review article physical exercise-induced adult...

Review ArticlePhysical Exercise-Induced Adult Neurogenesis A Good Strategyto Prevent Cognitive Decline in Neurodegenerative Diseases

Suk-yu Yau1 Joana Gil-Mohapel1 Brian R Christie1 and Kwok-fai So23456

1 Division of Medical Sciences University of Victoria 3800 Finnerty Road Victoria BC Canada V8P 5C22Department of Ophthalmology The University of Hong Kong 21 Sassoon Road Pokfulam Hong Kong3 State Key Laboratory of Brain and Cognitive Science The University of Hong Kong 21 Sassoon Road Pokfulam Hong Kong4Department of Anatomy Li Ka Shing Faculty of Medicine The University of Hong Kong 21 Sassoon Road Pokfulam Hong Kong5 Guangdong-Hong Kong-Macau Institute of CNS Regeneration Jinan University 601 Huangpu Avenue WestGuangdong 5106032 China

6Guangdong Key Laboratory of Brain Function andDiseases JinanUniversity 601 Huangpu AvenueWest Guangzhou 5106032 China

Correspondence should be addressed to Suk-yu Yau syyauuvicca and Kwok-fai So hrmaskfhkuhk

Received 14 November 2013 Revised 16 February 2014 Accepted 16 February 2014 Published 9 April 2014

Academic Editor Marıa Llorens-Martın

Copyright copy 2014 Suk-yu Yau et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Cumulative evidence has indicated that there is an important role for adult hippocampal neurogenesis in cognitive function Withthe increasing prevalence of cognitive decline associated with neurodegenerative diseases among the ageing population physicalexercise a potent enhancer of adult hippocampal neurogenesis has emerged as a potential preventative strategytreatment to reducecognitive decline Here we review the functional role of adult hippocampal neurogenesis in learning and memory and how thisform of structural plasticity is altered in neurodegenerative diseases known to involve cognitive impairment We further discusshow physical exercise may contribute to cognitive improvement in the ageing brain by preserving adult neurogenesis and reviewthe recent approaches for measuring changes in neurogenesis in the live human brain

1 Introduction

Given the overwhelming evidence showing adult neuro-genesis in the mammalian brain [1ndash5] and its potentialrole in cognitive function [6ndash11] the relationship betweenadult neurogenesis cognitive deficits and neurodegenerativediseases has become an emerging topic of interest Thisis of particular relevance in the ageing population giventhe increasing prevalence of cognitive deficits associatedwith neurodegenerative diseases Therefore manipulation ofadult neurogenesis has currently been targeted as a potentialtreatment for ageing-related cognitive deficits

Newborn neurons are mainly produced from neuralstem cells in two neurogenic zones of the adult brain thesubventricular zone (SVZ)olfactory bulb (OB) and the sub-granular zone (SGZ) of the hippocampal dentate gyrus (DG)[12] In the SVZ neural stem cells give rise to committed

progenitor cells that migrate through the rostral migratorystream (RMS) into the OB where they differentiate intolocal interneurons specifically granular and periglomerularneurons Adult neurogenesis in the hippocampus is morelocally confined when compared to neurogenesis in the SVZIn theDGof the hippocampus newbornneuronsmigrate justa short distance (approximately 20 to 25 120583m two cell nucleiwide) from the SGZ to the granule cell layer (GCL) wherethey integrate into the existing circuitry [12] A dividingprogenitor cell gives rise to daughter cells which differentiatemigrate and integrate integrate into the existing circuityTheir dendrites extend to themolecular layer of the DGwhiletheir axons project to the cornus ammonis (CA) 3 regionthrough the mossy fiber pathway [13] (Figure 1) Retrovirallabeling of newborn cells with green fluorescent proteins hasrevealed that newborn neurons can form synaptic contactwith its target cells by the third week of neuronal maturation

Hindawi Publishing CorporationBioMed Research InternationalVolume 2014 Article ID 403120 20 pageshttpdxdoiorg1011552014403120

2 BioMed Research International

Progenitors Immatureneurons

Matureneurons

Physical exercise

Neurodegenerative diseases (eg AD PD and HD)

sim1ndash3 days of proliferation

sim2 weeks ofdiferentiation

sim4ndash6 weeks ofmaturation integration

GCL

(a) (b)

Figure 1 Development and integration of adult-born neurons in the dentate gyrus of the hippocampus (a) The neural progenitors thatare divided from neural stem cells start expressing either neuronal or glial phenotypes after just a few days of division Newborn neuronsgradually migrate from the subgranular zone (SGZ) into the granular cell layer (GCL) where they undergomaturation followed by functionalintegration into the existing neural circuitry in the hippocampus This process of hippocampal neurogenesis is known to be promoted byphysical exercise and to be compromised in several neurodegenerative diseases such as AD PD and HD (b) Confocal image of 4-week-oldretroviral-labeled newborn neurons with green fluorescence protein (GFP) in the GCL (scale bar 200 120583m)

[14]Therefore synaptic connections between theDGand theCA3 hippocampal subregions (which form the mossy fibertract) can potentially bemodified by changes in hippocampalneurogenesis About 9000 new cells are generated eachday in the rodent hippocampus (hundreds of thousands ofcells each month accounting for 6 of the total granuleneuronal population) of which about 80ndash90 differentiateinto neurons [15]

Clinical studies have confirmed that similar processesalso occur in the corresponding regions of the human brain[16ndash19]The first evidence of adult neurogenesis in the humanbrain came from a study showing the presence of positivestaining for 5-bromo-21015840-deoxyuridine (BrdU a thymidineanalog) in the SVZ and the DG region of postmortembrain sections from cancer patients who had received BrdUinjections in life [5] These findings have since then beenconfirmed and a recent study has revealed that approximately700 new neurons are added to the adult human hippocampuseach day [20] However adult neurogenesis is age dependentwith the production of new neurons declining with age [21ndash28]

The hippocampus plays an integral role in the consolida-tion of declarative memory as well as context dependent andspatial learning processes [29 30] in both humans [31 32] androdents [33ndash36] New hippocampal neurons are believed tocontribute to the functioning of the hippocampus and thereis evidence that they are recruited into hippocampal neuronalcircuits known to be involved in spatial learning [9] and

possess particular physiological properties that make themmore susceptible to behavioral-dependent synaptic plasticity[11 37 38] Thus it is reasonable to speculate that these newneuronsmight be integral for hippocampal-dependent learn-ing and memory [11] and in particular pattern separation[39ndash41] In agreement with this hypothesis numerous correl-ative studies have shown that hippocampal neurogenesis canbemodulated by learning and behavioural experience [6 42ndash45] and that a loss in hippocampal neurogenic function canadversely affect memory formation [7 8 10 38 46]

Using exercise training as an upregulator for hippocam-pal neurogenesis an in vivo imaging study in humanshas indicated a positive association between hippocampal-dependent cognitive performance and change of cerebralblood volume (CBV served as an indirectmeasure of changesin hippocampal neurogenesis in the human brain) [47] Fur-thermore exercise intervention has been shown to improveperformance in a neurogenesis-dependent cognitive test thevisual pattern separation task in human subjects [48] Inspite of the technical limitations associated with the directmeasurement of neurogenesis in the human brain these twostudies have suggested that adult-born new neurons in thehippocampus might play a functional role in learning andmemory in the human brain

Neurodegenerative diseases such as Alzheimerrsquos disease(AD) Parkinsonrsquos disease (PD) and Huntingtonrsquos disease(HD) share the common characteristic of progressive loss ofstructure andor function of neurons in the brain Although

BioMed Research International 3

neuronal degeneration predominantly affects specific neu-ronal populations (ie dopaminergic neurons in PD striatalgamma-aminobutyric acid (GABA) ergic neurons inHD andcortical and hippocampal neurons in AD) all these neu-rodegenerative diseases are characterized by a more or lesssevere loss of certain cognitive functions including learningand memory Concomitantly several lines of evidence haveshown that adult hippocampal neurogenesis might be alteredin these neurodegenerative processes [49 50]

Physical activity has been repeatedly shown to improvecognition and prevent age-related cognitive decline inhumans [51] particularly in individuals affected with certainneurodegenerative diseases [52 53] However the underlyingmechanisms responsible for the beneficial effects of physicalexercise are still unclear Nevertheless animal studies havesuggested that an increase in hippocampal neurogenesis maymediate at least in part the exercise-induced increase incognitive function [54 55]

Here we review the functional role of adult neurogenesisin cognitive function and the emerging association betweenadult hippocampal neurogenesis and cognitive impairmentin neurodegenerative diseases We further discuss physicalexercise-induced hippocampal neurogenesis and its relation-ship with cognitive improvement Finally we address theemerging techniques formeasuring adult neurogenesis in livehuman brain

2 Adult Neurogenesis inLearning and Memory

The functions of adult neurogenesis in the adult brain havebeen extensively investigated in the past decade Numerousstudies have suggested that neurogenesis in the DGmay playan important role in hippocampal-dependent learning andmemory [6ndash11 56] as well as affective disorders such asdepression and anxiety [56ndash59] while neurogenesis in theSVZ may be involved in olfactory learning and discrimina-tion [60] and sexual behavior [61 62]

Importantly newly generated neurons have particularphysiological properties that make them more susceptibleto behavioral-dependent synaptic plasticity [11] Using retro-viral labeling of newborn neurons with green fluorescenceprotein Toni and colleagues have demonstrated that new-born neurons could form synapses and receive synaptic inputfrom existing neurons [14] Furthermore immature neuronsexhibit a lower threshold for long-term potentiation (LTP)induction in response to theta-burst stimulation [37] whichmight be due to their specific membrane properties such asgreater N-methyl-D-aspartate (NMDA) receptor sensitivityand calcium entry upon synaptic activation [63]On the otherhand LTP has also been shown to induce adult hippocam-pal neurogenesis [64] which further strengthens the linkbetween structural and functional hippocampal plasticity

Since these newly generated neurons are linked tothe functioning of the hippocampus it is reasonable tospeculate that they might play a role in mechanisms ofhippocampal-dependent learning andmemory In agreementwith this hypothesis it has recently been shown that new

neurons are indeed recruited into neuronal circuits involvedin spatial learning and memory in the hippocampus [9]Furthermore other studies have shown that disrupting orablating adult hippocampal neurogenesis results in im-paired hippocampal-dependent learning and memory Ex-perimental reduction of adult neurogenesis impaired hip-pocampal-dependent trace eye-blink conditioning but nothippocampal-independent delay conditioning [7] Similarresults were obtained with other hippocampal-dependenttasks including place-recognition tasks [46] contextual fearconditioning [8 38] and a non-matching-to-sample taskwhich measured conditional rule learning and memory forspecific events [8]

Although details of how newborn neurons modulatelearning and memory are still unclear recent findings havesuggested that adult born neurons in the DG play a criticalrole in pattern separation preventing memory interferencefrom overlapping contexts [39 65 66] Garthe and colleagueshave demonstrated that inhibiting neurogenesis in miceresults in impairments in the reverse protocol of the MorrisWater Maze test (ie an increased preference for the oldposition of the hidden platformand failure to identify the newposition) These results suggest that adult neurogenesis inthe DG prevents memory interference from similar contextsthus allowing formation of a new memory that is similar to apreviously acquired one [67] In agreement with this findingtwo recent studies have demonstrated an association betweenlower levels of hippocampal neurogenesis and impairmentsin spatial pattern separation in mice [39 68] Converselyexercised mice with enhanced neurogenesis perform betterin spatial pattern separation tasks [66]

To test the hypothesis concerning the functional roleof neurogenesis on pattern separation in the human brainDery and colleagues used the visual pattern separationtask a cognitive test that is believed to be neurogenesis-dependent and that uses some objects that are repeatedlypresented across trials and some objects that are new buthighly similar to previously presented ones They observed asignificant enhancement in performance on the visual patternseparation task together with lower depression scores insubjects who participated in exercise training a well-knownenhancer of neurogenesis [48] This finding corroboratesthe hypothesis that adult hippocampal neurogenesis may beinvolved in learning and memory in the human brain

In summary it is currently believed that hippocampalnew neurons are required for the separation of events basedon their spatial and temporal characteristics (a process thatpreserves the uniqueness of a memory representation) aswell as space representation long-term memory retentionand flexible inferential memory expression [69]

3 Altered Adult Neurogenesis inNeurodegenerative Diseases

The contribution of altered adult hippocampal neurogenesisto the cognitive deficits that are characteristic of variousneurodegenerative conditions such as AD PD andHD is stillnot fully elucidated Nevertheless since alterations in adult


Table 1 Modulation of adult neurogenesis by neurodegenerative diseases and physical exercise

Neurodegenerative disease Alteration of adult neurogenesis Effect of physical exercise on adultneurogenesis

AD

Rodent models uarr or darr SGZ neurogenesis depending on the transgenic model[78ndash88]

uarr Learning and memory in varioustransgenic models [189 190 192ndash195]uarr or no effect on proliferation andneuronal differentiation in APP23transgenic mice

Human patientsuarr Proliferationdifferentiation in human SGZ from ADpatients [89]darrMaturation in human SGZ from AD patients [90]

mdash

PD

Rodent modelsdarr SGZ proliferation in lesion models [108]uarr SGZ proliferation in MPTP lesion model [107]darr SGZ proliferation and survival in 120572-synuclein transgenicmice [111 112]

Rescue of behavioral deficits in lesionmodels [175 204 205 207]

Human patients darr Proliferationdifferentiation in human SGZ from PDpatients [108]

uarrMotor and cognitive function in humanPD patients [209 210]

HD

Rodent models darr SGZ neurogenesis in HD transgenic and knock-in models[128ndash131 136 141 143]

No effect on SGZ neurogenesis intransgenic models [132 211 212]darr Behavioral and cognitive deficits intransgenic models [158 213]

Human patients No changes in cell proliferation in human SGZ from HDpatients [159] mdash

neurogenesis have been repeatedly shown in various animalmodels of these disorders [70] (Table 1) it is speculatedthat cognitive decline in neurodegenerative diseases couldbe partly due to alterations in the neurogenic processWithin this scenario therapeutic strategies such as physicalexercise that can restore or increase adult neurogenesis mightbe of therapeutic value for the treatment of the cognitivedeficits associated with these devastating neurodegenerativedisorders

31 Hippocampal Neurogenesis in Alzheimerrsquos Disease (AD)AD is manifested by progressive cognitive deteriorationmemory loss behavioural changes and eventually dementiaAt the pathological level AD is characterized by acetylcholinedepletion the accumulation of amyloid (or senile) plaquesand the formation of neurofibrillary tangles (NFT) whichcan lead to neuronal loss by apoptosis particularly in thecortex and hippocampus and severe brain atrophy [71]Whilethe majority (95) of cases of AD are sporadic complexarrays of environmental and genetic factors have also beenlinked to the etiology of this disorder Gene mutations inthe presenilin (PS) 1 andor 2 genes or the apolipoprotein(APO) E gene can increase the risk of developing AD [72 73]PS1 and PS2 are key components of 120574-secretase the enzymeresponsible for cleaving the amyloid precursor protein (APP)into toxic amyloid-120573 (A120573) peptides the building blocks ofsenile plaques [74]

