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Long-term regular exercise promotes memory and learning in young but not in older rats
Pathophysiology 15 (2008) 9–12
Long-term regular exercise promotes memory and learning in young but not in older rats Naser Ahmadi Asl a,∗ , Farzam Sheikhzade b , Mahmood Torchi b , Leila Roshangar a , Saeed Khamnei a a
Drug Applied Research Center, Tabriz University of Medical Science, Tabriz, Iran b Department of Biotechnology, Agriculture Faculty, Tabriz University, Iran
Received 1 September 2007; received in revised form 9 October 2007; accepted 12 October 2007
Abstract Background and objective: By aging, some functions in nervous system like spatial memory are reduced. It has been shown that short-time physical activity can improve memory but there is much less data on the long-term exercising. In the present study, the aim was to clarify the effect of regular long-term physical activity on spatial memory and learning of young and middle aged and older male Wistar rats. Materials and methods: Sixty 3 months old rats were randomly divided in six equal groups. Experimental groups were treadmill exercised at speed 22 m/min for 1 h 6 days per week, and the program lasted 3, 6 and 9 months, respectively. At the end of training period, spatial memory of rats was tested using Morris Water Maze. Results: Results indicated that regular physical activity significantly increased spatial memory (p < 0.05) in young rats (6 months old) as compared to controls, but not in the older ones (9 and 12 months old). Nonetheless, spatial memory of these rats was significantly better than in younger ones in both groups (p < 0.05). Conclusion: Spatial memory and learning increased due regular exercise in young rats. With progression of age up to 9 and 12 months the memory improved, but the programmed exercise had no positive effect on learning. © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Physical activity; Spatial memory; Middle aged; Treadmill; Rat
1. Introduction There is evidence that regular exercise has positive effect on memory [1]. It has been shown that short exercise program can increase memory and learning in young rats [2] possibly mediated by neurotrophic factors and in brain plasticity [3]. Exercises have effects in hippocampus, which is an important location for spatial memory and learning [4]. It is known that physical activity can increase hippocampal neuron number [5]. Some studies suggest that motion (e.g. running, jumping and walking) increases electrical activity and neurotransmitter secretion in hippocampus [6,7]. It has been reported that physical activity reduces loss of memory and learning which results from cell loss in brain [8]. Most experiments, however, have studied either the effects of short-term exercise ∗
Corresponding author. Tel.: +98 411 3364664; fax: +98 411 3364664. E-mail address: [email protected] (N.A. Asl).
0928-4680/$ – see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.pathophys.2007.10.002
procedures or long-term voluntary exercise [9]. In the present study the aim has been to clarify the effects of regular exercise program in order to have enough time physiological adaptation and assess its effect on memory and learning in male rats. 2. Methods Sixty 3 months old male Wistar rats were obtained from Animal House, Tabriz University of Medical Sciences. They (five per cage) were housed at 22 ± 2 ◦ C in humiditycontrolled room. The animals were maintained on a reversed light cycle, with lights on at 7:00. Food and water provided ad libitum except for the periods of exercise and behavioral testing in Morris Water Maze (MWM). The animals were randomly divided into two main groups: test (exercised rats) and control (nonexercised rats) each of which were subdivided into the three subgroups of 10 rats.
10
N.A. Asl et al. / Pathophysiology 15 (2008) 9–12
The subgroups of test rats for were subjected to running exercise a period of 3 months (up to 6 months old: T6), 6 months (up to 9 months old: T9) and 9 months (up to 12 months old: T12). Control subgroups underwent similar allocations without any training program (C6, C9 and C12). The animals in test groups were initially familiarized to treadmill apparatus in order to eliminate exercise stress as much as possible. Test groups were trained on a running treadmill for 1 h at 22 m/min and 6 days per week, as a mild exercise [10]. MWM was carried out in four trials per day for 7 days. The platform was hidden 1 cm below the surface of water and the starting points were changed every day. Each trial lasted until either the rat found the platform or for a maximum of 40 s. At the end of each trial, the rats were allowed to rest on the platform for 10 s [11]. The time to reach the platform (latency), the length of swim path, and the swim speed were recorded semi-automatically with a video tracking system. Statistical comparisons between two groups were performed using the unpaired Student’s t-test. Comparisons among several groups were performed using one-way analysis of variance. When a significant P-value was obtained, the LSD Tukey post-hoc test was employed to determine the differences between groups. A level of P < 0.05 was chosen to indicate statistical significance.
