Brain Plasticity 1 (2015) 93–123 DOI 10.3233/BPL-150016 ... article Oct. 2015.pdf · Brain Plasticity 1 (2015) 93–123 DOI 10.3233/BPL-150016 IOS Press 93 The Beneﬁts of Exercise

Brain Plasticity 1 (2015) 93ndash123DOI 103233BPL-150016IOS Press

93

The Benefits of Exercise on Structuraland Functional Plasticity in the RodentHippocampus of Different Disease Models

Anna R Pattena Suk Yu Yaua Christine J Fontainea Alicia Meconia Ryan C Wortmana

and Brian R ChristieabcdlowastaDivision of Medical Sciences Island Medical Program University of Victoria Victoria British Columbia CanadabDepartment of Biology University of Victoria Victoria British Columbia CanadacBrain Research Centre and Program in Neuroscience University of British Columbia VancouverBritish Columbia CanadadDepartment of Cellular and Physiological Sciences University of British Columbia VancouverBritish Columbia Canada

Abstract In this review the benefits of physical exercise on structural and functional plasticity in the hippocampus are discussedThe evidence is clear that voluntary exercise in rats and mice can lead to increases in hippocampal neurogenesis and enhancedsynaptic plasticity which ultimately result in improved performance in hippocampal-dependent tasks Furthermore in modelsof neurological disorders including fetal alcohol spectrum disorders traumatic brain injury stroke and neurodegenerativedisorders including Alzheimerrsquos Parkinsonrsquos and Huntingtonrsquos disease exercise can also elicit beneficial effects on hippocampalfunction Ultimately this review highlights the multiple benefits of exercise on hippocampal function in both the healthy and thediseased brain

Keywords Exercise hippocampus Cornu Ammonis dentate gyrus neurogenesis synaptic plasticity behaviour

ABBREVIATIONS

AD Alzheimerrsquos diseaseBDNF brain derived neurotrophic factorCA Cornu AmmonisCFC contextual fear conditioningDGC dentate granule cellDG dentate gyrusEC entorhinal cortexfMRI functional magnetic resonance imagingGABA gamma amino butyric acidGCL granule cell layerHD Huntington disease

lowastCorrespondence to Brian R Christie (PhD) Division of Med-ical Sciences Island Medical Program University of VictoriaVictoria BC V8W 2Y2 Canada Tel +1 250 472 4244 Fax+1 250 772 5505 E-mail brain64uvicca

LPP lateral perforant pathLTD long-term depressionLTP long-term potentiationMPP medial perforant pathMWM Morris water mazeNMDA N-methyl D-aspartatePD Parkinsonrsquos diseasePND postnatal dayRAM radial arm mazeTBI traumatic brain injury

INTRODUCTION

The hippocampus is a bilateral structure that isfound in the medial temporal lobe of the mammalianbrain and is considered part of the limbic system

ISSN 2213-630415$3500 copy 2015 ndash IOS Press and the authors All rights reserved

This article is published online with Open Access and distributed under the terms of the Creative Commons Attribution Non-Commercial License

94 AR Patten et al Exercise and Hippocampal Plasticity

The hippocampus consists of the dentate gyrus (DG)the Cornu Ammonis (CA) 1 and CA3 regions (alsoknown as the hippocampus proper) and the subicu-lum (reviewed by [1]) The hippocampus has been thefocus of intensive research due to its important role inlearning and memory particularly that associated withdeclarative (ie explicit) and spatial memory [1]

The hippocampus displays both structural and func-tional plasticity into adulthood This plasticity can bepositively manipulated by interventions such as physi-cal exercise In this review we summarize the benefitsof voluntary physical exercise on hippocampal neu-rogenesis (which is referred to structural plasticity inthis review) and function (which is referred to synapticplasticity and behavioral improvement in this review)in rodents We also review the potential benefits ofphysical exercise on hippocampal plasticity in rodentmodels of neurological disorders including traumaticbrain injury stroke and neurodevelopmental and neu-rodegenerative disorders For purposes of simplicitywe have focused on studies utilizing rats and miceand where voluntary physical exercise paradigms havebeen employed Finally we have limited our review tostudies examining adult animals except for the sectionon neurodegenerative diseases While exercise has alsobeen shown to be beneficial in juvenile and aging ani-mals [2ndash7] these studies are outside the scope of thisreview

The hippocampus

Information flow in the hippocampusInformation flow in the hippocampus is generally

unidirectional and is known as the trisynaptic circuit[8] (Fig 1) The first connection in the trisynaptic cir-cuit originates from Layer II of the entorhinal cortex(EC) and projects to the DG via a group of fibres knownas the perforant path The fibres synapse on the den-drites of the dentate granule cells (DGCs) located in themolecular cell layer There are two subdivisions of theperforant path medial (MPP) and lateral (LPP) TheMPP originates in the medial EC and projects to themiddle one-third of the molecular cell layer whereasthe LPP originates in the lateral EC and projects tothe outermost third of the molecular cell layer Boththe MPP and LPP provide excitatory input onto theDGCs but are physiologically distinct and have dif-ferent short-term and long-term plasticity properties[9ndash11] The MPP and LPP are the major inputs ofcortical information into the hippocampus and theDGCs play an important role in processing and fil-tering information before it is sent to other regions of

Fig 1 A simplified hippocampal circuitry illustrating trisynapticand monosynaptic circuits The basic circuitry of the hippocampusis commonly termed the trisynaptic circuit Layer II of the entorhinalcortex provides input to the granule cells of the dentate gyrus via themedial (light blue) and lateral (purple) perforant paths The dentategranule cells project to pyramidal cells of the CA3 via the mossyfibre pathway (green) CA3 pyramidal neurons project to the CA1via schaffer collaterals (pink) The CA1 pyramidal cells project toboth the subiculum and to layers V and VI of the entorhinal cor-tex Abbreviations Cornu Ammonis (CA) Dentate Gyrus (DG)Entorhinal Cortex (EC) Lateral Perforant Path (LPP) Medial Per-forant Path (LPP) Mossy Fibres (MF) Schaffer Collaterals (SC)Subiculum (S)

the hippocampus via the trisynaptic circuit [8] Fromthe DG DGC axons project onto pyramidal cells in theCA3 region of the hippocampus (Fig 1) This pathwayis unique in that the bundles of axons are unmyeli-nated and are therefore known as the mossy fibres Thethird component of the trisynaptic circuit is the CA3to CA1 projection known as the Schaffer CollateralsPyramidal cells of the CA3 send axons into the stratumradiatum and stratum oriens of the CA1 and innervateapical and basal dendrites of the CA1 pyramidal cells[1] The CA1 then projects information to the subicu-lum and both the CA1 and the subiculum project fibresback to Layers V and VI of the EC to complete thecortical information loop (Fig 1) It should be notedthat the CA1 also receives projections from the EC andthis pathway is known as the temporoammonic path-way [1] These projections arise from layers III andV of the EC This pathway may play a more promi-nent role in stress and anxiety related behaviours asopposed to spatial memory [12] (which is discussedbelow (Section 112))

The role of the hippocampus in spatial memoryIn the 1950 s Dr William Scoville performed

a bilateral limbic surgery on patient Henry Mola-sion (commonly known as HM) giving the firstreal insight into the function of the hippocampus[13] In order to treat HMrsquos recurrent seizures thehippocampus amygdala collateral sulcus perihinalcortex EC and the medial mammillary nucleus were

AR Patten et al Exercise and Hippocampal Plasticity 95

removed [14] Following surgery HM was afflictedwith severe memory deficits he lacked the abilityto form and retain long-term memories of new facts(semantic memory) and events (episodic memory)This was the first case where a strong link was madebetween the hippocampus and explicit (ie intentionaland conscious) memory

Numerous studies have now refined the role of thehippocampus in the formation and maintenance ofexplicit spatial memory [15 16] In the 1980rsquos DrRichard Morris created the Morris water maze (MWM)test with the purpose of training rodents to learn thespatial location of a hidden platform submerged incloudy water as a test for hippocampal function [17]He observed that hippocampal lesions significantlyimpaired performance in this task [17]

Other studies have identified place cells in the hip-pocampus which has led to the cognitive map theoryof hippocampal function [18 19] These are cells thatbecome active when a rodent is in a specific locationin a specific environment [18] and such cells have alsobeen detected in humans [20] The presence of placecells within the hippocampus provides evidence thatthis structure organizes and stores stimuli with respectto a spatial framework (ie a cognitive map) and maybe used for spatial navigation [21 22] Indeed recentstudies have suggested that the hippocampal forma-tion acts as a network that encodes events and theircontexts with each distinct region playing a specificbut complementary role in the processing of spatialinformation

Within this scenario the DG is believed to play aunique role in spatial pattern separation (reviewed by[23]) Spatial pattern separation is the enhancement ofcontrast between two similar spatial patterns or eventsAt the neuronal level this is thought to occur eitherthrough change in neuronal firing rate or through thefiring of different neuronal sets [24 25] The DGCsdisplay sparse firing characteristics and there are veryfew connections between DGCs and CA3 pyramidalcells [26] which make the DG optimally structured forspatial pattern separation Furthermore the existenceof populations of DGCs that fire only when a rodent isin a given environment indicate that the DG containsplace fields that are important for pattern separation[27ndash29]

The CA3 region has been implicated in spatial pat-tern completion ndash the capacity to retrieve previouslystored information when presented with partial orincomplete inputs [30] Evidence for this comes fromstudies where mice that lacked N-methyl-D-aspartate(NMDA) receptor expression in the CA3 were trained

on the MWM While these mice were able to performthe task as well as control mice if the external environ-ment was altered by removing a subset of the externalcues so the mice only had an incomplete set of visualcues to recall the location of the platform deficits inperformance were observed [31] These results indi-cate that the ability to use partialincomplete spatialinput was compromised and implicate the CA3 inspatial pattern completion

The CA1 region of the hippocampus has been impli-cated in the processing of the temporal order of spatialpatterns or events This function is important to ensurethat spatial events separated by time are encoded withminimum overlap [32] The CA1 region also plays amajor role in spatial memory (see Section 321) andcontextual fear conditioning (see Section 322) and isthe most widely studied area of the hippocampus [1]Ablating or impairing the function of the CA1 regionleads to deficits in delayed spatial discrimination [33]Morris Water Maze performance [34] temporal order-ing tasks [35] and contextual fear conditioning [36] inrodents and spatial memory impairments in monkeys[37]

Together the three major regions of the hippocam-pus ndash the DG CA3 and CA1 encode spatial memorybut each region has its own distinct role within thisfunction The DG is associated with pattern separa-tion the CA3 with spatial pattern completion and theCA1 with temporal order processing The three regionswork in concert to encode spatial memory

Structural and functional plasticity in thehippocampus

The hippocampus is a dynamic structure thatdisplays both structural and functional plasticity Struc-tural plasticity can occur through the process of adulthippocampal neurogenesis which occurs only in theDG sub-region of the hippocampus [38 39] Throughthis process new neurons are produced and integratedinto existing CNS circuitry throughout the life spanProgenitor cells create neuroblasts in the subgranularzone of the DG that migrate into the granule cell layer(GCL) and differentiate into DGCs (reviewed by [40])These new neurons incorporate themselves into exist-ing neuronal circuits and display action potentials andfunctional synaptic inputs similar to DG granule cellsformed during the developmental period (reviewed by[41])

Functional or synaptic plasticity in the hippocam-pus is the process by which neurons alter their abilityto communicate with one another Enhancing synapticefficacy also known as long-term potentiation (LTP)


is largely dependent upon kinase activation and pro-tein synthesis and serves as the primary biologicalmechanism for understanding how learning and mem-ory processes operate in the brain [42 43] Long-termdepression (LTD) is the opposite of LTP and is char-acterized by a decrease in synaptic efficacy [43 44]This process has been linked to forgetting

PHYSICAL EXERCISE-INDUCEDENHANCEMENTS IN STRUCTURALPLASTICITY IN THE HIPPOCAMPUS

The beneficial effects of physical exercise on adulthippocampal neurogenesis were first reported by vanPraag et al (1999) showing that voluntary wheelrunning promotes hippocampal neurogenesis in adultmice [45] A positive correlation between runningdistance and levels of hippocampal neurogenesishas been repeatedly demonstrated in mice [46ndash48]Notably enhancement of neurogenesis by runningcan be affected by variables including genetic back-ground [48 49] age [4 50] form of running (forcedvs voluntary 39 45ndash47) housing environment (sin-gle or group housing [54] and duration (days tomonths) of exercise training [7 47 55] Despite thevariability among different studies exercise-inducedenhancements in hippocampal neurogenesis have beenconsistently reported in mice and rats in the literature[4 5 45ndash49 52 56ndash58 54 59] (Table 1)

