lifestyle factors such as exercise can reduce the risk of age - related cognitive decline and neurodegeneration .
this study focused on exercise as a lifestyle change for enhanced cognitive function depends on a neurobiological understanding .
the neurogenesis in the brain of adult animals and humans overturned the long - held dogma that the adult brain has no capacity for generating new neurons ( altman and das , 1965 ; deng et al . , 2010 ) .
in recent studies , exercise has emerged as the most effective and successful way for optimal aging .
exercise in the healthy adults brings behavioral benefits , including significant increments in memory , attention , processing speed , and executive functions ( smith et al . , 2010 ) .
regular engagement of exercise in midlife is associated with decreased risk of dementia later in life , presenting that exercise might have preventive effects on age - related cognitive decline ( hamer and chida , 2009 ) .
abundant evidences from animal studies have reported that an enhancement in adult hippocampal neurogenesis may underlie the beneficial effects of exercise on cognition .
indeed , exercise not only increased hippocampal neurogenesis but also improved morris water maze performance ( cho et al . , 2013 ; heo et al . ,
therefore , exercise can upregulate the neuronal cell proliferation process and increase the ability to maintain neuronal plasticity . three - month regular exercise increased the volume of blood in the dentate gyrus as evaluated by functional magnetic resonance imaging and improved the cognitive scores in humans ( pereira et al . , 2007 ) .
exercise undoubtedly increased cerebral blood flow , angiogenesis , and the permeability of blood brain barrier ( black et al .
2014 ) . positive relationship between angiogenesis and neurogenesis was presented in the animal studies .
for example , the improvement of cognition through 3-month exercise is conjectured as a result of enhanced hippocampal neurogenesis via increased hippocampal angiogenesis in the human brain ( pereira et al . , 2007 ) .
these positive influences of exercise in the brain recommend that physical exercise and activity could be applied as a scheme to prevent the age - related cognitive dysfunction .
age - related decline in hippocampal neurogenesis has been associated with decrease in neurotrophins such as brain - derived neurotrophic factor ( bdnf ) , insulin - like growth factor 1 ( igf-1 ) , and vascular endothelial growth factor ( vegf ) ( lai et al . , 2000 ;
bndf , igf-1 , and vegf have a crucial role in exercise - induced adult hippocampal neurogenesis .
thus , these neurotrophin factors might be worked for mediating exercise - induced adult hippocampal neurogenesis . here
, this study was reviewed the functional and molecular role of physical exercise in cognitive function through neural plasticity , neurotrophic factors , and adult hippocampal neurogenesis .
this study discussed the exercise - induced hippocampal neurogenesis and its relationship with cognitive enhancement , and concluded with a brief analysis to optimize the impact of exercise on brain function .
exercise - induced improvements in learning and memory have been associated with exercise - dependent neural synaptic plasticity and hippocampal neurogenesis ( baek et al . , 2012 ; cho et al . , 2013 ; heo et al . ,
long - term potentiation ( ltp ) in a neurophysiological model of learning and memory was assessed in hippocampal slices from running mice .
however , a significantly greater ltp was shown in the hippocampal dentate gyrus of running mice compared to the sedentary mice ( van praag et al . , 1999 ) .
the enhancement in ltp following exercise is consistent with an increment of bdnf in the hippocampus , which can mediate neural plasticity ( cowansage et al . , 2010 ) .
exercise may adjust the neural plasticity of the hippocampal dentate gyrus though the increased neurogenesis .
newborn granule cells may have a unique role in synaptic plasticity of the hippocampus , and the role of these cells can be increased with exercise ( vivar et al . ,
the enhanced plasticity was appeared in a specific time of maturation process and was dependent on increased synaptic expression of nr2b containing n - methyl - d - asparate ( nmda ) receptors ( ge et al . , 2007 ) .
ltd induced by low - frequency stimulation is relatively unaffected by exercise ( vasuta et al . , 2007 )
. however , ltd depends on the activation of nr2b containing nmda receptors in running mice ( vasuta et al . , 2007 ) .
neural plasticity has been associated with morphological changes that occur in response to neural activity ( ngerl et al .
some studies suggested that morphological changes in dentate gyrus of hippocampus have been observed with exercise ( eadie et al .
exercise significantly increased the total length , complexity , and spine density of granule cell dendrites ( eadie et al . , 2005 ) .
also exercise enhanced dendritic complexity in all zones of the granule cell layer such as subgranular , inner and outer granule cell zones ( redila and christie , 2006 ) .
additionally 2-month exercise caused morphological changes not only in the dentate gyrus but also in the entorhinal cortex and ca1 pyramidal cells ( stranahan et al .
there was no difference in spine density of new neurons between young and aged mice , suggesting that fewer cells proliferated in aging brain may be functionally equivalent to those generated at early period ( morgenstern et al . , 2008 ) .
exercise modifies the morphology of dentate granule cells and other parameters related to memory function , and may also affect the rate of integration of newborn granule cells into the hippocampal circuitry ( vivar et al . ,
neurotrophic factors , including bdnf , igf-1 , and vegf are essential regulators for the effects of physical exercise on brain plasticity during development and adulthood ( mcallister et al . , 1999 ) .
bdnf is a critical mediator for the beneficial effect of physical exercise on brain function because it supports neural survival , growth , and synaptic plasticity ( cowansage et al . , 2010 ) .
indeed , bdnf is considered to be the most downstream factor mediating the upregulation of hippocampal neurogenesis by exercise ( yau et al . , 2014 ) .