3. Results The 3 months long running exercise of the youngest group T6 significantly shortened the average total time (ATT) and short average total path (ATP) in Morris Water Maze compared to controls in group C6 (P < 0.05; Fig. 1), i.e. spatial memory development in T6 subgroup was significantly better due to regular exercise program than that of controls in group C6. In the older rats the difference between the trained group T9 and control group C9 the ATT and ATP results were not statistically significant (Fig. 1). The same was true for the trained group T12 and control in group C12 (Fig. 1). The ATT and ATP were in subgroups T9 and T12 were, however, less than subgroup T6, although reaching statistically to significant level only with respect to ATP (P < 0.05; Fig. 1). Data obtained for average swimming speed (ASS) in fourth day of training was unexpectedly higher in group C6 as compared to other control groups. Because using these odd data yielded a significant difference between ASS of three control subgroups (P < 0.05; Fig. 1), data for the fourth day were not considered for analysis. In older rats (groups C12 and C9) ATP and ATT were higher than groups C6 (P < 0.05; Fig. 1).
Fig. 1. Comparison of average total path (ATP), time (ATT) and swimming speed (ASS) within 7 days of trial in controls and runners. Rats were trained over 7 days to find the hidden platform in the Morris Water Maze. Different alphabet above the columns indicated significant difference between combinations at 5% probability level. Data expressed as mean ± S.E.M. C6: Six months old control group; T6: 6 months old test group; C9: 9 months old control group; T9: 9 months old test group; C12: 12 months old control group; T12: 12 months old test group.
N.A. Asl et al. / Pathophysiology 15 (2008) 9–12
Fig. 2. Water maze learning in control and runners trained with four trials per day. Different alphabet above the points indicates significant difference between combinations at 5% probability level in ATT, ATP and 1% probability level in ASS. Data expressed as mean ± S.E.M.
Trend comparison of all groups over 7 days of experiment, indicated day by day reduction in ATT and ATP (P < 0.05; Fig. 2). These results were not confounded by ASS, because this was not significant different between groups (P < 0.01; Fig. 2).
4. Discussion The present study suggests that regular physical activity in young rats improves the spatial memory and learning (P < 0.05; Fig. 1) compared to controls active only in their cages. There is a wealth of studies in support of this obser-
11
vation. These studies, however, have been based on shorter exercise programs. Exercise is shown to facilitate expression of genes encoding neurotrophins and other proteins [12], and they regulate downstream anatomical changes which support the brain plasticity [13]. It has been demonstrated that exercise increases the number of new neurons in the dentate gyrus in adult animals [5]. Trophic factors, such as BDNF and IGF-1, might mediate this effect [14]. Exercise increases the levels of BDNF in the dentate gyrus (the progenitor-cell layer of the hippocampus). It has been shown that BDNF promotes the survival of newly differentiated neurons [15]. Exercise increases brain uptake of circulating IGF-1, which promotes the neuronal differentiation of progenitor cells and increases BDNF gene expression in hippocampus [16]. In addition, levels of IGF-1 and BDNF, the molecules that stimulate proliferation and differentiation of hippocampal neuroprogenitor cells, are increased in hippocampal astrocytes after exercise [17]. Finally, microarray analysis reveals increased expression of additional neurogenesis related genes (e.g. those encoding Krox-24 and VGF) that are likely to act in concert with IGF-1, BDNF and FGF-2 to modulate neurogenesis [18]. Thus, exercise activates a number of factors that converge on neurogenesis. Our results suggest that this kind of exercise does not induce positive effect on spatial memory in middle aged (i.e. 9 and 12 months old) rats. The spatial