## 4 Discussion
The behavioral effects of antidepressants have been linked to their ability to increase BDNF expression and activate TrkB signaling in the hippocampus and prefrontal cortex, which are mediated in part by CREB1 [40; 45]. In the present study, the BDNF, CREB1, and TrkB levels were significantly higher in the MICT, HICT, and HIIT groups than in the RST group. Moderate-to-vigorous aerobic exercises, such as running and swimming, increase BDNF biosynthesis, resulting in up to a threefold increase in plasma and brain BDNF [46; 47]. These results suggest that exercise enhances the effectiveness of antidepressants by acting through neurochemical pathways similar to those of BDNF [48]. Astrocytes are glial cells that support the survival and function of neurons and maintain nervous system stability. GFAP, a marker of astrocyte reactivity, is expressed in the CNS and is neurotoxic when accumulated by stress and disease [49]. As a proto-oncogene, c-fos is an immediate early gene that plays a role in cell division and differentiation and mediates cellular responses. The results of this study showed that c-fos and GFAP levels increased with RST and decreased with exercise. This is consistent with the finding that 12 weeks of treadmill exercise increased GFAP levels in the hippocampus of animals. However, previous studies have reported that c-fos levels increase with increasing exercise intensity in the DG of animal brains, which is inconsistent with our results. c-Fos levels increased until day 7 of exercise and then began to decline [50]. The c-fos gene product, Fos protein, is activated and increased in certain areas of the brain in response to brain injury or stress, and its expression is reduced when depression is improved by antidepressant medications [51; 52]. One possible explanation for these results is that the exercise itself is perceived as stressful. Collectively, astrocytes regulate neurogenesis and neuoplasticity by providing neurotrophic factors, such as BDNF, to neighboring neuronal cell bodies [53], which consequently inhibit cell death by protecting neurons from oxidative stress [54]. Oxidative stress is closely associated with neurogenesis and neuoplasticity in depressive disorders. The levels of 4 HNE and MDA, markers of lipid peroxidation, are elevated in depressive disorders, and increased lipid peroxidation damages proteins and DNA, leading to cell membrane permeability and the dysfunction of enzymes and receptors [55]. Exercise inhibits oxidative stress by effectively increasing the activities of antioxidant enzymes. The present study demonstrated that treadmill exercise of varying intensities suppressed 4 HNE and MDA levels in RST-induced depressive disorders. However, no significant differences in the effects of exercise type or intensity were found. [PERSON] [56] reported that 15 days of voluntary wheel exercise in an animal model of depressive disorder alleviated depressive behaviors and reduced the levels of oxidative stress markers, such as MDA and lipid peroxidation. In addition, exercise reduces oxidative stress by modulating the balance of antioxidant enzymes in depressive disorders [57; 58]. RST-induced depressive disorders decrease the levels of serotonin, a neurotransmitter involved in mood and emotion regulation, and increase the levels of CORT [59]. In the present study, serotonin levels were higher in the MICT, HICT, and HIIT groups than in the RST group. In particular, serotonin levels in the HIIT group significantly increased, similar to those in the CON group. CORT levels were higher in the RST group than in the CON group but lower in the exercise groups, although the difference was not significant. Previous clinical studies have reported that serotonin levels tend to increase numerically [60]. In addition, high-intensity exercise increases the amount of serotonin in the CNS because tryptophan is displaced by lipolysis from its attachment to albumin, a free fatty acid.