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Attribution- ShareAlike 4.0 International (CC BY-SA 4.0)
Vol.!03,!No.!11,!November!2023!
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Can$Exercise$Make$Us$Smarter,$Happier,$and$Have$More$
Neurons?$A$Hormetic$Perspective$
$
Roy$Ardian$
Faculty!of!Sports!and!Health!Sciences,!Universitas!Negeri!Yogyakarta,!Indonesia!
Email:!royardian2023@student.uny!
Keywords$
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ABSTRACT$
Exercise,)Neurons,)Hormetic)
Perspective.$
)
The$ level$ of$ intensity$ in$ a$ fitness$ regimen$ determines$ its$ impact:$
exercising$can$enhance$intelligence,$boost$happiness,$and$increase$
the$ number$ of$ neurons.$ It$ is$ commonly$ accepted$ that$ exercise$
programs$yield$both$positive$and$negative$outcomes,$depending$on$
their$ intensity,$ among$ other$ factors,$ following $ a$ patter n $ like$
hormesis$with$ a$two-phase$dose$response.$In$simp le $terms,$hormetic$
stress$is$the$exact$amount$of$stress$to$which$our$body$is$challenged,$
but$we$are$not$too$tired.$Therefore,$your$body$is$not$weakened$by$
lack$of$exposure$to$stress,$but$you$are$spared$from$the$harmful$side$
effects$of$toxic$stress.$Nevertheless,$no$proof$has$emerged$thus$far$
regarding$ a$ two-phase$ reaction$ of$ specific$ agents$ responsible$ for$
these$ exercise-induced$ effects.$ The$ discu s s io ns$ and$ concepts$ will$
revolve$ around$ adult$ hippocampal$ neurogenesis$ (AHN)$ as$ a$
plausible$physiological$basis$for$the$hermetic$reaction$to$exercise$in$
relation$to$its$impact$ o n$cognition$and$mood,$including$the$potential$
molecular$pathways$that$might$facilitate$these$effects.!
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$
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INTRODUCTION)
Dishman!et!al.!(2006)!discovered!that!physical!activity!had!wide-ranging!effects!on!the!entire!body,!
including!the! brain.!The!positive! impacts!of! physical! exercise! on! cognition! and! mood! can! be! elucidated!
through!hormetic!(biphasic)!dose-response!patterns,!as!Mattson!(2012)!suggested.!Many!of!these!effects!
are!intricately!connected!to!Adult!Hippocampal!Neurogenesis!(AHN)!in!adults,!a!discovery!made!over!the!
past! decade! (Kempermann,! 2011),! which! refers! to! the! generation! of! new! neurons! in! adults,! mainly!
influenced! by! exercise.! These! newly! formed! neurons! are! notably! responsive! to! physical! activity.!
Additionally,!AHN!has! been! associated!with!various!behaviours!and!moods!related!to!the!hippocampus,!
irrespective!of!their!association!with!exercise!(Kempermann,!2011).!
Using!this!knowledge,!we!first!assessed!the!literature!on!the!impacts!of!exercise's!hormetic!profile!
and! the! molecular! agents! affecting! the! brain.! Based! on! this! information,! the! authors! proposed! and!
investigated!whether!the!reaction!of!AHN!to!exercise!demonstrates!a!biphasic/hormetic!dosage!response!
and!whether!specific!potential!mechanisms!supporting!this!reaction!pattern!might!be!identified!in!existing!
literature.!
The!response!to!this!statement!is!critical!not!only!for!our!understanding!of!exercise!neurobiology!
but!also!for!improving!AHN!(hormesis),!which!can!readily!affect!and!increase!our!efforts!to!modify!adult!
neurogenesis!outside!of!exercise!(drugs!or!other!therapies).!
Exercise!has!long!been!acknowledged!to!have!a! favourable!impact!on! a!person's!brain! and!well-
being.!Exercise!not!only!increases!intelligence!but!also!increases!happiness!and!even!the!number!of!neurons!
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in!the! brain.! However,! it! is! crucial! to! note! that! the! impacts! of! exercise!are! not! consistent! for! everyone;!
instead,!they!vary!based!on!the!dosage!of!the!exercise!regimen.!The!concept!of!hormetic!stress,!that!is,!when!
the!body!is!exposed!to!sufficient!stress!to!stimulate!an!adaptive!response!without!damaging!it,!becomes!
relevant! in! this! context.! Therefore,! it! is! essential! to! understand! the! biphasic! dose! response! to! exercise,!
where! appropriate! exercise! intensity! produces! benefits,! while! exercise! that! is! too! vigorous! can! have!
adverse!effects.!However,!to!date,!there!is!insufficient!evidence!regarding!the!potential!mediators!involved!
in!this!biphasic!dose!response.!