The pioneer study by van Praag and colleagues(1999) indicated that long-term voluntary wheel run-ning for 2 to 4 months significantly increased theprocess of neuronal survival in female adult C57mice and concurrently enhanced synaptic plasticityand learning and memory performance in the MWM[45] Further studies by this group have also foundsignificant increases in neuronal differentiation andsurvival following 45 days voluntary wheel runningin both young and aged C57BL male mice [5]

Recent studies have revealed that physical exerciseexerts its promoting effects on cells at different stagesof neurogenesis In adult male and female C57BLmice voluntary running increases the number of pro-liferating cells with a peak occurring after 3-days ofshort-term running followed by a return to basal levelsafter 32 [60] or 35 days of running [61] Converselysignificant increases in differentiating neuronal cellscan only be observed after 10 days of running [7]These data indicate that voluntary running-induced cellproliferation occurs only in the initial period of run-ning and longer periods of running mainly promote

neuronal differentiation and survival rate of newbornneurons

Adult neurogenesis is derived from self-renewingneural stem cells (type-1 cells radial glial-like stemcells nestin and GFAP positive) which can give riseto intermediate progenitor cells (type-2a cells nestinpositive GFAP negative) that undergo amplificationand acquire neural cell fate to neural progenitors (type2b cells nestin and doublecortin positive) These neu-ral progenitors will then differentiate into migratingneuroblasts (type-3 cells nestin negative doublecortinpositive) that exit cell cycle to become post-mitoticneurons (reviewed by [62]) It is elusive whetherrunning induces adult neurogenesis by influencingproliferation or survival of distinct populations ofprecursor cells or both Suh and colleagues (2007)reported that voluntary wheel running activated prolif-eration of early lineage radial glial-like stem cells [63]which is echoed by the findings of Bednarczyk et al[64] showing an increase in the number of early lineagestems cells which are Ki67 (a endogenous marker forproliferating cells) and GFAP positive Similar resultswere also reported by Lugert et al (2010) who showedthat running activates quiescent radial precursor cells toenter into the cell cycle [65] In female adult C57BL1mice voluntary wheel running for 7 days induces atransient increase in proliferative precursor cells aswell as a reduced portion of DCX positive type-2b3cells that re-entered S-phase [61] suggesting that run-ning induces neurogenesis not only by enhancing cellproliferation but also by promoting cell cycle exit ofprogenitor cells Farioli-Vecchioli and colleagues haveshown that 12-days of running shortens the cell cycleof NeuroD1-positive progenitor cells (type-2b and -3) in wild-type mice and also appears to shorten thelength of the S-phase as well as the length of the wholecell cycle of both GFAP and Sox2 positive neural stemcells and NeuroD1-positive progenitors in Btg1-nullmice that lack the anti-proliferative gene Btg1 [66]Conversely Fischer and colleagues only observed atrend towards a shorter cell cycle length in mice show-ing increased cell proliferation following 5- days ofrunning and concluded that the effect of running onprogenitor cell proliferation was not caused by shorten-ing of cell cycle length [67] The contradictory resultsreported by Fischer et al [67] and Farioli-Vecchioliet al [66] may be due to the fact that the cellcycle length was examined on the entire proliferat-ing population vs specific progenitor cell populationsFurthermore the duration of running (5 days vs12 days) could have impacted these results Takentogether running may exert its pro-neurogenic effect


Table 1Effect of voluntary running on hippocampal plasticity in healthy rodents

Hippocampal neurogenesis

Animal age Species Running period Markers examined Effect of running Reference

3 months old Mouse 12 days BrdU Increased cell van Praag et al(Proliferation and proliferation 1999Survival) cell survival andNeuN net neurogenesis(neurogenesis)

3 months old Mouse 30 days BrdU (survival) Increased cell van Praag et alBrdUNeuN survival and 1999(neuronal neuronaldifferentiation) differentiation

3 months old Mouse 45 days BrdU (survival) Increased cell van Praag et al 2005or 19 months old survival and

neuronal differentiationBrdUNeuNS100

triple labeling6ndash8 weeks old Mouse selectively 40 days BrdU (survival) Increased cell Rhodes et al 2003

bred for high proliferationlevels of running survival and

BrdUNeuro neuronalS100 triple differentiationlabeling

6 weeks old Mouse 12 days or 19 days BrdU (survival) Increased cell Synder et al 2009PCNA (cell proliferationproliferation) after 14 days

runningIncreased cell

survival in afterboth 14 daysand 19 days ofrunning

3 months old Mouse 12 days BrdU(Proliferation Increased cell Brown et al 2003and survival) proliferation and

survival8-9 weeks old Mouse 14 days BrdU Ki67 (cell Increased cell Yau et al 2014

proliferation) proliferationDCX neuronal(neurogenesis) differentiationBrdUDCX and net(neuronal neurogenesisdifferentiation)

8 weeks old Mouse 24 hours 3 BrdU IdU CldU Increased cell Brandt et al 2010days 7 days or proliferation at35 days 24 hours 3 days

and 7 days(peak at 3days) Return tobaseline at 35days

12 weeks old Transgenic 4 weeks BrdU and nestin- Specific Kronenberg et al 2003mouse GFP positive cells increase in typeexpressing 2b transientGFP driven by amplifyingnestin gene progenitor cellspromotor

(Continued)


Table 1(Continued)

74 days at end Mouse 3 10 or 32 days BrdU Ki67 Increased cell Kronenberg et al 2006of experiment DCX calretinin proliferation at 3

days and 10days (peak at 3days) Returnedto baseline at 35days DCX andCalretininincreased at 10days and 32 days

2 months old Mouse 12 days BrdU and PCNA Increased cell Kannangara et al 2009(cell proliferation) proliferation

6ndash8 weeks old Rat 7 days or 28 days Brdu (cell Increased cell Yau et al 2012proliferation) proliferation andBrdUDCX differentiation(neuronal following 28differentiation) days of running

6ndash8 weeks old Rat 14 days BrdU (cell Increased cell Yau et al 2011proliferation) proliferation andBrdUDCX co- neuronallabeling (Neuronal differentiationdifferentiation)

2 months old Rat 3 7 14 28 56 days Ki 67 (cell Increased cell Patten et al 2013proliferation) proliferationNeuroD (neuronal after 37 or 28differentiation) days of running

Increasedneuronaldifferentiationafter 14 or 28days of running

Hippocampal synaptic plasticity

Animal age Species Running Area(s) analyzed Effect of Referenceperiod running

3 months old Mouse 30 days DG and CA1 Enhanced LTP Van Praag et al 1999In vitro in the DG but

not CA12 months old Rat 3 7 14 28 56 days DG Enhanced LTP Patten et al 2013

In vivo following 56days of running

Adult (exact Rat 7+ days DG Enhanced STP Farmer et al 2004age not In vivo and LTPspecified) reduced

threshold forLTP

3ndash5 weeks old Mouse 7ndash10 days DG Enhanced LTP Vasuta et al 2007In vitro no effect on

LTD bothabolished byNR2A blockade

Hippocampal dependent behavior

Animal age Species Running period Behavioral test Effect of Referencerunning

3 months old Mouse 30 days MWM Rapid Van Praag et al 1999acquisition(day 3) bettermemory inprobe test

(Continued)


Table 1(Continued)

2 months old Rat 3 weeks MWM Rapid Adlard et al 2004acquisition(day 2)

6ndash8 weeks old Mouse 34 days MWM Rapid Rhodes et al 2003acquisition incontrol runnersbut notselectively-bredrunners

3 months old Rat 1 week MWM CAMKII Vaynman et al 2007blockadeimprovesacquisition inrunners butimpairs memoryon probe test

sim7ndash9 weeks old Rat 30 days Contextual fear Increased Baruch et al 2004conditioning freezing 24hr

latersim4ndash6 weeks old Rat 8 weeks Contextual fear Increased Burghardt et al 2006

conditioning freezing 24hrlater mostfreezing in ratsthat ran themost

Adult (exact Rat 6 weeks Contextual fear Increased Greenwood et al 2009age not conditioning freezing whenspecified) running

occurred beforeconditioning butno effect whenrunningoccurredbetweenconditioning andtesting

2 months old Mouse 3 weeks Contextual fear Reduced fear Akers et al 2014conditioning memory in

runners6ndash8 weeks old Mouse 5 weeks Contextual fear No effect on Kitamura et al 2009

conditioning memoryexpressionspeed up decayrate ofhippocampaldependency ofmemory

5 months old Rat 7 weeks Radial arm maze Fewer trials to Anderson et al 2000criterion

10 weeks old Mouse 14 days Y-Maze Rapid Van der Borght et alacquisition by 2006trial 2 afterlearning in non-runners 14days of runningimprovedmemoryretention

Abbreviations BrdU bromodeoxyuridine CA Cornu Ammonis DG dentate gyrus DCX doublecortin MWM Morris Water Maze PCNAproliferating cell nuclear antigen


by cell cycle shortening on specific subpopulations ofneural stem cells and its effect may depend on durationof running

Prolonged wheel running also increases the num-ber of neuroblasts and mature neurons in the DG [64]Of note the presence of a running wheel itself isa form of environmental enrichment which can pro-mote the processes of adult neurogenesis becauseboth locked wheel and running wheel mice showincreases in proliferating cells as indicated by signif-icant increases in co-labeled Ki67 and GFAP positivecells [68] Importantly Bednarczyk and colleaguesreported that increased number of neuroblasts (DCXpositive cells) and newborn neurons (co-labeled withBrdU and NeuN) were only observed in running micebut not in the mice with locked wheels indicatingthat running is needed to increase maturation andsurvival of post-mitotic neuroblasts Taken togetherthere appear to be running-independent and -dependentstages of adult hippocampal neurogenesis [68]

Environmental enrichment that includes supplyingcages with toys tunnels and running wheels inducesrobust increases in cell proliferation and neurogene-sis [69] However a recent study has indicated thatthe running wheel is the critical stimulus for induc-ing neurogenesis in an enriched environment [70]When mice are exposed sequentially to the runningand then the environment enrichment there is an addi-tive increase in neurogenesis [71] Increasing the poolof proliferating precursor cells by running togetherwith an appropriate survival-promoting stimulus suchas environmental enrichment follows the idea that thecombination of exercise and environmental enrichmentmay potentially lead to more adult neurogenesis whichmay benefit hippocampal function

PHYSICAL EXERCISE-INDUCEDENHANCEMENTS IN FUNCTIONALPLASTICITY IN THE HIPPOCAMPUS

Synaptic plasticity

Synaptic plasticity refers to changes in neural com-munication as a result of experience and can bemeasured throughout the brain Two forms of synap-tic plasticity have been assessed in the hippocampusLTP commonly associated with memory formationand LTD which has more recently been associatedwith memory clearance or forgetting

The effects of exercise on synaptic plasticity in thehippocampus have been understudied (reviewed by[72]) despite the fact that exercise can reliably enhanceperformance on a range of hippocampal behaviors

(see Section 32) The effects of exercise on in vitrohippocampal synaptic plasticity were first shown infemale mice in 1999 [45] where one week of vol-untary wheel running resulted in greater LTP in theDG These findings were replicated both in vivo and invitro in male rats where voluntary and forced runningenhanced LTP in the DG [59 73 74] and CA3 [75]In the DG exercise may enhance LTP by lowering theinduction threshold for LTP though the mechanism forthis change in induction threshold is unknown [73]

Interestingly in van Praagrsquos seminal study of femalemice there was no effect of wheel running on CA1 LTP[45] Conversely forced exercise in sleep-deprived ratsovercame impairments in in vivo late-phase LTP in theCA1 to the level of non-sleep deprived rats [76] Inter-estingly in this study forced exercise had no effecton CA1 LTP in healthy rats suggesting that exercise-mediated enhancements of LTP in the CA1 are onlyevident in models where CA1 LTP is already depletedsuch as in sleep deprivation aging and neurodegen-erative disease [76ndash78] (see section 44) While theseregional differences between DG and CA1 LTP wereoriginally thought to be a direct result of increased neu-rogenesis following exercise this group later showedthat new neurons display enhanced LTP induction andonly develop normal synaptic responses when they are4-5 weeks old [79]

