Rev. Neurosci.

2021; aop

Juan Liang, Huiqing Wang, Yan Zeng, Yi Qu, Qian Liu, Fengyan Zhao, Jianan Duan, Yin Jiang,
Shiping Li, Junjie Ying, Jinhui Li* and Dezhi Mu*

Physical exercise promotes brain remodeling by

regulating epigenetics, neuroplasticity and
neurotrophins
https://doi.org/10.1515/revneuro-2020-0099
Received September 1, 2020; accepted October 26, 2020;
published online February 15, 2021
Abstract: Exercise has been shown to have beneficial effects
on brain functions in humans and animals. Exercise can
improve memory and learning in age-related neurodegener-
ative diseases. In animal models, physical exercise regulates
epigenetics, promotes synaptic plasticity and hippocampal
neurogenesis, regulates the expression levels of neurotrophic
factors, and improves cognitive function. Therefore, exercise
is very important for brain rehabilitation and remodeling. The
purpose of this review is to explore the mechanisms by which
exercise exerts positive effects on brain function. This
knowledge implies that physical exercise can be used as a
non-drug therapy for neurological diseases.
Keywords: brain; epigenetics; improvement; neurotrophic
factors; physical exercise; plasticity.
Introduction
The central nervous system plays important roles in ho-
meostasis, learning, memory function, and information
Juan Liang and Huiqing Wang contributed equally to this review.
*Corresponding authors: Jinhui Li and Dezhi Mu, Department of
Pediatrics, West China Second University Hospital, Sichuan
University, Chengdu 610041, China; and Key Laboratory of Birth
Defects and Related Diseases of Women and Children (Ministry of
Education), West China Second University Hospital, Sichuan
University, Chengdu 610041, China, E-mail: yoyolee824@163.com
(J. Li), mudz@scu.edu.cn (D. Mu).
Juan Liang, Huiqing Wang, Yan Zeng, Yi Qu, Qian Liu, Fengyan Zhao,
Yin Jiang, Shiping Li and Junjie Ying, Department of Pediatrics, West
China Second University Hospital, Sichuan University, Chengdu
610041, China; and Key Laboratory of Birth Defects and Related
Diseases of Women and Children (Ministry of Education), West China
Second University Hospital, Sichuan University, Chengdu 610041,
China
Jianan Duan, West China Hospital, Sichuan University, Chengdu
610041, China
analysis. It is composed of billions of nerve cells. They
connect through synapses to form a complex neural
network, finely regulating a multitude of body functions.
Although it has been reported that brain damage is usually
irreversible, increasing evidence shows that physical ex-
ercise plays a protective role in various diseases, such as
Alzheimer’s disease (AD), Parkinson’s disease (PD),
depression, and stroke (Cass 2017; Ignacio et al. 2019; Pin-
Barre and Laurin 2015; Xu et al. 2019). The positive effects
are reflected in improved memory and cognition, enhanced
motor function, better-regulated mood, and strengthened
motor rehabilitation (Cass 2017; Kvam et al. 2016; Pin-Barre
and Laurin 2015; Sharp and Hewitt 2014). Over the life span
of a human, brain atrophy can be demonstrated by using
neuroimaging techniques (Nosheny et al. 2019), and the
plasma levels of some neurotrophic factors, such as brain-
derived neurotrophic factor (BDNF), insulin-like growth
factor 1 (IGF-1), and vascular endothelial growth factor
(VEGF), are decreased in the aged population (Ashpole
et al. 2015; Muñoz et al. 2018; Siuda et al. 2017). Researchers
have found that exercise can upregulate the levels of
neurotrophic factors, enhance angiogenesis, and promote
hippocampal neurogenesis from animal studies (Cotman
et al. 2007; Ding et al. 2006a,b; Trejo et al. 2001). This
review summarizes various mechanisms such as epige-
netic, neuroplasticity, and neurotrophic factors by which
exercise may improve brain function. We think that these
mechanisms will help brain rehabilitation and remodeling
in patients with brain disorders. Furthermore, these find-
ings can be used as the basic theory to support exercise-
induced improvements and enhance the quality of life in
patients with various neurological diseases.
Exercise benefits neuroprotection
by regulating epigenetics
Epigenetic inheritance refers to the change of gene
expression and regulation without changing the DNA
sequence. Epigenetic information differs from classical
genetic information that involves changes in gene quality
2 J. Liang et al.: Exercise promotes brain remodeling
and gene expression levels caused by alterations of the
gene sequence. Although epigenetic information does not
change genes, the quantity of the encoded protein can be
changed. Epigenetics was originally defined as the heri-
table but reversible effect on gene expression without
altering DNA base pairs, primarily including histone
modification, DNA methylation, chromatin remodeling,
and microRNAs (miRNAs) (Burggren 2016; Tammen et al.
2013). Figure 1A shows exercise-induced epigenetic factors
regulation on brain remodeling.
Histone modification
Histone modification is one of the key mechanisms of gene
transcription regulation, achieved by both histone acetyl-
transferase (HAT) and histone deacetylase (HDAC). The
HAT can activate the transcription process of specific
genes, whereas HDAC can inhibit this process (Ali et al.
