Investigating the Role of Glucocorticoids in Mediating Dopamine-dependent Cue-reward Learning

Abstract

The way individuals respond to their surrounding environment can be advantageous or deleterious to survival. Importantly, individuals vary in their response to discrete environmental cues and this variation may be a key determinant of psychopathology. The ability of previously neutral cues to promote aberrant behavior is a hallmark of several psychiatric disorders including, addiction, 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. This dissertation will address the role of glucocorticoids in the attribution of incentive value to cues, a psychological process that transforms such cues into powerful motivators of behavior, that may be adaptive/ maladaptive. Additionally, it will focus on the relationship between glucocorticoids and dopamine, the latter of which is critical to the process of incentive salience attribution.

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. Our understanding of this hormone in incentive learning stems from work demonstrating differences in peripheral levels of glucocorticoids in rats that learn a predictive cue-reward association (goal-trackers) compared to those that also attribute incentive value to the cue (sign-trackers). However, whether these differences pertained to differences in stress-responsivity was unknown. In Chapter 2, we assessed neuroendocrine and behavioral profiles associated with negative valence in male rats that show a preference for incentive learning (sign-trackers), compared to those that purely learn the cue-reward association (goal-trackers). We found that they do not differ in negative valence indices; rather differences in neuroendocrine measures, like glucocorticoids, can be attributed to distinct cue-reward learning styles. In Chapter 3, we studied whether pharmacological alterations in glucocorticoid levels prior to training affected the goal- and sign-tracking tendencies of male and female rats. We found that, in males, elevated levels of glucocorticoids promote incentive learning, whereas in females there is an attenuation that is reversed when treatment is removed. Finally, in chapter 4, we captured peripheral and brain levels of glucocorticoids and dopamine, specifically within the nucleus accumbens shell of male and female goal- and sign-trackers. Glucocorticoids and dopamine differed based on sex and preferred cue-reward learning strategies; but no significant relationship was found between accumbens glucocorticoids and dopamine. Collectively, these studies serve as evidence for a role of glucocorticoids, beyond negative valence systems, and in particular in cue-reward learning. It appears that while glucocorticoids influence the propensity to attribute incentive value to reward cues, the state under which they are acting may impact their interaction with dopamine and subsequent influence on behavior. This work will serve as a foundation for future studies probing the role of glucocorticoids in cue-motivated behaviors relevant to psychopathology.