Recent!research!in!this!area!has!highlighted!the!importance!of!exercise!intensity!in!influencing!the!
exercise!response!to!cognition!and!mood.!Recent!research!has!also!identified!variables!that!influence!AHN!
as!a!potential!physiological!foundation!for!the!hormetic!reaction!to!exercise.!However,! a!limitation!of!recent!
studies!is!that!they!have!yet!to!reveal!the!molecular!mechanisms!that!may!mediate!these!effects!fully.!
Although!there!have!been!several!studies!leading!to!an!understanding!of!the!relationship!between!
exercise!intensity,!adult!hippocampal!neurogenesis,!and!hormetic!effects,!there!still!needs!to!be!a!gap!in!
understanding! the! molecular! mechanisms! that! link! these.! Some! studies! also! noted! differences! between!
their!findings!and!those!of!other!studies,!which!require!further!clarification.!Therefore,!we!need!to!explore!
further!how!exercise!influences!neurogenesis!and!mood!through!a!comprehensive!and!integrated!approach.!
Based!on!the!identified!gap!analysis,!this!study!aimed!to!provide!more!clarity!on!the!biphasic!dose!
response! concerning! exercise,! explicitly! concentrating! on! adult! hippocampal! neurogenesis! (AHN)! as! a!
potential!intermediary.!The!authors!will!seek!a!deeper!understanding!of!the!molecular!mechanisms!that!
play!a!role!in!linking!exercise,!neurogenesis,!cognition,!and!mood.!The!study!will!also!seek!to!differentiate!
the! impacts! of! varying! exercise! intensities! on! the! body! and! brain.! Thus,! this! research! will! make! a! new!
contribution!to!the!understanding!of!the!link!between!exercise,!neurogenesis,!and!mental!well-being.!
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METHODS)
The! method! of! conducting! a! literature! review! is! a! systematic! process! that! involves! defining! the!
research! objectives,! establishing! a! search! strategy,! selecting! relevant! sources,! critically! evaluating! their!
quality,! categorising! and! grouping! them! based! on! emerging! themes,! and! finally,! synthesizing! the! main!
findings! to! provide! a! comprehensive! understanding! of! the! research! area.! A! literature! review! helps!
researchers!build!a!strong!foundation!for!their!investigations,!identifies!gaps!in!the!existing!knowledge,!and!
contributes!to!the!broader!academic!discourse.!
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RESULTS)
Exercise$and$the$Brain!
Furthermore,!the!connection!between!physical!exercise!and!cognitive!function!in!the!brain!is!not!a!
mere!coincidence;!instead,!it!closely! aligns!with!the!individual's!level! of!physical!activity!(Foster,!2015).!
What!is!noteworthy!is!that!physical!activity!triggers!both!structural!and!functional!changes!in!the!brain.!
This!adaptive!plasticity!in!the! brain!enables!it!to! adapt!its!neuronal!resources!to!meet!the!varying!dem ands!
of!information!processing!(Chen & Tonegawa, 1997).!These!changes!encompass!aspects!such!as!neuronal! cell!
metabolism,!gene!expression,!cell!size,!dendritic!structure,!synaptic!count,!blood-brain!barrier!properties,!
and! synaptic! plasticity.! Beyond! these! alterations! to! existing! cells,! neural! resources! also! encompass! a!
concept! known! as! meta! plasticity,! particularly! adult! neurogenesis,! which! involves! recruiting! additional!
neurons!through!cellular!and!synaptic! m odifications!in!specific!regions!of!the!adult!brain!(García-Capdevila!
et!al.,!2009).!
In!this!context,!it!is!unsurprising!that!physical!exercise!regimens!have!frequently!been!documented!
to!actively!enhance!synaptic!plasticity,!nerve!cell!metabolism,!and!blood!circulation!in!specific!brain!regions.!
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This!improvement!in!neural!processing!abilities!has!been!observed!in!various!human!populations,!including!
adults,!children,!and!tee nagers.!Furthermore,!when!compared!to! other!primates,!hum ans!have!a!distinctive!
talent!for!endurance!running!(Mattson,!2012).!Regular!exercise!improves!numerous!parameters!related!to!
neurodegenerative!illnesses!and!produces!neuroprotection!in!all!investigated!brain!areas.!Finally,!exercise!
has! been! reported! to! be! an! effective! technique! for! reversing! the! symptoms! of! some! neurodegenerative!
diseases!as!well!as!numerous!brain!impairments!and!disorders!(Dishman!et!al.,!2006;!Mattson,!2012).!
