Pavlovian-instrumental Transfer Research Articles

NAS 255NM

Abstract NAS 255NM is a 6% Mo grade with alloying to be a very resistant stainless steel to general pitting and crevice corrosion. This datasheet provides information on composition, physical properties, hardness, elasticity, and tensile properties. It also includes information on corrosion resistance as well as forming, heat treating, machining, and joining. Filing Code: SS-1267. Producer or source: Nippon Yakin Kogyo Company Ltd.

Dissociable corticostriatal circuits underlie goal-directed vs. cue-elicited habitual food seeking after satiation: evidence from a multimodal MRI study.

The present multimodal MRI study advances our understanding of the corticostriatal circuits underlying goal-directed vs. cue-driven, habitual food seeking. To this end, we employed a computerized Pavlovian-instrumental transfer paradigm. During the test phase, participants were free to perform learned instrumental responses (left and right key presses) for popcorn and Smarties outcomes. Importantly, prior to this test half of the participants had been sated on popcorn and the other half on Smarties - resulting in a reduced desirability of those outcomes. Furthermore, during a proportion of the test trials, food-associated Pavlovian cues were presented in the background. In line with previous studies, we found that participants were able to perform in a goal-directed manner in the absence of Pavlovian cues, meaning that specific satiation selectively reduced responding for that food. However, presentation of Pavlovian cues biased choice toward the associated food reward regardless of satiation. Functional MRI analyses revealed that, in the absence of Pavlovian cues, posterior ventromedial prefrontal cortex tracked outcome value. In contrast, during cued trials, the BOLD signal in the posterior putamen differentiated between responses compatible and incompatible with the cue-associated outcome. Furthermore, we identified a region in ventral amygdala showing relatively strong functional connectivity with posterior putamen during the cued trials. Structural MRI analyses provided converging evidence for the involvement of corticostriatal circuits: diffusion tensor imaging data revealed that connectivity of caudate-seeded white-matter tracts to the ventromedial prefrontal cortex predicted responding for still-valuable outcomes; and gray matter integrity in the premotor cortex predicted individual Pavlovian cueing effects.

Conditioned Stimulus Form Does Not Explain Failures to See Pavlovian-Instrumental-Transfer With Ethanol-Paired Conditioned Stimuli.

Pavlovian-Instrumental-Transfer (PIT) examines the effects of associative learning upon instrumental responding. Previous studies examining PIT with ethanol (EtOH)-maintained responding showed increases in responding following presentation of an EtOH-paired conditioned stimulus (CS). Recently, we conducted 2 studies examining PIT with an EtOH-paired CS. One of these found increases in responding, while the other did not. This less robust demonstration of PIT may have resulted from the form of the CS used, as we used a 120-second light stimulus as a CS, while the previous studies used either a 120-second auditory stimulus or a 10-second light stimulus. This study examined whether using conditions similar to our earlier study, but with either a 120-second auditory or a 10-second light stimulus as a CS, resulted in more robust PIT. We also examined the reliability of our previous failure to observe PIT. Three experiments were conducted examining whether PIT was obtained using (i) a 120-second light stimulus, (ii) a 10-second light stimulus, or (iii) a 120-second auditory stimulus as CSs. We found PIT was not obtained using (i) a 120-second light stimulus as a CS, (ii) a 10-second light stimulus as a CS, or (iii) a 120-second auditory stimulus as a CS. These results suggest that CS form does not account for our earlier failure to see PIT. Rather, factors like rat strain or how EtOH drinking is induced may account for when PIT is or is not observed.

Stress associated changes in Pavlovian-instrumental transfer in humans.

