Antidepressant effects of omega-3 PUFA on depression induced by two-hit stress in adult male offspring through hypothalamic-pituitary-adrenal axis-related mechanism

Abstract

A two-hit stress, a combination of stresses in early life and adulthood, proposes that a first hit during early brain development increases the vulnerability to develop mental illness and a second hit on adulthood triggers the onset of depression. Previous studies reported that omega-3 polyunsaturated fatty acids (PUFA) have antidepressant-like effects on depression in rats with acute or chronic stress. The purpose of the present study was to investigate the hypothesis that supplementation of omega-3 PUFA had antidepressant-like effects in adult male offspring with chronic mild stress (CMS) alone or two-hit stress through regulation of hypothalamic-pituitary-adrenal (HPA) axis-related neurobiological mechanism. Male offspring were fed a modified AIN-93G diet with 0% or 1% omega-3 PUFA relative to total energy intake during the pre-weaning, post-weaning, or lifetime period. In addition, male offspring were allocated to daily 3-h maternal separation (MS) in early life, and CMS including seven different stressors in adulthood. Both types of stress significantly increased concentrations of adrenocorticotropic hormone (ACTH), corticosterone (CORT), and hippocampal expressions of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), N-methyl-D-aspartate receptor 2B (NR2B), phosphorylated NR2B (pNR2B), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor 1 (GluR1), phosphorylated GluR1 (pGluR1), but decreased hippocampal expressions of glucocorticoid receptor (GR), serotonin concentrations compared to non-stress. In addition, immunofluorescence staining showed elevated expressions of corticotropin releasing factor (CRF) in CMS alone and two-hit stress. Two-hit stress had more significant effects than CMS alone. Regardless of stress type, supplementation of omega-3 PUFA decreased CRF expressions, ACTH and CORT concentrations, hippocampal expressions of TNF-α, IL-6, but increased hippocampal GR expressions, serotonin concentrations. The stress-affected microRNAs (miRs), such as miR-218, -155 and -132, were modulated by supplementation of omega-3 PUFA, but glutamate receptors were not affected. Furthermore, supplementation of lifetime omega-3 PUFA had more significant effects than pre-weaning or post-weaning supplementation. The present study suggested that omega-3 PUFA supplementation had similar antidepressant-like effects on depression through regulation of HPA axis, inflammatory cytokines and miRs in adult male offspring with CMS alone or two-hit stress.