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Low-intensity treadmill exercise and bright light upregulate brain-derived neurotrophic factor expression and intracellular signaling pathway in rat hippocampus and cerebral cortex Low-intensity treadmill exercise and bright light upregulate brain-derived neurotrophic factor...
Kwon, Sung Jin; Song, Kwang Seop; Kim, Hwajin; Kim, Yoon Sook; Choi, Wan Sung; Kwon, Sun Ok
2014-03-04 00:00:00
MOLECULAR & CELLULAR BIOLOGY Animal Cells and Systems, 2014 Vol. 18, No. 2, 135–142, http://dx.doi.org/10.1080/19768354.2014.891536 Low-intensity treadmill exercise and bright light upregulate brain-derived neurotrophic factor expression and intracellular signaling pathway in rat hippocampus and cerebral cortex a a b b b* a* Sung Jin Kwon , Kwang Seop Song , Hwajin Kim , Yoon Sook Kim , Wan Sung Choi and Sun Ok Kwon Department of Physical Education, Gyeongsang National University, 900 Gajwa-Dong, Jinju, Gyeongnam 660-701, Republic of Korea; Department of Anatomy and Neurobiology, Medical Research Center for Neural Dysfunction, Institute of Health Science, School of Medicine, Gyeongsang National University, 816 Beongil 15 Jinju-daero, Jinju, Gyeongnam 660-290, Republic of Korea (Received 3 December 2013; received in revised form 3 January 2014; accepted 2 February 2014) Continuous exercise and bright light affect brain function, particularly in seasonal affective disorders. However, the underlying mechanism of action remains unclear. In this study, we examined whether low-intensity treadmill exercise and 4 weeks of bright light exposure change the expression of brain-derived neurotrophic factor (BDNF), phosphoinositide 3-kinase/AKT (PI3K/AKT) pathway, protein kinase C (PKC), extracellular signal- regulated kinases (ERK1/2), cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB), vascular endothelial growth factor (VEGF), and glycogen synthase kinase-3β (GSK-3β) in the brain of 5-week old Sprague–Dawley male rats by performing western blot analysis. We demonstrated that BDNF expression significantly increased with exercise and light exposure compared to a control group. Moreover, we found that the expression levels of PI3K, PKC, p-ERK1/2, p-CREB, p-AKT, and VEGF increased significantly in the hippocampus and cortex with exercise and light exposure compared to the levels from a control group. However, phosphorylated GSK-3β level was unchanged, and even slightly decreased with exercise and light exposure. These results suggest that low-intensity treadmill exercise and bright light exposure induce BDNF expression and activate its downstream kinase signaling pathway, which in turn activate CREB-mediated transcription of neurotrophic factors and may stimulate neurogenesis and improve neuronal functions. Keywords: exercise; bright light; BDNF; ERK; CREB; hippocampus; cortex Introduction signaling pathways of phosphoinositide 3-kinase/AKT (PI3K/AKT), extracellular signal-regulated kinases (ERK1/ Exercise is known to increase the neurogenesis through 2), mitogen-activated protein kinase (MAPK), or calcium/ induction of neurotrophic factors in the hippocampus, calmodulin dependent protein kinase (CaMKII), and indu- which is associated with improved cognitive function cing phospho-CREB-mediated transcription (Mai et al. 2002; (Neeper et al. 1995; van Praag et al. 1999; Trejo et al. Garoflos et al. 2005; Luikart et al. 2008). Phosphorylation 2001). Bright light can relieve the symptoms of seasonal of GSK-3β mediated by PI3K/AKT inactivates GSK-3β mood disorders through neurobiological changes (Kasper which is known to inhibit cyclic adenosine monophosphate et al. 1990; Partonen & Lonnqvist 2000; Lau et al. 2011). (cAMP) response element-binding protein (CREB) transcrip- It is well accepted that physical activity and phototherapy tional activity (Grimes & Jope 2001; Mai et al. 2002). The can regulate hippocampal neurogenesis and neuronal cell CREB target genes include neurotrophic factors such as function. We previously showed that low-intensity tread- BDNF and VEGF (Gass & Riva 2007; Lee et al. 2009)and mill exercise and/or bright light promote neurogenesis and many neuropeptides, which play important roles in neuronal brain-derived neurotrophic factor (BDNF) expression in plasticity and memory formation (Suzuki et al. 2011). an animal model (Kwon et al. 2013). However, their Here, we investigated the combined effect of exercise molecular mechanisms of action remain largely unknown. and light exposure on expression of BDNF and down- BDNF is a nerve growth factor and critical for survival, stream signaling proteins to support their beneficial effect growth, and differentiation of neurons and thus, is critical to on brain functions. maintain proper neuronal functions. BDNF is active in the hippocampus