Chronically elevated corticosterone impairs dopaminergic transmission in the dorsomedial striatum by sex-divergent mechanisms

Background Major depressive disorder (MDD) is a leading cause of disability worldwide. Individuals with MDD exhibit decreased motivation and deficits in reward processing along with chronically elevated levels of the ‘stress hormone,’ cortisol. However, the mechanistic relationship between chronically elevated cortisol and behavioral deficits in motivation and reward processing remains unclear. Given that women are diagnosed with MDD at twice the rate of men, it is important to understand whether the mechanisms linking chronically elevated cortisol to the symptoms of MDD differ by sex. Methods We used subcutaneous implants to chronically elevate free plasma corticosterone (rodent homolog of cortisol; ‘CORT’) in male and female mice and examined changes in behavior and dopamine system function. We used operant training to assay reward-guided motivation and high-performance liquid chromatography to quantify striatal dopamine content. We assessed dopamine transporter (DAT) function using ex vivo slice imaging and in vivo fiber photometry in combination with a fluorescent dopamine sensor, dLight1.3b. We further quantified DAT expression and phosphorylation using western blot. Results We found that chronic CORT treatment impaired reward-seeking in both sexes. In female but not male mice, CORT treatment reduced dopamine content in the dorsomedial striatum (DMS). In male but not female mice, the function of the dopamine transporter (DAT) was impaired in DMS. Conclusions Chronic elevation of CORT impairs reward-seeking by impairing dopaminergic transmission in the DMS, but via different mechanisms in male and female mice. A better understanding of these sex-specific mechanisms could lead to new directions in MDD diagnosis and treatment. ### Competing Interest Statement The authors have declared no competing interest.