Predictive learning is known to influence instrumental responding for reward. Cues associated with an instrumental outcome can influence performance in two ways: (a) by selectively promoting actions associated with the outcome predicted by the cue (specific transfer), and (b) by increasing motivation and the vigour of instrumental responding (general transfer). To examine these two distinct processes in humans we developed a novel behavioural task in which participants were able to liberate junk-food snacks from a virtual vending machine. Additionally, the relationship between stress and cue-driven reward seeking was examined using participant scores on the Depression Anxiety and Stress Scale (DASS). Reward-paired cues were found to separately bias action selection and influence the rate of responding for rewards. Furthermore, the effects of reward-paired cues on the rate of responding for reward was influenced by increased stress and anxiety. Increased levels of stress and anxiety were associated particularly with changes in cue-driven response vigour; whereas high levels of stress and anxiety were associated with elevated responding above baseline in the presence of a cue associated with a non-rewarding outcome, participants with low levels of anxiety and stress showed appropriate suppression of responding during this cue. These differences in performance between high and low anxiety and stress participants provides initial evidence that, as has been demonstrated in rodents, stress affects the influence of cue-driven response vigour in humans.

Changes in the Influence of Alcohol-Paired Stimuli on Alcohol Seeking across Extended Training.

Previous work has demonstrated that goal-directed control of alcohol-seeking and other drug-related behaviors is reduced following extended self-administration and drug exposure. Here, we examined how the magnitude of stimulus influences on responding changes across similar training and drug exposure. Rats self-administered alcohol or sucrose for 2 or 8 weeks. Previous work has shown that 8 weeks, but not 2 weeks of self-administration produces habitual alcohol seeking. Next, all animals received equivalent Pavlovian conditioning sessions where a discrete stimulus predicted the delivery of alcohol or sucrose. Finally, the impact of the stimuli on ongoing instrumental responding was examined in a Pavlovian–instrumental transfer (PIT) test. While a significant PIT effect was observed following 2 weeks of either alcohol or sucrose self-administration, the magnitude of this effect was greater following 8 weeks of training. The specificity of the PIT effect appeared unchanged by extended training. While it is well established that evaluation of the outcome of responding contributes less to behavioral control following extended training and/or drug exposure, our data indicate that reward–predictive stimuli have a stronger contribution to responding after extended training. Together, these findings provide insight into the factors that control behavior after extended drug use, which will be important for developing effective methods for controlling and ideally reducing these behaviors.

Extinction and renewal of cue-elicited reward-seeking

Reward cues can contribute to overconsumption of food and drugs and can relapse. The failure of exposure therapies to reduce overconsumption and relapse is generally attributed to the context-specificity of extinction. However, no previous study has examined whether cue-elicited reward-seeking (as opposed to cue-reactivity) is sensitive to context renewal. We tested this possibility in 160 healthy volunteers using a Pavlovian-instrumental transfer (PIT) design involving voluntary responding for a high value natural reward (chocolate). One reward cue underwent Pavlovian extinction in the same (Group AAA) or different context (Group ABA) to all other phases. This cue was compared with a second non-extinguished reward cue and an unpaired control cue. There was a significant overall PIT effect with both reward cues eliciting reward-seeking on test relative to the unpaired cue. Pavlovian extinction substantially reduced this effect, with the extinguished reward cue eliciting less reward-seeking than the non-extinguished reward cue. Most interestingly, extinction of cue-elicited reward-seeking was sensitive to renewal, with extinction less effective for reducing PIT when conducted in a different context. These findings have important implications for extinction-based interventions for reducing maladaptive reward-seeking in practice.

Ghrelin receptor activation in the ventral tegmental area amplified instrumental responding but not the excitatory influence of Pavlovian stimuli on instrumental responding

