Compound Stimulus Presentation Research Articles

A study protocol testing pre-exposure dose and compound pre-exposure on the mechanisms of latent inhibition of dental fear

BackgroundDental stimuli can evoke fear after being paired - or conditioned - with aversive outcomes (e.g., pain). Pre-exposing the stimuli before conditioning can impair dental fear learning via a phenomenon known as latent inhibition. Theory suggests changes in expected relevance and attention are two mechanisms responsible for latent inhibition. In the proposed research, we test whether pre-exposure dose and degree of pre-exposure novelty potentiate changes in expected relevance and attention to a pre-exposed stimulus. We also assess if the manipulations alter latent inhibition and explore the possible moderating role of individual differences in pain sensitivity.MethodsParticipants will be healthy individuals across a wide range of ages (6 to 35 years), from two study sites. Participants will undergo pre-exposure and conditioning followed by both a short-term and long-term test of learning, all in a novel virtual reality environment. The unconditioned stimulus will be a brief pressurized puff of air to a maxillary anterior tooth. Pre-exposure dose (low vs. high) and pre-exposure novelty (element stimulus vs. compound stimuli) will be between-subject factors, with stimulus type (pre-exposed to-be conditioned stimulus, a non-pre-exposed conditioned stimulus, and an unpaired control stimulus) and trial as within-subject factors. Pain sensitivity will be measured through self-report and a cold pressor test. It is hypothesized that a larger dose of pre-exposure and compound pre-exposure will potentiate the engagement of the target mechanisms and thereby result in greater latent inhibition in the form of reduced fear learning. Further, it is hypothesized that larger effects will be observed in participants with greater baseline pain sensitivity.DiscussionThe proposed study will test whether pre-exposure dose and compound stimulus presentation change expected relevance and attention to the pre-exposed stimulus, and thereby enhance latent inhibition of dental fear. If found, the results will add to our theoretical understanding of the latent inhibition of dental fear and inform future interventions for dental phobia prevention.

Compound Stimulus Presentation Does Not Deepen Extinction in Human Causal Learning.

Models of associative learning have proposed that cue-outcome learning critically depends on the degree of prediction error encountered during training. Two experiments examined the role of error-driven extinction learning in a human causal learning task. Target cues underwent extinction in the presence of additional cues, which differed in the degree to which they predicted the outcome, thereby manipulating outcome expectancy and, in the absence of any change in reinforcement, prediction error. These prediction error manipulations have each been shown to modulate extinction learning in aversive conditioning studies. While both manipulations resulted in increased prediction error during training, neither enhanced extinction in the present human learning task (one manipulation resulted in less extinction at test). The results are discussed with reference to the types of associations that are regulated by prediction error, the types of error terms involved in their regulation, and how these interact with parameters involved in training.

Extinction of alcohol seeking is enhanced by compound extinction and the noradrenaline reuptake inhibitor atomoxetine.

Alcohol-related stimuli can trigger relapse of alcohol-seeking behaviors even after extended periods of abstinence. Extinction of such stimuli provides a means for reducing their impact on relapse. However, the expression of extinction can be disrupted by exposure to the previous reinforcer as well as the simple passage of time. We investigated whether augmentation of prediction error or of noradrenaline neurotransmission by the reuptake inhibitor atomoxetine would enhance long-term extinction of alcohol-seeking behavior. Rats received Pavlovian conditioning of multiple stimuli signaling the delivery of an alcohol reward before individual extinction was given to each of these stimuli. Further extinction was then given to a target stimulus presented in compound with another alcohol-predictive stimulus intended to augment prediction error (Experiment 1) or after a systemic injection of atomoxetine (1.0 mg/kg; Experiment 2). Experiment 3 examined whether the compound stimulus effect relied on noradrenergic activity by testing the effects of the β-adrenergic antagonist propranolol, given prior to compound stimulus trials. Long-term retention of extinction learning was assessed a week later. Compound stimulus presentations enhanced long-term extinction as the stimulus extinguished in compound elicited less responding than a stimulus receiving equal extinction alone when tested a week later. This effect was mimicked by atomoxetine and blocked by propranolol given during extinction training. Thus, extinction of alcohol-seeking behavior can be improved by extinguishing multiple alcohol-predictive stimuli or enhancing noradrenaline neurotransmission during extinction training. Both behavioral and neurobiological processes could be exploited to enhance the outcome of extinction-based treatments for alcohol use disorders.