memory was definitely improved in these middle aged rats, when compared to young ones. This consistently occurred in both control and runner groups (P < 0.05; Fig. 1). Both exerciser and nonexerciser rats reached to a similar level of memory improvement at 9 and 12 months of age. It seems thus that memory reaches to its optimum level in middle aged male rats. To our knowledge, no other report has been published on the effect of regular exercise on the memory and learning capability of middle aged rats and its comparison with that of young ones is present to date. Many studies, however, are in favor of memory loss in older ages, for instance, Frick et al. demonstrated a significant memory loss in 17 and 24 months old groups [19]. Age-related deficits in declarative memory functions have been observed in a variety of animal species, including primates and rodents [20]. Putting our finding together with these studies, it seems that after reaching an optimum, memory is subject to a gradual reduction from middle age onward in male rats. There is, however, considerable variability in individual performance particularly in older ages [21]. Environmental and genetic factors may be responsible for this difference [22]. There are changes within the brain during the course of aging [23]. Of these, a loss of neurons would provide the most unambiguous indication of reduced function. The CA1 region of the hippocampus shows no significant loss with aging, nor does the entorhinal cortex. However, some neurons are lost from parts of the dentate gyrus and from the subiculum [24],
12
N.A. Asl et al. / Pathophysiology 15 (2008) 9–12
although these changes in brain have not been completely confirmed [25]. The other inference made from our data in that exercise is an impartial factor in memory capability of middle aged male rats, as there was no statistical difference between test and control groups of this age (Fig. 1).
5. Conclusion Present results suggest an improvement in spatial memory through regular physical activity in young rats, but not in middle aged ones. The learning and memory reaches independently from physical activity its optimum level in middle aged rats. Because exercise is a simple and widely practiced behavior that activates molecular and cellular cascades that support and maintain brain plasticity, we suggest that molecular approach in hippocampus would help to explain the findings.
References [1] C.W. Cotman, N.C. Berchtold, Exercise: a behavioral intervention to enhance brain health and plasticity, Trends neurosci. 25 (6) (2002) 295–300. [2] N. Uysal, K. Tugyan, B.M. Kayatekin, O. Acikgoz, H.A. Bagriyanik, S. Gonenc, D. Ozdemir, I. Aksu, A. Topcu, I. Semin, The effects of regular aerobic exercise in adolescent period on hippocampal neuron density, apoptosis and spatial memory, Neurosci. Lett. 383 (3) (2005) 241–245. [3] S.A. Neeper, F. Gomez-Pinilla, J. Choi, C.W. Cotman, Physical activity increases mRNA for brain-derived neurotrophic factor and nerve growth factor in rat brain, Brain Res. 726 (1996) 49–56. [4] L. Tong, H. Shen, V.M. Perreau, R. Balazs, C.W. Cotman, Effects of exercise on gene expression profile in the rat hippocampus, Neurobiol. Dis. 8 (2001) 1046–1056. [5] Y.P. Kima, H. Kim, M.S. Shin, H.K. Chang, M.H. Jang, M.C. Shin, S.J. Lee, H.H. Lee, J.H. Yoon, I.G.C.J. Jeong, C.J. Kim, Age-dependence of the effect of treadmill exercise on cell proliferation in the dentate gyrus of rats, Neuroscience Lett. 355 (2004) 152–154. [6] H. Van Praag, B.R. Christie, T.J. Sejnowski, F.H. Gage, Running enhances neurogenesis, learning and longterm potentiation in mice, Proc. Natl. Acad. Sci. USA 96 (1999) 13427–13431. [7] N. Ahmadiasl, H. Alaei, O. H¨anninen, Effect of exercise on learning, memory and levels of epinephrine in rats’ hippocampus, J. Sports Sci. Med. 2 (2003) 106–109. [8] S.J. Colcombe, K.I. Erickson, N. Raz, A.G. Webb, N.J. Cohen, E. McAuley, A.F. Kramer, Aerobic fitness reduces brain tissue loss in aging humans, J. Gerontol. A. Biol. Sci. Med. Sci. 58 (2) (2003) 176–180.
