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Journal of Bodywork & Movement Therapies (2014) xx, 1e8
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevier.com/jbmt
ORIGINAL RESEARCH
Preventive and therapeutic effect of treadmill running on chronic stress-induced memory deficit in rats Maryam Radahmadi, PhD , Hojjatallah Alaei, PhD*, Mohammad Reza Sharifi, PhD , Nasrin Hosseini, PhD Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran Received 13 January 2014; received in revised form 28 March 2014; accepted 9 April 2014
KEYWORDS Memory; Exercise; Chronic stress; Passive avoidance; Rat
Summary Previous results indicated that stress impairs learning and memory. In this research, the effects of preventive, therapeutic and regular continually running activity on chronic stress-induced memory deficit in rats were investigated. 70 male rats were randomly divided into seven groups as follows: Control, Sham, StresseRest, ResteStress, StresseExercise, ExerciseeStress and ExerciseeStress & Exercise groups. Chronic restraint stress was applied 6 h/day for 21days and treadmill running 1 h/day. Memory function was evaluated by the passive avoidance test. The results revealed that running activities had therapeutic effect on mid and long-term memory deficit and preventive effects on short and mid-term memory deficit in stressed rats. Regular continually running activity improved mid and long-term memory compared to ExerciseeStress group. The beneficial effects of exercise were time-dependent in stress conditions. Finally, data corresponded to the possibility that treadmill running had a more important role on treatment rather than on prevention on memory impairment induced by stress. ª 2014 Elsevier Ltd. All rights reserved.
Introduction Exposure to stressors causes an array of biochemical, physiological and behavioral changes in the brain (Martı´
* Corresponding author. Tel.: þ98 0311 7922407; fax: þ98 0311 6688597. E-mail address: [email protected] (H. Alaei).
et al., 1994). It has previously been reported that chronic stress impairs neuronal plasticity (Krishnan and Nestler, 2008), learning (Radahmadi et al., 2013b) and memory processes (Bowman et al., 2003) via glucocorticoids (Heffelfinger and Newcomer, 2001). Also, it could affect the onset or degree of cognitive dysfunction and psychopathology disorders (Krishnan and Nestler, 2008). In this regard, stress acts via different mechanisms such as, cell damage of, DNA, genes, changes of various receptors and their mRNA levels (e.g. receptors of glucocorticoids,
http://dx.doi.org/10.1016/j.jbmt.2014.04.007 1360-8592/ª 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Radahmadi, M., et al., Preventive and therapeutic effect of treadmill running on chronic stress-induced memory deficit in rats, Journal of Bodywork & Movement Therapies (2014), http://dx.doi.org/10.1016/j.jbmt.2014.04.007
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2 glutamate and GABA), synaptic transmission, and neurotransmitters, inhibition of LTP and many other mechanisms that can directly affect brain functions on learning and memory (Calabrese et al., 2012; Fontella et al., 2005; Harvey et al., 2004; Liu et al., 1996; Popoli et al., 2012; Schwendt and Jezova, 2000). In contrast, previous studies indicated that physical activity has beneficial and neuroprotective effects on brain function. Exercise leads to changes at neuronal activity, synaptic structure and the synthesis of neurotransmitters which are important in memory processing (Shen et al., 2001). It has been documented that some kinds of physical activities improve passive avoidance memory and spatial learning (Alaei et al., 2006; Chen and Shen, 2002; Huang et al., 2006). However, the relationship between physical activity and cognitive function remains unclear. Since humans cannot spend much time during the day for exercise (Radak et al., 2006), treadmill running is more similar to human exercise training. Therefore, treadmill running was used in this experiment because it has the feature that allows animals to run only for a limited time per day. There are few studies that have systematically investigated the association between physical activity and stress effect on cognitive function. Some researchers demonstrated that running activity reversed harmful stress effects. It enhanced learning and memory in the open field and Morris water tasks and improved object recognition memory in the temporal order task (Grace et al., 2009; Zheng et al., 2006). We previously reported that although treadmill running alone has beneficial effects on learning and memory consolidation, that when synchronized with stress there are no significant protective effects on chronic stress-induced memory deficit (Radahmadi et al., 2013a,b). Based on this information, the aim of this study was to investigate the effects of long-term treadmill running (before, after and continual) on chronic stress-induced memory deficit by the passive avoidance task. The best time for exercise on improvement of memory impairment in stressed rats was investigated. Also, the effect of time depending on exercise on memory in stressed rats to prevent the onset or degree of psychopathology disorders is established.
M. Radahmadi et al. the rats. Also, environmental factors (such as cage size, colony grouping, room humidity, and background noise levels) were completely similar in all groups. All behavioral experiments (passive avoidance test) were carried out at 13:00e14:00 h. The experiment lasted for 42 days and passive avoidance test was performed after 21 days in all groups (Fig. 1). Rats were randomly divided into seven groups (n Z 10 in each group) as follows: 1 Control group (Co); rats were transported to the laboratory room and handled similarly to the experimental animals throughout the study period with no special treatment. 2 Sham group (Sh); rats were put on the treadmill without running for 1 h/day for 21 days. 3 Stress before rest group (SeR); chronic restraint stress was applied 6 h/day for 21 days, then the rats remained undisturbed in the cage for 21 days (they had a recovery period). 4 Stress after rest group (ReS); rats had no special treatment for 21 days, and then chronic restraint stress was applied 6 h/day for 21 days. 5 ExerciseeStress group (EeS); rats were exercised for 21 days before applying 21 days stress. 6 StresseExercise group (SeE), rats were under stress for 21 days then exercised for 21 days. 7 ExerciseeStress & Exercise (EeSE); rats were exercised continually (before and associated with stress), exercise for 21 days, and then the rats had 21 days stress and exercise together to investigate continuous exercise effects. All experiments were performed during the light period of the circadian cycle.
Experimental procedures Stress paradigms In the current study, rats were placed in Plexiglas cylindrical restrainers and fitted tightly there for 6 h/day
Materials and methods Experimental animals Experiments were performed on 70 male Wistar rats, with an initial weight of 250e300 g obtained from Jondishapour Institute, Ahvaz, Iran. All the experimental protocols were approved by the Ethics Committee of the Isfahan University of Medical Science (Isfahan, Iran), followed by the “Principles of laboratory animal care” and carried out in accordance with the European Communities Council Directive of 24 November 1986 (86/609/EEC). Five rats were housed in each cage, under light-controlled condition (12-h light/dark; lights on 07:00e19:00 h) in a room with a temperature of 22 2 C and humidity (55 10%). Food and water were available ad libitum, except during the stressing procedure. In addition, to prevent any human interactions, only one person was responsible for handling
Figure 1 Schematic diagram of different groups. Co: Control (ResteRest) group; SeR: StresseRest group; ReS: ResteStress; EeS: Exerciseestress group; SeE: StresseExercise group; EeSE: ExerciseeStress & Exercise group.
