Physical activity elicits sustained activation of the cyclic AMP response element-binding protein and mitogen-activated protein kinase in the rat hippocampus

Shen, Hong; Tong, Liqi; Balázs, R.; Cotman, Carl W.

doi:10.1016/s0306-4522(01)00315-3

Cited by 109 publications

(71 citation statements)

References 56 publications

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“…At the end of 12 weeks of treadmill running, the runners would have covered an approximate total distance of 90km, averaging about 1.5km/day. This is well above the threshold of 0.5km/day previously indicated for activation of signaling molecules that influence synaptic plasticity, including learning and memory (Shen et al, 2001). While the voluntary paradigm (running wheel) also allowed estimation of distance covered, it is felt that the running speed might differ over time.…”

Section: Discussionmentioning

confidence: 62%

“…A forced exercise regime is more akin to human physical training and arguably more objective in terms of outcome measure as it allows for more accurate correlation between the amounts of exercise to any potential benefits arising therefrom. For instance, it was documented that a certain distance must be covered before any biochemical changes were observed (Shen et al, 2001). Fordyce and Farrar (1991a, b) reported that F344 rats exhibited enhanced performance on certain spatial tasks after a 14-week treadmill running program.…”

Section: Introductionmentioning

confidence: 99%

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Alterations in spatial learning and memory after forced exercise

et al. 2006

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A B S T R A C TExercise has been shown to influence learning and memory. Most studies were performed with a voluntary running paradigm (e.g. running wheel) in mice. However, such effects of exercise on learning and memory are less well demonstrated using a forced running paradigm (e.g. treadmill). The present study was designed to examine the effects of 12 weeks of forced treadmill running on learning and memory performance in rats. We have previously shown that forced running resulted in qualitative and quantitative changes in the cholinergic neurons of the horizontal diagonal band of Broca (HDB) in the septum. This study was conducted in order to determine whether or not these changes occur simultaneously with enhanced learning and memory. The one-day version of the Morris water maze (MWM) test [Frick, K.M., Stillner, E.T., Berger-Sweeney, J., 2000. Mice are not little rats: species differences in a one-day water maze task. NeuroReport 11, 3461-3465] was used to test spatial learning and memory after the exercise period. Our data showed that runners displayed better spatial learning and memory when compared to nonrunners. This was evidently shown by a reduction in the time required for spatial acquisition (p < 0.05) and superior probe trial performance (p < 0.05). A shorter distance swam by the runners also suggested improved learning over the nonrunners (p < 0.05). In an attempt to revalidate our earlier quantitative results, we used design-based stereology (DBS) to estimate the number of cholinergic neuronal profile population in the medial septum and diagonal band (MSDB).We confirmed that forced running increased the cholinergic neuronal profile subpopulation in the HDB (Coefficient of Error < 0.2). Taken together, these results indicate that forced exercise could influence learning and memory with a concomitant increase in the number of cholinergic neurons in the HDB.⁎ Corresponding authors. E.-T. Ang is to be contacted at

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Section: Discussionmentioning

confidence: 62%

Section: Introductionmentioning

confidence: 99%

Alterations in spatial learning and memory after forced exercise

et al. 2006

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“…A more likely scenario, however, is that exercise is modulating APP metabolism directly (for review, see Turner et al, 2003) by increases in neuronal activity (Lee et al, 2003). For example, APP processing can be augmented by PKC, MAPK (mitogen-activated protein kinase), and phospholipase C (for review, see Turner et al, 2003), and these pathways are known to be activated by exercise (Shen et al, 2001;Molteni et al, 2002;our unpublished observations). In support of the neuronal activity hypothesis, it has also been shown that M 1 muscarinic agonist treatment decreases A␤ load in a triple transgenic model of AD (Caccamo et al, 2004), consistent with existing reports (for review, see Rossner et al, 1998).…”

Section: Discussionmentioning

confidence: 91%

Voluntary Exercise Decreases Amyloid Load in a Transgenic Model of Alzheimer's Disease

