Hypothalamic circuitry underlying stress-induced insomnia and peripheral immunosuppression
Hypothalamic circuitry underlying stress-induced insomnia and peripheral immunosuppression
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DOI：
10.1126/sciadv.abc2590
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发表时间：
2020-09-01
期刊：
影响因子：
13.6
通讯作者：
de Lecea, Luis
中科院分区：
文献类型：
--
作者：
Li, Shi-Bin;Borniger, Jeremy C.;de Lecea, Luis
应激引起的失眠/过度觉醒的神经基础仍不清楚。在这里，我们发现束缚应激导致高觉醒与下丘脑室旁核促肾上腺皮质激素释放激素神经元(CRHPVN)和下丘脑外侧核内下丘脑下丘脑促肾上腺皮质激素释放激素神经元(Hcrt(Lh))的强烈激活有关。CRHPVN神经元直接支配HcrtLh神经元，光发生刺激投射Lh的CRHPVN神经元引起高度觉醒。CRISPR-Cas9介导的CRHPVN神经元CRH基因敲除可消除刺激投射黄体生成素的CRHPVN神经元引起的过度觉醒。基因消融Hcrt神经元或CRH基因敲除可显著对抗束缚应激诱导的高度觉醒。单细胞飞行时间质谱仪(CyTOF)显示，模拟应激性失眠的CRHPVN神经元在高度觉醒过程中，免疫细胞分布和功能反应发生了广泛的变化。我们的发现表明，中枢和外周系统都通过CRHPVN回路协同参与应激反应。
The neural substrates of insomnia/hyperarousal induced by stress remain unknown. Here, we show that restraint stress leads to hyperarousal associated with strong activation of corticotropin-releasing hormone neurons in the paraventricular nucleus of hypothalamus (CRHPVN) and hypocretin neurons in the lateral hypothalamus (Hcrt(LH)). CRHPVN neurons directly innervate HcrtLH neurons, and optogenetic stimulation of LH-projecting CRHPVN neurons elicits hyperarousal. CRISPR-Cas9-mediated knockdown of the crh gene in CRHPVN neurons abolishes hyperarousal induced by stimulating LH-projecting CRHPVN neurons. Genetic ablation of Hcrt neurons or crh gene knockdown significantly counteracts restraint stress-induced hyperarousal. Single-cell mass cytometry by time of flight (CyTOF) revealed extensive changes to immune cell distribution and functional responses in peripheral blood during hyperarousal upon optogenetic stimulation of CRHPVN neurons simulating stress-induced insomnia. Our findings suggest both central and peripheral systems are synergistically engaged in the response to stress via CRHPVN circuitry.