Please cite this article in press as: Radahmadi, M., et al., Preventive and therapeutic effect of treadmill running on chronic stress-induced memory deficit in rats, Journal of Bodywork & Movement Therapies (2014), http://dx.doi.org/10.1016/j.jbmt.2014.04.007
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Treadmill running and chronic stress on memory for 21 days in the chronic stress model. It was not possible for them to move or turn around. Hence, restraint was a powerful stressor in rats (Avishai-Eliner et al., 2001). The experimental period was between 8:00 am and 14:00 pm. Exercise paradigms The exercise protocol consisted of 1 h/day for 6 consecutive days at 20e21 m/min, 0 slope, for 21 days running. For adaptation, three days before training, animals were left on the treadmill for 60 min once a day while the treadmill was turned off. Rats ran on the treadmill during the morning (between 07:00 and 8:00 h). They were forced to run at the speed of the treadmill and received a mild electric shock from the grid, located just behind the treadmill. Electric shocks were used sparingly to motivate the animals to run. The stress associated with the likelihood of getting shock was controlled by exposing the sham groups to the treadmill apparatus without switching on the treadmill. These rats would receive the same electric shock when they stepped onto the grid. Behavioral apparatus and method Aversive learning was evaluated by passive avoidance task .The passive avoidance test has been widely used to evaluate rodent working memory ability in association with cortical and hippocampal functions (Crawley, 2007) and this test, based on negative reinforcement (Dhingra et al., 2004), was used to examine the short, mid and long-term memory. The passive avoidance (PA) task determines the ability of a rat to remember a foot shock delivered for 1, 7 and 21days (Alaei et al., 2008). The passive avoidance (PA) apparatus (Shuttle box 75 20 15 cm) was divided into two compartments that had a grid floor and wooden walls. It consisted of a small light compartment (25 25 20 cm) and a larger dark compartment (50 25 20 cm). The two compartments were separated by a sliding guillotine door. After 21 days of experiment (Fig. 1), first, each rat was placed in the apparatus without the electric shock for 5 min to habituate to the apparatus. On a later day, a single acquisition trial was performed. Accordingly, rats were placed individually in the light compartment for 1 min and then the guillotine door was raised, when the rat entered the dark compartment the door was closed and an inescapable scrambled single foot electric shock (50 Hz, 0.2 mA, 3 s) was delivered through the grid floor by an isolated stimulator. In probe trials, the rat was placed in the light compartment again with access to the dark compartment without any shock. The delay to enter the dark compartment from light compartment was recorded as latency (up to a maximum of 300 s); each rat had three trial sessions in 1, 7 and 21 days after receiving foot shock of passive avoidance test (Hosseini et al., 2013). In general, there were three probe trials of passive avoidance assessment for three different days (one probe trial/each day). In the current study, days 1, 7 and 21 were named with respect to probe trials (retention times). If an animal did not enter the dark compartment within 300 s, the trial was terminated (Wang and Cai, 2008). Absence of entry to the dark compartment or a longer duration in the light compartment indicated a positive response (Kumar et al., 2009). The PA task
3 determined the ability of a rat to remember the foot shock. Absence of entry to the dark compartment or a longer duration in the light compartment indicated a positive response (Kumar et al., 2009). Estimation of body weight Body weights of animals were measured on days 1, 21 and 42 of the experiment. Moreover, body weight differences (BWDInitial Z BW21Days BW1Day) and (BWDFinal Z BW42Days BW21Days) were evaluated.
Data analysis Since data of the latency of entrance to the dark compartment (1, 7 and 21 days) in the passive avoidance test was not normal, nonparametric tests were used. These latencies (between groups) were compared using a KruskaleWallis nonparametric one-way analysis of variance corrected for ties, followed by a two-tailed ManneWhitney U test with groups as the independent variable, and performance in each session (the latency to enter the dark chamber after 1, 7 and 21 days) as the dependent variable. The comparisons of retention time in 1, 7 and 21 days after foot shock (within groups) were analyzed by Friedman test, followed by a Wilcoxon signed ranks test. Behavioral values are presented as mean SD. Initial and final body weight differences were analyzed by ANOVA followed by Tukey’s post hoc test for multiple groups. Body weight data are reported as the mean SD. Two-tailed P-values less than 0.05 (P < 0.05) were considered as significant. Calculations were performed using SPSS 19 software (SPSS Inc., Chicago, Illinois, USA).
Results The latency of entrance to dark compartment The latency of each three trials in different time intervals (1, 7 and 21 days after an electrical foot shock) showed no significant (P > 0.05) difference between control (Co) and sham (Sh) groups, indicating that the treadmill electrical shock had no significant effect on latency of each of the three trials (Fig. 2). There were significant (KruskaleWallis, ManneWhitney: P < 0.05) differences on probe trial days 1 and 21, but not on trial day 7 compared to ExerciseeStress group (EeS) with the Co group (Fig. 3). The latency of EeS group had significant (P < 0.01 and P < 0.001; respectively) enhancement during the first and second trials (1 and 7 days after foot shock), whereas there was no significant (P > 0.05) difference during the third trial (21 days after foot shock) compared to ResteStress group (ReS) (Fig. 3). In ExerciseeStress & Exercise (EeSE) group, each three probe trials did not show significant differences compared to the Co group (Fig. 3). Fig. 3 shows that in EeSE group, there was no significant (P < 0.05) difference in latency of day 1 compared to EeS group (Fig. 4), whereas the latencies of days 7 and 21 in EeSE group were significantly more than the EeS group (P < 0.05 and P < 0.001, respectively) (Fig. 3).
Please cite this article in press as: Radahmadi, M., et al., Preventive and therapeutic effect of treadmill running on chronic stress-induced memory deficit in rats, Journal of Bodywork & Movement Therapies (2014), http://dx.doi.org/10.1016/j.jbmt.2014.04.007
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Figure 2 Latencies to entrance of the dark compartment of passive avoidance apparatus during memory retention test 1, 7 and 21 days after receiving foot shock in control and sham groups (n Z 10). Results are expressed as mean SD (KruskaleWallis test, ManneWhitney U test; There was no significant (P > 0.05) difference between these groups in each of the three trials. Co: Control group; Sh: Sham group.
M. Radahmadi et al.
Figure 4 Latencies to entrance of the dark compartment of passive avoidance apparatus during memory retention test 1, 7 and 21 days after receiving electrical foot shock in different groups (between groups, n Z 10). Results are expressed as mean SD (KruskaleWallis test, ManneWhitney U test; )P < 0.05 when compared to the Co group; qP 0.05) difference in comparison to the SeR group (Fig. 4).