While the exact neurobiological mechanisms underlyingthe symptoms of AD are still unclear severe neuronal lossin areas of the brain involved in learning and memory

such as the hippocampus and prefrontal cortex is evidentin the AD brain Transgenic mouse models of AD showimpairments in several hippocampal-dependent learning andmemory tasks such as spatial learning object recognitionand contextual fear conditioning [75] Additionally adulthippocampal neurogenesis has been investigated in severalof these models and contradictory results have been obtained[50 76 77] Briefly while a decrease in neurogenic functionhas been reported in transgenic or knock-in mice carryingthe Swedish mutation in the APP gene [78ndash81] the PDAPPmutation [82] mutations in the PS1 gene [80 81 83 84]as well as in double-transgenic mice for APP and PS1[80 81] and in triple-transgenic mice for APP PS1 andtau protein [85] others have found increased hippocampalneurogenesis in transgenic mice that express APP with theSwedish and the Indiana mutations [86 87] or with theSwedish Dutch and London mutations [88] Differencesamong the various transgenic mouse models used the stagesof disease progression when neurogenesis was evaluated anddifferences in the protocols used to evaluate neurogenesisare factors that might have contributed to the discrepanciesreported in the literature [50]

In human AD patients the expression of several imma-ture neuronal markers (doublecortin (DCX) polysialylatednerve cell adhesion molecule (PSA-NCAM) neurogenicdifferentiation factor (NeuroD) and 120573III-tubulin) appearsto be increased [89] while the expression of the matureneuronal marker microtubule-associated protein (MAP) wasfound to be dramatically decreased [90] in the DG ofthe hippocampus These results suggest that regardless of


an increase in neuronal differentiation the later stages ofneuronal maturation during the neurogenic process mightbe compromised in the human AD brain While the exactmechanism responsible for this dysregulation is still unclearA120573 aggregates have been found to accumulate near neuralprecursor cells in the hippocampal DG [91 92] suggestingthat these aggregates can influence hippocampal neurogen-esis in the AD brain Furthermore many of the moleculesinvolved in the development of AD can also play a roleduring the neurogenic process for example PS1 is thought toregulate neuronal differentiation [93] whereas soluble APP120572may be important during cell proliferation [94]

32 Hippocampal Neurogenesis in Parkinsonrsquos Disease (PD)PD is caused by death of dopaminergic neurons that projectfrom the substantia nigra (SN) pars compacta to the striatumof the basal ganglia PD is manifested by (1) severe motorsymptoms characterized by a progressive impairment ofmovement control akinesia rigidity and tremor and (2)nonmotor symptoms such as cognitive decline olfactorydysfunction anxiety [95] and depression [96] At the neu-ropathological level the disease is also characterized by thepresence of 120572-synuclein-positive Lewy bodies and dystrophicLewy neurites throughout the brain which initially occur inthe vagal nerve and OB and thereafter spread to other nucleiand cortical areas [97]

The neurogenic regions of the adult brain are innervatedby dopaminergic projections from the SN and the ventraltegmental area (VTA) [98ndash100] therefore the reduction ofdopamine (DA) levels that occurs in PD may potentiallyaffect the production of new neurons in the SVZ and DGMoreover some of the nonmotor symptoms linked to PDthat are not directly associated with neurodegeneration in theSN such as olfactory dysfunction or depression and cognitivealterations [101 102] may be related to deficits in the stemcell populations of the SVZOB system and the hippocampusrespectively [103 104]

The animalmodels that have beenmostwidely used in PDresearch are the unilateral 6-hydroxydopamine (6-OHDA)lesion rat model and the bilateral 1-methyl-4-phenyl-1236-tetrahydropyridine (MPTP) lesion mouse model whichdevelop PD-like symptoms [105] Park and Enikolopovshowed that experimental ablation of dopaminergic neuronsin the MPTP mouse model of PD resulted in a transientincrease in cell division in the SGZ of the DG [106] Thesefindings are in agreement with the ones by Peng et al whoreported an increase in the incorporation of BrdU aswell as inthe number of cells that coexpressed BrdU and the immatureneuronal marker DCX in the DG SVZ and striatum butnot in the SN of MPTP-treated mice [107] Despite theseresults various studies have also shown a decrease in adultneurogenesis in the SGZ and SVZ of MPTP-treated animalsFor example Hoglinger et al demonstrated that proliferationof C cells (which are targeted by dopaminergic innervations)was impaired both in the SVZand SGZofMPTP-treatedmice[108] Furthermore using both the 6-OHDA and the MPTPmodels to induce DA depletion in rats andmice respectivelythe same group also found a marked decrease in precursor

cell proliferation in both the SGZ of the DG and the SVZa deficit that was completely reversed by the administrationof the selective agonist of D2-like DA receptors [108 109]further supporting the idea that the dopaminergic depletionobserved in PD brainsmight result in impaired neurogenesis

Several in vivo studies have also evaluated how hip-pocampal neurogenesis is altered by the expression of 120572-synuclein Transgenic mice overexpressing human wild-type120572-synuclein showed significantly fewer neurons both in theOB as well as in the DG of the hippocampus as comparedto their control littermates an effect that seems to resultfrom a decrease in neuronal precursor survival [110] whereastransgenic mice expressing mutant 120572-synuclein were shownto have impaired hippocampal neurogenesis due to a decreasein proliferation and survival of neural precursor cells [111]In a different study Nuber and collaborators also showedreduced hippocampal neurogenesis and cognitive deficitsin a conditional 120572-synuclein mouse model Turning offthe transgene expression did halt the progression of thesesymptoms although no regression was observed [112]

Finally a decrease in the number of proliferating cellnuclear antigen (PCNA) positive cells (a marker of cell pro-liferation) in SVZ and a reduction in the number of nestin-and 120573III-tubulin-positive cells in the DG of the hippocampushave also been found in postmortem tissue from PD patientspresumably as a consequence of dopaminergic denervationof these neurogenic regions [108] providing further evidenceof altered hippocampal neurogenesis in the human PD brain

33 Hippocampal Neurogenesis in Huntingtonrsquos Disease (HD)HD is caused by an expansion of cytosine-adenine-guanine(CAG) trinucleotide repeats in the HD gene which resultsin an expanded polyglutamine tract in the NH

2-terminal

of the protein huntingtin [113] In most cases the onset ofthe disease occurs in midlife between the ages of 35 and50 years The disease progresses over time and is invariablyfatal 15 to 20 years after the onset of the first symptomsMotor disturbances associated with the loss of voluntarymovement coordination are the classical symptoms of HDwith bradykinesia and rigidity appearing in later stages of thedisease Cognitive capacities are also severely affected duringthe course of the disease with the slowing of intellectualprocesses being the first sign of cognitive impairment in HDpatients [114] In fact deficits in some cognitive functions canin some cases be detected decades before the onset of motorsymptoms These cognitive impairments worsen over timeand late-stage HD patients show profound dementia [115ndash120]

Mutant huntingtin is ubiquitously expressed throughoutthe organism However cell degeneration occurs mainly inthe brain particularly in the striatum and certain layers of thecortex [114 121] Nevertheless cell loss can also be detectedin other brain regions including the hippocampus [121ndash123]raising the possibility that HD might also be associated withalterations in the endogenous neurogenic capacity

Several rodent models are currently available to study theeffects of the altered HD gene These models primarily differin the size of the expressed huntingtin fragment the number


of CAG repeats the promoter driving the transgene andconsequently the expression of the mutant protein as well asthe background strainAs a consequence eachmodel exhibitsunique phenotypes Neverthelessmost demonstrate progres-sive neurological phenotypes (eg progressive dysfunctionin motor ability and cognitive decline) that mimic well thehuman condition [124ndash127] The first studies that analyzedhow adult hippocampal neurogenesis is altered in HD usedR61 [128 129] andR62 [130ndash132] transgenicHDmice whichexpress exon 1 of the human HD gene (corresponding toapproximately 3 of the entire gene) with 115 and 150 CAGrepeats respectively [133] and show cognitive impairments[134 135] In both cases a dramatic and progressive reductionin adult hippocampal neurogenesis was found Of note and inaccordance with the faster disease progression characteristicof the R62 line [133] a reduction in hippocampal cell prolif-eration can be detected in these HD mice as early as 2 weeksof age before the onset of any behavioral abnormalities Thisdecrease progresses with the course of the disease [131] andby 12 weeks of age (ie when animals reach the end stageof the disease) R62 mice show a 70 reduction in thenumber of new cells present in the DG [130] In agreementwith the results obtained with the R6 lines it has recentlybeen demonstrated that adult hippocampal neurogenesis isalso selectively affected in yeast artificial chromosome (YAC)128 mice [136] This transgenic mouse model expresses thefull-length human HD gene with 128 CAG repeats [137]and replicates the slow progression of the human condition[138] while also displaying depressive-like behavior [139]and hippocampal-dependent cognitive deficits [140] In thisstudy a significant decrease in cell proliferation neuronaldifferentiation and overall neurogenesis was detected in theDG of early symptomatic to end-stage YAC128 mice [136]once again demonstrating the progressive nature of thisneurogenic deficit Additionally Kandasamy and colleagues[141] also found a significant and progressive decline in adulthippocampal cell proliferation in a rat model of HD thatexpresses a truncated cDNA fragment of the HD gene with51 CAG repeats under the control of the endogenous rat Hdhpromotor [142] Finally a recent study using knock-in Hdh(Q111) mice which carry an expanded polyglutamine stretchin the mouse huntingtin protein has also observed alteredDG neuronal maturation along with increased anxiety-likephenotypes [143]

Although it is still unclear how the expression of mutanthuntingtin gene might lead to a dysregulation of the neu-rogenic process various mechanisms have been proposedto contribute to this disturbance [127] These include (1)transcriptional dysregulation of key genes known to play arole in neurogenesis such as NeuroD [144] (2) decreasedneurotrophic support including a reduction in the levels ofbrain-derived neurotrophic factor (BDNF) [145ndash152] as wellas (3) deficits in neurotransmission namely alterations in thedopaminergic [125 153] and serotonergic [154ndash158] systems

Taken together these studies support the possible roleof mutant huntingtin in disrupting the process of adulthippocampal neurogenesis in the HD brain These neuro-genic deficits can in turn contribute at least in part to thecognitive decline and depressive-like symptoms found in HD

transgenic models However studies in postmortem humanHD brains have shown no changes in hippocampal cellproliferation [159] and an actual increase in SVZ neurogene-sis [160ndash163] Methodological considerations and differencesin the numbers of CAG repeats and the levels of expressionof the mutant gene might account for the discrepanciesobserved between the human and the rodent studies [50 127]Future studies are thus warranted in order to fully elucidatethe role of adult neurogenesis in the development of thecognitive symptoms associated with HD

4 Physical Exercise Prevents Cognitive Declineand Increases Adult Neurogenesis

Even though tremendous advances have been made overthe past few decades with regard to our understanding ofthe etiology of age-related neurodegenerative disorders todate no effective treatments are available for individualsafflicted with these devastating neurodegenerative diseasesIn recent years physical exercise has emerged as the mosteffective low-cost and low-tech way for successful ageingand therefore it has the potential to represent a preventiveor disease-slowing therapeutic strategy for age-related neu-rodegenerative diseases [53]

In support of this hypothesis a meta-analysis study hasshown that 1 to 12 months of exercise in healthy adultsbrings behavioral benefits including significant increases inmemory attention processing speed and executive function[164] Moreover regular engagement in physical exercisein midlife is associated with reduced risks of developingdementia later on in life [52] suggesting that physical exercisemight indeed have preventative effects with regard to thedevelopment of age-related cognitive decline In agreement aprospective observational study has found a reduction in therisk for AD and other forms of dementia in individuals whoexercise regularly as compared to those who did not activelyengage in physical activity [165]

Evidence from animal studies has suggested that anenhancement in hippocampal neurogenesis may underlie thereported beneficial effects of exercise on cognitive functionIndeed pioneer studies by van Praag and collaboratorsshowed that physical running not only increased hippocam-pal neurogenesis [42 43] but can also improve Morris watermaze performance and selectively increase LTP in the DG ofthree-month-oldmice [43]Thus in addition to upregulatingthe neurogenic process physical activity can also increase thecapacity for neurons in the hippocampus to sustain synapticplasticity and facilitate hippocampal-dependent learningin the same animals Similarly in humans three months ofphysical exercise were shown to correlate with increasedblood volume in the DG as assessed by functional magneticresonance imaging (fMRI) as well as an improvement incognitive scores [47] Indeed exercise is known to increasecerebral blood flow [166] the permeability of the blood brainbarrier [167] and angiogenesis [168ndash171] Given the possiblepositive relationship between angiogenesis and neurogenesisfound in animal studies [172 173] the observation thatthree months of exercise resulted in improved cognition is


therefore speculated as a result of increased hippocampalangiogenesis and hence neurogenesis in the human brain[47]

These beneficial effects of physical exercise on cognitivefunction suggest that exercise might indeed be used as astrategy to prevent cognitive decline in age-related neurode-generative diseases Physical exercise has been shown toprevent the age-induced decrease in hippocampal cell pro-liferation neurogenesis [174] LTP and neurotrophin levels[175] as well as enhance hippocampal-dependent learning[55] in aged mice Moreover submitting rats to a regime ofphysical exercise during postnatal development was shownto increase hippocampal neurogenesis and spatial memorylater on during adult life [176] highlighting the long-lastingbenefits of physical exercise on brain plasticity [176]

The exact unerlyingmechanisms of how physical exercisepromotes adult hippocampal neurogenesis is still unclearNeurotrophins such as BDNF insulin-like growth factor 1(IGF-1) and vascular endothelial growth factor (VEGF) havebeen recognized as primary mediators of adult neurogenesis[172 177ndash179] Age-related decline in neurogenesis [21ndash28]has been associated with decreases in the levels of thesetrophic factors [180 181] Expression of BDNF and IGF-1genes in hippocampal neurons has been shown in responseto exercise training [182] Both peripheral levels of IGF-1 andVEGF are increased following exercise and enter into thebrain by crossing the blood brain barrier [183ndash185] VEGF[184] and IGF-1 [183 186] appear to have an importantrole in physical exercise-induced hippocampal neurogenesissince blocking one of these neurotrophic factors substantiallydiminishes running-induced neurogenesis in rodent studiesSimilarly the knock-out of the BDNF receptor (tyrosinereceptor kinase B TrkB Receptor) in hippocampal progenitorcells diminishes the running-induced increase in hippocam-pal neurogenesis in mice [187] Therefore it is thoughtthat these three neurotrophin factors were suggested towork in concert formediating exercise-induced hippocampalneurogenesis [188]

5 Hippocampal Neurogenesis in AnimalModels of Neurodegenerative Diseasesfollowing Physical Exercise

Animal models of neurodegenerative diseases constitutevaluable tools to unmask the underlying mechanisms bywhich exercise enhances adult neurogenesis brain plasticityand hence cognitive function in the diseased brain (Table 1)

