Sudden detraining deteriorates swimming traininginduced enhancement of short-term and spatial learning memories in mice

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1 Originl Article Journl of Exercise Rehilittion 213;9(2): Sudden detrining deteriortes swimming trininginduced enhncement of short-term nd sptil lerning memories in mice You-Mi Kim 1, Eun-Sng Ji 2, Sung-Jin Yoon 3, Jin-Hwn Yoon 1, * 1 Deprtment of Sports Science, College of Life Science nd Nno Technology, Hnnm University, Dejeon, Kore 2 Deprtment of Sport & Helth Science, College of Nturl Science, Sngmyung University, Seoul, Kore 3 Deprtment of Physicl Eduction, College of Eduction, Kore University, Seoul, Kore In the present study, we investigted the effect of swimming trining nd sudden detrining on lerning ility nd sptil memory cpility nd on neurogenesis nd rin-derived neurotrophic fctor (BDNF) expression in the hippocmpus of mice. Mle ICR mice were rndomly ssigned into three groups (n= 15 in ech group): the control group, the swimming trining group, nd the detrining group. The mice in the swimming trining group were mde to swim (6 dys/week, 6 min/dy) for 8 weeks. The mice in the detrining group were ccomplished the sme swimming progrm for 4 weeks nd then discontinued exercise for 4 weeks. In the present results, enhnced short-term nd sptil lerning memories nd incresed hippocmpl neurogenesis nd BDNF expression were oserved in the mice of the swimming trining group. In contrst, decresed short-term nd sptil lerning memories were oserved in the mice of the swimming detrining group compred to the control level. Hippocmpl neurogenesis nd BDNF expression were lso decresed in the mice of the detrining group ner to the control level. Here in this study, we suggest tht sudden cesstion of exercise trining might ring decline of the rin functions. Keywords: Trining, Detrining, Short-term memory, Sptil lerning memory, Neurogenesis, Brin-derived neurotrophic fctor INTRODUCTION Neurogenesis continues throughout dulthood in vriety of species, including humns (Eriksson et l., 1998; Gould et l., 1999; Kuhn et l., 1996). This new cell irth nd neurogenesis occur in the rostrl suventriculr zone (SVZ) of the lterl ventricles nd the sugrnulr zone (SGZ) of the dentte gyrus (Jin et l., 21). Neurogenesis is known to ply n importnt role in lerning nd memory processes of the hippocmpus (Shors et l., 22). Neurotrophins ply crucil roles in the development of centrl nervous system (CNS), exerting influence on cell survivl, differentition, nd cell deth (Hung nd Reichrdt, 21). Brin-derived neurotrophic fctor (BDNF) is smll dimeric protein, nd works through its receptor, tyrosine kinse B (Trk-B). BDNF modultes neurl growth nd survivl, nd BDNF is implicted in lerning nd memory processes; therefore, dysfunction in BDNF is ccompnied y cognitive deficits (Gomez-Pinill nd Vynmn, 25). BDNF enhnces hippocmpl-dependent memory nd long-term potentition, form of synptic plsticity, vi Trk-B (Minichiello, 29). A high level of BDNF is concentrted in the hippocmpus, nd BDNF is selectively incresed following ctivity-dependent lerning nd memory tsks (Zimmererg et l., 29). Exercise trining is lso known to improve rin functions such s short-term nd sptil lerning memories nd cognitive function, increse neurogenesis nd neurotrophic fctors expression, nd enhnces long-term potentition (Kim et l., 27; Krmer nd Erickson, 27; Lee et l., 26; O Cllghn et l., 27). The exercise-induced neurogenesis is known to e coincided with incresed expression of BDNF (Frmer et l., 24). In prticulr, *Corresponding uthor: Jin-Hwn Yoon Deprtment of Sports Science, College of Life Science nd Nno Technology, Hnnm University, 7 Hnnm-ro, Dedeok-gu, Dejeon , Kore Tel.: , Fx: , E-mil: yoonjh@hnnm.c.kr Received: Mrch 5, 213/ Revised: Mrch 12, 213/ Accepted: Mrch 3, 213 This is n Open Access rticle distriuted under the terms of the Cretive Commons Attriution Non-Commercil License ( which permits unrestricted non-commercil use, distriution, nd reproduction in ny medium, provided the originl work is properly cited. Copyright 213 Koren Society of Exercise Rehilittion pissn X 243 eissn