2018). Exercise can activate both HAT and HDAC, thereby
influencing histone modification and DNA replication
(Maejima et al. 2018a,b). Recently, evidence has shown
that exercise can upregulate HAT activity, increase histone
acetylation level, and downregulate HDAC activity in the
hippocampus (Elsner et al. 2011). The decrease in HDAC
activity may be related to neuronal apoptosis (Elsner et al.
2011; Ryu et al. 2003; Saha and Pahan 2006). In
senescence-accelerated mice prone 8 (SAMP8) model, ex-
ercise was found to increase HAT activity and decrease the
activity of HDAC thereby improving cognitive function. The
results of this study suggest that exercise-induced alter-
ations of HAT and HDAC in SAMP8 mice have an impact on
chromatin remodeling, autophagy, and memory formation
(Cosin-Tomas et al. 2014). In rat models of stress (novelty
exposure, forced swimming, etc.), exercise induced his-
tone H3 phospho-acetylation and increased the number of
cFos-positive neurons in the dentate gyrus, which may be
associated with an increased ability to cope with stress. The
researchers also found that the intervention group showed
more immobility behavior than the control group (Collins
et al. 2009). In addition, previous research has shown that
histone H3 phospho-acetylation and cFos induction in
dentate granule cells are related to the immobility response
after re-test forced swimming (Bilang-Bleuel et al. 2005;
Chandramohan et al. 2008), which may be involved in the
memory formation of post-traumatic stress disorder (Reul
and Chandramohan 2007). This behavior after stressful
events may be associated with the activation of glucocor-
ticoid receptor-dependent histone modifications and the
N-methyl-D-aspartate (NMDA)/extracellular signal-regulated
kinase/mitogen- and stress-activated kinase signaling
pathway (Bilang-Bleuel et al. 2005; Chandramohan et al. 2008;
Reul and Nutt 2008). The adaptive response of epigenetics and
gene expression is a part of hippocampal neuroplasticity,
which may be involved in memory formation for events to
avoid anxiety and improve cognition in depression and stress-
related psychiatric disorders (Collins et al. 2009).
DNA methylation and chromatin remodeling
Besides the effect on HAT and HDAC, exercise has an in-
fluence on DNA methylation (Kashimoto et al. 2016). DNA
methylation, which is related to gene expression, refers to
the process in which the enzyme DNA methyltransferase
adds a methyl group to a cytosine moiety of a genomic
CpG dinucleotide at its 5′ carbon position (Jung and
Pfeifer 2015). Both acute and chronic exercise can signif-
icantly affect DNA methylation in a highly gene-specific
manner (Voisin et al. 2015). Exercise can improve the
cognitive processes in mouse models of aging, upregu-
late BDNF levels, and downregulate the hippocampal
expression of the neurotrophic factor receptor p75, which
is related to necrosis and apoptosis of neurons (Maejima
et al. 2018a,b). It has been reported that exercise can
reduce CpG methylation in the Bdnf promoter IV, leading
to DNA demethylation of this promoter (Gomez-Pinilla
et al. 2011).
Chromatin remodeling, an epigenetic mechanism, is a
biological process characterized by a series of changes in
chromatin nucleosomes mediated by the chromatin
remodeling complex (Tammen et al. 2013). Exercise can
increase the transcription and translation of BDNF and
promote the chromatin remodeling of the Bdnf gene, which
may be associated with the exercise-induced hypo-
methylation of the Bdnf promoter IV (Gomez-Pinilla et al.
2011; Vaynman et al. 2004). Exercise also up-regulates the
phosphorylation level of methyl-CpG binding protein
(MeCP2), which can increase the release of MeCP2 and
activate BDNF transcription (Gomez-Pinilla et al. 2011).
Without stimulus, MeCP2 suppresses BDNF transcription,
but this inhibitory MeCP2 effect disappears when neurons
are depolarized (Chen et al. 2003; Martinowich et al. 2003).
In addition, exercise can improve the activated stage of
both Ca2+/calmodulin-dependent protein kinase II (CaM-
KII) and cyclic adenosine monophosphate (cAMP)-
response element-binding protein (CREB) in the hippo-
campus (Gomez-Pinilla et al. 2011), which is vital for
exercise-induced effects on synaptic plasticity and cogni-
tion (Vaynman et al. 2003). Therefore, exercise can regu-
late brain function and plasticity to play a neuroprotective
role via chromatin remodeling of the Bdnf gene.
 J. Liang et al.: Exercise promotes brain remodeling 3

Figure 1: The mechanisms of physical exercise on neuroplasticity promotion.

(A) The influence of epigenetics, neurogenesis, and neurotrophins on brain remodeling. (B) Peripheral metabolic and hormonal substances
involved in brain remodeling. HAT, histone acetyltransferase; HDAC, histone deacetylase; Bdnf/BDNF, brain-derived neurotrophic factor;
MiRNA, microRNA; IGF-1, insulin-like growth factor 1; Gpld1, glycosylphosphatidylinositol phospholipase D1; CTSB, cathepsin B; VEGF,
vascular endothelial growth factor; FNDC5, fibronectin type III domain-containing protein 5; AMPK, AMP-activated protein kinase; mTOR,
mammalian target of rapamycin; Nrf2, Nuclear Factor E2-Related Factor 2; DCX, doublecortin; MCT, monocarboxylate transporter; Flk-1, fetal
liver kinase 1; TrkB, tyrosine kinase receptor B; LTP, long-term potentiation.

