Comprehensive Physiology Wiley Online Library

The Influence of Exercise on Cognitive Abilities

Full Article on Wiley Online Library



Abstract

Scientific evidence based on neuroimaging approaches over the last decade has demonstrated the efficacy of physical activity improving cognitive health across the human lifespan. Aerobic fitness spares age‐related loss of brain tissue during aging, and enhances functional aspects of higher order regions involved in the control of cognition. More active or higher fit individuals are capable of allocating greater attentional resources toward the environment and are able to process information more quickly. These data are suggestive that aerobic fitness enhances cognitive strategies enabling to respond effectively to an imposed challenge with a better yield in task performance. In turn, animal studies have shown that exercise has a benevolent action on health and plasticity of the nervous system. New evidence indicates that exercise exerts its effects on cognition by affecting molecular events related to the management of energy metabolism and synaptic plasticity. An important instigator in the molecular machinery stimulated by exercise is brain‐derived neurotrophic factor, which acts at the interface of metabolism and plasticity. Recent studies show that exercise collaborates with other aspects of lifestyle to influence the molecular substrates of cognition. In particular, select dietary factors share similar mechanisms with exercise, and in some cases they can complement the action of exercise. Therefore, exercise and dietary management appear as a noninvasive and effective strategy to counteract neurological and cognitive disorders. © 2013 American Physiological Society. Compr Physiol 3:403‐428, 2013.

Comprehensive Physiology offers downloadable PowerPoint presentations of figures for non-profit, educational use, provided the content is not modified and full credit is given to the author and publication.

Download a PowerPoint presentation of all images


Figure 1. Figure 1.

Grand averaged response‐locked waveforms for subjects exposed to cardiorespiratory fitness (left side) and acute exercise (right side) showing error and correct trials at the FCz and Pz electrode sites. Reprinted, with permission, from reference (), p. 763.

Figure 2. Figure 2.

Characterization of a stimulus‐locked event‐related potential denoting the N1, P2, N2, and P3 components.

Figure 3. Figure 3.

P3 latencies for young and older men undergoing low and high aerobic fitness. While P3 latency occurred significantly later for the older as compared to young men, the age effect was mostly due to very long P3 latencies of the older low fit men. Each mean was based on data for 15 subjects. The error bars are standard errors of the mean. Reprinted, with permission, from reference (), p. 198.

Figure 4. Figure 4.

P3 latency by group across both conditions of the Eriksen flankers task. Reprinted, with permission, from reference (), p. 180.

Figure 5. Figure 5.

Topographical amplitude maps for the P3a and P3b components for each age and fitness from each stimulus. Note different voltage scales for each task. Reprinted, with permission, from reference (), p. 384.

Figure 6. Figure 6.

Distribution of P3 amplitude across both conditions of the Eriksen flankers at midline sites by group. Reprinted, with permission, from reference (), p. 181.

Figure 7. Figure 7.

Role of brain‐derived neurotrophic factor (BDNF) on the action of exercise on learning and memory assessed in the Morris Water Maze task. (A) Exercise improved learning ability as depicted by the enhanced aptitude of exercised animals to locate the platform in a significantly shorter time (shorter escape latencies in the exc/cytC group). Blocking BDNF action during exercise resulted in escape latency comparable to sedentary control animal (exc/TrkB‐IgG vs. sed/cytC). The BDNF receptor blocker TrkB‐IgG was injected into the hippocampus and cytochrome C (cytC) was used as a vehicle control. Data are expressed as mean ± SEM (ANOVA; Fischer test; Scheffe Fischer test; *, P < 0.05; **,‡‡, P < 0.01; * represents comparison between groups, ‡‡ represents comparison within groups). (B) Exercise increased the memory retention as indicated by significantly more time in quadrant P than sedentary controls (exc/cytC vs. sed/cytC). Blocking BDNF action during exercise abolished this exercise‐induced preference for the P quadrant (exc/TrkB‐IgG vs. exc/cytC), to sedentary control levels (exc/TrkB‐IgG vs. sed/cytC). Representative samples of trials traveled during the probe test (B, begin, E, end, P, quadrant which previously housed the platform). Each value represents the mean ± SEM (ANOVA; Fischer test; *, P < 0.05). Reprinted, with permission, from reference (), pp. 2582, 2584.

Figure 8. Figure 8.

Potential mechanism through which insulin‐like growth factor 1 (IGF‐1) may interface with brain‐derived neurotrophic factor (BDNF)‐mediated synaptic plasticity in the hippocampus during exercise. Exercise can induce IGF‐1 production in the hippocampus. IGF‐1 and BDNF are shown to have similar downstream signaling mechanisms, incorporating both p‐CAMKII and p‐MAPKII signaling cascades. In turn, these affect the state of vesicular release and gene expression by modulating synapsin I and CREB, respectively. IGF‐1 may modulate BDNF possibly at the pro‐BDNF level. The regulation of IGF‐1 and BDNF mRNA expression, BDNF, and pro‐BDNF protein is illustrated on the postsynaptic membrane for concise purposes, although this type of regulation likely occurs on the presynaptic neuron as well. Reprinted, with permission, from reference (), p. 831.

Figure 9. Figure 9.

Proteomic analysis showing preponderant action of exercise on proteins associated with energy metabolism and synaptic plasticity. Representative two‐dimensional gels of the hippocampus from sedentary (panel A) and exercise (panel B) rats. The boxes in A and B represent the areas enlarged in C and D showing the position of protein spots. The diagram on the right illustrates the relative proportion of protein types stimulated by voluntary exercise. Modified, with permission, from reference (), p. 1270

Figure 10. Figure 10.

Proposed mechanism by which exercise enhances cognitive function by engaging aspects of cellular energy metabolism. There is a crucial association between metabolic energy and synaptic plasticity, in which brain‐derived neurotrophic factor (BDNF) plays a crucial role. The effects of exercise on hippocampal BDNF would activate several molecular systems involved in the metabolism of energy, thereby modulating the capacity of the synapse to process information relevant to cognitive function. In particular, molecular systems such as uMtCK, AMPK, and UCP‐2 may work at the interface between energy and synaptic plasticity. Energy related‐molecules can interact with BDNF to modulate synaptic plasticity and cognitive function. Therefore, BDNF appears to be a central integrator for the effects of exercise on synaptic markers and energy metabolic processes to affect cognitive function. Reprinted, with permission, from reference (), p. 2284.

Figure 11. Figure 11.

Exercise regulates brain‐derived neurotrophic factor (BDNF) using epigenetic mechanisms. (A) Voluntary exercise increased histone H3 acetylation in hippocampi of rats assessed using chromatin immunoprecipitation (ChIP) assay. Primers specific to BDNF promoter IV were used to amplify the DNA from the AceH3 immunoprecipitates, and the relative enrichments of the BDNF promoter IV in the AceH3 immunoprecipitates were measured using real‐time PCR. Equal amounts of DNA from sedentary (Sed) or exercised (Exc) rat hippocampi were used for immunoprecipitation. Data are presented as means ± SEM; *, P < 0.05. (B) Levels of AceH3 and H3 were assessed by Western blot analysis in the same hippocampal tissue used for the ChIP assay, and found a significant (**, P < 0.01) increase in the ratio AceH3/H3 in the exercise group compared to sedentary rats. Reprinted, with permission, from reference (), p. 387.

Figure 12. Figure 12.

Exercise regulates brain‐derived neurotrophic factor (BDNF) using epigenetic mechanisms. Exercise reduced DNA methylation of BDNF exon IV promoter in rat hippocampus. (A) The bar graph shows the DNA methylation levels of exercise and sedentary control animals on six CpG sites. Bisulfite sequencing analysis showed that the DNA methylation level was less in animals exposed to exercise, −148 CpG site showing the most dramatic DNA demethylation. (B) The number on top of the diagram labels the position of CpG sites relative to the transcription starting site (+1), and each horizontal line represents result for one clone (opened circles: unmethylated CpGs, filled circles: methylated CpGs). The DNA methylation level was calculated by the number of methylated CpG divided by the total number of CpGs analyzed, values represent the mean ± SEM; *, P < 0.05. (Sed: Sedentary; Exc: exercise). Reprinted, with permission, from reference (), p. 385.

Figure 13. Figure 13.

Proposed mechanism by which exercise impacts synaptic plasticity and cognitive abilities by engaging aspects of epigenetic regulation. As discussed in the text, changes in energy metabolism may be an important mediator for the effects of exercise on synaptic plasticity, in a process engaging mechanisms of epigenetic regulation. Exercise promotes DNA demethylation in BDNF promoter IV, involving phosphorylation of methyl CpG binding protein 2 (MeCP2), and acetylation of histone H3. These events may result in dissociation of MeCP2 and chromatin remodeling events leading to BDNF gene transcription. The effects of exercise on brain‐derived neurotrophic factor (BDNF) regulation may also involve the action of histone deacetylases (HDACs) such as HDAC5 implicated in the regulation of BDNF gene (Tsankova et al., 2006). Exercise elevates the activated stages of calcium/calmodulin‐dependent protein kinase II (p‐CaMKII) and cAMP response element binding protein (p‐CREB), which in turn can contribute to regulate BDNF transcription, as well as participate in the signaling events by which BDNF influences synaptic plasticity and cognitive abilities. The impact of exercise on the remodeling of chromatin containing the BDNF gene emphasizes the importance of exercise on the control of gene transcription in the context of brain function and plasticity. Reprinted, with permission, from reference (), p. 388.

