Kent State University, Biological Sciences Department, Kent, Ohio 44240, United States.
Kent State University, School of Biomedical Sciences, Kent, Ohio 44240, United States.
Psychoneuroendocrinology. 2019 May;103:203-211. doi: 10.1016/j.psyneuen.2019.01.026. Epub 2019 Jan 25.
Elevations in brain interleukin-1 beta (IL-1β) during chronic stress exposure have been implicated in behavioral and cognitive impairments associated with depression and anxiety. Two critical regulators of brain IL-1β production during times of stress are glucocorticoids and catecholamines. These hormones work in opposition to one another to inhibit (via glucocorticoid receptors) or stimulate (via beta-adrenergic receptors: β-AR) IL-1β production. While chronic stress often heightens both corticosterone and catecholamine levels, it remains unknown as to how chronic stress may affect the "yin-yang" balance between adrenergic stimulation and glucocorticoid suppression of brain IL-1β. To investigate this further, male and female rats underwent 4 days of stress exposure or served as non-stressed controls. On day 5, animals were administered propranolol (β-AR antagonist), metyrapone (a glucocorticoid synthesis inhibitor), vehicle, or both drugs and brain IL-1β mRNA was measured by rtPCR in limbic brain areas. In males, administration of propranolol had no effect on IL-1β expression in non-stressed controls but significantly reduced IL-1β in the hippocampus and amygdala of chronically stressed animals. In females, propranolol significantly reduced IL-1β in the amygdala and hypothalamus of both control and stressed rats. In male rats, metyrapone treatment significantly increased IL-1β mRNA regardless of stress treatment in all brain areas, while in female rats metyrapone only increased IL-1β in the hypothalamus. Interestingly, propranolol treatment blocked the metyrapone-induced increase in brain IL-1β indicating the increase in brain IL-1β following metyrapone treatment was due to increase β-AR activation. Additional studies revealed that metyrapone significantly increases norepinephrine turnover in the hypothalamus and medial prefrontal cortex in male rats and that microglia appear to be the cell type contributing to the production of IL-1β. Overall, data reveal that stress exposure in male rats affects the regulation of brain IL-1β by the norepinephrine-β-AR pathway, while stress had no effect in the regulation of brain IL-1β in female rats.
慢性应激暴露期间大脑白细胞介素-1β（IL-1β）水平升高与抑郁和焦虑相关的行为和认知障碍有关。在应激期间，大脑 IL-1β产生的两个关键调节剂是糖皮质激素和儿茶酚胺。这些激素相互拮抗，通过糖皮质激素受体抑制（via glucocorticoid receptors）或通过β-肾上腺素受体刺激（via beta-adrenergic receptors: β-AR）IL-1β的产生。虽然慢性应激通常会增加皮质酮和儿茶酚胺的水平，但尚不清楚慢性应激如何影响肾上腺素刺激和糖皮质激素抑制大脑 IL-1β之间的“阴阳”平衡。为了进一步研究这一点，雄性和雌性大鼠接受了 4 天的应激暴露或作为非应激对照。在第 5 天，动物给予普萘洛尔（β-AR 拮抗剂）、美替拉酮（糖皮质激素合成抑制剂）、载体或两种药物，并通过 rtPCR 测量边缘脑区的脑 IL-1β mRNA。在雄性中，普萘洛尔给药对非应激对照动物的 IL-1β表达没有影响，但显著降低了慢性应激动物海马体和杏仁核中的 IL-1β。在雌性中，普萘洛尔显著降低了应激和非应激大鼠杏仁核和下丘脑中的 IL-1β。在雄性大鼠中，美替拉酮处理无论应激处理如何，都显著增加了所有脑区的 IL-1β mRNA，而在雌性大鼠中，美替拉酮仅增加了下丘脑中的 IL-1β。有趣的是，普萘洛尔处理阻断了美替拉酮诱导的脑 IL-1β增加，表明美替拉酮处理后脑 IL-1β的增加是由于β-AR 激活增加。进一步的研究表明，美替拉酮显著增加了雄性大鼠下丘脑和内侧前额叶皮质中的去甲肾上腺素周转，并且似乎是产生 IL-1β的细胞类型。总的来说，数据表明，雄性大鼠的应激暴露会影响去甲肾上腺素-β-AR 途径对大脑 IL-1β的调节，而应激对雌性大鼠大脑 IL-1β的调节没有影响。