Pavlovian stimuli predictive of food are able to amplify instrumental responding for food. This phenomenon termed Pavlovian-instrumental transfer (PIT) critically depends on intact VTA function and mesoaccumbens dopamine transmission. Considerable evidence suggests that food-predictive stimuli can enhance the release of ghrelin, an orexigen hormone that promotes food-directed responding. The ventral tegmental area (VTA) appears to be a key region through which stimulation of ghrelin receptors (GHS-R1A) invigorates food-directed responding, in part by activating the mesoaccumbens dopamine system. Thus, it is conceivable that stimulation of GHS-R1A in the VTA can amplify PIT, i.e. stimulus-elicited increase in lever pressing for food. Here we examined in rats the effects of VTA ghrelin microinfusion on PIT. Our results demonstrate that ghrelin microinfusion into the VTA failed to enhance PIT suggesting that VTA GHS-R1A stimulation was unable to enhance the motivational significance of food-predictive stimuli. Consistent with previous studies, our results further indicate that intra-VTA ghrelin microinfusion invigorated instrumental responding under a progressive ratio schedule. These data provide support to the notion that VTA GHS-R1A stimulation increases the tendency to work for food.

Dopamine D2/3- and μ-opioid receptor antagonists reduce cue-induced responding and reward impulsivity in humans.

Increased responding to drug-associated stimuli (cue reactivity) and an inability to tolerate delayed gratification (reward impulsivity) have been implicated in the development and maintenance of drug addiction. Whereas data from animal studies suggest that both the dopamine and opioid system are involved in these two reward-related processes, their role in humans is less clear. Moreover, dopaminergic and opioidergic drugs have not been directly compared with regard to these functions, even though a deeper understanding of the underlying mechanisms might inform the development of specific treatments for elevated cue reactivity and reward impulsivity. In a randomized, double-blind, between-subject design we administered the selective dopamine D2/D3 receptor antagonist amisulpride (400 mg, n=41), the unspecific opioid receptor antagonist naltrexone (50 mg, n=40) or placebo (n=40) to healthy humans and measured cue-induced responding with a Pavlovian-instrumental transfer task and reward impulsivity with a delay discounting task. Mood was assessed using a visual analogue scale. Compared with placebo, amisulpride significantly suppressed cue-induced responding and reward impulsivity. The effects of naltrexone were similar, although less pronounced. Both amisulpride and naltrexone decreased average mood ratings compared with placebo. Our results demonstrate that a selective blockade of dopamine D2/D3 receptors reduces cue-induced responding and reward impulsivity in healthy humans. Antagonizing μ-opioid receptors has similar effects for cue-induced responding and to a lesser extent for reward impulsivity.

Habitual Alcohol Seeking: Neural Bases and Possible Relations to Alcohol Use Disorders.

Loss of flexible control over alcohol use may contribute to the development of alcohol use disorders. An increased contribution of response habits to alcohol-related behaviors may help explain this loss of control. Focusing on data from outcome devaluation and Pavlovian-instrumental transfer procedures, we review evidence for loss of goal-directed control over alcohol seeking and consumption drawing from both preclinical findings and clinical data where they exist. Over the course of extended alcohol self-administration and exposure, the performance of alcohol-seeking responses becomes less sensitive to reduction in the value of alcohol and more vulnerable to the influences of alcohol-predictive stimuli. These behavioral changes are accompanied by a shift in the corticostriatal circuits that control responding from circuits centered on the dorsomedial to those centered on the dorsolateral striatum. These changes in behavioral and neural control could help explain failures to abstain from alcohol despite intention to do so. Understanding and ultimately ameliorating these changes will aid development of more effective treatment interventions.

Motivational state, reward value, and Pavlovian cues differentially affect skilled forelimb grasping in rats.

Motor skills represent high-precision movements performed at optimal speed and accuracy. Such motor skills are learned with practice over time. Besides practice, effects of motivation have also been shown to influence speed and accuracy of movements, suggesting that fast movements are performed to maximize gained reward over time as noted in previous studies. In rodents, skilled motor performance has been successfully modeled with the skilled grasping task, in which animals use their forepaw to grasp for sugar pellet rewards through a narrow window. Using sugar pellets, the skilled grasping task is inherently tied to motivation processes. In the present study, we performed three experiments modulating animals’ motivation during skilled grasping by changing the motivational state, presenting different reward value ratios, and displaying Pavlovian stimuli. We found in all three studies that motivation affected the speed of skilled grasping movements, with the strongest effects seen due to motivational state and reward value. Furthermore, accuracy of the movement, measured in success rate, showed a strong dependence on motivational state as well. Pavlovian cues had only minor effects on skilled grasping, but results indicate an inverse Pavlovian-instrumental transfer effect on movement speed. These findings have broad implications considering the increasing use of skilled grasping in studies of motor system structure, function, and recovery after injuries.