and cortex where it regulates neuronal excitability, synaptic plasticity, long-term potentiation Materials and methods (LTP), and neurogenesis (Acheson et al. 1995;Huang & Animals Reichardt 2001; Ninan et al. 2010). BDNF is known to bind the tyrosine kinase receptor B (TrkB) receptor, modulating Male Sprague–Dawley rats weighing 160 ± 10 g (5-week neurotransmitter receptors to activate various kinase old) were obtained from a commercial breeder (KOATECH, *Corresponding authors. Email: choiws@gnu.ac.kr; kwon502@gnu.ac.kr © 2014 Korean Society for Integrative Biology 136 S.J. Kwon et al. Gyeonggi, Korea). Experimental procedures were performed Technology), p-AKT (Cell Signaling Technology), CREB in accordance with the animal care guidelines of National (Cell Signaling Technology), p-CREB (Cell Signaling Tech- Institutes of Health (NIH). Animals were housed under nology), GSK3β (Cell Signaling Technology), p-GSK3β controlled temperature (22 ± 2°C) with an alternating (Cell Signaling Technology), and VEGF (Santa Cruz). After 12-hour light/dark cycle (lights were turned on between washing in Tween 20 in Tris-buffered saline (0.5% TBST), 6 am and 6 pm), and provided food and water ad libitum. the membranes were incubated with their corresponding Rats were randomly divided into four experimental groups; secondary antibodies. The proteins were detected with the control group (CG), exercise group (EG), light group (LG), enhanced chemiluminescence (ECL) solution (Pierce, Rock- and exercise plus light group (ELG; n = 5 per group). ford, IL) and images were capturedbythe LAS-4000 system (Fujifilm, Tokyo, Japan). The protein levels were normalized to those of α-tubulin (Sigma). Treadmill exercise regimen Animals from exercise groups were subjected to treadmill (PARK TECH, Daegu, Korea) exercise for 30 min per day Statistical analysis for 5 consecutive days, each week for 4 weeks. The Differences between control and experimental groups exercise load consisted of a running speed of 2 m/min for were determined by using unpaired Student’s t-test, and the first 5 min, 5 m/min for the next 5 min, and 8 m/min one-way repeated measures analysis of variance were used for the last 20 min at 0° inclination. The exercise was to analyze the differences among all the groups. Multiple performed in the morning (between 10 am and 12 pm). comparisons were performed with Duncan’s method. Values are expressed as mean ± standard error of the Bright light exposure mean (SEM) and a p value <0.05 was considered as Light therapy was administered at an intensity of 10,000 lx statistically significant. (Gagné et al. 2007). A lamp for artificial light of 10,000 lx illumination was obtained from a commercial company (Danbee, Gyeonggi, Korea), and placed at a distance of Results 80 cm from animals during the experiments. For the LG, the Exercise and light exposure increased BDNF protein bright light was exposed for 30 min, which is the matched levels time period with the EG. ELG was treated at the same time We examined whether BDNF expression in the for 30 min. hippocampus and cortex is altered by low-intensity treadmill exercise and bright light by performing west- Tissue preparation ern blot analysis. BDNF expression was increased in the Animals were sacrificed 24 hours after 4 weeks of EG, LG, and ELG compared to the CG in both treatment. Rats were anesthetized with an intraperitoneal hippocampus and cortex (Figure 1). Moreover, there injection of 10 mg/kg of Zoletil 50 (Virbac, Carros, was an additive effect on BDNF expression in the ELG France). The brains were quickly removed and hippocam- in cortex (Figure 1B). The statistical significance was pus and cortex were dissected and frozen. The frozen indicated. samples were transferred to sterile 1.5 mL microcentrifuge tubes containing 550 µL of lysis buffer (T-buffer; Themo Scientific) with protease inhibitors. Homogenized tissues Exercise and light exposure increased the protein levels were incubated for 10 min on ice and sonicated. Samples of PI3K, PKC, and p-ERK were centrifuged at 4°C for 30 min at 12,000 rpm and Once BDNF binds to its receptor, TrkB, it activates supernatants were collected. Protein concentration was downstream targets leading to various neuronal processes. determined using a bicinchoninic acid protein assay The signaling cascade is mediated through PLC/PKC, (Bio-Rad, Hercules, CA, USA), and samples were stored PI3K/AKT, and ERK1/2 (p44/p42 MAPK) and regulates at –80°C. synaptic plasticity, proliferation, differentiation, and neur- onal survival. Thus, we examined the expression of PI3K, Western blot analysis PKCα, PKCδ (Figure 2), and phosphorylated Erk1/2 (p44/ p42; Figure 3) in the hippocampus and cortex by western Protein extracts were separated by SDS-polyacrylamide gel blot