YNLME 6101
No. of Pages 11, Model 5G
25 April 2014 Neurobiology of Learning and Memory xxx (2014) xxx–xxx 1
Contents lists available at ScienceDirect
Neurobiology of Learning and Memory journal homepage: www.elsevier.com/locate/ynlme 5 6
Exercise reduces diet-induced cognitive decline and increases hippocampal brain-derived neurotrophic factor in CA3 neurons
3 4 7
Q1
8 9 10 11 12 13
Emily E. Noble b,c,1, Vijayakumar Mavanji a,b,1, Morgan R. Little b,c, Charles J. Billington a,b,c,d, Catherine M. Kotz a,b,c,e, ChuanFeng Wang a,b,c,⇑ a
Veterans Affairs Medical Center, One Veterans Drive, Research Route 151, Minneapolis, MN 55417, USA Minnesota Obesity Center, 1334 Eckles Avenue, Saint Paul, MN 55108, USA Department of Food Science and Nutrition, University of Minnesota, 1334 Eckles Avenue, Saint Paul, MN 55108, USA d Department of Medicine, University of Minnesota, Minneapolis, MN 554553, USA e Graduate Program in Neuroscience, University of Minnesota, 321 Church Street SE, Minneapolis, MN 55455, USA b c
Q2
14 16 15
a r t i c l e
1 3 8 3 19 20 21 22 23
i n f o
Article history: Received 22 October 2013 Revised 1 April 2014 Accepted 7 April 2014 Available online xxxx
24 25 26 27 28 29 30 31 32
Keywords: BDNF Hippocampus Two-way active avoidance Treadmill Running wheel High-fat diet Memory
a b s t r a c t Background: Previous studies have shown that a western diet impairs, whereas physical exercise enhances hippocampus-dependent learning and memory. Both diet and exercise influence expression of hippocampal brain-derived neurotrophic factor (BDNF), which is associated with improved cognition. We hypothesized that exercise reverses diet-induced cognitive decline while increasing hippocampal BDNF. Methods: To test the effects of exercise on hippocampal-dependent memory, we compared cognitive scores of Sprague–Dawley rats exercised by voluntary running wheel (RW) access or forced treadmill (TM) to sedentary (Sed) animals. Memory was tested by two-way active avoidance test (TWAA), in which animals are exposed to a brief shock in a specific chamber area. When an animal avoids, escapes or has reduced latency to do either, this is considered a measure of memory. In a second experiment, rats were fed either a high-fat diet or control diet for 16 weeks, then randomly assigned to running wheel access or sedentary condition, and TWAA memory was tested once a week for 7 weeks of exercise intervention. Results: Both groups of exercised animals had improved memory as indicated by reduced latency to avoid and escape shock, and increased avoid and escape episodes (p < 0.05). Exposure to a high-fat diet resulted in poor performance during both the acquisition and retrieval phases of the memory test as compared to controls. Exercise reversed high-fat diet-induced memory impairment, and increased brain-derived neurotrophic factor (BDNF) in neurons of the hippocampal CA3 region. Conclusions: These data suggest that exercise improves memory retrieval, particularly with respect to avoiding aversive stimuli, and may be beneficial in protecting against diet induced cognitive decline, likely via elevated BDNF in neurons of the CA3 region. Published by Elsevier Inc.
34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56
57
1. Introduction
58 59 60 61 62 63 64 65
Several lines of evidence illustrate that physical activity is beneficial toward maintaining and improving cognitive function in humans and animals. Physical exercise enhances learning, memQ4 ory retention, and cognitive task performance (Molteni et al., 2004; Vaynman, Ying, & Gomez-Pinilla, 2007). In addition, physical activity enhances both acquisition rate and performance on spatial learning task (Churchill & et al., 2002). The cognition enhancing Q3
⇑ Corresponding author at: Veterans Affairs Medical Center, One Veterans Drive, Research Route 151, Minneapolis, MN 55417, USA. Fax: +1 612 725 2093. E-mail address: [email protected] (C. Wang). 1 These authors contributed equally to this work.