From!a!mechanistic!viewpoint,!physical!activity!can!enhance!blood!circulation!(Lucas!et!al.,!2015)!
and!modulate!growth!factor!signalling!pathways,!particularly!insulin-like!growth!factor!1!(IGF-1),!which!
functions! as! a! hormone! that! governs! the! impacts! of! growth! hormone! (GH)! in! the! body,! promoting! the!
average!growth!of!bones!and!tissues!(Llorens-Martín!et!al.,!2008).!Additionally,!exercise!influences!brain-
derived!neurotrophic!factor!(BDNF),!as!highlighted!by!Gomez-Pinilla!and!Hillman!in!(2013).!Moreover,!it!
impacts!the!Vascular!Endothelial!Growth!Factor!(VEGF),!a!protein!pivotal!in!the!process!of!angiogenesis.!
Angiogenesis! refers! to! the! creation! of! fresh! blood! vessels.! According! to! Meng! (2006)! VEGF! is! a!
protein!that!improves!the!availability!and!activity!of!neurotransmitters!(particularly!dopamine,!glutamate,!
norepinephrine,! and! serotonin).! Sport,! on! the! other! hand,! has! negative! consequences! that! cannot! be!
separated.!These!stressors!include!thermal,!metabolic,!hypoxic,!and!oxidative!stress,!as!well!as!mechanical!
stress!(Peake!et!al.,!2015).!!
Humans!exhibit!increased!running!endurance,!representing!one!aspect!of!the!hormetic!response.!
This! response! involves! a! low-dose! stressor! that! triggers! an! adaptive! reaction,! improving! the! ability! to!
endure! and! cope! with! moderate! to! intense! levels! of! stress! (Calabrese! et! al.,! 2007;! Mattson,! 2012).!
Nonetheless,! multiple! research! endeavours! have! shown! an! inverted! U! performance! curve! in! cognitive!
function!following!exercise!in!humans!(Tomporowski,!2003).!This!correlation!is!complex!and!significantly!
affected!by!the!duration!of!the!intense!but! short-lived!effort,!which!often!results!in!a!swift!restoration!of!an!
individual's! abilities! alongside! the! individual's! initial! fitness! level! before! the! research.! This! factor!
contributes!to!the!absence!of!a!clear-cut!impact!concerning!brief,!intense!workout!routines!(Tomporow ski,!
2003).!Additionally,!motivation!to!engage!in!acute!exercise!or!long-term!resistance!training!significantly!
influences!any!conclusions!drawn!about!the!association!between!exercise!and!cognitive!performance!in!
humans.!
Continuous! aerobic! activity,! however,! results! in! reduced! information! processing! and! cognitive!
function,!which!is!contingent!upon!the!level!of!dehydration,!a!factor!varying!with!the!workout!duration.!As!
anticipated,!exercise!leads!to!increased!oxidative!stress!due!to!heightened!oxygen!utilisation!by!the!body!
during!physical!activity,! which!is!closely!linked!to!fluctuations!in!the!way!energy!is!metabolised.!This!aspect!
of!an!exercise!regimen!significantly!contributes!to!the!adverse!impacts!of!intense!workouts.!
While! it! is! widely! acknowledged! that! exercise! produces! non-linear! response! patterns,! including!
hormetic!effects,!across!various!studied!outcomes!(Radak!et!al.,!2008),!it!is!essential!to!understand!that!this!
biphasic!reaction!is!closely!linked!to!oxidative!stress,!oxygen!consumption,!and! mitochondrial!metabolism.!
All! available! evidence! underscores! its! influence! on! the! entire! body,! especially! on! muscles! and! the!
cardiovascular!system.!Regarding!the!brain,!it!is!essential!to!note!that!exercise!enhances!the!production!of!
reactive! oxygen! species! (ROS),! antioxidant! enzymes,! and! redox! signalling! within! the! body.! Circulating!
factors!also!have!the!potential!to!induce!oxidative!stress!(Calabrese!et!al.,!2007).!Since!the!generally!positive!
effects!of!exercise!on!brain!oxidative!stress!are!primarily!attributed!to!the!increased!activity!of!antioxidant!
enzymes!as!summarised!by!Radak!et!al.,!(200 8),!it!is!recommended!that!there!be!a!sophisticated!regulation!
and!balance!between!the!induction!of!exercise-related!systemic!stress.!
ROS!can!modify!unsaturated!fats!through!oxidation,!influencing!the!brain's!flexibility!and!physical!
condition.!Brain!antioxidant!enzymes!participate!in!the!brain's!reaction!to!exercise!following!a!bell-shaped!
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hormesis!curve.!High!ROS! levels!can!induce! oxidative! harm,! while!moderate! ROS!levels! might! stimulate!
adaptive!reactions!(Radak!et!al.,!2008).!