Figure 14. Figure 14.

Hypothetical mechanism by which the interaction of exercise with other aspects of lifestyle such as feeding would affect cognitive abilities. Exercise activates molecular systems involved in energy metabolism and synaptic plasticity, and the interaction between these systems influences cognitive function. The same type of interaction may involve epigenetic mechanisms with long‐lasting effects on cognition. Diet and exercise can affect mitochondrial energy production, which is important for maintaining neuronal excitability and synaptic function. The combined applications of select diets and exercise can have synergistic effects on synaptic plasticity and cognitive function. Specific energy events may regulate the activation of molecules such as BDNF and IGF‐1 that support synaptic plasticity and cognitive function. The mitochondrion manages the balance of energy so that excess energy production caused by high caloric intake or strenuous exercise results in formation of reactive oxygen species (ROS). When ROS levels exceed the buffering capacity of the cell, synaptic plasticity and cognitive function are compromised. Failure to maintain energy homeostasis can gradually affect the cellular machinery associated with cognitive function, and increase the risk for mental disorders. Healthy diets and physiological levels of exercise, which have the capacity to reestablish cellular homeostasis, that is, energy metabolism and buffer ROS, can help to maintain cognitive function under challenging situations. Reprinted, with permission, from reference (), p. 571.

Figure 15. Figure 15.

Brain‐derived neurotrophic factor (BDNF) works at the interface of energy and cognition. Dietary omega‐3 fatty acids can affect synaptic plasticity and cognition. The omega‐3 fatty acid DHA that is mainly found in fish, can affect synaptic function and cognitive abilities by providing plasma membrane fluidity at synaptic regions. The fact that docosahexaenoic (DHA) constitutes more than the 30% of the total phospholipids composition in brain plasma membranes, makes DHA crucial for maintaining neuronal excitability and synaptic function that rely on membrane integrity. Dietary DHA is indispensable for maintaining membrane ionic permeability and function of transmembrane receptors that support synaptic transmission and cognitive abilities. Omega‐3 fatty acids also activate energy‐generating metabolic pathways that subsequently affect molecules such as BDNF and insulin‐like growth factor 1 (IGF‐1). IGF‐1 can also be produced in the gastrointestinal system (liver) and skeletal muscle such that IGF‐1 can convey peripheral messages to the brain in the context of diet and exercise. BDNF and IGF‐1 signaling can activate pathways associated with learning and memory such as the mitogen‐activated protein (MAP) kinase, and CaMKII signaling systems and modulations of synapsin I and cAMP response element binding protein (CREB). BDNF has also been involved in modulating synaptic plasticity and neuronal function through the PI3K/Akt and the mTOR‐PI3K signaling systems. The activity of the mTOR and Akt signaling pathways are also modulated by metabolic signals such as insulin and leptin. Reprinted, with permission, from reference (), p. 572.

Figure 16. Figure 16.

Cartoonish representation that illustrates the interaction between exercise and diet on the regulation of brain plasticity and cognitive function. (A) Based on experimental evidence (), exercise or a diet rich in the omega‐3 fatty acid docosahexaenoic can increase the expression of genes involved in synaptic plasticity and function while a high‐saturated fat and sucrose (HF) diet has the opposite effects. Dietary supplementation with omega‐3 fatty acids elevates levels of brain‐derived neurotrophic factor (BDNF)‐mediated synaptic plasticity in the hippocampus, a brain region important for learning and memory. Molecular changes are associated with an enhancement in hippocampal‐dependent spatial learning performance in the Morris water maze (MWM). (B) In turn, animals exposed for three weeks to a HF diet showed opposite effects to the omega‐3 fatty acid diet on BDNF levels and cognitive capacity. Concomitant exposure of the animals to voluntary running wheel exercise enhanced the effects of the omega‐3 fatty acid diet, while counteracted the effects of the HF diet on synaptic markers and cognitive ability. Values are expressed as a percentage of control (regular diet, no exercise). Modified, with permission, from reference (), p. 575

Figure 17. Figure 17.

Exercise contributes to the action of an omega‐3 diet by supporting plasma membrane homeostasis. Exercise enhanced the effects of docosahexaenoic (DHA) dietary supplementation on syntaxin 3 (STX‐3), a protein associated with synaptic membrane (A). The values were converted to percent of RD‐Sed controls (mean ± SEM; ANOVA; **, P < 0.01). (B) The levels of STX‐3 changed proportionally to the amount of exercise in animals fed the DHA diet (DHA‐Exc). (C‐F) Immunofluorescence for STX‐3 in coronal sections of the hippocampus after DHA diet combined with exercise. Representative sections show STX‐3 red fluorescence label (Cy3 secondary antibody) in RD‐Sed (C and E) controls and DHA‐Exc (D and F) rats. High magnification photomicrographs of CA3 hippocampal areas highlighted in E and F show a marked increase in STX‐3 immunofluorescence (white arrows) in a (F) DHA‐Exc rat compared to a (E) RD‐Sed control. Immunofluorescence for myelin‐associated glycoprotein was performed in the same brain sections to label myelinated axons in green (FITC secondary antibody). Reprinted, with permission, from reference (), p. 34.



Figure 1.

Grand averaged response‐locked waveforms for subjects exposed to cardiorespiratory fitness (left side) and acute exercise (right side) showing error and correct trials at the FCz and Pz electrode sites. Reprinted, with permission, from reference (), p. 763.



Figure 2.

Characterization of a stimulus‐locked event‐related potential denoting the N1, P2, N2, and P3 components.



Figure 3.

P3 latencies for young and older men undergoing low and high aerobic fitness. While P3 latency occurred significantly later for the older as compared to young men, the age effect was mostly due to very long P3 latencies of the older low fit men. Each mean was based on data for 15 subjects. The error bars are standard errors of the mean. Reprinted, with permission, from reference (), p. 198.



Figure 4.

P3 latency by group across both conditions of the Eriksen flankers task. Reprinted, with permission, from reference (), p. 180.



Figure 5.

Topographical amplitude maps for the P3a and P3b components for each age and fitness from each stimulus. Note different voltage scales for each task. Reprinted, with permission, from reference (), p. 384.



Figure 6.

Distribution of P3 amplitude across both conditions of the Eriksen flankers at midline sites by group. Reprinted, with permission, from reference (), p. 181.



Figure 7.

Role of brain‐derived neurotrophic factor (BDNF) on the action of exercise on learning and memory assessed in the Morris Water Maze task. (A) Exercise improved learning ability as depicted by the enhanced aptitude of exercised animals to locate the platform in a significantly shorter time (shorter escape latencies in the exc/cytC group). Blocking BDNF action during exercise resulted in escape latency comparable to sedentary control animal (exc/TrkB‐IgG vs. sed/cytC). The BDNF receptor blocker TrkB‐IgG was injected into the hippocampus and cytochrome C (cytC) was used as a vehicle control. Data are expressed as mean ± SEM (ANOVA; Fischer test; Scheffe Fischer test; *, P < 0.05; **,‡‡, P < 0.01; * represents comparison between groups, ‡‡ represents comparison within groups). (B) Exercise increased the memory retention as indicated by significantly more time in quadrant P than sedentary controls (exc/cytC vs. sed/cytC). Blocking BDNF action during exercise abolished this exercise‐induced preference for the P quadrant (exc/TrkB‐IgG vs. exc/cytC), to sedentary control levels (exc/TrkB‐IgG vs. sed/cytC). Representative samples of trials traveled during the probe test (B, begin, E, end, P, quadrant which previously housed the platform). Each value represents the mean ± SEM (ANOVA; Fischer test; *, P < 0.05). Reprinted, with permission, from reference (), pp. 2582, 2584.



Figure 8.

Potential mechanism through which insulin‐like growth factor 1 (IGF‐1) may interface with brain‐derived neurotrophic factor (BDNF)‐mediated synaptic plasticity in the hippocampus during exercise. Exercise can induce IGF‐1 production in the hippocampus. IGF‐1 and BDNF are shown to have similar downstream signaling mechanisms, incorporating both p‐CAMKII and p‐MAPKII signaling cascades. In turn, these affect the state of vesicular release and gene expression by modulating synapsin I and CREB, respectively. IGF‐1 may modulate BDNF possibly at the pro‐BDNF level. The regulation of IGF‐1 and BDNF mRNA expression, BDNF, and pro‐BDNF protein is illustrated on the postsynaptic membrane for concise purposes, although this type of regulation likely occurs on the presynaptic neuron as well. Reprinted, with permission, from reference (), p. 831.



Figure 9.