( 1995 ) were the first reporting a positive correlation between physical exercise and bdnf mrna levels . both bdnf gene and protein expression
are increased in the hippocampus after short- or long - period of exercise ( abel and rissman , 2013 ; marlatt et al . , 2012 ) , and remained at least 2 weeks after exercise has ended ( berchtold et al . , 2010 ) .
bdnf is a neuroprotective growth factor that enhances synaptic plasticity and memory through its actions on the tyrosine receptor kinase b ( trkb ) ( mattson et al . , 2004 ) .
2008 ) and central bdnf in rodents ( neeper et al . , 1995 ) .
blocking bdnf expression prevented the enhancement of cognitive function following physical exercise ( vaynman et al .
the effects of exercise on synaptic plasticity are related to bdnf ( messaoudi et al . ,
it has been estimated that the brain is the major source of circulating bdnf ( 70%80% ) both at rest and during exercise ( rasmussen et al . , 2009 ) .
in blood , more than 90% of the bdnf is stored in platelets and is released during clotting processes . therefore , serum is likely to reflect stored and circulating bdnf in the blood ( fujimura et al . , 2002 ) , while plasma seems to reflect only freely circulating bdnf ( lommatzsch et al . , 2005 ) .
for that reason , peripheral bdnf and other factors that regulate platelet storage and release should be considered for making inferences between peripherally measured bdnf and central expression .
particularly , these factors may influence the acute changes in peripheral bdnf levels following single bout of aerobic exercise ( griffin et al . , 2011 ) .
other neurotrophins , such as igf-1 and vegf have been reported as essential factors in exercise - induced adult hippocampal neurogenesis ( trejo et al . , 2008 ) .
igf-1 was shown to be involved in memory , plasticity , and neurogenic processes , especially in the aging brain ( maher et al . , 2006 ) .
for instance , lack of igf-1 results in memory loss and ltp impairment ( trejo et al . , 2007 )
. increased igf-1 production following exercise may interact with bdnf to modulate synaptic plasticity ( mattson et al . , 2004 ) .
igf-1 receptor activity also appears to be closely associated with the expression of bdnf following physical exercise .
for example , igf-1 signaling via the igf-1 receptor is necessary for the exercise - induced bdnf expression .
blockade of igf-1 prevented the exercise - induced upregulation of bdnf ( ding et al .
on the other hand , blocking bdnf pathway prevented the exercise - induced upregulation of igf-1 in the hippocampus .
based on these results , it seems that igf-1 and bdnf interact to mediate changes in hippocampal function following exercise ( gomez - pinilla et al . ,
interestingly , it has been reported that adult hippocampal neurogenesis occurs near the local microvasculature of hippocampus ( fabel et al . , 2003 ) .
both igf-1 and vegf in the periphery are increased by exercise and mediate stimulation of neurogenesis and angiogenesis in the brain ( fabel et al . , 2003 ) .
peripheral igf-1 is necessary for exercise - induced vessel remodeling in the brain ( lopez - lopez et al . , 2004 ) .
also , vegf level in the brain is associated with exercise - induced angiogenesis ( ding et al . , 2006 ) .
the enhancement of brain vegf has mitotic activity specific to vascular endothelial cells , affecting proliferation , survival , and migration ( ferrara and davis - smyth , 1997 ) .
blockade of peripheral vegf restricted the increment in neurogenesis by exercise ( fabel et al . , 2003 ) . in addition ,
exercise for 50 days increased density of blood vessels in the dentate gyrus , and enhanced spatial working memory in the water maze ( clark et al . , 2009 ) .
exercise increased cerebral blood volume with neurogenesis ( van der borght et al . , 2009 ) and improved cognitive function ( pereira et al . , 2007 ) .
however , van praag et al . ( 2007 ) reported that an increment in angiogenesis is not necessarily correlated with increased neurogenesis .
new neuron production can be regulated by many different extrinsic and intrinsic factors . in the healthy brain ,
at least two constitutive neurogenic regions exist ( ortega - perez et al . , 2007 ) : the subventricular zone ( svz ) of olfactory bulb and the subgranular zone ( sgz ) of hippocampal dentate gyrus .
