Early-life stress (ELS) exposure increases the risk for mental disorders, including cognitive impairments later in life. We have previously demonstrated that an early diet with low ω6/ω3 polyunsaturated fatty acid (PUFA) ratio protects against ELS-induced cognitive impairments. Several studies have implicated the neuroimmune system in the ELS and diet mediated effects, but currently the molecular pathways via which ELS and early diet exert their long-term impact are not yet fully understood. Here we study the effects of ELS and dietary PUFA ratio on hippocampal mRNA and miRNA expression in adulthood, both under basal as well as inflammatory conditions.

Male mice were exposed to chronic ELS by the limiting bedding and nesting material paradigm from postnatal day(P)2 to P9, and provided with a diet containing a standard (high (15:1.1)) or protective (low (1.1:1)) ω6 linoleic acid to ω3 alpha-linolenic acid ratio from P2 to P42. At P120, memory was assessed using the object location task. Subsequently, a single lipopolysaccharide (LPS) injection was given and 24 h later hippocampal genome-wide mRNA and microRNA (miRNA) expression was measured using microarray.

Spatial learning deficits induced by ELS in mice fed the standard (high ω6/ω3) diet were reversed by the early-life protective (low ω6/ω3) diet. An integrated miRNA – mRNA analysis revealed that ELS and early diet induced miRNA driven mRNA expression changes into adulthood. Under basal conditions both ELS and the diet affected molecular pathways related to hippocampal plasticity, with the protective (low ω6/ω3 ratio) diet leading to activation of molecular pathways associated with improved hippocampal plasticity and learning and memory in mice previously exposed to ELS (e.g., CREB signaling and endocannabinoid neuronal synapse pathway). LPS induced miRNA and mRNA expression was strongly dependent on both ELS and early diet. In mice fed the standard (high ω6/ω3) diet, LPS increased miRNA expression leading to activation of inflammatory pathways. In contrast, in mice fed the protective diet, LPS reduced miRNA expression and altered target mRNA expression inhibiting inflammatory signaling pathways and pathways associated with hippocampal plasticity, which was especially apparent in mice previously exposed to ELS.

This data provides molecular insights into how the protective (low ω6/ω3) diet during development could exert its long-lasting beneficial effects on hippocampal plasticity and learning and memory especially in a vulnerable population exposed to stress early in life, providing the basis for the development of intervention strategies.

生命早期的压力（ELS）暴露会增加患精神疾病的风险，包括晚年认知障碍。我们之前已经证明，低 ω6/ω3 多不饱和脂肪酸 (PUFA) 比例的早期饮食可以预防 ELS 引起的认知障碍。多项研究表明神经免疫系统与 ELS 和饮食介导的影响有关，但目前 ELS 和早期饮食发挥长期影响的分子途径尚未完全了解。在这里，我们研究了 ELS 和膳食 PUFA 比例对成年期海马 mRNA 和 miRNA 表达的影响，无论是在基础条件还是炎症条件下。

从出生后第2天到第9天，雄性小鼠通过限制垫料和筑巢材料范式暴露于慢性ELS，并提供含有标准（高（15:1.1））或保护性（低（1.1:1） ) ω6 亚油酸与 ω3 α-亚麻酸的比例从 P2 到 P42。在 P120 时，使用物体定位任务评估记忆力。随后，进行单次脂多糖 (LPS) 注射，24 小时后使用微阵列测量海马全基因组 mRNA 和 microRNA (miRNA) 表达。

在喂食标准（高 ω6/ω3）饮食的小鼠中，由 ELS 引起的空间学习缺陷被生命早期保护性（低 ω6/ω3）饮食所逆转。整合的 miRNA-mRNA 分析表明，ELS 和早期饮食诱导 miRNA 驱动 mRNA 表达变化直至成年。在基础条件下，ELS和饮食都会影响与海马可塑性相关的分子途径，保护性（低ω6/ω3比率）饮食会导致先前暴露于ELS的小鼠中与改善海马可塑性以及学习和记忆相关的分子途径的激活（例如、CREB ​​信号传导和内源性大麻素神经元突触途径）。 LPS 诱导的 miRNA 和 mRNA 表达强烈依赖于 ELS 和早期饮食。在喂食标准（高 ω6/ω3）饮食的小鼠中，LPS 增加 miRNA 表达，导致炎症通路激活。相比之下，在喂食保护性饮食的小鼠中，LPS 减少了 miRNA 表达，并改变了抑制炎症信号通路和与海马可塑性相关通路的靶标 mRNA 表达，这在之前暴露于 ELS 的小鼠中尤其明显。

这些数据提供了关于发育过程中的保护性（低 ω6/ω3）饮食如何对海马可塑性以及学习和记忆发挥长期有益影响的分子见解，特别是在生命早期暴露于压力的弱势群体中，为制定干预策略。