The latencies of each of the three trials were analyzed by related sample to evaluate within group latency changes; hence in this study, latency of 1 day vs. days, 7 days vs. 21 days and 1 day vs. 21 days were compared (Fig. 5). In this part, data showed that there were not significant (Friedman, Wilcoxon: P > 0.05) differences in latencies 1 vs. 7 days, 7 vs. 21 and 1 vs. 21 days after receiving the electrical foot shock in Co with Sham and SeE groups (Fig. 5).
Figure 3 Latencies to entrance of the dark compartment of passive avoidance apparatus during memory retention test 1, 7 and 21 days after receiving electrical foot shock in different groups (between groups, n Z 10). Results are expressed as mean SD (KruskaleWallis test, ManneWhitney U test; )P < 0.05, ))P < 0.01, )))P < 0.001 when compared to the Co group; VVP < 0.01 and VVVP < 0.001 when compared to the ReS group; DP 0.05) differences between Co and Sh groups in body weight difference (BWDInitial Z BW21Days BW1Day and BWDFinal Z BW42DayseBW21Days), indicating that the treadmill electrical shock had no significant effect in these parameters (Graph is not shown). As shown in Fig. 6, the BWDInitial had significant (P < 0.01; in both them) decreases in EeS and EeSE groups compared to Co and ReS groups. Also, the BWDInitial showed significant (P < 0.01) decreases only in EeS group compared to ReS groups (Fig. 6). In EeS and EeSE groups, the BWDFinal was significantly (P < 0.05 and P < 0.01; respectively) lower than Co group (Fig. 6). In EeS group, the BWDFinal was significantly (P < 0.05) higher than ReS group (Fig. 6). The BWDFinal had significant (P < 0.05) differences in EeSE group compared to EeS group (Fig. 6), indicating that associated running activity with stress causes more weight loss than merely stress. As shown in Fig. 7, the BWDInitial had significant (P < 0.001) decreases in SeE group compared to Co group. However, this group did not show significant differences in the BWDInitial in comparison to the SeR group.
Figure 7 Comparison of body weight differences (BWDInitial Z BW21Days BW1Day and BWDFinal Z BW42Days e BW21Days) in different groups (n Z 10). Results are expressed as mean SEM (ANOVA test, Tukey’s post hoc test; )P < 0.05 and )))P < 0.001 when compared to the Co group; qP < 0.05 when compared to the SeR group in BWDInitial and BWDFinal, separately; ¢¢P < 0.01 when BWDInitial compared to the BWDFinal in similar groups). Co: Control (ResteRest) group; SeR: StresseRest group; SeE: StresseExercise group.
In SeE group, the BWDFinal was significantly (P < 0.05; in both them) lower than Co and SeR groups (Fig. 7), indicating exercise effect after chronic psychical stress on body weight gain. In the current study, the BWDFinal did not show significant (P > 0.05) differences compared to the BWDInitial in EeS, EeSE and SeE groups (Figs. 6 and 7).
Discussion
Figure 6 Comparison of body weight differences (BWDInitial Z BW21Days BW1Day and BWDFinal Z BW42Days BW21Days) in different groups (n Z 10). Results are expressed as mean SEM (ANOVA test, Tukey’s post hoc test; )P < 0.05 and ))P < 0.01 when compared to the Co group; qP < 0.05 and qq P < 0.01 when compared to the SeR group; DP < 0.05 when compared to the EeS group in BWDInitial and BWDFinal, separately; ¢¢¢P < 0.001 when BWDInitial compared to the BWDFinal in similar groups). Co: Control (ResteRest) group; ReS: ResteStress; EeS: ExerciseeStress group; EeSE: ExerciseeStress & Exercise group.
We and other researchers previously reported that chronic stress is a negative modulator of learning and memory process (McEwen and Sapolsky, 1995; Sandi and PineloNava, 2007). Therefore stress can probably impair cognitive processes (e.g. learning and memory) via disturbances in multiple systems such as changes of glucocorticoids (Heffelfinger and Newcomer, 2001) brain derived neurotrophic factor (BDNF) (Falkenberg et al., 1992; Yamada and Nabeshima, 2003), cholinergic system (Gold, 2003), 5-HT system (Chen et al., 2008), free radical formation (Mates et al., 1999; Onodera et al., 2003) and other transmitters that involve learning and memory (Kim and Diamond, 2002; Mizoguchi et al., 2000). Our previous results unexpectedly revealed that synchronized exercise with stress (exercise along with stress at one time period) partially enhanced short, mid and long-term memory (Radahmadi et al., 2013a). Therefore, associated exercise with stress did not have significant protective effects on encountering memory impairment in stressed rats and can probably prevent more serious damage of brain induced by chronic stress. Hence, the dual effects of stress along with exercise may create conflicting physiological changes (Radahmadi et al., 2013a). In this study, the effect of different timing of exercise with respect to chronic stress on memory was examined. Therefore, running activity was induced before and after
Please cite this article in press as: Radahmadi, M., et al., Preventive and therapeutic effect of treadmill running on chronic stress-induced memory deficit in rats, Journal of Bodywork & Movement Therapies (2014), http://dx.doi.org/10.1016/j.jbmt.2014.04.007
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6 chronic stress for 21 days (transitional exercise) and for 42 days (regular continual exercise) on improvement of memory deficit in stressed rats (Figs. 3e5). Our results revealed that exercise before stress (EeS group) had a significant effect on improvement in memory deficits during both the short and mid-term memory when compared to the ReS group (Fig. 4); whereas the effect of exercise before stress did not remain until the end of experimental period (Fig. 3). It is suggested that chronic stress has a much greater effect than running activity on long term-memory (the probe trial of day 21) that can overcome beneficial effects of running activity. Therefore, exercise before stress had a preventive effect on stressinduced memory impairment but ultimately it could not improve cognitive function for a long period. Similarly, Radak and coworkers (Radak et al., 2006) proposed that exercise training (swimming) increased the memory of rats in passive avoidance test, but this enhancement was temporary after stopping exercise. Other results demonstrated improvement of memory deficit in EeSE group compared to EeS group (Fig. 3). Hence, if animals continued running activity during stress period (EeSE group), chronic stress would not disrupt the beneficial effect of physical activity on memory. It should be noted that the kinds of memories had no significant enhancement compared to control group (Fig. 3). This suggests that although regular continual exercise is better than preventive effects of exercise, it only recompenses harmful stress effect on memory. Our data also showed that exercise after stress (SeE group) had a significant improvement on mid and long-term memory deficit which compensated memory deficit in stressed rats (Figs. 4 and 5). This suggests that exercise after stress can overcome stress-induced memory deficit, and is successful in removing most of the chronic stress effects on potential process of memory impairments over a long time period. Some researchers have shown that exercise can enhance both cognition and neuron proliferation (Alaei et al., 2006; Van Praag et al., 1999a) or decrease cell death (Kim et al., 2002). Other beneficial mechanisms of exercise