Proteomic analysis showing preponderant action of exercise on proteins associated with energy metabolism and synaptic plasticity. Representative two‐dimensional gels of the hippocampus from sedentary (panel A) and exercise (panel B) rats. The boxes in A and B represent the areas enlarged in C and D showing the position of protein spots. The diagram on the right illustrates the relative proportion of protein types stimulated by voluntary exercise. Modified, with permission, from reference (), p. 1270



Figure 10.

Proposed mechanism by which exercise enhances cognitive function by engaging aspects of cellular energy metabolism. There is a crucial association between metabolic energy and synaptic plasticity, in which brain‐derived neurotrophic factor (BDNF) plays a crucial role. The effects of exercise on hippocampal BDNF would activate several molecular systems involved in the metabolism of energy, thereby modulating the capacity of the synapse to process information relevant to cognitive function. In particular, molecular systems such as uMtCK, AMPK, and UCP‐2 may work at the interface between energy and synaptic plasticity. Energy related‐molecules can interact with BDNF to modulate synaptic plasticity and cognitive function. Therefore, BDNF appears to be a central integrator for the effects of exercise on synaptic markers and energy metabolic processes to affect cognitive function. Reprinted, with permission, from reference (), p. 2284.



Figure 11.

Exercise regulates brain‐derived neurotrophic factor (BDNF) using epigenetic mechanisms. (A) Voluntary exercise increased histone H3 acetylation in hippocampi of rats assessed using chromatin immunoprecipitation (ChIP) assay. Primers specific to BDNF promoter IV were used to amplify the DNA from the AceH3 immunoprecipitates, and the relative enrichments of the BDNF promoter IV in the AceH3 immunoprecipitates were measured using real‐time PCR. Equal amounts of DNA from sedentary (Sed) or exercised (Exc) rat hippocampi were used for immunoprecipitation. Data are presented as means ± SEM; *, P < 0.05. (B) Levels of AceH3 and H3 were assessed by Western blot analysis in the same hippocampal tissue used for the ChIP assay, and found a significant (**, P < 0.01) increase in the ratio AceH3/H3 in the exercise group compared to sedentary rats. Reprinted, with permission, from reference (), p. 387.



Figure 12.

Exercise regulates brain‐derived neurotrophic factor (BDNF) using epigenetic mechanisms. Exercise reduced DNA methylation of BDNF exon IV promoter in rat hippocampus. (A) The bar graph shows the DNA methylation levels of exercise and sedentary control animals on six CpG sites. Bisulfite sequencing analysis showed that the DNA methylation level was less in animals exposed to exercise, −148 CpG site showing the most dramatic DNA demethylation. (B) The number on top of the diagram labels the position of CpG sites relative to the transcription starting site (+1), and each horizontal line represents result for one clone (opened circles: unmethylated CpGs, filled circles: methylated CpGs). The DNA methylation level was calculated by the number of methylated CpG divided by the total number of CpGs analyzed, values represent the mean ± SEM; *, P < 0.05. (Sed: Sedentary; Exc: exercise). Reprinted, with permission, from reference (), p. 385.



Figure 13.

Proposed mechanism by which exercise impacts synaptic plasticity and cognitive abilities by engaging aspects of epigenetic regulation. As discussed in the text, changes in energy metabolism may be an important mediator for the effects of exercise on synaptic plasticity, in a process engaging mechanisms of epigenetic regulation. Exercise promotes DNA demethylation in BDNF promoter IV, involving phosphorylation of methyl CpG binding protein 2 (MeCP2), and acetylation of histone H3. These events may result in dissociation of MeCP2 and chromatin remodeling events leading to BDNF gene transcription. The effects of exercise on brain‐derived neurotrophic factor (BDNF) regulation may also involve the action of histone deacetylases (HDACs) such as HDAC5 implicated in the regulation of BDNF gene (Tsankova et al., 2006). Exercise elevates the activated stages of calcium/calmodulin‐dependent protein kinase II (p‐CaMKII) and cAMP response element binding protein (p‐CREB), which in turn can contribute to regulate BDNF transcription, as well as participate in the signaling events by which BDNF influences synaptic plasticity and cognitive abilities. The impact of exercise on the remodeling of chromatin containing the BDNF gene emphasizes the importance of exercise on the control of gene transcription in the context of brain function and plasticity. Reprinted, with permission, from reference (), p. 388.



Figure 14.

Hypothetical mechanism by which the interaction of exercise with other aspects of lifestyle such as feeding would affect cognitive abilities. Exercise activates molecular systems involved in energy metabolism and synaptic plasticity, and the interaction between these systems influences cognitive function. The same type of interaction may involve epigenetic mechanisms with long‐lasting effects on cognition. Diet and exercise can affect mitochondrial energy production, which is important for maintaining neuronal excitability and synaptic function. The combined applications of select diets and exercise can have synergistic effects on synaptic plasticity and cognitive function. Specific energy events may regulate the activation of molecules such as BDNF and IGF‐1 that support synaptic plasticity and cognitive function. The mitochondrion manages the balance of energy so that excess energy production caused by high caloric intake or strenuous exercise results in formation of reactive oxygen species (ROS). When ROS levels exceed the buffering capacity of the cell, synaptic plasticity and cognitive function are compromised. Failure to maintain energy homeostasis can gradually affect the cellular machinery associated with cognitive function, and increase the risk for mental disorders. Healthy diets and physiological levels of exercise, which have the capacity to reestablish cellular homeostasis, that is, energy metabolism and buffer ROS, can help to maintain cognitive function under challenging situations. Reprinted, with permission, from reference (), p. 571.



Figure 15.

Brain‐derived neurotrophic factor (BDNF) works at the interface of energy and cognition. Dietary omega‐3 fatty acids can affect synaptic plasticity and cognition. The omega‐3 fatty acid DHA that is mainly found in fish, can affect synaptic function and cognitive abilities by providing plasma membrane fluidity at synaptic regions. The fact that docosahexaenoic (DHA) constitutes more than the 30% of the total phospholipids composition in brain plasma membranes, makes DHA crucial for maintaining neuronal excitability and synaptic function that rely on membrane integrity. Dietary DHA is indispensable for maintaining membrane ionic permeability and function of transmembrane receptors that support synaptic transmission and cognitive abilities. Omega‐3 fatty acids also activate energy‐generating metabolic pathways that subsequently affect molecules such as BDNF and insulin‐like growth factor 1 (IGF‐1). IGF‐1 can also be produced in the gastrointestinal system (liver) and skeletal muscle such that IGF‐1 can convey peripheral messages to the brain in the context of diet and exercise. BDNF and IGF‐1 signaling can activate pathways associated with learning and memory such as the mitogen‐activated protein (MAP) kinase, and CaMKII signaling systems and modulations of synapsin I and cAMP response element binding protein (CREB). BDNF has also been involved in modulating synaptic plasticity and neuronal function through the PI3K/Akt and the mTOR‐PI3K signaling systems. The activity of the mTOR and Akt signaling pathways are also modulated by metabolic signals such as insulin and leptin. Reprinted, with permission, from reference (), p. 572.



Figure 16.

Cartoonish representation that illustrates the interaction between exercise and diet on the regulation of brain plasticity and cognitive function. (A) Based on experimental evidence (), exercise or a diet rich in the omega‐3 fatty acid docosahexaenoic can increase the expression of genes involved in synaptic plasticity and function while a high‐saturated fat and sucrose (HF) diet has the opposite effects. Dietary supplementation with omega‐3 fatty acids elevates levels of brain‐derived neurotrophic factor (BDNF)‐mediated synaptic plasticity in the hippocampus, a brain region important for learning and memory. Molecular changes are associated with an enhancement in hippocampal‐dependent spatial learning performance in the Morris water maze (MWM). (B) In turn, animals exposed for three weeks to a HF diet showed opposite effects to the omega‐3 fatty acid diet on BDNF levels and cognitive capacity. Concomitant exposure of the animals to voluntary running wheel exercise enhanced the effects of the omega‐3 fatty acid diet, while counteracted the effects of the HF diet on synaptic markers and cognitive ability. Values are expressed as a percentage of control (regular diet, no exercise). Modified, with permission, from reference (), p. 575



Figure 17.

Exercise contributes to the action of an omega‐3 diet by supporting plasma membrane homeostasis. Exercise enhanced the effects of docosahexaenoic (DHA) dietary supplementation on syntaxin 3 (STX‐3), a protein associated with synaptic membrane (A). The values were converted to percent of RD‐Sed controls (mean ± SEM; ANOVA; **, P < 0.01). (B) The levels of STX‐3 changed proportionally to the amount of exercise in animals fed the DHA diet (DHA‐Exc). (C‐F) Immunofluorescence for STX‐3 in coronal sections of the hippocampus after DHA diet combined with exercise. Representative sections show STX‐3 red fluorescence label (Cy3 secondary antibody) in RD‐Sed (C and E) controls and DHA‐Exc (D and F) rats. High magnification photomicrographs of CA3 hippocampal areas highlighted in E and F show a marked increase in STX‐3 immunofluorescence (white arrows) in a (F) DHA‐Exc rat compared to a (E) RD‐Sed control. Immunofluorescence for myelin‐associated glycoprotein was performed in the same brain sections to label myelinated axons in green (FITC secondary antibody). Reprinted, with permission, from reference (), p. 34.

