Several lines of evidence have consistently indicated that physical exercise has antidepressant effects by improving hippocampal function, although the signaling pathways underpinning these responses are not well established. Therefore, this study investigated the role of mechanistic target of rapamycin complex 1 (mTORC1) and fibronectin type III domain-containing protein 5 (FNDC5)/irisin signaling in the antidepressant-like effect of physical exercise. We showed that physical exercise (treadmill running – 45 min/day/5 days/week for 4 weeks) produced an antidepressant-like effect as indicated by a reduction on the immobility time in mice subjected to the forced swimming test (FST) without altering locomotor activity in the open field test (OFT). Rapamycin (a selective mTORC1 inhibitor, 0.2 nmol/site, i.c.v.) administration completely abolished the antidepressant-like effect of physical exercise in the FST, suggesting that mTORC1 activation plays a role for its behavioral effect. Accordingly, physical exercise increased the number of phosphorylated mTORC1 (Ser2448)-positive cells in the entire and ventral subgranular zone of the hippocampal dentate gyrus. Physical exercise was also effective in augmenting the hippocampal FNDC5/irisin immunocontent, but rapamycin administration did not alter this effect. Our results reinforce the notion that physical exercise exerts an antidepressant-like effect and identifies the mTORC1-mediated signaling pathway as a target for its behavioral effects. This study provides additional evidence that physical exercise increases hippocampal FNDC5/irisin immunocontent, but this effect seems to be independent on hippocampal mTORC1 activation. Altogether the results contribute to elucidate possible molecular targets implicated in the antidepressant effects of physical exercise and highlight the role of mTORC1 signaling for its behavioral response.

多项证据一致表明，体育锻炼通过改善海马功能具有抗抑郁作用，尽管支持这些反应的信号通路尚未完全确定。因此，本研究调查了雷帕霉素复合物 1 (mTORC1) 和纤连蛋白 III 型结构域蛋白 5 (FNDC5)/鸢尾素信号传导在体育锻炼的抗抑郁样作用中的作用。我们表明，体育锻炼（跑步机跑步 – 45 分钟/天/5 天/周，持续 4 周）产生了类似抗抑郁药的作用，这可以通过强迫游泳试验 (FST) 小鼠的不动时间减少而不改变旷场试验 (OFT) 中的运动活动。雷帕霉素（一种选择性 mTORC1 抑制剂，0.2 nmol/位点，icv ) 给药完全消除了 FST 中体育锻炼的抗抑郁样作用，表明 mTORC1 激活对其行为影响起作用。因此，体育锻炼增加了海马齿状回整个和腹侧颗粒下区磷酸化 mTORC1 (Ser2448) 阳性细胞的数量。体育锻炼在增加海马 FNDC5/鸢尾素免疫含量方面也有效，但雷帕霉素给药并没有改变这种效果。我们的结果强化了体育锻炼产生抗抑郁样作用的观点，并将 mTORC1 介导的信号通路确定为其行为影响的目标。这项研究提供了额外的证据，表明体育锻炼会增加海马 FNDC5/鸢尾素的免疫含量，但这种影响似乎与海马 mTORC1 的激活无关。总之，这些结果有助于阐明与体育锻炼的抗抑郁作用有关的可能分子靶标，并强调 mTORC1 信号传导对其行为反应的作用。