51 Alzheimerrsquos Disease Several mouse models of AD haveshown that running can promote neurogenesis and cognitivefunction in the AD brain Short-term running is able toenhance cognitive function in aged Tg2576 mice [189]Long-term voluntary running for five months not onlydecreases extracellular A120573 plaques in the frontal cortex andhippocampus of TgCRND8 AD mice but also enhancestheir hippocampal-dependent learning in the Morris watermaze [190] Similar results were obtained with the APPPS1double-transgenic AD mouse model where treadmill

exercise improved learning and memory function and LTP[191] while also ameliorating some of the neuropathologicalcharacteristics of the disease including a reduction inA120573 deposition and tau phosphorylation as well as adecrease in APP phosphorylation and PS1 expressionin the hippocampus [192] However since hippocampalneurogenesis was not examined in these studies it is unclearwhether the observed behavioral improvements are linkedto an increase in hippocampal neurogenesis in these ADtransgenic mice

On the other hand studies using the APOE-e4 transgenicmouse model have demonstrated the effect of running onrestoring hippocampal plasticity and improving cognitivefunctions in this AD transgenic mouse model [193ndash195]Additionally the effects of physical exercise on hippocampalneurogenesis have also been evaluated in the APP23 ADtransgenic mouse model In one study mice were allowedaccess to a running wheel for 10 days at the ages of 6 and18 months In the 6-month-old cohort proliferation wasdecreased as compared to control animals and no effect ofrunning was observed However at the 18-month time pointa running-induced increase in proliferation and neuronaldifferentiation was detected in APP23 runners [196] indi-cating that the AD brain retains the ability to upregulatecell proliferation and neuronal differentiation in response tophysical exercise However in a different study where APP23transgenic mice were given access to a running wheel for 11months starting at 10 weeks of age the authors failed to detectan increase in cell proliferation and neuronal differentiationin the running group [197] It is possible that by the time ofanalysis (ie at 17 months of age) the disease progression wasalready too advanced to allow for detection of any changesin endogenous neurogenesis Alternatively these findingsmight also be a consequence of the well-known age-induceddecrease in adult hippocampal neurogenesis [21ndash26 28]However since previous studies have shown that voluntaryphysical exercise can still increase hippocampal neurogenesisin wild-type aged mice [55 174 198] it is likely that theadvancement of the disease was a more prominent factor

Epidemiological studies have reported a reduced risk ofdeveloping dementia in elderlies with higher physical activity[199ndash201] Neuroimaging studies indicate that elderlies withhigher aerobic fitness have larger hippocampal volumes andperform better on a spatial memory task [202] Furthermorea longitudinal study has shown that in cognitively normaladults participation in greater amounts of physical activity 9years earlier was associated with greater gray matter volumein several brain areas such as the frontal cortex parietalcortex and temporal cortex including the hippocampuswhich in turn was associated with a reduced risk of cognitiveimpairment [203]

Despite the fact that there is abundant evidence suggest-ing that physical activity might be effective in reducing therisk of developing AD in humans the exact mechanismsby which physical exercise reduces the risk of AD are stillunknown Animal studies have suggested that physical exer-cise might result in structural changes in the hippocampusthat in turn may reduce the risk for AD future researchlinking the possible changes of the brain (eg changes in


hippocampal neurogenesis) with functional outcomes in ADpatients or individuals with higher risk for AD will shed lighton how physical exercise benefits these individuals

52 Parkinsonrsquos Disease Several studies have shown thatphysical exercise can be beneficial in ameliorating some ofthe neuropathological and behavioural deficits characteristicof various PD rodent models [204ndash207] However to dateonly a single study has evaluated how physical exercisemodulates the endogenous neurogenic capacity in PD bysubmitting 6-OHDA-lesioned rats to a regime of treadmillexercise (30minday 5 daysweek for 4 weeks) [208] Forcedexercise resulted in the upregulation of the trophic factorsBDNF and glial cell-derived neurotrophic factor (GDNF)in the striatum as well as an increase in cell proliferationand the migration of neural stem cells towards the lesionsite Additionally exercise promoted the preservation oftyrosine hydroxylase (TH the rate-limiting enzyme duringthe synthesis of DA) positive fibres in the striatum andTH-positive neurons in the SN [208] These results suggestthat exercise can be a promising noninvasive therapeuticintervention to minimize neuronal degeneration in the PDbrain Despite these promising findings there are currentlyno studies evaluating how physical exercise modulates theneurogenic capacity in the DG of the hippocampus of PDrodent models

A few clinical studies have reported that physical exercisecan improve motor function and cognitive performancein human PD patients [209 210] There is however apaucity of studies addressing the possible interaction amonghippocampal neurogenesis cognitive function and physicalexercise in both lesion and transgenic rodent models of PDThus whether the beneficial effects that physical exercisewas shown to have in human PD patients [209 210] aremediated at least in part through a decrease in SN neuronaldegeneration andor an increase in hippocampal neurogene-sis is a hypothesis that remains to be elucidated Neverthelessthese findings suggest that physical exercise may constitute anoninvasive therapeutic option to improve cognition in PDpatients

53 Huntingtonrsquos Disease The use of voluntary physicalexercise as a means to promote adult neurogenesis wasinitially tested in 5-week-old R62 HD mice [132] Howeveraccess to a running wheel during an uninterrupted period of4 weeks was unable to induce an increase in neurogenesis(ie cell proliferation and neuronal survival) in these HDtransgenic mice Similarly running also failed to rescue thedeficits in hippocampal neurogenesis observed in R61 HDmice [211] and presymptomatic N171-82Q HD mice [212]Although it is feasible that the cellular pathways underlyingthe proneurogenic effects of physical exercisemight be alteredby mutant huntingtin it is also possible that the developmentof motor deficits (which appear early on particularly inthe R62 line [133]) might have incapacitated these mice toactively engage in physical exercise Additionally the housing

conditions involving social isolation that were employed insome of these studies might have also had a negative impacton the running activity of the mice [211] thus contributingto the ineffective effect of exercise on adult hippocampalneurogenesis

Nevertheless other authors have found that exposure ofR61 mice to physical exercise delayed the onset of rear-paw clasping and improved cognition in adulthood [158]while also delaying the onset of locomotor deficits thatcan be detected in the juvenile period [213] In additionalthough Pang and collaborators observed that running didnot alter the protein levels of the neurotrophin BDNF bothin the striatum and the hippocampus of R61 HD mice[158] a subsequent study by Zajac and colleagues reported arunning-induced increase in bdnf gene expression that wasspecifically observed in R61 females but not in their malecounterparts [151] Sex-specific differences in the amount ofrunning the animals engaged in might underlie at least inpart the dichotic effect that physical exercise had on bdnfexpression levels in R61 females versus males Of note it isreasonable to speculate that the inability of physical exerciseto consistently upregulate bdnf gene expression and proteinlevels in the hippocampus of R6 mice [151 158] may beresponsible for the lack of proneurogenic effects that wasobserved in the hippocampus of theseHDmice upon exercise[132]

Of note it has also been reported that R61HDmice showdecreases in dendritic spine density and spine length both instriatal and cortical neurons [214] However it is unknownwhether a similar dendritic pathology could be found in thehippocampus of theseHDmice Nevertheless it is reasonableto speculate that the running-induced cognitive improve-ment that was observed in this HD transgenic mouse model[158] may result at least in part from structural remodelingof the existing hippocampal neurons In agreement with thishypothesis physical exercise is known to increase dendriticcomplexity spine density and synaptic plasticity [43 215216]

In contrast to physical exercise treatment of R61 micewith fluoxetine a selective serotonin reuptake inhibitor(SSRI) antidepressant was shown to abolish the impairmentin adult hippocampal neurogenesis while also increasing cog-nitive performance (hippocampal-dependent spatial learningand memory) [155] These preclinical findings highlight thefact that increasing hippocampal neurogenic capacity in theHD brain might result in improved cognition

6 Assessment of Adult HippocampalNeurogenesis in Live Human Brain

61 In Vivo Imaging of Neurogenesis The first evidence forthe occurrence of adult neurogenesis in the human braincame from a study by Eriksson and colleagues showing thepresence of BrdU-positive cells in postmortem hippocampaland SVZ human tissue obtained from cancer patients thatreceived BrdU injections in life for diagnostic purposes[5] However due to technological limitations it is virtu-ally impossible to evaluate adult neurogenesis in the live


human tissue This has in turn halted the analysis of thefunctional role of adult neurogenesis in humans Indeedthe current methods employed to examine adult humanneurogenesis mainly rely on immunostaining of postmortemfixed tissues obtained in the clinical setting [5] or on theisolation of human neural progenitor cells from tissue biop-sies [17 18 217] However these methods cannot providefurther information on the possible roles of adult neuro-genesis during neurodegenerative processes in the humanbrain

The development of alternate methods that can be usedto assess adult human neurogenesis in vivo has emerged as anessential research area within the neurogenesis field Withinthis scenario the recent detection of adult neurogenesisin live human brains using magnetic resonance imaging(MRI) [47] has provided a possible method to discoverthe functional role of adult neurogenesis in the humanbrain In this study Pereira and colleagues measured cerebralblood volume (CBV known to correlate with angiogenesisin the brain) as an indirect measure of neurogenesis [47]based on the positive correlation between neurogenesis andangiogenesis reported in animal studies [172 173] Addi-tionally using physical exercise as a well-known upregulatorof hippocampal neurogenesis and angiogenesis [55 218]this group also demonstrated that the increase in CBVwas specifically observed in the human hippocampus andcorrelated with cognitive improvement following a 12-weekregime of physical training The results from human subjectswere consistent with the observation that a similar processoccurred in mice where there was a positive correlationbetween a specific increase in CBV and an increase in thenumber of BrdU-positive cells in the DG following physicalexercise [47] An alternate in vivo imaging method that hasbeen employed to detect neurogenesis in humans consistsin using proton nuclear magnetic resonance spectroscopy(1H-NMR) This technique uses the magnetic properties ofprotons to detect a specific biomarker of neural progenitorcells N-acetylaspartate (NAA a small metabolite producedby neural progenitor cells) in living tissue [219] Since thesetwo methods have not yet been validated by other studies sofar further clinical studies would help to validate the feasi-bility and reliability of using these emerging in vivo imagingmethods as indirect ways to measure adult neurogenesis inthe live human brain

62 Peripheral Neurotrophins as Biomarkers for Adult Neuro-genesis Another indirect and noninvasive measure of adultneurogenesis in humans might be the measurement ofperipheral biomarkers that correlate well with changes inadult neurogenesis However such peripheral biomarkershave not yet been clearly identified

621 Brain-Derived Neurotrophin Factor As mentionedabove BDNF IGF-1 and VEGF have been recognized asprimary mediators of adult neurogenesis [172 177ndash179]Indeed BDNF is considered to be the most downstreamfactor mediating the upregulation of hippocampal neuro-genesis by exercise [188] In agreement with this idea

Erickson and colleagues reported that exercise trainingas a fitness intervention for the aging population effec-tively attenuates the age-related loss in hippocampal vol-ume while also increasing serum levels of BDNF [220]Additionally increases in hippocampal BDNF levels arethought to contribute to the upregulation of adult hippocam-pal neurogenesis that is observed following antidepressanttreatment [221] Indeed clinical studies have shown thatserum BDNF levels are decreased in depressive patientsand that antidepressant treatment can ameliorate this deficit[222]

Given this well-established relationship between var-ious neurotrophins and adult hippocampal neurogenesisit is reasonable to speculate that the peripheral levels ofthese trophic factors might be reliable biomarkers of adulthippocampal neurogenesis However the exact relationshipbetween peripheral levels of neurotrophins and levels ofhippocampal neurogenesis is still unclear Rachman andcolleagues have provided the first evidence that brain BDNFis the major contributor to the increase in plasma BDNFthat is observed in response to exercise [223] Yau andcolleagues have also investigated the relationship betweenlevels of hippocampal neurogenesis plasma neurotrophinslevels and cognitive performance in a rat model of stressThey reported that acute stress-induced enhancement inspatial learning and increase in hippocampal BDNF levelswere accompanied by a correspondent increase in plasmaBDNF levels However this effect was independent of adulthippocampal neurogenesis [224] Furthermore exposure tochronic stress significantly decreased hippocampal BDNFlevels neurogenesis and impaired spatial learning withoutaffecting plasma BDNF levels [224] Additionally a periodof 28 days of running was also shown to increase hip-pocampal neurogenesis and improve spatial learning withoutsignificantly changing plasma BDNF levels in rats [224]Thus the relationship between peripheral BDNF levels andhippocampal neurogenesis appears to be far from linear andchanges in peripheral levels of BDNF may only be detectedupon substantial changes in brain levels of this neurotrophin

In agreement with the findings from animal studies adissociation between central and peripheral BDNF levels hasalso been shown in the clinical setting Thus an increasein the brain levels of BDNF was detected in blood sam-ples from the internal jugular vein following 3 months ofendurance training in healthy subjects but no changes inperipheral BDNF levels were observed in these individuals[225] Indeed the responses of plasma or serum BDNFlevels to exercise vary considerably among studies with themajority reporting a transient increase in the plasmaserumlevels of this neurotrophin following acute exercise [226]Thetiming of blood collection after exercise may contribute tothese discrepancies as elevated BDNF levels seem to returnto baseline within 10ndash60 minutes after exercise and thendecrease to a level lower than baseline [226] In agreementothers have found that peripheral levels of BDNF significantlydrop below baseline 2 and 3 hours following acute exercise[227 228] while a significant decrease in resting serumlevels of BDNF was found in trained subjects [229 230]Additionally Lee and colleagues have recently reported a


significant reduction in resting serum levels of both BDNFand VEGF in adolescent athletes who showed improvedbrain function (specifically in the medial-temporal andfrontal areas) when compared to their age-matched controls[231]

622 Insulin-Like Growth Factor 1 IGF-1 is secreted primar-ily in the liver [232] and can enter into the brain via trans-port across the blood-brain and blood-cerebrospinal fluidbarriers [233] Transgenic overexpression of IGF-1 promotesneurogenesis and synaptogenesis in the hippocampus duringpostnatal development [234] Furthermore administration ofexogenous IGF-1 (after 6 and 20 days) increases the numberof hippocampal proliferative cells [178] Animal studies haveshown that physical exercise could stimulate the release ofIGF-1 from the liver and increase the brain uptake and levelsof IGF-1 in rodents [186] with a concomitant enhancement ofneurogenesis and cognitive function [183]

A positive correlation between serum levels of IGF-1 andcognitive function has also been demonstrated in several clin-ical studies [235ndash237] For example an increase in peripherallevels of IGF-1 following acute exercise training has beenshown in middle-aged men after two trials of 60min cyclingexercise [238] and in road cyclist athletes [239] Howeverthe exact relationship between changes in IGF-1 levels andhippocampal-dependent cognitive function following acutephysical interventions has not yet been elucidated In contrastto acute exercise sustained exercise training was shown tohave no effect [240] or even a negative effect [241] on IGF-1 levels in healthy subjects Decreased IGF-1 levels were alsofound in athletes [231] and subjects after 6 weeks of lowintensity cycling [242] Indeed the relationship between IGF-1 and sustained physical exercise is equivocal