References
 1. Ang ET, Tai YK, Lo SQ, Seet R, Soong TW. Neurodegenerative diseases: Exercising toward neurogenesis and neuroregeneration. Front Aging Neurosci 2: pii. 25, 2010.
 2. Anlar B, Sullivan KA, Feldman EL. Insulin‐like growth factor‐I and central nervous system development. Horm Metab Res 31: 120‐125, 1999.
 3. Baker LD, Frank LL, Foster‐Schubert K, Green PS, Wilkinson CW, McTiernan A, Plymate SR, Fishel MA, Watson GS, Cholerton BA, Duncan GE, Mehta PD, Craft S. Effects of aerobic exercise on mild cognitive impairment: A controlled trial. Arch Neurol 67: 71‐79, 2010.
 4. Barrientos RM, Frank MG, Crysdale NY, Chapman TR, Ahrendsen JT, Day HE, Campeau S, Watkins LR, Patterson SL, Maier SF. Little exercise, big effects: Reversing aging and infection‐induced memory deficits, and underlying processes. J Neurosci 31: 11578‐11586, 2011.
 5. Baylor AM, Spirduso WW. Systematic aerobic exercise and components of reaction time in older women. J Gerontol 43: P121‐P126, 1988.
 6. Beise D, Peaseley V. The relationship of reaction time, speed, and agility of big muscle groups and certain sport skills. Research Quarterly 8: 133‐142, 1937.
 7. Berchtold NC, Castello N, Cotman CW. Exercise and time‐dependent benefits to learning and memory. Neuroscience 167: 588‐597, 2010.
 8. Berchtold NC, Chinn G, Chou M, Kesslak JP, Cotman CW. Exercise primes a molecular memory for brain‐derived neurotrophic factor protein induction in the rat hippocampus. Neuroscience 133: 853‐861, 2005.
 9. Bernstein PS, Scheffers MK, Coles MG. “ Where did I go wrong?” A psychophysiological analysis of error detection. J Exp Psychol Hum Percept Perform 21: 1312‐1322, 1995.
 10. Black JE, Isaacs KR, Anderson BJ, Alcantara AA, Greenough WT. Learning causes synaptogenesis, whereas motor activity causes angiogenesis, in cerebellar cortex of adult rats. Proc Natl Acad Sci U S A 87: 5568‐5572, 1990.
 11. Blair C, Zelazo PD, Greenberg MT. The measurement of executive function in early childhood. Dev Neuropsychol 28: 561‐571, 2005.
 12. Booth FW, Chakravarthy MV, Gordon SE, Spangenburg EE. Waging war on physical inactivity: Using modern molecular ammunition against an ancient enemy. J Appl Physiol 93: 3‐30, 2002.
 13. Botvinick MM, Braver TS, Barch DM, Carter CS, Cohen JD. Conflict monitoring and cognitive control. Psychol Rev 108: 624‐652, 2001.
 14. Buck SM, Hillman CH, Castelli DM. The relation of aerobic fitness to stroop task performance in preadolescent children. Med Sci Sports Exerc 40: 166‐172, 2008.
 15. Buckley PF, Pillai A, Howell KR. Brain‐derived neurotrophic factor: Findings in schizophrenia. Curr Opin Psychiatry 24: 122‐127, 2011.
 16. Bugg JM, Head D. Exercise moderates age‐related atrophy of the medial temporal lobe. Neurobiol Aging 32: 506‐514, 2011.
 17. Burdette JH, Laurienti PJ, Espeland MA, Morgan A, Telesford Q, Vechlekar CD, Hayasaka S, Jennings JM, Katula JA, Kraft RA, Rejeski WJ. Using network science to evaluate exercise‐associated brain changes in older adults. Front Aging Neurosci 2: 23, 2010.
 18. Burpee RH, Stroll W. Measuring reaction time of athletes. Research Quarterly 7: 110‐118, 1936.
 19. Burzynski SR. Gene silencing–a new theory of aging. Med Hypotheses 60: 578‐583, 2003.
 20. Carro E, Trejo JL, Busiguina S, Torres‐Aleman I. Circulating insulin‐like growth factor I mediates the protective effects of physical exercise against brain insults of different etiology and anatomy. J Neurosci 21: 5678‐5684, 2001.
 21. Carter CS, Braver TS, Barch DM, Botvinick MM, Noll D, Cohen JD. Anterior cingulate cortex, error detection, and the online monitoring of performance. Science 280: 747‐749, 1998.
 22. Castelli DM, Hillman CH. Physical activity, cognition, and school performance: From neurons to neighborhoods. In: Meyer A, and Gulotta T, editors. Physical Activity as Interventions: Application to Depression, Obesity, Drug Use, and Beyond, (in press).
 23. Chaddock L, Erickson KI, Prakash RS, Kim JS, Voss MW, Vanpatter M, Pontifex MB, Raine LB, Konkel A, Hillman CH, Cohen NJ, Kramer AF. A neuroimaging investigation of the association between aerobic fitness, hippocampal volume, and memory performance in preadolescent children. Brain Res 1358: 172‐183, 2010.
 24. Chaddock L, Hillman CH, Buck SM, Cohen NJ. Aerobic fitness and executive control of relational memory in preadolescent children. Med Sci Sports Exerc 43: 344‐349, 2011.
 25. Chao HT, Zoghbi HY. The yin and yang of MeCP2 phosphorylation. Proc Natl Acad Sci U S A 106: 4577‐4578, 2009.
 26. Chen WG, Chang Q, Lin Y, Meissner A, West AE, Griffith EC, Jaenisch R, Greenberg ME. Derepression of BDNF transcription involves calcium‐dependent phosphorylation of MeCP2. Science 302: 885‐889, 2003.
 27. Chytrova G, Ying Z, Gomez‐Pinilla F. Exercise contributes to the effects of DHA dietary supplementation by acting on membrane‐related synaptic systems. Brain Res 1341: 32‐40, 2009.
 28. Clapp JF, Kim H, Burciu B, Schmidt S, Petry K, Lopez B. Continuing regular exercise during pregnancy: Effect of exercise volume on fetoplacental growth. Am J Obstet Gynecol 186: 142‐147, 2002.
 29. Clark PJ, Brzezinska WJ, Puchalski EK, Krone DA, Rhodes JS. Functional analysis of neurovascular adaptations to exercise in the dentate gyrus of young adult mice associated with cognitive gain. Hippocampus 19: 937‐950, 2009.
 30. Colcombe S, Kramer AF. Fitness effects on the cognitive function of older adults: A meta‐analytic study. Psychol Sci 14: 125‐130, 2003.
 31. Colcombe SJ, Erickson KI, Raz N, Webb AG, Cohen NJ, McAuley E, Kramer AF. Aerobic fitness reduces brain tissue loss in aging humans. J Gerontol A Biol Sci Med Sci 58: 176‐180, 2003.
 32. Colcombe SJ, Erickson KI, Scalf PE, Kim JS, Prakash R, McAuley E, Elavsky S, Marquez DX, Hu L, Kramer AF. Aerobic exercise training increases brain volume in aging humans. J Gerontol A Biol Sci Med Sci 61: 1166‐1170, 2006.
 33. Colcombe SJ, Kramer AF, Erickson KI, Scalf P, McAuley E, Cohen NJ, Webb A, Jerome GJ, Marquez DX, Elavsky S. Cardiovascular fitness, cortical plasticity, and aging. Proc Natl Acad Sci U S A 101: 3316‐3321, 2004.
 34. Coles MGH, Gratton G, Fabiani M. Event‐related potentials. In: Cacioppo JT, Tassinary LG, editors. Principles of Psychophysiology: Physical, Social, and Inferential Elements, New York, NY: Cambridge University Press, 1990, pp. 413‐455.
 35. Coles MGH, Rugg MD. Event‐related brain potentials: An introduction. In: Rugg MD, Coles MGH, editors. Electrophysiology of Mind: Event‐Related Brain Potentials and Cognition, New York, NY: Oxford University Press, 1995, pp. 1‐26.
 36. Collins A, Hill LE, Chandramohan Y, Whitcomb D, Droste SK, Reul JM. Exercise improves cognitive responses to psychological stress through enhancement of epigenetic mechanisms and gene expression in the dentate gyrus. PLoS One 4: e4330, 2009.
 37. Cordain L, Gotshall RW, Eaton SB. Physical activity, energy expenditure and fitness: An evolutionary perspective. Int J Sports Med 19: 328‐335, 1998.
 38. Cowley MA, Smith RG, Diano S, Tschöp M, Pronchuk N, Grove KL, Strasburger CJ, Bidlingmaier M, Esterman M, Heiman ML, Garcia‐Segura LM, Nillni EA, Mendez P, Low MJ, Sotonyi P, Friedman JM, Liu H, Pinto S, Colmers WF, Cone RD, Horvath TL. The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron 37: 649‐661, 2003.
 39. Cusi K, DeFronzo R. Recombinant human insulin‐like growth factor I treatment for 1 week improves metabolic control in type 2 diabetes by ameliorating hepatic and muscle insulin resistance. J Clin Endocrinol Metab 85: 3077‐3084, 2000.
