Department of Neuroscience, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
Northwestern University Interdepartmental Neuroscience Program (NUIN), Evanston, IL, 60208, USA.
Neuropsychopharmacology. 2023 Aug;48(9):1328-1337. doi: 10.1038/s41386-023-01551-1. Epub 2023 Feb 21.
Major depressive disorder (MDD) is a leading cause of disability worldwide. Individuals with MDD exhibit decreased motivation and deficits in reward processing. In a subset of MDD patients, chronic dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis occurs, resulting in increased levels of the 'stress hormone' cortisol during the normal rest period (i.e., evening and night). However, the mechanistic relationship between chronically elevated resting 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 cortisol to the symptoms of MDD differ by sex. In this study, we used subcutaneous implants to chronically elevate free plasma corticosterone (the rodent homolog of cortisol; 'CORT') during the rest period in male and female mice and examined changes in behavior and dopamine system function. We found that chronic CORT treatment impaired motivated 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, CORT treatment impaired the function of the dopamine transporter (DAT) in DMS. From these studies, we conclude that chronic CORT dysregulation impairs motivation 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.
重度抑郁症（MDD）是全球范围内导致残疾的主要原因。患有 MDD 的个体表现出动机减退和奖励处理缺陷。在 MDD 患者的亚组中，下丘脑-垂体-肾上腺（HPA）轴会出现慢性失调，导致正常休息期间（即晚上和夜间）“应激激素”皮质醇水平升高。然而，慢性静息皮质醇升高与动机和奖励处理行为缺陷之间的机制关系仍不清楚。鉴于女性被诊断出患有 MDD 的比率是男性的两倍，因此了解将皮质醇与 MDD 症状联系起来的机制是否因性别而异非常重要。在这项研究中，我们使用皮下植入物在雄性和雌性小鼠的休息期间慢性增加游离血浆皮质酮（皮质醇的啮齿动物同源物；“CORT”），并检查行为和多巴胺系统功能的变化。我们发现慢性 CORT 处理会损害两性的动机性奖励寻求。在雌性但不是雄性小鼠中，CORT 处理会减少背内侧纹状体（DMS）中的多巴胺含量。在雄性但不是雌性小鼠中，CORT 处理会损害 DMS 中的多巴胺转运蛋白（DAT）的功能。从这些研究中，我们得出结论，慢性 CORT 失调通过损害 DMS 中的多巴胺传递来损害动机，但在雄性和雌性小鼠中通过不同的机制。更好地了解这些性别特异性机制可能为 MDD 的诊断和治疗开辟新的方向。
