Research reportBeneficial effects of exercise and its molecular mechanisms on depression in rats
Introduction
Exercise was shown to be beneficial to improve depressive symptoms in depressed sufferers [1], [2], but the biological mechanisms sustained unclear. Animal models of depression were useful for examining the effects of exercise on brain function and investigating their mechanisms. Chronic unpredictable stress (CNS), consisting of several relatively mild and unpredictable stressors, was considered to be a valid animal model of depression [3], [4] and could induce anhedonia, a core symptom of depression in human, as measured by changes in sucrose consumption in rats [5]. The model was proven to be successful in the functional identification of antidepressant, and therefore had a high degree of predictive validity [6], [7]. The alterations reported in the model were stable for a long time [8], which made a significant difference with respect to the transitory disturbances observed in other animal models of depression. Aforementioned characteristic of CMS as an animal model of depression made it possible for the more profound studies for the etiology of depression and the mechanisms of chronic antidepressive treatments.
Apart from mood disorder, cognitive impairment was frequently observed in depressed sufferers [9], [10]. However, only a few studies investigated memory performance in animal models of depression. Previous studies reported a deficiency in spatial leaning in the Morris water maze and/or the eight-arm radial maze in olfactory bulbectomized rats and Wistar-Kyoto rats [11], [12]. On the other hand, voluntary exercise reported could improve cognitive function in human and in animals [13], [14], [15], but few studies had investigated the effect of exercise on cognitive function in animal models of depression.
Chronic stress was thought to play an important role in the etiology of depression [16]. Depressed patients often exhibited hyperactivity in the HPA axis such as hypersecretion of basal CORT [17] and increased adrenal weight [18]. Sustained exposure to chronic stress or excessive glucocorticoids had adverse effects on the hippocampus [19], [20], [21], a region of the brain that is intrinsically linked to mood and cognitive function, and might cause the hippocampal atrophy. There was a significant correlation between the duration of the depression and the extent of hippocampal atrophy [22]. The effect of CORT on hippocampus might be relative to hippocampal GR. Under a stress situation, hippocampal GR was sensitive to elevated CORT levels and played a crucial role in the normalization of the HPA axis [23].
Recent studies had indicated that brain-derived neurotrophic factor (BDNF), expressed at high levels in the hippocampus [24], was involved in the pathogenesis of depression. BDNF was decreased in serum of depressed sufferers [25] and increased by antidepressant treatments [26]. Local cerebral administration of BDNF was reported exert antidepressant-like effects in animal models of depression [27]. Previous studies had examined the effects of various forms of chronic stress and CORT on hippocampal BDNF mRNA. Repeated immobilization stress was shown to result in a significant decrease in hippocampal BDNF mRNA [28], [29]. Similarly, the administration of high doses of CORT resulted in a transient decrease in BDNF mRNA in multiple subregions of the hippocampus [30], [31]. The interaction of stress and CORT on BDNF might, therefore, be relative to hippocampal atrophy and contribute to mood disorder and memory impairments.
It was reported that voluntary exercise increased BDNF mRNA level in the hippocampus in normal rats [32], [33]. It was possible that exercise might protect against the effects of chronic stress and exert antidepressant-like effects by counteracting a decrease in hippocampal BDNF mRNA caused by chronic stress. The present study was designed (1) to evaluate the effects of exercise on depressive behaviors and spatial performance in chronic unpredictable stress rats and (2) to identify whether these effects were associated with the circulating CORT and the hippocampal BDNF mRNA.
Section snippets
Subjects
Male Sprague-Dawley rats, weighing 150–200 g, were used. Rats were acclimated to the surroundings for 1 week before experimentation and were individually housed in a temperature (22 ± 2 °C), humidity (55 ± 10%), and light (12 h light:12 h dark cycle; lights on at 7 a.m.) controlled environment and were fed food and water ad libitum. All animal experiments were performed in accordance with the local, international and institutional guidelines. The experiments in the present study were designed to
Body weight
As shown in Fig. 1, the CNS used significantly affected body weight. Stressed animals gained significantly less weight than non-stressed objects, and a more pronounced effect was seen in animals without exercise, whereas, the non-stressed rats with exercise gained less weight than the non-stressed rats without exercise. ANOVA indicated a significant effect of time (F3,26 = 200.78, P < 0.001) and a significant interaction of time × CNS (F3,26 = 18.52, P < 0.001). ANOVA also showed a significant effect of
Discussion
Our results showed that CNS resulted in depressive behaviors and impaired spatial performance in rats. Stressed subjects showed a significant increased circulating CORT levels, reduced GR and BDNF mRNA levels in the hippocampus. Exercise diminished or even reversed the effects of CNS on depressive behaviors, spatial performance, CORT and hippocampal BDNF mRNA.
During the CNS session and the recovery session, stressed rats consumed significantly less 1% sucrose solution, exhibited lower open
Conclusions
This study demonstrated that exercise by free running wheel could reduce adverse effects of CNS on depressive behaviors and spatial performance in rats. Furthermore, the results indicated that both the beneficial effects of exercise and the harmful effects of CNS were relative to a common molecular, BDNF, in the hippocampus. In addition, circulating CORT might play different roles in the two processes. In summary, first, CNS was a good model for the study for biological mechanisms of the
Acknowledgements
This study was supported by the National Nature Science Foundation of China (no. 39970275; no. 30070288 to Z. Wang; no. 30070198 to C. Wan).
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