[9] S.R. Davidson, M. Burnett, L. Hoffman-Goetz, Training effects in mice after long-term voluntary exercise, Med. Sci. Sports Exerc. 38 (2) (2006) 250–255. [10] A. Rachel, H. Schemmel Scott, A. Hannum Jill, W.H. Rosekrans, Moderate exercise in young female S5B/P1 rats does not reduce body fat, Physiol. Behav. 52 (3) (1992) 577–581. [11] R. D’Hooge, P.P. De Deyn, Review applications of the Morris water maze in the study of learning and memory, Brain Res. Rev. 36 (2001) 60–90. [12] N.C. Berchtold, J.P. Kesslak, C.W. Cotman, Hippocampal brain-derived neurotrophic factor gene regulation by exercise and the medial septum, J. Neurosci. Res. 68 (5) (2002) 511–521. [13] J. Farmer, X. Zhao, H. Van Praag, K. Wodtke, F.H. Gage, B.R. Christie, Effects of voluntary exercise on synaptic plasticity and gene expression in the dentate gyrus of adult male Sprague-Dawley rats in vivo, Neuroscience 124 (1) (2004) 71–79. [14] N.D. Aberg, K.G. Brywe, J. Isgaard, Aspects of growth hormone and insulin-like growth factor-I related to neuroprotection, regeneration, and functional plasticity in the adult brain, Scientific World J. 6 (2006) 53–80. [15] G.S. Griesbach, D.A. Hovda, R. Molteni, A. Wu, F. Gomez-Pinilla, Voluntary exercise following traumatic brain injury: brain-derived neurotrophic factor upregulation and recovery of function, Neuroscience 125 (1) (2004) 129–139. [16] E. Carro, A. Nunez, S. Busiguina, I. Torres-Aleman, Circulating insulin-like growth factor I mediates effects of exercise on the brain, J. Neurosci. 20 (2000) 2926–2933. [17] Q. Ding, S. Vaynman, M. Akhavan, Z. Ying, F. Gomez-Pinilla, Insulinlike growth factor I interface with brain-derived neurotrophic factormediated synaptic plasticity to modulate aspects of exercise-induced cognitive function, Neuroscience 140 (3) (2006) 823–833. [18] R. Molteni, Z. Ying, F. G´omez-Pinilla, Differential effects of acute and chronic exercise on plasticity-related genes in the rat hippocampus revealed by microarray, Eur. J. Neurosci. 16 (6) (2002) 1107–1110. [19] K.M. Frick, M.G. Baxter, A.L. Markowska, D.S. Olton, D.L. Price, Age-related spatial reference and working memory deficits assessed in the water maze, Neurobiol. Aging 16 (1995) 149–160. [20] D.H. Aitken, M.J. Meaney, Temporally graded age-related impairments in spatial memory in the rat, Neurobiol. Aging 10 (1989) 273–276. [21] A.L. Markowska, W.S. Stone, D.K. Ingram, J. Reynolds, P.E. Gold, L.H. Conti, M.J. Pontecorvo, G.L. Wenk, D.S. Olton, Individual differences in aging: behavioral and neurobiological correlates, Neurobiol. Aging 10 (1989) 31–43. [22] D.K. Ingram, M. Jucker, E.L. Spangler, Behavioral manifestations of aging, Pathobiol. Aging Rat 2 (1994) 149–170. [23] I. Driscoll, D.A. Hamilton, H. Petropoulos, R.A. Yeo, W.M. Brooks, R.N. Baumgartner, R.J. Sutherland, The aging hippocampus: cognitive, biochemical and structural findings, Cereb. Cortex 13 (2003) 1344–1351. [24] R.L. Squire, in: E.R. Kandel, R.L. Squire (Eds.), Memory from Mind to Molecules, Scientific American Library, New York, 1999, pp. 200–215. [25] G. Simic, I. Kostovic, B. Winblad, N. Bogdanovic, Volume and number of neurons of the human hippocampal formation in normal aging and Alzheimer’s disease, J. Comp. Neurol. 379 (1997) 482–494.