effect of exercise is observed both in young and aged animals (Churchill et al., 2002; Radak et al., 2001). Similarly, in humans, regular aerobic exercise prevents brain tissue loss and decline in hippocampal volume during aging, ameliorates age-related cognitive decline (Colcombe et al., 2006; Zhao et al., 2014), and improves spatial memory (Churchill et al., 2002; Erickson & et al., 2011; Kramer & Erickson, 2007; Kramer, Erickson, & Colcombe, 2006). The hippocampus is an important area for spatial, contextual, and avoidance learning as well as memory processing. In particular, the dorsal hippocampus has long been considered the site of temporal integration of the sequence of events that ultimately forms a memory, including spatial and contextual learning (reviewed in Datta and et al. (2005)). Hippocampal neurons play a critical role in the retrieval of information related to memory
http://dx.doi.org/10.1016/j.nlm.2014.04.006 1074-7427/Published by Elsevier Inc.
Please cite this article in press as: Noble, E. E., et al. Exercise reduces diet-induced cognitive decline and increases hippocampal brain-derived neurotrophic factor in CA3 neurons. Neurobiology of Learning and Memory (2014), http://dx.doi.org/10.1016/j.nlm.2014.04.006
66 67 68 69 70 71 72 73 74 75 76 77 78 79
YNLME 6101
No. of Pages 11, Model 5G
25 April 2014 2 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145
E.E. Noble et al. / Neurobiology of Learning and Memory xxx (2014) xxx–xxx
tasks (Deadwyler, Bunn, & Hampson, 1996). Within the dorsal hippocampus, the CA3 region is important for memory retention, which likely involves both neurogenesis and long-term potentiation. For example, atrophy of apical dendrites of the CA3 neurons leads to memory impairments in the rat (McEwen, 1999) and smaller hippocampal CA3/dentate volumes in humans is associated with learning and memory problems (Yassa & et al., 2010). Evidence shows that neurogenesis, maturation and synaptogenesis in the hippocampal formation is critical for learning and memory (Deng & et al., 2009). High fat diet impairs neurogenesis, whereas, voluntary exercise in the form of wheel running promotes neurogenesis in the dentate gyrus of adult mice (Churchill et al., 2002; van Praag et al., 1999). Furthermore, exercise induced hippocampal neurogenesis is shown to be rapid and robust in nature (Kerr & Swain, 2011). In addition, voluntary exercise increases the length and complexity of dendritic spines of the hippocampal neurons (Redila & Christie, 2006). Brain derived neurotrophic factor (BDNF) plays a key role in regulating adult hippocampal neurogenesis and synaptogenesis, both of which are critical to learning and memory. Dense expression of BDNF is observed in the hippocampus (Noble & et al., 2011). BDNF increases occur in the dorsal hippocampus during TWAA memory consolidation (Ulloor & Datta, 2005), and during contextual fear conditioning (Chen & et al., 2007). Genetic manipulation studies show that decreased levels of BDNF impairs hippocampus-dependent behavioral tasks such as spatial learning in the Morris water maze in rats and mice (Gorski et al., 2003; Linnarsson, Bjorklund, & Ernfors, 1997; Mizuno et al., 2000). Additionally, central lenti-virus mediated infusions and acute injections of BDNF enhance learning in animals (Moguel-Gonzalez, GomezPalacio-Schjetnan, & Escobar, 2008; Nagahara et al., 2009). Similarly, higher levels of BDNF were associated with enhanced memory, cognition and increased hippocampal volumes in human subjects (Erickson & et al., 2010). Taken together, these studies indicate that elevated hippocampal BDNF is essential to memory (Datta, Siwek, & Huang, 2009). Similar to physical exercise enhancing cognition, physical exercise is known to robustly enhance BDNF signaling, and hence neural cell proliferation, neurogenesis, and synaptic plasticity in rodents (Eadie, Redila, & Christie, 2005; Farmer et al., 2004; Kerr & Swain, 2011; Li et al., 2008; Stranahan, Khalil, & Gould, 2007). These changes result in enhanced long-term potentiation, learning and retention, and enhance performance in cognitive tasks (Cotman & Berchtold, 2002; Stranahan et al., 2010; Vaynman et al., 2007). A recent study confirmed these findings, showing direct correlation between increased hippocampal volume and memory performance improvements in people who exercised (Erickson & et al., 2011). Additionally, human exercisers have been shown to outperform non-exercisers on tasks such as reasoning, working memory, Stroop, Trails-B, Symbol digit, vigilance monitoring, and fluid intelligence tests (Churchill et al., 2002). These beneficial effects of exercise are attributed to increased BDNF signaling (Erickson et al., 2010; Neeper et al., 1996). While exercise is reportedly beneficial for memory function, a high-energy, high-saturated fat diet is associated with cognitive impairment, with a specific effect on learning and memory functions that are dependent on the integrity of the hippocampus (Davidson & et al., 2012). Similarly, saturated fat intake is associated with impaired memory (Kalmijn & et al., 2004) and greater cognitive decline with aging (Okereke et al., 2012; Ortega et al., 1997). As mentioned before, hippocampal BDNF is increased with exercise (Adlard et al., 2004; Neeper et al., 1996; Oliff et al., 1998), it is reduced by a high-fat diet (Molteni et al., 2002, 2004). An elegant study by Molteni and et al. (2004) showed that physical exercise initiated simultaneously with 2 months of high-fat diet prevents the spatial memory impairing effects of high-fat diet.
