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      Neuroprotective effects of physical activity on the brain: a closer look at trophic factor signaling

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          Abstract

          While the relationship between increased physical activity and cognitive ability has been conjectured for centuries, only recently have the mechanisms underlying this relationship began to emerge. Convergent evidence suggests that physical activity offers an affordable and effective method to improve cognitive function in all ages, particularly the elderly who are most vulnerable to neurodegenerative disorders. In addition to improving cardiac and immune function, physical activity alters trophic factor signaling and, in turn, neuronal function and structure in areas critical for cognition. Sustained exercise plays a role in modulating anti-inflammatory effects and may play a role in preserving cognitive function in aging and neuropathological conditions. Moreover, recent evidence suggests that myokines released by exercising muscles affect the expression of brain-derived neurotrophic factor synthesis in the dentate gyrus of the hippocampus, a finding that could lead to the identification of new and therapeutically important mediating factors. Given the growing number of individuals with cognitive impairments worldwide, a better understanding of how these factors contribute to cognition is imperative, and constitutes an important first step toward developing non-pharmacological therapeutic strategies to improve cognition in vulnerable populations.

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          Most cited references126

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          Exercise induces hippocampal BDNF through a PGC-1α/FNDC5 pathway.

          Exercise can improve cognitive function and has been linked to the increased expression of brain-derived neurotrophic factor (BDNF). However, the underlying molecular mechanisms driving the elevation of this neurotrophin remain unknown. Here we show that FNDC5, a previously identified muscle protein that is induced in exercise and is cleaved and secreted as irisin, is also elevated by endurance exercise in the hippocampus of mice. Neuronal Fndc5 gene expression is regulated by PGC-1α, and Pgc1a(-/-) mice show reduced Fndc5 expression in the brain. Forced expression of FNDC5 in primary cortical neurons increases Bdnf expression, whereas RNAi-mediated knockdown of FNDC5 reduces Bdnf. Importantly, peripheral delivery of FNDC5 to the liver via adenoviral vectors, resulting in elevated blood irisin, induces expression of Bdnf and other neuroprotective genes in the hippocampus. Taken together, our findings link endurance exercise and the important metabolic mediators, PGC-1α and FNDC5, with BDNF expression in the brain. Copyright © 2013 Elsevier Inc. All rights reserved.
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            The role of exercise and PGC1alpha in inflammation and chronic disease.

            Inadequate physical activity is linked to many chronic diseases. But the mechanisms that tie muscle activity to health are unclear. The transcriptional coactivator PGC1alpha has recently been shown to regulate several exercise-associated aspects of muscle function. We propose that this protein controls muscle plasticity, suppresses a broad inflammatory response and mediates the beneficial effects of exercise.
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              Running enhances neurogenesis, learning, and long-term potentiation in mice.

              Running increases neurogenesis in the dentate gyrus of the hippocampus, a brain structure that is important for memory function. Consequently, spatial learning and long-term potentiation (LTP) were tested in groups of mice housed either with a running wheel (runners) or under standard conditions (controls). Mice were injected with bromodeoxyuridine to label dividing cells and trained in the Morris water maze. LTP was studied in the dentate gyrus and area CA1 in hippocampal slices from these mice. Running improved water maze performance, increased bromodeoxyuridine-positive cell numbers, and selectively enhanced dentate gyrus LTP. Our results indicate that physical activity can regulate hippocampal neurogenesis, synaptic plasticity, and learning.
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                Author and article information

                Contributors
                Journal
                Front Cell Neurosci
                Front Cell Neurosci
                Front. Cell. Neurosci.
                Frontiers in Cellular Neuroscience
                Frontiers Media S.A.
                1662-5102
                20 June 2014
                2014
                : 8
                : 170
                Affiliations
                [1] 1Department of Physical Therapy, Arkansas State University Jonesboro, AR, USA
                [2] 2Department of Physiology, Erciyes University Kayseri, Turkey
                [3] 3Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine Palo Alto, CA, USA
                [4] 4Department of Biological Sciences, Arkansas State University Jonesboro, AR, USA
                [5] 5VA Palo Alto Health Care System Palo Alto, CA, USA
                Author notes

                Edited by: Arianna Maffei, SUNY Stony Brook, USA

                Reviewed by: Mazahir T. Hasan, Charité-Universitätsmedizin-Berlin, Germany; Alexander K. Murashov, East Carolina University, USA

                *Correspondence: Cristy Phillips, Department of Physical Therapy, Arkansas State University, PO Box 910, 2713 Pawnee, Jonesboro, AR 72401, USA e-mail: cphillips@ 123456astate.edu

                This article was submitted to the journal Frontiers in Cellular Neuroscience.

                Article
                10.3389/fncel.2014.00170
                4064707
                24999318
                667b110b-b165-4647-8e05-8c838403fa95
                Copyright © 2014 Phillips, Baktir, Srivatsan and Salehi.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 22 April 2014
                : 02 June 2014
                Page count
                Figures: 4, Tables: 0, Equations: 0, References: 168, Pages: 16, Words: 14303
                Categories
                Neuroscience
                Review Article

                Neurosciences
                physical activity,neurotrophins,brain-derived neurotrophic factor,irisin,fndc5,myokines,val66met

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