Long-term regular exercise promotes memory and learning in young but not in older rats Naser Ahmadi Asl a,∗ , Farzam Sheikhzade b , Mahmood Torchi b , Leila Roshangar a , Saeed Khamnei a a
Drug Applied Research Center, Tabriz University of Medical Science, Tabriz, Iran b Department of Biotechnology, Agriculture Faculty, Tabriz University, Iran
Received 1 September 2007; received in revised form 9 October 2007; accepted 12 October 2007
Abstract Background and objective: By aging, some functions in nervous system like spatial memory are reduced. It has been shown that short-time physical activity can improve memory but there is much less data on the long-term exercising. In the present study, the aim was to clarify the effect of regular long-term physical activity on spatial memory and learning of young and middle aged and older male Wistar rats. Materials and methods: Sixty 3 months old rats were randomly divided in six equal groups. Experimental groups were treadmill exercised at speed 22 m/min for 1 h 6 days per week, and the program lasted 3, 6 and 9 months, respectively. At the end of training period, spatial memory of rats was tested using Morris Water Maze. Results: Results indicated that regular physical activity significantly increased spatial memory (p < 0.05) in young rats (6 months old) as compared to controls, but not in the older ones (9 and 12 months old). Nonetheless, spatial memory of these rats was significantly better than in younger ones in both groups (p < 0.05). Conclusion: Spatial memory and learning increased due regular exercise in young rats. With progression of age up to 9 and 12 months the memory improved, but the programmed exercise had no positive effect on learning. © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Physical activity; Spatial memory; Middle aged; Treadmill; Rat
1. Introduction There is evidence that regular exercise has positive effect on memory [1]. It has been shown that short exercise program can increase memory and learning in young rats [2] possibly mediated by neurotrophic factors and in brain plasticity [3]. Exercises have effects in hippocampus, which is an important location for spatial memory and learning [4]. It is known that physical activity can increase hippocampal neuron number [5]. Some studies suggest that motion (e.g. running, jumping and walking) increases electrical activity and neurotransmitter secretion in hippocampus [6,7]. It has been reported that physical activity reduces loss of memory and learning which results from cell loss in brain [8]. Most experiments, however, have studied either the effects of short-term exercise ∗
Corresponding author. Tel.: +98 411 3364664; fax: +98 411 3364664. E-mail address: [email protected] (N.A. Asl).
0928-4680/$ – see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.pathophys.2007.10.002
procedures or long-term voluntary exercise [9]. In the present study the aim has been to clarify the effects of regular exercise program in order to have enough time physiological adaptation and assess its effect on memory and learning in male rats. 2. Methods Sixty 3 months old male Wistar rats were obtained from Animal House, Tabriz University of Medical Sciences. They (five per cage) were housed at 22 ± 2 ◦ C in humiditycontrolled room. The animals were maintained on a reversed light cycle, with lights on at 7:00. Food and water provided ad libitum except for the periods of exercise and behavioral testing in Morris Water Maze (MWM). The animals were randomly divided into two main groups: test (exercised rats) and control (nonexercised rats) each of which were subdivided into the three subgroups of 10 rats.
10
N.A. Asl et al. / Pathophysiology 15 (2008) 9–12
The subgroups of test rats for were subjected to running exercise a period of 3 months (up to 6 months old: T6), 6 months (up to 9 months old: T9) and 9 months (up to 12 months old: T12). Control subgroups underwent similar allocations without any training program (C6, C9 and C12). The animals in test groups were initially familiarized to treadmill apparatus in order to eliminate exercise stress as much as possible. Test groups were trained on a running treadmill for 1 h at 22 m/min and 6 days per week, as a mild exercise [10]. MWM was carried out in four trials per day for 7 days. The platform was hidden 1 cm below the surface of water and the starting points were changed every day. Each trial lasted until either the rat found the platform or for a maximum of 40 s. At the end of each trial, the rats were allowed to rest on the platform for 10 s [11]. The time to reach the platform (latency), the length of swim path, and the swim speed were recorded semi-automatically with a video tracking system. Statistical comparisons between two groups were performed using the unpaired Student’s t-test. Comparisons among several groups were performed using one-way analysis of variance. When a significant P-value was obtained, the LSD Tukey post-hoc test was employed to determine the differences between groups. A level of P < 0.05 was chosen to indicate statistical significance.