Biphasic$Responses$to$Exercise$Cognition$and$Mood$
This! study! did! not! try! to! discover! which! specific! qualities! are! ideal! for! obtaining! favorable! or!
adverse! effects! with! exercise! training! protocols,! as! comparisons! between! different! activities! have! been!
found!in!several!meta-analyses!to!be!highly!challenging!due!to!the!difficulty!of!comparing!training!intensity!
degrees!between!research,!and!since!more!is!needed!about!the!numerous!training!regime!characteristics!
that!influence!training!results.!What!is!most!important!in!this!study!is!whether!the!authors!discovered!a!
biphasic! response! regardless! of! the! methodology! used.! The! cognitive! approach! is! the! framework! in!
psychology!which!focuses!on!understanding!how!humans!process!information,!organize!knowledge,!and!
apply!it!in!problem-solving!and!decision-making.!
To!the!best!of!the!authors'!knowledge,!very!few!research!have!found!that!high-intensity!exercise!
improves!cognition.!One!study!that!stands!out!is!one!that!found!increased!memory!performance!in!a!heavy!
exercise!program!and!overtraining!in!a!passive!avoidance!test!(Ogonovszky!et!al.,!2005).!Surprisingly,!the!
study! found! increased! BDNF! (Brain-derived!neurotrophic!factor)! levels.! It! is! a! neurotrophin! factor! that!
influences!supporting!the!formation!and!development!of!neurons!and!maintaining!the!existence!of!neurons!
only!in!the!group!that!did!the!most!intense!exercise.!
The!response!of!hormesis!to!exercise!has!biological!significance.!A!sedentary!lifestyle!has!a!negative!
impact!on!brain!function,!whereas!exercise!is!one!of!the!critical!behaviors!that!help!maintain!health.!It!is!
rational!to!anticipate!that!the!benefits!of!exercise! becom e!more!favourable!as!one!transitions!from!inactive!
tasks!to!exercise!of!moderate!and!high!intensity.!The!exercise!response!is!expected!to!display!a!sigmoidal!
pattern,!constrained!by!certain!thresholds:!past!a!certain!point!of!exercise!intensity,!duration,!or!frequency,!
there!will!not!be!further!accumulation!of!positive!effects!due!to!the!inherent!limits!of!the!body!and!brain's!
exercise!capacity.!Alterations!in!reaction!to!physical!activity!and!maximal!capacity!to!modify!body!and!brain!
performance!do! not! always! increase! linearly.! The! evidence! that! has! been! highlighted! suggests! this.! The!
response!to!exercise!typically!aligns!more!with!hormesis!profiles,!where!increments!in!intensity,!duration,!
or!frequency!of!training!can!lead!to!the!loss!of!the!favourable!effects!experienced!with!low!to!moderate-
intensity! exercise.! Why! does! this! occur?! As! mentioned! earlier,! exercise! serves! as! a! form! of! stress.! The!
beneficial! effects! of! exercise! on! different! body! systems! like! muscles,! bones,! the! immune! system,! the!
cardiovascular! system,! and! the! brain! improve! overall! health! and! increase! the! body's! ability! to! manage!
additional!stress.!However,!there!is!a!specific!level!of!intensity!where!exercise-induced!stress!can!result!in!
less!favourable!outcomes,!and!sometimes,!it!might!even!cause!adverse!effects!(exhibiting!inverted!U-shaped!
or! even! inverted! J-shaped! hormesis! curves).! This! is! due! to! the! prolonged! influence! of! hormonal! stress!
throughout!the!entire!body.!Thus,!the!natural!stress!linked!to!physical!activity!is!believed!to!significantly!
impact!the!hormesis!pattern!observed!in!the!response!to!exercise.!However,!the!following!will!present!an!
explanation!of!the!second!biological!evolutionary!advantage!of!the!hormetic!response!to!exercise,!focusing!
on!AHN.!
Molecular$Mediators$of$Exercise$Action$
Exercise!exerts!both!beneficial!and!detrimental!influences!on!the!brain.!Among!the!critical!factors!
at! play! is! the! array! of! growth! factors! stimulated! by! physical! activity,! including! IGF1,! BDNF,! and! VEGF!
(Dishman! et! al.,! 2006;! Llorens-Martín! et! al.,! 2008),! which! are! believed! to! underlie! most! of! the! positive!
effects,!in! addition!to!its!anti-inflammatory!actions!(Silverman & Deuster, 2014).!Conversely,!oxidative!stress!
signalling! is! recognised! as! the! most! significant! adverse! factor! post-exercise.! Another! critical! element!
influencing! the! outcomes! of! exercise! training! programs! is! the! individual's! dietary! and! lifestyle! choices!
