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N-3 PUFA improved post-menopausal depression induced by maternal separation and chronic mild stress through serotonergic pathway in rats—effect associated with lipid mediators

Jeong-Eun Choi, Kamil Borkowski, John W. Newman, Yongsoon Park
Journal of nutritional biochemistry 2021 v.91 pp. 108599
animal disease models, animal stress, behavior change, cannabinoids, corticosterone, corticotropin, corticotropin-releasing hormone, dietary fat, dietary supplements, females, glucocorticoid receptors, glutamates, glutamic acid, hippocampus, interleukin-1beta, interleukin-6, lipid metabolism, mental depression, metabolites, microRNA, omega-3 fatty acids, ovariectomy, oxylipins, postmenopause, prostaglandins, rats, serotonin, serotonin receptors, stress response, tumor necrosis factor-alpha, weaning
Early life maternal separation (MS) increases the vulnerability to depression in rats with chronic mild stress (CMS). N-3 polyunsaturated fatty acids (PUFA) improved depressive behaviors in rats with acute stress; however, their effects on rats with MS+CMS were not apparent. The purpose of the present study was to investigate the hypothesis that lifetime n-3 PUFA supplementation improves post-menopausal depression through the serotonergic and glutamatergic pathways while modulating n-3 PUFA-derived metabolites. Female rats were fed diets of either 0% n-3 PUFA during lifetime or 1% energy n-3 PUFA during pre-weaning, post-weaning, or lifetime periods. Rats were allocated to non-MS or MS groups and underwent CMS after ovariectomy. N-3 PUFA increased brain n-3 PUFA-derived endocannabinoid/oxylipin levels, and reversed depressive behaviors. N-3 PUFA decreased blood levels of adrenocorticotropic hormone and corticosterone, and brain expressions of corticotropin-releasing factor and miRNA-218, which increased the expression of the glucocorticoid receptor. N-3 PUFA decreased the expression of tumor necrosis factor-α, interleukin (IL)-6, IL-1β, and prostaglandin E₂, while increased the expression of miRNA-155. N-3 PUFA also increased brainstem serotonin levels and hippocampal expression of the serotonin-1A receptor, cAMP response element-binding protein (CREB), phospho-CREB, and brain-derived neurotrophic factor. However, n-3 PUFA did not affect brain expression of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor subtype 1, N-methyl-D-aspartate receptor subtype 2B, or miRNA-132. Moreover, n-3 PUFA exposure during lifetime caused greater effects than pre- and post-weaning periods. The present study suggested that n-3 PUFA improved depressive behaviors through serotonergic pathway while modulating the metabolites of n-3 PUFA in post-menopausal depressed rats with chronic stress.