623 Vascular Endothelial Growth Factor VEGF a 45 kDaheparin-binding homodimeric glycoprotein is secreted byskeletal muscle and could be released into the circulation[243] Acute exercise has been shown to increase levels ofVEGF in skeletal muscle [244 245] An animal study hasdemonstrated that expression of VEGF mRNA reaches thepeak levels immediately after exercise training and grad-ually declines within 2 hours and then returns to basallevels within 8 hr [246] In human muscle VEGF mRNAexpression has been shown to be elevated after 30min ofcessation of exercise [244] Interestingly circulating VEGFlevels were increased immediately after a marathon run in amoderate-altitude condition [247] but were decreased aftera marathon run in high-altitude condition [248] A differentstudy has also shown that plasma VEGF proteins levels weredecreased in the femoral vein following 3 hours of two-leggedkicking training though this training paradigm significantlyincreased VEGF mRNA levels in the skeletal muscle [249]Similarly plasma arterial VEGF is lower following exercisetraining for 10 levels following acute systemic exercise imme-diately and 2 hours after exercise in well-trained enduranceathletes but not in sedentary controlswith regards to the peakresponse obtained after exercise These results suggest thatperipheral levels of VEGF are differently affected in trained

and sedentary subjects following physical exercise at any timepoint [250] However they found a significant elevation inVEGF levels in both groups

Voss and colleagues have shown the first link betweenexercise-induced functional connectivity in the temporalcortex and changes in BDNF IGF-1 and VEGF in healthyelderlies [251] They reported that increased temporal lobeconnectivity between the bilateral parahippocampus andthe bilateral middle temporal gyrus was associated withincreased peripheral levels of BDNF IGF-1 and VEGF inelderlies following 7 weeks of aerobic aerobic walking Simi-larly Lee and colleagues reported a significant improvementof brain function specifically in the frontal and temporal brainregions in teens who regularly exercise when compared toage-matched controls [231] However this group observeda negative correlation between neurotrophic factors (BDNFand VEGF) and frontal and medial temporal lobe functionThese two studies indicate that the duration of the physicalintervention an the age of the individuals may affect howexercise modulate the levels of certain trophic factors

In conclusion the relationship between exercise-inducedchanges in peripheral and central levels of neurotrophicfactors has not yet been fully validated and as such it isstill not feasible to use peripheral levels of neurotrophinsas biomarkers for predicting changes in adult neurogenesisin human subjects Further investigations will be neededto discern the interactions between hippocampal neuroge-nesis and peripheral and central changes in the levels ofneurotrophic factors in animal models and humans both inbasal conditions and following different intervals of physicalexercise

7 Conclusion

Several animal studies have provided evidence for a func-tional role of adult hippocampal neurogenesis in specificforms of hippocampal-dependent learning and memoryThemultifactorial nature of adult neurogenesis implies that thiscomplex process can be compromised by a variety of diseaseconditions and mounting evidence from rodent modelsover the last two decades suggests that alterations in thenormal neurogenic capacity can either contribute to or bea consequence of a wide range of neurological disordersincluding AD PD and HD Despite some inconsistencies inthe literature there seems to be an overall trend towards adecrease in neurogenesis with neurodegeneration Howeverin some cases an upregulation of the endogenous neurogenicfunction has also been found which may reflect an intrinsicattempt of the brain to regenerate itself and replace the neu-rons that are lost during the degenerative process Further-more discrepancies between studies performed in animalmodels and postmortem human brains are also present inthe literature and may reflect differences in the amount ofprogenitor cell proliferation present in the diseased humanbrains and the respective rodent models [252]

Nevertheless the discovery that adult neurogenesis isaltered in these chronic neurodegenerative conditions sug-gests that some of the cognitive deficits associated with


these disorders could be caused at least in part by thesealterations and that therapies aimed at restoring or improvingthe endogenous neurogenic capacity might be of therapeuticvalue As such various studies have now used rodent modelsof these disorders to test the potential beneficial effects oftherapeutic strategies that are known to promote neuroge-nesis In particular physical activity is a noninvasive andrelatively inexpensive strategy that has repeatedly been shownto upregulate adult neurogenesis Numerous preclinical stud-ies have now demonstrated that these strategies have thepotential to mitigate several aspects of the neuropathologyand behavioural abnormalities (including cognitive decline)characteristic of various animal models of these disorderswhile also promoting neurogenesis Further clinical stud-ies are warranted to further elucidate the exact relation-ship between adult hippocampal neurogenesis and cognitivedecline in various neurodegenerative diseases within thehuman population The development and refinement of thecurrent in vivo imaging techniques for measurement of adultneurogenesis in the live human brain as well as the discoveryof peripheral biomarkers that can be used to determinechanges in hippocampal neurogenesis will certainly opennew avenues to not only answer these questions but also todiagnose and follow the progression of cognitive decline invarious neurodegenerative conditions as well as to measurethe effectiveness of treatments aimed at manipulating adulthippocampal neurogenesis The in vivo imaging techniquesare promising and applications of these methods in clinicalpopulations with neurodegenerative diseases merit futureresearch to validate their reliability in clinical settings Onthe other hand with emerging knowledge about the func-tional significance of hippocampal neurogenesis in patternseparation of learning andmemory formation neurogenesis-dependent cognitive tasks (eg visual pattern separation task[48]) would be an alternatemethod for studying alterations inhippocampal neurogenesis in clinical studies

To conclude although the exact links between physi-cal exercise increase adult hippocampal neurogenesis andimproved cognition are still unclear due to the currenttechnical limitations it is undisputable that exercise hasa positive impact in the brain both during ageing andneurodegenerative processes that are associated with poorcognitive function including dementia Therefore physicalexercise has now emerged as the most effective way to delaythe aged-related cognitive decline associated with variousneurodegenerative diseases Finally the development of newpharmacological cognitive enhancers that mimic the effectsof physical exercise on the brain may also emerge as anew teherapeutic strategy to prevent cognitive decline in theageing population

Abbreviations

A120573 Amyloid-120573AD Alzheimerrsquos diseaseAPO ApolipoproteinAPP Amyloid precursor proteinBDNF Brain-derived neurotrophic factorBrdU 5-Bromo-21015840-deoxyuridine

CA Cornus ammonisCAG Cytosine-adenine-guanineCBV Cerebral blood volumeDA DopamineDCX DoublecortinDG Dentate gyrusfMRI Functional magnetic resonance imagingGABA Gamma-aminobutyric acidGDNF Glial cell-derived neurotrophic factorGCL Granule cell layer1H-NMR Proton nuclear magnetic resonance

spectroscopyHD Huntingtonrsquos diseaseIGF-1 Insulin growth factor 1LTP Long-term potentiationMAP Microtubule-associated proteinMPTP 1-Methyl-4-phenyl-1236-

tetrahydropyridineMRI Magnetic resonance imagingNAA N-acetylaspartateNeuroD Neurogenic differentiation factorNFT Neurofibrillary tanglesNMDA N-methyl-D-aspartateOB Olfactory bulbPCNA Proliferating cell nuclear antigenPD Parkinsonrsquos diseasePS PresenilinPSA-NCAM Polysialylated nerve cell adhesion

moleculeRMS Rostral migratory streamSGZ Subgranular zoneSN Substantia nigraSSRI Serotonin reuptake inhibitorSVZ Subventricular zoneTH Tyrosine hydroxylaseTrkB Tyrosine receptor kinase BVEGF Vascular endothelial growth factorVTA Ventral tegmental areaYAC Yeast artificial chromosome6-OHDA 6-Hydroxydopamine

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

The authors thank Ms Alicia Meconi for helping with theconfocal image of GFP-labeled newborn neurons in thehippocampus Suk-yu Yau received a postdoctoral fellow-ship from the Research Centre of Heart Brain Hormoneand Healthy Ageing and the Small Project Funding fromThe University of Hong Kong Hong Kong Suk-yu Yauacknowledges the funding from Canadian Institute of HealthResearch in partnership with Fragile X Research Foundationof Canada Joana Gil-Mohapel acknowledges the fundingfrom the Ciencia Sem Fronteiras funding program (Science


Without Borders Brazil) Brian R Christie is a MichaelSmith Senior Scholar and is supported by grants fromthe Natural Sciences and Engineering Research Council ofCanada (NSERC) the Canadian Institutes ofHealth Research(CIHR) the Michael Smith Foundation for Health Research(MSFHR) and the Canada Foundation for Innovation (CFI)Kwok-fai So received funding from Jessie Ho Professorshipin Neuroscience (The University of Hong Kong Foundationfor Educational Development and Research Limited) theFundamental Research Funds for the Central Universities(Grant 21609101)

References

[1] J Altman ldquoAre new neurons formed in the brains of adultmammalsrdquo Science vol 135 no 3509 pp 1127ndash1128 1962

[2] J Altman and G D Das ldquoAutoradiographic and histologicalevidence of postnatal hippocampal neurogenesis in ratsrdquo Jour-nal of Comparative Neurology vol 124 no 3 pp 319ndash335 1965

[3] M S Kaplan and J W Hinds ldquoNeurogenesis in the adult ratelectronmicroscopic analysis of light radioautographsrdquo Sciencevol 197 no 4308 pp 1092ndash1094 1977

[4] H A Cameron C S Woolley B S McEwen and E GouldldquoDifferentiation of newly born neurons and glia in the dentategyrus of the adult ratrdquo Neuroscience vol 56 no 2 pp 337ndash3441993

[5] P S Eriksson E Perfilieva T Bjork-Eriksson et al ldquoNeurogen-esis in the adult human hippocampusrdquo Nature Medicine vol 4no 11 pp 1313ndash1317 1998

[6] E Gould A Beylin P Tanapat A Reeves and T J ShorsldquoLearning enhances adult neurogenesis in the hippocampalformationrdquoNature Neuroscience vol 2 no 3 pp 260ndash265 1999

[7] T J Shors G Miesegaes A Beylin M Zhao T Rydel and EGould ldquoNeurogenesis in the adult is involved in the formationof tracememoriesrdquoNature vol 410 no 6826 pp 372ndash376 2001

[8] G Winocur J M Wojtowicz M Sekeres J S Snyderand S Wang ldquoInhibition of neurogenesis interferes withhippocampus-dependentmemory functionrdquoHippocampus vol16 no 3 pp 296ndash304 2006

[9] N Kee C M Teixeira A H Wang and P W FranklandldquoPreferential incorporation of adult-generated granule cellsinto spatial memory networks in the dentate gyrusrdquo NatureNeuroscience vol 10 no 3 pp 355ndash362 2007

[10] S Jessberger R E Clark N J Broadbent et al ldquoDentategyrus-specific knockdown of adult neurogenesis impairs spatialand object recognition memory in adult ratsrdquo Learning andMemory vol 16 no 2 pp 147ndash154 2009

[11] E Bruel-Jungerman C Rampon and S Laroche ldquoAdult hip-pocampal neurogenesis synaptic plasticity and memory factsand hypothesesrdquo Reviews in the Neurosciences vol 18 no 2 pp93ndash114 2007

[12] D C Lie H Song S A Colamarino G-L Ming and F HGage ldquoNeurogenesis in the adult brain new strategies for cen-tral nervous system diseasesrdquo Annual Review of Pharmacologyand Toxicology vol 44 pp 399ndash421 2004

[13] G Kempermann LWiskott and FHGage ldquoFunctional signif-icance of adult neurogenesisrdquo Current Opinion in Neurobiologyvol 14 no 2 pp 186ndash191 2004

[14] N Toni EM Teng E A Bushong et al ldquoSynapse formation onneurons born in the adult hippocampusrdquo Nature Neurosciencevol 10 no 6 pp 727ndash734 2007

[15] H A Cameron and R DMcKay ldquoAdult neurogenesis producesa large pool of new granule cells in the dentate gyrusrdquo Journalof Comparative Neurology vol 435 no 4 pp 406ndash417 2001

[16] C B Johansson M Svensson L Wallstedt A M Jansonand J Frisen ldquoNeural stem cells in the adult human brainrdquoExperimental Cell Research vol 253 no 2 pp 733ndash736 1999

[17] V G Kukekov E D Laywell O Suslov et al ldquoMultipotentstemprogenitor cells with similar properties arise from neuro-genic regions of adult human brainrdquo Experimental Neurologyvol 156 no 2 pp 333ndash344 1999

[18] N S Roy S Wang L Jiang et al ldquoIn vitro neurogenesis byprogenitor cells isolated from the adult human hippocampusrdquoNature Medicine vol 6 no 3 pp 271ndash277 2000

[19] S F Pagano F Impagnatiello M Girelli et al ldquoIsolation andcharacterization of neural stem cells from the adult humanolfactory bulbrdquo Stem Cells vol 18 no 4 pp 295ndash300 2000

[20] K L Spalding O Bergmann K Alkass et al ldquoDynamics ofhippocampal neurogenesis in adult humansrdquo Cell vol 153 no6 pp 1219ndash1227 2013

[21] J Ninkovic T Mori and M Gotz ldquoDistinct modes of neuronaddition in adult mouse neurogenesisrdquo The Journal of Neuro-science vol 27 no 40 pp 10906ndash10911 2007

[22] I Imayoshi M Sakamoto T Ohtsuka and R KageyamaldquoContinuous neurogenesis in the adult brainrdquo DevelopmentGrowth and Differentiation vol 51 no 3 pp 379ndash386 2009

[23] R Knoth I Singec M Ditter et al ldquoMurine features ofneurogenesis in the human hippocampus across the lifespanfrom 0 to 100 yearsrdquo PLoS ONE vol 5 no 1 Article ID e88092010

[24] M S Rao B Hattiangady and A K Shetty ldquoThe window andmechanisms of major age-related decline in the production ofnew neurons within the dentate gyrus of the hippocampusrdquoAging Cell vol 5 no 6 pp 545ndash558 2006

[25] H G Kuhn H Dickinson-Anson and F H Gage ldquoNeurogen-esis in the dentate gyrus of the adult rat age-related decrease ofneuronal progenitor proliferationrdquoThe Journal of Neurosciencevol 16 no 6 pp 2027ndash2033 1996

[26] G Kempermann H G Kuhn and F H Gage ldquoExperience-induced neurogenesis in the senescent dentate gyrusrdquo TheJournal of Neuroscience vol 18 no 9 pp 3206ndash3212 1998

[27] N M Ben Abdallah L Slomianka A L Vyssotski andH-P Lipp ldquoEarly age-related changes in adult hippocampalneurogenesis in C57 micerdquo Neurobiology of Aging vol 31 no1 pp 151ndash161 2010

[28] J Gil-Mohapel P S Brocardo W Choquette R Gothard J MSimpson and B R Christie ldquoHippocampal neurogenesis levelspredict WATERMAZE search strategies in the aging brainrdquoPLoS ONE vol 8 no 9 Article ID e75125 2013

[29] L R Squire ldquoMemory and the hippocampus a synthesis fromfindingswith ratsmonkeys andhumansrdquoPsychological Reviewvol 99 no 2 pp 195ndash231 1992

