Glucocorticoid Regulation of Striatal Dopamine Transmission

Holloway, Ashley

doi:https://doi.org/10.21985/n2-5y7b-hq72

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Glucocorticoid Regulation of Striatal Dopamine Transmission

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Chronic stress is a significant risk factor for the development of numerous psychiatric disorders, including major depressive disorder (MDD). Individuals with MDD exhibit impairments in reward processing and decreased motivation to engage in previously-rewarding activities. Importantly, there is a large sex disparity in MDD diagnosis, such that it affects nearly twice as many women as men. However, it is still unknown how chronic stress contributes to motivational impairments in either men or women with MDD. Chronic stress significantly impairs activity of the hypothalamic-pituitary-adrenal (HPA) axis in the body, leading to elevated levels of the ‘stress hormone,’ cortisol (corticosterone in rodents; ‘CORT’). In a subset of MDD patients, CORT is elevated during the rest period. It has remained unclear if, and how, dysregulation of CORT during the rest period affects motivation to attain rewards in either sex.In this dissertation, I examined how chronic dysregulation of CORT affected motivation to attain rewards in male and female mice. Using subcutaneous pellet implants, I found that the HPA axes of male and female mice respond differently to the same dose of exogenous CORT, consistent with documented sex differences in HPA axis function. I further went on to show that chronic CORT dysregulation impaired motivation to attain rewards in an operant task in both sexes, but this behavioral deficit was associated with sex-specific alterations in dopaminergic transmission in a part of the brain called the dorsomedial striatum (DMS). In females, CORT dysregulation decreased the amount of dopamine within the DMS. In males, CORT dysregulation impaired activity of the dopamine transporter (DAT) in the DMS. The results of this study indicate there are latent sex differences in how CORT dysregulation impairs DMS dopaminergic transmission to drive deficits in reward-guided motivation. This work provides the scaffolding for future experiments disentangling the molecular bases for sex-specific effects of glucocorticoids on dopaminergic transmission.

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