Treadmill exercise alleviates chronic mild stress-induced depression in rats

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1 Originl Article lulr nd ehviorl mechnisms of lerning nd memory process (Dumn, 22). Neuronl plsticity is solutely necessry for dequte functioning of n individul in the continuously chnging environment (Fuchs et l., 24). In the prefrontl nd cingulted cortex, metolism nd volume re reduced in depression ptients (Mnji et l., 21; Mnji nd Dumn, 21). Postmortem morphometric rin studies in mood disorders demonstrted cellulr trophy nd/or loss (Mnji et l., 23). One of the most consistent effects of stress is trophy of hippocmpl neurons, nd depression lso induces hippocmpl trophy (Sheline et l., 23). Mjor depressive disorders my e ssocited with n impirment of structurl plsticity nd cellulr resilience, nd ntidepressnts ct y normlizing these impirments (Mnji nd Dumn, 21). Moleculr elements regulting neuronl plsticity re lso in Journl of Exercise Rehilittion 215;11(6):33-31 Tredmill exercise llevites chronic mild stress-induced depression in rts Teck-Hyun Lee 1, Kijeong Kim 2, Ml-Soon Shin 3, Chng-Ju Kim 3, Bek-Vin Lim 4, * 1 Deprtment of Fmily Medicine, De Dong Hospitl, Busn, Kore 2 School of Exercise & Sport Science, College of Nturl Sciences, University of Ulsn, Ulsn, Kore 3 Deprtment of Physiology, College of Medicine, Kyung Hee University, Seoul, Kore 4 Division of Leisure & Sports Science, Deprtment of Exercise Prescription, Dongseo University, Busn, Kore Depression is mjor cuse of disility nd one of the most common pulic helth prolems. In the present study, ntidepressive effect of tredmill exercise on chronic mild stress (CMS)-induced depression in rts ws investigted. For this, sucrose intke test, immunohistochemistry for 5-romo-2 -deoxyuridine, terminl deoxynucleotidyl trnsferse-medited dutp nick end-leling stining, nd Western lot nlysis for rin-derived neurotrophic fctor, cyclic denosine monophosphte response element inding protein, nd endothelil nitric oxide synthse were conducted. Following dpttion to the niml vivrium nd two seline fluid intke tests, the nimls were divided into four groups: the control group, the CMS-induced depression group, the CMS-induced depression nd exercise group, nd the CMS-induced depression nd fluoxetine-treted group. The nimls in the CMS groups were exposed to the CMS conditions for 8 weeks nd those in the control group were exposed to the control conditions for 8 weeks. After 4 weeks of CMS, the rts in the CMS-induced depression nd exercise group were mde to run on motorized tredmill for 3 min once dy for 4 weeks. In the present results, tredmill exercise llevited CMS-induced depressive symptoms. Tredmill exercise restored sucrose consumption, incresed cell prolifertion, nd decresed poptotic cell deth. The present results suggest the possiility tht exercise my improve symptoms of depression. Keywords: Depression, Tredmill exercise, Chronic mild stress, Fluoxetine INTRODUCTION Depression is mjor cuse of disility nd one of the most common pulic helth prolems, with 1% to 2% lifetime prevlence in worldwide. Antidepressnts, such s tricyclic ntidepressnts nd monomine oxidse inhiitors, re minly ttriutle to the modultion of nordrenergic nd serotonergic functions (Delgdo, 2). Unfortuntely, these drugs hve mny dverse effects s result of direct or indirect interctions with multiple receptors (Kent et l., 2). Selective serotonin reuptke inhiitors led to the indiscriminte ctivtion of ll serotonin (5-hydroxytryptmine) receptors, nd re consequently ssocited with numer of dverse effects (Sthl, 1998). Neuronl plsticity or remodeling is closely ssocited with cel- *Corresponding uthor: Bek-Vin Lim Division of Leisure & Sports Science, Deprtment of Exercise Prescription, Dongseo University, 47 Jurye-ro, Ssng-gu, Busn 4711, Kore Tel: , Fx: , E-mil: todd64@nver.com Received: : Novemer 13, 215 / Accepted: Decemer 13, 215 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 215 Koren Society of Exercise Rehilittion pissn X 33 eissn

