Ehavior in TD animals and that TD alone is not attributable to the onset of depression. One possible explanation for the exercise-induced prevention of depression-like order Eledoisin behavior is the enhancement of hippocampal noradrenaline in the mice that exercised. In this study, regular exercise, whether moderate or intense, prevented the onset of depression-like behavior (Fig. 4). It has been reported that the exercise-induced improvement of major depression is dependent on restoring brain 5-HT [32]. However, in the present study, the hippocampal 5-HT level of the mice that exercised was Bexagliflozin significantly lower than that of the control mice and equal to that 15481974 of the stressed mice that did not perform exercise (Fig. 3b). These findings suggested that regular exercise, whether moderate or intense, results in no increase of brain 5-HT, which corresponds with the finding of a previous study that prolonged exercise results in no significant 16574785 increase of 5-HT level in the brain [33]. Therefore, we think that regular exercise prevents depression-like behavior independent of the level of brain 5-HT. On the other hand, hippocampal noradrenaline was significantly higher in the mice that exercised than in the stressed mice (Fig. 3c). This increase of brain noradrenaline in the exercised mice corresponds to findings in previous studies that the brain noradrenaline level gradually increases with time during prolonged exercise [34,35]. Brain noradrenaline is a target substance for the pharmacologicalExercise Prevents Depression in TD MiceFigure 8. Effects of tryptophan deficiency, CUS and regular exercise on number of BrdU-positive cells in the dentate gyrus of the hippocampus. Data are expressed as mean 6 SEM. *, p,0.05 vs. C; 1, p,0.05 vs. TD; #, p,0.05 vs. TD+CUS. doi:10.1371/journal.pone.0066996.gtreatment of depressed patients using serotonin-noradrenaline reuptake inhibitors (SNRIs) and tricyclic antidepressants. Noradrenaline has neuroprotective effects in cultured neuronal cells by stimulating the activation of cAMP-response element binding protein (CREB) and the induction of brain-derived neurotrophic factor (BDNF) [36,37]. Therefore, we supposed that the enhancement of brain noradrenaline via exercise is a factor that may have contributed to prevent the onset of depression-like behavior in the mice that exercised. In addition, vaccine growth factor (VEG) [38] and vascular endothelial growth factor (VEGF) [16] were identified as other factors related to the prevention of depression-like behavior in animals that exercise. We expect that the antidepressant effect induced by exercise is attributable to complexactions caused by the factors (noradrenaline, VEG, VEGF) influenced by the exercise. Therefore, further investigation is necessary to elucidate the causal relationship between the exerciseinduced prevention of depression and these factors. Another possible factor for examination of the exercise-induced prevention of depression-like behavior is the improvement of the proliferation and survival of newly born cells in the hippocampus of mice that exercised (Fig. 7 and 8). Adult hippocampal neurogenesis is impaired by CUS [39,40]. A therapeutic effect via antidepressants is concomitant with the improvement of adult hippocampal neurogenesis [41]. Therefore, it is possible that the improvement of adult hippocampal neurogenesis is one of the physiological events that improve depression-like behavior. The present findings demonstrated that regular exercise, whethe.Ehavior in TD animals and that TD alone is not attributable to the onset of depression. One possible explanation for the exercise-induced prevention of depression-like behavior is the enhancement of hippocampal noradrenaline in the mice that exercised. In this study, regular exercise, whether moderate or intense, prevented the onset of depression-like behavior (Fig. 4). It has been reported that the exercise-induced improvement of major depression is dependent on restoring brain 5-HT [32]. However, in the present study, the hippocampal 5-HT level of the mice that exercised was significantly lower than that of the control mice and equal to that 15481974 of the stressed mice that did not perform exercise (Fig. 3b). These findings suggested that regular exercise, whether moderate or intense, results in no increase of brain 5-HT, which corresponds with the finding of a previous study that prolonged exercise results in no significant 16574785 increase of 5-HT level in the brain [33]. Therefore, we think that regular exercise prevents depression-like behavior independent of the level of brain 5-HT. On the other hand, hippocampal noradrenaline was significantly higher in the mice that exercised than in the stressed mice (Fig. 3c). This increase of brain noradrenaline in the exercised mice corresponds to findings in previous studies that the brain noradrenaline level gradually increases with time during prolonged exercise [34,35]. Brain noradrenaline is a target substance for the pharmacologicalExercise Prevents Depression in TD MiceFigure 8. Effects of tryptophan deficiency, CUS and regular exercise on number of BrdU-positive cells in the dentate gyrus of the hippocampus. Data are expressed as mean 6 SEM. *, p,0.05 vs. C; 1, p,0.05 vs. TD; #, p,0.05 vs. TD+CUS. doi:10.1371/journal.pone.0066996.gtreatment of depressed patients using serotonin-noradrenaline reuptake inhibitors (SNRIs) and tricyclic antidepressants. Noradrenaline has neuroprotective effects in cultured neuronal cells by stimulating the activation of cAMP-response element binding protein (CREB) and the induction of brain-derived neurotrophic factor (BDNF) [36,37]. Therefore, we supposed that the enhancement of brain noradrenaline via exercise is a factor that may have contributed to prevent the onset of depression-like behavior in the mice that exercised. In addition, vaccine growth factor (VEG) [38] and vascular endothelial growth factor (VEGF) [16] were identified as other factors related to the prevention of depression-like behavior in animals that exercise. We expect that the antidepressant effect induced by exercise is attributable to complexactions caused by the factors (noradrenaline, VEG, VEGF) influenced by the exercise. Therefore, further investigation is necessary to elucidate the causal relationship between the exerciseinduced prevention of depression and these factors. Another possible factor for examination of the exercise-induced prevention of depression-like behavior is the improvement of the proliferation and survival of newly born cells in the hippocampus of mice that exercised (Fig. 7 and 8). Adult hippocampal neurogenesis is impaired by CUS [39,40]. A therapeutic effect via antidepressants is concomitant with the improvement of adult hippocampal neurogenesis [41]. Therefore, it is possible that the improvement of adult hippocampal neurogenesis is one of the physiological events that improve depression-like behavior. The present findings demonstrated that regular exercise, whethe.
