously were identified following behavioral conditioning and has led to the identification of several new learning-related neural changes. In addition, the pairing-specific enhancement of the CS response in CBI-2 indicates that some aspects of associative plasticity may occur at the level of the cerebral sensory neurons.     

Concomitant Pavlovian conditioning of heart rate and leg flexion responses in the rat

Pavlovian conditioning was studied in male Fischer 344 rats using tones as the conditioned stimulus (CS) and footshock as the unconditioned stimulus (UCS). Different groups of animals received (a) contiguous CS-UCS pairings with a 0.5 sec CS, (b) contiguous CS-UCS pairings with a 4.0 sec CS, or (c) a random sequence of noncontiguous tones and shocks using either a 0.5 sec or a 4.0 sec CS. Heart rate (HR) and leg flexion (LF) responses were recorded. Leg flexion conditioning occurred only in the 0.5 sec contiguous group. Decelerative HR CRs occurred only in the 4.0 sec contiguous group. Accelerative HR changes occurred in the other two groups but were significantly greater in the 0.5 sec contiguous group. These results are similar to but not identical to those obtained during eyeblink or nictitating membrane conditioning in rabbits, and suggest that the topography of the Pavlovian HR CR is dependent on the simultaneous occurrence of other classically conditioned responses.     

Form and characteristics of the cardiovascular conditional response in Rhesus monkeys

Three Rhesus monkeys restrained in primate chairs were exposed to several Pavlovian control procedures, followed by 13 sessions of cardiac conditioning under a delay paradigm. The conditional stimulus (CS) was a vertical line and the unconditional stimulus (US) was electric foot shock. Heart rate (HR) was analyzed in successive fivesecond intervals beginning five seconds before CS onset. The major finding was that the conditional response was consistently biphasic and consisted of an initial acceleration followed by deceleration toward the baseline, but rarely reaching it before onset of US. The subjects differed in magnitude of acceleration and subsequent deceleration as well as the location of the maximum rate in the CS-US interval. A breakdown of trials on the basis of the pre-CS HR revealed that the magnitude of effect was inversely related to the pre-CS rate.     

Cardiac pacing and the law of initial value in rhesus monkeys

A cardiac pacemaker was used to produce a wide range of pre-CS heart rates in Pavlovian conditioning, and correlations were computed between pre-CS and CS heart rates. Two rhesus monkeys were presented trials in which 30 sec of light (CS) was followed by a brief electric shock (UCS). Pacing rates during the inter-trial intervals were varied from 150 to 350 bpm. Pacing was discontinued during CS. Unpaced control sessions showed that the maximum heart rate in CS on each trial was proportional to the pre-CS heart rate. Following pacing, however, heart rate in CS did not depend on the pacing rate; rather, the rates were not different from those of the unpaced control sessions. Pacing at high rates shifted the maximum heart rate toward the end of CS.     

Implicit threat learning involves the dorsolateral prefrontal cortex and the cerebellum

Background/ObjectiveMost studies investigating the neural correlates of threat learning were carried out using an explicit Pavlovian conditioning paradigm where declarative knowledge on contingencies between conditioned (CS) and unconditioned stimuli (US) is acquired. The current study aimed at understanding the neural correlates of threat conditioning when contingency awareness is limited or even absent.MethodWe conducted an fMRI report of threat learning in an implicit associative learning paradigm called multi-CS conditioning, in which a number of faces were associated with aversive screams (US) such that participants could not report contingencies between the faces and the screams.ResultsThe univariate results showed support for the recruitment of threat-related regions including the dorsolateral prefrontal cortex (dlPFC) and the cerebellum during acquisition. Further analyses by the multivariate representational similarity technique identified learning-dependent changes in the bilateral dlPFC.ConclusionOur findings support the involvement of the dlPFC and the cerebellum in threat conditioning that occurs with highly limited or even absent contingency awareness.     

