Depression-like behaviors are accompanied by disrupted mitochondrial energy metabolism in chronic corticosterone-induced mice
Introduction
Depression is a common but serious mood disorder linked to negative effects on daily activities and decreasing quality of life for millions of people worldwide [1]. It is projected to be one of three leading causes of disease burden in 2030 [2], and becomes an important cause of disability and suicidal behavior [3]. The previous studies demonstrated that there was a high incidence of suicide (10–15 %) in depressive patients [4]. Depression is also known to exert its negative effects by, at one hand, interference with mitochondrial energy production in chronic mild stress- [5] and corticosterone (CORT) -induced depressive rats [6]. Mitochondria are the cellular sites of aerobic respiration and produce majority of cellular ATP through oxidative phosphorylatioin [7]. Nicotinamide adenine dinucleotide (NAD+)-dependent enzymes are important in oxidative metabolism, and nicotinamidephospho-ribosyltransferase (NAMPT) is the rate-limiting enzyme in NAD+ synthesis, thus the increase of NAD+ is associated with enforced mitochondrial function [8]. The dysfuncction of mitochondria was observed in depressive animals [9]; the reduced adenosine triphosphate (ATP) production was also found in the depressed patients [10], suggesting the association of depression with mitochondrial energy metabolism.
Excessive circulating CORT level leads to the dysfunction of hypothalamic pituitary adrenal (HPA) axis through negative feedback inhibitory mediation in depressed patients [11], which was also tested in the depressed animals [12]. Accumulated studies have demonstrated that chronic CORT injection can increase the probability of depression-like behaviors in sucrose preference [13], and forced swimming test (FST) in rats [14]. The decrease in sucrose intake and elevation in immobility time in FST may be caused by dysregulation of the HPA axis due to the injection of CORT [15]. Also, CORT injection was corrected with the eukaryotic electron transport process via induction of oxidase activity in mitochondria, and impairs mitochondrial bioenergetics [9,16], thus, it results in the reduction of ATP production [15]. Patients with mitochondrial diseases often display symptoms representing mood disorders [17]. The alterations in the processes of mitochondria including oxidative phosphorylation and membrane polarity can increase oxidative stress and apoptosis, preceding the development of depressive symptoms [18]. Moreover, CORT injection is involved in the metabolic perturbations taking place in mitochondria, and these metabolites, such as pyruvate and creatine, were closely associated with energy metabolism [19]. In the present study, identification of the mitochondrial energy metabolism disruption produced by CORT administration suggests a new implication for understanding the mechanisms of stress pathophysiology.
Section snippets
Material and method
For detailed procedures, see the Supplemental Experimental Procedures
Corticosterone affects physiological parameters in mice expressing depression-like behaviors
After 3 weeks of CORT injection, mice displayed depressive behaviors as evidenced by increased duration of immobility in both TST (p < 0.01, Fig. 1A) and FST (p < 0.01, Fig. 1B), along with reduced time in center zone and number of entries in the OFT (p < 0.01, Fig. 1C, D), when compared to non-stressed control animals. As expected, CORT significantly decreased the body weight of mice after one week (p < 0.01, Fig. 1E), but it significantly enhanced the average food intake per day as compared
Discussion
This study is to combine transcriptome sequencing and metabolomics analysis to investigate the pathophysiological mechanisms association with depression-like behaviors and the disruption of energy metabolism in CORT-induced individuals.
Stress is a critical environmental trigger for the production of clinical depression, and accumulated animal models have been developed in an attempt to determine the impacts of stress on the physiological metabolism [24]. Chronic administration of hormone CORT
Author contributions
Conceived and designed the experiments: Zhengwei Fu and Zezhi Li. Performed the experiments: Qichen Shen, Xiaoxian Xie, Chunan Yu, Jiafeng Zhou, and Qingfeng Xiao. Analyzed the data: Qichen Shen and Ze Xiong. Wrote the paper: Xiaoxian Xie and Qichen Shen.
Funding
This work was supported by a grant from the National Natural Science Foundation of China (No. 31701028), Program for Changjiang Scholars and Innovative Research Team in University (IRT_17R97) and the National Key Research and Development Program of China (2017YFD0200503).
Declaration of Competing Interest
The authors declare no competing financial interests.
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These authors contributed equally to this work.