miRNAs 22 nucleotides encoded by endogenous genes (Tammen

et al. 2013). After physical exercise, the levels of miR-129-1-
miRNAs have been reported to play an important role in 3p, miR-144-5p, and miR-10b-5p are transiently increased,
posttranscriptional gene regulation, which are a type of whereas that of miR-708-5p is decreased (Fernandes et al.
noncoding single-stranded RNA molecule with a length of 2018). Studies have shown that miR-129-1-3p is related to
4 J. Liang et al.: Exercise promotes brain remodeling
cell proliferation, whereas miR-144-5p, miR-10b-5p, and
miR-708-5p are involved in neurological diseases such as
depression, AD, and PD (Forstner et al. 2015; Hoss et al.
2016; Mo et al. 2017; Satoh et al. 2015; Wang et al. 2015).
Some miRNAs such as miRNA-7, miRNA-9, and miRNA-34a
are significantly increased in patients with AD, whereas
miRNA-132 is increased in the SAMP8 mouse mode (Dong
et al. 2018; Zhao et al. 2015). Furthermore, abnormal
miRNA gene expression is involved in the pathogenesis of
SAMP8 mice (Cheng et al. 2013). Interestingly, exercise can
inhibit the high expression levels of miRNA-132 and,
thereby, improve the cognition in the SAMP8 model (Dong
et al. 2018).
It has been reported that physical exercise can promote
adult hippocampal neurogenesis, and this effect may be
used as a preventive measure for age-related diseases
(Farioli-Vecchioli et al. 2014; Kronenberg et al. 2006;
Overall et al. 2013). The study by Pons-Espinal et al. (2019)
discovered that exercise can promote the proliferation of
neural precursor cells through the downregulation of
miRNA 135a-5p, indicating that this miRNA may be a novel
target for therapeutic strategies in pathological brain ag-
ing. In addition, Mojtahedi et al. (2013) showed that the
level of miRNA-124 is significantly increased in both low-
and high-intensity exercise. miRNA-124, a specific miRNA
that is highly conserved, has a higher content in adult
mammalian brain tissue (Lagos-Quintana et al. 2002; Lewis
et al. 2005), and is associated with the transformation of
neurons from proliferation to differentiation (Krichevsky
et al. 2003; Krichevsky et al. 2006; Smirnova et al. 2005).
However, another study has indicated that exercise may
downregulate miRNA-124 levels and upregulate hippo-
campal glucocorticoid receptor expression, leading to a
positive effect on stress resilience in single-housed mice
(Pan-Vazquez et al. 2015). These findings suggest that
exercise-induced regulation of miRNAs may be involved in
neurological diseases.
Exercise benefits neuroprotection
by enhancing neuroplasticity
Neuroplasticity refers to the ability of the nervous system to
initiate adaptive responses by improving its structure,
function, and connection following stimulation (von
Bernhardi et al. 2017). Neuroplasticity involves various
mechanisms such as synaptic plasticity, dendritic remod-
eling, and neurogenesis (Amtul and Atta Ur 2015; Ismail
et al. 2017). It has been reported that the developing brain
has more patterns of neuroplasticity compared to the adult
brain (Ismail et al. 2017). However, some studies show that
neuroplasticity can be enhanced after adult brain injury
and may be stimulated by physical exercise or functional
electrical stimulation (Figure 1A) (Cassilhas et al. 2016;
Cramer et al. 2011; Hara 2015).
Synaptic plasticity
Synaptic plasticity includes short-term synaptic plasticity
and long-term synaptic plasticity (Citri and Malenka 2008).
Exercise increases the synaptic strength of the perforant
pathway connecting the entorhinal cortex with the dentate
gyrus, which can enhance long-term potentiation (LTP)
(van Praag et al. 1999a,b). In age-related neurodegenera-
tive diseases, the decline of cognitive function is accom-
panied by a decrease in hippocampal neurogenesis (Ma
et al. 2017). The main pathological features of AD are the
formation of neurofibrillary tangles and amyloid-β (Aβ)
plaques (DeTure and Dickson 2019). Aβ1–42 can suppress
LTP in the dentate gyrus through NMDA receptor signal
transduction (Babri et al. 2012). BDNF-mediated excitatory
synaptic regulation is reported to be involved in LTP. At the
level of post-synaptic regulation, BDNF-tyrosine kinase
receptor B (TrkB) signal induces NMDA phosphorylation
and increases the opening of ion channels; the influx of
calcium ions can activate CaMKII to maintain enhanced
synaptic efficiency (Leal et al. 2017). In a rat model of AD,
exercise can protect synaptic transmission and LTP in the
dentate gyrus and normalize the levels of synaptic
plasticity-related molecules like CaMKII, calcineurin, and
BDNF (Dao et al. 2015). Thus, exercise can prevent
AD-induced negative effects on dentate gyrus LTP and
AD-related pathways. Farmer et al. (2004) showed that
exercise can significantly increase the transcription levels
of the NR2B subtype of the NMDA receptor, as well as BDNF
and glutamate receptor-5 in the dentate gyrus. This
observation may be related to the phenomenon that exer-
cise can reduce the LTP threshold and promote neuro-
genesis (Farmer et al. 2004). Exercise can also reduce the
load of argentophilic senile plaques, inflammatory re-
sponses, and mitochondrial dysfunction, leading to a
reduction in cognitive impairment and enhanced hippo-
campal neurogenesis in AD model mice (Kim et al. 2019). In
a vascular dementia rat model, exercise was found to in-
crease the level of synapsin I, postsynaptic density-95,
microtubule-associated proteins, and tau protein in the
hippocampus (Lin et al. 2015). In the same study, exercise
could also prevent the loss of neuronal dendrites and
neurons in the hippocampal CA1 and CA2 zones, enhance
the growth of dendrites, and improve cognition (Lin et al.

