Abstract
While androgen receptor (AR) and stress may influence the development of the major depressive disorder (MDD), the detailed relationship, however, remains unclear. Here we found loss of AR accelerated development of depressive-like behaviors in mice under chronic mild stress (CMS). Mechanism dissection indicated that AR might function via altering the expression of miR-204-5p to modulate the brain-derived neurotrophic factor (BDNF) expression to influence the depressive-like behaviors in the mice under the CMS. Adding the antiandrogen flutamide with the stress hormone corticosterone can additively decrease BDNF mRNA in mouse hippocampus mHippoE-14 cells, which can then be reversed via down-regulating the miR-204-5p expression. Importantly, targeting this newly identified AR-mediated miR-204-5p/BDNF/AKT/MAPK signaling with small molecules including 7,8-DHF and fluoxetine, all led to alter the depressive-like behavior in AR knockout mice under CMS exposure. Together, results from these preclinical studies conclude that decreased AR may accelerate the stress-induced MDD via altering miR-204-5p/BDNF/AKT/MAPK signaling, and targeting this newly identified signaling may help in the development of better therapeutic approaches to reduce the development of MDD.
Highlights
Major depressive disorder (MDD) is highly associated with marked personal, social and economic impact, and the susceptibility of major depressive disorder (MDD) is affected by the interactions of multiple functional genetic variants and environmental factors
We found that decreased androgen receptor (AR) may accelerate the stress-induced MDD via altering the miRNA-204-5p/brain-derived neurotrophic factor (BDNF)/AKT/MAPK signaling, and targeting this newly identified signaling with small molecules may help in the development of better therapeutic approaches to reduce the development of MDD
To link the function of AR to the chronic mild stress (CMS)-mediated depressive-like behavior in male mice, we first set up the protocol of CMS model of depression in wild type (WT) mice under CMS in different periods of time, and compared to the control group of non-stressed WT mice by Sucrose preference test (Figure 1A)
Summary
Major depressive disorder (MDD) is highly associated with marked personal, social and economic impact, and the susceptibility of MDD is affected by the interactions of multiple functional genetic variants and environmental factors. Under low plasma testosterone levels, older men often exhibit depressive symptoms [4,5], and results from androgen replacement therapy indicated that older men receiving testosterone showed better moods and lower severity of depressive symptoms than those who received placebo [6]. These clinical evidences strongly suggest that androgens may have protective effects on adult men against MDD.
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