Nucleus accumbens core and shell are differentially involved in general and outcome-specific forms of Pavlovian-instrumental transfer with alcohol and sucrose rewards.

Alcohol-associated stimuli contribute to relapse risk. Therefore, understanding the behavioural and neural mechanisms underlying the ability of such stimuli to promote alcohol-seeking is important for developing effective treatments for alcohol-use disorders. The Pavlovian-instrumental transfer (PIT) paradigm can be used to study the influence of Pavlovian cues on independently-trained instrumental responses earning reward. The effects can be either general, increasing the vigour of reward-related behaviours, or specific to responses that earn a common outcome. These different forms of PIT are mediated by distinct neural circuits involving the nucleus accumbens (NAC) core and shell, respectively. Here we examined the effects of pharmacological inactivation of either the NAC core or shell on PIT generated by alcohol-predictive and sucrose-predictive stimuli in rats. We found that presentations of a stimulus predicting sucrose enhanced responding for sucrose but not alcohol, suggesting an outcome-specific effect. In contrast, presentations of an alcohol-predictive stimulus enhanced responding for both alcohol and sucrose, suggesting a generally arousing effect. Inactivation of the NAC core reduced PIT and, in particular, the effect of the alcohol stimulus. Inactivation of the NAC shell reduced the specificity of the stimulus effects but left the ability of the stimuli to non-specifically invigorate responding intact, consistent with a role in mediating the specificity of PIT. Together, these results suggest that the NAC core plays a particularly important role in mediating the influence of alcohol-predictive cues on reward-seeking behaviours.

The specificity of Pavlovian regulation is associated with recovery from depression.

Changes in reflexive emotional responses are hallmarks of depression, but how emotional reflexes make an impact on adaptive decision-making in depression has not been examined formally. Using a Pavlovian-instrumental transfer (PIT) task, we compared the influence of affectively valenced stimuli on decision-making in depression and generalized anxiety disorder compared with healthy controls; and related this to the longitudinal course of the illness. A total of 40 subjects with a current DSM-IV-TR diagnosis of major depressive disorder, dysthymia, generalized anxiety disorder, or a combination thereof, and 40 matched healthy controls performed a PIT task that assesses how instrumental approach and withdrawal behaviours are influenced by appetitive and aversive Pavlovian conditioned stimuli (CSs). Patients were followed up after 4-6 months. Analyses focused on patients with depression alone (n = 25). In healthy controls, Pavlovian CSs exerted action-specific effects, with appetitive CSs boosting active approach and aversive CSs active withdrawal. This action-specificity was absent in currently depressed subjects. Greater action-specificity in patients was associated with better recovery over the follow-up period. Depression is associated with an abnormal influence of emotional reactions on decision-making in a way that may predict recovery.

Conditioned stimuli's role in relapse: preclinical research on Pavlovian-Instrumental-Transfer.