2015). Furthermore, researchers also illustrate that invol-
untary exercise induced by functional electrical stimula-
tions has more protective effects on cognition compared to
forced and voluntary exercise.
Dendritic remodeling
Dendritic morphology is a critical factor for the normal
functioning of the nervous system and shows great di-
versity among different types of neurons (Ascoli 2006;
Bozelos et al. 2016). The complexity of the dendritic
morphology directly affects the function of neural tissues
(Chklovskii 2004; Spruston 2008). Dendritic remodeling
can be observed under physiological conditions and
following neuropathological stimuli, indicating that den-
drites are dynamic structures (Bozelos et al. 2016).
The degeneration of dendrites and loss of synapses
may be one of the mechanisms underlying brain impair-
ment after neurological disorders, such as PD, AD,
depression, and other brain injuries (Qiao et al. 2016; Reza-
Zaldivar et al. 2020; Xiong et al. 2019). Recent studies have
shown that exercise can enhance the dendritic complexity
in various subregions of the hippocampus including the
dentate gyrus, cornu ammonis, and entorhinal cortex
(Eadie et al. 2005; Redila and Christie 2006; Stranahan
et al. 2007). In patients with PD, the loss of dopaminergic
neurons in the substantia nigra and the degeneration of the
substantia nigra-striatum pathway causes a dysfunction of
the cortical-basal ganglia loop. PD patients present
symptoms related to a hypodopaminergic and relative
hypercholinergic state (Kalia and Lang 2015). In a mouse
model of PD, the density of dendritic spines containing
dopamine receptors is reduced but exercise can prevent the
density loss of dendritic spines in striatal medium spiny
neurons and upregulate the expression of the postsynaptic
density-95 protein, leading to symptom improvements in
PD mice (Toy et al. 2014).
Similarly, evidence indicates that stress-induced
reduction in neurogenesis, dendritic atrophy, and loss of
spines in hippocampal and prefrontal cortex neurons
are involved in the pathophysiology of depression
(Qiao et al. 2016; Yau et al. 2011). Using an animal model of
corticosterone-induced stress, Yau et al. (2011) demon-
strated that the inhibited hippocampal neurogenesis and
diminished spine density were reversed by physical exer-
cise. Wheel-running can enhance hippocampal neuro-
genesis, increase dendritic length, and recover spine
density, leading to improvements in spatial memory and
depressive behavior in a rat stress model (Yau et al. 2011).
In line with these results, Ghalandari-Shamami et al.
J. Liang et al.: Exercise promotes brain remodeling 5
(Ghalandari-Shamami et al. 2019) found that exposure to
exercise can improve behavioral and morphological im-
pairments induced by stress. They demonstrated that ex-
ercise can reverse the deficits regarding dendritic length
and branching in the prefrontal cortex. Another study
showed that the treadmill exercise in a rat model of stroke
can improve the neurological deficits induced by ischemia-
reperfusion injury through enhancement of dendritic and
synaptic plasticity, which may be due to the upregulation
of the caveolin-1/VEGF signal transduction pathway (Xie
et al. 2019). These exercise-induced benefits indicate that
the promotion of dendritic remodeling can be used as a
therapeutic target in some neurological diseases to
improve the outcome in affected patients and support
medication effects.
Adult hippocampal neurogenesis
Not long ago, it was generally believed that neurons cannot
regenerate following the physiological or pathological
death of a neuron. However, the discovery of neural stem
cells raised the possibility of plasticity and post-injury
repair of central nervous tissue (Altman 1962; Altman and
Das 1965; Bond et al. 2015; Martínez-Cerdeño and Noctor
2018). Neural stem cells, having the characteristics of self-
renewal and pluripotency, exist in the hippocampal sub-
granular zone and the subventricular zone of the adult
mammalian central nervous system (Bond et al. 2015; Li
et al. 2019).