Bidirectional plasticityMore recently studies of the effects of exercise on

bidirectional plasticity have emerged Vasuta et al[80] studied exercise-induced changes in in vitrosynaptic plasticity in the mouse DG and the con-tributions of different NMDAR-subunits on thesephysiological changes The effects of voluntary wheelrunning on DG LTP were replicated however wheelrunning had no effect on DG LTD LTP in the DGis generally NMDAR-dependent [73] however until2007 the physiological contributions of the differ-ent NMDAR subunits on exercise-mediated plasticitywere unknown In this study selective NR2A or NR2Bblockade abolished DG LTP in non-exercised miceIn exercised animals however only NR2A blockadeabolished DG LTP and NR2B blockade significantlyreduced but did not block DG LTP Conversely neitherexercise nor selective blockade of NR2A or NR2B sub-units had an effect on DG LTD in sedentary animalsbut NR2A blockade abolished LTD while NR2B block-ade left LTD intact in exercised mice Interestinglywhile exercise increases NR2B mRNA specifically inthe DG region it does not affect NR1 or NR2A sub-unit mRNA nor either of these subunits in the CA1


region [73] Together these data indicate a unique rolefor the NR2A subunit in both LTP and LTD in the DGthat emerges following exercise

A great disparity exists in the study of hippocam-pal physiology following exercise in non-diseasedanimals The exercise-induced changes in NMDAR-subunit composition in the hippocampus discussedhere are likely just one component of the benefits ofexercise as others have reported increases in dendriticcomplexity [81] and neurotrophic factors [82] to namea few which all have implications on synaptic plastic-ity in the hippocampus [83 84] Indeed there are manymechanisms that may underlie the exercise-inducedchanges (or lack thereof) in synaptic plasticity in dif-ferent sub-regions of the hippocampus (many of whichare reviewed in this issue) however more work mustbe done in order to fully understand how each of theseputative mechanisms contributes to exercise-inducedhippocampal plasticity

Behavioral plasticity

The effect of voluntary wheel running onhippocampal-dependent behaviors has been exten-sively studied in both healthy and diseased rodentsHere we will summarize the most commonly usedbehaviors in the study of exercise in healthy animals

Morris water mazeThe Morris water maze task (MWM) is a classic

hippocampal behavioral task that has been modified inorder to assess different aspects and types of memorysuch as working memory long-term memory acquisi-tion and retrieval Fundamentally in this task animalsare placed in a pool of opaque water and must use distalvisual cues in order to locate a hidden platform wherethey may escape the water Following multiple learn-ing trials over multiple days the swim path or latencyto reach the platform can be measured as an indicationof spatial memory acquisition The platform can beremoved for a probe trial where the time spent search-ing the trained platform location can be assessed tomeasure reference memory

The MWM is the most studied behavioral task inexercise literature Runners acquire the MWM taskmore readily than non-runners where by the third dayof training runners take a more direct path and take lesstime to reach the platform than non-runners [45] Atthe time of the probe trial runners spend a significantlygreater proportion of time in the correct quadrantthan incorrect quadrants and the improvements in per-formance in runners were paralleled by increases in

hippocampal neurogenesis The rapid acquisition ofthe MWM task by runners has been extensively repli-cated [46 85] and this acquisition by runners may bemore rapid than mice housed in enriched environments[70] though together environmental enrichment andexercise might have additive effects on behavioralimprovement in the MWM [71] Curiously when hip-pocampal neurogenesis is disrupted by irradiationrunning-induced improvements in performance in theMWM are no longer evident [86]

Fear conditioningIn contextual fear conditioning (CFC) tasks an ani-

mal is conditioned to fear a context by providing atone followed by a footshock After a pre-determineddelay the animal is returned to the fearful context with-out the footshock and the freezing response to eitherthe context or the tone in that context is measured Thisbehavioral task requires the activity of the amygdalahippocampus as well as frontal and cingulate cortices(reviewed by [87])

CFC has been commonly used to assess learningand memory improvements following exercise Fol-lowing 30 days of voluntary wheel running malerats exhibited more freezing in the fearful contextwhen returned to that context 24 hours after footshocktraining [88] This evidence of increased freezingto the fearful context has been reported in othergroups following exercise [89 90] In a study byBurghardt et al [89] male rats that ran voluntarilyfroze more than rats that were in the locked con-trol condition indicating that the voluntary aspect ofexercise plays a role in this type of learning Therealso appears to be a sensitive period during whichvoluntary exercise has an effect on this fear condi-tioning where running between footshock training andtesting has no effect on freezing times while run-ning before training results in increased freezing tothe fearful context [90] Unlike spatial memories inthe MWM the exercise-mediated behavioral improve-ments in CFC are not dependent on intact hippocampalneurogenesis [86]

Arm mazesThe radial arm maze (RAM) is a spatial memory task

that is sensitive to hippocampal damage This task canbe modified for a multitude of memory types and hasclassically been used to assess working memory Forthis version of the task the animal can exit a centralzone and visit a multitude of arms (from 8ndash48) in orderto collect a food or water reward located at the end ofeach rewarded arm The animal must remember which


arms it has already visited in order to not visit the samearm again

Female rats that underwent voluntary wheel run-ning required fewer trials to reach criterion than theirnon-runner counterparts [91] Similarly in male ratsrunners made fewer reference errors and more correctchoices than non-runners [92]

The Y maze is another spatial memory task whereanimals must make a choice to pick either the left orright arm in order to receive a reward at the end of onearm which is hidden from the view of the animal As inthe MWM runner mice showed rapid acquisition of theY-maze task reaching over 80 correct arm choices bythe second trial during the first training session [93]Once non-runners had learned the Y-maze task andwere allowed 14 days of voluntary running they hadbetter memory retention than mice that did not run atall In this same task when after the 14-day running (ornon-running) delay the reward location was reversedthose mice that ran acquired the reversal learning taskmore rapidly [93]

Novel object recognitionNovel object recognition is another classic

hippocampal-dependent task (reviewed by [94])which has been used to study different types ofmemory In its most simple version animals areallowed to freely explore an environment containingtwo identical objects followed by a pre-determinedinterval before being returned to the environment for atest phase In the test phase one of the familiar objectsis replaced with a novel object which the animal willspend more time investigating if it remembers thefamiliar object This task is known to require the intactfunction of both the hippocampus and the perirhinalcortex in rats [95 96]

Voluntary wheel running also has been shown toimprove novel object recognition in mice [97] and rats[77 98] where improved performance was correlatedwith increases in BDNF expression in the perirhinalcortex [98] There also appears to be a temporal rela-tionship between the time that exercise stops and thebehavioral test begins where testing immediately afterexercise produces the greatest improvements in objectrecognition and BDNF expression in the hippocampusand perirhinal cortex [99]

Learning and forgetting ofhippocampus-dependent memories

New avenues of study have sought to understand therelationship between neurogenesis and forgetting (see[100] for a review) Feng et al (2001) demonstrated

that impaired neurogenesis causes increased memoryretention in the CFC task suggesting that hippocam-pal neurogenesis may play a role in memory clearance[101] Similarly when hippocampal neurogenesis isablated working memory was improved in the RAM[102] This ablation of hippocampal neurogenesisslows the decay of the hippocampal dependency ofremote CFC memories whereas in controls remoteCFC memories become less hippocampal depen-dent over time Running increases the rate at whichthese CFC memories become hippocampal indepen-dent without affecting the expression of the memoryan effect that is blocked by irradiation [103] Mostrecently Akers et al (2014) have shown a clear linkbetween neurogenesis and forgetting where runninginduced forgetting of a CFC task in adult mice Usingguinea pigs and degus species that both have low levelsof postnatal neurogenesis they showed intact memoryretention except when neurogenesis was stimulated bymemantine [104] Together these studies begin to sug-gest a role for neurogenesis and memory retention andclearance in the hippocampus

EFFECTS OF EXERCISE INNEUROLOGICAL DISORDERS

Fetal alcohol spectrum disorders

Ethanol can cause significant damage to the fetus[105 106] and can result in fetal alcohol spectrum dis-orders (FASD) with the extent of damage caused byethanol varying due to the timing frequency and vol-ume of ethanol consumed as well as the genetics andmetabolism of the mother

FASD can be modelled in rodents using a vari-ety of methodologies which are outlined in recentreviews from our laboratory [107 108] The mostcommonly used methods are the liquid diet modelwhere a pregnant dam receives a liquid diet contain-ing 36 (vv) ethanol throughout pregnancy and thegavage model where ethanol is administered via oralintubation

FASD and structural plasticityFASD can lead to a variety of structural deficits in the

hippocampus including decreases in adult hippocam-pal neurogenesis [109ndash113] The effect of exercise hasbeen examined in a variety of models of FASD to deter-mine whether beneficial effects on neurogenesis andneuron structure occur [111 114 115]

Redila et al (2006) were the first to show thatdecreases in cell proliferation that occur with prenatal


ethanol exposure can be rescued in rats with oneweek of exercise [115] Using a different model ofFASD where animals were exposed to ethanol dur-ing the third trimester equivalent (corresponding toPND1-10 in the rat) Helfer et al (2009) found that12 days of voluntary running wheel exercise dur-ing adolescence increased proliferation of cells in theDG but long-term survival of these neurons was notincreased [111] It is important to note that in thisstudy baseline levels of proliferation and neurogenesiswere comparable between the control and the ethanol-exposed animals which differs from the study byRedila et al (2006)

The effect of exercise on neurogenesis was alsoexamined using the gavage model where ethanol wasadministered throughout all three trimester equivalents[114] Ethanol exposure reduced cell proliferation andincreased early neuronal maturation but did not affectcell survival [114] When ethanol exposed animalswere given access to voluntary running wheels for 12days beginning at PND 48 increases in cell prolifer-ation and maturation were observed which indicatesthat despite deficits caused by ethanol exposure thebrain still has the capacity to respond to the beneficialeffects of exercise [114] Remarkably increases in theproliferation marker Ki67 were actually much greaterin ethanol exposed animals than in control animals fol-lowing exercise This may be linked to the fact thatethanol exposed animals ran significantly more thancontrols which could indicate a hyperactive phenotypein these animals [114]

These varied results between studies are proba-bly due to the different models of ethanol exposureemployed However results from Helfer et al (2009)and Boehme et al (2011) suggest that while exercisemay be able to stimulate proliferation and differenti-ation additional therapies may need to be utilized toensure that the new neurons are able to survive andintegrate into functional networks of the hippocam-pus For example Hamilton et al (2014) combinedexercise followed by environmental enrichment UsingBrdU labeling the authors found that ethanol-exposedanimals had lower rates of cell survival than con-trol animals However in ethanol-exposed animalswho were given voluntary access to a running wheel(started at PND 30 for 12 days) followed by accessto an enriched environment (from PND 42 ndash 72)the levels of cell survival were comparable to thoseof control animals [110] These results indicate thatboth exercise and enrichment may be needed inorder to enhance cell proliferation as well as cellsurvival

FASD and synaptic plasticityEthanol exposure causes long lasting deficits in

synaptic plasticity in the DG ndash in particular LTPis decreased in adolescent and adult male offspring[116ndash121] Interestingly in females LTP in the DG isincreased in adolescent animals and there are no dif-ferences in LTP between control and ethanol-exposedoffspring in adulthood [117121ndash123] Only one studyhas examined the effect of exercise on synaptic plas-ticity in the DG of animals exposed to ethanol duringdevelopment Only males were examined in this studybut the results clearly indicate that access to a runningwheel from PND 28 ndash 60 (32 days) was enough tocompletely reverse the deficits in LTP observed in theethanol-exposed offspring [118]

FASD and behaviourLearning and memory and executive function are

impaired in individuals with FASD [124ndash127] Func-tional brain abnormalities can be examined in humanpopulations using functional MRI (fMRI) technologyfMRI has been used to examine spatial working mem-ory in adults and children with FASD and impairmentscompared to control subjects are commonly observed[128 129] fMRI has also indicated that subjects withFASD exhibit abnormal patterns of brain activationduring tasks involving verbal learning [130] verbalworking memory [131] and visual working memory[132]

There is a multitude of data indicating that learningand memory particularly spatial reference and work-ing memory are impaired in animals that were exposedto ethanol during development Deficits in the MWMwhere animals show impairments in spatial acqui-sition reference and place memory are observed inanimals when ethanol exposure occurs both in the pre-natal [118 133ndash141] and postnatal [142ndash148] periods

Only two studies to date have examined the effectsof exercise on behaviour in the MWM in animals withFASD Christie et al (2005) examined the effects ofvoluntary wheel running from PND 54 ndash 64 in animalswhere the liquid diet model of ethanol administrationwas used In this study the two trial version of theMWM was conducted over a five day period and bothreference and working memory were assessed Ani-mals exposed to ethanol displayed significant deficitsin both reference and working memory when comparedto control groups however this deficit was completelyreversed in the animals that were allowed access to arunning wheel [118] Similar findings were obtainedby Thomas et al (2008) using the postnatal gavagemodel of ethanol exposure (3rd trimester equivalent)