Whether exercise can reverse cognitive impairments associated with prior exposure to high-fat diet remains unanswered. The aim of this study was to test whether exercise enhances performance on a hippocampus dependent memory test and reverses hippocampus dependent memory impairment produced by high-fat diet exposure, and if exercise-induced cognitive improvement is associated with increased hippocampal BDNF.
146
2. Results
153
2.1. Experiment 1
154
At baseline, animals were randomized to groups such that there were no differences in fat, % fat, weight, lean mass, or % lean mass between groups prior to the initiation of exercise (Table 1A) to avoid potential differences in physical abilities between groups. After the intervention animals with voluntary wheel access weighed less and had lower body fat, % body fat, and elevated lean mass compared with sedentary controls (p < 0.05) (Table 1B). After 5 weeks of either running wheel exercise, treadmill exercise or being sedentary, there was a significant effect of exercise on latency (F2, 24 = 33.10, p < 0.0001) (A) number of escapes (F2, 24 = 105.3, p < 0.0001) (B), avoidances (F2, 24 = 8.9, p = 0.001) (C) and the total response (escape plus avoidance) (F2, 24 = 77.8, p < 0.0001) (D). Five weeks of exercise significantly increased retention of contextual memory, as indicated by decreased latency (p < 0.05) (Fig. 1A), increased number of escapes (p < 0.05) (Fig. 1B) and avoidance episodes, as well as total response (p < 0.05) (Fig. 1D). Treadmill exercised animals had a significantly greater number of shock avoidances (p < 0.05) compared with running wheel and sedentary animals, indicating enhanced capacity to pair the conditioned stimulus of sound and light to the impending shock. The number of avoidances in animals exercising on running wheels tended to be positively related to running distance, although the correlation was not significant (data not shown, R2 = 0.42, p = 0.057). After 5 weeks, running distance was positively correlated with total responses (R2 = 0.58, p < 0.02) (Fig. 2A) and negatively with response latency (R2 = 0.74, p < 0.01) (Fig. 2B) in the TWAA test. Animals were 6 months old at the start of the study and those in voluntary running wheels ran an average of 0.95 ± 0.20 (SEM) km/day (Fig. 2C), which is similar to what has been reported previously for rats 5 months of age fed standard chow (Judge & et al., 2008). Cumulatively, animals on running wheels ran an average
155
Table 1 Comparison of body compositions at baseline and post-five weeks of exercise intervention (experiment one). Characteristics of treadmill (TM), running wheel (RW) and sedentary (Sed) animals were not different from each other prior to exercise intervention (A). After 5 weeks of exercise RW animals had significantly improved body composition compared with Sed animals (B); N = 9–10. TM
RW
Sed
p Value
Mean
SEM
Mean
SEM
Mean
SEM
A Fat (g) Lean (g) Weight (g) %Fat %Lean
102.2 444.1 622.9 16.3 71.4
8.0 9.0 11.9 1.1 1.2
101.5 436.4 619.9 16.3 70.5
7.3 12.1 15.5 1.0 1.3
100.9 443.3 619.6 16.2 71.6
7.2 13.6 18.1 1.0 0.9
0.99 0.88 0.99 0.99 0.98
B Fat (g) Lean (g) Weight (g) %Fat %Lean
105.9 455.2 637.9 16.5 71.4
10.0 11.3 11.8 1.4 1.4
81.6⁄ 435.4 588.5⁄ 13.8⁄ 74.1⁄
8.4 10.4 14.9 1.2 1.2
130.7 445.5 648.9 20.0 68.8
11.3 12.6 18.6 1.5 1.3
0.01 0.49 0.02 0.01 0.03
Please cite this article in press as: Noble, E. E., et al. Exercise reduces diet-induced cognitive decline and increases hippocampal brain-derived neurotrophic factor in CA3 neurons. Neurobiology of Learning and Memory (2014), http://dx.doi.org/10.1016/j.nlm.2014.04.006
147 148 149 150 151 152
156 157 158 159 160 161 162 163 164 165 166
167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187
Q8
YNLME 6101
No. of Pages 11, Model 5G
25 April 2014 3
E.E. Noble et al. / Neurobiology of Learning and Memory xxx (2014) xxx–xxx
A
B
30
* *
10
# Escapes
Latency (sec)
15
*
5
d Se
d Se
TM
W R
D
8
*
6 4
# 2
TM
W R
30
Total response
Avoidance
10
0
0
C
*
20
*
*
20
10
# 0
d Se
TM
R W
Se d
0
TM
W R