 40. Darios F, Davletov B. Omega‐3 and omega‐6 fatty acids stimulate cell membrane expansion by acting on syntaxin 3. Nature 440: 813‐817, 2006.
 41. Davatzikos C, Resnick SM. Degenerative age changes in white matter connectivity visualized in vivo using magnetic resonance imaging. Cereb Cortex 12: 767‐771, 2002.
 42. Davidson MC, Amso D, Anderson LC, Diamond A. Development of cognitive control and executive functions from 4 to 13 years: Evidence from manipulations of memory, inhibition, and task switching. Neuropsychologia 44: 2037‐2078, 2006.
 43. Deeny SP, Poeppel D, Zimmerman JB, Roth SM, Brandauer J, Witkowski S, Hearn JW, Ludlow AT, Contreras‐Vidal JL, Brandt J, Hatfield BD. Exercise, APOE, and working memory: MEG and behavioral evidence for benefit of exercise in epsilon4 carriers. Biol Psychol 78: 179‐187, 2008.
 44. Dehaene S, Posner MI, Tucker DM. Localization of a neural system for error detection and compensation. Psychol Sci 5: 303‐305, 1994.
 45. Diamond A. The early development of executive functions. In: Bialystok EF, editor. Lifespan Cognition: Mechanisms of Change, New York: Oxford University Press, 2006, pp. 70‐95.
 46. Diano S, Farr SA, Benoit SC, McNay EC, da Silva I, Horvath B, Gaskin FS, Nonaka N, Jaeger LB, Banks WA, Morley JE, Pinto S, Sherwin RS, Xu L, Yamada KA, Sleeman MW, Tschöp MH, Horvath TL. Ghrelin controls hippocampal spine synapse density and memory performance. Nat Neurosci 9: 381‐388, 2006.
 47. Ding Q, Vaynman S, Akhavan M, Ying Z, Gomez‐Pinilla F. Insulin‐like growth factor I interfaces with brain‐derived neurotrophic factor‐mediated synaptic plasticity to modulate aspects of exercise‐induced cognitive function. Neuroscience 140: 823‐833, 2006.
 48. Ding Q, Vaynman S, Souda P, Whitelegge JP, Gomez‐Pinilla F. Exercise affects energy metabolism and neural plasticity‐related proteins in the hippocampus as revealed by proteomic analysis. Eur J Neurosci 24: 1265‐1276, 2006.
 49. Ding Q, Ying Z, Gómez‐Pinilla F. Exercise influences hippocampal plasticity by modulating brain‐derived neurotrophic factor processing. Neuroscience 192: 773‐780, 2011.
 50. Dipietro L, Caspersen CJ, Ostfeld AM, Nadel ER. A survey for assessing physical activity among older adults. Med Sci Sports Exerc 25: 628‐642, 1993.
 51. Donchin E. Presidential address, 1980. Surprise!…Surprise? Psychophysiology 18: 493‐513, 1981.
 52. Donchin E, Coles MGH. Is the P300 component a manifestation of context updating? Behav Brain Sci 11: 355‐372, 1988.
 53. Duncan‐Johnson CC. Young Psychophysiologist Award address, 1980. P300 latency: A new metric of information processing. Psychophysiology 18: 207‐215, 1981.
 54. During MJ, Cao L. VEGF, a mediator of the effect of experience on hippocampal neurogenesis. Curr Alzheimer Res 3: 29‐33, 2006.
 55. Dustman RE, Emmerson RY, Ruhling RO, Shearer DE, Steinhaus LA, Johnson SC, Bonekat HW, Shigeoka JW. Age and fitness effects on EEG, ERPs, visual sensitivity, and cognition. Neurobiol Aging 11: 193‐200, 1990.
 56. Dustman RE, Emmerson RY, Shearer DE. Physical activity, age, and cognitive‐neurophysiological function. J Aging Phys Activ 2: 143‐181, 1994.
 57. Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A, Zaitsev E, Gold B, Goldman D, Dean M, Lu B, Weinberger DR. The BDNF val66met polymorphism affects activity‐dependent secretion of BDNF and human memory and hippocampal function. Cell 112: 257‐269, 2003.
 58. Erickson KI, Prakash RS, Voss MW, Chaddock L, Heo S, McLaren M, Pence BD, Martin SA, Vieira VJ, Woods JA, McAuley E, Kramer AF. Brain‐derived neurotrophic factor is associated with age‐related decline in hippocampal volume. J Neurosci 30: 5368‐5375, 2010.
 59. Erickson KI, Prakash RS, Voss MW, Chaddock L, Hu L, Morris KS, White SM, Wójcicki TR, McAuley E, Kramer AF. Aerobic fitness is associated with hippocampal volume in elderly humans. Hippocampus 19: 1030‐1039, 2009.
 60. Erickson KI, Raji CA, Lopez OL, Becker JT, Rosano C, Newman AB, Gach HM, Thompson PM, Ho AJ, Kuller LH. Physical activity predicts gray matter volume in late adulthood: The Cardiovascular Health Study. Neurology 75: 1415‐1422, 2010.
 61. Erickson KI, Voss MW, Prakash RS, Basak C, Szabo A, Chaddock L, Kim JS, Heo S, Alves H, White SM, Wojcicki TR, Mailey E, Vieira VJ, Martin SA, Pence BD, Woods JA, McAuley E, Kramer AF. Exercise training increases size of hippocampus and improves memory. Proc Natl Acad Sci U S A 108: 3017‐3022, 2011.
 62. Etnier JL, Salazar W, Landers DM, Petruzello SJ, Han M, Nowell P. The influence of physical fitness and exercise upon cognitive functioning: A meta‐analysis. J Sports Exerc Psychol 19: 249‐277, 1997.
 63. Fabel K, Tam B, Kaufer D, Baiker A, Simmons N, Kuo CJ, Palmer TD. VEGF is necessary for exercise‐induced adult hippocampal neurogenesis. Eur J Neurosci 18: 2803‐2812, 2003.
 64. Falkenstein M, Hohnsbein J, Hoormann J, Blanke L. Effects of crossmodal divided attention on late ERP components. II. Error processing in choice reaction tasks. Electroencephalogr Clin Neurophysiol 78: 447‐455, 1991.
 65. Fehm HL, Kern W, Peters A. The selfish brain: Competition for energy resources. Prog Brain Res 153: 129‐140, 2006.
 66. Feng J, Fouse S, Fan G. Epigenetic regulation of neural gene expression and neuronal function. Pediatr Res 61: 58R‐63R, 2007.
 67. Flöel A, Ruscheweyh R, Krüger K, Willemer C, Winter B, Völker K, Lohmann H, Zitzmann M, Mooren F, Breitenstein C, Knecht S. Physical activity and memory functions: Are neurotrophins and cerebral gray matter volume the missing link? Neuroimage 49: 2756‐2763, 2010.
 68. Friedman D, Simpson G, Hamberger M. Age‐related changes in scalp topography to novel and target stimuli. Psychophysiology 30: 383‐396, 1993.
 69. Fukunaga K, Muller D, Miyamoto E. CaM kinase II in long‐term potentiation. Neurochem Int 28: 343‐358, 1996.
 70. Gehring WJ, Goss B, Coles MGH, Meyer DE, Donchin E. A neural system for error detection and compensation. Psychol Sci 4: 385‐390, 1993.
 71. Gilmore JH, Jarskog LF, Vadlamudi S. Maternal infection regulates BDNF and NGF expression in fetal and neonatal brain and maternal‐fetal unit of the rat. J Neuroimmunol 138: 49‐55, 2003.
 72. Gomes da Silva S, Unsain N, Mascó DH, Toscano‐Silva M, de Amorim HA, Silva Araújo BH, Simões PS, da Graça Naffah‐Mazzacoratti M, Mortara RA, Scorza FA, Cavalheiro EA, Arida RM. Early exercise promotes positive hippocampal plasticity and improves spatial memory in the adult life of rats. Hippocampus 22: 347‐358, 2010.
 73. Gomez‐Pinilla F. Brain foods: The effects of nutrients on brain function. Nat Rev Neurosci 9: 568‐578, 2008.
 74. Gomez‐Pinilla F, Vaynman S, Ying Z. Brain‐derived neurotrophic factor functions as a metabotrophin to mediate the effects of exercise on cognition. Eur J Neurosci 28: 2278‐2287, 2008.
 75. Gomez‐Pinilla F, Zhuang Y, Feng J, Ying Z, Fan G. Exercise impacts brain‐derived neurotrophic factor plasticity by engaging mechanisms of epigenetic regulation. Eur J Neurosci 33: 383‐390, 2011.
 76. Griesbach GS, Hovda DA, Gomez‐Pinilla F. Exercise‐induced improvement in cognitive performance after traumatic brain injury in rats is dependent on BDNF activation. Brain Res 1288: 105‐115, 2009.
 77. Gómez‐Pinilla F, Huie JR, Ying Z, Ferguson AR, Crown ED, Baumbauer KM, Edgerton VR, Grau JW. BDNF and learning: Evidence that instrumental training promotes learning within the spinal cord by up‐regulating BDNF expression. Neuroscience 148: 893‐906, 2007.
