Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, SC711 Sparks Center, 1720 7th Avenue South, Birmingham, AL, 35294, USA.
Mol Neurobiol. 2019 Jan;56(1):394-405. doi: 10.1007/s12035-018-1085-x. Epub 2018 Apr 28.
Affective disorders show sex-specific differences in prevalence, symptoms, and complications. One hypothesis for this discrepancy is the interaction between the hypothalamic-pituitary-adrenal (HPA) axis and hypothalamic-pituitary-gonadal (HPG) axis. The present study investigates the influence of androgen on the behavioral phenotype and explores how it interacts with HPA axis genes. Gonadectomized (GDX) and GDX rats treated with testosterone propionate (T) were tested for learned helplessness (LH) behavior and compared with tested controls (TC). Prefrontal cortex was used for analyses of HPG- axis-related genes (androgen receptor, (Ar); estrogen receptor-β (Er-β)) and HPA axis-related genes (corticotropin-releasing hormone, (Crh); glucocorticoid receptor, (Nr3c1); corticotropin-releasing hormone receptor 1, (Crhr1); corticotropin-releasing hormone receptor 2, (Crhr2); FK506 binding protein 5, (Fkbp5)). Promoter-specific CpG methylation in the Crh gene was determined by bisulfite sequencing. Chromatin immunoprecipitation (ChIP) assay was used for determining ER-β binding on the proximal promoter region of Crh gene. Serum testosterone levels confirmed a testosterone-depleted GDX group, a group with supraphysiological levels of testosterone (T) and another group with physiological levels of testosterone (control (C)). Unlike GDX rats, T group exhibited significantly higher LH score when compared with any other group. Crh and Fkbp5 genes were significantly upregulated in GDX group compared with controls, whereas Er-β showed a significant downregulation in the same group. Methylation analysis showed no significant differences in-between groups. ChIP assay was unable to determine a significant change in ER-β binding but revealed a notable contrast in Crh promoter occupancy between T and GDX groups. Altogether, the present study reveals an increased susceptibility to depression-like behavior due to chronic supraphysiological level of androgen via HPA axis inhibition.
情感障碍在患病率、症状和并发症方面存在性别特异性差异。这种差异的一个假设是下丘脑-垂体-肾上腺（HPA）轴和下丘脑-垂体-性腺（HPG）轴之间的相互作用。本研究调查了雄激素对行为表型的影响，并探讨了它如何与 HPA 轴基因相互作用。去势（GDX）和去势大鼠用丙酸睾酮（T）处理，用于测试习得性无助（LH）行为，并与测试对照（TC）进行比较。使用前额叶皮质分析 HPG-轴相关基因（雄激素受体（Ar）；雌激素受体-β（Er-β））和 HPA 轴相关基因（促肾上腺皮质激素释放激素（Crh）；糖皮质激素受体（Nr3c1）；促肾上腺皮质激素释放激素受体 1（Crhr1）；促肾上腺皮质激素释放激素受体 2（Crhr2）；FK506 结合蛋白 5（Fkbp5））。通过亚硫酸氢盐测序确定 Crh 基因启动子特异性 CpG 甲基化。染色质免疫沉淀（ChIP）测定用于确定 ER-β 在 Crh 基因近端启动子区域的结合。血清睾酮水平证实 GDX 组睾酮耗竭，T 组睾酮水平高于生理水平（T），C 组睾酮水平正常。与 GDX 大鼠不同，T 组的 LH 评分明显高于其他任何组。与对照组相比，GDX 组的 Crh 和 Fkbp5 基因显著上调，而 Er-β 基因在同一组中显著下调。甲基化分析显示各组之间无显著差异。ChIP 测定未能确定 ER-β 结合的显著变化，但显示 T 组和 GDX 组之间 Crh 启动子占有率有明显差异。总的来说，本研究揭示了由于慢性生理水平的雄激素通过 HPA 轴抑制导致的对抑郁样行为的易感性增加。