(Gomez-Pinilla & Hillman, 2013).!However,!this!review's!scope!is!insufficient!for!an!exhaustive!exploration!of!
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the!various!molecular!agents!that!govern!the!effects!of!exercise.!A!well-established!consensus!(Mattson,!
2012)!identifies!physical!and!cognitive!activity,!along!with!control!of!nutrient!intake,!as!triggers!for!mild!
metabolic!stress!in!neuronal!cells.!This!pathway!activates!multiple!transcription!factors,!such!as!CREB!and!
NF-kB,! which,! in! turn,! regulate! the! expression!of! BDNF! and! anti-apoptotic! genes! (such! as! Bcl-2).! These!
factors!promote!cell!survival,!synaptic!plasticity,!and!neurogenesis!processes.!
The!objective!of!this!study!is!to!emphasize!the!growing!body!of!evidence!indicating!that!both!the!
positive!and!negative!effects!of!exercise!are!typically!regulated!by!the!same!factors,!following!a!biphasic!
dose-response!pattern!akin!to!hormesis.!For!example,!many!of!the!beneficial!outcomes!of!exercise!depend!
on!the!concurrent!increase!in!BDNF!(Mattson,!2012)!and!IGF1!(Llorens-Martín!et!al.,!2008),!in!conjunction!
with!the!interplay!between!caloric!restriction!and!an!individual's!activity!level!(Mattson,!2012)!However,!
elevated!levels!of!BDNF!and!IGF1!can!be!detrimental!to!the!brain,!and!dietary!intake!is!associated!with!the!
risk! of! neurodegenerative! diseases! following! a! biphasic! dose-response! curve.! Furthermore,! it! is! not!
surprising!that!all!these!factors!and!lifestyle!choices!are!linked!to!energy!balance.!
While!all!the!factors!discussed!above!play!a!direct!role!in!the!effects!of!physical!exercise!on!cognition!
and! mood,! recent! research! over! the! past! decade! has! revealed! a! strong! connection! between! adult!
neurogenesis!and!these!changes,!with!adult!neurogenesis! being!directly!influenced!by!such!growth!factors.!
Actions$of$Exercise$and$Adult$Hippocampal$Neurogenesis$
Adult!neurogenesis!refers!to!the!process!of!generating!functional!new!neurons!in!the!adult!brain!
(Kempermann,!2011).!It!is!widely!recognised!that!exercise!impacts!the!rate!of!mature!neurogenesis!and!
influences! the! creation! of! new! nerve! cells! in! both! the! hippocampus! and! olfactory! system.! Additionally,!
enriched!environments!are!known!to!enhance!the!survival!of!immature!nerve!cells,!as!outlined!in!seminal!
reviews!by!Mattson!(2012),!Olson!et!al.!(2006),!and!in!a!comprehensive!recent!review.!While!some!data!
suggest!that!exercise!may!affect!the!olfactory!system,!there!are!conflicting!reports!as!well!(Bekinschtein!et!
al.,! 2011).! This! experience-induced! plasticity! has! been! suggested! as! a! necessary! process! for! optimising!
brain!function!(Opendak & Gould, 2015).!Several!mechanisms!have!been!strongly!linked!to!the! impact!of!
exercise!on!AHN,!the!most!notable!of!which!include!IGF1!(Llorens-Martín!et!al.,!2008),!BDNF!(Bekinschtein
et al., 2011; Chen & Tonegawa, 1997; Rothmann & Cooper, 2015).!
The$Biphasic$Response$of$Adult$Hippocampal$Neurogenesis$
AHN!shows!a!response!pattern!like!hormesis,!displaying!a!non-linear!curve!after!various!treatments!
or!interventions.!At!low!concentrations,!glucocorticoids!(Glucocorticoid!hormones!are!steroids!that!have!
21! carbon! atoms! with! the! primary! function! of! increasing! gluconeogenesis)! stimulate! beneficial! and!
protective! responses! in! hippocampal! dentate! granule! neurons! through! mineralocorticoid! receptors.! In!
contrast,!at!higher!concentrations,!deleterious!effects!are!achieved!via!glucocorticoid!receptors.!A!situation!
like!this!occurs!when!we!talk!about!the!impact!of!glucocorticoids!on!AHN!(Leuner!et!al.,!2012)!When!the!
glucocorticoid!receptor!(GR)! is! minimally! activated,!like! in! less!stimulating! environments! or!with!a! less!
active!lifestyle,!adult!neurogenesis!remains!at!low!levels—both!in!cell!production!and!maturation.!However,!
in! enriched! environments,! frequent! moderate! physical! activity! or! acquiring! knowledge,! the! GR! gets!
activated!to!an!average!level,!resulting!in!a!baseline!of!AHN.!On!the!flip!side,!high!GR!activity!caused!by!
uncontrolled! stress! significantly! reduces! neurogenesis! by! affecting! the! creation! and! development! of!
immature!brain!cells.!This!situation!creates!a!response!pattern!shaped!like!an!upside-down!U!(Saaltink &
Vreugdenhil, 2014).! The! mechanism!that!stops!the! cell! growth! caused!by! adrenal!steroids!in!the! dentate!
gyrus!(Gould & Tanapat, 1999)!is!influenced!by!the!N-Methyl-D-aspartate!receptor.!