Fig. 1. Five weeks of exercise enhances memory. There was a significant effect of exercise on latency (F(2, 24) = 33.10, p < 0.0001) (A) number of escapes (F(2, 24) = 105.3, p < 0.0001) (B), avoidances (F(2, 24) = 8.9, p = 0.001) (C) and total response (escape plus avoidance) (F(2, 24) = 77.8, p < 0.0001) (D). Compared with sedentary (Sed) animals, both running wheel (RW) and treadmill (TM) exercise reduced latency (A), increased the number of escapes (B), and total response (D), (escape plus avoidance). TM and RW animals did not differ from each other except in the number of avoidances (C), where TM exercise resulted in a significantly greater number of total avoidances. Indicates significantly different compared with Sed; # indicates significantly different compared with TM; indicates significantly different compared with RW; p < 0.05, N = 9–10.
A
B
30 20
12
Latency (sec)
Total response
40
R2=0.58 P
No. of Pages 11, Model 5G
25 April 2014 Neurobiology of Learning and Memory xxx (2014) xxx–xxx 1
Contents lists available at ScienceDirect
Neurobiology of Learning and Memory journal homepage: www.elsevier.com/locate/ynlme 5 6
Exercise reduces diet-induced cognitive decline and increases hippocampal brain-derived neurotrophic factor in CA3 neurons
3 4 7
Q1
8 9 10 11 12 13
Emily E. Noble b,c,1, Vijayakumar Mavanji a,b,1, Morgan R. Little b,c, Charles J. Billington a,b,c,d, Catherine M. Kotz a,b,c,e, ChuanFeng Wang a,b,c,⇑ a
Veterans Affairs Medical Center, One Veterans Drive, Research Route 151, Minneapolis, MN 55417, USA Minnesota Obesity Center, 1334 Eckles Avenue, Saint Paul, MN 55108, USA Department of Food Science and Nutrition, University of Minnesota, 1334 Eckles Avenue, Saint Paul, MN 55108, USA d Department of Medicine, University of Minnesota, Minneapolis, MN 554553, USA e Graduate Program in Neuroscience, University of Minnesota, 321 Church Street SE, Minneapolis, MN 55455, USA b c
Q2
14 16 15
a r t i c l e
1 3 8 3 19 20 21 22 23
i n f o
Article history: Received 22 October 2013 Revised 1 April 2014 Accepted 7 April 2014 Available online xxxx
24 25 26 27 28 29 30 31 32
Keywords: BDNF Hippocampus Two-way active avoidance Treadmill Running wheel High-fat diet Memory
a b s t r a c t Background: Previous studies have shown that a western diet impairs, whereas physical exercise enhances hippocampus-dependent learning and memory. Both diet and exercise influence expression of hippocampal brain-derived neurotrophic factor (BDNF), which is associated with improved cognition. We hypothesized that exercise reverses diet-induced cognitive decline while increasing hippocampal BDNF. Methods: To test the effects of exercise on hippocampal-dependent memory, we compared cognitive scores of Sprague–Dawley rats exercised by voluntary running wheel (RW) access or forced treadmill (TM) to sedentary (Sed) animals. Memory was tested by two-way active avoidance test (TWAA), in which animals are exposed to a brief shock in a specific chamber area. When an animal avoids, escapes or has reduced latency to do either, this is considered a measure of memory. In a second experiment, rats were fed either a high-fat diet or control diet for 16 weeks, then randomly assigned to running wheel access or sedentary condition, and TWAA memory was tested once a week for 7 weeks of exercise intervention. Results: Both groups of exercised animals had improved memory as indicated by reduced latency to avoid and escape shock, and increased avoid and escape episodes (p < 0.05). Exposure to a high-fat diet resulted in poor performance during both the acquisition and retrieval phases of the memory test as compared to controls. Exercise reversed high-fat diet-induced memory impairment, and increased brain-derived neurotrophic factor (BDNF) in neurons of the hippocampal CA3 region. Conclusions: These data suggest that exercise improves memory retrieval, particularly with respect to avoiding aversive stimuli, and may be beneficial in protecting against diet induced cognitive decline, likely via elevated BDNF in neurons of the CA3 region. Published by Elsevier Inc.