2 Lee TH, et l. Tredmill exercise llevites depression in rts volved in the ctions of ntidepressnts. These elements include up-regultion of trnscription fctors, such s the cyclic denosine monophosphte response element inding protein (CREB) nd rin-derived neurotrophic fctor (BDNF) (Dumn, 22). Antidepressnts exert mjor effects through signling pthwys of neuroplsticity nd cell survivl (D S nd Dumn, 22; Mnji et l. 21). Voluntry physicl ctivity enhnced BDNF trnscription in severl hippocmpl res, oth on its own nd in comintion with nti-depressnts (Russo-Neustdt et l., 2). Endothelil nitric oxide synthse (enos) is downstrem meditor for vsculr endothelil growth fctor nd ngiogenesis. enos regultes BDNF expression in the ischemic rin disese nd influences progenitor cell prolifertion, neuronl migrtion, nd neurite outgrowth nd enos ffects functionl recovery fter stroke (Chen et l., 25). The levels of oth plsm NOx nd pltelet enos ctivity were significntly lower in the sujects with mjor depression compred with the helthy control sujects (Chrpko et l., 24). In the present study, ntidepressive effect of tredmill exercise on chronic mild stress (CMS)-induced depression in rts ws investigted. For this, sucrose intke test, immunohistochemistry for 5-romo-2 -deoxyuridine (BrdU), terminl deoxynucleotidyl trnsferse-medited dutp nick end-leling (TUNEL) stining, nd western lot nlysis for BDNF, CREB, nd enos were conducted. MATERIALS AND METHODS Animls nd tretments Mle Sprgue-Dwley rts weighing 1±1 g (4 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 nd the Koren Acdemy of Medicl Sciences. The nimls were housed under lortory conditions t controlled temperture (2 C±2 C) nd mintined under lightdrk cycles, ech consisting of 12 hr of light nd 12 hr of drkness (lighting from 7:.m. to 7: p.m.) with food nd wter mde ville d liitum. Sucrose solution (1%) ws ville d liitum for 1 week preceding the experimentl procedures to llow for dpttion to the tste of the sucrose (Grippo et l., 25). Following dpttion to the niml vivrium nd two seline fluid intke tests, the nimls were divided into four groups (n=12 in ech group): the control group, the CMS-induced depression group, the CMS-induced depression nd exercise group, nd the CMS-induced depression nd fluoxetine (Eli Lilly nd Compny, Indinpolis, IN, USA)-treted group. The nimls in the CMS groups were exposed to the CMS conditions for 8 weeks nd those in the control group were exposed to the control conditions for 8 weeks. Sucrose intke tests were conducted weekly during the CMS period (Grippo et l., 25). After 4 weeks of CMS, ech niml ws injected intrperitonelly with BrdU (5 mg/kg; Sigm Chemicl Co., St. Louis, MO, USA) for 4 weeks (5 times per week). Sucrose intke test Sucrose intke test ws employed to ssess nhedoni. Anhedoni is defined s reduction in sucrose intke nd sucrose preference reltive to the control group nd seline vlue. Sucrose intke test consisted of first removing the food nd wter from ech rt s cge for period of 2 hr. All nimls (oth CMS group nd control group) were deprived of food nd wter prior to the sucrose intke test. Wter nd 1% sucrose were then plced on the cges in preweighed plstic ottles, nd