Apart!from!the!widely!recognised!instances!of!hormetic !reactions,!recent!evidence!has!accumulated!
with!more!examples.!For!instance,!when!neural!stem!cells!are!exposed!to!mild!doses!of!chemical,!physical,!
or!drug-induced!stimuli!(while!high!levels!co uld!be!toxic),!they!protect!these!cell!precursors!in!situations!of!
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neurodegenerative! diseases! (Wang,! 2014).! A! new! study! revealed! that! the! positive! effects! of! calorie!
restriction!on!generating!new!brain!cells!are!controlled!by!the! appetite-stimulating!hormone!receptor!acyl-
ghrelin! and! the! gene! activator! Egr1! (Hornsby! et! al.,! 2016).! This! hormone! receptor! plays! a! role! in! the!
hormesis-like!reaction!of!AHN!to!maintain!a!balance!in!energy!levels.!Similarly,!specific!components!found!
in!ginseng!exhibit!beneficial!effects!on!forming!new!neurons!but!in!a!manner!that!depends!on!the!dose!and!
time,!as!shown!by!Liu!et!al.!(2008).!This!characteristic!is!also!found!in!many!plant-based!chemicals!reviewed!
by!Mattson!et!al.!(2012).!The!range!of!reactions!of!adult!neurogenesis!to!different!substances!is!extensive,!
including!oxytocin,!bisphenol,! allopregnanolone,! exposure!to!lead!poisoning,!statin,!and!even!fluoxetine.!
However,!both!VEGF!and!TGF-β!exhibit!dual!effects!on!the!process!of!neurogenesis.!Higher!doses!of!VEGF!
reduce!the!presence!of!natural!VEGF!receptors!leading!to!more!mature!neurons!but!less!production!of!new!
cells).!Lower!doses!increase!the!number!of!VEGF!receptors!(without!a!noticeable!effect!on!producing!new!
cells!or!their!maturity,!Meng!et!al.,!(2006).!Lower!amounts!of! TGF-β!promote!the!creation!of!new!brain!cells,!
while!higher!levels!trigger!programmed!cell!death!in!the!growth!of!the!autonomic!nervous!system.!
As!more!evidence!supports!the!biphasic!reaction!to!exercise!impacting!diverse!brain!aspects!like!
cognition! and! mood,! along! with! the! biphasic! reaction! of! AHN! to! different! factors,! the! AHN! has! been!
suggested! as! a! pivotal! mediator! in! multiple! aspects.! When! examining! the! impacts! of! exercise,! the!
subsequent!query!arises!about!whether!there!exists!a!biphasic!response!of!the!AHN!to!exercise.!
First$Hypothesis$and$Evidence$Supporting$a$Biphasic$Response$of$Adult$Hippocampal$Neurogenesis$
to$Exercise$
Based!on!indirect!evidence!and!two!recent!direct!findings,!the!authors!propose!the!theory!that!AH N!
serves!as!a!physiological!basis!for!hormetic!responses!induced!by!physical!activity,!influencing!cognition!
and!mood.!To!verify!this!hypothesis,!they!propose!examining!various!AHN-related!parameters'!responses!
to!different!levels!of!exercise!intensity,!particularly!intensities!higher!than!the!lactate!(anaerobic)!threshold.!
They!argue! that!this! hypothesis!aligns! better! with! the!mentioned! literature,! recent!direct! evidence,!and!
prospective! data! testing! this! effect,! as! opposed! to! the! currently! established! sigmoidal! dose-response.!
However,!it!is!acknowledged!that!the!dose!response!of!AHN!to!exercise!is!a!well-established!fact!(Holmes!
et!al.,!2004).!Initially,!this!answer!is!monotonous,!as!increases!in!training!intensity!(training!volume)!from!
a!sedentary!basal!level!rapid ly!led!to!an!increase!in!the!rate!of!neurogenesis.!Only!a!little!evidence!has!been!
gathered!regarding!a!biphasic!response!when!the!intensity!of!the!exercise!reaches!a!gruelling!or!very!high!
level.!As!far! as!the!authors!are!aware,!there!are!only!a!few!findings!have!presented!evidence!in!this!direction.!