Intra-medial prefrontal administration of SCH-23390 attenuates ERK phosphorylation and long-term memory for trace fear conditioning in rats

The prefrontal cortex is known to be involved in the acquisition of trace conditioning, a higher-cognitive form of Pavlovian conditioning in which a conditioned stimulus and an unconditioned stimulus are separated by a time gap. We have recently reported that medial prefrontal (mPFC) extracellular-signal regulated kinase (Erk) phosphorylation is involved in the long-term memory storage of trace fear conditioning. Because of the important role dopamine D1 receptors play in prefrontal function, such as working memory, and due to evidence that dopamine D1 receptor activity can modulate plasticity, we investigated their role in prefrontal Erk phosphorylation following trace fear conditioning. We found that inhibition of dopamine D1 receptors through intra-mPFC infusion of SCH-23390 (1 microg/0.5 microL) 15 min prior to trace fear conditioning resulted in a decrease in training-related Erk phosphorylation. Additionally, pre-training intra-mPFC infusion of SCH-23390 also resulted in the impairment of long-term retention of CS-US association. These findings implicate mPFC dopamine D1 receptor activity in the storage of long-term memory for higher-cognitive associative tasks.     

Human trace fear conditioning: right-lateralized cortical activity supports trace-interval processes

Pavlovian conditioning requires the convergence and simultaneous activation of neural circuitry that supports conditioned stimulus (CS) and unconditioned stimulus (US) processes. However, in trace conditioning, the CS and US are separated by a period of time called the trace interval, and thus do not overlap. Therefore, determining brain regions that support associative learning by maintaining a CS representation during the trace interval is an important issue for conditioning research. Prior functional magnetic resonance imaging (fMRI) research has identified brain regions that support trace-conditioning processes. However, relatively little is known about whether this activity is specific to the trace CS, the trace interval, or both periods of time. The present study was designed to disentangle the hemodynamic response produced by the trace CS from that associated with the trace interval, in order to identify learning-related activation during these distinct components of a trace-conditioning trial. Trace-conditioned activity was observed within dorsomedial prefrontal cortex (PFC), dorsolateral PFC, insula, inferior parietal lobule (IPL), and posterior cingulate (PCC). Each of these regions showed learning-related activity during the trace CS, while trace-interval activity was only observed within a subset of these areas (i.e., dorsomedial PFC, PCC, right dorsolateral PFC, right IPL, right superior/middle temporal gyrus, and bilateral insula). Trace-interval activity was greater in right than in left dorsolateral PFC, IPL, and superior/middle temporal gyrus. These findings indicate that components of the prefrontal, cingulate, insular, and parietal cortices support trace-interval processes, as well as suggesting that a right-lateralized fronto-parietal circuit may play a unique role in trace conditioning.     

Heart rate changes accompanying jaw movement Pavlovian conditioning in rabbits: Concomitant blood pressure adjustments and effects of peripheral autonomic blockade

Two experiments were conducted to ascertain the cardiovascular accompaniments of differential Pavlovian jaw movement (JM) conditioning. The first examined the blood pressure (BP) changes that accompany the tachycardiac conditioned responses (CRs) associated with JM conditioning. The BP response in all instances consisted of a depressor response that was greater to the reinforced CS+ than CS-, although the magnitude of the CR was quite small. The second experiment determined the effects of peripheral autonomic antagonists on the cardiac accelerations associated with JM conditioning. It was found that the peripheral vagal antagonist methyl scopolamine completely abolished responses to both CS+ and CS-, whereas atenolol, a beta adrenergic antagonist, augmented the response, compared to saline control injections. The JM responses were also affected by the autonomic blockades, with minimal responding occurring in the scopolamine group but slightly more JM CRs in the atenolol group, compared to saline control animals. These results suggest that the major cardiovascular response to an appetitive stimulus, which evokes JM conditioning, consists of cardiac accelerations with the BP depressor responses playing a minimal, if any, role. Moreover, these conditioned cardiac increases appear to be due solely to the release of vagal inhibition.     