[30] N Burgess ldquoThe hippocampus space and view points inepisodic memoryrdquo Quarterly Journal of Experimental Psychol-ogy A vol 55 no 4 pp 1057ndash1080 2002

[31] V D Bohbot and S Corkin ldquoPosterior parahippocampal placelearning in HMrdquoHippocampus vol 17 no 9 pp 863ndash872 2007

[32] L E James and D G MacKay ldquoHM word knowledgeand aging support for a new theory of long-term retrogradeamnesiardquo Psychological Science vol 12 no 6 pp 485ndash492 2001

[33] R G M Morris ldquoSpatial localization does not require thepresence of local cuesrdquo Learning and Motivation vol 12 no 2pp 239ndash260 1981


[34] H Eichenbaum C Stewart and R G Morris ldquoHippocampalrepresentation in place learningrdquo The Journal of Neurosciencevol 10 no 11 pp 3531ndash3542 1990

[35] J M Lassalle T Bataille andHHalley ldquoReversible inactivationof the hippocampalmossy fiber synapses inmice impairs spatiallearning but neither consolidation normemory retrieval in theMorris navigation taskrdquoNeurobiology of Learning and Memoryvol 73 no 3 pp 243ndash257 2000

[36] G F Xavier and V C Costa ldquoDentate gyrus and spatialbehaviourrdquo Progress in Neuro-Psychopharmacology and Biologi-cal Psychiatry vol 33 no 5 pp 762ndash773 2009

[37] J S Snyder N Kee and J M Wojtowicz ldquoEffects of adultneurogenesis on synaptic plasticity in the rat dentate gyrusrdquoJournal of Neurophysiology vol 85 no 6 pp 2423ndash2431 2001

[38] M D Saxe F Battaglia J W Wang et al ldquoAblation of hip-pocampal neurogenesis impairs contextual fear conditioningand synaptic plasticity in the dentate gyrusrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 103 no 46 pp 17501ndash17506 2006

[39] C D ClellandM Choi C Romberg et al ldquoA functional role foradult hippocampal neurogenesis in spatial pattern separationrdquoScience vol 325 no 5937 pp 210ndash213 2009

[40] T Nakashiba J D Cushman K A Pelkey et al ldquoYoung dentategranule cells mediate pattern separation whereas old granulecells facilitate pattern completionrdquo Cell vol 149 no 1 pp 188ndash201 2012

[41] A Sahay D A Wilson and R Hen ldquoPattern separationa common function for new neurons in hippocampus andolfactory bulbrdquo Neuron vol 70 no 4 pp 582ndash588 2011

[42] H van Praag G Kempermann and F H Gage ldquoRunningincreases cell proliferation and neurogenesis in the adult mousedentate gyrusrdquo Nature Neuroscience vol 2 no 3 pp 266ndash2701999

[43] H van Praag B R Christie T J Sejnowski and F H GageldquoRunning enhances neurogenesis learning and long-termpotentiation in micerdquo Proceedings of the National Academy ofSciences of the United States of America vol 96 no 23 pp13427ndash13431 1999

[44] V Lemaire M Koehl M Le Moal and D N Abrous ldquoPrenatalstress produces learning deficits associated with an inhibition ofneurogenesis in the hippocampusrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 97 no20 pp 11032ndash11037 2000

[45] B Leuner S Mendolia-Loffredo Y Kozorovitskiy D SamburgE Gould and T J Shors ldquoLearning enhances the survivalof new neurons beyond the time when the hippocampus isrequired for memoryrdquo The Journal of Neuroscience vol 24 no34 pp 7477ndash7481 2004

[46] TMMadsen P E Kristjansen T G Bolwig and GWortweinldquoArrested neuronal proliferation and impaired hippocampalfunction following fractionated brain irradiation in the adultratrdquo Neuroscience vol 119 no 3 pp 635ndash642 2003

[47] A C Pereira D E Huddleston A M Brickman et al ldquoAnin vivo correlate of exercise-induced neurogenesis in the adultdentate gyrusrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 104 no 13 pp 5638ndash56432007

[48] N Dery M Pilgrim M Gibala et al ldquoAdult hippocampalneurogenesis reduces memory interference in humans oppos-ing effects of aerobic exercise and depressionrdquo Frontiers inNeuroscience vol 7 article 66 2013

[49] AThompsonK BoekhoornAM vanDam andP J LucassenldquoChanges in adult neurogenesis in neurodegenerative diseasescause or consequencerdquo Genes Brain and Behavior vol 7supplement 1 pp 28ndash42 2008

[50] P Brocardo A Patten and J Gil-Mohapel ldquoAltered adultneurogenesis in neurodegenerative diseaserdquo in NeurogenesisResearch NewDevelopments pp 1ndash54 Nova Science NewYorkNY USA 2012

[51] C H Hillman K I Erickson and A F Kramer ldquoBe smartexercise your heart exercise effects on brain and cognitionrdquoNature Reviews Neuroscience vol 9 no 1 pp 58ndash65 2008

[52] M Hamer and Y Chida ldquoPhysical activity and risk of neurode-generative disease a systematic review of prospective evidencerdquoPsychological Medicine vol 39 no 1 pp 3ndash11 2009

[53] J E Ahlskog Y E Geda N R Graff-Radford and RC Petersen ldquoPhysical exercise as a preventive or disease-modifying treatment of dementia and brain agingrdquoMayo ClinicProceedings vol 86 no 9 pp 876ndash884 2011

[54] S Y Yau B W Lau J B Tong et al ldquoHippocampal neurogen-esis and dendritic plasticity support running-improved spatiallearning and depression-like behaviour in stressed ratsrdquo PLoSONE vol 6 no 9 Article ID e24263 2011

[55] H van Praag T Shubert C Zhao and F H Gage ldquoExerciseenhances learning and hippocampal neurogenesis in agedmicerdquo The Journal of Neuroscience vol 25 no 38 pp 8680ndash8685 2005

[56] W Deng J B Aimone and F H Gage ldquoNew neurons and newmemories how does adult hippocampal neurogenesis affectlearning and memoryrdquo Nature Reviews Neuroscience vol 11no 5 pp 339ndash350 2010

[57] L Santarelli M Saxe C Gross et al ldquoRequirement of hip-pocampal neurogenesis for the behavioral effects of antidepres-santsrdquo Science vol 301 no 5634 pp 805ndash809 2003

[58] C Ernst A K Olson J P Pinel R W Lam and B RChristie ldquoAntidepressant effects of exercise evidence for anadult-neurogenesis hypothesisrdquo Journal of Psychiatry and Neu-roscience vol 31 no 2 pp 84ndash92 2006

[59] S Y Yau B W Lau and K F So ldquoAdult hippocampalneurogenesis a possible way how physical exercise counteractsstressrdquo Cell Transplantation vol 20 no 1 pp 99ndash111 2011

[60] F Lazarini and P M Lledo ldquoIs adult neurogenesis essential forolfactionrdquo Trends in Neurosciences vol 34 no 1 pp 20ndash302011

[61] F Boccalandro A Muench J Salloum et al ldquoInteratrial defectsizing by intracardiac and transesophageal echocardiographycompared with fluoroscopic measurements in patients under-going percutaneous transcatheter closurerdquo Catheterization andCardiovascular Interventions vol 62 no 3 pp 415ndash420 2004

[62] F E Barton Jr R Ha and M Awada ldquoFat extrusion and septalreset in patients with the tear trough triad a critical appraisalrdquoPlastic and Reconstructive Surgery vol 113 no 7 pp 2115ndash21132004

[63] C Schmidt-Hieber P Jonas and J Bischofberger ldquoEnhancedsynaptic plasticity in newly generated granule cells of the adulthippocampusrdquo Nature vol 429 no 6988 pp 184ndash187 2004

[64] E Bruel-Jungerman S Davis C Rampon and S LarocheldquoLong-term potentiation enhances neurogenesis in the adultdentate gyrusrdquo The Journal of Neuroscience vol 26 no 22 pp5888ndash5893 2006

[65] A Sahay K N Scobie A S Hill et al ldquoIncreasing adulthippocampal neurogenesis is sufficient to improve patternseparationrdquo Nature vol 472 no 7344 pp 466ndash470 2011


[66] D J Creer C Romberg L M Saksida H Van Praag and T JBussey ldquoRunning enhances spatial pattern separation in micerdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 107 no 5 pp 2367ndash2372 2010

[67] A Garthe J Behr and G Kempermann ldquoAdult-generatedhippocampal neurons allow the flexible use of spatially preciselearning strategiesrdquo PLoS ONE vol 4 no 5 Article ID e54642009

[68] S Tronel L Belnoue N Grosjean et al ldquoAdult-born neuronsare necessary for extended contextual discriminationrdquo Hip-pocampus vol 22 no 2 pp 292ndash298 2012

[69] M Koehl and D N Abrous ldquoA new chapter in the field ofmemory adult hippocampal neurogenesisrdquo European Journalof Neuroscience vol 33 no 6 pp 1101ndash1114 2011

[70] BWinner Z Kohl and F H Gage ldquoNeurodegenerative diseaseand adult neurogenesisrdquo European Journal of Neuroscience vol33 no 6 pp 1139ndash1151 2011

[71] J Hardy and D J Selkoe ldquoThe amyloid hypothesis ofAlzheimerrsquos disease progress and problems on the road totherapeuticsrdquo Science vol 297 no 5580 pp 353ndash356 2002

[72] E H Corder A M Saunders W J Strittmatter et al ldquoGenedose of apolipoprotein E type 4 allele and the risk of Alzheimerrsquosdisease in late onset familiesrdquo Science vol 261 no 5123 pp 921ndash923 1993

[73] C K Chai ldquoThe genetics of Alzheimerrsquos diseaserdquo AmericanJournal of Alzheimerrsquos Disease and other Dementias vol 22 no1 pp 37ndash41 2007

[74] M Bentahir O Nyabi J Verhamme et al ldquoPresenilin clinicalmutations can affect 120574-secretase activity by different mecha-nismsrdquo Journal of Neurochemistry vol 96 no 3 pp 732ndash7422006

[75] K H Ashe ldquoLearning and memory in transgenic mice model-ing Alzheimerrsquos diseaserdquo Learning andMemory vol 8 no 6 pp301ndash308 2001

[76] Y Mu and F H Gage ldquoAdult hippocampal neurogenesis and itsrole in Alzheimerrsquos diseaserdquo Molecular Neurodegeneration vol6 article 85 2011

[77] J Gil-Mohapel J Simpson and B R Christie ldquoModulationof adult neurogenesis by physical exercise and environmentalenrichment insights for the treatment of neurological dis-ordersrdquo in Adult Neurogenesis and CNS Diseases pp 125ndash150 Research Signpost Transworld Research Network KeralaIndia 2009

[78] N J Haughey A Nath S L Chan A C Borchard M S Raoand M P Mattson ldquoDisruption of neurogenesis by amyloid 120573-peptide and perturbed neural progenitor cell homeostasis inmodels of Alzheimerrsquos diseaserdquo Journal of Neurochemistry vol83 no 6 pp 1509ndash1524 2002

[79] H Dong B GoicoMMartin C A Csernansky A Bertchumeand J G Csernansky ldquoModulation of hippocampal cell pro-liferation memory and amyloid plaque deposition in APPsw(Tg2576)mutantmice by isolation stressrdquoNeuroscience vol 127no 3 pp 601ndash609 2004

[80] L Verret J L Jankowsky GM Xu D R Borchelt and C Ram-pon ldquoAlzheimerrsquos-type amyloidosis in transgenic mice impairssurvival of newborn neurons derived from adult hippocampalneurogenesisrdquo The Journal of Neuroscience vol 27 no 25 pp6771ndash6780 2007

[81] C Zhang E McNeil L Dressler and R Siman ldquoLong-lasting impairment in hippocampal neurogenesis associatedwith amyloid deposition in a knock-in mouse model of familial

Alzheimerrsquos diseaserdquoExperimental Neurology vol 204 no 1 pp77ndash87 2007

[82] M H Donovan U Yazdani R D Norris D Games D CGerman and A J Eisch ldquoDecreased adult hippocampal neu-rogenesis in the PDAPP mouse model of Alzheimerrsquos diseaserdquoJournal of Comparative Neurology vol 495 no 1 pp 70ndash832006

[83] P H Wen P R Hof X Chen et al ldquoThe presenilin-1 familialAlzheimer disease mutant P117L impairs neurogenesis in thehippocampus of adult micerdquo Experimental Neurology vol 188no 2 pp 224ndash237 2004

[84] N L Chevallier S Soriano D E Kang E Masliah G Hu andE H Koo ldquoPerturbed neurogenesis in the adult hippocampusassociated with presenilin-1 A246E mutationrdquo The AmericanJournal of Pathology vol 167 no 1 pp 151ndash159 2005

[85] J J Rodrıguez V C Jones M Tabuchi et al ldquoImpaired adultneurogenesis in the dentate gyrus of a triple transgenic mousemodel of Alzheimerrsquos diseaserdquo PLoS ONE vol 3 no 8 ArticleID e2935 2008

[86] K Jin V Galvan L Xie et al ldquoEnhanced neurogenesis inAlzheimerrsquos disease transgenic (PDGF-APPSwInd) micerdquo Pro-ceedings of the National Academy of Sciences of the United Statesof America vol 101 no 36 pp 13363ndash13367 2004

[87] MA Lopez-Toledano andM L Shelanski ldquoIncreased neuroge-nesis in young transgenic mice overexpressing human APP(SwInd)rdquo Journal of Alzheimerrsquos Disease vol 12 no 3 pp 229ndash2402007

[88] R Kolecki G LaFauci R Rubenstein B Mazur-Kolecka WKaczmarski and J Frackowiak ldquoThe effect of amyloidosis-120573 and ageing on proliferation of neuronal progenitor cellsin APP-transgenic mouse hippocampus and in culturerdquo ActaNeuropathologica vol 116 no 4 pp 419ndash424 2008

[89] K Jin A L Peel X O Mao et al ldquoIncreased hippocampal neu-rogenesis in Alzheimerrsquos diseaserdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 101 no1 pp 343ndash347 2004

[90] B Li H Yamamori Y Tatebayashi et al ldquoFailure of neuronalmaturation in Alzheimer disease dentate gyrusrdquo Journal ofNeuropathologyampExperimental Neurology vol 67 no 1 pp 78ndash84 2008

[91] J D Buxbaum G Thinakaran V Koliatsos et al ldquoAlzheimeramyloid protein precursor in the rat hippocampus transportand processing through the perforant pathrdquo The Journal ofNeuroscience vol 18 no 23 pp 9629ndash9637 1998

[92] J MorysM Sadowski M Barcikowska BMaciejewska andONarkiewicz ldquoThe second layer neurones of the entorhinal cortexand the perforant path in physiological ageing and Alzheimerrsquosdiseaserdquo Acta Neurobiologiae Experimentalis vol 54 no 1 pp47ndash53 1994

[93] A Gadadhar R Marr and O Lazarov ldquoPresenilin-1 regulatesneural progenitor cell differentiation in the adult brainrdquo TheJournal of Neuroscience vol 31 no 7 pp 2615ndash2623 2011

