Department of Animal Biology, Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Endocrinology. 2012 Oct;153(10):4830-7. doi: 10.1210/en.2012-1601. Epub 2012 Aug 14.
Dysregulated stress responsivity is a hallmark of neuropsychiatric disease. The regulation of stress activation and recovery involves tight coordination between neuronal and glial networks. At a certain threshold of sensitivity, stress exposure can evoke a neuroimmune response. Astrocytes are potential mediators of these effects because they are able to respond to neuroimmune effector molecules and regulate neuronal activity. Mice deficient in corticotropin-releasing factor receptor-2 display increased stress sensitivity and are therefore a useful model in which to examine the intersection of neuroimmune activation and stress pathway dysregulation. We hypothesized that a component of elevated stress reactivity may involve an engagement of neuroimmune effectors, including astrocytes. Therefore, we hypothesized that this phenotype may be rescued by concomitant nonsteroidal antiinflammatory drug (NSAID) treatment. To examine this, mice exposed to chronic stress were treated with NSAID in their drinking water, and changes in hypothalamic-pituitary-adrenal stress axis function were examined. As a correlate of altered astrocyte function, levels of glial fibrillary acidic protein were measured. Supportive of our hypothesis, NSAID treatment rescued the hypothalamic-pituitary-adrenal stress axis dysfunction in stress-sensitive corticotropin-releasing factor receptor-2(-/-) mice and also reversed the stress-induced increase in glial fibrillary acidic protein in stress-regulating brain regions including the paraventricular nucleus of the hypothalamus, ventral hippocampus, and prefrontal cortex. These findings support the local involvement of astrocytes in the exacerbation of stress pathway dysregulation. The specificity of these effects in a stress-sensitive genotype highlights the importance of utilizing a model of stress dysregulation in the examination of factors that may translate to neuropsychiatric disease.
应激反应失调是神经精神疾病的一个标志。应激激活和恢复的调节涉及神经元和神经胶质网络之间的紧密协调。在一定的敏感阈值下，应激暴露会引发神经免疫反应。星形胶质细胞是这些效应的潜在介导者，因为它们能够对神经免疫效应分子做出反应并调节神经元活性。缺乏促肾上腺皮质释放因子受体-2 的小鼠表现出应激敏感性增加，因此是研究神经免疫激活和应激通路失调交叉点的有用模型。我们假设，应激反应性升高的一个组成部分可能涉及神经免疫效应物的参与，包括星形胶质细胞。因此，我们假设这种表型可以通过同时使用非甾体抗炎药（NSAID）治疗来挽救。为了检验这一点，我们用 NSAID 处理暴露于慢性应激的小鼠，并检查下丘脑-垂体-肾上腺应激轴功能的变化。作为星形胶质细胞功能改变的相关指标，测量了神经胶质纤维酸性蛋白的水平。支持我们的假设，NSAID 治疗挽救了应激敏感型促肾上腺皮质释放因子受体-2(-/-) 小鼠的下丘脑-垂体-肾上腺应激轴功能障碍，还逆转了应激调节脑区（包括下丘脑室旁核、腹侧海马和前额叶皮质）中应激诱导的神经胶质纤维酸性蛋白增加。这些发现支持星形胶质细胞在应激通路失调加剧中的局部参与。在应激敏感基因型中观察到这些效应的特异性强调了在检查可能转化为神经精神疾病的因素时，利用应激失调模型的重要性。