Compound Stimulus Presentation and the Norepinephrine Reuptake Inhibitor Atomoxetine Enhance Long-Term Extinction of Cocaine-Seeking Behavior

Drug abstinence is frequently compromised when addicted individuals are re-exposed to environmental stimuli previously associated with drug use. Research with human addicts and in animal models has demonstrated that extinction learning (non-reinforced cue-exposure) can reduce the capacity of such stimuli to induce relapse, yet extinction therapies have limited long-term success under real-world conditions (Bouton, 2002; O'Brien, 2008). We hypothesized that enhancing extinction would reduce the later ability of drug-predictive cues to precipitate drug-seeking behavior. We, therefore, tested whether compound stimulus presentation and pharmacological treatments that augment noradrenergic activity (atomoxetine; norepinephrine reuptake inhibitor) during extinction training would facilitate the extinction of drug-seeking behaviors, thus reducing relapse. Rats were trained that the presentation of a discrete cue signaled that a lever press response would result in cocaine reinforcement. Rats were subsequently extinguished and spontaneous recovery of drug-seeking behavior following presentation of previously drug-predictive cues was tested 4 weeks later. We find that compound stimulus presentations or pharmacologically increasing noradrenergic activity during extinction training results in less future recovery of responding, whereas propranolol treatment reduced the benefit seen with compound stimulus presentation. These data may have important implications for understanding the biological basis of extinction learning, as well as for improving the outcome of extinction-based therapies.

Deepened extinction following compound stimulus presentation: Noradrenergic modulation

Behavioral extinction is an active form of new learning involving the prediction of nonreward where reward has previously been present. The expression of extinction learning can be disrupted by the presentation of reward itself or reward-predictive stimuli (reinstatement) as well as the passage of time (spontaneous recovery) or contextual changes (renewal). The following experiments replicated the demonstration that presenting multiple previously rewarded stimuli in compound during extinction enhances extinction learning. To explore the pharmacological basis for this we next examined the effects of pharmacological treatments that either facilitated or blocked noradrenergic activity to test the hypothesis that increased noradrenergic activity at the time of extinction training would improve, whereas blockade of noradrenergic activity would impair the extinction of appetitive stimulus-reward memories. Different groups of rats were trained in a discriminative stimulus paradigm to lever-press for food reward. Once stable responding was achieved, responding was extinguished for 2 d. Prior to a third extinction session, rats received systemic administration of either saline, yohimbine (α2 antagonist), atomoxetine (norepinephrine reuptake inhibitor), or propranolol (β-receptor antagonist). Spontaneous recovery of responding to the stimuli was tested 4 wk later. Our results indicate that increasing noradrenergic activity during extinction augments extinction learning resulting in less recovery of responding at test. These results have important implications for models of relapse to drug seeking and the development of extinction-based therapies.

Deepened extinction from compound stimulus presentation.

Three experiments with rats and 2 with pigeons explored the effect of presenting 2 extinguished excitatory stimuli in compound. Four learning situations were used: Pavlovian magazine approach, Pavlovian fear conditioning, and instrumental discriminative instrumental learning in rats, as well as Pavlovian sign tracking in pigeons. All 5 experiments confirmed D. Reberg's (1972) observation that even after extinction of the individual stimuli, presenting them in compound evoked substantial responding. Moreover, nonreinforcement of that compound deepened extinction of an element more substantially than did additional presentation of that element alone. Such compound exposure reduced spontaneous recovery, reduced reinstatement, and slowed subsequent reconditioning. The primary determinant seemed to be the enhanced associative strength rather than the enhanced conditioned responding that occurred during the nonreinforced compound.

Thalamic Reticular Nucleus Activation Reflects Attentional Gating during Classical Conditioning

All senses, except olfaction, are routed through the thalamus to cerebral cortex. Thus, the thalamus is often referred to as the sensory gateway to cortex. Located between thalamus and cortex is a thin lamina of neurons called the thalamic reticular nucleus, which may function as an attentional gate. The phenomenon of blocking in classical conditioning provides an opportunity to test whether an attended stimulus activates the thalamic reticular nucleus more than an unattended stimulus: when a second stimulus is presented together with a previously conditioned stimulus, conditioned responding to the second stimulus is inhibited. Different groups of rats were given conditioning sessions with a single stimulus, a light or a tone, and then given conditioning sessions with compound (light and tone) stimuli. Blocking was confirmed using probe trials of single stimulus presentations. After a final test session of compound stimulus presentations, the brains were processed for the presence of Fos protein. Here we show that Fos-positive neurons were more numerous in the sector of the thalamic reticular nucleus associated with the attended conditioned stimulus than in the sector associated with the unattended stimulus. Thus, we provide evidence for an involvement of the thalamic reticular nucleus in selective attention.