may relate to increased antioxidant enzymes activity by regular physical activity (Radak et al., 2001) and down regulation of glucocorticoids receptors (Hwang et al., 2011; Zheng et al., 2006). It is indicated that exercise alters the release of some hormones and neurotransmitters and/or increases neurotrophic factors, muscarinic receptor density, acetylcholine release in the memory regions (Van Praag et al., 1999b). Previous studies suggested that aerobic exercise such as repetitive running can promote angiogenesis in the animal’s brain (Foster et al., 2011; Swain et al., 2003). Our findings also indicated that memory had an ascending trend with the passage of time only in exercise after stress group. The therapeutic protocol of exercise decreases the sensitivity to the stress effects (Fig. 5). It seems that treadmill running after stress is better than other protocols of physical activity in our previous and current studies. It can probably reduce damage to the brain in individuals and can prevent other disorders due to chronic stress. Some studies reported that physical activity protects neurons from various brain damages and had beneficial effects on neural health and function (Carro et al., 2001; Tillerson et al., 2003). Similarly, several
M. Radahmadi et al. studies have indicated that exercise can increase the speed of learning and memory and improve cognitive performance (Fabre et al., 2002; Van Praag et al., 1999a). Chen et al. (Chen et al., 2008) showed that treadmill exercise training facilitated passive avoidance aversive learning; but Barnes et al. (Barnes et al., 1991) did not observe any beneficial effects of exercise on memory. Overall, previous human and animal studies indicated that physical activity has neuroprotective effects on brain function. It has been documented that some kinds of physical activity such as swimming, voluntary wheel running and treadmill running improve passive avoidance memory and spatial learning (Alaei et al., 2006; Chen and Shen, 2002; Huang et al., 2006). Therefore, exercise probably enhances memory and cognitive function via different mechanisms. Some researchers reported that in the brain, physical activity caused biochemical and structural changes including changes in neuronal activity and synaptic structure (Shen et al., 2001; Uysal et al., 2005), enhancing the neuron number (Churchill et al., 2002), increasing the length and number of dendrites connection between neurons, as well as synaptic plasticity in different regions of CNS such as hippocampus, which is involved in memory (Stranahan et al., 2007; Van Praag et al., 1999b). Finally, our finding proposes that time of exercise with respect to stress period is considerable and the best time for the best effects of training is exercise after stress (Fig. 5). Hence, it implies that the influence of exercise in stressful conditions was probably time-dependent on memory estimated by passive avoidance performance. It is suggested that the effects of exercise on different aspects of cognition may depend on factors such as the duration of exercise, type of exercise performed (e.g. forced vs. voluntary), task difficulty, or other variables that have not yet been defined (Berchtold et al., 2010). We previously reported that body weight decreased in emotional stress conditions (Radahmadi et al., 2006) via release of catabolic hormones, the amount of food ingested (Martı´ et al., 1994), and decline of fatty mass and leptin (Chandralekha et al., 2005). In the current study, when BWDFinal and BWDInitial were compared, we observed that chronic stress has a much greater effect than exercise on body weight loss, whereas these comparisons did not have real differences in EeS, EeSE and SeE groups. HoffmanGoetz et al. (Hoffman-Goetz and MacDonald, 1983) reported weight loss was observed following exercise and it is mediated through an increased energy expenditure. In conclusion, our results at the behavioral level emphasize the hypothesis that running activity plays a pivotal and beneficial role in the improvement of chronic stress-induced memory deficit. It seems that in particular, exercise after stress is the best program of exercise. Therefore it is proposed that a strong corollary exists between stress-induced memory deficit and the exercise time. Therefore, to exercise is time-dependent in stress condition. This implies that physical activity enhanced memory functions probably via the activation of some mechanisms in regions of the brain that are involved with memory. Also, chronic stress has a much greater effect than exercise on body weight loss, although initial and final body weight differences in EeS, EeSE and SeE groups did not have any real differences. This suggests that
Please cite this article in press as: Radahmadi, M., et al., Preventive and therapeutic effect of treadmill running on chronic stress-induced memory deficit in rats, Journal of Bodywork & Movement Therapies (2014), http://dx.doi.org/10.1016/j.jbmt.2014.04.007
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Treadmill running and chronic stress on memory further research is needed to determine memory mechanisms such as signaling system in the different phases of memory.
Acknowledgments This research was supported by Isfahan University of Medical Sciences, Isfahan, Iran.
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8 Onodera, K., Omoi, N.O., Fukui, K., Hayasaka, T., Shinkai, T., Suzuki, S., Abe, K., Urano, S., 2003. Oxidative damage of rat cerebral cortex and hippocampus, and changes in antioxidative defense systems caused by hyperoxia. Free Radic. Res. 37, 367e372. Popoli, M., Yan, Z., McEwen, B.S., Sanacora, G., 2012. The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission. Nat. Rev. Neurosci. 13, 22e37. Radahmadi, M., Alaei, H., Sharifi, M.R., Hosseini, N., 2013a. The effect of synchronized forced running with chronic stress on short, mid and long- term memory in rats. Asian J. Sports Med. 4, 54e62. Radahmadi, M., Alaei, H., Sharifi, M.R., Hosseini, N., 2013b. The effect of synchronized running activity with chronic stress on passive avoidance learning and body weight in rats. Int. J. Prev. Med. 4, 430e437. Radahmadi, M., Shadan, F., Karimian, S.M., Sadr, S.S., Nasimi, A., 2006. Effects of stress on exacerbation of diabetes mellitus, serum glucose and cortisol levels and body weight in rats. Pathophysiology 13, 51e55. Radak, Z., Kaneko, T., Tahara, S., Nakamoto, H., Pucsok, J., Sasvari, M., Nyakas, C., Goto, S., 2001. Regular exercise improves cognitive function and decreases oxidative damage in rat brain. Neurochem. Int. 38, 17e23. Radak, Z., Toldy, A., Szabo, Z., Siamilis, S., Nyakas, C., Silye, G., Jakus, J., Goto, S., 2006. The effects of training and detraining on memory, neurotrophins and oxidative stress markers in rat brain. Neurochem. Int. 49, 387e392. Sandi, C., Pinelo-Nava, M.T., 2007. Stress and memory: behavioral effects and neurobiological mechanisms. Neural Plast., 1e20. Schwendt, M., Jezova, D., 2000. Gene expression of two glutamate receptor subunits in response to repeated stress exposure in rat hippocampus. Cell. Mol. Neurobiol. 20, 319e329. Shen, H., Tong, L., Balazs, R., Cotman, C.W., 2001. Physical activity elicits sustained activation of the cyclic AMP response element-binding protein and mitogen-activated protein kinase in the rat hippocampus. Neuroscience 107, 219e229.
