Appetitive Conditioning Research Articles

Ventral hippocampal interneurons govern extinction and relapse of contextual associations

Contextual memories are critical for survival but must be extinguished when new conditions render them nonproductive. By most accounts, extinction forms a new memory that competes with the original association for control over behavior, but the underlying circuit mechanisms remain largely enigmatic. Here, we demonstrate that extinction of contextual fear conditioning recruits somatostatin interneurons (SST-INs) in the ventral hippocampus. Correspondingly, real-time activity of SST-INs correlates with transitions between immobility and movement, signaling exit from defensive freezing bouts. Optogenetic manipulation of SST-INs but not parvalbumin interneurons (PV-INs) elicits bidirectional changes in freezing that are specific to the context in which extinction was acquired. Finally, similar effects were obtained following extinction of sucrose-based appetitive conditioning, in which SST-IN inhibition triggers relapse to reward seeking. These data suggest that ventral hippocampal SST-INs play a fundamental role in extinction that is independent of affective valence and may be related to their disruption of spontaneous emotional responses.

Valenced tactile information is evoked by neutral visual cues following emotional learning

Abstract Learning which stimuli in our environment co-occur with painful or pleasurable events is critical for survival. Previous research has established the basic neural and behavioral mechanisms of aversive and appetitive conditioning; however, it is unclear precisely what information content is learned. Here we examined the degree to which aspects of the unconditioned stimulus (US)—sensory information versus affective salience—are transferred to the conditioned stimulus (CS). To decode what stimuli features (e.g., valence vs. discriminative somatosensation) are represented in patterns of brain activation elicited during appetitive (soft touch) and aversive (painful touch) conditioning to faces, a novel approach to using modeling with representational similarity analysis (RSA) based on theoretically driven representational patterns of interest (POIs) was applied to fMRI data. Once associations were learned through conditioning, globally, the CS reactivated US representational patterns showing conditioning-dependent reactivation in specific high-order brain regions: In the dorsal anterior cingulate cortex, the CS reactivated patterns associated with the affective salience of the US—suggesting that, with affective conditioning, these regions carry forward the affective associations of the experience.

Twists to Classical Conditioning of Adult Drosophila.

Memory has been extensively studied in Drosophila since the early 1970s. Straightforward aversive and appetitive conditioning paradigms train populations of flies to associate the pairing of one of two odors with either punishment or reward. After training, the flies show either preferential avoidance or approach behavior, to the appropriate odor, when given a choice between the two odors in a simple T-maze apparatus. These basic experimental approaches have proven useful in understanding the genetic, molecular, cellular, and neuronal network bases of various valence-specific memories in the fly brain. In addition, numerous modifications to these assays have permitted the study of a broad range of memory-related phenomena. Labile short-term avoidance and approach memories can be readily distinguished from more stable "consolidated" long-term memory equivalents. Prior or subsequent experience of the training cues, and manipulations of the flies' condition, have revealed how parallel competing memories and incompatible states can temporarily interfere with memory retrieval, providing insight into mechanisms of forgetting. Recent studies have also modified the training and testing apparatus to allow simultaneous presentation of odors and colors, providing insight into mechanisms of multisensory learning.

Both probability and rate of reinforcement can affect the acquisition and maintenance of conditioned responses.

In Pavlovian conditioning, the strength of a conditioned response is a function of the probability of reinforcement. However, manipulations of probability are often confounded with changes in the rate of reinforcement. Two between-group experiments in mice evaluated the effect of the probability of reinforcement, while controlling the rate of reinforcement, on appetitive conditioning and extinction. Experiment 1 equated the reinforcement rate by manipulating the number of reinforcements received in each reinforced trial in a critical group (one vs. two consecutive rewards). The results of this experiment showed that probability influenced the rate of responses in acquisition, even when controlling the reinforcement rate. Experiment 2 further assessed the role of probability on behavior while controlling the rate of reinforcement during the conditioned stimulus (CS) using a split-trial design, in which the total CS time was held constant but presented in different numbers of discrete trials (e.g., 50% reinforcement with two 12 s CS's vs. 100% reinforcement with a 24 s average CS duration). This experiment confirmed that probability influenced response rates, and both the probability and rate of reinforcement affected the proportion of trials with responses. Together, these results suggest that the probability of reinforcement, while having little effect on the speed at which responses emerged, affects responding even when the rate of reinforcement is held constant. The results challenge formal learning theories to account for the effects of both the probability and rate of reinforcement. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Renewal of conditioned fear in male and female rats.