Adult hippocampal neurogenesis takes place in the
hippocampal subgranular zone, which is the process of
neural progenitor cells renewing and regenerating neurons
in the hippocampus (Abbott and Nigussie 2020; Eriksson
et al. 1998). Exercise can enhance cell proliferation, sur-
vival, and neuronal differentiation in the hippocampus of
adult mice, leading to an increased hippocampal storage
capacity (van Praag et al. 1999a,b). Conversely, aging-
related cognitive decline may be due to decreased neuro-
genesis in the dentate gyrus (Bizon et al. 2004; Kemper-
mann et al. 1998). van Praag et al. (2005) found that the
numbers of bromodeoxyuridine (BrdU)-positive cells were
increased in both young and old groups after wheel
running, and more cells tended to become neurons in the
exercise group compared with age-matched controls (van
Praag et al. 1999a,b). Additionally, enhanced neurogenesis
stimulated by increased exercise levels or enriched envi-
ronment did not affect the percentage of glial cells in either
age group (Kempermann et al. 1998; van Praag et al. 2005).
Exercise can also promote hippocampal neurogenesis in
an animal model of corticosterone-induced stress, leading
6 J. Liang et al.: Exercise promotes brain remodeling
to improvements in spatial memory and depression-like
symptoms (Yau et al. 2011). Moreover, exercise can reverse
the suppression of cell proliferation in the subventricular
zone (Lee et al. 2016). Therefore, physical exercise can be
regarded as a therapy for stress-related disorders.
Exercise can promote the proliferation and differenti-
ation of neural progenitor cells in the hippocampus by
activating extracellular signal-regulated kinases pathways
in a rat model of stroke (Liu et al. 2018). It has been reported
that voluntary exercise can reverse the reduction of cell
proliferation and neurogenesis in adults following prena-
tal ethanol exposure (Redila et al. 2006). However, the
underlying mechanism by which exercise reverses cell
proliferation and neurogenesis after injury remains to be
elucidated. Farioli-Vecchioli et al. (2014) demonstrated
that running can shorten the cell cycle length, especially in
proliferating neural progenitor cells of the dentate gyrus.
They found that in mice with a silenced antiproliferative
gene Btg1, running reversed the excessive proliferation of
the dentate gyrus stem cell pool due to weakened inhibi-
tion and increased the cell proliferation and neurogenesis
in the adult dentate gyrus. Exercise selectively affected the
cell cycle of specific neurogenic differentiation 1 (Neu-
roD1)-positive progenitor cells, shortened the cycle of cells
positive for glial fibrillary acidic protein and sex-
determining region Y related HMG box 2(Sox2), as well as
NeuroD1-positive progenitor cells, and reactivated the
plasticity of neural stem cells (Farioli-Vecchioli et al. 2014).
Their study illustrates that running-induced proliferation
reversal is associated with cell cycle dynamics and pro-
vides the first evidence that a shortening of the S phase is
the main target for the running-induced enhancement of
neurogenesis (Farioli-Vecchioli et al. 2014). It seems that
regulation of cell cycle dynamics maybe the fundamental
effect of running-induced adult neurogenesis in the hip-
pocampus (Farioli-Vecchioli et al. 2014; Farioli-Vecchioli
and Tirone 2015).
Furthermore, exercise-induced cardiorespiratory
fitness may reflect in cerebral blood flow (CBF) alterations,
leading to neurogenesis. Using arterial spin-labeling
magnetic resonance imaging, Binnewijzend et al. (Binne-
wijzend et al. 2013) showed that the CBF is reduced in pa-
tients with mild cognitive impairment or AD. In mice,
exercise mainly increases the CBF in the dentate gyrus,
which may be related to the increase in neurogenesis
(Pereira et al. 2007). Meanwhile, MacIntosh et al. (MacIn-
tosh et al. 2014) showed that cerebral perfusion is robustly
affected after a single 1-h aerobic exercise for healthy
adults. Using a voxel-wise analysis, they demonstrated
that the left medial postcentral gyrus presented an elevated
perfusion level after 40 min of aerobic exercise, and they
found differences were dependent on the brain region.
After 10 min of exercise, the CBF of the gray matter was
decreased, but this change was not significant after 40 min,
whereas an increase in CBF was detected in the white
matter (MacIntosh et al. 2014). This difference may reflect
that physical exercise has selective acute effects on CBF
due to region-specific reactions of blood vessels to
exercise-induced alterations. Besides, neurogenesis is
associated with angiogenesis, and angiogenesis is associ-
ated with the microvascular blood volume (Aronen et al.
2000; Louissaint et al. 2002; Palmer et al. 2000). Thus, the
increase of CBF may indicate there is a relationship on
exercise-induced angiogenesis and neurogenesis. Howev-
er, a multicenter single-blind randomized controlled trial
did not confirm that the CBF is changed by physical exer-
cise over 16 weeks. The exercise-induced cardiorespiratory
fitness was not reflected in CBF alterations. This may be
due to the 16-week exercise for this relatively small sample
is too short for MRI to detect the effect (van der Kleij et al.
2018).