neurons born in the sgz differentiate and integrate into the local neural network as granule cells of the dentate gyrus . in the dentate gyrus of the hippocampus
the origin of adult hippocampal neurogenesis is adult neural stem cells , which can grow into functionally matured neurons through a development process that is divided into three main stages  cell proliferation , differentiation , and functional maturity  over 4 to 6 weeks ( duan et al . , 2008 ) .
about 9,000 new cells are generated each day in the rodent hippocampus of which about 80%90% differentiated into neurons ( cameron and mckay , 2001 ) . in humans , approximately 700 new neurons are added to the adult hippocampus each day from a study reporting the presence of positive staining for 5-bromo-2-deoxyuridine ( a thymidine analog ) in the svz and the dentate gyrus region of postmortem brain sections ( eriksson et al . ,
however , adult neurogenesis is dependent on the production of new neurons and declines with aging ( yau et al . ,
enhanced hippocampal neurogenesis is one of the most notable effects of exercise in the brain ( clark et al . , 2009 ) , and might be a key mechanism intermediating exercise - related improvement in the brain functions .
adult hippocampal neurogenesis is doubled by exercise ( van praag et al . , 1999 ) .
exercise influences on all aspects of new neuronal maturation , including cell proliferation , survival , and differentiation in the dentate gyrus ( speisman et al . , 2013 ) .
furthermore , exercise - enhanced adult hippocampal neurogenesis plays an important role in learning , memory , and neural plasticity ( van praag et al . , 1999 ) . in rodents , voluntary
running increased the proliferation of cells in the sgz of both young and aged animals ( van praag et al . , 1999 ) .
moreover , voluntary running for three weeks enhanced the survival of adult - born neurons in the hippocampus ( muotri et al . , 2009 ) .
in addition , voluntary running increased the amplitude of ltp in the dentate gyrus and improved the hippocampus - dependent task in the morris water maze ( van praag et al . , 2005 ) , indicating that increased neurogenesis correlates with improved cognition .
mild exercise , but not of intense exercise , is effective for the enhancing adult hippocampal neurogenesis , especially the number of mature neurons that improve the spatial memory ( inoue et al . , 2015 ) .
, 2013 ) and several neurological disorders causing cognitive decline ( zhao et al . , 2008 ) .
neurogenesis declines as early as middle - age , and may refer the age - related decline of cognitive function ( erickson and barnes , 2003 ) . however , the effect of exercise on neurogenesis is retained over the lifespan .
neuroimaging studies indicated that elderly humans with higher aerobic fitness have larger hippocampal volumes and better scores in cognition tasks ( erickson et al . , 2009 ) .
young and aged rodents performed running wheel exercise showed enhanced plasticity and better performances on hippocampus - dependent tasks ( van praag et al . , 2005 ) .
short- and long - term exercise improved memory function and prevented hippocampal impairments in alzheimer disease ( ad ) model ( parachikova et al . , 2008 ) .
also , physical exercise is beneficial for ameliorating some of the neuropathological and behavioral deficits in parkinson disease animal models ( yau et al . , 2014 ) .
exercise promoted the preservation of tyrosine hydroxylase ( th ; the rate - limiting enzyme during the synthesis of dopamine)-positive fibers in the striatum and th - positive neurons in the substantia nigra ( tajiri et al . , 2010 ) .
several clinical studies reported that physical exercise can improve motor function and cognitive performance in parkinson disease patients ( petzinger et al . , 2013 ) .
these findings suggest that exercise may represent a noninvasive therapeutic intervention to attenuate cognitive decline in neurodegenerative diseases .
the present study presented evidences suggesting that exercise - induced improvements in cognitive functions are correlated with neurogenesis , synaptic plasticity , and neurotrophins in the hippocampus .
exercise has a positive impact on the aged brain with neurodegenerative disorders that are associated with cognitive decline . within the hippocampus ,
the most noticeable changes with exercise are increased production of new neurons and neurotrophic factors .
understanding of neurobiological mechanisms of exercise on brain functions and behaviors may lead to the development of novel therapeutic strategy for neurodegenerative disorders .
 the functions of adult hippocampal neurogenesis have been extensively investigated during the past decade . 
 numerous studies have shown that adult neurogenesis may play an important role in the hippocampal - dependent learning and memory . 
 this study evaluated the influence of exercise on hippocampal neurogenesis , neural plasticity , neurotrophic factors , and cognition . 
 areas of research focused on enhancing effect of exercise for adult hippocampal neurogenesis and protective role of exercise against brain diseases . 
 the present study suggests that exercise improves brain functions and prevents decline of cognition across the lifespan . 
 understanding of neurobiological mechanisms of exercise on brain functions may lead to the development of novel therapeutic strategy for neurodegenerative disorders . 
INTRODUCTION
EXERCISE AND NEURAL PLASTICITY
EXERCISE AND NEUROTROPHIC FACTORS
EXERCISE AND ADULT HIPPOCAMPAL NEUROGENESIS
CONCLUSIONS