In this study animals were allowed access to a run-ning wheel from PND 21 ndash 51 and then from PND52 ndash 57 they were tested in the MWM (4 trials a dayplus a probe trial on the final day) Ethanol-exposedanimals that did not exercise had significant deficitsin performance however these deficits were greatlyreduced in the animals allowed access to a runningwheel [147] Performance in the probe trial was notaffected by ethanol-exposure however exercise alsoincreased performance in this task in both ethanol-exposed and control animals

The effect of exercise on other hippocampalbehaviours has also been examined using the gav-age model of FASD Schreiber et al (2012) haveshown that neonatal ethanol exposure causes sig-nificant deficits in CFC tasks [149] Interestinglyif ethanol-exposed animals were given access to arunning wheel from PND 30 ndash 42 and then environ-mental enrichment from PND 42 ndash 72 these deficitsin behaviour were not overcome [149] In contrast asimilar study from the same laboratory showed thatexercise could benefit other forms of contextual fearconditioning [110] Ethanol-exposure causes deficitsin trace eyeblink conditioning [150] and a variant ofcontextual fear conditioning called the context pre-exposure facilitation effect [112 151] Hamilton et al(2014) examined the effects of exercise (PND 30 ndash42) followed by environmental enrichment (PND 42ndash 72) on these behaviours following ethanol-exposurefrom PND 4 ndash 9 They determined that the combinationof exercise and enrichment was able to overcome thedeficits induced by neonatal ethanol exposure [110]

Other behavioural phenotypes which may be medi-ated through the hippocampus and are commonwith FASD include increased depression and anxiety[152ndash155] Brocardo et al (2012) showed that animalsexposed to ethanol throughout all three trimester equiv-alents (ie GD 1ndash21 plus PND 4ndash10) using the gavagemodel have increased depression-like and anxiety-likebehaviours These effects were present in both maleand female offspring A cohort of ethanol-exposedanimals was given access to a running wheel for 12days from PND 48 ndash 60 and at PND 60 was testedfor anxiety and depression-like behaviours Exercisedid not rescue anxiety-like behaviours measured usingthe elevated plus maze in male or female offspring[156] Ethanol-exposed females showed increaseddepressive-like behaviour in the forced swim test whencompared to control groups This effect was not res-cued by exercise [156] In males a similar increasein depression-like behaviours was observed follow-ing ethanol-exposure however unlike in females this

effect could be rescued by exercise [156] This studysuggests that gender may play a role in responseto exercise-elicited antidepressant effect in ethanol-exposed rats

SummaryFASD causes a variety of perturbations in hip-

pocampal structure and function which translate intodeficits in hippocampal behaviour Reductions in neu-rogenesis are commonly observed which may underliethe deficits in synaptic plasticity and hippocampalbehaviour

Although limited there are a handful of studieswhich have examined the benefits of exercise in FASDand the results from these studies provide evidencethat exercise may be able to overcome these struc-tural and functional deficits in the hippocampus toa point where ethanol-exposed animals can no longerbe distinguished from control animals These improve-ments also appear to translate into positive behaviouralchanges suggesting that exercise may be beneficialin overcoming some of the learning and memorydeficits associated with FASD However it is impor-tant to note that exercise may not be beneficial for allbehavioural phenotypes exhibited in animals exposedto ethanol during the perinatal period [149 156] Fur-thermore studies like those of Brocardo et al (2012)emphasize the importance of examining both malesand females because sex-specific differences in theeffects of ethanol and the benefits of exercise may beobserved

Traumatic brain injury

Traumatic brain injury (TBI) can occur when thehead hits or is hit by an object Up to 17 millionincident or recurrent TBIs occur annually in the USmost commonly caused by falls vehicular accidentsassault and sports injuries [157] Direct mechanicalinsult to brain tissue caused by the initial impact skullfracture or penetrating injury along with the stretch-ing and shearing of cell processes and vasculatureresult in a cascade of pathophysiological processesthroughout the brain that can cause immediate andpersistent symptoms Impaired learning and memoryare common symptoms of TBI regardless of the typeor severity of injury Despite its central and thereforerelatively protected location changes in hippocampalvolume have been reported in humans and rodents afterTBI [158ndash161] suggesting it is susceptible to damageby secondary injury mechanisms which likely con-tribute to persistent learning and memory impairment


resulting from TBI (reviewed by [162]) It is an impor-tant goal of experimental animal models of TBI toidentify mechanisms underlying TBI symptoms likelearning and memory impairment and to identify inter-ventions that can treat them (for a review of animalmodels of TBI see [163]) Owing to the heterogeneityof this type of injury there has been great difficulty infinding effective treatments The potential to promotestructural and functional plasticity in the hippocam-pus makes exercise an attractive means of rescuingcognitive deficits arising from TBI

Structural and functional plasticity in TBIThere is a paucity of information available on how

exercise directly affects hippocampal structure andfunctional plasticity following TBI however emergingevidence shows that initiating moderate exercise aftera short recovery period may elevate levels of plasticity-promoting proteins and reduce cognitive deficits afterexperimental TBI in rodents These effects are con-sistently mediated by elevations in the neurotrophinBDNF

An important focus of this research is to estab-lish a timeline to determine when exercise becomesrestorative after TBI as there is evidence that intensephysical and cognitive exertion in the acute recov-ery phase may exacerbate TBI pathology and increasesymptom severity [164] Due to the heterogeneity inexercise paradigms between studies there is contro-versy over the optimal time to initiate an exerciseintervention but the majority of literature suggeststhat delaying the onset of exercise is beneficial In amouse model of TBI MWM performance impairmentswere rescued CREB and BDNF expression were ele-vated and hippocampal neurogenesis was increasedby seven days of voluntary wheel running initiated5 weeks but not 1 week post-injury [165] In ratshowever seven days of voluntary wheel running initi-ated three days after TBI elevated hippocampal BDNFlevels and ameliorated the TBI-induced increase inhippocampal myelin-associated glycoprotein (MAG)and Nogo-A which are proteins that inhibit axonalgrowth [166] Another group found that adult malerats showed reduced deficits in acquisition of spatialreference memory the MWM and elevated hippocam-pal BDNF when given access to a running wheel14ndash20 days after mild TBI [167 168] However whenrunning wheel access was provided 0ndash6 days post-injury MWM impairments were increased and BDNFlevels were not changed [168] In these paradigmsadministration of a BDNF inactivator prior to exer-cise attenuated enhancements in MWM performance

[167] and elevations in plasticity related proteins[166]

Injury severity may dictate when it is best to beginan exercise intervention after TBI In adult male ratsexercise-induced elevations in BDNF were seen whenrunning wheel access was provided at 14ndash20 days aftera mild TBI but when a moderate TBI was inducedBDNF was only elevated when access to the run-ning wheel was withheld until 30ndash36 days post-injury[169] Interestingly the same group also found thathippocampal BDNF was elevated after voluntary run-ning 0ndash7 days after moderate TBI though they notedthat injured animals ran significantly less than controls[170] This highlights an important challenge in thisarea of research as injured animals are more likely toabstain from voluntary running making it difficult tocontrol for exercise duration and exertion It is pos-sible that in paradigms where voluntary exercise isinitiated immediately after TBI injured rats abstainedfrom exercise during the initial period where they weremore vulnerable to sustain further damage

SummaryThe available literature collectively suggests that

delayed exercise after TBI can reduce learning andmemory impairment and elevate plasticity-relatedproteins in the hippocampus However there is apaucity of information on precisely how elevatedneurotrophins affect structural plasticity and improvebehavioural recovery after brain injury Insight inthis matter could be gained through histological andelectrophysiological analysis of hippocampal tissuein order to determine whether these exercise-mediatechanges correlate with changes in structural andfunctional plasticity

Stroke

Ischemic and hemorrhagic stroke occur when bloodcirculation to a certain area of the brain is restricted dueto vessel blockade or rupture respectively This pro-duces metabolic distress tissue damage and cell deathin the affected area Stroke is an extremely prevalentcondition affecting up to 800 000 Americans annu-ally [171] Depending on which area of the brain isaffected symptomology can include debilitating andpersistent impairment to cognitive motor visual audi-tory and speech function When the affected areaincludes the hippocampus learning and memory canbe severely impaired (reviewed by [172]) Stroke oftenresults in motor deficits and the potential for exerciseto induce plasticity in sensory and motor cortices and


improve functional recovery in motor tasks has beenwell studied [173ndash175] There is evidence that exer-cise can augment hippocampal plasticity after strokeas well However the information available on thetherapeutic effects of voluntary exercise is extremelylimited likely due to difficulty implementing voluntaryexercise paradigms in motor-impaired animals Wherevoluntary exercise paradigms have been used out-come measures primarily focuses on exercise mediatedelevation in hippocampal plasticity-related proteinsindicating there is a need for further research directlymeasuring how exercise affects structural and func-tional plasticity in the hippocampus

Structural and functional plasticity in strokeMotor deficits resulting from stroke complicate the

application of an exercise intervention This is animportant consideration as controls may exercise morevigorously or longer duration in voluntary exerciseparadigms but forced exercise may not produce equiv-alent results For this reason information on howvoluntary exercise affects structural and functionalplasticity in the hippocampus is extremely limited Ina mouse model of ischemic stroke voluntary wheelrunning but not forced swimming rescued memoryimpairments in the MWM This was accompanied byelevated CREB phosphorylation and increased sur-vival of adult generated neurons in the hippocampus[176] Another mouse model found that 42 days ofvoluntary wheel running was sufficient to increasehippocampal neurogenesis and reduce learning impair-ments in the MWM after ischemia [177]

There is evidence that voluntary running elevateshippocampal BDNF after ischemic stroke but moreresearch is needed to determine if this effect translatesinto changes in hippocampal plasticity or cognitiveoutcome [174 175]

SummaryPhysical activity has the potential to improve stroke

outcome by augmenting hippocampal plasticity butthere is a lack of information on how exercise-mediatedimprovements in cognition and changes in plasticityrelated proteins correlate with structural and functionalchanges in the hippocampus Ongoing research shouldattempt to establish how exercise-mediated behavioralrecovery and neurotrophin expression correlate withneurogenic changes and electrophysiological analysisof hippocampal tissue

Neurodegenerative disorders

Neurodegenerative diseases such as Alzheimerrsquosdisease (AD) Parkinsonrsquos disease (PD) and Hunting-tonrsquos disease (HD) constitute a heterogeneous groupof disorders that commonly display a characteris-tic progressive loss of structure andor function ofpopulations of neurons and glia in the CNS [178]This neuronal degeneration primarily affects specificneuronal populations which include cortical and hip-pocampal neurons in AD [179] dopaminergic neuronsin PD [180] and striatal gamma-aminobutyric acid(GABA)ergic neurons in HD (reviewed by [181])Clinically these diseases are predominantly adult onsetand show chronic progression of cognitive deficits

Animal models of neurodegenerative diseases pro-vide valuable tools in assessing therapeutic strategiesfor these disorders Bearing in mind the well-definedbenefits of physical exercise on cognitive function itis reasonable to consider that exercise may in fact beused as a strategy to prevent or impair the cognitivedecline associated with age-related neurodegenerativediseases In this section we review the influence of vol-untary exercise on structural and functional plasticityin adult-aged rodent models of AD PD and HD

Alzheimerrsquos diseaseAD the leading cause of dementia in the elderly is

an age-related irreversible neurodegenerative disorderclinically characterized by progressive memory lossand multiple cognitive deficits (reviewed by [182])Important neuropathological hallmarks of AD in thebrain include the gradual accumulation of extracel-lular plaque depositions composed of amyloid-beta(A) peptide the formation of neurofibrillary tangles(NFT) consisting of hyperphosphorylated tau pro-tein and substantial neuronal death [183 184] Theetiology of AD is not yet known however two compet-ing hypotheses exist In the Amyloid hypothesis Aplaques are considered to be the causal component inAD pathogenesis [185] The second theory the Prese-nilin hypothesis is based on loss-of-function presenilinmutations that lead to neurodegeneration and memoryimpairment in AD [186] Despite this controversy thehippocampus is known to be particularly vulnerable toAD and is one of the first regions to be affected [187]

AD and structural plasticityStudies of adult hippocampal neurogenesis in a

variety of available transgenic rodent models of AD(reviewed by [188]) have generated contradictoryresults [156 189] Decreases in neurogenesis were


reported in transgenic or knock-in mice carrying thePDAPP mutation [190] the Swedish mutation in theAPP gene [191ndash194] PS1 gene mutations [193ndash196]as well as in double-transgenic mice for APP andPS1 [193 194] APP PS1 and tau protein triple-transgenic mice also show deficits in neurogenesis[197] In contrast transgenic mice that express APPwith the Swedish Dutch and London mutations [198]or with the Swedish and Indiana mutations [199 200]were found to have increased hippocampal neurogene-sis Discrepancies in the literature are likely based on avariety of factors such as transgenic model used stageof disease progression and difference in protocols usedto evaluate neurogenesis