One! research! study! noted! heightened! neurogenesis! (observed! through! BrdU/NeuN! labelling! without!
employing! stereological! methods)! and! increased! mRNA! levels! of! BDNF,! NMDAR1,! and! Flk-1,! solely!
following! low-intensity! exercise.! Conversely,! high-intensity! exercise! resulted! in! the! restoration! of! all!
parameters!to!baseline!levels!without!exhibiting!substantial!alterations!(Lou!et!al.,!2008).!!
Notably,!the!benefits!of!neurogenesis!induced!by!slightly!stressful!(mild)!exercise!are!contingent!
upon! the! activation! of! glucocorticoid! receptors,! implying! a! supportive! and! permissive! function! of! these!
receptors!and!moderate!glucocorticoid!levels!during!moderate!exercise.!This!information,!combined!with!
the! previously! discussed! hormetic-like! reaction! to! hippocampal! glucocorticoid! action,! suggests! that!
glucocorticoid!receptors!are! a! highly!likely! mechanism! mediating!the! hormetic! and! biphasic! reaction!of!
AHN!to!varying!levels!of!workout!intensity.!However,!the!glucocorticoid!receptor!is!not!the!sole!factor!at!
play!in!this!process.!
Ultimately,!several!studies!found!that!different!types!of!hormetic!responses!of!AHNs!to!training!exist!
despite!the!absence!of!pro-proliferative!solid!effects!produced!by!training!(Kronenberg!et!al.,!2006).!As!a!
result,!the!hormetic!reaction!in!adult!neurogenesis!due!to!training!is!observable!not!just!from!increasing!
doses!but!also!over!extended!periods!of!training.!
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It!is!essential!to!be!mindful!of!one's!biological!state!towards!exercise,!as!intrinsic!stress!associated!
with!exercise!beyond!a!certain!threshold!can!trigger!harmful!stress!hormones!that!eliminate!the!benefits!of!
exercise!on!the!body,!including!the!brain.!This!sensitivity!to!hormones!holds!more!relevance!for!the!adult!
hippocampus,!as!higher!brain!regions!regulate!stress!hormone!levels!in!the!body.!Additionally,!the!specific!
sensitivity! of! the! Adult! Hippocampal! Neurogenesis! (AHN)! to! stress! hormone! concentrations! should! be!
considered.!Moreover,!the!authors!put!forward!an!alternative!explanation!for!this!pattern,!specifically!in!
relation!to!adult-generated!neurons.!It!is!theorised!that!an!elevated!quantity!of!new!neurons!in!the!adult!
hippocampus!might!not!necessarily!be!beneficial;!instead,!an!excessively!high!number!of!new!neurons!could!
be! detrimental! to! the! functioning! of! the! tri-synaptic! hippocampal! circuits.! Excessive! immature! neurons!
exhibit! distinct! electrophysiological,! morphological,! and! connectivity! characteristics,! and! their!
incorporation!into!a!fully!mature!circuit,!which!includes!mature!granule!neurons!with!diverse!physiological!
properties,! could! potentially! disrupt! system! function,! especially! after! intense! exercise.! The! findings!
presented! in! this! study! are! most! accurately! understood! within! the! context! of! the! proposed! hypothesis,!
representing!an!adjustment!to!extremely!high-intensity!exercise,!preventing!the!excessiv e!accumulation!of!
new!neurons!beyond!a!certain!threshold,!leading!to!a!U-shaped!response.!
Mechanisms$of$the$Biphasic$Response$of$Adult$Hippocampal$Neurogenesis$to$Exercise$
Based!on!the!mentioned!literature,!as!a!second!part!of!the!Authors'!hypothesis,!they!also!suggest!
that!growth!factors!(such!as!IGF1!and!BDNF,!which!are!significant!key!factors)!that!mediate!the!effect!of!
exercise!on!AHN!can!control!this!response!curve.!Besides!GR,!various!other!mediators!responsible!for!the!
influence! of! exercise! on! adult! hippocampal! neurogenesis! (AHN)! have! been! observed! to! exhibit! dose-
response! patterns! reminiscent! of! hormesis! for! different! brain! parameters,! not! limited! to! neurogenesis.!