[94] M P Demars C Hollands T Zhao Kda and O LazarovldquoSoluble amyloid precursor protein-alpha rescues age-linkeddecline in neural progenitor cell proliferationrdquoNeurobiol Agingvol 34 no 10 pp 2431ndash2440 2013

[95] E Tolosa andW Poewe ldquoPremotor Parkinson diseaserdquo Neurol-ogy vol 72 no 7 supplement 2 S1 2009

[96] J S Reijnders U Ehrt W E Weber D Aarsland and A FG Leentjens ldquoA systematic review of prevalence studies ofdepression in Parkinsonrsquos diseaserdquoMovement Disorders vol 23no 2 pp 183ndash189 313 2008


[97] H Braak K Del Tredici U Rub R A I de Vos E N HJansen Steur and E Braak ldquoStaging of brain pathology relatedto sporadic Parkinsonrsquos diseaserdquo Neurobiology of Aging vol 24no 2 pp 197ndash211 2003

[98] A Gasbarri A Sulli and M G Packard ldquoThe dopaminergicmesencephalic projections to the hippocampal formation inthe ratrdquo Progress in Neuro-Psychopharmacology and BiologicalPsychiatry vol 21 no 1 pp 1ndash22 1997

[99] B Scatton H Simon M Le Moal and S Bischoff ldquoOrigin ofdopaminergic innervation of the rat hippocampal formationrdquoNeuroscience Letters vol 18 no 2 pp 125ndash131 1980

[100] C Verney M Baulac B Berger C Alvarez A Vigny and KB Helle ldquoMorphological evidence for a dopaminergic terminalfield in the hippocampal formation of young and adult ratrdquoNeuroscience vol 14 no 4 pp 1039ndash1052 1985

[101] T Ziemssen and H Reichmann ldquoNon-motor dysfunction inParkinsonrsquos diseaserdquo Parkinsonism amp Related Disorders vol 13no 6 pp 323ndash332 2007

[102] A Haehner S Boesveldt H W Berendse et al ldquoPrevalenceof smell loss in Parkinsonrsquos diseasemdasha multicenter studyrdquoParkinsonism amp Related Disorders vol 15 no 7 pp 490ndash4942009

[103] G LMing andH Song ldquoAdult neurogenesis in themammaliancentral nervous systemrdquoAnnual Review of Neuroscience vol 28pp 223ndash250 2005

[104] Z Zhao W D Taylor M Styner D C Steffens K R RKrishnan and J R MacFall ldquoHippocampus shape analysis andlate-life depressionrdquo PLoS ONE vol 3 no 3 Article ID e18372008

[105] H L Melrose S J Lincoln G M Tyndall and M J FarrerldquoParkinsonrsquos disease a rethink of rodent modelsrdquo ExperimentalBrain Research vol 173 no 2 pp 196ndash204 2006

[106] J H Park and G Enikolopov ldquoTransient elevation of adulthippocampal neurogenesis after dopamine depletionrdquo Experi-mental Neurology vol 222 no 2 pp 267ndash276 2010

[107] J Peng L Xie K Jin D A Greenberg and J K AndersenldquoFibroblast growth factor 2 enhances striatal and nigralneurogenesis in the acute 1-methyl-4-phenyl-1236-tetrahydropyridine model of Parkinsonrsquos diseaserdquoNeurosciencevol 153 no 3 pp 664ndash670 2008

[108] G U Hoglinger P Rizk M P Muriel et al ldquoDopaminedepletion impairs precursor cell proliferation in Parkinsondiseaserdquo Nature Neuroscience vol 7 no 7 pp 726ndash735 2004

[109] M G Baker and L Graham ldquoThe journey Parkinsonrsquos diseaserdquoBritish Medical Journal vol 329 no 7466 pp 611ndash614 2004

[110] B Winner D C Lie E Rockenstein et al ldquoHuman wild-type120572-synuclein impairs neurogenesisrdquo Journal ofNeuropathologyampExperimental Neurology vol 63 no 11 pp 1155ndash1166 2004

[111] L Crews H Mizuno P Desplats et al ldquo120572-synuclein altersNotch-1 expression and neurogenesis inmouse embryonic stemcells and in the hippocampus of transgenic micerdquoThe Journal ofNeuroscience vol 28 no 16 pp 4250ndash4260 2008

[112] S Nuber E Petrasch-Parwez B Winner et al ldquoNeurode-generation and motor dysfunction in a conditional model ofParkinsonrsquos diseaserdquoThe Journal of Neuroscience vol 28 no 10pp 2471ndash2484 2008

[113] M E MacDonald C M Ambrose M P Duyao et al ldquoA novelgene containing a trinucleotide repeat that is expanded andunstableon Huntingtonrsquos disease chromosomesrdquo Cell vol 72no 6 pp 971ndash983 1993

[114] J M Gil and A C Rego ldquoMechanisms of neurodegeneration inHuntingtonrsquos diseaserdquo European Journal of Neuroscience vol 27no 11 pp 2803ndash2820 2008

[115] S E Folstein M H Abbott and G A Chase ldquoThe associationof affective disorder with Huntingtonrsquos disease in a case seriesand in familiesrdquo Psychological Medicine vol 13 no 3 pp 537ndash542 1983

[116] S E Folstein and M F Folstein ldquoPsychiatric features of Hunt-ingtonrsquos disease recent approaches and findingsrdquo PsychiatricDevelopments vol 1 no 2 pp 193ndash205 1983

[117] S Pflanz J A Besson K P Ebmeier and S Simpson ldquoThe clin-ical manifestation of mental disorder in Huntingtonrsquos diseasea retrospective case record study of disease progressionrdquo ActaPsychiatrica Scandinavica vol 83 no 1 pp 53ndash60 1991

[118] S C Kirkwood J L Su P M Conneally and T ForoudldquoProgression of symptoms in the early and middle stages ofHuntington diseaserdquo Archives of Neurology vol 58 no 2 pp273ndash278 2001

[119] J R Slaughter M P Martens and K A Slaughter ldquoDepressionand Huntingtonrsquos disease prevalence clinical manifestationsetiology and treatmentrdquo CNS Spectrums vol 6 no 4 pp 306ndash326 2001

[120] K Duff J S Paulsen L J Beglinger D R Langbehn and JC Stout ldquoPsychiatric symptoms in Huntingtonrsquos disease beforediagnosis the predict-HD studyrdquo Biological Psychiatry vol 62no 12 pp 1341ndash1346 2007

[121] J P Vonsattel and M DiFiglia ldquoHuntington diseaserdquo Journalof Neuropathology amp Experimental Neurology vol 57 no 5 pp369ndash384 1998

[122] E Spargo I P Everall and P L Lantos ldquoNeuronal loss in thehippocampus in Huntingtonrsquos disease a comparison with HIVinfectionrdquo Journal of Neurology Neurosurgery and Psychiatryvol 56 no 5 pp 487ndash491 1993

[123] H D Rosas W J Koroshetz Y I Chen et al ldquoEvidence formorewidespread cerebral pathology in earlyHD anMRI-basedmorphometric analysisrdquo Neurology vol 60 no 10 pp 1615ndash1620 2003

[124] L B Menalled andM F Chesselet ldquoMouse models of Hunting-tonrsquos diseaserdquo Trends in Pharmacological Sciences vol 23 no 1pp 32ndash39 2002

[125] M A Hickey G P Reynolds and A J Morton ldquoThe role ofdopamine in motor symptoms in the R62 transgenic mousemodel of Huntingtonrsquos diseaserdquo Journal of Neurochemistry vol81 no 1 pp 46ndash59 2002

[126] M S Levine C Cepeda M A Hickey S M Fleming andM-F Chesselet ldquoGenetic mouse models of Huntingtonrsquos andParkinsonrsquos diseases illuminating but imperfectrdquo Trends inNeurosciences vol 27 no 11 pp 691ndash697 2004

[127] J Gil-Mohapel J M Simpson M Ghilan and B R ChristieldquoNeurogenesis in Huntingtonrsquos disease can studying adultneurogenesis lead to the development of new therapeuticstrategiesrdquo Brain Research vol 1406 pp 84ndash105 2011

[128] S E Lazic H Grote R J E Armstrong et al ldquoDecreasedhippocampal cell proliferation in R6I Huntingtonrsquos micerdquoNeuroReport vol 15 no 5 pp 811ndash813 2004

[129] S E Lazic H E Grote C Blakemore et al ldquoNeurogenesis in theR61 transgenic mouse model of Huntingtonrsquos disease effects ofenvironmental enrichmentrdquo European Journal of Neurosciencevol 23 no 7 pp 1829ndash1838 2006

[130] J Gil M Leist N Popovic P Brundin and A Petersen ldquoAsialo-erythropoetin is not effective in the R62 line of Huntingtonrsquosdisease micerdquo BMC Neuroscience vol 5 article 17 2004


[131] J M Gil P Mohapel I M Araujo et al ldquoReduced hippocampalneurogenesis in R62 transgenic Huntingtonrsquos disease micerdquoNeurobiology of Disease vol 20 no 3 pp 744ndash751 2005

[132] Z Kohl M Kandasamy B Winner et al ldquoPhysical activity failsto rescue hippocampal neurogenesis deficits in the R62 mousemodel ofHuntingtonrsquos diseaserdquoBrain Research vol 1155 pp 24ndash33 2007

[133] L Mangiarini K Sathasivam M Seller et al ldquoExon I of theHD gene with an expanded CAG repeat is sufficient to causea progressive neurological phenotype in transgenic micerdquo Cellvol 87 no 3 pp 493ndash506 1996

[134] K P Murphy R J Carter L A Lione et al ldquoAbnormal synapticplasticity and impaired spatial cognition in mice transgenic forexon 1 of the humanHuntingtonrsquos diseasemutationrdquoTheJournalof Neuroscience vol 20 no 13 pp 5115ndash5123 2000

[135] J Nithianantharajah C Barkus M Murphy and A J Han-nan ldquoGene-environment interactions modulating cognitivefunction and molecular correlates of synaptic plasticity inHuntingtonrsquos disease transgenic micerdquo Neurobiology of Diseasevol 29 no 3 pp 490ndash504 2008

[136] J M Simpson J Gil-Mohapel M A Pouladi et al ldquoAlteredadult hippocampal neurogenesis in the YAC128 transgenicmouse model of Huntington diseaserdquo Neurobiology of Diseasevol 41 no 2 pp 249ndash260 2011

[137] E J Slow J van Raamsdonk D Rogers et al ldquoSelective striatalneuronal loss in a YAC128mousemodel ofHuntington diseaserdquoHuman Molecular Genetics vol 12 no 13 pp 1555ndash1567 2003

[138] J M Gil-Mohapel ldquoScreening of therapeutic strategies forHuntingtonrsquos disease in YAC128 transgenic micerdquo CNS Neuro-science andTherapeutics vol 18 no 1 pp 77ndash86 2012

[139] MA Pouladi R KGraham JMKarasinska et al ldquoPreventionof depressive behaviour in the YAC128 mouse model of Hunt-ington disease by mutation at residue 586 of huntingtinrdquo Brainvol 132 part 4 pp 919ndash932 2009

[140] J M van Raamsdonk J Pearson E J Slow S M Hossain BR Leavitt and M R Hayden ldquoCognitive dysfunction precedesneuropathology andmotor abnormalities in the YAC128mousemodel of Huntingtonrsquos diseaserdquoThe Journal of Neuroscience vol25 no 16 pp 4169ndash4180 2005

[141] M Kandasamy S Couillard-Despres K A Raber et al ldquoStemcell quiescence in the hippocampal neurogenic niche is associ-ated with elevated transforming growth factor-120573 signaling in ananimalmodel of huntington diseaserdquo Journal of Neuropathologyamp Experimental Neurology vol 69 no 7 pp 717ndash728 2010

[142] S von Horsten I Schmitt H P Nguyen et al ldquoTransgenic ratmodel of Huntingtonrsquos diseaserdquoHumanMolecular Genetics vol12 no 6 pp 617ndash624 2003

[143] S Orvoen P Pla A M Gardier F Saudou and D JDavid ldquoHuntingtonrsquos disease knock-in male mice show specificanxiety-like behaviour and altered neuronal maturationrdquo Neu-roscience Letters vol 507 no 2 pp 127ndash132 2012

[144] E Marcora K Gowan and J E Lee ldquoStimulation of NeuroDactivity by huntingtin and huntingtin-associated proteinsHAP1and MLK2rdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 100 no 16 pp 9578ndash95832003

[145] I Ferrer E Goutan C Marın M J Rey and T RibaltaldquoBrain-derived neurotrophic factor in Huntington diseaserdquoBrain Research vol 866 no 1-2 pp 257ndash261 2000

[146] C Zuccato M Tartari A Crotti et al ldquoHuntingtin interactswith RESTNRSF to modulate the transcription of NRSE-controlled neuronal genesrdquo Nature Genetics vol 35 no 1 pp76ndash83 2003

[147] J M Canals J R Pineda J F Torres-Peraza et al ldquoBrain-derived neurotrophic factor regulates the onset and severity ofmotor dysfunction associated with enkephalinergic neuronaldegeneration in Huntingtonrsquos diseaserdquo The Journal of Neuro-science vol 24 no 35 pp 7727ndash7739 2004

[148] L R Gauthier B C Charrin M Borrell-Pages et al ldquoHunt-ingtin controls neurotrophic support and survival of neurons byenhancing BDNF vesicular transport along microtubulesrdquo Cellvol 118 no 1 pp 127ndash138 2004

[149] T L Spires H E Grote N K Varshney et al ldquoEnvironmentalenrichment rescues protein deficits in a mouse model ofHuntingtonrsquos disease indicating a possible disease mechanismrdquoThe Journal of Neuroscience vol 24 no 9 pp 2270ndash2276 2004

[150] A Ciammola J SassoneM Cannella et al ldquoLow brain-derivedneurotrophic factor (BDNF) levels in serum of Huntingtonrsquosdisease patientsrdquo American Journal of Medical Genetics B vol144 no 4 pp 574ndash577 2007

[151] M S Zajac T Y Pang N Wong et al ldquoWheel running andenvironmental enrichment differentially modify exon-specificBDNF expression in the hippocampus of wild-type and pre-motor symptomatic male and female Huntingtonrsquos diseasemicerdquo Hippocampus vol 20 no 5 pp 621ndash636 2010

[152] K Ben MrsquoBarek P Pla S Orvoen et al ldquoHuntingtin mediatesanxietydepression-related behaviors and hippocampal neuro-genesisrdquo The Journal of Neuroscience vol 33 no 20 pp 8608ndash8620 2013

[153] A Petersen Z Puschban J Lotharius et al ldquoEvidence fordysfunction of the nigrostriatal pathway in the R61 line oftransgenic Huntingtonrsquos disease micerdquo Neurobiology of Diseasevol 11 no 1 pp 134ndash146 2002

[154] G P Reynolds C F Dalton C L Tillery L Mangiarini S WDavies and G P Bates ldquoBrain neurotransmitter deficits inmicetransgenic for the Huntingtonrsquos disease mutationrdquo Journal ofNeurochemistry vol 72 no 4 pp 1773ndash1776 1999