the nimls were llowed to consume the fluids for period of 1 hr. The ottles were then removed nd weighed. Two seline fluid intke tests were performed, seprted during 5 dys, nd the results were verged. Sucrose intke tests were conducted weekly throughout the CMS period. Sucrose intke ws clculted on n solute sis (sucrose nd wter intke seprtely) similr to previous studies with the CMS protocol (Grippo et l., 25). Chronic mild stress Following two seline fluid intke tests, the nimls were rndomly seprted into four groups. The modified CMS procedure employed method descried elsewhere (Grippo et l., 25), nd this procedure ws designed to minimize pin nd discomfort while mximizing the unpredictle nture of the stressors (Tle 1). Briefly, the rts in the CMS groups were exposed to the following stressors in rndom order: continuous overnight illumintion (two 12-hr periods), 4 cge tilt long the verticl xis (one 6-hr period), pired housing (one 16-hr period nd one 4-hr period), dmp edding (3-mL wter spilled into edding; one 16-hr period), wter deprivtion (one 16-hr period) exposure to n empty wter ottle immeditely following the 16-hr period of cute wter deprivtion (one 1-hr period), nd white noise (-9 db; one 4-hr period of continuous noise nd one 3-hr period of continuous noise). Tle 1 shows the timing nd length of ll stressors used in the CMS procedure. The stressors were presented rndomly during 1 week, nd then repeted during 8 weeks. Control nimls were left undistured in their home cges throughout the 8-week period with the exception of generl hndling (i.e., regulr 34

3 Lee TH, et l. Tredmill exercise llevites depression in rts Tle 1. The timing nd length of ll stressors used in the chronic mild stress procedure Stressor Sundy Mondy Tuesdy Wednesdy Thursdy Fridy Sturdy Food deprivtion 16:" 12: Wter deprivtion 16:" 12: 18:" 1: Continuous lighting 19:" 7: 19:" 7: Cge tilt 1:"16: Pired housing 18:" 1: 18:"22: Dmp edding 22:" 14: Empty wter ottle 1:"11: White noise 13:"16: 11:"15: Fluid intke test 12:"13: cge clening nd mesuring ody weight), which ws mtched to tht of the CMS groups. All rts were decpitted 5 dys fter finishing CMS procedure. Tredmill exercise protocol After 4 weeks of CMS, the rts in the CMS-induced depression nd exercise group were mde to run on motorized tredmill for 3 min once dy for 4 weeks (5 times per week). The exercise regimen consisted of running t 3 m/min for the first 5 min, 5 m/ min for the next 5 min, nd then 8 m/min for the lst 2 min with % grde. The nimls in the other groups remined on tredmill without running for 3 min (Lee et l., 23). Fluoxetine tretment After 4 weeks of CMS, the rts in the CMS-induced depression nd fluoxetine-treted group received 1-mg/kg fluoxetine (Eli Lilly nd Compny) orlly, nd those in the other groups received equivlent mount of wter orlly once dy for 4 weeks (5 times per week). Tissue preprtion The nimls were first fully nesthetized with Zoletil 5 (1 mg/kg, intrperitonelly; Vic Lortories, Crros, Frnce), trnscrdilly perfused with 5 mm phosphte-uffered sline (PBS), nd then fixed with freshly prepred solution consisting of 4% prformldehyde in 1 mm phosphte uffer (PB, ph 7.4). The rins were then removed, postfixed in the sme fixtive overnight, nd trnsferred into 3% sucrose solution for cryoprotection. Coronl sections of 4-μm thickness were mde using freezing microtome (Leic, Nussloch, Germny). BrdU immunohistochemistry BrdU immunohistochemistry ws used for the detection of newly generted cells in the dentte gyrus, s previously descried method (Jng et l., 22; Sim, 214). The sections were first permeilized y