34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56
57
1. Introduction
58 59 60 61 62 63 64 65
Several lines of evidence illustrate that physical activity is beneficial toward maintaining and improving cognitive function in humans and animals. Physical exercise enhances learning, memQ4 ory retention, and cognitive task performance (Molteni et al., 2004; Vaynman, Ying, & Gomez-Pinilla, 2007). In addition, physical activity enhances both acquisition rate and performance on spatial learning task (Churchill & et al., 2002). The cognition enhancing Q3
⇑ Corresponding author at: Veterans Affairs Medical Center, One Veterans Drive, Research Route 151, Minneapolis, MN 55417, USA. Fax: +1 612 725 2093. E-mail address: [email protected] (C. Wang). 1 These authors contributed equally to this work.
effect of exercise is observed both in young and aged animals (Churchill et al., 2002; Radak et al., 2001). Similarly, in humans, regular aerobic exercise prevents brain tissue loss and decline in hippocampal volume during aging, ameliorates age-related cognitive decline (Colcombe et al., 2006; Zhao et al., 2014), and improves spatial memory (Churchill et al., 2002; Erickson & et al., 2011; Kramer & Erickson, 2007; Kramer, Erickson, & Colcombe, 2006). The hippocampus is an important area for spatial, contextual, and avoidance learning as well as memory processing. In particular, the dorsal hippocampus has long been considered the site of temporal integration of the sequence of events that ultimately forms a memory, including spatial and contextual learning (reviewed in Datta and et al. (2005)). Hippocampal neurons play a critical role in the retrieval of information related to memory
http://dx.doi.org/10.1016/j.nlm.2014.04.006 1074-7427/Published by Elsevier Inc.
Please cite this article in press as: Noble, E. E., et al. Exercise reduces diet-induced cognitive decline and increases hippocampal brain-derived neurotrophic factor in CA3 neurons. Neurobiology of Learning and Memory (2014), http://dx.doi.org/10.1016/j.nlm.2014.04.006
66 67 68 69 70 71 72 73 74 75 76 77 78 79
YNLME 6101
No. of Pages 11, Model 5G
25 April 2014 2 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145
E.E. Noble et al. / Neurobiology of Learning and Memory xxx (2014) xxx–xxx
tasks (Deadwyler, Bunn, & Hampson, 1996). Within the dorsal hippocampus, the CA3 region is important for memory retention, which likely involves both neurogenesis and long-term potentiation. For example, atrophy of apical dendrites of the CA3 neurons leads to memory impairments in the rat (McEwen, 1999) and smaller hippocampal CA3/dentate volumes in humans is associated with learning and memory problems (Yassa & et al., 2010). Evidence shows that neurogenesis, maturation and synaptogenesis in the hippocampal formation is critical for learning and memory (Deng & et al., 2009). High fat diet impairs neurogenesis, whereas, voluntary exercise in the form of wheel running promotes neurogenesis in the dentate gyrus of adult mice (Churchill et al., 2002; van Praag et al., 1999). Furthermore, exercise induced hippocampal neurogenesis is shown to be rapid and robust in nature (Kerr & Swain, 2011). In addition, voluntary exercise increases the length and complexity of dendritic spines of the hippocampal neurons (Redila & Christie, 2006). Brain derived neurotrophic factor (BDNF) plays a key role in regulating adult