Amygdala and hippocampal activity during acquisition and extinction of human fear conditioning

Previous functional magnetic resonance imaging (fMRI) studies have characterized brain systems involved in conditional response acquisition during Pavlovian fear conditioning. However, the functional neuroanatomy underlying the extinction of human conditional fear remains largely undetermined. The present study used fMRI to examine brain activity during acquisition and extinction of fear conditioning. During the acquisition phase, participants were either exposed to light (CS) presentations that signaled a brief electrical stimulation (paired group) or received light presentations that did not serve as a warning signal (control group). During the extinction phase, half of the paired group subjects continued to receive the same treatment, whereas the remainder received light alone. Control subjects also received light alone during the extinction phase. Changes in metabolic activity within the amygdala and hippocampus support the involvement of these regions in each of the procedural phases of fear conditioning. Hippocampal activity developed during acquisition of the fear response. Amygdala activity increased whenever experimental contingencies were altered, suggesting that this region is involved in processing changes in environmental relationships. The present data show learning-related amygdala and hippocampal activity during human Pavlovian fear conditioning and suggest that the amygdala is particularly important for forming new associations as relationships between stimuli change.     

Heart Rate Changes Accompanying Jaw Movement Pavlovian Conditioning in Rabbits: Concomitant Blood Pressure Adjustments and Effects of Peripheral Autonomic Blockade

Two experiments were conducted to ascertain the cardiovascular accompaniments of differential Pavlovian jaw movement (JM) conditioning. The first examined the blood pressure (BP) changes that accompany the tachycardiac conditioned responses (CRs) associated with JM conditioning. The BP response in all instances consisted of a depressor response that was greater to the reinforced CS+ than CS-, although the magnitude of the CR was quite small. The second experiment determined the effects of peripheral autonomic antagonists on the cardiac accelerations associated with JM conditioning. It was found that the peripheral vagal antagonist methyl scopolamine completely abolished responses to both CS+ and CS-, whereas atenolol, a beta adrenergic antagonist, augmented the response, compared to saline control injections. The JM responses were also affected by the autonomic blockades, with minimal responding occurring in the scopolamine group but slightly more JM CRs in the atenolol group, compared to saline control animals. These results suggest that the major cardiovascular response to an appetitive stimulus, which evokes JM conditioning, consists of cardiac accelerations with the BP depressor responses playing a minimal, if any, role. Moreover, these conditioned cardiac increases appear to be due solely to the release of vagal inhibition.     

Level of Muscular Tension as an Aspect of Personality

The purpose of this study was to compare two methods of analyzing the effects of exteroceptive feedback training on the voluntary bidirectional control of human cardiac rate with the use of a within-subject control design. In this design heart rate (HR) during an experimental period (increase or decrease) is compared with that recorded during some other control period, generally a baseline “rest” period. Ten male undergraduates were instructed to control HR and given visual feedback of heart activity. Trials on which Ss were to raise and to lower HR were both given in a single training session. The data were analyzed in two ways: (a) cardiac rate during HR control periods was compared to an initial pre-experiment baseline; (b) cardiac rate during HR control periods was compared to a running pretrial baseline. The results support the argument that the former procedure fails to take account of habituating levels of cardiac rate and favors finding large magnitude decreases in HR but small increases, whereas the latter procedure favors finding large magnitude increases but small decreases. It is suggested that magnitude of directional control will be artifactual when initial values are used to assess change. Contaminating influences on the running pretrial baseline were also discussed.     