M. Radahmadi et al. Stranahan, A.M., Khalil, D., Gould, E., 2007. Running induces widespread structural alterations in the hippocampus and entorhinal cortex. Hippocampus 17, 1017e1022. Swain, R.A., Harris, A.B., Wiener, E.C., Dutka, M.V., Morris, H.D., Theien, B.E., Konda, S., Engberg, K., Lauterbur, P.C., Greenough, W.T., 2003. Prolonged exercise induces angiogenesis and increases cerebral blood volume in primary motor cortex of the rat. Neuroscience 117, 1037e1046. Tillerson, J.L., Caudle, W.M., Reveron, M.E., Miller, G.W., 2003. Exercise induces behavioral recovery and attenuates neurochemical deficits in rodent models of Parkinson’s disease. Neuroscience 119, 899e911. Uysal, N., Tugyan, K., Kayatekin, B.M., Acikgoz, O., Bagriyanik, H.A., Gonenc, S., Ozdemir, D., Aksu, I., Topcu, A., Semin, I., 2005. The effects of regular aerobic exercise in adolescent period on hippocampal neuron density, apoptosis and spatial memory. Neurosci. Lett. 383, 241e245. Van Praag, H., Christie, B.R., Sejnowski, T.J., Gage, F.H., 1999a. Running enhances neurogenesis, learning, and long-term potentiation in mice. Proc. Natl. Acad. Sci. U S A 96, 13427e13431. Van Praag, H., Kempermann, G., Gage, F.H., 1999b. Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat. Neurosci. 2, 266e270. Wang, G.W., Cai, J.X., 2008. Reversible disconnection of the hippocampal-prelimbic cortical circuit impairs spatial learning but not passive avoidance learning in rats. Neurobiol. Learn. Mem. 90, 365e373. Yamada, K., Nabeshima, T., 2003. Brain-derived neurotrophic factor/TrkB signaling in memory processes. J. Pharmacol. Sci. 91, 267e270. Zheng, H., Liu, Y., Li, W., Yang, B., Chen, D., Wang, X., Jiang, Z., Wang, H., Wang, Z., Cornelisson, G., 2006. Beneficial effects of exercise and its molecular mechanisms on depression in rats. Behav. Brain Res. 168, 47e55.
Please cite this article in press as: Radahmadi, M., et al., Preventive and therapeutic effect of treadmill running on chronic stress-induced memory deficit in rats, Journal of Bodywork & Movement Therapies (2014), http://dx.doi.org/10.1016/j.jbmt.2014.04.007
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Journal of Bodywork & Movement Therapies (2014) xx, 1e8
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ORIGINAL RESEARCH
Preventive and therapeutic effect of treadmill running on chronic stress-induced memory deficit in rats Maryam Radahmadi, PhD , Hojjatallah Alaei, PhD*, Mohammad Reza Sharifi, PhD , Nasrin Hosseini, PhD Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran Received 13 January 2014; received in revised form 28 March 2014; accepted 9 April 2014
KEYWORDS Memory; Exercise; Chronic stress; Passive avoidance; Rat
Summary Previous results indicated that stress impairs learning and memory. In this research, the effects of preventive, therapeutic and regular continually running activity on chronic stress-induced memory deficit in rats were investigated. 70 male rats were randomly divided into seven groups as follows: Control, Sham, StresseRest, ResteStress, StresseExercise, ExerciseeStress and ExerciseeStress & Exercise groups. Chronic restraint stress was applied 6 h/day for 21days and treadmill running 1 h/day. Memory function was evaluated by the passive avoidance test. The results revealed that running activities had therapeutic effect on mid and long-term memory deficit and preventive effects on short and mid-term memory deficit in stressed rats. Regular continually running activity improved mid and long-term memory compared to ExerciseeStress group. The beneficial effects of exercise were time-dependent in stress conditions. Finally, data corresponded to the possibility that treadmill running had a more important role on treatment rather than on prevention on memory impairment induced by stress. ª 2014 Elsevier Ltd. All rights reserved.
Introduction Exposure to stressors causes an array of biochemical, physiological and behavioral changes in the brain (Martı´
* Corresponding author. Tel.: þ98 0311 7922407; fax: þ98 0311 6688597. E-mail address: [email protected] (H. Alaei).
et al., 1994). It has previously been reported that chronic stress impairs neuronal plasticity (Krishnan and Nestler, 2008), learning (Radahmadi et al., 2013b) and memory processes (Bowman et al., 2003) via glucocorticoids (Heffelfinger and Newcomer, 2001). Also, it could affect the onset or degree of cognitive dysfunction and psychopathology disorders (Krishnan and Nestler, 2008). In this regard, stress acts via different mechanisms such as, cell damage of, DNA, genes, changes of various receptors and their mRNA levels (e.g. receptors of glucocorticoids,
http://dx.doi.org/10.1016/j.jbmt.2014.04.007 1360-8592/ª 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Radahmadi, M., et al., Preventive and therapeutic effect of treadmill running on chronic stress-induced memory deficit in rats, Journal of Bodywork & Movement Therapies (2014), http://dx.doi.org/10.1016/j.jbmt.2014.04.007
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2 glutamate and GABA), synaptic transmission, and neurotransmitters, inhibition of LTP and many other mechanisms that can directly affect brain functions on learning and memory (Calabrese et al., 2012; Fontella et al., 2005; Harvey et al., 2004; Liu et al., 1996; Popoli et al., 2012; Schwendt and Jezova, 2000). In contrast, previous studies indicated that physical activity has beneficial and neuroprotective effects on brain function. Exercise leads to changes at neuronal activity, synaptic structure and the synthesis of neurotransmitters which are important in memory processing (Shen et al., 2001). It has been documented that some kinds of physical activities improve passive avoidance memory and spatial learning (Alaei et al., 2006; Chen and Shen, 2002; Huang et al., 2006). However, the relationship between physical activity and cognitive function remains unclear. Since humans cannot spend much time during the day for exercise (Radak et al., 2006), treadmill running is more similar to human exercise training. Therefore, treadmill running was used in this experiment because it has the feature that allows animals to run only for a limited time per day. There are few studies that have systematically investigated the association between physical activity and stress effect on cognitive function. Some researchers demonstrated that running activity reversed harmful stress effects. It enhanced learning and memory in the open field and Morris water tasks and improved object recognition memory in the temporal order task (Grace et al., 2009; Zheng et al., 2006). We previously reported that although treadmill running alone has beneficial effects on learning and memory consolidation, that when synchronized with stress there are no significant protective effects on chronic stress-induced memory deficit (Radahmadi et al., 2013a,b). Based on this information, the aim of this study was to investigate the effects of long-term treadmill running (before, after and continual) on chronic stress-induced memory deficit by the passive avoidance task. The best time for exercise on improvement of memory impairment in stressed rats was investigated. Also, the effect of time depending on exercise on memory in stressed rats to prevent the onset or degree of psychopathology disorders is established.