Biogenic monoamine turnover in discrete rat brain regions is correlated with conditioned emotional response and its conditioning history

The content and turnover of dopamine, norepinephrine and 5-hydroxytryptamine (serotonin), and the content of their respective major metabolites were evaluated in 19 discrete brain areas of rats exposed to conditioned emotional response (CER), and in control groups which received either equivalent yoked shock (shock only) or compound stimulus presentation (tone only). On test day, CER animals suppressed responding and exhibited forms of emotional behavior after presentation of the conditioned stimulus (CS); while shock only and tone only control groups, and CER animals which received an acute dose of diazepam prior to testing, did not suppress. Few changes were observed in content of the biogenic amines or their metabolites, suggesting that the behavioral manipulations were acting within normal physiological limits. On the other hand, numerous changes were observed in the utilization of the 3 biogenic monoamines, which were correlated with the conditioning-anxiety (comparisons of CER vs shock only) and the shock history (comparison of shock only vs tone only). These observations are consistent with putative neural pathways in the frontal cortex, septum, nucleus accumbens, amygdala, striatum, hippocampus and brain stem (which utilize specific monoamines), and with discrete brain areas which have been implicated in classical conditioning and CER-related phenomena. These observations suggest roles for biogenic monoamines in mediating or responding to the classical conditioning and emotional components of the paradigm.

Amino acid neurotransmitter utilization in discrete rat brain regions is correlated with conditioned emotional response.

The content and utilization of amino acid neurotransmitters were evaluated in discrete brain areas of rats exposed to a conditioned emotional response (CER) procedure and in control groups which received either equivalent yoked shock history (shock only) or compound stimulus presentation (tone only). On test day, CER animals suppressed responding and exhibited anxious behavior after presentation of the CS, while shock only and tone only control groups, or CER animals which received an acute dose of diazepam prior to testing, did not suppress. Few changes were observed in the content of amino acids, suggesting that the behavioral manipulations were acting within normal physiological limits. On the other hand, numerous changes were observed in the utilization (turnover, metabolism) of the amino acid neurotransmitters. The effects of a history of shock presentation (shock only versus tone only) were persistent long after the conditioning sessions were terminated, and resulted in decreased turnover of the amino acids in many areas. CER conditioning-emotion (CER versus shock only) produced an increase in the turnover of aspartate and glutamate in many structures, while changes in GABA turnover were generally limited to decreases in limbic areas. If CER represents an animal model of anxiety, these observations may suggest roles for neurons which utilize amino acids in mediating or responding to emotional components of the paradigm.

EARLY AND LATE INTRODUCTION OF PROBES AND STIMULUS CONTROL ACQUISITION IN FADING

College students learned to name Braille patterns presented visually using a fading procedure in which Braille patterns were superimposed on letter names after which letter names were attenuated. Measurement of acquisition was accomplished by presenting probes-consisting of the Braille stimuli only-throughout fading. Effects of probes upon acquisition were assessed by introducing probes early or late in fading. Fewer fading levels were needed for Braille elements to acquire control when probes were introduced early rather than late. When probes were introduced late, all subjects learned to name the Braille elements as the letters were being faded out. When probes were introduced early, however, most subjects learned to name the Braille elements as they were being faded in. Since virtually no errors occurred during compound-stimulus presentations, the probe procedure did not induce errors during acquisition. Quantitative analysis of probe data suggested that inclusion of probes enhanced the control acquired by the Braille elements during compound-stimulus presentations. The reported effects may have been due to differences in the relative frequency of reinforcement presented during compounds and probes.

Reversal and Nonreversal Shifts in a Goldfish (Carassiusa Ura Tus) Classical Conditioning Situation

Goldfish were trained in reversal, nonreversal, and irrelevant shift situations with 60 or 100 preshift trials. The relevant dimensions were click and light. The attributes on the click dimension were high versus low intensity click. The attributes on the light dimension were high versus low intensity light. If the relevant stimulus was in the compound, the fish experienced the unconditioned stimulus (shock) at the end of the compound stimulus presentation. The unconditioned response and the conditioned response were the decrease in breathing that was initiated by the shock. The fish took longer to learn the irrelevant shift than the reversal or nonreversal shift. Fish, unlike other lower animals, did not learn nonreversal shifts faster than reversal shifts. No evidence was obtained for an overtraining reversal effect.

Orienting responses to a change in stimulus significance

Female human subjects received either one, five, or nine tone-light compound stimulus presentations followed without interruption by presentations of tone alone. Task subjects were instructed to make a reaction time response to onset of the light stimulus. Control groups made no RT responses. The effect of omission of the light on the orienting response was evaluated by examining magnitude of GSRs to tone stimulus onset. In groups that performed the RT task, GSRs to stimulus change (compound to simple) were found to be a function of the number of trials prior to stimulus change. This was not the case when subjects had not performed the RT task. The RT task itself was demonstrated to affect GSR magnitude and frequency. It was concluded that the behavioral significance of the stimulus and the number of significant stimuli previously presented to the subjects directly affected GSR magnitude to stimulus change.