Pavlovian learning is central to many theories of addiction. In these theories, stimuli paired with drug ingestion become conditioned stimuli (CS) and subsequently elicit drug-seeking and drug-taking. However, in most relevant studies, Pavlovian and instrumental learning are confounded. This confound may be avoided in Pavlovian-Instrumental-Transfer (PIT) procedures. In PIT, Pavlovian and instrumental learning are established separately and then combined. In order to better understand the role of CSs in addiction, we review the relevant studies using PIT. We identified seven articles examining PIT effects of ethanol- or cocaine-paired CSs. Under at least one condition, six of these articles reported CS-elicited increases in responding previously maintained by drug. However, the only study using the optimal control condition failed to find a CS-elicited increase. Two studies examining CS specificity found the CS also increased responding maintained by a different reinforcer. Two studies examined if CSs elicit increases in actual drug-taking. Both failed to find CS-elicited increases, i.e., no study shows CS-elicited increases in actual drug-taking. Further, CS-elicited increases in extinguished responding are short-lived. These findings are not entirely consistent with Pavlovian learning playing a central role in addiction. However, design issues can explain most of these inconsistencies. Studies without these design issues are needed. Additionally, existing theories hypothesize drug-paired CSs increase drug-taking by increasing motivation, by eliciting conditioned responses that make drug-seeking more probable, or by a combination of these. Work distinguishing between these mechanisms would also be useful.

The effect of conditioned inhibition on the specific Pavlovian-instrumental transfer effect.

Four experiments examined the effect of Pavlovian conditioned inhibition on specific Pavlovian-instrumental transfer (PIT) in human participants. The task comprised an instrumental phase in which 2 responses (R1, R2) were each paired with 1 of 2 outcomes (O1, O2: R1→O1, R2→O2), and a Pavlovian phase, in which 2 conditioned stimuli (CSs), CS1 and CS2 each signaled 1 of the 2 outcomes (CS1→O1, CS2→O2). In Experiments 1-2 a conditioned inhibitor, X, predicted the omission of 1 of the outcomes (e.g., CS1→O1, CS1X→nothing). In a subsequent test, performance of R1 and R2 was examined in the presence of CS1 and CS2. A specific PIT effect was observed: R1 was performed more than R2 during CS1, and R2 more than R1 during CS2. This PIT effect was significantly reduced by the presence of the inhibitor X in Experiment 1, in which the Pavlovian phase followed the instrumental phase, and in Experiment 2 in which it preceded it. No such effect was observed when X was presented in the absence of any expectation of the outcomes during the PIT test (Experiment 3a), or when X was trained as a signal for an alternative outcome (Experiment 3b). These results are consistent with the suggestion that the specific PIT effect occurs through a stimulus-outcome-response (S-O-R) mechanism, according to which the CS evokes a representation of the outcome which in turn elicits the response (e.g., CS1→O1→R1). The conditioned inhibitor suppresses performance of the response by suppressing activation of the outcome representation.

Effects of nitrogen dopants on the atomic step kinetics and electronic structures of O-polar ZnO.

Oxygen-polar ZnO films are grown in step flow mode by molecular beam epitaxy. Driven by the step flow anisotropy, the growth leads to the occurrence of specific hexagonal pits in the surface. The specific pits are formed by interlacing steps of the {10̄1̄4} facets, thus quenching the macroscopic dipole moment along the c-axis and satisfying the stabilization principles. Nitrogen (N) doping trials are then performed on the basis of the stable surface. In doping, growth remains in step flow mode but the step flow anisotropy vanishes, resulting in an obvious change of the surface morphology. Besides, a distinct acceptor state appears by in situ scanning tunneling spectroscopy analysis. First-principles calculations reveal that N readily substitutes for step-edge Zn and acts as NO2 adsorbed at the step edge. Desorption of the NO2 facilitates the formation of NO-VZn shallow acceptor complexes, which contributes to the appearance of the acceptor state. According to the peculiarities of N dopants on the O-polar surface, vicinal O-polar substrates (e.g., {10̄1̄4} substrate) are promising in ZnO : N due to the easily achieved step flow growth and high density of step edges for N incorporation.

N-methyl-D-aspartate receptors in the ventral tegmental area mediate the excitatory influence of Pavlovian stimuli on instrumental performance.