M. Radahmadi et al. the rats. Also, environmental factors (such as cage size, colony grouping, room humidity, and background noise levels) were completely similar in all groups. All behavioral experiments (passive avoidance test) were carried out at 13:00e14:00 h. The experiment lasted for 42 days and passive avoidance test was performed after 21 days in all groups (Fig. 1). Rats were randomly divided into seven groups (n Z 10 in each group) as follows: 1 Control group (Co); rats were transported to the laboratory room and handled similarly to the experimental animals throughout the study period with no special treatment. 2 Sham group (Sh); rats were put on the treadmill without running for 1 h/day for 21 days. 3 Stress before rest group (SeR); chronic restraint stress was applied 6 h/day for 21 days, then the rats remained undisturbed in the cage for 21 days (they had a recovery period). 4 Stress after rest group (ReS); rats had no special treatment for 21 days, and then chronic restraint stress was applied 6 h/day for 21 days. 5 ExerciseeStress group (EeS); rats were exercised for 21 days before applying 21 days stress. 6 StresseExercise group (SeE), rats were under stress for 21 days then exercised for 21 days. 7 ExerciseeStress & Exercise (EeSE); rats were exercised continually (before and associated with stress), exercise for 21 days, and then the rats had 21 days stress and exercise together to investigate continuous exercise effects. All experiments were performed during the light period of the circadian cycle.
Experimental procedures Stress paradigms In the current study, rats were placed in Plexiglas cylindrical restrainers and fitted tightly there for 6 h/day
Materials and methods Experimental animals Experiments were performed on 70 male Wistar rats, with an initial weight of 250e300 g obtained from Jondishapour Institute, Ahvaz, Iran. All the experimental protocols were approved by the Ethics Committee of the Isfahan University of Medical Science (Isfahan, Iran), followed by the “Principles of laboratory animal care” and carried out in accordance with the European Communities Council Directive of 24 November 1986 (86/609/EEC). Five rats were housed in each cage, under light-controlled condition (12-h light/dark; lights on 07:00e19:00 h) in a room with a temperature of 22 2 C and humidity (55 10%). Food and water were available ad libitum, except during the stressing procedure. In addition, to prevent any human interactions, only one person was responsible for handling
Figure 1 Schematic diagram of different groups. Co: Control (ResteRest) group; SeR: StresseRest group; ReS: ResteStress; EeS: Exerciseestress group; SeE: StresseExercise group; EeSE: ExerciseeStress & Exercise group.
Please cite this article in press as: Radahmadi, M., et al., Preventive and therapeutic effect of treadmill running on chronic stress-induced memory deficit in rats, Journal of Bodywork & Movement Therapies (2014), http://dx.doi.org/10.1016/j.jbmt.2014.04.007
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Treadmill running and chronic stress on memory for 21 days in the chronic stress model. It was not possible for them to move or turn around. Hence, restraint was a powerful stressor in rats (Avishai-Eliner et al., 2001). The experimental period was between 8:00 am and 14:00 pm. Exercise paradigms The exercise protocol consisted of 1 h/day for 6 consecutive days at 20e21 m/min, 0 slope, for 21 days running. For adaptation, three days before training, animals were left on the treadmill for 60 min once a day while the treadmill was turned off. Rats ran on the treadmill during the morning (between 07:00 and 8:00 h). They were forced to run at the speed of the treadmill and received a mild electric shock from the grid, located just behind the treadmill. Electric shocks were used sparingly to motivate the animals to run. The stress associated with the likelihood of getting shock was controlled by exposing the sham groups to the treadmill apparatus without switching on the treadmill. These rats would receive the same electric shock when they stepped onto the grid. Behavioral apparatus and method Aversive learning was evaluated by passive avoidance task .The passive avoidance test has been widely used to evaluate rodent working memory ability in association with cortical and hippocampal functions (Crawley, 2007) and this test, based on negative reinforcement (Dhingra et al., 2004), was used to examine the short, mid and long-term memory. The passive avoidance (PA) task determines the ability of a rat to remember a foot shock delivered for 1, 7 and 21days (Alaei et al., 2008). The passive avoidance (PA) apparatus (Shuttle box 75 20 15 cm) was divided into two compartments that had a grid floor and wooden walls. It consisted of a small light compartment (25 25 20 cm) and a larger dark compartment (50 25 20 cm). The two compartments were separated by a sliding guillotine door. After 21 days of experiment (Fig. 1), first, each rat was placed in the apparatus without the electric shock for 5 min to habituate to the apparatus. On a later day, a single acquisition trial was performed. Accordingly, rats were placed individually in the light compartment for 1 min and then the guillotine door was raised, when the rat entered the dark compartment the door was closed and an inescapable scrambled single foot electric shock (50 Hz, 0.2 mA, 3 s) was delivered through the grid floor by an isolated stimulator. In probe trials, the rat was placed in the light compartment again with access to the dark compartment without any shock. The delay to enter the dark compartment from light compartment was recorded as latency (up to a maximum of 300 s); each rat had three trial sessions in 1, 7 and 21 days after receiving foot shock of passive avoidance test (Hosseini et al., 2013). In general, there were three probe trials of passive avoidance assessment for three different days (one probe trial/each day). In the current study, days 1, 7 and 21 were named with respect to probe trials (retention times). If an animal did not enter the dark compartment within 300 s, the trial was terminated (Wang and Cai, 2008). Absence of entry to the dark compartment or a longer duration in the light compartment indicated a positive response (Kumar et al., 2009). The PA task
3 determined the ability of a rat to remember the foot shock. Absence of entry to the dark compartment or a longer duration in the light compartment indicated a positive response (Kumar et al., 2009). Estimation of body weight Body weights of animals were measured on days 1, 21 and 42 of the experiment. Moreover, body weight differences (BWDInitial Z BW21Days BW1Day) and (BWDFinal Z BW42Days BW21Days) were evaluated.
Data analysis Since data of the latency of entrance to the dark compartment (1, 7 and 21 days) in the passive avoidance test was not normal, nonparametric tests were used. These latencies (between groups) were compared using a KruskaleWallis nonparametric one-way analysis of variance corrected for ties, followed by a two-tailed ManneWhitney U test with groups as the independent variable, and performance in each session (the latency to enter the dark chamber after 1, 7 and 21 days) as the dependent variable. The comparisons of retention time in 1, 7 and 21 days after foot shock (within groups) were analyzed by Friedman test, followed by a Wilcoxon signed ranks test. Behavioral values are presented as mean SD. Initial and final body weight differences were analyzed by ANOVA followed by Tukey’s post hoc test for multiple groups. Body weight data are reported as the mean SD. Two-tailed P-values less than 0.05 (P < 0.05) were considered as significant. Calculations were performed using SPSS 19 software (SPSS Inc., Chicago, Illinois, USA).
