The different roles of glucocorticoids in the hippocampus and hypothalamus in chronic stress-induced HPA axis hyperactivity.

Li-Juan Zhu,Huan Li,Meng-Ying Liu,Hai-Yin Wu,Dong-Ya Zhu,Xing Jing,Hai-Hui Zhou,Zhou Han,Xiao Liu,Chen Chen,Hoonkyo Suh,Qi-Gang Zhou,Judith Homberg

doi:10.1371/journal.pone.0097689

Abstract

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.

Highlights

Major depressive disorder (MDD) is a severe, life threatening, and highly prevalent mood disease
We used the chronic mild stress (CMS) as the model depression and measured CORT levels in the plasma and evaluated despair behaviors by the tail suspension test (TST), and forced swimming test (FST) and sensitivity to reward by sucrose preference tests (SPT), which are commonly used to estimate the depressive behavior in rodents
We observed that the corticotrophin-releasing factor (CRF) expression was significantly increased in the hypothalamus of mice exposed to CMS for 28 days, reversed by metyrapone treatment (F(2, 9) = 9.92; p = 0.007, control VS CMS; P = 0.031, CMS VS CMS + metyrapone; one-way ANOVA, Figure 1F)

Summary

Introduction

Major depressive disorder (MDD) is a severe, life threatening, and highly prevalent mood disease. It ranks the most common of all psychiatric disorders [1]. Despite the fact that several hypotheses have been postulated, the exact mechanisms underlying MDD remain not clear. Chronic stress has been demonstrated as a critical environmental trigger of the development of MDD. The elevated glucocorticoids arrive in multiple tissues throughout all the brain including the hippocampus, hypothalamus, pituitary and amygdala, et al Chronic glucocorticoids exposure exerts harmful effects on these tissues and induces HPA axis hyperactivity, considered as an important molecular mechanism underling the pathology of MDD [2,3]

Methods

Results

Conclusion