2 Kim Y-M, et l. Swimming trining nd detrining swimming is known to induce vrious chnges in the functions of the rt s rin (Senturk et l., 2). It ws demonstrted tht swimming increses neurogenesis in the hippocmpl dentte gyrus of rts (Lee et l., 26; R et l., 22). Rdk et l. (26) reported tht regulr exercise trining improves memory function through increment of expressions of BDNF nd nerve growth fctor (NGF) in rt rin. Detrining hs een defined s the cesstion of trining-induced dpttions (Mujik nd Pdill, 2). Detrining hs een reported to exert negtive effects on crdiovsculr dpttion (Gmelin et l., 27), muscle function (Gondin et l., 26), nd energy metolism (Mujik nd Pdill, 21; Slentz et l., 27). Although previous studies hve documented tht swimming exercise trining increses neurogenesis nd improves memory function (R et l., 22; Rdk et l., 26), the effects of detrining of swimming exercise on neurogenesis nd memory function re still scrce. In the present study, we investigted the effects of swimming trining nd sudden detrining on short-term memory, sptil lerning memory, nd BDNF expression in the hippocmpus using mice. MATERIALS AND METHODS Animls nd tretments Mle ICR mice weighing 4±1 g (6 weeks of ge) were used for the experiment. The experimentl procedures were performed in ccordnce with the niml cre guidelines of the Ntionl Institutes of Helth (NIH) nd the Koren Acdemy of Medicl Sciences. The mice were housed under the controlled temperture (2±2 C) nd the lighting (8:-2: h) conditions. Food nd wter were mde ville d liitum. The mice were rndomly ssigned to ech of three groups (n=15 in ech group): the control group, the trining group, nd detrining group. The nimls were lived in the cge (48 26 cm), nd 5 mice were plced per cge. The mice of ll groups were injected intrperitonelly with 5-romo-2 -deoxyuridine (BrdU; 5 mg/kg; Sigm Chemicl Co., St. Louis, MO, USA) once dy for 8 weeks. The nimls divided into the 3 groups: control group, trining group, nd detrining group. The nimls were scrificed immeditely fter ehvior tests. Swimming trining nd detrining The mice in the trining group were mde to swim for 6 min per dy, 6 dys week during 8 weeks. The mice in the detrining group were ccomplished the swimming trining for 6 min per dy, 6 dys week for 4 weeks, nd then discontinued trining during next 4 weeks. Wter temperture ws mintined t 32 C during swimming trining. The mice in the control group were lived in the cge without swimming trining for the sme durtion. Step-down voidnce test In order to investigte the short-term memory of the mice, the ltency time in the step-down voidnce test ws determined, s previous descried method (Cho et l., 212; Kim et l., 212). The mice were trined in step-down voidnce test on the 8 weeks fter strting experiment, nd they were tested on 24 h fter trining session in the step-down voidnce test. The mice were plced on 7 25 pltform, t height of 2.5 cm, nd llowed to rest on the pltform for 2 min. The pltform fced cm grid of prllel.1 cm-clier stinless steel rs, which were spced 1 cm prt. During trining session, the nimls received.5 ma scrmle foot shock for 3 sec immeditely upon stepping down. The time stying on the pltform until stepping down nd plcing ll four pws on the grid ws defined s the ltency of the step-down voidnce test. Ltencies over 3 sec were counted s 3 sec. Rdil-rm mze test The sptil lerning memory ws tested using rdil-rm mze pprtus, s previously descried (Cho et l., 212; Kim et l., 21). The rdil-rm mze pprtus consisted of centrl octgonl plte (3 cm in dimeter) nd rditing eight rms (5 cm in length nd 1 cm in width). A smll receptcle filled with wter (3 cm in dimeter nd 1 cm in depth) ws locted t the end of the rms. The mice were trined three times