In summary, exercise can promote hippocampal neu-
rogenesis by protecting the newly generated cells, and
regulating CBF. Study shows that hippocampal neuro-
genesis may persist during the whole life span (Eriksson
et al. 1998). Boldrini et al. (Boldrini et al. 2018) assessed
autoptic hippocampal specimens from individuals without
cognition impairment aged 14–79 years. They found that
neural progenitor cells were present in the dentate gyrus
even of elderly people. Cells with the ability to differentiate
and proliferate existed in the dentate gyrus of the elderly,
suggesting that aging may not lead to a functional decline
of neurons. However, in the dentate gyrus, the number of
cells with proliferative potential declines dramatically in
the first year after birth. The average density of prolifer-
ating neurons is about 1618/mm2 after birth and reduced to
0.14% of this value at the age of 13 years. By adulthood,
those cells have completely disappeared (Sorrells et al.
2018). Therefore, the existence of hippocampal neuro-
genesis in humans and other species demands more
research to confirm it.
Circulating factors on brain
remodeling
BDNF
Physical exercise can improve temporal lobe function, in-
crease serum BDNF levels, and participate in exercise-
induced changes in human cognitive function. This

suggests that the exercise-induced upregulation of this
neurotrophin may be important for neuroprotection
(Griffin et al. 2011). Depressive disorder is a common
chronic psychiatric disease characterized by mood
depression. According to recent statistics, 264 million
people are affected by this disorder worldwide (Collabo-
rators 2018). Serotonin (5-HT) is involved in mood regula-
tion, and a decrease in its secretion level and activity is
related to the occurrence of depression (Dell’Osso et al.
2016). Decreased 5-HT levels can cause depression (Kurdi
and Flora 2019), and the 5-HT transporter (SERT) is the
main target of various antidepressant drugs. Physical ex-
ercise can increase 5-HT levels of raphe and up-regulate the
expression of 5-HT transporter and 5-HT receptor 1A in the
cortex and hippocampus (Pietrelli et al. 2018), leading to
cognition improvements. BDNF-dependent hippocampal
neurogenesis following exercise also requires serotonin
regulation (Pietrelli et al. 2018). BDNF can promote the
maturation and sprouting of 5-HT neurons, and increased
activity of 5-HT neurons may regulate neuroplasticity
(Klempin et al. 2013). Physical exercise can significantly
increase hippocampus BDNF level (Uysal et al. 2015). The
relationship of BDNF and 5-HT system is bidirectional and
interacted through an auto/paracrine feedback loop
(Martinowich and Lu 2008). Serotonergic neurons in the
dorsal and median raphe co-express BDNF and its receptor
TrkB (Madhav et al. 2001). In addition, BDNF can be
transported retrogradely from 5-HT terminals of the stria-
tum and hippocampus to neuronal somata of the raphe
nucleus to exert physiological roles (Anderson et al. 1995).
Evidences showed that BDNF can promote the maturation
and sprouting of 5-HT neuron, which may lead to the
enhancement of 5-HT neurons functions to regulate the
neuroplasticity (Mamounas et al. 1995; Martinowich and
Lu 2008; Mattson et al. 2004; Pietrelli et al. 2018). BDNF
also can enhance the expression of serotonergic markers in
raphe neurons (Martinowich and Lu 2008). Djalali et al.
(Djalali et al. 2005) demonstrated that BDNF may indirectly
affect the serotonergic system via the regulation of S100β
and myelin basic protein in glial cells. Conversely, 5-HT
can also be involved in neuroplasticity mediated by BDNF
(Pietrelli et al. 2018). The activation of serotonin receptors
combined with cAMP production and CREB activation can
induce Bdnf gene transcription (Mattson et al. 2004).
Besides of the effects on serotonergic neurons, it has
been reported that BNDF contributes to the differentiation
and survival of neuronal progenitor cells and the prolifer-
ation of neural stem cells, and can also promote the sur-
vival of progenitor cells (Lee et al. 2002; Sairanen et al.
2005). And exercise can also protect the substantia nigra
dopaminergic neurons through BDNF signaling pathway
J. Liang et al.: Exercise promotes brain remodeling 7
(Wu et al. 2011). Nam at al (Nam et al. 2014). showed in an
animal model of D-galactose-induced aging that the num-
ber of Ki67-/doublecortin-positive cells is decreased after D-
galactose treatment, but treadmill exercises can signifi-
cantly increase their number. They also found that the
upregulation of BDNF and pCREB expression can reverse
the reduction in neural stem cell numbers, cell prolifera-
tion, and neural differentiation induced by D-galactose
administration. In an animal model of ischemia, long-time
treadmill exercise enhances cell proliferation, promotes
neuroblast differentiation, and significantly increases
BDNF levels in the hippocampus (Ahn et al. 2016). Recent
evidence revealed that BDNF is associated with the regu-
lation of synaptic plasticity in pyramidal neurons and
granule cells and that BDNF can enhance dendritic spine
density and LTP in hippocampal neurons (De Vincenti et al.
2019; von Bohlen und Halbach and von Bohlen und Hal-
bach 2018). Furthermore, exercise can reverse the loss of
dopaminergic neuron and improve the motor deficits,
which were induced by peripheral lipopolysaccharide
(LPS) injection. The researchers found that the LPS com-
bined with infusion of recombinant-BDNF group showed
that substantia nigra pars compacta had more tyrosine
hydroxylase-positive cells, which indicated BDNF can
protect the loss of dopaminergic neuron induced by LPS
(Wu et al. 2011). Therefore, BDNF plays a pivotal role in
exercise-induced neuroplasticity.
