Chronic intermittent hypoxia exacerbates depressive-like behaviors in high fat diet-fed mice

Abstract

BACKGROUND: There is a high prevalence of obstructive sleep apnea (OSA) in the obese population. Depressive symptoms are commonly manifested in obese and OSA patients as well as in animal models, but the pathophysiological mechanism remains elusive. Neuroinflammation plays an important role in major depressive disorder (MDD) with an activation of brain indoleamine 2,3, dioxygenase (IDO-1), a catabolic enzyme of tryptophan and serotonin, which depletes serotonin availability. We have shown that chronic intermittent hypoxia (CIH) manifested as episodic oxygen desaturation in severe OSA condition induces oxidative stress and inflammation in the rat hippocampus. Significant neuroinflammation was also observed in obese mice. AIMS AND HYPOTHESIS: We aim to examine whether CIH exacerbates high fat diet (HFD)-induced depressive-like behaviors. It is hypothesized that CIH aggravates HFD-induced depressive-like behaviors with an increased IDO-1 expression and activity mediated by oxidative stress and inflammation, leading to serotonin deficiency and apoptosis in the mice hippocampus. METHODS: Adult male C57BL/6N mice (4-week old after weaning) were either fed with HFD (45% fat) or regular diet for 13 weeks. The mice were treated with intermittent hypoxia (with inspired oxygen levels altering between 21-5% per min for 8 hours per day for a week, Apnea-Hyponea Index at 60) or in room air (normoxic control) starting at the 9th week for 4 weeks. Forced swimming test and sucrose preference test were employed to assess the behavioral despair and hedonic status of the mice. Hippocampi were harvested for the measurement of IDO-1 activity, oxidative stress, inflammatory and apoptotic markers assessed by Western blot and enzyme-linked Immunosorbent assay. RESULTS: The immobility time was increased in the forced swimming test and the percentage of sucrose consumption was decreased in the sucrose preference test in the HFD or hypoxic group when compared to the normoxic control; these changes were doubled in the mice co-treated with HFD and hypoxia. In addition, the level of lipid peroxidation was increased and the protein expressions of antioxidant enzymes (SOD-2, GPx-1) were decreased in the HFD or hypoxic group and these changes were significantly augmented in the co-treated mice. Moreover, inflammatory mediators (TNF-α, IL-1β and IL-6) and apoptotic markers (cleaved caspase-3, cleaved PARP-1) were increased in the HFD or hypoxic group and were significantly increased in the co-treated group. Furthermore, levels of the IDO expression and activity (ratio of KYN/TRP) were increased in the HFD or hypoxic group and were significantly elevated in the co-treated mice. CONCLUSION: CIH treatment aggravates depressive-like behaviors in HFD-fed mice with significant increased levels of oxidative stress, neuroinflammation and IDO-1 activity, which could augment the depletion of serotonin and apoptosis in the hippocampus.