analysis. The expression of PI3K, PKCα, PKCδ, and and transferred to nitrocellulose membranes. The membranes p-ERK was significantly increased in the EG, LG, and were incubated with the following primary antibodies ELG compared to the CG. Our results suggest that (diluted at 1:1000); BDNF (Santa Cruz), PI3K (Santa exercise and light exposure activate various kinase Cruz), PKCα (Santa Cruz), PKCδ (Santa Cruz), ERK1/2 (Cell Signaling Technology), AKT (Cell Signaling signaling molecules, downstream of BDNF. Animal Cells and Systems 137 Figure 1. Changes in BDNF protein expression in the hippocampus and cortex after low-intensity treadmill exercise and bright light exposure. Western blots of BDNF proteins from lysates of rat hippocampus (A) and cortex (B) and their quantification. a,p < 0.05, b,p < 0.001 vs. control group and p < 0.001, vs. exercise and light group. CG, control group; EG, exercise group; LG, light group; ELG, exercise plus light group. Figure 2. Changes in PI3K, PKCα, and PKCδ protein expression in the hippocampus and cortex after low-intensity treadmill exercise and bright light exposure. Western blots of PI3K, PKCα, and PKCδ proteins from lysates of rat hippocampus (A) and cortex (B) and # ## their quantification. a, p < 0.05, b, p < 0.01, c, p < 0.001 vs. control group, p < 0.01 vs. light group, and p < 0.001 vs. exercise group and light group. CG, control group; EG, exercise group; LG, light group; ELG, exercise plus light group. Exercise and light exposure increased the level of transcription (Gonzalez & Montminy 1989;Karin & p-CREB Hunter 1995; Mayr & Montminy 2001). CREB in the brain has well-known role in neuronal plasticity and LTP. The activated protein kinases are translocated to nucleus Thus, we examined p-CREB level in the hippocampus and and phosphorylate CREB to activate p-CREB-mediated 138 S.J. Kwon et al. Figure 3. Changes in ERK1/2 protein expression in the hippocampus and cortex after low-intensity treadmill exercise and bright light exposure. Western blots of p-ERK 1/2 proteins from lysates of rat hippocampus (A) and cortex (B) and their quantification. a, p < 0.01, † # b, p < 0.001 vs. control group and p < 0.001 vs. light group, p < 0.001 vs. exercise group and light group. CG, control group; EG, exercise group; LG, light group; ELG, exercise plus light group. Figure 4. Changes in CREB protein expression in the hippocampus and cortex after low-intensity treadmill exercise and bright light exposure. Western blots of p (phospho)-CREB and T (total)-CREB proteins from lysates of rat hippocampus (A) and cortex (B) and their # ## quantification. a, p < 0.01, b, p < 0.001 vs. control group and p < 0.01, p < 0.001 vs. exercise group and light group. CG, control group; EG, exercise group; LG, light group; ELG, exercise plus light group. cortex by western blot analysis. We found that p-CREB significance of increase was higher in the combined protein levels were increased in the EG, LG, and stimulus group (ELG) than in EG or LG with a single ELG compared to the CG (Figure 4). Notably, the stimulus. Animal Cells and Systems 139 Exercise and light exposure increased p-AKT levels, but (Figure 7). We propose a model that exercise and light not p-GSK-3β levels exposure stimulate BDNF receptors and the downstream kinase signaling pathways. The following activated CREB GSK-3β is a critical downstream target of the PI3K/AKT increases expression of various neurotrophic factors, pathway and its activity is inhibited by AKT-mediated possibly leading to neurogenesis. phosphorylation. GSK-3β is known to inhibit CREB binding activity. Thus, we examined whether exercise or light exposure affects the levels of p-AKT, activated AKT, Discussion by western blot analysis. We found p-AKT levels were significantly increased in the EG, LG, and ELG compared The main finding of this study was that low-intensity to the CG in the hippocampus (Figure 5A), and further, treadmill exercise and bright light activate signaling we observed an additive effect by exercise and light pathways leading to VEGF and BDNF induction, which exposure in the cortex (Figure 5B). Subsequently, we are closely related to neurogenesis. We showed increased examined expression of p-GSK-3, which is phosphory- p-ERK1/2, p-AKT and activation of PI3K and PKC lated by AKT. While p-AKT level was enhanced by pathway, as well as increased p-CREB and VEGF in the exercise and light exposure, p-GSK-3 level was not hippocampus and cortex of rats after exercise and light changed, and even slightly decreased in the hippocampus exposure. of EG, LG, and ELG and in the cortex of ELG (Figure 6), Exercise stimulates the sympathetic nervous system indicating that GSK-3β may be not the direct target of causing a neuronal and hormonal stress response which BDNF-PI3K/AKT-mediated