IGF-1
IGF is a versatile hormone, of which 95% is produced by the
liver. It can also be synthesized in the cartilage, muscle,
spinal cord, and other tissues. IGF-1 can promote cell
mitosis, differentiation, proliferation, and inhibit cell
apoptosis (Halmos and Suba 2019). Plasma IGF levels
change with age, they peak at adolescence and then
decrease gradually with age. The decrease in intracranial
vascular density in old mice is accompanied by the
decrease in growth hormone and IGF-1 in the plasma
(Sonntag et al. 1997).
Exercise induces the upregulation of IGF-1 (Trejo et al.
2001), whereas blocking of the IGF-1 receptor (IGF-1R) can
eliminate exercise-induced enhancements of Bdnf gene
expression, as well as synapsin I, phosphorylated-CaMKII,
and phosphorylated-mitogen activated protein kinase
(MAPK) II pathways (Ding et al. 2006a,b). And a previous
study showed that the activation of CaMKII can maintain
the BDNF-mediated excitatory synaptic regulation during
LTP (Leal et al. 2017). The CREB was an important molec-
ular on the transcription of essential prosurvival genes. The
8 J. Liang et al.: Exercise promotes brain remodeling
Ras–MAPK signal pathway, which can be activated by the
phosphorylated-TrkB, was combined with the activation
CREB (Reichardt 2006). In vivo, BDNF-induced LTP of
dentate gyrus was depended on the activation ERK coupled
to CREB (Ying et al. 2002). BDNF has powerful effects on
synapsin I during exercise, and the interactions among
CAMKII, MAPK, NMDA receptors, and BDNF can signifi-
cantly regulate exercise-induced neuroplasticity (Vayn-
man et al. 2004; Vaynman et al. 2003). Therefore, the IGF-1/
IGF-1R pathway might be involved in the regulation of
CaMKII, MAPKII, synapsin I, and BDNF, thereby modu-
lating neuroplasticity (Ding et al. 2006a,b; Dyer et al. 2016;
Vaynman et al. 2003).
The IGF-1R can be expressed by the neural stem cells
and all neural cells over the entire life span (Baron-Van
Evercooren et al. 1991; Popken et al. 2005). The IGF-1/
IGF-1R signal can be activated by PI3K-Akt-mTOR kinase
and Ras-Raf-MAP pathways (Sun and D’Ercole 2006; Ye
and D’Ercole 2006), which regulates neuronal precursor
proliferation, and neuronal differentiation (O’Kusky et al.
2000; Zhang et al. 2014). In treadmill mouse exercise
model (Chen et al. 2019a,b), the mTOR signaling pathway
can be activated to enhance the formation of cortical
synapses after exercise, and both in vivo and in vitro ex-
periments of exercise can enhance the postsynaptic
excitability and neuronal activity of layer five pyramidal
neurons in the motor cortex. These authors also found
that exercise promotes axonal myelination and dendritic
spine formation. Conversely, those positive enhance-
ments can be eliminated by rapamycin inhibition (Chen
et al. 2019a,b). Therefore, the mTOR/IGF-1/IGF-1R
pathway plays an important role in exercise-induced
brain remodeling. The Ras-related GTPase RIT1 may be
the key downstream component of the IGF-1 signaling
pathway to enhance exercise-induced hippocampal
neurogenesis, because IGF-1 can regulate Sox2 activation
and neuronal differentiation via RIT1. This IGF-
1-mediated response promotes pro-neuronal Ascl1 and
Neurod1 gene expression and regulates Sox2 stability and
transcriptional activity in hippocampal neural progenitor
cells (Mir et al. 2017). Besides, the level of exercise-
induced hippocampal neurogenesis is downregulated in
RIT1 knockdown mice (Mir et al. 2017). Thus, exercise-
induced hippocampal neurogenesis, mediated by IGF-1,
is associated with the RIT1-Sox2 signaling cascade.
In another study, researchers found that exercise upre-
gulates the expression of proteasomes through the
IGF-1/nuclear factor erythroid 2-related factor pathway,
suggesting that exercise may promote hippocampal
neurogenesis through effects involving hippocampal
proteasomes (Niu et al. 2019).
VEGF
VEGF, a homodimeric glycoprotein, can be induced under
hypoxia conditions. As an important factor to induce
angiogenesis, VEGF promotes vascular growth and
remodeling (Carmeliet 2005). Exercise increases VEGF
levels and angiogenesis in aged rats (Ding et al. 2006a,b).
VEGF expression is induced by exercise and may be
involved in the regulation of hippocampal blood flow and
neurogenesis. In humans, the inhibition of the VEGF signal
transduction pathway is related to anxiety and depression
(Gormanns et al. 2011).
Circulating VEGF was increased after exercise (Cotman
et al. 2007), which can cross the blood-brain barrier,
selectively act on specific areas of the brain, and promote
hippocampal neurogenesis (Fabel et al. 2003; Trejo et al.
