Hippocampal metabolic differences implicate distinctions between physical and psychological stress in four rat models of depression

Lining Yang,Juncai Pu,Chanjun Zhou,Shuai Yuan,Lanxiang Liu,Peng Xie,Libo Zhao,Hanping Zhang,Yuqing Zhang,Xinyu Zhou

doi:10.1038/s41398-017-0018-1

Abstract

Major depressive disorder (MDD) is a heterogeneous and multi-factorial disorder, and the underlying molecular mechanisms remain largely unknown. However, many studies have indicated that the molecular mechanisms underlying depression in response to different stress may differ. After screening, 28–30 rats were included in each model of depression (chronic unpredictable mild stress (CUMS); learned helplessness (LH); chronic restraint stress (CRS); or social defeat (SD)). Non-targeted gas chromatography-mass spectrometry was used to profile the metabolic changes in the hippocampus. As a result, all four models exhibited significant depression-like behavior. A total of 30, 24, 19, and 25 differential metabolites were identified in the CUMS, LH, CRS, and SD models, respectively. Interestingly, the hierarchical clustering results revealed two patterns of metabolic changes that are characteristic of the response to cluster 1 (CUMS, LH) and cluster 2 (CRS, SD) stress, which represent physical and psychological stress, respectively. Bioinformatic analysis suggested that physical stress was mainly associated with lipid metabolism and glutamate metabolism, whereas psychological stress was related to cell signaling, cellular proliferation, and neurodevelopment, suggesting the molecular changes induced by physical and psychological stress were different. Nine shared metabolites were opposite in the directions of change between physical and psychological models, and these metabolites were associated with cellular proliferation and neurodevelopment functions, indicating the response to physical and psychological stress was different in the activation and deactivation of the final common pathway to depression. Our results provide a further understanding of the heterogeneity in the molecular mechanisms of MDD that could facilitate the development of personalized medicine for this disorder.

Highlights

Pharmacotherapy and manual-driven psychotherapy are both frequently used treatments for major depressive disorder (MDD), either as monotherapies or in combination[1]
Body weight gain was significantly decreased in the stressed rats compared with the corresponding controls in the chronic unpredictable mild stress (CUMS) (P o 0.001; Fig. 2a), chronic restraint stress (CRS) (P o 0.001; Fig. 2c), and social defeat (SD) (P o 0.01; Fig. 2d) models, but no statistical difference was found between the two groups in the learned helplessness (LH) model (Fig. 2b)
The results show that each type of stress induced depression-like behavior, whereas CUMS enhanced anxiety-like behavior

Summary

Introduction

Pharmacotherapy and manual-driven psychotherapy are both frequently used treatments for major depressive disorder (MDD), either as monotherapies or in combination[1]. Scientists have suggested that heterogeneity in treatment response is the direct result of etiological heterogeneity in MDD6. Stress plays an important role in the pathogenesis of depression[7]. Dayas et al.[9] proposed that the brain categorizes at least two main categories of stressor, “physical” and “psychological”, which elicit distinctive response in the brain. Changes in hippocampal concentrations of extracellular zinc, a signaling factor in synaptic neurotransmission, differ between physical and psychological stress[11]. Different stressors can cause heterogeneous and even diametrically opposed stress responses[12,13]. On account of that the hippocampus is a main brain region involved in the pathogenesis of MDD14

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