Stress and ovarian hormone fluctuation are risk factors for postpartum depression (PPD). Previous studies suggested antidepressant-like effects of n-3 polyunsaturated fatty acids (PUFA), but their effect on dam animal with additional stress were not clear. The purpose of the present study was to investigate the hypothesis that n-3 PUFA improved PPD through the serotonergic and glutamatergic pathways by modulating miRNA. Rats were fed n-3 PUFA or control diet from gestation, with pup separation (PS) on postpartum days 2–14 and non-PS controls. N-3 PUFA reversed PS-induced depressive behaviors, including increased immobility, latencies to contact first pup and retrieve all pups, and decreased sucrose preference. N-3 PUFA also modulated the hypothalamic–pituitary–adrenal (HPA) axis by decreasing circulating levels of adrenocorticotropic hormone and corticosterone and expression of hypothalamic corticotrophin releasing factor and hippocampal miRNA-218 but increasing the hippocampal expression of glucocorticoid receptor. N-3 PUFA inhibited neuroinflammation by decreasing circulating levels of prostaglandin E₂ and hippocampal expression of tumor necrosis factor-α, interleukin-6, and miRNA-155. In addition, n-3 PUFA up-regulated the serotonergic pathway by increasing circulating levels of serotonin and hippocampal expression of serotonin-1A receptor, cAMP response element binding protein (CREB), pCREB, brain-derived neurotrophic factor, and miRNA-182 but did not affect the glutamatergic pathway according to the hippocampal expression of N-methyl-D-aspartate receptor-2B. The present study suggested that n-3 PUFA improved PPD through the serotonergic pathway by modifying the HPA axis, neuroinflammation, and related miRNAs.

压力和卵巢激素波动是产后抑郁症（PPD）的危险因素。先前的研究表明，n-3多不饱和脂肪酸（PUFA）具有抗抑郁样作用，但尚不清楚它们对附加压力的大坝动物的作用。本研究的目的是研究以下假设：n-3 PUFA通过调节miRNA通过血清素能和谷氨酸能途径改善PPD。妊娠期给大鼠喂n-3 PUFA或对照饮食，在产后2-14天进行幼仔分离（PS），而非PS对照。N-3 PUFA逆转了PS引起的抑郁行为，包括不动性增加，与第一只幼犬接触和收回所有幼犬的潜伏期以及蔗糖偏好的降低。N-3 PUFA还通过降低肾上腺皮质激素和肾上腺皮质激素的循环水平以及下丘脑促肾上腺皮质激素释放因子和海马miRNA-218的表达来调节下丘脑-垂体-肾上腺（HPA）轴，但增加了糖皮质激素受体的海马表达。N-3 PUFA通过降低前列腺素E的循环水平来抑制神经炎症₂，肿瘤坏死因子-α，白介素-6和miRNA-155在海马中的表达。此外，n-3 PUFA通过增加血清素的循环水平和血清素1A受体，cAMP反应元件结合蛋白（CREB），pCREB，脑源性神经营养因子和miRNA-182的海马表达来上调血清素能途径。 N-甲基-D-天冬氨酸受体2B的海马表达不影响谷氨酸能途径。本研究表明，n-3 PUFA通过修饰HPA轴，神经炎症和相关的miRNA，通过血清素能途径改善了PPD。