Cues in the environment become predictors of biologically relevant stimuli, such as food, through associative learning. These cues can not only act as predictors but can also be attributed with incentive motivational value and gain control over behavior. When a cue is imbued with incentive salience, it attains the ability to elicit maladaptive behaviors characteristic of psychopathology. We can capture the propensity to attribute incentive salience to a reward cue in rats using a Pavlovian conditioned approach paradigm, in which the presentation of a discrete lever-cue is followed by the delivery of a food reward. Upon learning the cue-reward relationship, some rats, termed sign-trackers, develop a conditioned response directed towards the lever-cue; whereas others, termed goal-trackers, approach the food cup upon lever-cue presentation. Here, we assessed the effects of systemic corticosterone (CORT) on the acquisition and expression of sign- and goal-tracking behaviors in male and female rats, while examining the role of the vendor (Charles River or Taconic) from which the rats originated in these effects. Treatment naïve male and female rats from Charles River had a greater tendency to sign-track than those from Taconic. Administration of CORT enhanced the acquisition of sign-tracking behavior in males from Charles River and females from both vendors. Conversely, administration of CORT had no effect on the expression of the conditioned response. These findings demonstrate a role for CORT in cue-reward learning and suggest that inherent tendencies towards sign- or goal-tracking may interact with this physiological mediator of motivated behavior.

Environmental cues attain the ability to guide behavior via learned associations. As predictors, cues can elicit adaptive behavior and lead to valuable resources (e.g., food). For some individuals, however, cues are transformed into incentive stimuli and elicit motivational states that can be maladaptive. The goal-tracker (GT)/sign-tracker (ST) animal model captures individual differences in cue-motivated behaviors, with reward-associated cues serving as predictors of reward for both phenotypes but becoming incentive stimuli to a greater degree for STs. While these distinct phenotypes are characterized based on Pavlovian conditioned approach (PavCA) behavior, they exhibit differences on a number of behaviors relevant to psychopathology. To further characterize the neurobehavioral endophenotype associated with individual differences in cue-reward learning, neuroendocrine and behavioral profiles associated with stress and anxiety were investigated in male GT, ST, and intermediate responder (IR) rats. It was revealed that baseline corticosterone (CORT) increases with Pavlovian learning, but to the same degree, regardless of phenotype. No significant differences in behavior were observed between GTs and STs during an elevated plus maze (EPM) or open field test (OFT), nor were there differences in CORT response to the OFT or physiological restraint. Upon examination of central markers associated with stress reactivity, we found that STs have greater glucocorticoid receptor (GR) mRNA expression in the ventral hippocampus, with no phenotypic differences in the dorsal hippocampus or prelimbic cortex (PrL). These findings demonstrate that GTs and STs do not differ on stress-related and anxiety-related behaviors, and suggest that differences in neuroendocrine measures between these phenotypes can be attributed to distinct cue-reward learning styles.

As a function of prior experience, cues in the environment can trigger maladaptive behaviors, as is often the case with impulse control disorders and addiction. The sign-tracker/goal-tracker animal model captures individual variation in cue-reward learning, enabling us to study the underlying neural processes. Here we investigate the role of “stress” hormones (i.e. corticosterone) and sex in mediating these individual differences.

Learning to respond appropriately to one's surrounding environment is fundamental to survival. Importantly, however, individuals vary in how they respond to cues in the environment and this variation may be a key determinant of psychopathology. The ability of seemingly neutral cues to promote maladaptive behavior is a hallmark of several psychiatric disorders including, substance use disorder, post-traumatic stress disorder, eating disorders and obsessive-compulsive disorder. Thus, it is important to uncover the neural mechanisms by which such cues are able to attain inordinate control and promote psychopathological behavior. Here, we suggest that glucocorticoids play a critical role in this process. Glucocorticoids are primarily recognized as the main hormone secreted in response to stress but are known to exert their effects across the body and the brain, and to affect learning and memory, cognition and reward-related behaviors, among other things. Here we speculate that glucocorticoids act to facilitate a dopamine-dependent form of cue-reward learning that appears to be relevant to a number of psychiatric conditions. Specifically, we propose to utilize the sign-tracker/goal-tracker animal model as a means to capture individual variation in stimulus-reward learning and to isolate the role of glucocorticoid-dopamine interactions in mediating these individual differences. It is hoped that this framework will lead to the discovery of novel mechanisms that contribute to complex neuropsychiatric disorders and their comorbidity.

Cues in the environment can elicit complex emotional states, and thereby maladaptive behavior, as a function of their ascribed value. Here we capture individual variation in the propensity to attribute motivational value to reward-cues using the sign-tracker/goal-tracker animal model. Goal-trackers attribute predictive value to reward-cues, and sign-trackers attribute both predictive and incentive value. Using chemogenetics and microdialysis, we show that, in sign-trackers, stimulation of the neuronal pathway from the prelimbic cortex (PrL) to the paraventricular nucleus of the thalamus (PVT) decreases the incentive value of a reward-cue. In contrast, in goal-trackers, inhibition of the PrL-PVT pathway increases both the incentive value and dopamine levels in the nucleus accumbens shell. The PrL-PVT pathway, therefore, exerts top-down control over the dopamine-dependent process of incentive salience attribution. These results highlight PrL-PVT pathway as a potential target for treating psychopathologies associated with the attribution of excessive incentive value to reward-cues, including addiction.