Glucocorticoid regulation of dopamine circuit function

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PROJECT ABSTRACT Stress precipitates and exacerbates numerous psychiatric disorders, including major depressive disorder (MDD). Symptoms of MDD include deficits in reward processing, which affect how individuals engage with their environment. Moreover, individuals with MDD exhibit higher levels of the ‘stress hormone’, cortisol (CORT; corticosterone in rodents), in their plasma relative to healthy individuals. However, it remains unclear if increased circulating plasma CORT contributes to symptoms of MDD, such as deficits in reward processing. Dopaminergic signaling plays a key role in reward processing, thus elucidating the mechanisms by which stress affects dopaminergic signaling is critical for understanding how stress impairs reward processing and contributes to the symptomology of MDD. The long-term goal of this project is to elucidate the mechanism by which the stress hormone, corticosterone (cortisol in humans), affects dopaminergic circuit function. Preliminary data in Aim 1.1 suggest that elevated circulating plasma CORT impairs reward-seeking behaviors by impairing dopamine homeostasis in the dorsomedial striatum via alteration of post-translational modifications on the dopamine transporter, DAT. Given the role of the glucocorticoid receptor (GR; a receptor for CORT) as a transcription factor, it’s possible that CORT-induced transcriptional changes in dopamine neurons may be driving the effect of CORT on DAT function. In Aim 1.2, I will investigate how endogenous, and elevated levels, of circulating CORT affect GR-induced gene expression in dopamine neurons. The results of these studies may inform the search for novel therapeutic targets for the treatment of stress-induced motivational deficits. The training plan under this award integrates professional development courses in grantsmanship and business management, with scientific training in gene editing and gene expression analysis. Northwestern University is well-suited to facilitate excellent professional development for the applicant due to the collaborative nature of its graduate schools in business and the life sciences. The applicant will conclude the fellowship period with expert training in multiple levels of scientific analysis due to the range of technical expertise between the sponsor and co-sponsor. Overall, training under this award will provide the applicant with exceptional preparation for independence in the biomedical workforce and beyond.