incuting in.5% Triton X-1 in PBS for 2 min. They were then incuted in 5% formmide-2 x stndrd sline citrte t 65 C for 2 hr, denturted in 2 N 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; Boehringer Mnnheim, Mnnheim, Germny). The sections were then wshed three times with PBS nd incuted for 1 hr with iotinylted mouse secondry ntiody (1:2; Vector Lortories, Burlingme, CA. USA). The sections were then incuted for nother 1 hr with VECTASTAIN Elite ABC Kit (1:1; Vector Lortories). For stining, the sections were incuted in rection mixture consisting of.2% 3,3 -diminoenzidine contining nickel chloride (4 mg/ml; nickel-dab) nd.3% H2O2 in 5 mm Tris-HCl (ph 7.6) for 5 min. The sections were then wshed three times with PBS nd mounted onto geltin-coted slides. The slides were ir-dried overnight t room temperture, nd coverslips were mounted using Permount (Fisher Scientific, Fir Lwn, NJ, USA). TUNEL stining For visuliztion of poptotic cell deth, TUNEL stining ws performed using the In Situ Cell Deth Detection Kit (Roche, Mnnheim, Germny) s previously descried (Heo et l., 214; Jng et l., 22). Briefly, sections were post-fixed in ethnol-cetic cid (2:1) nd rinsed. Then, the sections were incuted with proteinse K (1 μg/ml), rinsed, incuted in 3% H2O2, permeilized with.5% Triton X-1, rinsed gin, nd incuted in the TUNEL rection mixture. The sections were rinsed nd visulized using converter-pod with nickel-dab. The slides were ir-dried overnight t room temperture, nd coverslips were mounted using Permount. 35

4 Lee TH, et l. Tredmill exercise llevites depression in rts Western lot Western lot for BDNF, CREB, nd enos ws performed ccording to the previously descried method (Heo et l., 214; Kim et l., 215). The hippocmpus ws removed from the rt rin, nd trimmed off onto chilled surfce. Following tissue homogeniztion with ice-cold lysis uffer contining 5 mm Tris-HCl (ph 7.5), 15 mm NCl,.5% deoxycholic cid, 1% NP4,.1% sodium dodecyl sulfte (SDS), 1 mm phenylmethylsulfonyl fluoride, the smples were centrifuged t 3, g for 15 min t -4 C. The superntnt frction ws collected, nd the protein concentrtion determined y Brdford ssy. Thirty microgrms of totl protein were electrophoresed on the SDS-polycrylmide gels nd trnsferred onto nitrocellulose memrne (Schleicher & Schuell GmH, Dssel, Germny). Mouse ntictin ntiody, rit nti-bdnf ntiody (1:1,; Snt Cruz Biotechnology, Snt Cruz, CA, USA), rit nti-creb ntiody (1:1,; Upstte, Lke Plcid, NY, USA), nd mouse nti-enos ntiody (1:1,; BD Sciences, Frnklin Lkes, NJ, USA) were used s the primry ntiodies. Horserdish peroxidse-conjugted ntimouse ntiody (1:1,; Snt Cruz Biotechnology) for ctin, enos, nd ntirit ntiody (1:1,; Snt Cruz Biotechnology) for BDNF, CREB were used s the secondry ntiodies. Bnd detection ws performed using n enhnced chemiluminescence detection system (Amershm Phrmci Biotech GmH, Freiurg, Germny). Dt nlysis Imges were cptured with video cmer ttched to light microscope (Olympus, Tokyo, Jpn) nd dt were nlyzed using Imge-Pro Plus softwre (Medi Cyernetics Inc., Silver Spring, MD, USA). The numers of BrdU-positive nd TUNEL-positive cells in the dentte gyrus were counted hemilterlly using the Imge-Pro Plus softwre nd expressed s the numer of cells per squre millimeter (mm 2 ) of the grnulr lyer. In the western lotting, the men opticl density for ech group ws mesured using the Imge-Pro Plus softwre nd expressed s reltive intensity where control group ws ssigned s 1. Sttisticl nlysis ws performed using one-wy nlysis of vrince followed y Duncn post hoc test. The results re presented s the men±stndrd error of the men. Differences