Pavlovian extinction reduces the performance of conditioned responses and occurs when the conditioned stimulus (CS) is repeatedly presented in the absence of the unconditioned stimulus (US). However, when the CS is experienced in a context that is different from the extinction context, there is a recovery of the conditioned response, a phenomenon known as renewal. There is some evidence that the renewal of appetitive conditioning is influenced by sex, with females failing to exhibit renewed responding. Further, there is recent evidence that renewal of fear might also not occur in female rats. In both appetitive and fear preparations, the lack of renewal in females has been postulated to be related to cycling ovarian hormones. Therefore, in Experiments 1 and 2, we directly compared fear renewal in males and females (Experiment 1) as well as ovariectomized (OVX) females (Experiment 2) when conditioning occurred in Context A, extinction in B, and testing in A (ABA renewal). Experiments 3 and 4 examined renewal when conditioning and extinction occurred in A and testing occurred in B (AAB renewal). In all experiments, renewal was not significantly different between male and female rats. Further, in Experiments 2 and 4, renewal did not differ between males, intact females, and OVX females. Additionally, in each experiment, there was no evidence that context excitation and/or inhibition contributed to renewal; instead suggesting that renewal was controlled by an occasion-setting mechanism. Overall, these results suggest little evidence for the role of sex in renewal of conditioned freezing and also indicate that cycling ovarian hormones have little role in the strength of renewal in female rats. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

The effect of individual differences on Pavlovian conditioning in specific Internet-use disorders

The I-PACE model suggests that Internet-use disorders result from the interplay of individual vulnerabilities and cognitive and affective processes. As in substance use disorders, Pavlovian conditioning processes are attributed a key role. However, and despite progress in identifying individual vulnerabilities, factors influencing appetitive conditioning remain poorly understood. We therefore conducted a Pavlovian conditioning experiment in which individuals with risky as well as non-problematic use of either gaming or buying-shopping applications learned to associate different abstract stimuli with either gaming or buying-shopping. Regression analyses were used to identify individual characteristics influencing awareness of the experimental contingencies, speed of acquisition of awareness and the magnitude of the conditioned emotional responses regarding pleasantness and arousal ratings of the stimuli. Results demonstrated successful Pavlovian conditioning and an attentional bias towards reward-predicting cues. Awareness of the experimental contingencies was linked solely to cognitive abilities, while the speed of acquisition of awareness and the magnitude of conditioned responses was influenced by specific personality characteristics, experiences of compensation from using the application and severity of problematic use. Importantly, certain characteristics specifically predicted the magnitude of the conditioned response towards gaming, while others specifically predicted the response towards buying-shopping, highlighting differing vulnerabilities. These findings underscore the importance of targeted interventions and prevention strategies tailored to these specific vulnerability factors. Further implications and limitations are discussed.

Assessing midbrain neuromelanin and its relationship to reward learning in anorexia nervosa: Stage 1 of a registered report.

Anorexia nervosa (AN) is a debilitating and potentially chronic eating disorder, characterized by low hedonic drive toward food, which has been linked with perturbations in both reward processing and dopaminergic activity. Neuromelanin-sensitive magnetic resonance imaging (MRI) is an emerging method to index midbrain neuromelanin-a by-product of dopaminergic synthesis. The assessment of midbrain neuromelanin, and its association with AN psychopathology and reward-related processes, may provide critical insights into reward circuit function in AN. This study will incorporate neuromelanin-sensitive MRI into an existing study of appetitive conditioning in those with AN. Specifically, those with acute and underweight AN (N=30), those with weight-restored AN (N=30), and age-matched healthy controls (N=30) will undergo clinical assessment of current and previous psychopathology, in addition to structural neuromelanin-sensitive MRI, diffusion MRI, and functional MRI (fMRI) during appetitive conditioning. This study will be among the first to interrogate midbrain neuromelanin in AN-a disorder characterized by altered dopaminergic activity. Results will help establish whether abnormalities in the midbrain synthesis of dopamine are evident in those with AN and are associated with symptomatic behavior and reduced ability to experience pleasure and reward.

