Hippocampal Neuronal Nitric Oxide Synthase Mediates the Stress-Related Depressive Behaviors of Glucocorticoids by Downregulating Glucocorticoid Receptor
Hippocampal Neuronal Nitric Oxide Synthase Mediates the Stress-Related Depressive Behaviors of Glucocorticoids by Downregulating Glucocorticoid Receptor
复制标题
海马神经元一氧化氮合酶通过下调糖皮质激素受体介导糖皮质激素的应激相关抑郁行为
DOI：
10.1523/jneurosci.0004-11.2011
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发表时间：
2011-05-25
影响因子：
5.3
通讯作者：
Zhu, Dong-Ya
中科院分区：
文献类型：
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作者：
Zhou, Qi-Gang;Zhu, Li-Juan;Zhu, Dong-Ya
糖皮质激素行为影响的分子机制尚不清楚。我们在这里报告海马神经元一氧化氮合酶（nNOS）是一个重要的介质。慢性轻度应激和糖皮质激素暴露通过激活盐皮质激素受体导致海马 nNOS 过度表达。反过来，海马 nNOS 衍生的一氧化氮 (NO) 通过可溶性鸟苷酸环化酶 (sGC)/cGMP 和过氧亚硝酸盐 (ONOO−)/细胞外信号调节激酶信号通路显着下调局部糖皮质激素受体表达，从而升高下丘脑促肾上腺皮质激素释放因子（一种控制下丘脑-垂体-肾上腺轴的肽）。更重要的是，nNOS缺失或海马内nNOS抑制和NO-cGMP信号传导阻断（使用NO清除剂或sGC抑制剂）阻止了皮质酮诱导的行为改变，这表明海马nNOS对于糖皮质激素介导抑郁行为的作用是必要的。此外，直接将 ONOO− 供体输送到海马体会引起抑郁样行为。我们的研究结果揭示了海马 nNOS 在调节糖皮质激素行为效应中的作用。
The molecular mechanisms underlying the behavioral effects of glucocorticoids are poorly understood. We report here that hippocampal neuronal nitric oxide synthase (nNOS) is a crucial mediator. Chronic mild stress and glucocorticoids exposures caused hippocampal nNOS overexpression via activating mineralocorticoid receptor. In turn, hippocampal nNOS-derived nitric oxide (NO) significantly downregulated local glucocorticoid receptor expression through both soluble guanylate cyclase (sGC)/cGMP and peroxynitrite (ONOO−)/extracellular signal-regulated kinase signal pathways, and therefore elevated hypothalamic corticotrophin-releasing factor, a peptide that governs the hypothalamic-pituitary-adrenal axis. More importantly, nNOS deletion or intrahippocampal nNOS inhibition and NO-cGMP signaling blockade (using NO scavenger or sGC inhibitor) prevented the corticosterone-induced behavioral modifications, suggesting that hippocampal nNOS is necessary for the role of glucocorticoids in mediating depressive behaviors. In addition, directly delivering ONOO− donor into hippocampus caused depressive-like behaviors. Our findings reveal a role of hippocampal nNOS in regulating the behavioral effects of glucocorticoids.