Adlard¹,

Perreau²,

Pop³

et al. 2005

J. Neurosci.

701

454

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Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which there are few therapeutics that affect the underlying disease mechanism. Recent epidemiological studies, however, suggest that lifestyle changes may slow the onset/progression of AD. Here we have used TgCRND8 mice to examine directly the interaction between exercise and the AD cascade. Five months of voluntary exercise resulted in a decrease in extracellular amyloid-␤ (A␤) plaques in the frontal cortex (38%; p ϭ 0.018), the cortex at the level of the hippocampus (53%; p ϭ 0.0003), and the hippocampus (40%; p ϭ 0.06). This was associated with decreased cortical A␤1-40 (35%; p ϭ 0.005) and A␤1-42 (22%; p ϭ 0.04) (ELISA). The mechanism appears to be mediated by a change in the processing of the amyloid precursor protein (APP) after short-term exercise, because 1 month of activity decreased the proteolytic fragments of APP [for ␣-Cterminal fragment (␣-CTF), 54% and p ϭ 0.04; for ␤-CTF, 35% and p ϭ 0.03]. This effect was independent of mRNA/protein changes in neprilysin and insulin-degrading enzyme and, instead, may involve neuronal metabolism changes that are known to affect APP processing and to be regulated by exercise. Long-term exercise also enhanced the rate of learning of TgCRND8 animals in the Morris water maze, with significant ( p Ͻ 0.02) reductions in escape latencies over the first 3 (of 6) trial days. In support of existing epidemiological studies, this investigation demonstrates that exercise is a simple behavioral intervention sufficient to inhibit the normal progression of AD-like neuropathology in the TgCRND8 mouse model.

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“…This suggests that MAPK signaling mediates this behavioral response in exercising mice. Phosphorylation and expression of MAPK in hippocampus are increased in exercising animals (Shen et al, 2001;Molteni et al, 2002;Russell and Duman, unpublished observation) and MEK phosphorylation also appears to be increased (Russell and Duman, unpublished observation) suggesting upregulation of the MAPK signaling pathway by exercise. This is also consistent with our recent report that exercise increases the BDNF-MAPK signaling pathway, determined by analysis of gene expression profiling (Hunsberger et al, 2007).…”

Section: Discussionmentioning

confidence: 96%

“…5A). Exercise has been shown to regulate the expression and phosphorylation of MAPK I and II in hippocampus (Shen et al, 2001;Molteni et al, 2002). We have observed that levels of phosphorylated MAPK kinase (pMEK), as well as levels of phosphorylated ERK I and II were increased in hippocampus of exercising mice (not shown).…”

Section: Bdnf and Mapk Signaling In Wheel-running Micementioning

confidence: 90%

Voluntary exercise produces antidepressant and anxiolytic behavioral effects in mice

et al. 2008

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Reports of beneficial effects of exercise on psychological health in humans are increasingly supported by basic research studies. Exercise is hypothesized to regulate antidepressant-related mechanisms and we therefore characterized the effects of chronic exercise in mouse behavioral paradigms relevant to antidepressant actions. Mice given free access to running wheels showed antidepressant-like behavior in learned helplessness, forced-swim (FST) and tail suspension paradigms. These responses were similar to responses of antidepressant drug-treated animals. When tested under conditions where locomotor activity was not altered, exercising mice also showed reduced anxiety compared to sedentary control mice. In situ hybridization analysis showed that BDNF mRNA was increased in specific subfields of hippocampus after wheel running. We chose one paradigm, the FST, in which to investigate a functional role for brain-derived neurotrophic factor (BDNF) in the behavioral response to exercise. We tested mice heterozygous for a deletion of the BDNF gene in the FST after wheel-running. Exercising wild-type mice showed the expected antidepressant-like behavioral response in the FST but exercise was ineffective in improving FST performance in heterozygous BDNF knockout mice. A possible functional contribution of a BDNF signaling pathway to FST performance in exercising mice was investigated using the specific MEK inhibitor PD184161 to block the MAPK signaling pathway. Subchronic administration of PD184161 to exercising mice blocked the antidepressant-like behavioral response seen in vehicle-treated exercising mice in the FST. In summary, chronic wheel-running exercise in mice results in antidepressant-like behavioral changes that may involve a BDNF related mechanism similar to that hypothesized for antidepressant drug treatment.

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Physical activity elicits sustained activation of the cyclic AMP response element-binding protein and mitogen-activated protein kinase in the rat hippocampus

Cited by 109 publications

References 56 publications

Alterations in spatial learning and memory after forced exercise

Alterations in spatial learning and memory after forced exercise

Voluntary Exercise Decreases Amyloid Load in a Transgenic Model of Alzheimer's Disease

Voluntary exercise produces antidepressant and anxiolytic behavioral effects in mice

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