A successful treatment for AD has yet to be devel-oped A putative lifestyle treatment is exercise whichhas been shown to promote neurogenesis in rodentmodels of AD APPswe-PS1E9 mice provided 10weeks of voluntary wheel running showed enhancedlevels of hippocampal neurogenesis Moreover run-ning significantly prevented neuronal cell loss in theDG and CA3 hippocampal subregions but did notaffect the CA1 [201] In the Tg2576 AD model volun-tary runners were found to have greater hippocampalvolume compared to sedentary littermates following16 weeks of access to wheel running [202] An age-dependent effect of voluntary wheel running was foundin the APP23 AD mouse model where 10 days ofexercise induced an increase in adult hippocampal neu-rogenesis in 18 month-old animals but had no effect inthe 6 month-old cohort [203] These findings suggestthe ability of the AD brain to upregulate cell pro-liferation and neuronal differentiation in response tovoluntary physical exercise

AD and functional plasticityGarcıa-Mesa et al (2011) used electrophysiology

to investigate synaptic function and plasticity in 3xTg-AD mice that were subjected to 6-month wheel runningtreatment LTP could not be produced in the 3xTg-AD animals while exercise was found to only weaklyprotect the impairment of LTP induction at the CA1-medial prefrontal cortex synapse [204] Consideringthe limited evidence available that examines the roleof exercise on synaptic plasticity in AD the remain-der of this section focuses primarily on hippocampalbehaviour Various transgenic mouse models of ADshow deficits in several hippocampal-dependent learn-ing and memory tasks such as object recognitionspatial learning and fear conditioning (reviewed by[188 205])

Clinical studies with AD patients indicate that phys-ical and cognitive activities are associated with reducedrisk of disease [206ndash208] Similarly rodent models ofAD that undergo voluntary exercise display encour-aging results Using a Tg2576 mouse model Yuedeand colleagues (2009) found that voluntary runners(16 weeks of wheel running) displayed greater inves-tigation latencies of novel objects in a recognitionmemory paradigm in comparison to sedentary con-trols or forced exercise animals [202] Transgenicanimals containing the 4 allele of the APOE geneexhibit cognitive impairment on the hippocampus-dependent radial-arm water maze task Following 6weeks of free access to wheel-running 4 mice dis-played improvements in this task compared to theirsedentary counterparts [209] The TgCRND8 modelof AD also benefits from voluntary exercise 5-monthsof voluntary running decreased A plaques in thehippocampus and enhanced hippocampal-dependentlearning in the MWM [210] Another AD modelTHY-Tau22 displays progressive learning and mem-ory alterations [211 212] In response to a 9-monthvoluntary exercise period memory alterations wereprevented in the THY-Tau22 mice as assessed by a two-trial Y-maze task in which running animals spent moretime in the novel arm [213] Cognitive deteriorationas well as behavioural and psychological symptomsof dementia (BPSD)-like behaviours such as anxietyand the startle response were ameliorated by exercisein triple transgenic (3xTg) AD mice with access torunning wheel Of the different experimental cohortsstudied the best neuroprotection was identified in 7month-old 3xTg-AD mice that had undergone exercisetreatment for 6 months [204] APPswePS1E9 micedisplay spatial memory impairments in the MWMIn response to 10 weeks of voluntary-wheel runningthis cognitive decline is significantly decreased incomparison to sedentary controls [201]

In contrast to the above-mentioned studiesTgCRND8 mice with access to running wheel for a10 week period displayed no improvements in cogni-tive or neuropathological parameters in comparison tonon-runner controls Despite this spontaneous stereo-typic behaviours of TgCRND8 mice [214] such asrepetitive bouts of jumping climbing or bar-chewingwere significantly reduced in the wheel-running trans-genics [215] Furthermore APP23 mice that ran for85 months did not show enhancements in spatiallearning or hippocampal neurogenesis Interestinglyenvironmental enrichment lacking a running wheelimproved MWM performance and increased hip-pocampal neurogenesis [216] This is an important


distinction as other studies report enhanced cellularplasticity in TgCRND8 [217] and improved cogni-tion in PS1PDAPP [218] AD models in response toldquoenrichmentrdquo that includes running wheels

SummaryAlthough voluntary exercise is the focus of the

present review AD-related exercise research is byno means limited to this paradigm Treadmill andforced exercise experimental designs are also com-monly used in this field Similar to the majority ofvoluntary running studies they show the importanceof exercise in preventing the cognitive decline associ-ated with AD [219 220] repressing neuronal cell death[221] enhancing neurogenesis [222] improving hip-pocampal LTP [219] and improving cognitive function[223ndash226] Trends in current literature suggest thatexercise may help to prevent the cognitive declineassociated with AD and delay the onset of symp-toms Interestingly these benefits appear to requirerelatively long periods of exercise While cognitiveimprovements in AD studies require voluntary accessto running wheels for 10 weeks up to 9 months healthyanimals or FASD model animals for example typicallyundergo exercise paradigms ranging from 7 days to 2months (see previous sections)

Parkinsonrsquos diseasePD is characterized by the progressive loss of

dopamingeric neurons in the substantia nigra thatprojects to the striatum of the basal ganglia Physicalsymptoms of this disorder including motor dysfunctionsuch as rigidity tremor and bradykinesina are accom-panied by non-motor symptoms such as cognitivedeficits and depressive disorders Volumetric magneticresonance imaging studies have suggested a progres-sive hippocampal volume loss in PD patients [227]Intracellular accumulation of -synuclein is the patho-logical feature of Parkinsonrsquos disease and mutations inthe gene encoding for this protein is known to be linkedto this disease [228] Abnormalities in hippocampalplasticity have been observed in -synuclein-relatedtransgenic animal models [229 230] as well aslesion models of dopamine depletion using either the1-methyl-4-phenyl-1236-tetrhydropyridine (MPTP)or 6-hydroxydomine (6-OHDA) [231ndash233] whichleads to death of dopamingeric neurons and subsequentdepletion of dopamine in the dorsal striatum

PD and structural plasticityAltered structural plasticity including cell prolif-

eration differentiation and survival of adult-born

neurons as well as decreased dendritic complexity andspine formation has been related to the pathogenesis ofPD (reviewed by [234]) Decreased hippocampal neu-rogenesis is altered in 6-OHDA and MPTPndashinducedanimal models of PD [235 236] Similarly decreasedcell proliferation and neuronal survival are also foundin transgenic mice expressing mutant -synuclein[237 238] which echo the decreased hippocampal cellproliferation observed in postmortem brain from PDpatients [235]

There are currently no studies examining the effectsof voluntary wheel running on structural plasticity inPD However in the 6-OHDA- rat model of PD aregime of 4-weeks of treadmill exercise (30 minday5 daysweek) increased cell proliferation and themigration of neural stem cells towards the lesion siteaccompanied by up-regulated BDNF and glial cell-derived neurotrophic factor (GDNF) in the striatum[239] Exercise training also enhances survival andintegration of transplanted cells in animal model ofPD (reviewed by [240])

PD and functional plasticityImpaired synaptic plasticity in hippocampal sub-

regions has been reported in animal models ofPD Decreased LTP and enhanced LTD were foundin the CA1 region in mice injected with MPTP[233] while decreased LTP and impairment of long-term recognition memory was found in the DG ofmice with bilateral 6-hydroxydopamine (6-OHDA)lesions [231] The impaired LTD in the DG maybe linked to disrupted dopaminergic and noradren-ergic transmission in the DG [232] and decreasedNR2ANR2B subunit ratio in NMDA receptors[241]

Although clinical studies have demonstrated thatphysical training improved motor function as wellas cognitive performance in PD patients [242 243]currently there are no studies reporting changes ofhippocampal synaptic plasticity following physicaltraining in animal models of PD Thus it is unclearwhether exercise-induced beneficial effects on cog-nitive performance on PD patients are at least partlymediated by enhanced hippocampal neurogenesis orsynaptic plasticity

Studies examining the potential beneficial effectsof physical exercise on PD are primarily focusedon behavioral recovery on motor skill performance[244ndash248] In the MPTP mouse model improve-ment in motor function is likely linked to increaseddopamine transmission enhanced expression ofdopamine receptors or increased glutamate receptor


expression in the dorsal striatum following exercise[249 250]

SummaryIn summary there are very few studies examining

the benefits of voluntary wheel running on structuraland functional plasticity in the hippocampus This maybe due to the etiology of the disease and the difficultiesin motor function that are observed However evidencefrom human studies does suggest that voluntary exer-cise potentially in pre-symptomatic patients may bebeneficial for hippocampal function

Huntingtonrsquos diseaseHD is an autosomal dominant neurodegenerative

disease caused by a characteristic cytosine-adenine-guanine (CAG) repeat expansion within the HD genewhich results in an expansion of poly-glutamineresidues in the huntingtin protein Under normal con-ditions there are 6 ndash 35 CAG repeats whereas HDpatients may have up to 250 repeats [251] As a resultmutant huntingtin aggregates into insoluble ubiquiti-nated neuronal intranuclear inclusions (NIIs) [252]This mutation primarily causes neurodegeneration ofmedium spiny neurons in the caudate nucleus aswell as deterioration of certain populations of striatalinterneurons [253] and cortical atrophy in other brainregions as the disease progresses (reviewed by [169])

The characteristic clinical symptom of HD is pro-gressive involuntary choreatic movements followed bylater onset bradykinesia and rigidity [254] In additionto motor disturbances cognitive impairment and psy-chiatric symptoms are associated with the progressionof the disease which is invariably fatal 15 ndash 20 yearsafter onset (reviewed by [242])

HD and structural plasticityIn contrast to the contradictory results accompany-

ing neurogenesis in AD there is an apparent consensusthat HD reduces adult hippocampal neurogenesisLazic and colleagues (2004) were the first to iden-tify this using the R61 transgenic model of HD [256]Additional research of R61 [257ndash259] and R62 mice[260ndash263] as well as a transgenic rat model [264]have extended upon our understanding of adult neu-rogenesis deficits in the hippocampus of HD rodentmodels

To investigate the potential of physical exercise astherapeutic strategy in HD various studies have ana-lyzed the modulation of neurogenesis after voluntaryrunning in a variety of HD models Those that specif-ically investigated adult animals show that running

enhances adult hippocampal neurogenesis but only inwildtype controls and not in R61 HD mice [265 266]

HD and functional plasticitySedentary R61 HD mice develop phenotypic rear-

paw clasping by 16 weeks of age Additionally theydisplay abnormal rearing behavior as well as deficitsin motor coordination and spatial working memoryFollowing 10 weeks of access to a running wheelthe rear-paw clasping onset is delayed there arenormalized levels of rearing behavior and cognitiveimpairments are ameliorated Despite this motor coor-dination is not rescued [267] Voluntary exercise duringa 4 week period was found to have anti-depressiveeffects in R61 transgenic mice that showed reducedimmobility in forced-swim test [265]

In the current review we focus on adult ani-mals However characteristic motor dysfunction is anunavoidable confound with rodent HD models sincethey are known to run less than wildtype littermatesConsidering the progressive nature of HD several stud-ies have used juvenile animals to investigate the impactof exercise prior to overt symptoms In 5 week old R62HD mice a 4 week period of voluntary wheel-runningdid not rescue the observed reduction in adult hip-pocampal neurogenesis (60 of wildtype level) [268]More recently Potter and collaborators (2010) estab-lished that exercise was not beneficial in N171-82Qtransgenics and that it may in fact be detrimental tothe vulnerable HD nervous system [269] Converselyothers have reported that wheel running delays onsetof motor deficits [270] improves gait motor coordi-nation and slows progression of cognitive dysfunction[271] in juvenile R61 HD mice

SummaryThere is a paucity of data examining the effects

of exercise on hippocampal plasticity in HD Takentogether the effectiveness of exercise as an envi-ronmental therapy for HD is currently transgenicmodel-dependent with age-related discrepancies in theliterature

DISCUSSION AND CONCLUSIONS

There is a multitude of evidence that suggests thatphysical exercise can lead to significant benefits inhippocampal structure and function in rodents whichultimately results in behavioral benefits As high-lighted in the various sections there are some gaps inthe literature that need to be filled but the majority


Table 2Effects of voluntary running on adult hippocampal neurogenesis in animal models of neurological disorders

Disease model Animal age Model Running period Markers examined Effect of running Reference