 78. Gómez‐Pinilla F, Ying Z, Roy RR, Molteni R, Edgerton VR. Voluntary exercise induces a BDNF‐mediated mechanism that promotes neuroplasticity. J Neurophysiol 88: 2187‐2195, 2002.
 79. Hajcak G, Moser JS, Yeung N, Simons RF. On the ERN and the significance of errors. Psychophysiology 42: 151‐160, 2005.
 80. Hall J, Thomas KL, Everitt BJ. Rapid and selective induction of BDNF expression in the hippocampus during contextual learning. Nat Neurosci 3: 533‐535, 2000.
 81. Hardie DG. AMP‐activated protein kinase: A key system mediating metabolic responses to exercise. Med Sci Sports Exerc 36: 28‐34, 2004.
 82. Hariri AR, Goldberg TE, Mattay VS, Kolachana BS, Callicott JH, Egan MF, Weinberger DR. Brain‐derived neurotrophic factor val66met polymorphism affects human memory‐related hippocampal activity and predicts memory performance. J Neurosci 23: 6690‐6694, 2003.
 83. Hashimoto M, Hossain S, Shimada T, Shido O. Docosahexaenoic acid‐induced protective effect against impaired learning in amyloid beta‐infused rats is associated with increased synaptosomal membrane fluidity. Clin Exp Pharmacol Physiol 33: 934‐939, 2006.
 84. Hatta A, Nishihira Y, Kim SR, Kaneda T, Kida T, Kamijo K, Sasahara M, Haga S. Effects of habitual moderate exercise on response processing and cognitive processing in older adults. Jpn J Physiol 55: 29‐36, 2005.
 85. Heffernan AE. Exercise and pregnancy in primary care. Nurse Pract 25: 42, 49, 53‐46 passim, 2000.
 86. Hillman CH, Belopolsky AV, Snook EM, Kramer AF, McAuley E. Physical activity and executive control: Implications for increased cognitive health during older adulthood. Res Q Exerc Sport 75: 176‐185, 2004.
 87. Hillman CH, Castelli DM, Buck SM. Aerobic fitness and neurocognitive function in healthy preadolescent children. Med Sci Sports Exerc 37: 1967‐1974, 2005.
 88. Hillman CH, Erickson KI, Kramer AF. Be smart, exercise your heart: Exercise effects on brain and cognition. Nat Rev Neurosci 9: 58‐65, 2008.
 89. Hillman CH, Kramer AF, Belopolsky AV, Smith DP. A cross‐sectional examination of age and physical activity on performance and event‐related brain potentials in a task switching paradigm. Int J Psychophysiol 59: 30‐39, 2006.
 90. Hillman CH, Motl RW, Pontifex MB, Posthuma D, Stubbe JH, Boomsma DI, de Geus EJ. Physical activity and cognitive function in a cross‐section of younger and older community‐dwelling individuals. Health Psychol 25: 678‐687, 2006.
 91. Hillman CH, Pontifex MB, Raine LB, Castelli DM, Hall EE, Kramer AF. The effect of acute treadmill walking on cognitive control and academic achievement in preadolescent children. Neuroscience 159: 1044‐1054, 2009.
 92. Hillman CH, Weiss EP, Hagberg JM, Hatfield BD. The relationship of age and cardiovascular fitness to cognitive and motor processes. Psychophysiology 39: 303‐312, 2002.
 93. Holroyd CB, Coles MG. The neural basis of human error processing: Reinforcement learning, dopamine, and the error‐related negativity. Psychol Rev 109: 679‐709, 2002.
 94. Honea RA, Thomas GP, Harsha A, Anderson HS, Donnelly JE, Brooks WM, Burns JM. Cardiorespiratory fitness and preserved medial temporal lobe volume in Alzheimer disease. Alzheimer Dis Assoc Disord 23: 188‐197, 2009.
 95. Horrocks LA, Farooqui AA. Docosahexaenoic acid in the diet: Its importance in maintenance and restoration of neural membrane function. Prostaglandins Leukot Essent Fatty Acids 70: 361‐372, 2004.
 96. Hugdahl K. Psychophysiology: The Mind‐Body Perspective. Cambridge, MA: Harvard University Press, 1995, p. 429.
 97. Itoh T, Imano M, Nishida S, Tsubaki M, Hashimoto S, Ito A, Satou T. Exercise increases neural stem cell proliferation surrounding the area of damage following rat traumatic brain injury. J Neural Transm 118: 193‐202, 2011.
 98. Josselyn SA, Nguyen PV. CREB, synapses and memory disorders: Past progress and future challenges. Curr Drug Targets CNS Neurol Disord 4: 481‐497, 2005.
 99. Jung RT. Obesity as a disease. Br Med Bull 53: 307‐321, 1997.
 100. Kamijo K, Takeda Y. General physical activity levels influence positive and negative priming effects in young adults. Clin Neurophysiol 120: 511‐519, 2009.
 101. Kernie SG, Liebl DJ, Parada LF. BDNF regulates eating behavior and locomotor activity in mice. EMBO J 19: 1290‐1300, 2000.
 102. Kernie SG, Parent JM. Forebrain neurogenesis after focal Ischemic and traumatic brain injury. Neurobiol Dis 37: 267‐274, 2010.
 103. Kerns JG, Cohen JD, MacDonald AW, Cho RY, Stenger VA, Carter CS. Anterior cingulate conflict monitoring and adjustments in control. Science 303: 1023‐1026, 2004.
 104. Kesslak JP, So V, Choi J, Cotman CW, Gomez‐Pinilla F. Learning upregulates brain‐derived neurotrophic factor messenger ribonucleic acid: A mechanism to facilitate encoding and circuit maintenance? Behav Neurosci 112: 1012‐1019, 1998.
 105. Kim HY. Novel metabolism of docosahexaenoic acid in neural cells. J Biol Chem 282: 18661‐18665, 2007.
 106. Kleim JA, Chan S, Pringle E, Schallert K, Procaccio V, Jimenez R, Cramer SC. BDNF val66met polymorphism is associated with modified experience‐dependent plasticity in human motor cortex. Nat Neurosci 9: 735‐737, 2006.
 107. Knight RT. Distributed cortical networks for visual attention. J Cogn Neurosci 9: 75‐91, 1997.
 108. Kramer AF, Erickson KI. Capitalizing on cortical plasticity: Influence of physical activity on cognition and brain function. Trends Cogn Sci 11: 342‐348, 2007.
 109. Kramer AF, Hahn S, Cohen NJ, Banich MT, McAuley E, Harrison CR, Chason J, Vakil E, Bardell L, Boileau RA, Colcombe A. Ageing, fitness and neurocognitive function. Nature 400: 418‐419, 1999.
 110. Krueger F, Pardini M, Huey ED, Raymont V, Solomon J, Lipsky RH, Hodgkinson CA, Goldman D, Grafman J. The role of the Met66 brain‐derived neurotrophic factor allele in the recovery of executive functioning after combat‐related traumatic brain injury. J Neurosci 31: 598‐606, 2011.
 111. Laske C, Banschbach S, Stransky E, Bosch S, Straten G, Machann J, Fritsche A, Hipp A, Niess A, Eschweiler GW. Exercise‐induced normalization of decreased BDNF serum concentration in elderly women with remitted major depression. Int J Neuropsychopharmacol 13: 595‐602, 2010.
 112. Lawther JD. Psychology of Coaching. Englewood Cliffs, NJ: Prentice Hall, Inc., 1951, p. 333.
 113. Lopez‐Lopez C, LeRoith D, Torres‐Aleman I. Insulin‐like growth factor I is required for vessel remodeling in the adult brain. Proc Natl Acad Sci U S A 101: 9833‐9838, 2004.
 114. Luck SJ. An Introduction to the Event‐Related Potential Technique. Cambridge, MA: The MIT Press, 2005, p. 388.
 115. Lyons WE, Mamounas LA, Ricaurte GA, Coppola V, Reid SW, Bora SH, Wihler C, Koliatsos VE, Tessarollo L. Brain‐derived neurotrophic factor‐deficient mice develop aggressiveness and hyperphagia in conjunction with brain serotonergic abnormalities. Proc Natl Acad Sci U S A 96: 15239‐15244, 1999.
 116. Ma YL, Wang HL, Wu HC, Wei CL, Lee EH. Brain‐derived neurotrophic factor antisense oligonucleotide impairs memory retention and inhibits long‐term potentiation in rats. Neuroscience 82: 957‐967, 1998.
 117. Martin JL, Finsterwald C. Cooperation between BDNF and glutamate in the regulation of synaptic transmission and neuronal development. Commun Integr Biol 4: 14‐16, 2011.
 118. McDowell K, Kerick SE, Santa Maria DL, Hatfield BD. Aging, physical activity, and cognitive processing: An examination of P300. Neurobiol Aging 24: 597‐606, 2003.
 119. McNay EC. Insulin and ghrelin: Peripheral hormones modulating memory and hippocampal function. Curr Opin Pharmacol 7: 628‐632, 2007.