3. Results The 3 months long running exercise of the youngest group T6 significantly shortened the average total time (ATT) and short average total path (ATP) in Morris Water Maze compared to controls in group C6 (P < 0.05; Fig. 1), i.e. spatial memory development in T6 subgroup was significantly better due to regular exercise program than that of controls in group C6. In the older rats the difference between the trained group T9 and control group C9 the ATT and ATP results were not statistically significant (Fig. 1). The same was true for the trained group T12 and control in group C12 (Fig. 1). The ATT and ATP were in subgroups T9 and T12 were, however, less than subgroup T6, although reaching statistically to significant level only with respect to ATP (P < 0.05; Fig. 1). Data obtained for average swimming speed (ASS) in fourth day of training was unexpectedly higher in group C6 as compared to other control groups. Because using these odd data yielded a significant difference between ASS of three control subgroups (P < 0.05; Fig. 1), data for the fourth day were not considered for analysis. In older rats (groups C12 and C9) ATP and ATT were higher than groups C6 (P < 0.05; Fig. 1).
Fig. 1. Comparison of average total path (ATP), time (ATT) and swimming speed (ASS) within 7 days of trial in controls and runners. Rats were trained over 7 days to find the hidden platform in the Morris Water Maze. Different alphabet above the columns indicated significant difference between combinations at 5% probability level. Data expressed as mean ± S.E.M. C6: Six months old control group; T6: 6 months old test group; C9: 9 months old control group; T9: 9 months old test group; C12: 12 months old control group; T12: 12 months old test group.
N.A. Asl et al. / Pathophysiology 15 (2008) 9–12
Fig. 2. Water maze learning in control and runners trained with four trials per day. Different alphabet above the points indicates significant difference between combinations at 5% probability level in ATT, ATP and 1% probability level in ASS. Data expressed as mean ± S.E.M.
Trend comparison of all groups over 7 days of experiment, indicated day by day reduction in ATT and ATP (P < 0.05; Fig. 2). These results were not confounded by ASS, because this was not significant different between groups (P < 0.01; Fig. 2).
4. Discussion The present study suggests that regular physical activity in young rats improves the spatial memory and learning (P < 0.05; Fig. 1) compared to controls active only in their cages. There is a wealth of studies in support of this obser-
11
vation. These studies, however, have been based on shorter exercise programs. Exercise is shown to facilitate expression of genes encoding neurotrophins and other proteins [12], and they regulate downstream anatomical changes which support the brain plasticity [13]. It has been demonstrated that exercise increases the number of new neurons in the dentate gyrus in adult animals [5]. Trophic factors, such as BDNF and IGF-1, might mediate this effect [14]. Exercise increases the levels of BDNF in the dentate gyrus (the progenitor-cell layer of the hippocampus). It has been shown that BDNF promotes the survival of newly differentiated neurons [15]. Exercise increases brain uptake of circulating IGF-1, which promotes the neuronal differentiation of progenitor cells and increases BDNF gene expression in hippocampus [16]. In addition, levels of IGF-1 and BDNF, the molecules that stimulate proliferation and differentiation of hippocampal neuroprogenitor cells, are increased in hippocampal astrocytes after exercise [17]. Finally, microarray analysis reveals increased expression of additional neurogenesis related genes (e.g. those encoding Krox-24 and VGF) that are likely to act in concert with IGF-1, BDNF and FGF-2 to modulate neurogenesis [18]. Thus, exercise activates a number of factors that converge on neurogenesis. Our results suggest that this kind of exercise does not induce positive effect on spatial memory in middle aged (i.e. 9 and 12 months old) rats. The spatial