Signaling pathways mediated by corticotropin-releasing factor and its receptor 1 (CRF1) play a central role in stress responses. Dysfunction of the CRF system has been associated with neuropsychiatric disorders. However, dynamic changes in the CRF system during brain development and aging are not well investigated. In this study, we characterized CRF1, CRF, and corticotropin-releasing factor binding protein (CRFBP) expression in different brain regions in both male and female C57BL/6J mice from 1 to 18 months of age under basal conditions as well as after an acute 2-hr-restraint stress. We found that CRF and CRF1 levels tended to increase in the hippocampus and hypothalamus, and to decrease in the prefrontal cortex with aging, especially at 18 months of age, whereas CRFBP expression followed an opposite direction in these brain areas. We also observed area-specific sex differences in the expression of these three proteins. For example, CRF expression was lower in females than in males in all the brain regions examined except the prefrontal cortex. After acute stress, CRF and CRF1 were up-regulated at 1, 6, and 12 months of age, and down-regulated at 18 months of age. Females showed more robust changes compared to males of the same age. CRFBP expression either decreased or remained unchanged in most of the brain areas following acute stress. Our findings suggest that brain CRF1, CRF, and CRFBP expression changes dynamically across the lifespan and under stress condition in a sex- and regional-specific manner. Sex differences in the CRF system in response to stress may contribute to the etiology of stress-related neuropsychiatric disorders.

中文翻译：

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C57BL/6J 小鼠大脑中 CRF1、CRF 和 CRFBP 表达的性别差异在整个生命周期和对急性应激的反应

由促肾上腺皮质激素释放因子及其受体 1 (CRF1) 介导的信号通路在应激反应中起着核心作用。CRF 系统的功能障碍与神经精神疾病有关。然而，大脑发育和衰老过程中 CRF 系统的动态变化尚未得到很好的研究。在这项研究中，我们描述了 1 至 18 个月大的雄性和雌性 C57BL/6J 小鼠在基础条件下以及急性2 小时约束应力。我们发现 CRF 和 CRF1 水平在海马体和下丘脑中趋于增加，并且随着年龄的增长在前额叶皮层中降低，尤其是在 18 个月大时，而 CRFBP 表达在这些大脑区域遵循相反的方向。我们还观察了这三种蛋白质表达的区域特异性性别差异。例如，除了前额皮质外，在所有检查的大脑区域中，女性的 CRF 表达低于男性。急性应激后，CRF 和 CRF1 在 1、6 和 12 月龄时上调，在 18 月龄时下调。与同龄男性相比，女性表现出更强烈的变化。在急性应激后，大部分大脑区域的 CRFBP 表达下降或保持不变。我们的研究结果表明，大脑 CRF1、CRF 和 CRFBP 表达在整个生命周期和压力条件下以性别和区域特异性方式动态变化。CRF 系统响应压力的性别差异可能导致与压力相关的神经精神疾病的病因学。