hippocampal neurogenesis and synaptogenesis, both of which are critical to learning and memory. Dense expression of BDNF is observed in the hippocampus (Noble & et al., 2011). BDNF increases occur in the dorsal hippocampus during TWAA memory consolidation (Ulloor & Datta, 2005), and during contextual fear conditioning (Chen & et al., 2007). Genetic manipulation studies show that decreased levels of BDNF impairs hippocampus-dependent behavioral tasks such as spatial learning in the Morris water maze in rats and mice (Gorski et al., 2003; Linnarsson, Bjorklund, & Ernfors, 1997; Mizuno et al., 2000). Additionally, central lenti-virus mediated infusions and acute injections of BDNF enhance learning in animals (Moguel-Gonzalez, GomezPalacio-Schjetnan, & Escobar, 2008; Nagahara et al., 2009). Similarly, higher levels of BDNF were associated with enhanced memory, cognition and increased hippocampal volumes in human subjects (Erickson & et al., 2010). Taken together, these studies indicate that elevated hippocampal BDNF is essential to memory (Datta, Siwek, & Huang, 2009). Similar to physical exercise enhancing cognition, physical exercise is known to robustly enhance BDNF signaling, and hence neural cell proliferation, neurogenesis, and synaptic plasticity in rodents (Eadie, Redila, & Christie, 2005; Farmer et al., 2004; Kerr & Swain, 2011; Li et al., 2008; Stranahan, Khalil, & Gould, 2007). These changes result in enhanced long-term potentiation, learning and retention, and enhance performance in cognitive tasks (Cotman & Berchtold, 2002; Stranahan et al., 2010; Vaynman et al., 2007). A recent study confirmed these findings, showing direct correlation between increased hippocampal volume and memory performance improvements in people who exercised (Erickson & et al., 2011). Additionally, human exercisers have been shown to outperform non-exercisers on tasks such as reasoning, working memory, Stroop, Trails-B, Symbol digit, vigilance monitoring, and fluid intelligence tests (Churchill et al., 2002). These beneficial effects of exercise are attributed to increased BDNF signaling (Erickson et al., 2010; Neeper et al., 1996). While exercise is reportedly beneficial for memory function, a high-energy, high-saturated fat diet is associated with cognitive impairment, with a specific effect on learning and memory functions that are dependent on the integrity of the hippocampus (Davidson & et al., 2012). Similarly, saturated fat intake is associated with impaired memory (Kalmijn & et al., 2004) and greater cognitive decline with aging (Okereke et al., 2012; Ortega et al., 1997). As mentioned before, hippocampal BDNF is increased with exercise (Adlard et al., 2004; Neeper et al., 1996; Oliff et al., 1998), it is reduced by a high-fat diet (Molteni et al., 2002, 2004). An elegant study by Molteni and et al. (2004) showed that physical exercise initiated simultaneously with 2 months of high-fat diet prevents the spatial memory impairing effects of high-fat diet.
Whether exercise can reverse cognitive impairments associated with prior exposure to high-fat diet remains unanswered. The aim of this study was to test whether exercise enhances performance on a hippocampus dependent memory test and reverses hippocampus dependent memory impairment produced by high-fat diet exposure, and if exercise-induced cognitive improvement is associated with increased hippocampal BDNF.