FASD 7 weeks old 7 days BrdU Rescued deficit Redila et al 2006Rat (proliferation in proliferation

and survival) and survival4 weeks old 12 days BrdU Increased Helfer et al 2009

Rat (proliferation proliferation noand survival) effect on

survival7 weeks old 12 days Ki67 BrdU Increased Boehme et al 2011

Rat NeuroD proliferationand neuronaldifferentiation

4 weeks old 12 days (followed by BrdU (survival) Rescued deficit Hamilton et al 2014Rat 30 days enrichment) in cell survival

TBI Not reportedStroke Adult Mouse 42 days (beginning day BrdU (Proliferaion) Increased Geibig et al 2012

of infarct) proliferationphotothrombotic relative tocortical infarct sedentary

stroke groupAdult Mouse 42 days (beginning 7 BrdU (Proliferation) No change in Chun et al 2007

days after MCAO) proliferationMCAOAdult Mouse 42 days (beginning 7 BrdU (Survival) Increased Chun et al 2007

days after MCAO)MCAO survival relative

to sedentarystroke

AD 5 months old 10 weeks Nissl staining Prevented Tapia-Rojas et al 2015Mouse BrdU (proliferation neuronal lossAPPswePS1 and survival) IncreasedE 9 proliferation

and neuronaldifferentiation

5 months old 16 weeks Nissl staining Greater Yuede et al 2009Mouse hippocampalTg2576 volume6 and 18 months 10 days BrdU DCX NeuN Increased Mirochnic et al 2009old Mouse proliferationAPP23 and neuronal

differentiationin 18 month-oldmice only

PD Not reportedHD 8ndash12 weeks old 4 weeks BrdU No effect Renoir et al 2012

Mouse (proliferationR61 and survival)3 months old 8 days Ki67 BrdU No effect Ransome and Hannan 2013Mouse NeuNR61

Abbreviations AD Alzheimerrsquos Disease BrdU bromodeoxyuridine DCX doublecortin FASD fetal alcohol spectrum disorder HDHuntingtonrsquos Disease MCAO intraluminal middle cerebral artery occlusion PD Parkinsonrsquos Disease TBI traumatic brain injury

of the evidence suggests that exercise can be ben-eficial not only in healthy adult animals (Table 1)but also in disease models including developmental

disorders mood disorders traumatic brain injury andneurodegeneration (Tables 2ndash4) How exercise leadsto these substantial benefits in hippocampal function


Table 3Effects of voluntary running on hippocampal synaptic plasticity in animal models of neurological disorders

Animal model Animal age Running period Area analyzed Effect of running Reference

FASD 8 weeks old Rat 10 days DG Rescued deficit in LTP Christie et al 2005TBI Not reportedStroke Not reportedAD 7 months old Mouse

3xTg-AD 6 months CA1 Rescued deficit in LTP Garcıa-Mesa et al 2011PD Not reportedHD Not reported

Abbreviations AD Alzheimerrsquos disease CA Cornu Ammonis DG dentate gyrus FASD fetal alcohol spectrum disorders HD Huntingtonrsquosdisease LTP long-term potentiation PD Parkinsonrsquos disease TBI traumatic brain injury

Table 4Effects of voluntary running on hippocampal dependent behaviours in animal models of neurological disorders

Animal model Animal age Model Running period Behaviour examined Effect of running Reference

FASD 8 weeks old 10 days MWM Deficits in Christie et al 2005Rat reference and

workingmemory werereversed

3 weeks old 30 days MWM Rescued Thomas et al 2008Rat deficits in

referencememory

4 weeks old 12 days Contextual fear No effect Schreiber et al 2012Rat (followed by conditioning

30 daysenrichment)

4 weeks old 12 days Context pre- Rescued Hamilton et al 2014Rat (followed by exposure deficits

30 days facilitationenrichment)

TBI Adult Rat 7 days MWM Reduced Grace et al 2009Lateral FPI (starting 14 deficits in

days post acquisition ofinjury) spatial memory

Adult Mouse 4 weeks MWM Reduced Piao et al 2013Left parietal (starting 1 or impairment inCCI 5 weeks post acquisition of

injury) spatial memoryreferencememoryreversalmemoryacquisition andreversalreferencememory after 5week delay inexercise onsetNo change after1-week delay inexercise onset

Adult Rat 7 days MWM Increased Griesbach et al 2004Lateral FPI (starting day impairment in

of injury) acquisition ofspatial memory

Adult Rat 7 days MWM Decreased Griesbach et al 2004Lateral FPI (starting 14 impairment in

days post injury) acquisition of

(Continued)


Table 4(Continued)

spatial memoryafter delayedexerciseinitiation

Stroke Adult Mouse 42 days MWM Increased rate Geibig et al 2012photothrombotic (beginning of spatialcortical infarct day of infarct) memory

acquisition Nochange inreferencememory

Adult Mouse MCAO 42 days MWM Rescued Chun et al 2007(beginning 7 impairment indays after acquisition ofMCAO) spatial memory

AD 5 months old 16 weeks Novel object recognition Reduced Yuede et al 2009Mouse Tg2576 decline in

recognitionmemory

10ndash12 months 6 weeks Radial-arm water maze Improved Nichol et al 2009old Mouse performanceAPOE 4 (less errors)1 month old 5 months MWM Enhanced Adlard et al 2005Mouse learning rateTgCRND83 months old 10 weeks One-trial object No effect Richter et al 2008

recognition paradigmBarnes maze

MouseTgCRND83 months old 9 months Two-trial Y-maze Prevented Belbarbi et al 2011Mouse development ofTHY-Tau22 memory

alterations4 and 7 months 1 month and MWM Startle Response Rescued Garcıa-Mesa et al 2011

Dark and Lightbox test

old Mouse 6 months retention3xTg-AD deficiency

reduced BPSD-like behaviours

5 months old 10 weeks MWM Prevented Tapia-Rojas et al 2015Mouse impairment inAPPswe- spatial acuityPS1E9 and memory

acquisitionPD Not reportedHD 10 weeks old 10 weeks T-maze Y-maze Rear-paw Pang et al 2006

Mouse R61 clasping onsetdelayedrescued deficitin spatialworkingmemory

8ndash12 weeks old 4 weeks Forced-swim test Anti-depressive Renoir et al 2012Mouse R61 effects

(reducedimmobility)

Abbreviations AD Alzheimerrsquos disease CCI controlled cortical impact FASD fetal alcohol spectrum disorder FPI fluid percussion injuryHD Huntingtonrsquos disease MCAO middle cerebral artery occlusion MWM Morris Water Maze PD Parkinsonrsquos disease TBI traumatic braininjury


is still under debate Exercise increases blood vascula-ture and enhances angiogenesis in the brain and boostslevels of neurotrophins including brain derived neu-rotrophic factor (BDNF) [272 273] These increasesare observed with short or long periods of runningand appear to remain upregulated for a period of timeafter exercise has ceased [73 82 272 274] BDNF canincrease the production of cell survival genes and pro-teins important for synaptic plasticity and neurogenesiswhich may explain the benefits observed in synap-tic plasticity and learning and memory [275 276]Other factors to consider include enhancements indendritic complexity and spine density as well asglial cell function The many potential mechanismsthrough which exercise can boost hippocampal func-tion are discussed in great detail in recent reviews[277ndash279]

This review focussed primarily on rodent mod-els of disease but it is important to note that manyof the benefits of exercise found in rodents arealso observed in humans Many human studies havefound significant benefits of exercise not only inhealthy individuals but also in individuals with neu-ropsychiatric and neurodegenerative disorders It isdifficult to assess neurogenesis and synaptic plas-ticity in humans however there is ample evidenceto suggest that exercise can enhance learning andmemory and other aspects of hippocampal function(reviewed by [277]) Exercise has been shown toenhance hippocampal learning and memory tasks inchildren [280 281] adolescents [282] adults [283]and the elderly [284 285] In fact many studies haveinvestigated whether exercise can reduce or preventage-related cognitive decline Studies have indicatedthat exercise can boost gray matter volume in the hip-pocampus of aged individuals [286] which leads toenhanced memory [284] and may delay the onsetof dementia or Alzheimerrsquos disease (reviewed by[287288])

In conclusion exercise interventions can beextremely beneficial for hippocampal structure andfunction The benefits of exercise on hippocampal neu-rogenesis synaptic plasticity and behaviour have beenextensively studied and have been summarized in thisreview The mechanisms responsible for these bene-ficial effects appear to be vast and diverse but manyeffects appear to converge on enhancing BDNF in thebrain Importantly the benefits of physical exercise arealso observed in humans indicating that exercise inter-ventions should be considered at any age in order toenhance hippocampal learning and memory and delaycognitive decline

CONFLICTS OF INTEREST

The authors have no conflicts of interest to declareregarding this manuscript

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[156] Brocardo PS Boehme F Patten A Cox A Gil-MohapelJ Christie BR Anxiety- and depression-like behaviorsare accompanied by an increase in oxidative stress in arat model of fetal alcohol spectrum disorders Protectiveeffects of voluntary physical exercise Neuropharmacology2012621607-18

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and global brain changes 10 years after childhood traumaticbrain injury Int J Dev Neurosci 201129(2)137-43

[159] Monti JM Voss MW Pence A McAuley E KramerAF Cohen NJ History of mild traumatic brain injury isassociated with deficits in relational memory reduced hip-pocampal volume and less neural activity later in life FrontAging Neurosci 20135(August)1-9

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[162] Vakil E The effect of moderate to severe traumatic braininjury (TBI) on different aspects of memory A selectivereview Journal of Clinical and Experimental Neuropsychol-ogy 2005

[163] Xiong Y Mahmood A Chopp M Animal models oftraumatic brain injury Nat Rev Neurosci [Internet]201314(2)128-42 Available from httpwwwpubmedcentralnihgovarticlerenderfcgiartid=3951995amptool=pmcentrezamprendertype=abstract

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[167] Griesbach GS Hovda DA Gomez-Pinilla F Exercise-induced improvement in cognitive performance aftertraumatic brain injury in rats is dependent on BDNF activa-tion Brain Res 20091288(6)105-15

[168] Griesbach GS Hovda D a Molteni R Wu a Gomez-PinillaF Voluntary exercise following traumatic brain injuryBrain-derived neurotrophic factor upregulation and recov-ery of function Neuroscience 2004125(1)129-39

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[170] Griesbach GS Hovda D a Gomez-Pinilla F Sutton RLVoluntary exercise or amphetamine treatment but not thecombination increases hippocampal brain-derived neu-rotrophic factor and synapsin I following cortical contusioninjury in rats Neuroscience IBRO 2008154(2)530-40

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[172] Lim C Alexander MP Stroke and episodic memory disor-ders Neuropsychologia 2009473045-58

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[175] Ploughman M Granter-Button S Chernenko G TuckerBA Mearow KM Corbett D Endurance exercise regimensinduce differential effects on brain-derived neurotrophic fac-tor synapsin-I and insulin-like growth factor I after focalischemia Neuroscience 2005136(4)991-1001

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[212] Van der Jeugd A Ahmed T Burnouf S Belarbi KHamdame M Grosjean M-E et al Hippocampal tauopathyin tau transgenic mice coincides with impaired hippo-campus-dependent learning and memory and attenuatedlate-phase long-term depression of synaptic transmissionNeurobiol Learn Mem 201195(3)296-04

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[215] Richter H Ambree O Lewejohann L Herring A KeyvaniK Paulus W et al Wheel-running in a transgenic mousemodel of Alzheimerrsquos disease Protection or symptomBehav Brain Res 200819074-84

[216] Wolf SA Kronenberg G Lehmann K Blankenship AOverall R Staufenbiel M et al Cognitive and PhysicalActivity Differently Modulate Disease Progression in theAmyloid Precursor Protein (APP)-23 Model of AlzheimerrsquosDisease Biol Psychiatry 200660(Mdc)1314-23

[217] Herring A Ambree O Tomm M Habermann H Sachser NPaulus W et al Environmental enrichment enhances cellularplasticity in transgenic mice with Alzheimer-like pathologyExp Neurol Elsevier Inc 2009216(1)184-92

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[219] Liu HL Zhao G Cai K Zhao HH Shi L De Treadmillexercise prevents decline in spatial learning and memoryin APPPS1 transgenic mice through improvement of hip-pocampal long-term potentiation Behav Brain Res ElsevierBV 2011218(2)308-14

[220] Liu HL Zhao G Zhang H Shi L De Long-term treadmillexercise inhibits the progression of Alzheimerrsquos disease-likeneuropathology in the hippocampus of APPPS1 trans-genic mice Behav Brain Res Elsevier BV 2013256261-72

[221] Um H-S Kang E-B Koo J-H Kim H-T Jin-Lee Kim E-Jet al Treadmill exercise represses neuronal cell death inan aged transgenic mouse model of Alzheimerrsquos diseaseNeurosci Res Elsevier Ireland Ltd and Japan NeuroscienceSociety 201169(2)161-73

