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

Authors: CHOI, JEONG-EUN - Hanyang University; BORKOWSKI, KAMIL - University Of California, Davis; Newman, John; PARK, YONGSOON - Hanyang University

Submitted to: Journal of Nutritional Biochemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/30/2020
Publication Date: 2/3/2021
Publication URL: https://handle.nal.usda.gov/10113/7276640
Citation: Choi, J., Borkowski, K., Newman, J.W., Park, Y. 2021. 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. Journal of Nutritional Biochemistry. 91. Article 108599. https://doi.org/10.1016/j.jnutbio.2021.108599.
DOI: https://doi.org/10.1016/j.jnutbio.2021.108599

Interpretive Summary: Supplementation with n-3 polyunsaturated fatty acids (PUFA) can improve depressive behaviors in rats with acute stress. However, the effect of n3-PUFAs on depression in rats exposed to chonic mild stress (CMS) alone or in conjunction with early life maternal separation (MS) which increases the vulnerability to depression is unclear. This study investigated the hypothesis that lifetime supplementation of n-3 PUFA improves post-menopausal depression in rats the CMS alone or parid with MS by through changes in the serotonergic and glutamatergic pathways and concordant modulation of n-3 PUFA-derived metabolites. Female rats were fed diets with either 0% n-3 PUFA over their lifetime or 1 % energy n-3 PUFA over their pre-weaning, post-weaning, or lifetime periods. Rats were allocated to non-MS or MS groups, and underwent CMS after ovariectomy. N-3 PUFA reversed depressive behaviors including increased immobility and decreased sucrose preference. N-3 PUFA modulated components of the hypothalamic-pituitary-adrenal axis, a major neuroendocrine system that controls reactions to stress and regulates many body processes, including digestion, the immune system, mood and emotions, sexuality, and energy storage and expenditure. Specifically, n3-PUFA supplementation decreased blood levels of adrenocorticotropic hormone and corticosterone the brain expression of corticotrophin releasing factor and miRNA-218, while increasing brain expression of glucocorticoid receptor. N-3 PUFA feeding also inhibited neuroinflammation, increasing expression of miRNA-155 while decreasing expression of tumor necrosis factor-alpha and interleukin-6, presumably by increasing brain anti-inflammatory n-3 PUFA-derived metabolites including various endocannabinoids and oxylipins. N-3 PUFA also up-regulated the serotonergic pathway, increasing blood serotonin levels and hippocampal expression of serotonin-1A receptor, cAMP response element binding protein (CREB), phospho-CREB and brain-derived neurotrophic factor. However, n-3 PUFA had no effect on brain expression of alpha amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor subtype 1, N-methyl-D-aspartate receptor subtype 2B or miRNA-132. Moreover, lifetime n-3 PUFA exposure caused greater effects than pre- and post-weaning period exposures. The present study suggests that n-3 PUFA improved depressive behaviors through serotonergic pathway by modulating the metabolites of n-3 PUFA in post-menopausal depressed rats with chronic stress.

Technical Abstract: Early life maternal separation (MS) increased 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, but their effects on rats with MS+CMS were not clear. The purpose of the present study was to investigate the hypothesis that lifetime supplementation of n-3 PUFA improved post-menopausal depression through the serotonergic and glutamatergic pathways by modulating n-3 PUFA-derived metabolites. Female rats were fed diets either 0% n-3 PUFA over their lifetime or 1 % energy n-3 PUFA over their pre-weaning, post-weaning, or lifetime periods. Rats were allocated to non-MS or MS groups, and underwent CMS after ovariectomy. N-3 PUFA reversed depressive behaviors including increased immobility and decreased sucrose preference. N-3 PUFA also modulated the hypothalamic-pituitary-adrenal axis, decreasing blood adrenocorticotropic hormone and corticosterone levels, and brain expressions of corticotrophin releasing factor and miRNA-218, and increasing expression of glucocorticoid receptor. N-3 PUFA inhibited neuroinflammation, increasing brain n-3 PUFA-derived endocannabinoid and oxylipin levels and expression of miRNA-155, while decreasing expression of tumor necrosis factor-alpha and interleukin-6. N-3 PUFA also up-regulated the serotonergic pathway, increasing blood serotonin levels and hippocampal expression of serotonin-1A receptor, cAMP response element binding protein (CREB), phospho-CREB and brain-derived neurotrophic factor. However, n-3 PUFA had no effect on brain expression of alpha amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor subtype 1, N-methyl-D-aspartate receptor subtype 2B or miRNA-132. Moreover, lifetime n-3 PUFA exposure caused greater effects than pre- and post-weaning period exposures. The present study suggests that n-3 PUFA improved depressive behaviors through serotonergic pathway by modulating the metabolites of n-3 PUFA in post-menopausal depressed rats with chronic stress.