were considered significnt t P<.5. RESULTS Sucrose intke test Sucrose intke ws decresed in the rts of the CMS-induced Sucrose intke (g) Week Fig. 1. Effect of exercise on sucrose intke. ( ) Control group, ( ) chronic mild stress (CMS)-induced depression group, ( ) CMS-induced depression nd exercise group, ( ) CMS-induced depression nd fluoxetine-treted group. Letters (, ) men sttisticl significnce P<.5. group, however, sucrose intke ws restored in the rts of the CMS-induced depression nd exercise group nd in the CMS-induced depression nd fluoxetine-treted group (Fig. 1). Numers of BrdU-positive cells The numer of BrdU-positive cells in the dentte gyrus ws decresed in the rts of the CMS-induced depression group, however, the numer of BrdU-positive cells ws incresed in the rts of the CMS-induced depression nd exercise group nd in the CMS-induced depression nd fluoxetine-treted group (Fig. 2). Numers of TUNEL-positive cells The numer of TUNEL-positive cells in the dentte gyrus ws incresed in the rts of the CMS-induced depression group, however, the numer of TUNEL-positive cells ws decresed in the rts of the CMS-induced depression nd exercise group nd in the CMS-induced depression nd fluoxetine-treted group (Fig. 3). BDNF expression The expression of BDNF in the dentte gyrus ws decresed in the rts of the CMS-induced depression group, however, BDNF expression ws incresed in the rts of the CMS-induced depression nd exercise group nd in the CMS-induced depression nd fluoxetine-treted group (Fig. 4). CREB expression The expression of CREB in the dentte gyrus ws not chnged 36

5 Lee TH, et l. Tredmill exercise llevites depression in rts 3 d 3 No. of BrdU-positive cells (mm 2 ) 2 1 c No. of TUNEL-positive cells (mm 2 ) 2 1 c Fig. 2. Effect of exercise on the numer of 5-romo-2 -deoxyuridine (BrdU)-positive cells in the dentte gyrusn. Upper: Photomicrogrphs of BrdU-positive cells in the dentte gyrus. Arrows indicte BrdU-positive cells. The scle r represents 2 μm. Below: Numer of BrdU-positive cells in ech group. (A) Control group, (B) chronic mild stress (CMS)-induced depression group, (C) CMS-induced depression nd exercise group, (D) CMS-induced depression nd fluoxetine-treted group. Letters (,, c) men sttisticl significnce P<.5. in the rts of the CMS-induced depression group compred to the control rts, however, CREP expression ws incresed in the rts of the CMS-induced depression nd exercise group nd in the CMS-induced depression nd fluoxetine-treted group compred to the depression rts (Fig. 5). enos expression The expression of enos in the dentte gyrus ws not chnged in the rts of the CMS-induced depression group compred to the control rts, however, enos expression ws incresed in the rts of the CMS-induced depression nd exercise group compred to the depression rts (Fig. 6). Fig. 3. Effect of exercise on the numer of terminl deoxynucleotidyl trnsferse-medited dutp nick end-leling (TUNEL)-positive cells in the dentte gyrus. Upper: Photomicrogrphs of TUNEL-positive cells in the dentte gyrus. Arrows indicte TUNEL-positive cells. The scle r represents 2 μm. Below: Numer of TUNEL-positive cells in ech group. (A) Control group, (B) chronic mild stress (CMS)-induced depression group, (C) CMS-induced depression nd exercise group, (D) CMS-induced depression nd fluoxetine-treted group. Letters (,, c) men sttisticl significnce P<.5. DISCUSSION In the present study, CMS procedure reduced sucrose intke of the rts, while exercise nd fluoxetine-tretment incresed CMS-induced decrement in sucrose intke. It ws reported tht nhedoni is one of the core symptoms of depression in humns (Rygul et l., 25). This nhedoni demonstrte n opertionl chnge in rewrd sensitivity ssocited with CMS nd they re in line with previous studies tht hve employed the CMS procedure (Grippo et l., 25). In the present study, CMS procedure reduced cell prolifertion, while exercise nd fluoxetine-tretment incresed CMS-induced decrement in cell prolifertion in the dentte gyrus. It ws report- 37