efore the sptil lerning test. During the trining sessions, the mice ws deprived of wter for 24 h nd llowed to explore the wter for 5 min fter finishing ech session. On the 8 weeks fter strting experiment, the sptil lerning memory ws determined. The time spent for the seeking of wter t the end of the rms ws counted. The test ws terminted when mouse found wter in ll eight rms or over 8 min elpsed. The numer of correct choice efore the first error ws counted, nd re-entry into the previously visited rms ws counted s the numer of error choice. Tissue preprtion The mice were scrificed fter the completion of ehvior tests. The nimls were weighed nd nesthetized using Zoletil 5 (1 mg/kg, i.p.; Vic Lortories, Crros, Frnce). After complete

3 Kim Y-M, et l. Swimming trining nd detrining lck of response ws oserved, the mice were trnscrdilly perfused with 5 mm phosphte-uffered sline (PBS) nd fixed with freshly prepred solution consisting of 4% prformldehyde (PFA) in 1 mm phosphte uffer (PB, ph 7.4). The rins were dissected nd post-fixed in the sme fixtive overnight nd trnsferred into 3% sucrose solution for cryoprotection. Seril coronl sections of 4 μm thickness were mde with freezing microtome (Leic, Nussloch, Germny). Immunohistochemistry BrdU immunohistochemistry ws used for the detection of newly generted cells in the hippocmpl dentte gyrus, s the previously descried method (Cho et l., 212; Kim et l., 212). In rief, the sections were initilly permeilized y incution in.5% Triton X-1 in PBS for 2 min, then pretreted with 5% formmide-2 stndrd sline citrte (SSC) t 65 C for 2 h, denturted in 2N HCl t 37 C for 3 min, nd rinsed twice in 1 mm sodium orte (ph 8.5). Afterwrds, the sections were incuted overnight t 4 C with BrdU-specific mouse monoclonl ntiody (1:6; Roche, Mnnheim, Germny). The sections were then wshed three times with PBS nd incuted for 1 h with iotinylted mouse secondry ntiody (1:2; Vector Lortories, Burlingme, CA, USA). The sections were then incuted for nother 1 h with vidin-peroxidse complex (1:1; Vector Lortories). For visuliztion, the sections were incuted in 5 mm Tris-HCl (ph 7.6) contining.3% H2O2,.2% 3,3 -diminoenzidine (DAB), nd 4 mg/ml nickel chloride (nickel-dab) for 5 min. After BrdU-specific stining, we performed counter-stining on the sme sections using mouse nti-neuronl nuclei (NeuN) ntiody (1:1,; Chemicon Interntionl, Temecul, CA, USA). The sections were then wshed three times with PBS, incuted for 1 h with iotinylted nti-mouse secondry ntiody, nd processed with the VECTASTAIN ABC Kit (1:1; Vector Lortories). For stining, the sections were llowed to rect with.2% DAB nd.3% H2O2 in 5 mm Tris-HCl (ph 7.6) for 5 min nd the sections were finlly mounted onto geltin-coted slides. The slides were ir-dried overnight t room temperture, nd the coverslips were mounted using Permount (Fisher Scientific, Fir Lwn, NJ, USA). Western lot nlysis BDNF expression in the hippocmpus ws determined, s the previously descried method (Cho et l., 212; Kim et l., 21). Tissue smples hrvested from the hippocmpus were lysed in the protein lysis uffer contining 5 mm Tris-HCI (ph 7.5), 15 mm NCl,.5% deoxycholic cid, 1% nonidet-p4 (NP4),.1% sodium dodecyl sulfte (SDS), 1 mm phenylmethylsulfonyl fluoride (PMSF), nd 1 μg/ml leupeptin. Protein concentrtion ws mesured using Bio-Rd colorimetric protein ssy kit (Bio-Rd, Hercules, CA, USA). Protein of 5 μg ws seprted on SDS-polycrylmide gels nd trnsferred onto nitrocellulose memrne (Schleicher & Schuell GmH, Dssel, Germny). Rit nti-bd- NF ntiody (1:1,; Snt Cruz Biotechnology, CA, USA), Horserdish peroxidse-conjugted nti-rit ntiody for BDNF were used s secondry ntiodies. Bnd detection ws performed using s enhnced chemiluminescence (ECL) detection system (Amershm Phrmci Biotech GmH, Freiurg, Germny). The finl mount of western lot product for BDNF expression ws clculted densitometriclly using Imging-Pro Plus (Medi Cyernetics Inc., Silver