Effects of n-3 PUFA on depression triggered by mother-pup separation

Abstract

Early mother-infant separation increases the vulnerability to depression in both mother and child. Previous studies showed that supplementation with n-3 polyunsaturated fatty acids (PUFA), including eicosapentaenoic acid and docosahexaenoic acid, had antidepressant-like effects in human and animals. Therefore, the purpose of the present study was to investigate the antidepressant-like mechanism of n-3 PUFA in postpartum dam and postmenopausal pup rats following the mother-pup separation. First study was conducted to determine the antidepressant-like effects of n-3 PUFA via microRNA (miRNA)-regulated neurobiological systems in dam rats with postpartum depression induced by pup separation. After mating, the female rats were fed a modified AIN-93G diet containing 0% or 1% n-3 PUFA relative to total energy intake during gestation and lactation periods. After birth, dam rats were separated from their pups for 15 min (control) or 180 min (pup separation) every day on postpartum day 2-14. N-3 PUFA decreased depressive behaviors during forced swimming test, sucrose preference test, and pup retrieval test, which were elevated by pup separation. In addition, the antidepressant-like effects of n-3 PUFA were shown to be due to regulation of hypothalamic-pituitary-adrenal (HPA) axis activity, cAMP response element binding protein (CREB)/brain derived neurotrophic factor (BDNF)-serotonergic neurotransmission, and neuroinflammation. Consistently, n-3 PUFA modified hippocampal expressions of miRNA-218, miRNA-155, and miRNA-182, which regulate HPA axis system, CREB/BDNF pathway, and neuroinflammation. However, n-3 PUFA did not affect the glutamatergic pathway, which is reflected in hippocampal expressions of N-methyl-D-aspartate receptor-2B and its regulator, miRNA-132. Second study was conducted to investigate the antidepressant-like effect of n-3 PUFA through serotonergic pathway in maternal separation (MS)-exposed pup rats with chronic mild stress (CMS) during postmenopausal period. Female pup rats were fed diets with 0% or 1 % n-3 PUFA of total energy intake during lifetime from embryonic day (ED) 0 to postnatal day (PND) 112, or 1% n-3 PUFA before weaning (ED 0-PND 20), or after weaning (PND 20-112). The rats in four diet group were divided to brief separation from dam (control) or long-term separation (maternal separation) on PND 2-14, and then underwent CMS on PND 91-105 after ovariectomy. N-3 PUFA decreased depressive behaviors during forced swimming test and sucrose preference test, which were increased by CMS and MS+CMS. N-3 PUFA increased the level of n-3 PUFA-derived endocannabinoids and oxylipins in prefrontal cortex. Accordingly, n-3 PUFA upregulated serotonergic pathway by modifying HPA axis activity, CREB/BDNF pathway, and neuroinflammation, and related miRNA-218 and miRNA-155. However, n-3 PUFA had no effect on glutamatergic pathway including α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor and N-methyl-D-aspartate receptor, which are regulated by miRNA-132. In addition, lifetime supplementation of n-3 PUFA had greater effect than pre- or post-weaning supplementation. In conclusion, n-3 PUFA supplementation improved mother-pup separation-induced depression through modulation of serotonergic pathway by regulating related miRNAs, but not glutamatergic pathway, in postpartum dam rats and postmenopausal pup rats with CMS. In addition, the antidepressant-like effects of n-3 PUFA were related with n-3 PUFA-derived endocannabinoids and oxylipins. Moreover, in postmenopausal pup rats, n-3 PUFA supplementation during lifetime showed greater effects on postmenopausal depression induced by CMS alone or MS+CMS as compared to the supplementation during pre-weaning or post-weaning period.