6 Lee TH, et l. Tredmill exercise llevites depression in rts Actin Actin BDNF enos c,c Reltive BDNF expression (O.D) 1..5 c d Reltive enos expression (O.D) 1..5, Fig. 4. Western lot nlysis of rin-derived neurotrophic fctor (BDNF) expression in the dentte gyrus. (A) Control group, (B) chronic mild stress (CMS)-induced depression group, (C) CMS-induced depression nd exercise group, (D) CMS-induced depression nd fluoxetine-treted group. Letters (,, c, d) men sttisticl significnce P<.5. Fig. 6. Actin Western lot nlysis of expression level of endothelil nitric oxide synthse (enos) expression in the dentte gyrus. (A) Control group, (B) chronic mild stress (CMS)-induced depression group, (C) CMS-induced depression nd exercise group, (D) CMS-induced depression nd fluoxetine-treted group. Letters (,, c) men sttisticl significnce P<.5. Reltive CREB expression (O.D) Actin CREB, Fig. 5. Actin Western lot nlysis of expression level of cyclic denosine monophosphte response element inding protein (CREB) expression in the dentte gyrus. (A) Control group, (B) chronic mild stress (CMS)-induced depression group, (C) CMS-induced depression nd exercise group, (D) CMS-induced depression nd fluoxetine-treted group. Letters (,, c, d) men sttisticl significnce P<.5.,c c,d ed tht stress nd glucocorticoides impir hippocmpl neurogenesis (Mnji et l., 23), nd chronic stressed nimls showed suppressed prolifertion (Heine et l., 24). Suppression of cell prolifertion in the hippocmpus could constitute one of the mechnisms of the depression (Bjørneekk et l., 25). Vrious experimentl studies on the stress nd nti-depressnts indicte neurogenesis s the etiology of mjor depressive disorder (Kempermnn nd Kronenerg, 23). Anti-depressnt-like effect of running is ssocited with incresed hippocmpl cell prolifertion (Bjørneekk et l., 25). In the present study, CMS procedure incresed the numer of TUNEL-positive cells in the dentte gyrus, while exercise nd fluoxetine-tretment decresed the numer of TUNEL-positive cells. One of the most consistent effects of stress on cell morphology is trophy of hippocmpl neurons (Spolsky, 2). Severl clinicl studies indicted tht suset of ptients with depression showed glucocorticoid hypersecretion or exhiited hyperctivity of the hypothlmic-pituitry-drenl (HPA) xis (Spolsky, 2). Moreover, reduction in hippocmpl volume ws seen in ptients with HPA hyperctivity (Spolsky, 2). Stresses nd elevted glucocorticoids induced glutmte excitotoxicity, distured clcium homeostsis, inhiited glucose trnsport, nd in- 38

7 Lee TH, et l. Tredmill exercise llevites depression in rts cresed oxygen rdicl genertion (Spolsky, 2). Tredmill exercise is known to inhiit stress-induced poptosis in the dentte gyrus (Kim nd Seo, 213). In the present study, CMS procedure decresed expression of BDNF, while exercise nd fluoxetine-tretment incresed expression of BDNF nd CREB in the dentte gyrus. Decresed BDNF level is crucil phenomenon ssocited with stress, prticulrly relevnt to stress-relted depressive disorders (D S nd Dumn, 22). Dysfunction of the camp-creb signling cscde cused stress-induced BDNF down-regultion (Dumn et l., 1997). The up-regultion of CREB expression ws oserved y dministrtion of ntidepressnts nd