signaling pathway in our induces calcium influx and cAMP signaling cascades regimen of exercise and light exposure. resulting in activation of BDNF transcription (Zheng et al. 2012). A recent study showed that exercise affects epigenetic regulation of BDNF, inducing promoter Exercise and light exposure increased VEGF protein demethylation and activation of methyl-CpG-binding levels protein 2 in rat hippocampus (Gomez-Pinilla et al. 2011). CREB activation increases expression of neurotrophic Light received by the retina stimulates hypothalamic factors, such as BDNF and VEGF. Therefore, we exam- orexinergic neurons in the hypothalamic suprachiasmatic ined whether exercise or light exposure affects VEGF nucleus (SCN) and in the serotonergic nucleus in the dorsal raphe (DRN; Adidharma et al. 2012). The SCN is a level by western blot analysis. We found that VEGF levels principal circadian clock and orexin is a neuropeptide were significantly increased in the EG, LG, and ELG compared to the CG in the hippocampus and cortex regulating the sleep/wake cycle. Serotonin production Figure 5. Changes in AKT protein expression in the hippocampus and cortex after low-intensity treadmill exercise and bright light exposure. Western blots of p (phospho)-AKT and T (total)-AKT proteins from lysates of rat hippocampus (A) and cortex (B) and their quantification. a, p < 0.05, b, p < 0.01, c, p < 0.001 vs. control group and p < 0.01 vs. exercise group and light group. CG, control group; EG, exercise group; LG, light group; ELG, exercise plus light group. 140 S.J. Kwon et al. Figure 6. Changes in GSK-3β protein expression in the hippocampus and cortex after low-intensity treadmill exercise and bright light exposure. Western blots of p (phospho)-GSK-3β and T (total)-GSK-3β proteins from lysates of rat hippocampus (A) and cortex (B) and their quantification. a, p < 0.05, b, p < 0.01, c, p < 0.001 vs. control group and p < 0.001 vs. exercise group and light group. CG, control group; EG, exercise group; LG, light group; ELG, exercise plus light group. Figure 7. Changes in VEGF protein expression in the hippocampus and cortex after low-intensity treadmill exercise and bright light exposure. Western blots of VEGF proteins from lysates of rat hippocampus (A) and cortex (B) and their quantification. a, p < 0.05, b, p < 0.01, c, p < 0.001 vs. control group and p <0.001 vs. exercise group and light group. CG, control group; EG, exercise group; LG, light group; ELG, exercise plus light group. directly correlates with bright sunlight exposure and is BDNF promotes neuronal growth, development, and often decreased in people with depression. These neuronal survival, and is also associated with learning and memory and hormonal changes stimulate neurotransmission, indu- through regulation of synaptic plasticity (Bibel & Barde cing calcium influx and cAMP signaling cascades and 2000; Mizuno et al. 2000). A previous study has shown resulting in activation of BDNF transcription (Zheng that learning in water maze increases BDNF mRNA et al. 2012). expression in the rat hippocampus (Kesslak et al. 1998). Animal Cells and Systems 141 In agreement with our study, exercise such as treadmill factors. We also found that the combined treatment of running increased neurogenesis in hippocampus and exercise and light therapy more effectively stimulates enhanced spatial learning and LTP (Neeper et al. 1995; BDNF-mediated neuronal functions. van Praag et al. 1999; Kwon et al. 2013). A recent study has found that the improved spatial learning and memory Acknowledgments by exercise was correlated with an increase in the number We would like to thank Lauren Shields at the Gladstone Institutes affiliated with the University of California, San of cholinergic neurons (Ang et al. 2006). Thus, our study Francisco (UCSF) for editing our manuscript. This research supports that behaviors such as physical exercise and was supported by the Basic Science Research Program through learning protect neurons at risk in aging and neurodegen- the National Research Foundation (NRF) of Korea [No. 2005- erative diseases by BDNF signaling (Binder & Scharfman 0049415]. 2004). Additionally, BDNF was shown to produce an antidepressant effect in animal behavioral models of References depression through MAPK kinase signaling (MAPK/ Acheson A, Conover JC, Fandl JP, DeChiara TM, Russell M, ERK). BDNF heterozygote mice exhibited a depressive Thadani A, Squinto SP, Yancopoulos GD, Lindsay RM. phenotype when combined with a low-dose MEK inhib- 1995. A BDNF autocrine loop in adult sensory neurons prevents cell death. Nature. 374:450–453. itor or stress exposure (Shirayama et al. 2002; Duman Adidharma W, Leach G, Yan L. 2012. Orexinergic signaling et al. 2007). 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