Results The latency of entrance to dark compartment The latency of each three trials in different time intervals (1, 7 and 21 days after an electrical foot shock) showed no significant (P > 0.05) difference between control (Co) and sham (Sh) groups, indicating that the treadmill electrical shock had no significant effect on latency of each of the three trials (Fig. 2). There were significant (KruskaleWallis, ManneWhitney: P < 0.05) differences on probe trial days 1 and 21, but not on trial day 7 compared to ExerciseeStress group (EeS) with the Co group (Fig. 3). The latency of EeS group had significant (P < 0.01 and P < 0.001; respectively) enhancement during the first and second trials (1 and 7 days after foot shock), whereas there was no significant (P > 0.05) difference during the third trial (21 days after foot shock) compared to ResteStress group (ReS) (Fig. 3). In ExerciseeStress & Exercise (EeSE) group, each three probe trials did not show significant differences compared to the Co group (Fig. 3). Fig. 3 shows that in EeSE group, there was no significant (P < 0.05) difference in latency of day 1 compared to EeS group (Fig. 4), whereas the latencies of days 7 and 21 in EeSE group were significantly more than the EeS group (P < 0.05 and P < 0.001, respectively) (Fig. 3).
Please cite this article in press as: Radahmadi, M., et al., Preventive and therapeutic effect of treadmill running on chronic stress-induced memory deficit in rats, Journal of Bodywork & Movement Therapies (2014), http://dx.doi.org/10.1016/j.jbmt.2014.04.007
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Figure 2 Latencies to entrance of the dark compartment of passive avoidance apparatus during memory retention test 1, 7 and 21 days after receiving foot shock in control and sham groups (n Z 10). Results are expressed as mean SD (KruskaleWallis test, ManneWhitney U test; There was no significant (P > 0.05) difference between these groups in each of the three trials. Co: Control group; Sh: Sham group.
M. Radahmadi et al.
Figure 4 Latencies to entrance of the dark compartment of passive avoidance apparatus during memory retention test 1, 7 and 21 days after receiving electrical foot shock in different groups (between groups, n Z 10). Results are expressed as mean SD (KruskaleWallis test, ManneWhitney U test; )P < 0.05 when compared to the Co group; qP 0.05) difference in comparison to the SeR group (Fig. 4).
The latencies of each of the three trials were analyzed by related sample to evaluate within group latency changes; hence in this study, latency of 1 day vs. days, 7 days vs. 21 days and 1 day vs. 21 days were compared (Fig. 5). In this part, data showed that there were not significant (Friedman, Wilcoxon: P > 0.05) differences in latencies 1 vs. 7 days, 7 vs. 21 and 1 vs. 21 days after receiving the electrical foot shock in Co with Sham and SeE groups (Fig. 5).
Figure 3 Latencies to entrance of the dark compartment of passive avoidance apparatus during memory retention test 1, 7 and 21 days after receiving electrical foot shock in different groups (between groups, n Z 10). Results are expressed as mean SD (KruskaleWallis test, ManneWhitney U test; )P < 0.05, ))P < 0.01, )))P < 0.001 when compared to the Co group; VVP < 0.01 and VVVP < 0.001 when compared to the ReS group; DP 0.05) differences between Co and Sh groups in body weight difference (BWDInitial Z BW21Days BW1Day and BWDFinal Z BW42DayseBW21Days), indicating that the treadmill electrical shock had no significant effect in these parameters (Graph is not shown). As shown in Fig. 6, the BWDInitial had significant (P < 0.01; in both them) decreases in EeS and EeSE groups compared to Co and ReS groups. Also, the BWDInitial showed significant (P < 0.01) decreases only in EeS group compared to ReS groups (Fig. 6). In EeS and EeSE groups, the BWDFinal was significantly (P < 0.05 and P < 0.01; respectively) lower than Co group (Fig. 6). In EeS group, the BWDFinal was significantly (P < 0.05) higher than ReS group (Fig. 6). The BWDFinal had significant (P < 0.05) differences in EeSE group compared to EeS group (Fig. 6), indicating that associated running activity with stress causes more weight loss than merely stress. As shown in Fig. 7, the BWDInitial had significant (P < 0.001) decreases in SeE group compared to Co group. However, this group did not show significant differences in the BWDInitial in comparison to the SeR group.
Figure 7 Comparison of body weight differences (BWDInitial Z BW21Days BW1Day and BWDFinal Z BW42Days e BW21Days) in different groups (n Z 10). Results are expressed as mean SEM (ANOVA test, Tukey’s post hoc test; )P < 0.05 and )))P < 0.001 when compared to the Co group; qP < 0.05 when compared to the SeR group in BWDInitial and BWDFinal, separately; ¢¢P < 0.01 when BWDInitial compared to the BWDFinal in similar groups). Co: Control (ResteRest) group; SeR: StresseRest group; SeE: StresseExercise group.
In SeE group, the BWDFinal was significantly (P < 0.05; in both them) lower than Co and SeR groups (Fig. 7), indicating exercise effect after chronic psychical stress on body weight gain. In the current study, the BWDFinal did not show significant (P > 0.05) differences compared to the BWDInitial in EeS, EeSE and SeE groups (Figs. 6 and 7).
Discussion
Figure 6 Comparison of body weight differences (BWDInitial Z BW21Days BW1Day and BWDFinal Z BW42Days BW21Days) in different groups (n Z 10). Results are expressed as mean SEM (ANOVA test, Tukey’s post hoc test; )P < 0.05 and ))P < 0.01 when compared to the Co group; qP < 0.05 and qq P < 0.01 when compared to the SeR group; DP < 0.05 when compared to the EeS group in BWDInitial and BWDFinal, separately; ¢¢¢P < 0.001 when BWDInitial compared to the BWDFinal in similar groups). Co: Control (ResteRest) group; ReS: ResteStress; EeS: ExerciseeStress group; EeSE: ExerciseeStress & Exercise group.
