BACKGROUND Anxiety is a common disorder with high social burden worldwide. Dysfunction of serotonin-1A receptor (5-HT1A receptor) in the dentate gyrus (DG) of the hippocampus has been predominantly implicated in the anxiety behavior. However, the molecular mechanism underlying the deficiency of postsynaptic 5-HT1A receptor in regulating anxiety behavior remains unclear. METHODS Using pharmacological and genetic methods, we investigated the role of detate nNOS in 5-HT1A receptor decline and anxiety behavior induced by chronic mild stress (CMS) in mice. RESULTS Here we showed that local elevation of glucocorticoids in the DG accounted for chronic stress-induced anxiety behavior. Neuronal nitric oxide synthase (nNOS) mediated chronic stress-induced downregulation of 5-HT1A receptor in the DG through peroxynitrite anion (ONOO•) pathway but not cyclic guanosine monophosphate (cGMP) pathway. By using pharmacological tool drugs and nNOS knockout mice, we found that nNOS in the DG played a key role in chronic stress-induced anxiety behavior. CONCLUSIONS These findings uncovered an important role of nNOS-5-HT1A receptor pathway in the DG of the hippocampus in chronic stress-induced anxiety. Accordingly, we developed a "dentate nNOS-5-HT1A receptor closed-loop" theory (stress-glucocorticoids-nNOS-Nitric oxide-ONOO•-5-HT1A receptor -nNOS) of stress-related anxiety.

中文翻译：

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齿状nNOS解释了应激诱导的5-HT1A受体缺乏症：焦虑行为的涵义。

背景技术焦虑症是全世界范围内具有高社会负担的常见疾病。海马齿状回（DG）中5-羟色胺-1A受体（5-HT1A受体）的功能障碍主要与焦虑行为有关。然而，突触后5-HT1A受体缺乏调节焦虑行为的分子机制尚不清楚。方法使用药理和遗传学方法，我们研究了检测nNOS在慢性轻度应激（CMS）引起的小鼠5-HT1A受体下降和焦虑行为中的作用。结果在这里，我们表明DG中糖皮质激素的局部升高解释了慢性应激诱发的焦虑行为。神经元一氧化氮合酶（nNOS）通过过氧亚硝酸盐阴离子（ONOO•）途径而非环鸟苷单磷酸（cGMP）途径介导了DG中慢性应激诱导的5-HT1A受体下调。通过使用药理学工具药物和nNOS基因敲除小鼠，我们发现DG中的nNOS在慢性应激诱发的焦虑行为中起关键作用。结论这些发现揭示了nNOS-5-HT1A受体通路在慢性应激诱发的焦虑症海马DG中的重要作用。因此，我们开发了一种与压力相关的焦虑症的“齿nNOS-5-HT1A受体闭环”理论（应力-糖皮质激素-nNOS-一氧化氮-ONOO•-5-HT1A受体-nNOS）。我们发现DG中的nNOS在慢性应激诱发的焦虑行为中起着关键作用。结论这些发现揭示了nNOS-5-HT1A受体通路在慢性应激诱发的焦虑症海马DG中的重要作用。因此，我们开发了一种与压力相关的焦虑症的“齿nNOS-5-HT1A受体闭环”理论（应力-糖皮质激素-nNOS-一氧化氮-ONOO•-5-HT1A受体-nNOS）。我们发现DG中的nNOS在慢性应激诱发的焦虑行为中起着关键作用。结论这些发现揭示了nNOS-5-HT1A受体通路在慢性应激诱发的焦虑症海马DG中的重要作用。因此，我们开发了一种与压力相关的焦虑症的“齿nNOS-5-HT1A受体闭环”理论（应力-糖皮质激素-nNOS-一氧化氮-ONOO•-5-HT1A受体-nNOS）。