Appetitive conditioning with pornographic stimuli elicits stronger activation in reward regions than monetary and gaming-related stimuli.

Appetitive conditioning plays an important role in the development and maintenance of pornography-use and gaming disorders. It is assumed that primary and secondary reinforcers are involved in these processes. Despite the common use of pornography and gaming in the general population appetitive conditioning processes in this context are still not well studied. This study aims to compare appetitive conditioning processes using primary (pornographic) and secondary (monetary and gaming-related) rewards as unconditioned stimuli (UCS) in the general population. Additionally, it investigates the conditioning processes with gaming-related stimuli as this type of UCS was not used in previous studies. Thirty-one subjects participated in a differential conditioning procedure in which four geometric symbols were paired with either pornographic, monetary, or gaming-related rewards or with nothing to become conditioned stimuli (CS + porn, CS + game, CS + money, and CS-) in an functional magnetic resonance imaging study. We observed elevated arousal and valence ratings as well as skin conductance responses for each CS+ condition compared to the CS-. On the neural level, we found activations during the presentation of the CS + porn in the bilateral nucleus accumbens, right medial orbitofrontal cortex, and the right ventral anterior cingulate cortex compared to the CS-, but no significant activations during CS + money and CS + game compared to the CS-. These results indicate that different processes emerge depending on whether primary and secondary rewards are presented separately or together in the same experimental paradigm. Additionally, monetary and gaming-related stimuli seem to have a lower appetitive value than pornographic rewards.

Effects of sleep deprivation on food-related Pavlovian-instrumental transfer: a randomized crossover experiment.

Recent research suggests that insufficient sleep elevates the risk of obesity. Although the mechanisms underlying the relationship between insufficient sleep and obesity are not fully understood, preliminary evidence suggests that insufficient sleep may intensify habitual control of behavior, leading to greater cue-elicited food-seeking behavior that is insensitive to satiation. The present study tested this hypothesis using a within-individual, randomized, crossover experiment. Ninety-six adults underwent a one-night normal sleep duration (NSD) condition and a one-night total sleep deprivation (TSD) condition. They also completed the Pavlovian-instrumental transfer paradigm in which their instrumental responses for food in the presence and absence of conditioned cues were recorded. The sleep × cue × satiation interaction was significant, indicating that the enhancing effect of conditioned cues on food-seeking responses significantly differed across sleep × satiation conditions. However, this effect was observed in NSD but not TSD, and it disappeared after satiation. This finding contradicted the hypothesis but aligned with previous literature on the effect of sleep disruption on appetitive conditioning in animals-sleep disruption following learning impaired the expression of appetitive behavior. The present finding is the first evidence for the role of sleep in Pavlovian-instrumental transfer effects. Future research is needed to further disentangle how sleep influences motivational mechanisms underlying eating.

The effects of a retrieval cue on renewal of conditioned responses in human appetitive conditioning

Contextual renewal of reward anticipation may be one potential mechanism underlying relapse in eating and substance use disorders. We therefore tested retrieval cues, a method derived from an inhibitory retrieval-based model of extinction learning to attenuate contextual renewal using an appetitive conditioning paradigm. A pilot study was carried out in Experiment 1 to validate a differential chocolate conditioning paradigm, in which a specific tray was set up as a conditioned stimulus (CS) for eating chocolate (unconditioned stimulus, US). Using an ABA renewal design in Experiment 2, half of the participants were presented with a retrieval cue in the acquisition phase (group AC) and the other half in the extinction phase (group EC). Presentation of the retrieval cue in the EC was associated with reduced renewal of US-expectancy, while there was a clear renewal effect for US-expectancy in the AC. One limitation was the difference in cue presentations between both groups due to the number of trials in acquisition and extinction. Experiment 3 therefore aimed at replicating the results of Experiment 2, but with fewer cue presentations for the EC to match the AC. No significant group differences were observed indicating no effect of the retrieval cue. Theoretical and clinical implications in light of the differing results are discussed.

Encoding of Predictive Associations in Human Prefrontal and Medial Temporal Neurons During Pavlovian Appetitive Conditioning.