Pavlovian stimuli predictive of food can markedly amplify instrumental responding for food. This effect is termed Pavlovian-instrumental transfer (PIT). The ventral tegmental area (VTA) plays a key role in mediating PIT, however, it is yet unknown whether N-methyl-D-aspartate (NMDA)-type glutamate receptors in the VTA are involved in PIT. Here, we examined the effects of an NMDA-receptor blockade in the VTA on PIT. Immediately prior to PIT testing, rats were subjected to intra-VTA infusions of vehicle or of the NMDA-receptor antagonist 2-amino-5-phosphonopentanoic acid (AP-5) (1, 5µg/side). In rats that received AP-5 at the lower dose, the PIT effect was intact, i.e. presentation of the Pavlovian stimulus enhanced instrumental responding. By contrast, in rats that received AP-5 at the higher dose, the PIT effect was blocked. The data suggest that NMDA receptors in the VTA mediate the activating effects of Pavlovian stimuli on instrumental responding.

The Relationship Between Specific Pavlovian Instrumental Transfer and Instrumental Reward Probability.

Goal-directed behavior is influenced by environmental cues: in particular, cues associated with a reward can bias action choice toward actions directed to that same reward. This effect is studied experimentally as specific Pavlovian-instrumental transfer (specific PIT). We have investigated the hypothesis that cues associated to an outcome elicit specific PIT by rising the estimates of reward probability of actions associated to that same outcome. In other words, cues reduce the uncertainty on the efficacy of instrumental actions. We used a human PIT experimental paradigm to test the effects of two different instrumental contingencies: one group of participants had a 33% chance of being rewarded for each button press, while another had a 100% chance. The group trained with 33% reward probability showed a stronger PIT effect than the 100% group, in line with the hypothesis that Pavlovian cues linked to an outcome work by reducing the uncertainty of receiving it. The 100% group also showed a significant specific PIT effect, highlighting additional factors that could contribute to specific PIT beyond the instrumental training contingency. We hypothesize that the uncertainty about reward delivery due to testing in extinction might be one of these factors. These results add knowledge on how goal-directed behavior is influenced by the presence of environmental cues associated with a reward: such influence depends on the probability that we have to reach a reward, namely when there is less chance of getting a reward we are more influenced by cues associated with it, and vice versa.

Supplemental Material for The Effect of Conditioned Inhibition on the Specific Pavlovian-Instrumental Transfer Effect

Supplemental Material for The Effect of Conditioned Inhibition on the Specific Pavlovian-Instrumental Transfer Effect

NAS 325N

Abstract NAS 325N is one of the most resistant stainless steels to general pitting and crevice corrosion. This datasheet provides information on composition, physical properties, hardness, elasticity, and tensile properties. It also includes information on corrosion resistance as well as forming, heat treating, machining, and joining. Filing Code: SS-1225. Producer or source: Nippon Yakin Kogyo Company Ltd.

Basolateral amygdala rapid glutamate release encodes an outcome-specific representation vital for reward-predictive cues to selectively invigorate reward-seeking actions.

Environmental stimuli have the ability to generate specific representations of the rewards they predict and in so doing alter the selection and performance of reward-seeking actions. The basolateral amygdala participates in this process, but precisely how is unknown. To rectify this, we monitored, in near-real time, basolateral amygdala glutamate concentration changes during a test of the ability of reward-predictive cues to influence reward-seeking actions (Pavlovian-instrumental transfer). Glutamate concentration was found to be transiently elevated around instrumental reward seeking. During the Pavlovian-instrumental transfer test these glutamate transients were time-locked to and correlated with only those actions invigorated by outcome-specific motivational information provided by the reward-predictive stimulus (i.e., actions earning the same specific outcome as predicted by the presented CS). In addition, basolateral amygdala AMPA, but not NMDA glutamate receptor inactivation abolished the selective excitatory influence of reward-predictive cues over reward seeking. These data the hypothesis that transient glutamate release in the BLA can encode the outcome-specific motivational information provided by reward-predictive stimuli.