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[223] Ke HC Huang HJ Liang KC Hsieh-Li HM Selec-tive improvement of cognitive function in adult andaged APPPS1 transgenic mice by continuous non-shocktreadmill exercise Brain Res Elsevier BV 201114031-11

[224] Hoveida R Alaei H Oryan S Parivar K Reisi P Tread-mill running improves spatial memory in an animal model


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[225] Kang EB Cho JY Effects of treadmill exercise on braininsulin signaling and -amyloid in intracerebroventric-ular streptozotocin induced-memory impairment in rats201418(1)89-96

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[227] Camicioli R Moore MM Kinney A Corbridge E Glass-berg K Kaye JA Parkinsonrsquos disease is associatedwith hippocampal atrophy Mov Disord [Internet] 200318(7)784-90 Available from httpwwwncbinlmnihgovpubmed12815657

[228] Dawson TM Ko HS Dawson VL Genetic animal modelsof Parkinsonrsquos disease Neuron [Internet] 201066(5)646-61 Available from httpwwwncbinlmnihgovpubmed20547124

[229] Steidl J V Gomez-Isla T Mariash A Ashe KHBoland LM Altered short-term hippocampal synapticplasticity in mutant alpha-synuclein transgenic mice Neu-roreport [Internet] 200314(2)219-23 Available fromhttpwwwncbinlmnihgovpubmed12598733

[230] Gureviciene I Gurevicius K Tanila H Aging and alpha-synuclein affect synaptic plasticity in the dentate gyrusJ Neural Transm [Internet] 2009116(1)13-22 Availablefrom httpwwwncbinlmnihgovpubmed19002552

[231] Bonito-Oliva A Pignatelli M Spigolon G Yoshitake TSeiler S Longo F et al Cognitive impairment and dentategyrus synaptic dysfunction in experimental parkinsonismBiol Psychiatry [Internet] 201475(9)701-10 Availablefrom httpwwwncbinlmnihgovpubmed23541633

[232] Pendolino V Bagetta V Ghiglieri V Sgobio C MorelliE Poggini S et al l-DOPA reverses the impairment ofDentate Gyrus LTD in experimental parkinsonism viabeta-adrenergic receptors Exp Neurol [Internet] 2014261377-85 Available from httpwwwncbinlmnihgovpubmed25058044

[233] Zhu G Li J He L Wang X Hong X MPTP-inducedchanges in hippocampal synaptic plasticity and memoryare prevented by memantine through the BDNF-TrkB path-way Br J Pharmacol [Internet] 2015 Available fromhttpwwwncbinlmnihgovpubmed25560396

[234] Regensburger M Prots I Winner B Adult hippocampalneurogenesis in Parkinsonrsquos disease Impact on neuronalsurvival and plasticity Neural Plast [Internet] 2014 Jan[cited 2015 Mar 2]2014454696 Available from httpwwwpubmedcentralnihgovarticlerenderfcgiartid=4106176amptool=pmcentrezamprendertype=abstract

[235] Hoglinger GU Rizk P Muriel MP Duyckaerts C OertelWH Caille I et al Dopamine depletion impairs precursorcell proliferation in Parkinson disease Nat Neurosci[Internet] 20047(7)726-35 Available from httpwwwncbinlmnihgovpubmed15195095

[236] Lesemann A Reinel C Huhnchen P Pilhatsch M Hell-weg R Klaissle P et al MPTP-induced hippocampal effectson serotonin dopamine neurotrophins adult neurogene-sis and depression-like behavior are partially influenced byfluoxetine in adult mice Brain Res [Internet] 2012145751-69 Available from httpwwwncbinlmnihgovpubmed22520437

[237] Crews L Mizuno H Desplats P Rockenstein E Adame APatrick C et al Alpha-synuclein alters Notch-1 expressionand neurogenesis in mouse embryonic stem cells and in

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[238] Nuber S Petrasch-Parwez E Winner B Winkler J vonHorsten S Schmidt T et al Neurodegeneration and motordysfunction in a conditional model of Parkinsonrsquos disease JNeurosci [Internet] 200828(10)2471-84 Available fromhttpwwwncbinlmnihgovpubmed18322092

[239] Tajiri N Yasuhara T Shingo T Kondo A Yuan W Kadota Tet al Exercise exerts neuroprotective effects on Parkinsonrsquosdisease model of rats Brain Res [Internet] 20101310200-7 Available from httpwwwncbinlmnihgovpubmed19900418

[240] Dobrossy MD Nikkhah G Role of experience training andplasticity in the functional efficacy of striatal transplantsProg Brain Res 2012200303-28

[241] Costa C Sgobio C Siliquini S Tozzi A Tantucci MGhiglieri V et al Mechanisms underlying the impairment ofhippocampal long-term potentiation and memory in exper-imental Parkinsonrsquos disease Brain [Internet] 2012135(Pt6)1884-99 Available from httpwwwncbinlmnihgovpubmed22561640

[242] Fisher BE Wu AD Salem GJ Song J Lin CH Yip Jet al The effect of exercise training in improving motorperformance and corticomotor excitability in people withearly Parkinsonrsquos disease Arch Phys Med Rehabil [Inter-net] 200889(7)1221-9 Available from httpwwwncbinlmnihgovpubmed18534554

[243] Petzinger GM Fisher BE McEwen S Beeler JA WalshJP Jakowec MW Exercise-enhanced neuroplasticity target-ing motor and cognitive circuitry in Parkinsonrsquos diseaseLancet Neurol [Internet] 201312(7)716-26 Availablefrom httpwwwncbinlmnihgovpubmed23769598

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[245] Fisher BE Petzinger GM Nixon K Hogg E Brem-mer S Meshul CK et al Exercise-induced behavioralrecovery and neuroplasticity in the 1-methyl-4-phenyl-1236-tetrahydropyridine-lesioned mouse basal gangliaJ Neurosci Res [Internet] 200477(3)378-90 Availablefrom httpwwwncbinlmnihgovpubmed15248294

[246] Petzinger GM Walsh JP Akopian G Hogg E Abernathy AArevalo P et al Effects of treadmill exercise on dopamin-ergic transmission in the 1-methyl-4-phenyl-1236-tetrahydropyridine-lesioned mouse model of basal gangliainjury J Neurosci [Internet] 200727(20)5291-300 Avail-able from httpwwwncbinlmnihgovpubmed17507552

[247] Pothakos K Kurz MJ Lau YS Restorative effect ofendurance exercise on behavioral deficits in the chronicmouse model of Parkinsonrsquos disease with severe neurode-generation BMC Neurosci [Internet] 2009106 Availablefrom httpwwwncbinlmnihgovpubmed19154608

[248] Smith BA Goldberg NR Meshul CK Effects of tread-mill exercise on behavioral recovery and neural changesin the substantia nigra and striatum of the 1-methyl-4-phenyl-1236-tetrahydropyridine-lesioned mouse BrainRes [Internet] 2011138670-80 Available from httpwwwncbinlmnihgovpubmed21315689

[249] Calabresi P Picconi B Tozzi A Di Filippo M Dopamine-mediated regulation of corticostriatal synaptic plasticityTrends Neurosci [Internet] 200730(5)211-9 Availablefrom httpwwwncbinlmnihgovpubmed17367873


[250] Yin HH Mulcare SP Hilario MR Clouse E HollowayT Davis MI et al Dynamic reorganization of striatal cir-cuits during the acquisition and consolidation of a skill NatNeurosci [Internet] 200912(3)333-41 Available fromhttpwwwncbinlmnihgovpubmed19198605

[251] The Huntingtonrsquos Disease Collaborative Research Group Anovel gene containing a trinucleotide repeat that is expandedand unstable on Huntingtonrsquos disease chromosomes TheHuntingtonrsquos Disease Collaborative Research Group Cell199372(6)971-83

[252] DiFiglia M Sapp E Chase KO Davies SW Bates GPVonsattel JP et al Aggregation of huntingtin in neuronalintranuclear inclusions and dystrophic neurites in brain Sci-ence 1997277(5334)1990-3

[253] Li S-H Li X-J Huntingtin and its role in neuronal degener-ation Neuroscientist 200410(5)467-75

[254] Myers RH Vonsattel JP Stevens TJ Cupples LARichardson EP Martin JB et al Clinical and neuropatho-logic assessment of severity in Huntingtonrsquos diseaseNeurology 198838(3)341-7

[255] Gil JM Rego AC Mechanisms of neurodegeneration inHuntingtonrsquos disease Eur J Neurosci 200827(11)2803-20

[256] Lazic SE Grote H Armstrong RJE Blakemore CHannan AJ van Dellen A et al Decreased hippocampalcell proliferation in R61 Huntingtonrsquos mice Neuroreport200415(5)811-3

[257] Grote HE Bull ND Howard ML van Dellen A BlakemoreC Bartlett PF et al Cognitive disorders and neurogenesisdeficits in Huntingtonrsquos disease mice are rescued by fluox-etine Eur J Neurosci 200522(8)2081-8

[258] Lazic SE Grote HE Blakemore C Hannan AJ van DellenA Phillips W et al Neurogenesis in the R61 transgenicmouse model of Huntingtonrsquos disease Effects of environ-mental enrichment Eur J Neurosci 200623(7)1829-38

[259] Walker TL Turnbull GW Mackay EW Hannan AJ BartlettPF The Latent Stem Cell Population Is Retained in theHippocampus of Transgenic Huntingtonrsquos Disease Micebut Not Wild-Type Mice Zheng J editor PLoS One20116(3)e18153

[260] Gil J Mohapel P Araujo IM Popovic N Li J-Y Brundin Pet al Reduced hippocampal neurogenesis in R62 transgenicHuntingtonrsquos disease mice Neurobiol Dis 200520(3)744-51

[261] Peng Q Masuda N Jiang M Li Q Zhao M Ross CAet al The antidepressant sertraline improves the pheno-type promotes neurogenesis and increases BDNF levels inthe R62 Huntingtonrsquos disease mouse model Exp Neurol2008210(1)154-63

[262] Phillips W Morton AJ and Barker RA Abnormalitiesof Neurogenesis in the R62 Mouse Model of HuntingtonrsquosDisease Are Attributable to the In Vivo MicroenvironmentJ Neurosci 200525(50)11564-76

[263] Gil JMAC Leist M Popovic N Brundin P Petersen AAsialoerythropoietin is not effective in the R62 line ofHuntingtonrsquos disease mice BMC Neurosci 2004517

[264] Kandasamy M Couillard-Despres S Raber KA StephanM Lehner B Winner B et al Stem Cell Quiescence inthe Hippocampal Neurogenic Niche Is Associated WithElevated Transforming Growth Factor- Signaling in anAnimal Model of Huntington Disease J Neuropathol ExpNeurol 201069(7)717-28

[265] Renoir T Pang TY Zajac MS Chan G Du X Leang Let al Treatment of depressive-like behaviour in Hunting-tonrsquos disease mice by chronic sertraline and exercise Br JPharmacol 2012165(5)1375-89

[266] Ransome MI Hannan AJ Impaired basal and running-induced hippocampal neurogenesis coincides with reducedAkt signaling in adult R61 HD mice Mol Cell Neurosci20135493-107

[267] Pang TYC Stam NC Nithianantharajah J Howard MLHannan a J Differential effects of voluntary physical exer-cise on behavioral and brain-derived neurotrophic factorexpression deficits in huntingtonrsquos disease transgenic miceNeuroscience 2006141569-84

[268] Kohl Z Kandasamy M Winner B Aigner R Gross CCouillard-Despres S et al Physical activity fails to rescuehippocampal neurogenesis deficits in the R62 mouse modelof Huntingtonrsquos disease Brain Res 2007115524-33

[269] Potter MC Yuan C Ottenritter C Mughal M van PraagH Exercise is not beneficial and may accelerate symptomonset in a mouse model of Huntingtonrsquos disease PLoS Curr20101-17

[270] Van Dellen A Cordery PM Spires TL Blakemore C Han-nan AJ Wheel running from a juvenile age delays onset ofspecific motor deficits but does not alter protein aggregatedensity in a mouse model of Huntingtonrsquos disease BMCNeurosci 2008934

[271] Harrison DJ Busse M Openshaw R Rosser AE DunnettSB Brooks SP Exercise attenuates neuropathology and hasgreater benefit on cognitive than motor deficits in the R61Huntingtonrsquos disease mouse model Exp Neurol ElsevierInc 2013248457-69

[272] Neeper SA Gomez-Pinilla F Choi J Cotman C Exer-cise and brain neurotrophins Nature [Internet] 1995 Jan12 [cited 2011 Dec 4]373(6510)109 Available fromhttpwwwncbinlmnihgovpubmed7816089