Rapid associative learning: Conditioned bradycardia and its central nervous system substrates

It has become clear from the study of different response systems during classical conditioning that some responses are acquired quite rapidly and others show a much slower rate of acquisition. The most often studied rapidly acquired responses have been classically conditioned autonomic changes (e.g., heart rate); the slowly acquired responses most often studied are skeletal responses, such as the eyeblink or leg flexion response. Although there are various other differences between rapidly acquired and slowly acquired responses, we have suggested that the most important difference is the possibility that they represent different stages of the learning process. In the present review I describe research in our laboratory that has focused on conditioned bradycardia as a model system of a rapidly acquired associative system and contrast it with the more slowly acquired Pavlovian conditioned eyeblink response. I also describe the generality of conditioned bradycardia and discuss the differential role of subdivisions of the prefrontal cortex as a substrate for mediating this response. Finally, I briefly discuss the other brain areas involved in conditioned bradycardia, and its functional significance as it relates to the learning process.     

Cardiac conditioning in the white rat with food presentation as unconditional stimulus

Pavlovian conditioning of heart rate in the white rat was attempted using milk presentation as reinforcement, and with both trace and delay paradigms. Delay conditioning produced positive results that were statistically significant, whereas trace conditioning exhibited the same trends but did not reach statistical significance. In both cases, CR had the same direction as UCR to milk (acceleration of heart rate) and opposite to the unconditional reaction to CS. Extinction and reconditioning were both accomplished. Some indications of complex response interactions were noted in the occurrence of the cardiac CR on conditioning trials where the instrumental response to the UCS (drinking) eventually occurred, as against the absence of cardiac CR on trials where the instrumental response did not occur. The existence of such interactions was also indicated by the fact that CR on individual trials within any single session could vary in direction between acceleration and deceleration, although averages might be stable.     

Differential fear conditioning induces reciprocal changes in the sensory responses of lateral amygdala neurons to the CS(+) and CS(-)

In classical fear conditioning, a neutral sensory stimulus (CS) acquires the ability to elicit fear responses after pairing to a noxious unconditioned stimulus (US). As amygdala lesions prevent the acquisition of fear responses and the lateral amygdaloid (LA) nucleus is the main input station of the amygdala for auditory afferents, the effect of auditory fear conditioning on the sensory responsiveness of LA neurons has been examined. Although conditioning was shown to increase CS-evoked LA responses, the specificity of the changes in responsiveness was not tested. Because conditioning might induce nonspecific increases in LA responses to auditory afferents, we re-examined this issue in conscious, head-restrained cats using a differential conditioning paradigm where only one of two tones (CS(+) but not CS(-)) was paired to the US. Differential conditioning increased unit and field responses to the CS(+), whereas responses to the CS(-) decreased. Such changes have never been observed in the amygdala except in cases where the CS(-) had been paired to the US before and fear responses not extinguished. This suggests that fear conditioning is not only accompanied by potentiation of amygdalopetal pathways conveying the CS(+) but also by the depression of sensory inputs unpaired to noxious stimuli.     

Experimental extinction in Pavlovian conditioning: Behavioural and neuroscience perspectives

This paper reviews the behavioural and neuroscience literatures on extinction in Pavlovian conditioning with a view towards finding possible points of contact between these two often independent lines of investigation. Recent discoveries at the behavioural level indicate (1) that conditioned stimulus (CS)-unconditioned stimulus (US) associations specific in their sensory content are fully preserved during extinction, (2) that inhibitory stimulus-response associations appear to be learned during extinction, (3) that extinction is influenced by the level of activation of the US representation during nonreinforced trials, (4) that decreases in attention can influence conditioned performance during extinction, and (5) that contexts acquire an ability to modulate learning during both conditioning and extinction. Recent discoveries at the neural systems level suggest (1) that the hippocampus is important in context-specific learning during extinction, (2) that the prefrontal cortex is possibly important in long-term memory for extinction, (3) that the basolateral amygdala may be important in sustaining attention to a CS during extinction, (4) that NMDA receptors are important either in neural plasticity during extinction or by affecting the value of the US representation during extinction, and (5) that the GABAergic system may partially mediate inhibitory learning during extinction. It is concluded that both of these levels of analysis can benefit the other in the pursuit of a more comprehensive understanding of extinction.