 120. Miltner WH, Lemke U, Weiss T, Holroyd C, Scheffers MK, Coles MG. Implementation of error‐processing in the human anterior cingulate cortex: A source analysis of the magnetic equivalent of the error‐related negativity. Biol Psychol 64: 157‐166, 2003.
 121. Mizuno M, Yamada K, Olariu A, Nawa H, Nabeshima T. Involvement of brain‐derived neurotrophic factor in spatial memory formation and maintenance in a radial arm maze test in rats. J Neurosci 20: 7116‐7121, 2000.
 122. Molnár E. Long‐term potentiation in cultured hippocampal neurons. Semin Cell Dev Biol 22: 506‐513, 2011.
 123. Molteni R, Barnard RJ, Ying Z, Roberts CK, Gómez‐Pinilla F. A high‐fat, refined sugar diet reduces hippocampal brain‐derived neurotrophic factor, neuronal plasticity, and learning. Neuroscience 112: 803‐814, 2002.
 124. Molteni R, Wu A, Vaynman S, Ying Z, Barnard RJ, Gómez‐Pinilla F. Exercise reverses the harmful effects of consumption of a high‐fat diet on synaptic and behavioral plasticity associated to the action of brain‐derived neurotrophic factor. Neuroscience 123: 429‐440, 2004.
 125. Molteni R, Zheng JQ, Ying Z, Gómez‐Pinilla F, Twiss JL. Voluntary exercise increases axonal regeneration from sensory neurons. Proc Natl Acad Sci U S A 101: 8473‐8478, 2004.
 126. Mu JS, Li WP, Yao ZB, Zhou XF. Deprivation of endogenous brain‐derived neurotrophic factor results in impairment of spatial learning and memory in adult rats. Brain Res 835: 259‐265, 1999.
 127. Must A, Spadano J, Coakley EH, Field AE, Colditz G, Dietz WH. The disease burden associated with overweight and obesity. JAMA 282: 1523‐1529, 1999.
 128. Neeper SA, Gómez‐Pinilla F, Choi J, Cotman CW. Physical activity increases mRNA for brain‐derived neurotrophic factor and nerve growth factor in rat brain. Brain Res 726: 49‐56, 1996.
 129. Nestler EJ. Epigenetic mechanisms in psychiatry. Biol Psychiatry 65: 189‐190, 2009.
 130. Nichol K, Deeny SP, Seif J, Camaclang K, Cotman CW. Exercise improves cognition and hippocampal plasticity in APOE epsilon4 mice. Alzheimers Dement 5: 287‐294, 2009.
 131. O'Sullivan M, Jones DK, Summers PE, Morris RG, Williams SC, Markus HS. Evidence for cortical “disconnection” as a mechanism of age‐related cognitive decline. Neurology 57: 632‐638, 2001.
 132. Pajonk FG, Wobrock T, Gruber O, Scherk H, Berner D, Kaizl I, Kierer A, Müller S, Oest M, Meyer T, Backens M, Schneider‐Axmann T, Thornton AE, Honer WG, Falkai P. Hippocampal plasticity in response to exercise in schizophrenia. Arch Gen Psychiatry 67: 133‐143, 2010.
 133. Pang PT, Lu B. Regulation of late‐phase LTP and long‐term memory in normal and aging hippocampus: Role of secreted proteins tPA and BDNF. Ageing Res Rev 3: 407‐430, 2004.
 134. Pang PT, Teng HK, Zaitsev E, Woo NT, Sakata K, Zhen S, Teng KK, Yung WH, Hempstead BL, Lu B. Cleavage of proBDNF by tPA/plasmin is essential for long‐term hippocampal plasticity. Science 306: 487‐491, 2004.
 135. Parnpiansil P, Jutapakdeegul N, Chentanez T, Kotchabhakdi N. Exercise during pregnancy increases hippocampal brain‐derived neurotrophic factor mRNA expression and spatial learning in neonatal rat pup. Neurosci Lett 352: 45‐48, 2003.
 136. Patterson SL, Abel T, Deuel TA, Martin KC, Rose JC, Kandel ER. Recombinant BDNF rescues deficits in basal synaptic transmission and hippocampal LTP in BDNF knockout mice. Neuron 16: 1137‐1145, 1996.
 137. Pereira AC, Huddleston DE, Brickman AM, Sosunov AA, Hen R, McKhann GM, Sloan R, Gage FH, Brown TR, Small SA. An in vivo correlate of exercise‐induced neurogenesis in the adult dentate gyrus. Proc Natl Acad Sci U S A 104: 5638‐5643, 2007.
 138. Pierson WR, Montoye HJ. Movement time, reaction time, and age. J Gerontol 13: 418‐421, 1958.
 139. Polich J. Clinical application of the P300 event‐related brain potential. Phys Med Rehabil Clin N Am 15: 133‐161, 2004.
 140. Polich J. Updating P300: An integrative theory of P3a and P3b. Clin Neurophysiol 118: 2128‐2148, 2007.
 141. Polich J, Heine MR. P300 topography and modality effects from a single‐stimulus paradigm. Psychophysiology 33: 747‐752, 1996.
 142. Polich J, Lardon MT. P300 and long‐term physical exercise. Electroencephalogr Clin Neurophysiol 103: 493‐498, 1997.
 143. Pontifex MB, Hillman CH, Polich J. Age, physical fitness, and attention: P3a and P3b. Psychophysiology 46: 379‐387, 2009.
 144. Pontifex MB, Raine LB, Johnson CR, Chaddock L, Voss MW, Cohen NJ, Kramer AF, Hillman CH. Cardiorespiratory fitness and the flexible modulation of cognitive control in preadolescent children. J Cogn Neurosci 23: 1332‐1345, 2011.
 145. Posner MI. Attention as a cognitive neural system. Curr Dir Psychol Sci 1: 11‐14, 1992.
 146. Posner MI, Petersen SE. The attention system of the human brain. Annu Rev Neurosci 13: 25‐42, 1990.
 147. Prakash RS, Voss MW, Erickson KI, Lewis JM, Chaddock L, Malkowski E, Alves H, Kim J, Szabo A, White SM, Wójcicki TR, Klamm EL, McAuley E, Kramer AF. Cardiorespiratory fitness and attentional control in the aging brain. Front Hum Neurosci 4: 229, 2011.
 148. Ramsey MM, Adams MM, Ariwodola OJ, Sonntag WE, Weiner JL. Functional characterization of des‐IGF‐1 action at excitatory synapses in the CA1 region of rat hippocampus. J Neurophysiol 94: 247‐254, 2005.
 149. Raz N. Aging of the brain and its impact on cognitive performance: Integration of structural and functional findings. In: Craik F, Salthouse T, editors. Handbook of Aging and Cognition, II, Mahwah, NJ: Erlbaum, 2000, pp. 1‐90.
 150. Raz N, Gunning‐Dixon FM, Head D, Dupuis JH, Acker JD. Neuroanatomical correlates of cognitive aging: Evidence from structural magnetic resonance imaging. Neuropsychology 12: 95‐114, 1998.
 151. Reul JM, Hesketh SA, Collins A, Mecinas MG. Epigenetic mechanisms in the dentate gyrus act as a molecular switch in hippocampus‐associated memory formation. Epigenetics 4: 434‐439, 2009.
 152. Rosano C, Venkatraman VK, Guralnik J, Newman AB, Glynn NW, Launer L, Taylor CA, Williamson J, Studenski S, Pahor M, Aizenstein H. Psychomotor speed and functional brain MRI 2 years after completing a physical activity treatment. J Gerontol A Biol Sci Med Sci 65: 639‐647, 2010.
 153. Rovio S, Spulber G, Nieminen LJ, Niskanen E, Winblad B, Tuomilehto J, Nissinen A, Soininen H, Kivipelto M. The effect of midlife physical activity on structural brain changes in the elderly. Neurobiol Aging 31: 1927‐1936, 2010.
 154. Saatman KE, Contreras PC, Smith DH, Raghupathi R, McDermott KL, Fernandez SC, Sanderson KL, Voddi M, McIntosh TK. Insulin‐like growth factor‐1 (IGF‐1) improves both neurological motor and cognitive outcome following experimental brain injury. Exp Neurol 147: 418‐427, 1997.
 155. Sakamoto K, Karelina K, Obrietan K. CREB: A multifaceted regulator of neuronal plasticity and protection. J Neurochem 116: 1‐9, 2011.
 156. Salem N, Jr, Litman B, Kim HY, Gawrisch K. Mechanisms of action of docosahexaenoic acid in the nervous system. Lipids 36: 945‐959, 2001.
 157. Scheffers MK, Coles MG, Bernstein P, Gehring WJ, Donchin E. Event‐related brain potentials and error‐related processing: An analysis of incorrect responses to go and no‐go stimuli. Psychophysiology 33: 42‐53, 1996.
 158. Scheibel AB. Structural and functional changes in the aging brain. In: Birren JE, Schaie DW, editors. Handbook of the Psychology of Aging, San Diego: Academic Press, 1996, pp. 105‐128.
 159. Scisco JL, Leynes PA, Kang J. Cardiovascular fitness and executive control during task‐switching: An ERP study. Int J Psychophysiol 69: 52‐60, 2008.
