Effects of n-3 PUFAs on depression induced by chronic mild stress in adult male pups experienced maternal separation at early life

Abstract

A two-hit stress, a combination of stresses in early life and adulthood, increases vulnerability for mental illness and then triggers the onset of depression. Previous studies reported that n-3 polyunsaturated fatty acids (PUFAs) have antidepressantlike effects on depression in rats with acute or chronic stress. The purpose of the present study was to investigate the hypothesis that supplementation of n-3 PUFAs had antidepressant-like effects in adult male pups with two-hit stress through a brain-derived neurotrophic factor (BDNF)-serotonergic mechanism. Male pups were fed a modified AIN-93G diet with 0% or 1% n-3 PUFAs relative to total energy intake during the pre-weaning, post-weaning, or lifetime period. In addition, male pups were allocated to daily 3-h maternal separation (MS) in early life, and chronic mild stress (CMS) including seven different stressors in adulthood. CMS and two-hit stress significantly increased depressive behaviors in forced swimming test and sucrose preference test, and decreased hippocampal expressions of cAMP response element binding protein (CREB), phosphorylated CREB (pCREB), BDNF, serotonin 1A receptor (5-HT1AR) compared to non-stress and CMS alone, respectively. Moreover, two-hit stress had more severe depressive effects than CMS alone. Regardless of stress type, supplementation of n-3 PUFAs improved depressive behaviors and increased hippocampal expressions of CREB, pCREB, BDNF, 5-HT1AR. Furthermore, pre-weaning or post-weaning supplementation of n-3 PUFAs had similar antidepressant-like effects compared to control diet during lifetime. In addition, lifetime supplementation of n-3 PUFAs had the greatest antidepressant-like effects. The present study suggested that n-3 PUFA supplementation had antidepressant-like effects on depression induced by a two-hit stress through BDNF-serotonergic mechanism in adult male pups.