Pavlovian conditioning is thought to involve the formation of learned associations between stimuli and values, and between stimuli and specific features of outcomes. Here, we leveraged human single neuron recordings in ventromedial prefrontal, dorsomedial frontal, hippocampus, and amygdala while patients of both sexes performed an appetitive Pavlovian conditioning task probing both stimulus-value and stimulus-stimulus associations. Ventromedial prefrontal cortex encoded predictive value along with the amygdala, and also encoded predictions about the identity of stimuli that would subsequently be presented, suggesting a role for neurons in this region in encoding predictive information beyond value. Unsigned error signals were found in dorsomedial frontal areas and hippocampus, potentially supporting learning of non-value related outcome features. Our findings implicate distinct human prefrontal and medial temporal neuronal populations in mediating predictive associations which could partially support model-based mechanisms during Pavlovian conditioning.

Kamin blocking is disrupted by low-dose ketamine in mice: Further implications for aberrant stimulus processing in schizophrenia.

Previous studies have shown that low doses of ketamine, an N-methyl-D-aspartate receptor antagonist, produce aberrantly strong internal representations of associatively activated but absent stimuli in humans and nonhuman animals, suggesting the validity of ketamine treatment as a preclinical model of the positive symptoms of schizophrenia, including hallucinations and delusions. However, whether acute ketamine treatment also impairs the ability to ignore present but informationally redundant stimuli, which is another hallmark of schizophrenia, remains unclear. Accordingly, the present study investigated whether injections of low-dose ketamine attenuate Kamin blocking in an appetitive conditioning preparation in mice. Mice in the blocking group were initially trained with A+ conditioning (i.e., conditioned stimulus A paired with a sucrose solution), followed by compound AX+ training, before the conditioned responses to the cue X were tested in extinction. The animals in the control group received B+ training before the AX+ training. Half of the mice in each group received an injection of 16 mg/kg ketamine before each compound conditioning session and the extinction test, whereas the other half received saline. The results showed a reliable blocking effect in the saline-treated mice, whereas the blocking effect was absent in the ketamine-treated mice. Specifically, the absence of blocking was due to the ketamine-treated mice learning about the blocked cues. This finding further validates the use of low-dose ketamine as a preclinical model of schizophrenia. It also suggests a possible link between hallucination-like aberrant processing of absent events and a reduced ability to suppress attentional processing of task-irrelevant stimuli. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

A search for effective reinforcers in appetitive conditioning for adult zebrafish: Ecologically relevant unconditioned stimuli

Learning and memory related brain disorders represent a large unmet medical need. Laboratory studies with animals may model brain disorders and facilitate uncovering their mechanisms. The zebrafish has been proposed for such studies. However, numerous factors that influence performance in learning tasks have yet to be understood in zebrafish. One such factor is what motivates zebrafish. Here we introduce a novel reinforcer, an ecologically relevant unconditioned stimulus (US). We placed a photograph of gravel underneath quarter of the bottom of an experimental tank on one side and also positioned artificial plants there, the “natural” US. First, we showed that this stimulus was preferred by zebrafish. Next, we investigated whether this stimulus could serve as US for associative learning. We marked the walls of the tank on the side where the US was presented with red paper, the conditioned stimulus (CS+) we found neutral before, and we also marked the walls on the other side of the tank where no US was placed with blue paper (CS-). In addition to fish receiving this “paired” training, we also ran unpaired training with another group of zebrafish, in which the fish saw the US associated with blue and red in a random manner. After having trained the fish in this manner, we tested the performance of the paired and unpaired group of zebrafish in a memory probe trial during which no US was present, and only the CSs (blue and red walls) were shown. We found the paired group of zebrafish to show significant preference for the CS+, as they spent more time and swam closer to the red side compared to the unpaired group and compared to chance. We conclude that ecologically relevant stimuli can serve as efficient US in appetitive conditioning of zebrafish.

Tyramine and its Amtyr1 receptor modulate attention in honey bees (Apis mellifera).

