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      Treadmill exercise ameliorates social isolation-induced memory impairment by enhancing silent information regulator-1 expression in rats

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          Abstract

          The effect of treadmill exercise on the social isolation-induced memory impairment in relation with the silent information regulator-1 (SIRT-1) was investigated. The rats in the control groups lived four in the stan-dard cages for 8 weeks. The rats in the social isolation groups lived alone in the small cages for 8 weeks. The rats in the treadmill exercise groups were subjected to run on a treadmill for 30 min once a day for 8 weeks. We used step-through avoidance test for short-term memory and Morris water maze task for spatial working memory. Immunohisto-chemistry for SIRT-1 and western blot analysis for Bax, Bcl-2, cleaved caspase-3, brain-derived neurotrophic factor (BDNF), and tropomyosin receptor kinase B (TrkB) were performed. The rats in the social isolation group showed a decrease in short-term memory and spatial working memory. Treadmill exercise alleviated short-term memory and spatial working memory in the social isolation rats. SIRT-1 expression in the hippocampus was decreased in the rats of social isolation group. Treadmill exercise increased SIRT-1 expression in the social isolation rats. Bax expression was increased, Bcl-2 expression was decreased, and cleaved caspase-3 expression in the hippocampus was increased in the rats of social isolation group. Treadmill exercise decreased Bax expression, increased Bcl-2 expression, and decreased cleaved caspase-3 expression in the social isolation rats. Hippocampal BDNF and TrkB expression was decreased in the rats of social isolation group. Treadmill exercise increased BDNF and TrkB expression in the social isolation rats.

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          Most cited references22

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          Calorie restriction, SIRT1 and metabolism: understanding longevity.

          Calorie restriction (CR) is the only experimental manipulation that is known to extend the lifespan of a number of organisms including yeast, worms, flies, rodents and perhaps non-human primates. In addition, CR has been shown to reduce the incidence of age-related disorders (for example, diabetes, cancer and cardiovascular disorders) in mammals. The mechanisms through which this occurs have been unclear. CR induces metabolic changes, improves insulin sensitivity and alters neuroendocrine function in animals. In this review, we summarize recent findings that are beginning to clarify the mechanisms by which CR results in longevity and robust health, which might open new avenues of therapy for diseases of ageing.
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            Lactate mediates the effects of exercise on learning and memory through SIRT1-dependent activation of hippocampal brain-derived neurotrophic factor (BDNF)

            Exercise promotes learning and memory formation. These effects depend on increases in hippocampal BDNF, a growth factor associated with cognitive improvement and the alleviation of depression symptoms. Identifying molecules that are produced during exercise and that mediate hippocampal Bdnf expression will allow us to harness the therapeutic potential of exercise. Here, we report that an endogenous molecule produced during exercise in male mice induces the Mus musculus Bdnf gene and promotes learning and memory formation. The metabolite lactate, which is released during exercise by the muscles, crosses the blood-brain barrier and induces Bdnf expression and TRKB signaling in the hippocampus. Indeed, we find that lactate-dependent increases in BDNF are associated with improved spatial learning and memory retention. The action of lactate is dependent on the activation of the Sirtuin1 deacetylase. SIRT1 increases the levels of the transcriptional coactivator PGC1a and the secreted molecule FNDC5, known to mediate Bdnf expression. These results reveal an endogenous mechanism to explain how physical exercise leads to the induction of BDNF, and identify lactate as a potential endogenous molecule that may have therapeutic value for CNS diseases in which BDNF signaling is disrupted.SIGNIFICANCE STATEMENT It is established that exercise promotes learning and memory formation and alleviates the symptoms of depression. These effects are mediated through inducing Bdnf expression and signaling in the hippocampus. Understanding how exercise induces Bdnf and identifying the molecules that mediate this induction will allow us to design therapeutic strategies that can mimic the effects of exercise on the brain, especially for patients with CNS disorders characterized by a decrease in Bdnf expression and who cannot exercise because of their conditions. We identify lactate as an endogenous metabolite that is produced during exercise, crosses the blood-brain barrier and promotes hippocampal dependent learning and memory in a BDNF-dependent manner. Our work identifies lactate as a component of the "exercise pill."
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              Effects of voluntary exercise on synaptic plasticity and gene expression in the dentate gyrus of adult male Sprague-Dawley rats in vivo.

              We have previously shown that voluntary exercise produces enhanced neurogenesis and long-term potentiation (LTP) in the dentate gyrus (DG) of mice in vitro. In the present experiments we show that rats given access to a running wheel (Runners) exhibit significantly more short-term potentiation and LTP with theta-patterned conditioning stimulation in vivo than do age-matched litter mates (Controls). This increase in LTP appears to reflect an alteration in the induction threshold for synaptic plasticity that accompanies voluntary exercise. Weak theta-patterned stimulation, which did not produce LTP in control subjects, produced a robust and long-lasting LTP in Runners. LTP induction in both groups was dependent upon the activation of N-methyl-D-aspartate (NMDA) receptors, and could be blocked by the competitive antagonist [+/-]-3-[2-carboxypiperazin-4-yl] propanephosphonic acid. Consistent with these findings, we found that mRNA levels for NR2B subtype of NMDA receptor were increased specifically in the DG of Runners. In addition to changes in NR2B mRNA levels, quantitative polymerase chain reaction analysis revealed that brain-derived neurotrophic factor (BDNF) and glutamate receptor 5 mRNA levels were also significantly elevated in the DG of Runners, but not in other areas of the hippocampus. Thus, alterations in the expression of BDNF, and specific glutamate receptor subtypes, may underlie the ability of exercise to enhance neurogenesis and reduce the threshold for LTP in the DG.
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                Author and article information

                Journal
                J Exerc Rehabil
                J Exerc Rehabil
                Journal of Exercise Rehabilitation
                Korean Society of Exercise Rehabilitation
                2288-176X
                2288-1778
                June 2020
                30 June 2020
                : 16
                : 3
                : 227-233
                Affiliations
                [1 ]Department of Physiology, College of Medicine, Kyung Hee University, Seoul, Korea
                [2 ]Department of Sport & Health Care, College of Art & Culture, Sangmyung University, Seoul, Korea
                [3 ]School of Global Sport Studies, Korea University, Sejong, Korea
                [4 ]Department of Kinesiology, College of Public Health and Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA
                Author notes
                [* ]Corresponding author: Seung-Soo Baek, https://orcid.org/0000-0002-1340-2098, Department of Sport & Health Care, College of Art & Culture, Sangmyung University, 20 Hongjimun 2-gil, Jongno-gu, Seoul 03016, Korea, E-mail: ssoop@ 123456smu.ac.kr
                Article
                jer-16-3-227
                10.12965/jer.2040400.200
                7365728
                4181b156-35c7-43ed-8a7a-3c4c9aaf7660
                Copyright © 2020 Korean Society of Exercise Rehabilitation

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 27 April 2020
                : 28 May 2020
                Categories
                Original Article

                social isolation,treadmill exercise,silent information regu-lator-1,apoptosis,brain-derived neurotrophic factor

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