Spring, MD, USA). Sttisticl nlysis The numer of BrdU-positive cells in the hippocmpl dentte gyrus were counted hemilterlly using Imge-Pro Plus imge nlyzer (Medi Cyernetics Inc.). The numer of BrdU-positive cells in the hippocmpl dentte gyrus were expressed s the numer of cells per mm 2 of the cross sectionl re of the grnulr lyer. For the confirmtion of the expressions of BDNF, the detected nds were clculted densitometriclly using Moleculr Anlyst TM, version (Bio-Rd). All dt were nlyzed using the sttisticl softwre SPSS (version 2.), nd the results were expressed s the men±stndrd error of the men (SEM). For the comprison mong the groups, one-wy ANOVA nd Duncn s post-hoc test were performed, nd differences were considered sttisticlly significnt t P<.5. RESULTS Effect of trining nd detrining on step-down voidnce test The ltency in the step-down voidnce test ws 141.4±28.56 sec in the control group, ±19.48 sec in the trining group, nd 68.5±24.37 sec in the detrining group (Fig. 1). The ltency in the trining group ws significntly incresed compred to the control group. However, the mice in the detrining group showed more shortened ltency compred to the control group. Effect of trining nd detrining on rdil-rm mze test The time tken to complete eight successful performnces ws

4 Kim Y-M, et l. Swimming trining nd detrining ±11.48 sec in the control group, 165.5±1. sec in the trining group, nd ±26.35 sec in the detrining group (Fig. 2A). The numer of correct choices to complete eight successful performnces ws 4.22±.28 sec in the control group, 5.38±.18 sec in the trining group, nd 4.88±.16 sec in the detrining group (Fig. 2B). The numer of error response to complete eight successful performnces ws 8.56±.6 sec in the control group, 6.75±.73 sec in the trining group, nd 11.5±1.2 sec in the detrining group (Fig. 2C). Our dt demonstrted tht the time nd error numer tken to complete eight successful performnces were lower nd correct numer ws higher in the trining group compred to the control group. However, the mice in the detrining group showed more time nd error numer with no chnge in the correct numer compred to the control group. Step-down ltency time (sec) Fig. 1. Effects of the trining nd detrining on ltency in the step-down voidnce test. (A) Control group, (B) trining group, (C) detrining group. The dt re represented s the men± SEM. c Effect of trining nd detrining on the hippocmpl neurogenesis Photomicrogrphs of BrdU-positive cells re shown in Fig. 3. The numer of BrdU-positive cells in the dentte gyrus of the hi p- pocmpus ws ±6.78/mm 2 in the control group, ± 12.85/mm 2 in the trining group, nd ±7.16/mm 2 in the 1 2 Numer of BrdU-positive cells in the dentte gyrus (mm 2 ) Fig. 3. Effects of the trining nd detrining on neurogenesis in the hippocmpus. (A) Photomicrogrphs of 5-romo-2 -deoxyuridine (BrdU)-positive cells. The sections were stined for BrdU (lck) nd neuronl nuclei (NeuN; rown). The scle r represents 1 μm (1) nd 25 μm. (B) The numer of BrdU- positive cells in the dentte gyrus of hippocmpus. (A) Control group, (B) trining group, (C) detrining group. The dt re represented s the men± SEM. A B Time to complte performnce (sec) c , A B C Numer of correct choice Numer of error response Fig. 2. Effects of the trining nd detrining on time, correct numer, nd error numer in the rdil-rm mze test. (A) The time tken to complete eight successful performnces. (B) The numer of correct choice to complete eight successful performnces. (C) The numer of error response to complete eight successful performnces. (A) Control group, (B) trining group, (C) detrining group. The dt re represented s the men± SEM

