Neural mechanisms of the glucocorticoid withdrawal syndrome

Abstract The glucocorticoid withdrawal syndrome is increasingly recognized as a major barrier to the discontinuation of chronic glucocorticoid treatment. This withdrawal syndrome contributes to widespread use of chronic glucocorticoids, which are taken by 1-3% of the population despite high rates of adverse effects. The most prominent symptoms of glucocorticoid withdrawal included generalized pain and decreased pleasure in rewarding activities, which can only be managed by resuming high dose glucocorticoid treatment. There are no available treatments for glucocorticoid withdrawal, and its mechanisms are unknown. We developed a novel mouse model of glucocorticoid withdrawal to use for the first study of the neurobiological mechanisms. We found that withdrawal increased pain sensitivity in both male and female mice while decreasing preference for social contact in females. Thus, this model is capable of recapitulating some of the key aspects of the syndrome in humans. One candidate neural circuit for linking these behavioral phenotypes is the mesolimbic dopamine pathway, as it has been implicated in both pain and preference for natural rewards. Here we will test the central hypothesis that the glucocorticoid withdrawal syndrome results from decreased activity in the mesolimbic dopamine pathway. In Aim 1, we will more fully characterize the behavioral phenotype of glucocorticoid withdrawal in our newly developed mouse model, focusing on pain sensitivity and preference for natural rewards. To do this, we will use the von Frey and hotplate tests for pain sensitivity, and we will use social interaction, food preference, and longitudinal home cage behavior to look at preference for natural rewards. In Aim 2, we will investigate the role of the mesolimbic dopamine pathway in the glucocorticoid withdrawal syndrome. We will determine how withdrawal alters activity of dopamine neurons in the ventral tegmental area using in vivo calcium imaging. We will also test whether chemogenetic activation of these neurons can rescue the behavioral withdrawal phenotype. This work will be the first study of the neural mechanisms underlying the glucocorticoid withdrawal syndrome. Through these experiments, I will receive essential training in 1) behavioral assays for pain in a rodent model, 2) chemogenetic neural circuit manipulation 3) in vivo calcium imaging, and 4) computational modeling and analysis of big data sets. The skills and training opportunities described in this proposal will enable me to become a successful scientist, mentor, and educator in preparation for my future career in academia.