ppliction of chronic electroconvulsive seizure (Dumn et l., 2). The rin camp signl trnsduction pthwy is involved in the therpeutic ction of ntidepressnts (D S nd Dumn, 22; Mnji et l., 23). Overexpression of CREB in the hippocmpl dentte gyrus or infusion of BDNF into the hippocmpus produced nti-depressnt effect in niml models of depression (Shirym et l., 22). CREB is essentil for long-term trnscriptionl chnges ssocited with chronic ntidepressnt tretment (Conti et l., 22). Therefore, ntidepressnts could medite their effects y incresing neurogenesis nd modulting the signling pthwys involved in plsticity nd survivl (D S nd Dumn, 22). Exercise llevites stress-induced decrement in BDNF expression (Adlrd nd Cotmn, 24). Exercise-induced BDNF expression is ssocited with the expressions of severl key intermedites of the phosphtidylinositol-3 kinse/akt pthwy, which is known to enhnce neuronl survivl (Chen nd Russo-Neustdt, 25). In the present study, CMS procedure decresed expression of enos, while exercise incresed expression of enos in the dentte gyrus. Brin NO hs multiple functions, such s rin circuits nd plsticity, neuroprotection nd neurotoxicity, nd ehvior (Yermoliev et l., 2). Augmenttion of NO production y enos increses cererl lood flow, which exerts neuroprotection during rin ischemi (Hshiguchi et l., 25). Neuroprotection y exercise is medited y incresed enos expression nd ugmenttion of cererl lood flow (Endres et l., 23). enos in hippocmpl lood vessels my diffuse into neuronl prenchym to influence cell ctivity, nd correltion etween enos nd neuronl ctivity ws reported (Liu et l., 25). In the present study, tredmill exercise restored sucrose consumption, incresed cell prolifertion, nd decresed poptotic cell deth. This ntidepressive effect of tredmill exercise cn e scried to the ugmenttion of cererl lood flow through incresing enos expression, nd then this my increse BDNF expression. 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 ). REFERENCES Adlrd PA, Cotmn CW. Voluntry exercise protects ginst stress-induced decreses in rin-derived neurotrophic fctor protein expression. Neuroscience 24;124: Bjørneekk A, Mthé AA, Brené S. The ntidepressnt effect of running is ssocited with incresed hippocmpl cell prolifertion. Int J Neuropsychophrmcol 25;8: Chen J, Zchrek A, Zhng C, Jing H, Li Y, Roerts C, Lu M, Kpke A, Chopp M. Endothelil nitric oxide synthse regultes rin-derived neurotrophic fctor expression nd neurogenesis fter stroke in mice. J Neurosci 25;25: Chen MJ, Russo-Neustdt AA. Exercise ctivtes the phosphtidylinositol 3-kinse pthwy. Brin Res Mol Brin Res 25;135: Chrpko WE, Jursz P, Rdomski MW, Lr N, Archer SL, Le Mellédo JM. Decresed pltelet nitric oxide synthse ctivity nd plsm nitric oxide metolites in mjor depressive disorder. Biol Psychitry 24; 56: Conti AC, Cryn JF, Dlvi A, Lucki I, Blendy JA. camp response element-inding protein is essentil for the upregultion of rin-derived neurotrophic fctor trnscription, ut not the ehviorl or endocrine responses to ntidepressnt drugs. J Neurosci 22;22: Delgdo PL. Approches to the enhncement of ptient dherence to ntidepressnt mediction tretment. J Clin Psychitry 2;61 Suppl 2:6-9. D S C, Dumn RS. Antidepressnts nd neuroplsticity. Bipolr Disord 22;4: Dumn RS. Pthophysiology of depression: the concept of synptic plsticity. Eur Psychitry 22;17 Suppl 3: Dumn RS, Heninger GR, Nestler EJ. A moleculr nd cellulr theory of depression. Arch Gen Psychitry 1997;54: Dumn RS, Mlerg J, Nkgw S, D S C. Neuronl plsticity nd survivl in mood disorders. Biol Psychitry 2;48:

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