[155] H E Grote ND BullM LHoward et al ldquoCognitive disordersand neurogenesis deficits in Huntingtonrsquos disease mice arerescued by fluoxetinerdquo European Journal of Neuroscience vol22 no 8 pp 2081ndash2088 2005

[156] W Duan Q Peng N Masuda et al ldquoSertraline slows diseaseprogression and increases neurogenesis in N171-82Q mousemodel of Huntingtonrsquos diseaserdquoNeurobiology of Disease vol 30no 3 pp 312ndash322 2008

[157] Q Peng N Masuda M Jiang et al ldquoThe antidepressantsertraline improves the phenotype promotes neurogenesis andincreases BDNF levels in the R62 Huntingtonrsquos disease mousemodelrdquo Experimental Neurology vol 210 no 1 pp 154ndash1632008

[158] T Y Pang N C Stam J Nithianantharajah M L Howard andA J Hannan ldquoDifferential effects of voluntary physical exerciseon behavioral and brain-derived neurotrophic factor expressiondeficits in huntingtonrsquos disease transgenic micerdquo Neurosciencevol 141 no 2 pp 569ndash584 2006

[159] V F Low M Dragunow L J Tippett R L M Faull and MA Curtis ldquoNo change in progenitor cell proliferation in thehippocampus in Huntingtonrsquos diseaserdquo Neuroscience vol 199pp 577ndash588 2011

[160] M A Curtis R L Faull and M Glass ldquoA novel populationof progenitor cells expressing cannabinoid receptors in the


subependymal layer of the adult normal and Huntingtonrsquosdisease human brainrdquo Journal of Chemical Neuroanatomy vol31 no 3 pp 210ndash215 2006

[161] M A Curtis E B Penney A G Pearson et al ldquoIncreased cellproliferation and neurogenesis in the adult humanHuntingtonrsquosdisease brainrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 100 no 15 pp 9023ndash90272003

[162] M A Curtis E B Penney J PearsonM Dragunow B Connorand R L M Faull ldquoThe distribution of progenitor cells in thesubependymal layer of the lateral ventricle in the normal andHuntingtonrsquos disease human brainrdquo Neuroscience vol 132 no3 pp 777ndash788 2005

[163] M A Curtis H J Waldvogel B Synek and R L M FaullldquoA histochemical and immunohistochemical analysis of thesubependymal layer in the normal and Huntingtonrsquos diseasebrainrdquo Journal of Chemical Neuroanatomy vol 30 no 1 pp 55ndash66 2005

[164] P J Smith J A Blumenthal BMHoffman et al ldquoAerobic exer-cise and neurocognitive performance ameta-analytic review ofrandomized controlled trialsrdquo Psychosomatic Medicine vol 72no 3 pp 239ndash252 2010

[165] A Blugeot C Rivat E Bouvier et al ldquoVulnerability to depres-sion frombrain neuroplasticity to identification of biomarkersrdquoThe Journal of Neuroscience vol 31 no 36 pp 12889ndash128992011

[166] S L Yancey and J M Overton ldquoCardiovascular responses tovoluntary and treadmill exercise in ratsrdquo Journal of AppliedPhysiology vol 75 no 3 pp 1334ndash1340 1993

[167] H S Sharma J Cervos-Navarro and P K Dey ldquoIncreasedblood-brain barrier permeability following acute short-termswimming exercise in conscious normotensive young ratsrdquoNeuroscience Research vol 10 no 3 pp 211ndash221 1991

[168] J E Black K R Isaacs B J Anderson A A Alcantara and WT Greenough ldquoLearning causes synaptogenesis whereasmotoractivity causes angiogenesis in cerebellar cortex of adult ratsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 87 no 14 pp 5568ndash5572 1990

[169] K R Isaacs B J Anderson A A Alcantara J E Black andW T Greenough ldquoExercise and the brain angiogenesis in theadult rat cerebellum after vigorous physical activity and motorskill learningrdquo Journal of Cerebral Blood Flow and Metabolismvol 12 no 1 pp 110ndash119 1992

[170] J A Kleim N R Cooper and P M VandenBerg ldquoExerciseinduces angiogenesis but does not alter movement representa-tions within rat motor cortexrdquo Brain Research vol 934 no 1pp 1ndash6 2002

[171] R A Swain A BHarris E CWiener et al ldquoProlonged exerciseinduces angiogenesis and increases cerebral blood volume inprimary motor cortex of the ratrdquo Neuroscience vol 117 no 4pp 1037ndash1046 2003

[172] K Jin Y Zhu Y Sun X O Mao L Xie and D A GreenbergldquoVascular endothelial growth factor (VEGF) stimulates neuro-genesis in vitro and in vivordquoProceedings of theNational Academyof Sciences of the United States of America vol 99 no 18 pp11946ndash11950 2002

[173] A Louissaint Jr S Rao C Leventhal and S A GoldmanldquoCoordinated interaction of neurogenesis and angiogenesis inthe adult songbird brainrdquo Neuron vol 34 no 6 pp 945ndash9602002

[174] G Kronenberg A Bick-Sander E Bunk C Wolf D Ehningerand G Kempermann ldquoPhysical exercise prevents age-related

decline in precursor cell activity in the mouse dentate gyrusrdquoNeurobiology of Aging vol 27 no 10 pp 1505ndash1513 2006

[175] R M OrsquoCallaghan E W Griffin and A M Kelly ldquoLong-termtreadmill exposure protects against age-related neurodegenera-tive change in the rat hippocampusrdquo Hippocampus vol 19 no10 pp 1019ndash1029 2009

[176] S Gomes da Silva N Unsain D HMasco et al ldquoEarly exercisepromotes positive hippocampal plasticity and improves spatialmemory in the adult life of ratsrdquoHippocampus vol 22 no 2 pp347ndash358 2012

[177] T Zigova V Pencea S JWiegand andM B Luskin ldquoIntraven-tricular administration of BDNF increases the number of newlygenerated neurons in the adult olfactory bulbrdquo Molecular andCellular Neurosciences vol 11 no 4 pp 234ndash245 1998

[178] M A Aberg N D Aberg H Hedbacker J Oscarsson and PS Eriksson ldquoPeripheral infusion of IGF-I selectively inducesneurogenesis in the adult rat hippocampusrdquo The Journal ofNeuroscience vol 20 no 8 pp 2896ndash2903 2000

[179] J Lee W Duan and M P Mattson ldquoEvidence that brain-derived neurotrophic factor is required for basal neurogenesisand mediates in part the enhancement of neurogenesis bydietary restriction in the hippocampus of adult micerdquo Journalof Neurochemistry vol 82 no 6 pp 1367ndash1375 2002

[180] M Lai C J Hibberd P D Gluckman and J R Seckl ldquoReducedexpression of insulin-like growth factor 1messenger RNA in thehippocampus of aged ratsrdquo Neuroscience Letters vol 288 no 1pp 66ndash70 2000

[181] A K Shetty B Hattiangady and G A Shetty ldquoStemprogenitorcell proliferation factors FGF-2 IGF-1 and VEGF exhibit earlydecline during the course of aging in the hippocampus role ofastrocytesrdquo Glia vol 51 no 3 pp 173ndash186 2005

[182] Q Ding S Vaynman M Akhavan Z Ying and F Gomez-Pinilla ldquoInsulin-like growth factor I interfaces with brain-derived neurotrophic factor-mediated synaptic plasticity tomodulate aspects of exercise-induced cognitive functionrdquo Neu-roscience vol 140 no 3 pp 823ndash833 2006

[183] J L Trejo E Carro and I Torres-Aleman ldquoCirculating insulin-like growth factor I mediates exercise-induced increases in thenumber of new neurons in the adult hippocampusrdquoThe Journalof Neuroscience vol 21 no 5 pp 1628ndash1634 2001

[184] K Fabel K Fabel B Tam et al ldquoVEGF is necessary for exercise-induced adult hippocampal neurogenesisrdquo European Journal ofNeuroscience vol 18 no 10 pp 2803ndash2812 2003

[185] Y H Ding J Li Y Zhou J A Rafols J C Clark and Y DingldquoCerebral angiogenesis and expression of angiogenic factors inaging rats after exerciserdquo Current Neurovascular Research vol3 no 1 pp 15ndash23 2006

[186] E Carro A Nunez S Busiguina and I Torres-Aleman ldquoCircu-lating insulin-like growth factor Imediates effects of exercise onthe brainrdquoThe Journal of Neuroscience vol 20 no 8 pp 2926ndash2933 2000

[187] Y Li B W Luikart S Birnbaum et al ldquoTrkB regulateshippocampal neurogenesis and governs sensitivity to antide-pressive treatmentrdquo Neuron vol 59 no 3 pp 399ndash412 2008

[188] C W Cotman N C Berchtold and L A Christie ldquoExercisebuilds brain health key roles of growth factor cascades andinflammationrdquo Trends in Neurosciences vol 30 no 9 pp 464ndash472 2007

[189] A Parachikova K E Nichol and C W Cotman ldquoShort-termexercise in aged Tg2576 mice alters neuroinflammation andimproves cognitionrdquo Neurobiology of Disease vol 30 no 1 pp121ndash129 2008


[190] P A Adlard V M Perreau V Pop and C W CotmanldquoVoluntary exercise decreases amyloid load in a transgenicmodel of Alzheimerrsquos diseaserdquoThe Journal of Neuroscience vol25 no 17 pp 4217ndash4221 2005

[191] H L Liu G Zhao K Cai H H Zhao and L D ShildquoTreadmill exercise prevents decline in spatial learning andmemory in APPPS1 transgenic mice through improvementof hippocampal long-term potentiationrdquo Behavioural BrainResearch vol 218 no 2 pp 308ndash314 2011

[192] H L Liu G Zhao H Zhang and L D Shi ldquoLong-term tread-mill exercise inhibits the progression of Alzheimerrsquos disease-like neuropathology in the hippocampus of APPPS1 transgenicmicerdquo Behavioural Brain Research vol 256 pp 261ndash272 2013

[193] K Nichol S P Deeny J Seif K Camaclang and CW CotmanldquoExercise improves cognition and hippocampal plasticity inAPOE 1205764micerdquoAlzheimerrsquos andDementia vol 5 no 4 pp 287ndash294 2009

[194] K ENichol A I Parachikova andCWCotman ldquoThreeweeksof running wheel exposure improves cognitive performance inthe aged Tg2576 mouserdquo Behavioural Brain Research vol 184no 2 pp 124ndash132 2007

[195] K E Nichol W W Poon A I Parachikova D H CribbsC G Glabe and C W Cotman ldquoExercise alters the immuneprofile in Tg2576 Alzheimer mice toward a response coincidentwith improved cognitive performance and decreased amyloidrdquoJournal of Neuroinflammation vol 5 article 13 2008

[196] S Mirochnic S Wolf M Staufenbiel and G KempermannldquoAge effects on the regulation of adult hippocampal neuroge-nesis by physical activity and environmental enrichment in theAPP23 mouse model of Alzheimer diseaserdquo Hippocampus vol19 no 10 pp 1008ndash1018 2009

[197] S A Wolf G Kronenberg K Lehmann et al ldquoCognitive andphysical activity differently modulate disease progression inthe amyloid precursor protein (APP)-23 model of Alzheimerrsquosdiseaserdquo Biological Psychiatry vol 60 no 12 pp 1314ndash13232006

[198] T S Kannangara M J Lucero J Gil-Mohapel et al ldquoRunningreduces stress and enhances cell genesis in aged micerdquoNeurobi-ology of Aging vol 32 no 12 pp 2279ndash2286 2011

[199] A S Buchman P A Boyle L Yu R C Shah R S Wilson andD A Bennett ldquoTotal daily physical activity and the risk of ADand cognitive decline in older adultsrdquo Neurology vol 78 no 17pp 1323ndash1329 2012

[200] C Sattler K I Erickson P Toro and J Schroder ldquoPhysicalfitness as a protective factor for cognitive impairment in aprospective population-based study in Germanyrdquo Journal ofAlzheimerrsquos Disease vol 26 no 4 pp 709ndash718 2011

[201] K Yaffe D Barnes M Nevitt L-Y Lui and K Covinsky ldquoAprospective study of physical activity and cognitive decline inelderly womenwomenwhowalkrdquoArchives of InternalMedicinevol 161 no 14 pp 1703ndash1708 2001

[202] K I Erickson R S Prakash M W Voss et al ldquoAerobic fitnessis associated with hippocampal volume in elderly humansrdquoHippocampus vol 19 no 10 pp 1030ndash1039 2009

[203] K I Erickson C A Raji O L Lopez et al ldquoPhysical activitypredicts gray matter volume in late adulthood the cardiovascu-lar health studyrdquo Neurology vol 75 no 16 pp 1415ndash1422 2010

[204] J L Tillerson W M Caudle M E Reveron and G WMiller ldquoExercise induces behavioral recovery and attenuatesneurochemical deficits in rodentmodels of Parkinsonrsquos diseaserdquoNeuroscience vol 119 no 3 pp 899ndash911 2003

[205] M J Zigmond J L Cameron R K Leak et al ldquoTrigger-ing endogenous neuroprotective processes through exercisein models of dopamine deficiencyrdquo Parkinsonism amp RelatedDisorders vol 15 supplement 3 pp S42ndashS45 2009

[206] S J OrsquoDell N B Gross A N Fricks B D Casiano T BNguyen and J F Marshall ldquoRunning wheel exercise enhancesrecovery from nigrostriatal dopamine injury without inducingneuroprotectionrdquo Neuroscience vol 144 no 3 pp 1141ndash11512007

[207] B E Fisher G M Petzinger K Nixon et al ldquoExercise-inducedbehavioral recovery and neuroplasticity in the 1-methyl-4-phenyl-1236-tetrahydropyridine-lesioned mouse basal gan-gliardquo Journal of Neuroscience Research vol 77 no 3 pp 378ndash390 2004

[208] N Tajiri T Yasuhara T Shingo et al ldquoExercise exerts neuro-protective effects on Parkinsonrsquos disease model of ratsrdquo BrainResearch vol 1310 pp 200ndash207 2010

[209] B E Fisher A D Wu G J Salem et al ldquoThe effect of exercisetraining in improving motor performance and corticomotorexcitability in people with early Parkinsonrsquos diseaserdquo Archivesof Physical Medicine and Rehabilitation vol 89 no 7 pp 1221ndash1229 2008

[210] G M Petzinger B E Fisher S McEwen J A Beeler J PWalsh and MW Jakowec ldquoExercise-enhanced neuroplasticitytargeting motor and cognitive circuitry in Parkinsonrsquos diseaserdquoThe Lancet Neurology vol 12 no 7 pp 716ndash726 2013

[211] M I Ransome and A J Hannan ldquoImpaired basal and running-induced hippocampal neurogenesis coincides with reducedAkt signaling in adult R61 HD micerdquo Molecular and CellularNeuroscience vol 54 pp 93ndash107 2013

[212] M C Potter C Yuan C Ottenritter M Mughal and H vanPraag ldquoExercise is not beneficial and may accelerate symptomonset in a mouse model of Huntingtonrsquos diseaserdquo PLoS CurrentsHuntigton Disease vol 2 Article ID RRN1201 2010