These!factors!could!play!a!role!in!mediating!the!biphasic!response!of!neurogenesis.!IGF1!is!one!such!factor,!
with!repeated!exercise!sessions!either!showing!no!change!or!even!a!decrease!in!serum!levels,!as!reported!
by!Kramer!et!al.!in!(1995),!while!long-term!exercise!raised!IGF1!levels!above!their!pre-exercise!baseline,!as!
shown!by!Eliakim!et!al.!in!(2006).!IGF1!is!known!to!safeguard!neurons!at!lower!concentrations,!but!at!higher!
levels,! it! may! have! no! effect! or! even! produce! a! counteractive! impact.! This! biphasic! pattern! has! been!
observed!in!both! live! animal!studies! (Johnston! et! al.,!1996)!and!controlled!laboratory!experiments.!The!
precise!mechanism!behind!the!biphasic!effects!of!IGF1!on!the!brain!remains!somewhat!unclear.!However,!
one!plausible!explanation!is!the!well-documented!biphasic!effects!of!insulin-like!growth!hormone!binding!
proteins,!which!regulate!the!availability!of!IGF!at!conventional!IGF!receptors.!For!example,!in!the!choroid!
plexus,!IGFBP2!enhances!the!biological!effects!of!IGF1!at!lower!concentrations!but!diminishes!its!effects!at!
higher!concentrations,!as!demonstrated!by!Delhanty!and!Han!(1993).!This!biphasic!action!of!IGF1!has!also!
been!observed!in!other!organs,!such! as!the!kidney!(Wang,!2014)!and!muscle.!Similarly,!the!secretion!of!
VEGF! in! retinal! epithelial! cells,! which! regulates! cell! proliferation,! displays! a! hormesis-like! response! to!
hydroxynonenal!when!exposed!to!oxidative!stress.!(Vatsyayan!et!al.,!2012).!
In!the!end,!the!influence!of!reactive!oxygen!species!(ROS)!may!play!a!role!in!mediating!hormesis!in!
response!to!exercise!(Radak!et!al.,!2008).!As!previously!mentioned,!ROS!are!substances!generated!during!
exercise,!the! extent! of! which! depends! on!their!intensity.! Oxidative! stress! represents!a!fundamental! and!
crucial!reaction!to!the!"alterations!in!redox!homeostasis"!induced!by!exercise,!as!outlined!by!Nikolaidis!et!
al.! in! (2012).! Depending! on! their! concentrations,! ROS! can! serve! as! regulators! in! signalling! processes,!
maintaining! redox! balance,! or! they! can! be! harmful! to! essential! cellular! components.! Low! levels! of! ROS!
provoke!a!moderate!stress!response,!while!high!levels!can!lead!to!excessive!stress,!especially!during!high-
intensity!exercise,!exhibiting!a!typical!U-shaped!dose-response!pattern.!This!hormetic!profile!reflects!an!
adaptive!response!to!stress,!where! mild!to!moderate!challenges!enhance!the!resilience!of!various!organ!
systems! against! higher! levels! of! stress.! Although! ROS! produced! through! exercise! can! cause! oxidative!
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damage!to!lipids,!proteins,!and!DNA,!they!also!activate!redox-sensitive!transcription!factors!and!signalling!
pathways!necessary!for!adaptive!responses!(Mattson,!2012;!Radak!et!al.,!2008).!
Similarly,!various!other!factors!that!exhibit!biphasic!dose-response!curves,!such!as!hormones,!also!
have!significant! relevance.! An! example! that!illustrates! this! is! the! potential!detrimental! impact! of! forced!
exercise!on!a!treadmill!after!deep!brain!surgery!(Jun!et!al.,!2012).!These!findings!can!be!interpreted!that!
surgery! reduces! the! positive! reaction! to! exercise! and! shortens! the! hormesis! zone! in! a! biphasic! effect!
(Calabrese! et! al.,! 2007).! In! response! to! this,! recent! research! has! shown! that! exercise! intensity! must! be!
reduced! following! previously! experienced! stress! to! effectively! produce! positive! effects! that! are! often!
assessed!through!a!variety!of!physiological!parameters!(Kim!et!al.,!2015)!
$
CONCLUSION$
Multiple!studies!have!shown!that!adult!neurogenesis!(AHN)!demonstrates!effects!characterised!by!
a! biphasic! response! akin! to! hormesis! when! subjected! to! exercise.! Moreover,! various! research! reports!
indicate!that!the!molecular!agents!influencing!the!impact!of!exercise!on !neurogenesis!also!exhibit!a!biphasic!
pattern!regardless!of!their!direct!involvement!in!the!effects!on!AHN!caused!by!exercise.!Considering!these!
sets! of! evidence,! the! Authors! propose! a! hypothesis! suggesting! that! adult! neurogenesis! serves! as! the!
foundational! basis! for! the! hormetic! reactions! regarding! cognition! and! mood! resulting! from! exercise.!
Additionally,!growth!factors!like!IGF1!and!BDNF,!recognised!as!pivotal!elements!in!mediating!the! influence!
of!exercise!on!AHN,!are!considered!plausible!candidates!for!mediating!this!response!pattern!in!conjunction!
with!ROS.!
!
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