memory was definitely improved in these middle aged rats, when compared to young ones. This consistently occurred in both control and runner groups (P < 0.05; Fig. 1). Both exerciser and nonexerciser rats reached to a similar level of memory improvement at 9 and 12 months of age. It seems thus that memory reaches to its optimum level in middle aged male rats. To our knowledge, no other report has been published on the effect of regular exercise on the memory and learning capability of middle aged rats and its comparison with that of young ones is present to date. Many studies, however, are in favor of memory loss in older ages, for instance, Frick et al. demonstrated a significant memory loss in 17 and 24 months old groups [19]. Age-related deficits in declarative memory functions have been observed in a variety of animal species, including primates and rodents [20]. Putting our finding together with these studies, it seems that after reaching an optimum, memory is subject to a gradual reduction from middle age onward in male rats. There is, however, considerable variability in individual performance particularly in older ages [21]. Environmental and genetic factors may be responsible for this difference [22]. There are changes within the brain during the course of aging [23]. Of these, a loss of neurons would provide the most unambiguous indication of reduced function. The CA1 region of the hippocampus shows no significant loss with aging, nor does the entorhinal cortex. However, some neurons are lost from parts of the dentate gyrus and from the subiculum [24],
12
N.A. Asl et al. / Pathophysiology 15 (2008) 9–12
although these changes in brain have not been completely confirmed [25]. The other inference made from our data in that exercise is an impartial factor in memory capability of middle aged male rats, as there was no statistical difference between test and control groups of this age (Fig. 1).
5. Conclusion Present results suggest an improvement in spatial memory through regular physical activity in young rats, but not in middle aged ones. The learning and memory reaches independently from physical activity its optimum level in middle aged rats. Because exercise is a simple and widely practiced behavior that activates molecular and cellular cascades that support and maintain brain plasticity, we suggest that molecular approach in hippocampus would help to explain the findings.
References [1] C.W. Cotman, N.C. Berchtold, Exercise: a behavioral intervention to enhance brain health and plasticity, Trends neurosci. 25 (6) (2002) 295–300. [2] N. Uysal, K. Tugyan, B.M. Kayatekin, O. Acikgoz, H.A. Bagriyanik, S. Gonenc, D. Ozdemir, I. Aksu, A. Topcu, I. Semin, The effects of regular aerobic exercise in adolescent period on hippocampal neuron density, apoptosis and spatial memory, Neurosci. Lett. 383 (3) (2005) 241–245. [3] S.A. Neeper, F. Gomez-Pinilla, J. Choi, C.W. Cotman, Physical activity increases mRNA for brain-derived neurotrophic factor and nerve growth factor in rat brain, Brain Res. 726 (1996) 49–56. [4] L. Tong, H. Shen, V.M. Perreau, R. Balazs, C.W. Cotman, Effects of exercise on gene expression profile in the rat hippocampus, Neurobiol. Dis. 8 (2001) 1046–1056. [5] Y.P. Kima, H. Kim, M.S. Shin, H.K. Chang, M.H. Jang, M.C. Shin, S.J. Lee, H.H. Lee, J.H. Yoon, I.G.C.J. Jeong, C.J. Kim, Age-dependence of the effect of treadmill exercise on cell proliferation in the dentate gyrus of rats, Neuroscience Lett. 355 (2004) 152–154. [6] H. Van Praag, B.R. Christie, T.J. Sejnowski, F.H. Gage, Running enhances neurogenesis, learning and longterm potentiation in mice, Proc. Natl. Acad. Sci. USA 96 (1999) 13427–13431. [7] N. Ahmadiasl, H. Alaei, O. H¨anninen, Effect of exercise on learning, memory and levels of epinephrine in rats’ hippocampus, J. Sports Sci. Med. 2 (2003) 106–109. [8] S.J. Colcombe, K.I. Erickson, N. Raz, A.G. Webb, N.J. Cohen, E. McAuley, A.F. Kramer, Aerobic fitness reduces brain tissue loss in aging humans, J. Gerontol. A. Biol. Sci. Med. Sci. 58 (2) (2003) 176–180.
