Depression is a psychiatric disorder with several comorbidities that has a complicated pathophysiology. Multiple mechanisms such as abnormal hypothalamic-pituitary adrenal (HPA) axis activity, neurotransmission (namely serotonin), and immune-inflammatory responses are involved in the pathophysiology of disease. In this study, we hypothesized that applying exercise (running wheel (RW) and treadmill (TM)) or fluoxetine (FLX) during adolescence could protect adult rats against the negative impact of early-life stress. To do this, we applied maternal separation stress (MS) to neonatal rats from postnatal day (PND) 2 to 14 and at PND 28, rats were divided into 8 experimental groups and were subjected to TM or RW or FLX treatment. After four weeks of physical activity or FLX treatment, at PND 64, behaviors were assessed by applying forced swimming test, sucrose preference test, open-field test, and elevated plus maze test. Serum cortiscosterone (CORT) levels and expression of genes associated with inflammatory factors (Il1β, Hmgb1, and Il6) and serotonergic systems (5-ht2c and 5-ht3a) were studies in the hippocampus (HIPP) and prefrontal cortex (PFC). Our results revealed that RW and FLX treatment during adolescence are capable of attenuating MS-induced depressive- and anxiety-like disorders in adult male rats. These effects were accompanied by the normalization of both serum CORT and the expression of genes in the HIPP and PFC. TM exercise in adolescence showed anxiolytic effects but failed to produce antidepressant-like effects. Results of this study suggest that voluntary physical activity during adolescence can reduce the negative effects of early-life stress through different mechanisms.

抑郁症是一种精神疾病，有多种合并症，病理生理学复杂。疾病的病理生理学涉及多种机制，例如异常下丘脑 - 垂体肾上腺 (HPA) 轴活动、神经传递（即血清素）和免疫炎症反应。在这项研究中，我们假设在青春期进行运动（跑轮 (RW) 和跑步机 (TM)）或氟西汀 (FLX) 可以保护成年大鼠免受早期生活压力的负面影响。为此，我们从出生后第 2 天 (PND) 到第 14 天和第 28 天对新生大鼠施加母体分离应激 (MS)，将大鼠分为 8 个实验组，并接受 TM 或 RW 或 FLX 治疗。经过 4 周的体力活动或 FLX 治疗后，在 PND 64 时，通过应用强迫游泳测试来评估行为，蔗糖偏好试验、旷场试验和高架十字迷宫试验。血清皮质酮（CORT）水平和炎症因子相关基因的表达（Il1β、Hmgb1和Il6）和血清素能系统（5-ht2c和5-ht3a）是在海马 (HIPP) 和前额叶皮层 (PFC) 中进行的研究。我们的研究结果表明，青春期 RW 和 FLX 治疗能够减轻成年雄性大鼠 MS 诱发的抑郁和焦虑样障碍。这些影响伴随着血清 CORT 和 HIPP 和 PFC 中基因表达的正常化。青少年时期的 TM 运动显示出抗焦虑作用，但未能产生类似抗抑郁药的作用。这项研究的结果表明，青春期的自愿体育活动可以通过不同的机制减少早期生活压力的负面影响。