146
2. Results
153
2.1. Experiment 1
154
At baseline, animals were randomized to groups such that there were no differences in fat, % fat, weight, lean mass, or % lean mass between groups prior to the initiation of exercise (Table 1A) to avoid potential differences in physical abilities between groups. After the intervention animals with voluntary wheel access weighed less and had lower body fat, % body fat, and elevated lean mass compared with sedentary controls (p < 0.05) (Table 1B). After 5 weeks of either running wheel exercise, treadmill exercise or being sedentary, there was a significant effect of exercise on latency (F2, 24 = 33.10, p < 0.0001) (A) number of escapes (F2, 24 = 105.3, p < 0.0001) (B), avoidances (F2, 24 = 8.9, p = 0.001) (C) and the total response (escape plus avoidance) (F2, 24 = 77.8, p < 0.0001) (D). Five weeks of exercise significantly increased retention of contextual memory, as indicated by decreased latency (p < 0.05) (Fig. 1A), increased number of escapes (p < 0.05) (Fig. 1B) and avoidance episodes, as well as total response (p < 0.05) (Fig. 1D). Treadmill exercised animals had a significantly greater number of shock avoidances (p < 0.05) compared with running wheel and sedentary animals, indicating enhanced capacity to pair the conditioned stimulus of sound and light to the impending shock. The number of avoidances in animals exercising on running wheels tended to be positively related to running distance, although the correlation was not significant (data not shown, R2 = 0.42, p = 0.057). After 5 weeks, running distance was positively correlated with total responses (R2 = 0.58, p < 0.02) (Fig. 2A) and negatively with response latency (R2 = 0.74, p < 0.01) (Fig. 2B) in the TWAA test. Animals were 6 months old at the start of the study and those in voluntary running wheels ran an average of 0.95 ± 0.20 (SEM) km/day (Fig. 2C), which is similar to what has been reported previously for rats 5 months of age fed standard chow (Judge & et al., 2008). Cumulatively, animals on running wheels ran an average
155
Table 1 Comparison of body compositions at baseline and post-five weeks of exercise intervention (experiment one). Characteristics of treadmill (TM), running wheel (RW) and sedentary (Sed) animals were not different from each other prior to exercise intervention (A). After 5 weeks of exercise RW animals had significantly improved body composition compared with Sed animals (B); N = 9–10. TM
RW
Sed
p Value
Mean
SEM
Mean
SEM
Mean
SEM
A Fat (g) Lean (g) Weight (g) %Fat %Lean
102.2 444.1 622.9 16.3 71.4
8.0 9.0 11.9 1.1 1.2
101.5 436.4 619.9 16.3 70.5
7.3 12.1 15.5 1.0 1.3
100.9 443.3 619.6 16.2 71.6
7.2 13.6 18.1 1.0 0.9
0.99 0.88 0.99 0.99 0.98
B Fat (g) Lean (g) Weight (g) %Fat %Lean
105.9 455.2 637.9 16.5 71.4
10.0 11.3 11.8 1.4 1.4
81.6⁄ 435.4 588.5⁄ 13.8⁄ 74.1⁄
8.4 10.4 14.9 1.2 1.2
130.7 445.5 648.9 20.0 68.8
11.3 12.6 18.6 1.5 1.3
0.01 0.49 0.02 0.01 0.03
Please cite this article in press as: Noble, E. E., et al. Exercise reduces diet-induced cognitive decline and increases hippocampal brain-derived neurotrophic factor in CA3 neurons. Neurobiology of Learning and Memory (2014), http://dx.doi.org/10.1016/j.nlm.2014.04.006
147 148 149 150 151 152
156 157 158 159 160 161 162 163 164 165 166
167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187
Q8
YNLME 6101
No. of Pages 11, Model 5G
25 April 2014 3
E.E. Noble et al. / Neurobiology of Learning and Memory xxx (2014) xxx–xxx
A
B
30
* *
10
# Escapes
Latency (sec)
15
*
5
d Se
d Se
TM
W R
D
8
*
6 4
# 2
TM
W R
30
Total response
Avoidance
10
0
0
C
*
20
*
*
20
10
# 0
d Se
TM
R W
Se d
0
TM
W R
Fig. 1. Five weeks of exercise enhances memory. There was a significant effect of exercise on latency (F(2, 24) = 33.10, p < 0.0001) (A) number of escapes (F(2, 24) = 105.3, p < 0.0001) (B), avoidances (F(2, 24) = 8.9, p = 0.001) (C) and total response (escape plus avoidance) (F(2, 24) = 77.8, p < 0.0001) (D). Compared with sedentary (Sed) animals, both running wheel (RW) and treadmill (TM) exercise reduced latency (A), increased the number of escapes (B), and total response (D), (escape plus avoidance). TM and RW animals did not differ from each other except in the number of avoidances (C), where TM exercise resulted in a significantly greater number of total avoidances. Indicates significantly different compared with Sed; # indicates significantly different compared with TM; indicates significantly different compared with RW; p < 0.05, N = 9–10.
A
B
30 20
12
Latency (sec)
Total response
40
R2=0.58 P