[9] S.R. Davidson, M. Burnett, L. Hoffman-Goetz, Training effects in mice after long-term voluntary exercise, Med. Sci. Sports Exerc. 38 (2) (2006) 250–255. [10] A. Rachel, H. Schemmel Scott, A. Hannum Jill, W.H. Rosekrans, Moderate exercise in young female S5B/P1 rats does not reduce body fat, Physiol. Behav. 52 (3) (1992) 577–581. [11] R. D’Hooge, P.P. De Deyn, Review applications of the Morris water maze in the study of learning and memory, Brain Res. Rev. 36 (2001) 60–90. [12] N.C. Berchtold, J.P. Kesslak, C.W. Cotman, Hippocampal brain-derived neurotrophic factor gene regulation by exercise and the medial septum, J. Neurosci. Res. 68 (5) (2002) 511–521. [13] J. Farmer, X. Zhao, H. Van Praag, K. Wodtke, F.H. Gage, B.R. Christie, Effects of voluntary exercise on synaptic plasticity and gene expression in the dentate gyrus of adult male Sprague-Dawley rats in vivo, Neuroscience 124 (1) (2004) 71–79. [14] N.D. Aberg, K.G. Brywe, J. Isgaard, Aspects of growth hormone and insulin-like growth factor-I related to neuroprotection, regeneration, and functional plasticity in the adult brain, Scientific World J. 6 (2006) 53–80. [15] G.S. Griesbach, D.A. Hovda, R. Molteni, A. Wu, F. Gomez-Pinilla, Voluntary exercise following traumatic brain injury: brain-derived neurotrophic factor upregulation and recovery of function, Neuroscience 125 (1) (2004) 129–139. [16] E. Carro, A. Nunez, S. Busiguina, I. Torres-Aleman, Circulating insulin-like growth factor I mediates effects of exercise on the brain, J. Neurosci. 20 (2000) 2926–2933. [17] Q. Ding, S. Vaynman, M. Akhavan, Z. Ying, F. Gomez-Pinilla, Insulinlike growth factor I interface with brain-derived neurotrophic factormediated synaptic plasticity to modulate aspects of exercise-induced cognitive function, Neuroscience 140 (3) (2006) 823–833. [18] R. Molteni, Z. Ying, F. G´omez-Pinilla, Differential effects of acute and chronic exercise on plasticity-related genes in the rat hippocampus revealed by microarray, Eur. J. Neurosci. 16 (6) (2002) 1107–1110. [19] K.M. Frick, M.G. Baxter, A.L. Markowska, D.S. Olton, D.L. Price, Age-related spatial reference and working memory deficits assessed in the water maze, Neurobiol. Aging 16 (1995) 149–160. [20] D.H. Aitken, M.J. Meaney, Temporally graded age-related impairments in spatial memory in the rat, Neurobiol. Aging 10 (1989) 273–276. [21] A.L. Markowska, W.S. Stone, D.K. Ingram, J. Reynolds, P.E. Gold, L.H. Conti, M.J. Pontecorvo, G.L. Wenk, D.S. Olton, Individual differences in aging: behavioral and neurobiological correlates, Neurobiol. Aging 10 (1989) 31–43. [22] D.K. Ingram, M. Jucker, E.L. Spangler, Behavioral manifestations of aging, Pathobiol. Aging Rat 2 (1994) 149–170. [23] I. Driscoll, D.A. Hamilton, H. Petropoulos, R.A. Yeo, W.M. Brooks, R.N. Baumgartner, R.J. Sutherland, The aging hippocampus: cognitive, biochemical and structural findings, Cereb. Cortex 13 (2003) 1344–1351. [24] R.L. Squire, in: E.R. Kandel, R.L. Squire (Eds.), Memory from Mind to Molecules, Scientific American Library, New York, 1999, pp. 200–215. [25] G. Simic, I. Kostovic, B. Winblad, N. Bogdanovic, Volume and number of neurons of the human hippocampal formation in normal aging and Alzheimer’s disease, J. Comp. Neurol. 379 (1997) 482–494.