Animals must learn to ignore stimuli that are irrelevant to survival and attend to ones that enhance survival. When a stimulus regularly fails to be associated with an important consequence, subsequent excitatory learning about that stimulus can be delayed, which is a form of nonassociative conditioning called 'latent inhibition'. Honey bees show latent inhibition toward an odor they have experienced without association with food reinforcement. Moreover, individual honey bees from the same colony differ in the degree to which they show latent inhibition, and these individual differences have a genetic basis. To investigate the mechanisms that underly individual differences in latent inhibition, we selected two honey bee lines for high and low latent inhibition, respectively. We crossed those lines and mapped a Quantitative Trait Locus for latent inhibition to a region of the genome that contains the tyramine receptor gene Amtyr1 [We use Amtyr1 to denote the gene and AmTYR1 the receptor throughout the text.]. We then show that disruption of Amtyr1 signaling either pharmacologically or through RNAi qualitatively changes the expression of latent inhibition but has little or slight effects on appetitive conditioning, and these results suggest that AmTYR1 modulates inhibitory processing in the CNS. Electrophysiological recordings from the brain during pharmacological blockade are consistent with a model that AmTYR1 indirectly regulates at inhibitory synapses in the CNS. Our results therefore identify a distinct Amtyr1-based modulatory pathway for this type of nonassociative learning, and we propose a model for how Amtyr1 acts as a gain control to modulate hebbian plasticity at defined synapses in the CNS. We have shown elsewhere how this modulation also underlies potentially adaptive intracolonial learning differences among individuals that benefit colony survival. Finally, our neural model suggests a mechanism for the broad pleiotropy this gene has on several different behaviors.

Primacy and recency in snails (Cornu aspersum).

Pavlovian conditioning has been proven to be useful for the study of associative learning and animal cognition. This procedure can be used to observe certain memory phenomena. The appetitive conditioning of several neutral stimuli can result in higher response rates, and therefore a better memory, for the first and last stimuli of the series. This is equivalent to primacy and recency effects. In this work, the tentacle lowering procedure was employed to study these phenomena in the snail (Cornu aspersum). Subjects experienced five odorous conditioned stimuli (CS) paired with food (conditioning) in a specific order followed by the exposure to the CSs alone to measure the conditioned response (CR, conditioning test). For Experiment 1, the serial presentation of the five reinforced odors resulted in a higher CR for the initial and final odors in comparison with the middle ones. In Experiment 2, it was established that a 20-min trial is enough to produce appetitive conditioning in snail. For Experiment 3, the results of Experiment 1 were replicated while controlling for odor presentation order. Finally, in Experiment 4, the serial position effect was obtained when the interval between conditioning and test phases were minimized. The results observed in the present study provided evidence of the serial position effect in terrestrial snails. The theoretical implications of these are debated. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Neural correlates of naturalistic single-trial appetitive conditioning

BackgroundPrior research suggests naturalistic single-trial appetitive conditioning may be a potent phenomenon in humans, capable of modulating both motivation and attention. In this study, we aimed to characterise the neural correlates of this phenomenon using functional Magnetic Resonance Imaging (fMRI) paradigms MethodsTwenty-three healthy adults (12 males) underwent conditioning during which they ate a novel 3D object made from white chocolate (CS+) and handled a similar object made from plastic (CS-). Brain activity was recorded before and after conditioning during a passive viewing paradigm ResultsA naturalistic CS+ was rated as more highly craved, better-liked and elicited greater expectancies for chocolate than the CS− after conditioning. An exploration of the interaction between time (pre- and post-conditioning) and CS type (CS+, CS-) during the passive viewing task suggested enhanced activation from pre- to post-conditioning in the right superior frontal gyrus (R.SFG) in response to the CS-. ConclusionResults reveal neural correlates of single-trial appetitive conditioning and highlight a possible role of response inhibition during learning about non-rewards, perhaps optimizing motivated behaviour. These findings contribute to our understanding of the neural mechanisms underpinning rapid reward and non-reward learning, and may inform development of behavioural interventions for reward-driven overeating.