5 Kim Y-M, et l. Swimming trining nd detrining Reltive BDNF protein expression (O.D.) Actin BDNF Fig. 4. Effects of the trining nd detrining on the BDNF expression. Actin ws used s internl control. (A) Control group, (B) trining group, (C) detrining group. The dt re represented s the men± SEM. detrining group. The present results showed tht swimming trining incresed neurogenesis in the dentte gyrus, nd detrining decresed neurogenesis in the dentte gyrus ner to the control level. Effect of trining nd detrining on the BDNF protein expression BDNF expression is presented in Fig. 4. The expression of BDNF in the hippocmpus ws 1.±.41 in the control group, 1.19±.2 in the trining group, nd.93±.21 in the detrining group. The present results showed tht swimming trining incresed BDNF expression in the hippocmpus, nd detrining decresed BDNF expression in the hippocmpus ner to the control level. DISCUSSION In the present study, short-term memory ws improved y swimming trining, nd swimming trining lso incresed hippocmpl neurogenesis in the mice. Enhncing effect of exercise on hippocmpl neurogenesis is well documented, nd increment of lerning ility nd memory function y exercise hs een suggested to e medited through this increment of neurogenesis (Kim et l., 27; Lee et l., 26; Snyder et l., 25). Swimming lso incresed cell prolifertion in the dentte gyrus of rt hippocmpus (R et l., 22). The results of our present study corroorted tht swimming trining enhnced hippocmpl neurogenesis, nd this effect of swimming trining improved the memory function in mice. In the present study, BDNF expression ws incresed in the hippocmpus of mice tht performed swimming trining. Neurotrophins is implicted in neuronl survivl, differentition, connectivity, nd plsticity (Hung nd Reichrdt, 21; Schinder nd Poo, 2). Exercise is known to increse expressions of vriety of neurotrophic fctors, including sic firolst growth fctor (FGF), insulin-like growth fctor-1 (IGF-1), nd BDNF expression (Crro et l., 21; Gómez-Pinill nd Vynmn, 25). Of them, BDNF is known to enhnce synptic trnsmission nd neuronl plsticity in the CNS (Schinder nd Poo, 2), resulting in increse in lerning ility nd memory cpility (Mizuno et l., 2). BDNF enhnces hippocmpl-dependent memory nd long-term potentition, form of synptic plsticity, vi Trk-B (Minichiello, 29). A high level of BDNF is concentrted in the hippocmpus, nd BDNF is selectively incresed following ctivity-dependent lerning nd memory tsks (Zimmererg et l., 29). Exercise tends to increse the expression of BDNF mrna in the hippocmpus (Johnson et l., 23; Russo-Neustdt et l., 2). Exercise-induced BDNF expression is known to enhnce not only neurogenesis ut lso LTP in the hippocmpus (Frmer et l., 24). The results of our present study suggested the correltion of the increment of neurogenesis with enhncement of BDNF expression induced y swimming trining in mice. Unlike positive effects of the trining, detrining is defined s the prtil or complete loss of trining-induced performnce dpttion s consequence of reduction or cesstion of trining (Gmelin et l., 27; Gondin et l., 26; Slentz et l., 27). Detrining induced decrement in the cognitive function nd memory cpility (Hnsen et l., 24; Rdk et l., 26). In the present results, numer of BrdU-positive cells nd expression of BDNF in the detrining group were decresed ner to the control levels. However in the detrining group, ltency in the step-down voidnce test ws lower, nd time tken to complete eight successful performnces ws longer nd error numer in the rdilrm mze test ws higher compred to the control group. These results suggest tht detrining exerted deteriorting effects on short-term memory nd sptil lerning memory thn un-trined control group. Rdk et l. (26) reported tht regulr exercise trining improved memory function, decresed the level of rec