 160. Sibley BA, Etnier JL. The relationship between physical activity and cognition in children: A meta‐analysis. Pediatr Exerc Sci 15: 243‐256, 2003.
 161. Smith JC, Nielson KA, Woodard JL, Seidenberg M, Durgerian S, Antuono P, Butts AM, Hantke NC, Lancaster MA, Rao SM. Interactive effects of physical activity and APOE‐ɛ4 on BOLD semantic memory activation in healthy elders. Neuroimage 54: 635‐644, 2011.
 162. Smith PJ, Blumenthal JA, Hoffman BM, Cooper H, Strauman TA, Welsh‐Bohmer K, Browndyke JN, Sherwood A. Aerobic exercise and neurocognitive performance: A meta‐analytic review of randomized controlled trials. Psychosom Med 72: 239‐252, 2010.
 163. Spirduso WW. Reaction and movement time as a function of age and physical activity level. J Gerontol 30: 435‐440, 1975.
 164. Spirduso WW. Physical fitness, aging, and psychomotor speed: A review. J Gerontol 35: 850‐865, 1980.
 165. Spirduso WW, Clifford P. Replication of age and physical activity effects on reaction and movement time. J Gerontol 33: 26‐30, 1978.
 166. Squire LR, Kandel ER. Memory from Mind to Molecules. New York: W.H. Freeman and Co., 1999, p. 235.
 167. Sullivan EV, Pfefferbaum A, Adalsteinsson E, Swan GE, Carmelli D. Differential rates of regional brain change in callosal and ventricular size: A 4‐year longitudinal MRI study of elderly men. Cereb Cortex 12: 438‐445, 2002.
 168. Sutton S, Braren M, Zubin J, John ER. Evoked‐potential correlates of stimulus uncertainty. Science 150: 1187‐1188, 1965.
 169. Suzuki H, Park SJ, Tamura M, Ando S. Effect of the long‐term feeding of dietary lipids on the learning ability, fatty acid composition of brain stem phospholipids and synaptic membrane fluidity in adult mice: A comparison of sardine oil diet with palm oil diet. Mech Ageing Dev 101: 119‐128, 1998.
 170. Sweatt JD. Experience‐dependent epigenetic modifications in the central nervous system. Biol Psychiatry 65: 191‐197, 2009.
 171. Teague WE, Fuller NL, Rand RP, Gawrisch K. Polyunsaturated lipids in membrane fusion events. Cell Mol Biol Lett 7: 262‐264, 2002.
 172. Themanson JR, Hillman CH. Cardiorespiratory fitness and acute aerobic exercise effects on neuroelectric and behavioral measures of action monitoring. Neuroscience 141: 757‐767, 2006.
 173. Themanson JR, Hillman CH, Curtin JJ. Age and physical activity influences on action monitoring during task switching. Neurobiol Aging 27: 1335‐1345, 2006.
 174. Themanson JR, Pontifex MB, Hillman CH. Fitness and action monitoring: Evidence for improved cognitive flexibility in young adults. Neuroscience 157: 319‐328, 2008.
 175. Thiel G. Synapsin I, synapsin II, and synaptophysin: Marker proteins of synaptic vesicles. Brain Pathol 3: 87‐95, 1993.
 176. Tomporowski PD, Davis CL, Miller PH, Naglieri JA. Exercise and children's intelligence, cognition, and academic achievement. Educ Psychol Rev 20: 111‐131, 2008.
 177. Tonra JR, Ono M, Liu X, Garcia K, Jackson C, Yancopoulos GD, Wiegand SJ, Wong V. Brain‐derived neurotrophic factor improves blood glucose control and alleviates fasting hyperglycemia in C57BLKS‐Lepr(db)/lepr(db) mice. Diabetes 48: 588‐594, 1999.
 178. Trejo JL, Carro E, Torres‐Aleman I. Circulating insulin‐like growth factor I mediates exercise‐induced increases in the number of new neurons in the adult hippocampus. J Neurosci 21: 1628‐1634, 2001.
 179. Trudeau F, Shephard RJ. Physical education, school physical activity, school sports and academic performance. Int J Behav Nutr Phys Act 5: 10, 2008.
 180. Tsai SJ, Hong CJ, Liou YJ. Effects of BDNF polymorphisms on antidepressant action. Psychiatry Investig 7: 236‐242, 2010.
 181. Tsankova NM, Berton O, Renthal W, Kumar A, Neve RL, Nestler EJ. Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nat Neurosci 9: 519‐525, 2006.
 182. Uchida S, Inanaga Y, Kobayashi M, Hurukawa S, Araie M, Sakuragawa N. Neurotrophic function of conditioned medium from human amniotic epithelial cells. J Neurosci Res 62: 585‐590, 2000.
 183. Uzendoski AM, Latin RW, Berg KE, Moshier S. Physiological responses to aerobic exercise during pregnancy and post‐partum. J Sports Med Phys Fitness 30: 77‐82, 1990.
 184. van der Lely AJ, Tschöp M, Heiman ML, Ghigo E. Biological, physiological, pathophysiological, and pharmacological aspects of ghrelin. Endocr Rev 25: 426‐457, 2004.
 185. van Praag H. Exercise and the brain: Something to chew on. Trends Neurosci 32: 283‐290, 2009.
 186. Van Veen V, Carter CS. The timing of action‐monitoring processes in the anterior cingulate cortex. J Cogn Neurosci 14: 593‐602, 2002.
 187. Vasuta C, Caunt C, James R, Samadi S, Schibuk E, Kannangara T, Titterness AK, Christie BR. Effects of exercise on NMDA receptor subunit contributions to bidirectional synaptic plasticity in the mouse dentate gyrus. Hippocampus 17: 1201‐1208, 2007.
 188. Vaynman S, Gomez‐Pinilla F. Revenge of the “sit”: How lifestyle impacts neuronal and cognitive health through molecular systems that interface energy metabolism with neuronal plasticity. J Neurosci Res 84: 699‐715, 2006.
 189. Vaynman S, Ying Z, Gomez‐Pinilla F. Interplay between brain‐derived neurotrophic factor and signal transduction modulators in the regulation of the effects of exercise on synaptic‐plasticity. Neuroscience 122: 647‐657, 2003.
 190. Vaynman S, Ying Z, Gomez‐Pinilla F. Hippocampal BDNF mediates the efficacy of exercise on synaptic plasticity and cognition. Eur J Neurosci 20: 2580‐2590, 2004.
 191. Voss MW, Erickson KI, Prakash RS, Chaddock L, Malkowski E, Alves H, Kim JS, Morris KS, White SM, Wójcicki TR, Hu L, Szabo A, Klamm E, McAuley E, Kramer AF. Functional connectivity: A source of variance in the association between cardiorespiratory fitness and cognition? Neuropsychologia 48: 1394‐1406, 2010.
 192. Voss MW, Prakash RS, Erickson KI, Basak C, Chaddock L, Kim JS, Alves H, Heo S, Szabo AN, White SM, Wójcicki TR, Mailey EL, Gothe N, Olson EA, McAuley E, Kramer AF. Plasticity of brain networks in a randomized intervention trial of exercise training in older adults. Front Aging Neurosci 2: 1‐17, 2010.
 193. Waddington CH. Canalization of development and the inheritance of acquired characters. Nature 150: 563‐565, 1942.
 194. Wendorf M, Goldfine ID. Archaeology of NIDDM. Excavation of the “thrifty” genotype. Diabetes 40: 161‐165, 1991.
 195. Wren AM, Seal LJ, Cohen MA, Brynes AE, Frost GS, Murphy KG, Dhillo WS, Ghatei MA, Bloom SR. Ghrelin enhances appetite and increases food intake in humans. J Clin Endocrinol Metab 86: 5992, 2001.
 196. Wu A, Ying Z, Gomez‐Pinilla F. Docosahexaenoic acid dietary supplementation enhances the effects of exercise on synaptic plasticity and cognition. Neuroscience 155: 751‐759, 2008.
 197. Yeung N, Botvinick MM, Cohen JD. The neural basis of error detection: Conflict monitoring and the error‐related negativity. Psychol Rev 111: 931‐959, 2004.
 198. Zenobi PD, Holzmann P, Glatz Y, Riesen WF, Froesch ER. Improvement of lipid profile in type 2 (non‐insulin‐dependent) diabetes mellitus by insulin‐like growth factor I. Diabetologia 36: 465‐469, 1993.

Related Articles:

Maintenance and Regulation in Brain of Neurotransmission, Trophic Factors, and Immune Responses
Electrophysiology of Cognition
Mechanisms of Transmembrane Signaling
Mechanisms of Learning in Complex Neural Systems

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite

Fernando Gomez‐Pinilla, Charles Hillman. The Influence of Exercise on Cognitive Abilities. Compr Physiol 2013, 3: 403-428. doi: 10.1002/cphy.c110063