Dopamine-mediated striatal activity and function is enhanced in GlyRα2 knockout animals

The glycine receptor alpha 2 (GlyRα2) is a ligand-gated ion channel which upon activation induces a chloride conductance. Here, we investigated the role of GlyRα2 in dopamine-stimulated striatal cell activity and behavior. We show that depletion of GlyRα2 enhances dopamine-induced increases in the activity of putative dopamine D1 receptor-expressing striatal projection neurons, but does not alter midbrain dopamine neuron activity. We next show that the locomotor response to d-amphetamine is enhanced in GlyRα2 knockout animals, and that this increase correlates with c-fos expression in the dorsal striatum. 3-D modeling revealed an increase in the neuronal ensemble size in the striatum in response to D-amphetamine in GlyRα2 KO mice. Finally, we show enhanced appetitive conditioning in GlyRα2 KO animals that is likely due to increased motivation, but not changes in associative learning or hedonic response. Taken together, we show that GlyRα2 is an important regulator of dopamine-stimulated striatal activity and function.

Can you learn to starve yourself? Inducing food avoidance in the laboratory

The restriction of energy intake is a central and persistent symptom of anorexia nervosa. Recent models of the disorder suggest that food restrictions are learned avoidance behaviours, which are acquired and maintained by classical and operant conditioning. The present study aims to test this learning model of food restriction. It investigates whether introducing negative consequences for the intake of tasty high-calorie food and introducing positive consequences for its avoidance can create food avoidance, increase fear of food, and decrease eating desires in healthy individuals. 104 women were randomly assigned to an experimental or control condition and completed an appetitive conditioning and avoidance learning task. While the experimental condition received money after avoiding the tasty high-calorie food item and heard an aversive sound after not avoiding food intake, the control condition never received these consequences. In the extinction phase, reward and punishment discontinued for both conditions. We measured avoidance frequency, mouse movements, fear, eating desires and stimulus liking. Participants in the experimental condition avoided the food more often than controls and showed increased fear, reduced eating desires and less liking for cues associated with food intake. These results support the notion that food avoidance behaviours, reduced eating desires and fear of food can be learned via classical and operant conditioning. Conditioning paradigms might be a useful tool to study the development and maintenance of food restriction in anorexia nervosa.

Modulation of deep neural circuits with sonogenetics

Noninvasive control of neuronal activity in the deep brain can be illuminating for probing brain function and treating dysfunctions. Here, we present a sonogenetic approach for controlling distinct mouse behavior with circuit specificity and subsecond temporal resolution. Targeted neurons in subcortical regions were made to express a mutant large conductance mechanosensitive ion channel (MscL-G22S), enabling ultrasound to trigger activity in MscL-expressing neurons in the dorsal striatum and increase locomotion in freely moving mice. Ultrasound stimulation of MscL-expressing neurons in the ventral tegmental area could activate the mesolimbic pathway to trigger dopamine release in the nucleus accumbens and modulate appetitive conditioning. Moreover, sonogenetic stimulation of the subthalamic nuclei of Parkinson's disease model mice improved their motor coordination and mobile time. Neuronal responses to ultrasound pulse trains were rapid, reversible, and repeatable. We also confirmed that the MscL-G22S mutant is more effective to sensitize neurons to ultrasound compared to the wild-type MscL. Altogether, we lay out a sonogenetic approach which can selectively manipulate targeted cells to activate defined neural pathways, affect specific behaviors, and relieve symptoms of neurodegenerative disease.

From safety to frustration: The neural substrates of inhibitory learning in aversive and appetitive conditioning procedures

Inhibitory associative learning counters the effects of excitatory learning, whether appetitively or aversively motivated. Moreover, the affective responses accompanying the inhibitory associations are of opponent valence to the excitatory conditioned responses. Inhibitors for negative aversive outcomes (e.g. shock) signal safety, while inhibitors for appetitive outcomes (e.g. food reward) elicit frustration and/or disappointment. This raises the question as to whether studies using appetitive and aversive conditioning procedures should demonstrate the same neural substrates for inhibitory learning. We review the neural substrates of appetitive and aversive inhibitory learning as measured in different procedural variants and in the context of the underpinning excitatory conditioning on which it depends. The mesocorticolimbic dopamine pathways, retrosplenial cortex and hippocampus are consistently implicated in inhibitory learning. Further neural substrates identified in some procedural variants may be related to the specific motivation of the learning task and modalities of the learning cues. Finally, we consider the translational implications of our understanding of the neural substrates of inhibitory learning, for obesity and addictions as well as for anxiety disorders.