6 Kim Y-M, et l. Swimming trining nd detrining tive oxygen species, nd incresed the production of BDNF nd NGF. On the other hnd, the eneficil effects of trining were reversile in the rin, since detrining down-regulted the neurotrophin level nd memory function.. In the present study, swimming exercise showed enhncing effects on short-term nd sptil lerning memories through incresing neurogenesis with BDNF expression in the hippocmpus. In contrst, detrining showed deteriorting effects on shortterm nd sptil lerning memories without deleterious effects on neurogenesis nd BDNF expression in the hippocmpus. This memory deteriorting effect of detrining considered s the temporry event. Bsed on the present results, we suggest tht sudden stopping of exercise my induce trnsient memory deteriortion. CONFLICT OF INTEREST No potentil conflict of interest relevnt to this rticle ws reported. ACKNOWLEDGMENTS This work ws supported y the Ntionl Reserch Foundtion of Kore Grnt funded y the Koren Government (NRF G4). REFERENCES Crro E, Trejo JL, Busiguin S, Torres-Alemn I. Circulting insulin-like growth fctor I medites the protective effects of physicl exercise ginst rin insults of different etiology nd ntomy. J Neurosci 21;21: Cho HS, Kim TU, Ko IG, Bek SS, Sim YJ, Kim H. Effect of sptil lerning nd tredmill exercise on memory ility in mice. J Exer Rehil 212; Eriksson PS, Perfiliev E, Bjork-Eriksson T, Alorn AM, Norderg C, Peterson DA, Gge FH. Neurogenesis in the dult humn hippocmpus. Nt Med 1998;4: Frmer J, Zho X, vn Prg H, Wodtke K, Gge FH, Christie BR. Effects of voluntry exercise on synptic plsticity nd gene expression in the dentte gyrus of dult mle Sprgue-Dwley rts in vivo. Neuroscience 24;124: Gmelin FX, Berthoin S, Syh H, Liers C, Bosquet L. Effect of trining nd detrining on hert rte vriility in helthy young men. Int J Sports Med 27;28: Gómez-Pinill F, Vynmn S. A deficient environment in prentl life my compromise systems importnt for cognitive function y ffecting BDNF in the hippocmpus. Exp Neurol 25;192: Gondin J, Guette M, Blly Y, Mrtin A. Neurl nd musculr chnges to detrining fter electrostimultion trining. Eur J Appl Physiol 26; 97: Gould E, Tnpt P, Hstings NB, Shors TJ. Neurogenesis in dulthood: possile role in lerning. Trends. Cog Sci 1999;3: Hnsen AL, Johnsen BH, Sollers JJ 3rd, tenvik K., Thyer J F. Hert rte vriility nd its reltion to prefrontl cognitive function: the effects of trining nd detrining. Eur J Appl Physiol 24;93: Hung EJ, Reichrdt LF. Neurophins: roles in neuronl development nd function. Annu Rev Neurosci 21;24: Jin K, Minmi M, Ln JQ, Mo XO, Btteur S, Simon RP, Greenerg DA. Neurogenesis in dentte sugrnulr zone nd rostrl suventriculr zone fter focl cererl ischemi in the rt. Proc Ntl Acd Sci U S A 21;98: Johnson RA, Rhodes JS, Jeffrey SL, Grlnd T, Mitchell GS. Hippocmpl rin-derived neurotrophic fctor ut not neurotrophin-3 increses more in mice selected for incresed voluntry wheel running. Neuroscience 23;121:1-7. Kim BK, Shin MS, Lee HH, Sung YH, Kim H. Swimming llevites streptozotocin-induced short-term memory impirment in rts. J Exer Rehil 212;8: Kim H, Lee SH, Kim SS, Yoo JH, Kim CJ. The influence of mternl tredmill running during pregnncy on short-term memory nd hippocmpl cell survivl in rt pups. Int J Dev Neurosci 27;25: Kim SE, Ko IG, Kim BK, Shin MS, Cho S, Kim CJ, Kim SH, Bek SS, Lee EK, Jee YS. Tredmill exercise prevents ging-induced filure of memory through n increse in neurogenesis nd suppression of poptosis in rt hippocmpus. Exp Gerontol 21;45: Krmer AF, Erickson KI. Cpitlizing on corticl plsticity: influence of physicl ctivity on cognition nd rin function. Trends Cogn Sci 27;11: Kuhn HG, Dickinson-Anson H, Gge FH. Neurogenesis in the dentte gyrus of the dult rt: ge-relted decrese of neuronl progenitor prolifertion. J Neurosci 1996;16: Lee HH, Kim H, Lee JW, Kim YS, Yng HY, Chng HK, Lee TH, Shin MC, Lee MH, Shin MS, Prk S, Bek S, Kim CJ. Mternl swimming during pregnncy enhnces short-term memory nd neurogenesis in the hippocmpus of rt pups. Brin Dev 26;28: Minichiello L. TrkB signlling pthwys in LTP nd lerning. Nt Rev Neurosci 29;1: Mizuno M, Ymd K, Olriu A, Nw H, Neshim T. Involvement of rin-derived neurotrophic fctor in sptil memory formtion nd mintennce in rdil rm mze test in rts. J Neurosci 2;2:

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