Physical exercise is a robust lifestyle intervention known for its enhancement of cognitive abilities. Nevertheless, the extent to which these benefits can be transmitted across generations (intergenerational inheritance to F1, and transgenerational to F2 and beyond) remains a topic of limited comprehension. We have already shown that cognitive improvements resulting from physical exercise can be inherited from parents to their offspring, proving intergenerational effects. So, we set out to explore whether these enhancements might extend transgenerationally, impacting the F2 generation. In this study, we initially examined the behavioral traits of second generation (F2) male mice, whose grandfathers (F0) had an exercise intervention. Our findings revealed that F2 mice with physically active grandpaternal F0 progenitors displayed significantly improved memory recall, encompassing both spatial and non-spatial information when compared to their counterparts from sedentary F0 progenitors, and proving for the first time the transgenerational inheritance of physical exercise induced cognitive enhancement. Surprisingly, while F2 memory improved (as was the case with F1), adult hippocampal neurogenesis remained unchanged between experimental and control groups (unlike in F1). Additionally, our analysis of small RNA sequences in the hippocampus identified 35 differentially expressed miRNAs linked to important brain function categories. Notably, two of these miRNAs, miRNA-144 and miRNA-298, displayed a robust negative correlation with cognitive performance. These findings highlight the enduring transgenerational transmission of cognitive benefits associated with exercise, even after two generations, suggesting that moderate exercise training can have lasting positive effects, possibly orchestrated by a specific set of miRNAs that exert their influence across multiple generations.

体育锻炼是一种强有力的生活方式干预措施，以其增强认知能力而闻名。然而，这些益处在多大程度上可以跨代传递（F1 的代际遗传，F2 及以后的跨代遗传）仍然是一个有限理解的话题。我们已经证明，体育锻炼带来的认知改善可以从父母遗传给后代，从而证明了代际效应。因此，我们着手探索这些增强功能是否可能跨代延伸，从而影响 F2 代。在这项研究中，我们最初检查了第二代（F2）雄性小鼠的行为特征，其祖父（F0）接受了运动干预。我们的研究结果表明，与久坐的 F0 祖代小鼠相比，具有身体活跃的祖父 F0 祖代小鼠的 F2 小鼠表现出显着改善的记忆力，包括空间和非空间信息，并首次证明了体育锻炼诱导认知的跨代遗传。增强。令人惊讶的是，虽然 F2 的记忆力有所改善（与 F1 的情况相同），但实验组和对照组之间的成年海马神经发生保持不变（与 F1 不同）。此外，我们对海马体中小 RNA 序列的分析发现了 35 个与重要大脑功能类别相关的差异表达 miRNA。值得注意的是，其中两个 miRNA，miRNA-144 和 miRNA-298，与认知表现呈强负相关。 这些发现强调了与运动相关的认知益处的持久跨代传递，即使是在两代人之后，表明适度的运动训练可以产生持久的积极影响，这可能是由一组特定的 miRNA 精心策划的，这些 miRNA 在多代人中发挥影响。