Research reportPhysical activity–antidepressant treatment combination: impact on brain-derived neurotrophic factor and behavior in an animal model
Introduction
Brain-derived neurotrophic factor (BDNF), the most abundant of the neurotrophins in the brain, enhances the growth and maintenance of several neuronal systems, serves as a neurotransmitter modulator, and participates in use-dependent plasticity mechanisms such as long-term potentiation and learning [12], [20], [21]. In recent years, evidence has been gathering that BDNF expression may be a downstream target of catecholamine-enhancing, mood-stabilizing antidepressant treatments, and could be an important agent for therapeutic recovery from depression and the protection against stress-induced neuronal damage. The direct infusion of BDNF has been shown to lead to the recovery of hallmark behavioral deficits in depression-model animals [41]. Moreover, chronic treatment with a variety of antidepressant medications has been shown to up-regulate BDNF mRNA levels in the rat hippocampus and cerebral cortex [27]. Hippocampal BDNF has also been shown to be down-regulated in response to stress [42]. Both clinical and animal studies have indicated that prolonged and severe stress may play an important role in the pathophysiology of depression and other psychiatric disorders. Neuronal atrophy and death have been observed in the hippocampi of animals exposed to chronic stress [35], [44], and animals subjected to stress also show behavioral changes associated with a depressive state [2], [31]. Humans with a history of chronic, recurrent depression or post-traumatic stress disorder have shown significant hippocampal atrophy in imaging studies [4], [38].
Physical activity has been evidenced to lead to improvements in psychiatric status in some human clinical reports [15], [18]. In recent studies, physical activity appeared to both enhance and accelerate the BDNF up-regulation brought about by antidepressant treatment in the rat [34], [37]. After 1 week, levels of two BDNF mRNA transcripts were found to be significantly higher with the combination of exercise and antidepressant than with each intervention alone [34].
In this study, it is our aim to assess whether the enhancement of BDNF expression brought about by antidepressant treatment, exercise and the combination could overcome diminishment brought about by acute stress, and whether this enhancement could be associated with behavioral change in an animal model. We have assessed the immobilization time during forced swimming in a water tank in the absence of a platform (similar to Porsolt et al. [30]), a paradigm that is known to be stressful to animals [1], [17], [22]. Animals underwent forced swimming after one week of treatment with tranylcypromine, one week of exercise, or the combination of these two interventions. A fourth group of animals underwent the forced swim procedure after no treatment, and a sedentary control group was not subjected to forced swimming. Quantitative in situ hybridization was performed to assess hippocampal BDNF mRNA levels in these groups, and to test the hypothesis that behavioral improvement (decreased immobilization under stress) may correlate with BDNF mRNA expression in this brain area.
Section snippets
Animal subjects
Male Sprague–Dawley rats of approximately 3 months of age (source: Charles River) were housed singly with food and water ad libitum and a 12:12 h (06:00–18:00 h) light/dark cycle. The rats were allowed to acclimate to the vivarium for one week prior to the start of experiments. All animal use procedures, described below, were in strict accordance with the National Research Council's guide for the Care and Use of Laboratory Animals (1996), and all efforts were made to minimize the number of
BDNF mRNA levels were significantly down-regulated after the forced swim procedure
Quantitative in situ hybridization for BDNF mRNA in untreated animals revealed depressed mRNA levels in all hippocampal cellular fields after the 2 day forced swimming procedure (see Fig. 1 for example autoradiographs). ANOVA comparing BDNF mRNA levels in the various animal groups revealed a significant difference in several hippocampal areas: CA1 [F(4,30)=5.243, P=0.0025], CA3 [F(4,30)=7.257, P=0.0003], CA4 [F(4,30)=14.343, P<0.001] and DG (dentate gyrus) [F(4,30)=6.123, P=0.001]. BDNF mRNA
Discussion
The improvement of behavioral management, and a greater understanding of the mechanisms of antidepressant treatments, is an essential goal. In recent years, much evidence has emerged that BDNF plays a significant role in the maintenance and function of neurotransmitter systems involved in the pathology and treatment of mental disorders, and may itself have therapeutic effects [7], [23], [40], [41]. It has been demonstrated that general physical activity [26] and antidepressant treatment [27]
Acknowledgements
Thanks to Kenneth Chuang for assistance with behavioral testing. This work has been supported by US Public Health Service Grant MH-59776 to ARN, AG-13880 to JPK, and a NARSAD Young Investigator Award to ARN.
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