We and other researchers previously reported that chronic stress is a negative modulator of learning and memory process (McEwen and Sapolsky, 1995; Sandi and PineloNava, 2007). Therefore stress can probably impair cognitive processes (e.g. learning and memory) via disturbances in multiple systems such as changes of glucocorticoids (Heffelfinger and Newcomer, 2001) brain derived neurotrophic factor (BDNF) (Falkenberg et al., 1992; Yamada and Nabeshima, 2003), cholinergic system (Gold, 2003), 5-HT system (Chen et al., 2008), free radical formation (Mates et al., 1999; Onodera et al., 2003) and other transmitters that involve learning and memory (Kim and Diamond, 2002; Mizoguchi et al., 2000). Our previous results unexpectedly revealed that synchronized exercise with stress (exercise along with stress at one time period) partially enhanced short, mid and long-term memory (Radahmadi et al., 2013a). Therefore, associated exercise with stress did not have significant protective effects on encountering memory impairment in stressed rats and can probably prevent more serious damage of brain induced by chronic stress. Hence, the dual effects of stress along with exercise may create conflicting physiological changes (Radahmadi et al., 2013a). In this study, the effect of different timing of exercise with respect to chronic stress on memory was examined. Therefore, running activity was induced before and after
Please cite this article in press as: Radahmadi, M., et al., Preventive and therapeutic effect of treadmill running on chronic stress-induced memory deficit in rats, Journal of Bodywork & Movement Therapies (2014), http://dx.doi.org/10.1016/j.jbmt.2014.04.007
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6 chronic stress for 21 days (transitional exercise) and for 42 days (regular continual exercise) on improvement of memory deficit in stressed rats (Figs. 3e5). Our results revealed that exercise before stress (EeS group) had a significant effect on improvement in memory deficits during both the short and mid-term memory when compared to the ReS group (Fig. 4); whereas the effect of exercise before stress did not remain until the end of experimental period (Fig. 3). It is suggested that chronic stress has a much greater effect than running activity on long term-memory (the probe trial of day 21) that can overcome beneficial effects of running activity. Therefore, exercise before stress had a preventive effect on stressinduced memory impairment but ultimately it could not improve cognitive function for a long period. Similarly, Radak and coworkers (Radak et al., 2006) proposed that exercise training (swimming) increased the memory of rats in passive avoidance test, but this enhancement was temporary after stopping exercise. Other results demonstrated improvement of memory deficit in EeSE group compared to EeS group (Fig. 3). Hence, if animals continued running activity during stress period (EeSE group), chronic stress would not disrupt the beneficial effect of physical activity on memory. It should be noted that the kinds of memories had no significant enhancement compared to control group (Fig. 3). This suggests that although regular continual exercise is better than preventive effects of exercise, it only recompenses harmful stress effect on memory. Our data also showed that exercise after stress (SeE group) had a significant improvement on mid and long-term memory deficit which compensated memory deficit in stressed rats (Figs. 4 and 5). This suggests that exercise after stress can overcome stress-induced memory deficit, and is successful in removing most of the chronic stress effects on potential process of memory impairments over a long time period. Some researchers have shown that exercise can enhance both cognition and neuron proliferation (Alaei et al., 2006; Van Praag et al., 1999a) or decrease cell death (Kim et al., 2002). Other beneficial mechanisms of exercise may relate to increased antioxidant enzymes activity by regular physical activity (Radak et al., 2001) and down regulation of glucocorticoids receptors (Hwang et al., 2011; Zheng et al., 2006). It is indicated that exercise alters the release of some hormones and neurotransmitters and/or increases neurotrophic factors, muscarinic receptor density, acetylcholine release in the memory regions (Van Praag et al., 1999b). Previous studies suggested that aerobic exercise such as repetitive running can promote angiogenesis in the animal’s brain (Foster et al., 2011; Swain et al., 2003). Our findings also indicated that memory had an ascending trend with the passage of time only in exercise after stress group. The therapeutic protocol of exercise decreases the sensitivity to the stress effects (Fig. 5). It seems that treadmill running after stress is better than other protocols of physical activity in our previous and current studies. It can probably reduce damage to the brain in individuals and can prevent other disorders due to chronic stress. Some studies reported that physical activity protects neurons from various brain damages and had beneficial effects on neural health and function (Carro et al., 2001; Tillerson et al., 2003). Similarly, several
M. Radahmadi et al. studies have indicated that exercise can increase the speed of learning and memory and improve cognitive performance (Fabre et al., 2002; Van Praag et al., 1999a). Chen et al. (Chen et al., 2008) showed that treadmill exercise training facilitated passive avoidance aversive learning; but Barnes et al. (Barnes et al., 1991) did not observe any beneficial effects of exercise on memory. Overall, previous human and animal studies indicated that physical activity has neuroprotective effects on brain function. It has been documented that some kinds of physical activity such as swimming, voluntary wheel running and treadmill running improve passive avoidance memory and spatial learning (Alaei et al., 2006; Chen and Shen, 2002; Huang et al., 2006). Therefore, exercise probably enhances memory and cognitive function via different mechanisms. Some researchers reported that in the brain, physical activity caused biochemical and structural changes including changes in neuronal activity and synaptic structure (Shen et al., 2001; Uysal et al., 2005), enhancing the neuron number (Churchill et al., 2002), increasing the length and number of dendrites connection between neurons, as well as synaptic plasticity in different regions of CNS such as hippocampus, which is involved in memory (Stranahan et al., 2007; Van Praag et al., 1999b). Finally, our finding proposes that time of exercise with respect to stress period is considerable and the best time for the best effects of training is exercise after stress (Fig. 5). Hence, it implies that the influence of exercise in stressful conditions was probably time-dependent on memory estimated by passive avoidance performance. It is suggested that the effects of exercise on different aspects of cognition may depend on factors such as the duration of exercise, type of exercise performed (e.g. forced vs. voluntary), task difficulty, or other variables that have not yet been defined (Berchtold et al., 2010). We previously reported that body weight decreased in emotional stress conditions (Radahmadi et al., 2006) via release of catabolic hormones, the amount of food ingested (Martı´ et al., 1994), and decline of fatty mass and leptin (Chandralekha et al., 2005). In the current study, when BWDFinal and BWDInitial were compared, we observed that chronic stress has a much greater effect than exercise on body weight loss, whereas these comparisons did not have real differences in EeS, EeSE and SeE groups. HoffmanGoetz et al. (Hoffman-Goetz and MacDonald, 1983) reported weight loss was observed following exercise and it is mediated through an increased energy expenditure. In conclusion, our results at the behavioral level emphasize the hypothesis that running activity plays a pivotal and beneficial role in the improvement of chronic stress-induced memory deficit. It seems that in particular, exercise after stress is the best program of exercise. Therefore it is proposed that a strong corollary exists between stress-induced memory deficit and the exercise time. Therefore, to exercise is time-dependent in stress condition. This implies that physical activity enhanced memory functions probably via the activation of some mechanisms in regions of the brain that are involved with memory. Also, chronic stress has a much greater effect than exercise on body weight loss, although initial and final body weight differences in EeS, EeSE and SeE groups did not have any real differences. This suggests that
Please cite this article in press as: Radahmadi, M., et al., Preventive and therapeutic effect of treadmill running on chronic stress-induced memory deficit in rats, Journal of Bodywork & Movement Therapies (2014), http://dx.doi.org/10.1016/j.jbmt.2014.04.007
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Treadmill running and chronic stress on memory further research is needed to determine memory mechanisms such as signaling system in the different phases of memory.
Acknowledgments This research was supported by Isfahan University of Medical Sciences, Isfahan, Iran.
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Please cite this article in press as: Radahmadi, M., et al., Preventive and therapeutic effect of treadmill running on chronic stress-induced memory deficit in rats, Journal of Bodywork & Movement Therapies (2014), http://dx.doi.org/10.1016/j.jbmt.2014.04.007