[213] A van Dellen P M Cordery T L Spires C Blakemoreand A J Hannan ldquoWheel running from a juvenile age delaysonset of specific motor deficits but does not alter proteinaggregate density in a mouse model of Huntingtonrsquos diseaserdquoBMC Neuroscience vol 9 article 34 2008

[214] T L Spires H E Grote S Garry et al ldquoDendritic spine pathol-ogy and deficits in experience-dependent dendritic plasticity inR61 Huntingtonrsquos disease transgenic micerdquo European Journal ofNeuroscience vol 19 no 10 pp 2799ndash2807 2004

[215] A M Stranahan D Khalil and E Gould ldquoRunning induceswidespread structural alterations in the hippocampus andentorhinal cortexrdquo Hippocampus vol 17 no 11 pp 1017ndash10222007

[216] B D Eadie V A Redila and B R Christie ldquoVoluntaryexercise alters the cytoarchitecture of the adult dentate gyrusby increasing cellular proliferation dendritic complexity andspine densityrdquo Journal of Comparative Neurology vol 486 no 1pp 39ndash47 2005

[217] C B Johansson S Momma D L Clarke M Risling ULendahl and J Frisen ldquoIdentification of a neural stem cell inthe adult mammalian central nervous systemrdquo Cell vol 96 no1 pp 25ndash34 1999

[218] K van der Borght D E Kobor-Nyakas K Klauke et alldquoPhysical exercise leads to rapid adaptations in hippocampalvasculature temporal dynamics and relationship to cell prolif-eration and neurogenesisrdquoHippocampus vol 19 no 10 pp 928ndash936 2009


[219] L N Manganas X Zhang Y Li et al ldquoMagnetic resonancespectroscopy identifies neural progenitor cells in the live humanbrainrdquo Science vol 318 no 5852 pp 980ndash985 2007

[220] K I Erickson M W Voss R S Prakash et al ldquoExercisetraining increases size of hippocampus and improves memoryrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 108 no 7 pp 3017ndash3022 2011

[221] R S Duman S Nakagawa and J Malberg ldquoRegulation of adultneurogenesis by antidepressant treatmentrdquo Neuropsychophar-macology vol 25 no 6 pp 836ndash844 2001

[222] E Shimizu K Hashimoto N Okamura et al ldquoAlterations ofserum levels of brain-derived neurotrophic factor (BDNF) indepressed patients with or without antidepressantsrdquo BiologicalPsychiatry vol 54 no 1 pp 70ndash75 2003

[223] I M Rachman J R Unnerstall D W Pfaff and R S CohenldquoEstrogen alters behavior and forebrain c-fos expression inovariectomized rats subjected to the forced swim testrdquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 95 no 23 pp 13941ndash13946 1998

[224] S Y Yau B W Lau E D Zhang et al ldquoEffects of voluntaryrunning on plasma levels of neurotrophins hippocampal cellproliferation and learning andmemory in stressed ratsrdquoNeuro-science vol 222 pp 289ndash301 2012

[225] T Seifert P BrassardMWissenberg et al ldquoEndurance trainingenhances BDNF release from the human brainrdquo AmericanJournal of Physiology vol 298 no 2 pp R372ndashR377 2010

[226] K Knaepen M Goekint E M Heyman and R MeeusenldquoNeuroplasticity exercise-induced response of peripheral brain-derived neurotrophic factor a systematic review of experimen-tal studies in human subjectsrdquo Sports Medicine vol 40 no 9pp 765ndash801 2010

[227] V Castellano and L J White ldquoSerum brain-derived neu-rotrophic factor response to aerobic exercise in multiple scle-rosisrdquo Journal of the Neurological Sciences vol 269 no 1-2 pp85ndash91 2008

[228] J F Yarrow L J White S C McCoy and S E Borst ldquoTrainingaugments resistance exercise induced elevation of circulatingbrain derived neurotrophic factor (BDNF)rdquo Neuroscience Let-ters vol 479 no 2 pp 161ndash165 2010

[229] J Currie R Ramsbottom H Ludlow A Nevill and M GilderldquoCardio-respiratory fitness habitual physical activity and serumbrain derived neurotrophic factor (BDNF) inmen and womenrdquoNeuroscience Letters vol 451 no 2 pp 152ndash155 2009

[230] K L Chan K Y Tong and S P Yip ldquoRelationship of serumbrain-derived neurotrophic factor (BDNF) and health-relatedlifestyle in healthy human subjectsrdquo Neuroscience Letters vol447 no 2-3 pp 124ndash128 2008

[231] T M Lee M L Wong B W Lau J C Lee S Y Yau and KF So ldquoAerobic exercise interacts with neurotrophic factors topredict cognitive functioning in adolescentsrdquo Psychoneuroen-docrinology vol 39 pp 214ndash224 2014

[232] A A Butler and D LeRoith ldquoMinireview tissue-specific versusgeneralized gene targeting of the igf1 and igf1r genes and theirroles in insulin-like growth factor physiologyrdquo Endocrinologyvol 142 no 5 pp 1685ndash1688 2001

[233] B E Pulford and D N Ishii ldquoUptake of circulating insulin-like growth factors (IGFs) into cerebrospinal fluid appears tobe independent of the IGF receptors as well as IGF-bindingproteinsrdquo Endocrinology vol 142 no 1 pp 213ndash220 2001

[234] J R OrsquoKusky P Ye and A J DrsquoErcole ldquoInsulin-like growthfactor-I promotes neurogenesis and synaptogenesis in the

hippocampal dentate gyrus during postnatal developmentrdquoTheJournal of Neuroscience vol 20 no 22 pp 8435ndash8442 2000

[235] L I Arwert J B Deijen andM L Drent ldquoThe relation betweeninsulin-like growth factor I levels and cognition in healthyelderly a meta-analysisrdquo Growth Hormone and IGF Researchvol 15 no 6 pp 416ndash422 2005

[236] A Aleman W R de Vries E H de Haan H J J Verhaar MM Samson and H P F Koppeschaar ldquoAge-sensitive cognitivefunction growth hormone and insulin-like growth factor 1plasma levels in healthy oldermenrdquoNeuropsychobiology vol 41no 2 pp 73ndash78 2000

[237] A Aleman H J Verhaar E H de Haan et al ldquoInsulin-likegrowth factor-I and cognitive function in healthy older menrdquoJournal of Clinical Endocrinology andMetabolism vol 84 no 2pp 471ndash475 1999

[238] J Manetta J F Brun L Maımoun C Fedou C Prefaut and JMercier ldquoThe effects of intensive training on insulin-like growthfactor I (IGF-I) and IGF binding proteins 1 and 3 in competitivecyclists relationships with glucose disposalrdquo Journal of SportsSciences vol 21 no 3 pp 147ndash154 2003

[239] A Zebrowska Z Gasior and J Langfort ldquoSerum IGF-I andhormonal responses to incremental exercise in athleteswith andwithout left ventricular hypertrophyrdquo Journal of Sports Scienceand Medicine vol 8 no 1 pp 67ndash76 2009

[240] DM Cearlock andN A Nuzzo ldquoEffects of sustainedmoderateexercise on cholesterol growth hormone and cortisol bloodlevels in three age groups of womenrdquo Clinical LaboratoryScience vol 14 no 2 pp 108ndash111 2001

[241] S Karatay K Yildirim M A Melikoglu F Akcay and K SenelldquoEffects of dynamic exercise on circulating IGF-1 and IGFBP-3 levels in patients with rheumatoid arthritis or ankylosingspondylitisrdquo Clinical Rheumatology vol 26 no 10 pp 1635ndash1639 2007

[242] YNishida TMatsubara T Tobina et al ldquoEffect of low-intensityaerobic exercise on insulin-like growth factor-I and insulin-likegrowth factor-binding proteins in healthy menrdquo InternationalJournal of Endocrinology vol 2010 Article ID 452820 8 pages2010

[243] T P Gavin J L Drew C J Kubik W E Pofahl and R CHickner ldquoAcute resistance exercise increases skeletal muscleangiogenic growth factor expressionrdquoActa Physiologica vol 191no 2 pp 139ndash146 2007

[244] T Gustafsson A Knutsson A Puntschart et al ldquoIncreasedexpression of vascular endothelial growth factor in humanskeletal muscle in response to short-term one-legged exercisetrainingrdquo Pflugers Archiv vol 444 no 6 pp 752ndash759 2002

[245] L Hoffner J J Nielsen H Langberg and Y Hellsten ldquoExercisebut not prostanoids enhance levels of vascular endothelialgrowth factor and other proliferative agents in human skeletalmuscle interstitiumrdquo The Journal of Physiology vol 550 part 1pp 217ndash225 2003

[246] E C Breen E C Johnson H Wagner H M Tseng L ASung and P D Wagner ldquoAngiogenic growth factor mRNAresponses in muscle to a single bout of exerciserdquo Journal ofApplied Physiology vol 81 no 1 pp 355ndash361 1996

[247] W Schobersberger P Hobisch-Hagen D Fries et al ldquoIncreasein immune activation vascular endothelial growth factor anderythropoietin after an ultramarathon run atmoderate altituderdquoImmunobiology vol 201 no 5 pp 611ndash620 2000


[248] H C Gunga K Kirsch L Rocker et al ldquoVascular endothelialgrowth factor in exercising humans under different environ-mental conditionsrdquo European Journal of Applied Physiology andOccupational Physiology vol 79 no 6 pp 484ndash490 1999

[249] N Hiscock C P Fischer H Pilegaard and B K PedersenldquoVascular endothelial growth factor mRNA expression andarteriovenous balance in response to prolonged submaximalexercise in humansrdquo American Journal of Physiology vol 285no 4 pp H1759ndashH1763 2003

[250] R M Kraus H W Stallings III R C Yeager and T P GavinldquoCirculating plasma VEGF response to exercise in sedentaryand endurance-trainedmenrdquo Journal of Applied Physiology vol96 no 4 pp 1445ndash1450 2004

[251] MW Voss K I Erickson R S Prakash et al ldquoNeurobiologicalmarkers of exercise-related brain plasticity in older adultsrdquoBrain Behavior and Immunity vol 28 pp 90ndash99 2013

[252] M A Curtis V F Low and R L Faull ldquoNeurogenesis andprogenitor cells in the adult human brain a comparisonbetween hippocampal and subventricular progenitor prolifer-ationrdquoDevelopmental Neurobiology vol 72 no 7 pp 990ndash10052012

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of


Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology


Molecular Biology International

GenomicsInternational Journal of


The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014


BioinformaticsAdvances in

Marine BiologyJournal of



Signal TransductionJournal of


BioMed Research International

Evolutionary BiologyInternational Journal of



Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


Genetics Research International


Advances in

Virolog y

Hindawi Publishing Corporationhttpwwwhindawicom

Nucleic AcidsJournal of

Volume 2014

Stem CellsInternational



Enzyme Research



Microbiology


Progenitors Immatureneurons

Matureneurons

Physical exercise

Neurodegenerative diseases (eg AD PD and HD)

sim1ndash3 days of proliferation

sim2 weeks ofdiferentiation

sim4ndash6 weeks ofmaturation integration

GCL

(a) (b)

Figure 1 Development and integration of adult-born neurons in the dentate gyrus of the hippocampus (a) The neural progenitors thatare divided from neural stem cells start expressing either neuronal or glial phenotypes after just a few days of division Newborn neuronsgradually migrate from the subgranular zone (SGZ) into the granular cell layer (GCL) where they undergomaturation followed by functionalintegration into the existing neural circuitry in the hippocampus This process of hippocampal neurogenesis is known to be promoted byphysical exercise and to be compromised in several neurodegenerative diseases such as AD PD and HD (b) Confocal image of 4-week-oldretroviral-labeled newborn neurons with green fluorescence protein (GFP) in the GCL (scale bar 200 120583m)

[14]Therefore synaptic connections between theDGand theCA3 hippocampal subregions (which form the mossy fibertract) can potentially bemodified by changes in hippocampalneurogenesis About 9000 new cells are generated eachday in the rodent hippocampus (hundreds of thousands ofcells each month accounting for 6 of the total granuleneuronal population) of which about 80ndash90 differentiateinto neurons [15]

Clinical studies have confirmed that similar processesalso occur in the corresponding regions of the human brain[16ndash19]The first evidence of adult neurogenesis in the humanbrain came from a study showing the presence of positivestaining for 5-bromo-21015840-deoxyuridine (BrdU a thymidineanalog) in the SVZ and the DG region of postmortembrain sections from cancer patients who had received BrdUinjections in life [5] These findings have since then beenconfirmed and a recent study has revealed that approximately700 new neurons are added to the adult human hippocampuseach day [20] However adult neurogenesis is age dependentwith the production of new neurons declining with age [21ndash28]

The hippocampus plays an integral role in the consolida-tion of declarative memory as well as context dependent andspatial learning processes [29 30] in both humans [31 32] androdents [33ndash36] New hippocampal neurons are believed tocontribute to the functioning of the hippocampus and thereis evidence that they are recruited into hippocampal neuronalcircuits known to be involved in spatial learning [9] and

possess particular physiological properties that make themmore susceptible to behavioral-dependent synaptic plasticity[11 37 38] Thus it is reasonable to speculate that these newneuronsmight be integral for hippocampal-dependent learn-ing and memory [11] and in particular pattern separation[39ndash41] In agreement with this hypothesis numerous correl-ative studies have shown that hippocampal neurogenesis canbemodulated by learning and behavioural experience [6 42ndash45] and that a loss in hippocampal neurogenic function canadversely affect memory formation [7 8 10 38 46]

Using exercise training as an upregulator for hippocam-pal neurogenesis an in vivo imaging study in humanshas indicated a positive association between hippocampal-dependent cognitive performance and change of cerebralblood volume (CBV served as an indirectmeasure of changesin hippocampal neurogenesis in the human brain) [47] Fur-thermore exercise intervention has been shown to improveperformance in a neurogenesis-dependent cognitive test thevisual pattern separation task in human subjects [48] Inspite of the technical limitations associated with the directmeasurement of neurogenesis in the human brain these twostudies have suggested that adult-born new neurons in thehippocampus might play a functional role in learning andmemory in the human brain

Neurodegenerative diseases such as Alzheimerrsquos disease(AD) Parkinsonrsquos disease (PD) and Huntingtonrsquos disease(HD) share the common characteristic of progressive loss ofstructure andor function of neurons in the brain Although


















AD




mdash

PD





HD


















2-terminal



















































7 Conclusion






Abbreviations








Acknowledgments




References
















































































































































































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology


















AD




mdash

PD





HD


















2-terminal



















































7 Conclusion






Abbreviations








Acknowledgments




References
















































































































































































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology










2-terminal



















































7 Conclusion






Abbreviations








Acknowledgments




References
















































































































































































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology
















































7 Conclusion






Abbreviations








Acknowledgments




References
















































































































































































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology




Abbreviations








Acknowledgments




References
















































































































































































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology



References
















































































































































































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology















































































































































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology

review article physical exercise-induced adult...

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