[273] Van Der Borght K Kobor-Nyakas DE Klauke K EggenBJL Nyakas C Van Der Zee EA et al Physical exerciseleads to rapid adaptations in hippocampal vasculature Tem-poral dynamics and relationship to cell proliferation andneurogenesis Hippocampus 200919(10)928-36

[274] Molteni R Ying Z Gomez-Pinilla F Differential effects ofacute and chronic exercise on plasticity-related genes in therat hippocampus revealed by microarray Eur J Neurosci200216(6)1107-16

[275] Lipsky RH Marini AM Brain-derived neurotrophic factorin neuronal survival and behavior-related plasticity Annalsof the New York Academy of Sciences 2007 pp 130-43

[276] Cowansage KK LeDoux JE Monfils M-H Brain-derivedneurotrophic factor A dynamic gatekeeper of neural plas-ticity Curr Mol Pharmacol 20103(1)12-29

[277] Voss MW Vivar C Kramer AF van Praag H Bridginganimal and human models of exercise-induced brain plas-ticity Trends Cogn Sci [Internet] 2013 Oct [cited 2014 Jul15]17(10)525-44 Available from httpwwwncbinlmnihgovpubmed24029446

[278] Hotting K Roder B Beneficial effects of physicalexercise on neuroplasticity and cognition Neurosci Biobe-hav Rev [Internet] 2013 Nov [cited 2014 Aug 21]37(9 Pt B)2243-57 Available from httpwwwncbinlmnihgovpubmed23623982

[279] Gomez-Pinilla F Ying Z Roy RR Molteni R Edger-ton VR Voluntary exercise induces a BDNF-mediatedmechanism that promotes neuroplasticity J Neurophysiol200288(5)2187-95

[280] Chaddock L Erickson KI Prakash RS Kim JS Voss MWVanpatter M et al A neuroimaging investigation of the asso-ciation between aerobic fitness hippocampal volume andmemory performance in preadolescent children Brain Res[Internet] 2010 Oct 28 [cited 2011 Aug 25]1358172-83


Available from httpdxdoiorg101016jbrainres201008049

[281] Monti JM Hillman CH Cohen NJ Aerobic fitness enhancesrelational memory in preadolescent children The FITKidsrandomized control trial Hippocampus 201222(9)1876-82

[282] Herting MM Nagel BJ Aerobic fitness relates to learningon a virtual Morris Water Task and hippocampal volume inadolescents Behav Brain Res 2012233(2)517-25

[283] Stroth S Hille K Spitzer M Reinhardt R Aerobicendurance exercise benefits memory and affect in youngadults Neuropsychol Rehabil 200919(2)223-43

[284] Erickson KI Voss MW Prakash RS Basak C Szabo AChaddock L et al Exercise training increases size of hip-pocampus and improves memory Proc Natl Acad Sci U S A[Internet] 2011 Feb 15 [cited 2014 Jul 11]108(7)3017-22Available from httpwwwpnasorgcontent10873017abstract

[285] Erickson KI Miller DL Roecklein KA The aging hip-pocampus Interactions between exercise depression and

BDNF Neuroscientist [Internet] 2012 Feb 1 [cited 2015Mar 2]18(1)82-97 Available from httpnrosagepubcomcontent18182short

[286] Erickson KI Leckie RL Weinstein AM Physical activityfitness and gray matter volume Neurobiol Aging [Internet]2014 Sep [cited 2015 Mar 7]35 Suppl 2S20-8 Availablefrom httpwwwncbinlmnihgovpubmed24952993

[287] Erickson KI Weinstein AM Lopez OL Physical activitybrain plasticity and Alzheimerrsquos disease Arch Med Res[Internet] 2012 Nov [cited 2015 Jun 9]43(8)615-21Available from httpwwwpubmedcentralnihgovarticlerenderfcgiartid=3567914amptool=pmcentrezamprendertype=abstract

[288] Intlekofer KA Cotman CW Exercise counteracts declininghippocampal function in aging and Alzheimerrsquos dis-ease Neurobiol Dis [Internet] 2013 Sep [cited 2015Mar 4]5747-55 Available from httpwwwsciencedirectcomsciencearticlepiiS0969996112002264


The hippocampus consists of the dentate gyrus (DG)the Cornu Ammonis (CA) 1 and CA3 regions (alsoknown as the hippocampus proper) and the subicu-lum (reviewed by [1]) The hippocampus has been thefocus of intensive research due to its important role inlearning and memory particularly that associated withdeclarative (ie explicit) and spatial memory [1]

The hippocampus displays both structural and func-tional plasticity into adulthood This plasticity can bepositively manipulated by interventions such as physi-cal exercise In this review we summarize the benefitsof voluntary physical exercise on hippocampal neu-rogenesis (which is referred to structural plasticity inthis review) and function (which is referred to synapticplasticity and behavioral improvement in this review)in rodents We also review the potential benefits ofphysical exercise on hippocampal plasticity in rodentmodels of neurological disorders including traumaticbrain injury stroke and neurodevelopmental and neu-rodegenerative disorders For purposes of simplicitywe have focused on studies utilizing rats and miceand where voluntary physical exercise paradigms havebeen employed Finally we have limited our review tostudies examining adult animals except for the sectionon neurodegenerative diseases While exercise has alsobeen shown to be beneficial in juvenile and aging ani-mals [2ndash7] these studies are outside the scope of thisreview

The hippocampus

Information flow in the hippocampusInformation flow in the hippocampus is generally

unidirectional and is known as the trisynaptic circuit[8] (Fig 1) The first connection in the trisynaptic cir-cuit originates from Layer II of the entorhinal cortex(EC) and projects to the DG via a group of fibres knownas the perforant path The fibres synapse on the den-drites of the dentate granule cells (DGCs) located in themolecular cell layer There are two subdivisions of theperforant path medial (MPP) and lateral (LPP) TheMPP originates in the medial EC and projects to themiddle one-third of the molecular cell layer whereasthe LPP originates in the lateral EC and projects tothe outermost third of the molecular cell layer Boththe MPP and LPP provide excitatory input onto theDGCs but are physiologically distinct and have dif-ferent short-term and long-term plasticity properties[9ndash11] The MPP and LPP are the major inputs ofcortical information into the hippocampus and theDGCs play an important role in processing and fil-tering information before it is sent to other regions of

Fig 1 A simplified hippocampal circuitry illustrating trisynapticand monosynaptic circuits The basic circuitry of the hippocampusis commonly termed the trisynaptic circuit Layer II of the entorhinalcortex provides input to the granule cells of the dentate gyrus via themedial (light blue) and lateral (purple) perforant paths The dentategranule cells project to pyramidal cells of the CA3 via the mossyfibre pathway (green) CA3 pyramidal neurons project to the CA1via schaffer collaterals (pink) The CA1 pyramidal cells project toboth the subiculum and to layers V and VI of the entorhinal cor-tex Abbreviations Cornu Ammonis (CA) Dentate Gyrus (DG)Entorhinal Cortex (EC) Lateral Perforant Path (LPP) Medial Per-forant Path (LPP) Mossy Fibres (MF) Schaffer Collaterals (SC)Subiculum (S)

the hippocampus via the trisynaptic circuit [8] Fromthe DG DGC axons project onto pyramidal cells in theCA3 region of the hippocampus (Fig 1) This pathwayis unique in that the bundles of axons are unmyeli-nated and are therefore known as the mossy fibres Thethird component of the trisynaptic circuit is the CA3to CA1 projection known as the Schaffer CollateralsPyramidal cells of the CA3 send axons into the stratumradiatum and stratum oriens of the CA1 and innervateapical and basal dendrites of the CA1 pyramidal cells[1] The CA1 then projects information to the subicu-lum and both the CA1 and the subiculum project fibresback to Layers V and VI of the EC to complete thecortical information loop (Fig 1) It should be notedthat the CA1 also receives projections from the EC andthis pathway is known as the temporoammonic path-way [1] These projections arise from layers III andV of the EC This pathway may play a more promi-nent role in stress and anxiety related behaviours asopposed to spatial memory [12] (which is discussedbelow (Section 112))

The role of the hippocampus in spatial memoryIn the 1950 s Dr William Scoville performed

a bilateral limbic surgery on patient Henry Mola-sion (commonly known as HM) giving the firstreal insight into the function of the hippocampus[13] In order to treat HMrsquos recurrent seizures thehippocampus amygdala collateral sulcus perihinalcortex EC and the medial mammillary nucleus were









































(Continued)


Table 1(Continued)














threshold forLTP






(Continued)


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Synaptic plasticity



































































Stroke





































































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referencememory


30 daysenrichment)











(Continued)


Table 4(Continued)






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(reducedimmobility)








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(Continued)


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threshold forLTP






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Stroke





































































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referencememory


30 daysenrichment)











(Continued)


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(Continued)


Table 1(Continued)














threshold forLTP






(Continued)


Table 1(Continued)




















Synaptic plasticity



































































Stroke





































































to sedentarystroke





















referencememory


30 daysenrichment)











(Continued)


Table 4(Continued)






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(reducedimmobility)








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(Continued)


Table 1(Continued)














threshold forLTP






(Continued)


Table 1(Continued)




















Synaptic plasticity



































































Stroke





































































to sedentarystroke





















referencememory


30 daysenrichment)











(Continued)


Table 4(Continued)






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(reducedimmobility)








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Table 1(Continued)














threshold forLTP






(Continued)


Table 1(Continued)




















Synaptic plasticity



































































Stroke





































































to sedentarystroke





















referencememory


30 daysenrichment)











(Continued)


Table 4(Continued)






recognitionmemory












(reducedimmobility)








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Table 1(Continued)




















Synaptic plasticity



































































Stroke





































































to sedentarystroke





















referencememory


30 daysenrichment)











(Continued)


Table 4(Continued)






recognitionmemory












(reducedimmobility)








REFERENCES























































































































































































































































































































Synaptic plasticity



































































Stroke





































































to sedentarystroke





















referencememory


30 daysenrichment)











(Continued)


Table 4(Continued)






recognitionmemory












(reducedimmobility)








REFERENCES














































































































































































































































































































































































Stroke





































































to sedentarystroke





















referencememory


30 daysenrichment)











(Continued)


Table 4(Continued)






recognitionmemory












(reducedimmobility)








REFERENCES
































































































































































































































































































































































Stroke





































































to sedentarystroke





















referencememory


30 daysenrichment)











(Continued)


Table 4(Continued)






recognitionmemory












(reducedimmobility)








REFERENCES















































































































































































































































































































































Stroke





































































to sedentarystroke





















referencememory


30 daysenrichment)











(Continued)


Table 4(Continued)






recognitionmemory












(reducedimmobility)








REFERENCES





































































































































































































































































































































Stroke





































































to sedentarystroke





















referencememory


30 daysenrichment)











(Continued)


Table 4(Continued)






recognitionmemory












(reducedimmobility)








REFERENCES



























































































































































































































































































































Stroke





































































to sedentarystroke





















referencememory


30 daysenrichment)











(Continued)


Table 4(Continued)






recognitionmemory












(reducedimmobility)








REFERENCES





















































































































































































































































































































































































to sedentarystroke





















referencememory


30 daysenrichment)











(Continued)


Table 4(Continued)






recognitionmemory












(reducedimmobility)








REFERENCES







































































































































































































































































































































































to sedentarystroke





















referencememory


30 daysenrichment)











(Continued)


Table 4(Continued)






recognitionmemory












(reducedimmobility)








REFERENCES
































































































































































































































































































































































to sedentarystroke





















referencememory


30 daysenrichment)











(Continued)


Table 4(Continued)






recognitionmemory












(reducedimmobility)








REFERENCES


















































































































































































































































































































































to sedentarystroke





















referencememory


30 daysenrichment)











(Continued)


Table 4(Continued)






recognitionmemory












(reducedimmobility)








REFERENCES
































































































































































































































































































































to sedentarystroke





















referencememory


30 daysenrichment)











(Continued)


Table 4(Continued)






recognitionmemory












(reducedimmobility)








REFERENCES





























































































































































































































































































































referencememory


30 daysenrichment)











(Continued)


Table 4(Continued)






recognitionmemory












(reducedimmobility)








REFERENCES



















































































































































































































































































































Table 4(Continued)






recognitionmemory












(reducedimmobility)








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Documents

Brain Plasticity 1 (2015) 93–123 DOI 10.3233/BPL-150016 ... article Oct. 2015.pdf · Brain Plasticity 1 (2015) 93–123 DOI 10.3233/BPL-150016 IOS Press 93 The Beneﬁts of Exercise