Zhu Li-Juan, Liu Meng-Ying, Li Huan, Liu Xiao, Chen Chen, Han Zhou, Wu Hai-Yin, Jing Xing, Zhou Hai-Hui, Suh Hoonkyo, Zhu Dong-Ya, Zhou Qi-Gang
Department of Pharmacology, Pharmacy College, Nanjing Medical University, Nanjing, China; Institute of Neuroscience, Coochow University, Su zhou, China.
Department of Pharmacology, Pharmacy College, Nanjing Medical University, Nanjing, China.
PLoS One. 2014 May 15;9(5):e97689. doi: 10.1371/journal.pone.0097689. eCollection 2014.
Hypothalamus-pituitary-adrenal (HPA) hyperactivity is observed in many patients suffering from depression and the mechanism underling the dysfunction of HPA axis is not well understood. Chronic stress has a causal relationship with the hyperactivity of HPA axis. Stress induces the over-synthesis of glucocorticoids, which will arrive at all the body containing the brain. It is still complicated whether glucocorticoids account for chronic stress-induced HPA axis hyperactivity and in which part of the brain the glucocorticoids account for chronic stress-induced HPA axis hyperactivity. Here, we demonstrated that glucocorticoids were indispensable and sufficient for chronic stress-induced hyperactivity of HPA axis. Although acute glucocorticoids elevation in the hippocampus and hypothalamus exerted a negative regulation of HPA axis, we found that chronic glucocorticoids elevation in the hippocampus but not in the hypothalamus accounted for chronic stress-induced hyperactivity of HPA axis. Chronic glucocorticoids exposure in the hypothalamus still exerted a negative regulation of HPA axis activity. More importantly, we found mineralocorticoid receptor (MR) - neuronal nitric oxide synthesis enzyme (nNOS) - nitric oxide (NO) pathway mediated the different roles of glucocorticoids in the hippocampus and hypothalamus in regulating HPA axis activity. This study suggests that the glucocorticoids in the hippocampus play an important role in the development of HPA axis hyperactivity and the glucocorticoids in the hypothalamus can't induce hyperactivity of HPA axis, revealing new insights into understanding the mechanism of depression.
在许多抑郁症患者中观察到下丘脑 - 垂体 - 肾上腺（HPA）轴功能亢进，而HPA轴功能障碍的潜在机制尚未完全明确。慢性应激与HPA轴功能亢进存在因果关系。应激诱导糖皮质激素过度合成，这些糖皮质激素会到达包括大脑在内的全身。糖皮质激素是否导致慢性应激诱导的HPA轴功能亢进以及在大脑的哪个部位导致这种亢进仍很复杂。在此，我们证明糖皮质激素对于慢性应激诱导的HPA轴功能亢进是不可或缺且充分的。虽然海马体和下丘脑急性糖皮质激素升高对HPA轴发挥负调节作用，但我们发现海马体而非下丘脑的慢性糖皮质激素升高导致慢性应激诱导的HPA轴功能亢进。下丘脑慢性暴露于糖皮质激素仍对HPA轴活动发挥负调节作用。更重要的是，我们发现盐皮质激素受体（MR） - 神经元型一氧化氮合酶（nNOS） - 一氧化氮（NO）途径介导了糖皮质激素在海马体和下丘脑对HPA轴活动调节中的不同作用。本研究表明，海马体中的糖皮质激素在HPA轴功能亢进的发生中起重要作用，而下丘脑中的糖皮质激素不会诱导HPA轴功能亢进，这为理解抑郁症机制提供了新的见解。
