Wilhelm Clare J, Hashimoto Joel G, Roberts Melissa L, Bloom Shelley H, Beard Douglas K, Wiren Kristine M
VA Portland Health Care System, Portland, OR 97239, USA; Department of Psychiatry, Oregon Health & Science University, Portland, OR 97239, USA.
VA Portland Health Care System, Portland, OR 97239, USA; Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239, USA.
Brain Res. 2015 Mar 19;1601:102-16. doi: 10.1016/j.brainres.2015.01.002. Epub 2015 Jan 16.
Women are more sensitive to the harmful effects of alcohol (EtOH) abuse than men, yet the underlying mechanisms remain poorly understood. Previous gene expression analysis of the medial prefrontal cortex (mPFC) following a chronic intoxication paradigm using continuous 72 h vapor inhalation found that females, but not males, exhibit an inflammatory response at peak withdrawal that is associated with cell damage. Given that glucocorticoids can function as anti-inflammatories, are known to increase with EtOH exposure, and influence neurotoxicity, we hypothesized that males and females may exhibit an altered corticosterone (CORT) response following chronic intoxication. Analysis of serum CORT levels revealed the expected increase during withdrawal with no difference between males and females, while control males but not females exhibited higher CORT concentrations than naive animals. Glucocorticoid signaling characterized using focused qPCR arrays identified a sexually dimorphic response in the mPFC during withdrawal, particularly among astrocyte-enriched genes. These genes include aquaporin-1 (Aqp1), sphingosine kinase 1 (Sphk1) and connective tissue growth factor (Ctgf); genes associated with inflammatory signaling, and tissue damage and repair. Bioinformatic analysis also revealed activation of inflammatory signaling and cell death pathways in females. Confirmation studies showed that female mice exhibited significant neuronal degeneration within the anterior cingulate cortex (ACC). By contrast, EtOH exposure lead to a significant reduction in cell death in males. Thus, distinct glucocorticoid signaling pathways are associated with sexually dimorphic neurotoxicity, suggesting one mechanism by which EtOH-exposed females are particularly vulnerable to the damaging effects of alcohol in the CNS.
女性对酒精滥用的有害影响比男性更敏感，但其潜在机制仍知之甚少。先前使用连续72小时蒸汽吸入的慢性中毒范式对内侧前额叶皮质（mPFC）进行基因表达分析发现，雌性而非雄性在戒断高峰期表现出与细胞损伤相关的炎症反应。鉴于糖皮质激素可发挥抗炎作用，已知其会随着酒精暴露而增加，并影响神经毒性，我们推测雄性和雌性在慢性中毒后可能表现出皮质酮（CORT）反应改变。血清CORT水平分析显示，戒断期间CORT水平如预期升高，雄性和雌性之间无差异，而对照雄性而非雌性的CORT浓度高于未接触酒精的动物。使用聚焦qPCR阵列对糖皮质激素信号进行表征，发现在戒断期间mPFC中存在性别差异反应，特别是在富含星形胶质细胞的基因中。这些基因包括水通道蛋白-1（Aqp1）、鞘氨醇激酶1（Sphk1）和结缔组织生长因子（Ctgf）；与炎症信号、组织损伤和修复相关的基因。生物信息学分析还揭示了雌性中炎症信号和细胞死亡途径的激活。确证研究表明，雌性小鼠在前扣带回皮质（ACC）内表现出明显的神经元变性。相比之下，酒精暴露导致雄性细胞死亡显著减少。因此，不同的糖皮质激素信号通路与性别差异神经毒性相关，这表明酒精暴露的雌性对中枢神经系统中酒精的损害作用特别敏感的一种机制。