2001). In a murine middle cerebral artery occlusion (MCAO)
model, the numbers of BDNF- and BrdU-/NeuN-, BrdU-/
synapsin I- and CYFIP1-positive cells were significantly
increased in the MCAO exercise group, whereas the
administration of a caveolin-1 inhibitor to this MCAO ex-
ercise group significantly reduced the numbers of these
cells that are related to neurogenesis and neuroplasticity
(Chen et al. 2019a,b). Moreover, the caveolin-1 inhibitor
group showed more severe morphological alterations of
cortical neurons (Chen et al. 2019a,b), and the upregulation
of the caveolin-1/VEGF signal transduction pathway can
enhance dendritic and synaptic plasticity (Xie et al. 2019).
Depression-like behavior, reduction of hippocampal
vascular density and neurogenesis under chronic stress
stimulations can be improved through regular exercise and
the newly generated neurons survival can also increase,
whereas the VEGF receptor fetal liver kinase one inhibitor
exercise group eliminated those exercise-induced im-
provements (Kiuchi et al. 2012). Therefore, exercise-
induced neurogenesis and angiogenesis, and anti-
depression may be partly depended on VEGF signal.
Metabolic and hormonal substances
Physical exercise can increase the plasma level of adipo-
nectin (de Carvalho et al. 2018). Adiponectin, which is an
adipocyte-secreted hormone, is known as an important
protein related to glucose and fat metabolism. Adiponectin
can relieve metabolic disorders, regulate inflammation and
oxidative stress, and promote regeneration (Abou-Samra
et al. 2020). Furthermore, adiponectin has neuroprotective
effects. Voluntary running rescues impaired hippocam-
pal neurogenesis in a diabetic mouse model, but voluntary
exercise cannot restore neurogenesis in diabetic

adiponectin knockdown mice (Yau et al. 2018). Yau et al.
(2014) revealed that the enhanced hippocampal neuro-
genesis and antidepressant effects of adiponectin may be
associated with adiponectin receptor 1-mediated activation
of the AMP-activated protein kinase (Yau et al. 2014).
Therefore, adiponectin is a vital mediator of exercise-
induced neuroprotection.
In mice and humans, exercise induces in stimulated
muscles the gene expression of fibronectin type III domain-
containing protein 5 (FNDC5), leading to irisin increases
(Bostrom et al. 2012). Irisin, a circulating hormone pro-
duced after exercise, regulates energy metabolism. Irisin is
involved in neuroplasticity and memory improvement
(Lourenco et al. 2019). The levels of FNDC5/irisin are
decreased in the hippocampus and cerebrospinal fluid of
mouse models of AD and AD patients. Blocking FNDC5/
irisin can cause LTP and memory impairments, whereas
increasing FNDC5/irisin can protect synaptic plasticity and
memory function. Upregulation of FNDC5/irisin levels in
the hippocampus via peripheral adenovirus delivery of
FNDC5 prevented Aβ-induced memory impairments
(Lourenco et al. 2019). Therefore, exercise can increase the
level of FNDC5/irisin, which in turn can improve neuro-
plasticity and cognition.
It has been reported that exercise can enhance the
expression of plasma cathepsin B (CTSB), leading to in-
creases in doublecortin and BDNF expression in mice,
rhesus monkeys, and humans. Plasma CTSB levels are
correlated with memory, and spatial memory and hippo-
campal neurogenesis are inhibited in CTSB knockout mice.
Therefore, increased CTSB levels induced by exercise may
serve as a mediator of brain remodeling (Moon et al. 2016).
Glycosylphosphatidylinositol phospholipase D1 (Gpld1),
which is related to high-density lipoprotein, is abundant in
mammalian serum (Deeg et al. 2001). High levels of Gpld1
are synthesized by the liver of mice following exercise, and
these elevated Gpld1 levels promote hippocampal neuro-
genesis and improve cognition in aging mice. Besides,
Gpld1 levels are increased in the blood of healthy elderly
people who regularly exercise (Horowitz et al. 2020). Hor-
owitz et al. (2020) suggested that Gpld1 can stimulate
hippocampal neurogenesis and improves cognition by
cleaving the GPI-anchored substrate and triggering a
downstream signaling cascade.
Furthermore, it is well-known that lactate is produced
after exercise (Wahl et al. 2018). It can cross the blood-brain
barrier to upregulate BDNF expression in the brain and
activate the TrkB signal transduction pathway (El Hayek
et al. 2019). Lev-Vachnish et al. (Lev-Vachnish et al. 2019)
injected mice with 1.75 g/kg L-lactate to mimic exercise-
induced lactate levels. They found that the numbers of
J. Liang et al.: Exercise promotes brain remodeling 9
NeuN+/BrdU+ cells in the dorsal gyrus are higher compared
to phosphate buffered saline injection controls. Interest-
ingly, lactate-induced neurogenesis increases the survival
of newly generated neurons (Lev-Vachnish et al. 2019),
whereas exercise is not only associated with neuronal
proliferation, but also neuronal maturation (Ma et al. 2017).
Lactate can enter neurons through the monocarboxylate
transporter (MCT)-1 and MCT-2 or activate them via the
hydroxycarboxylic acid receptor 1. Inhibition of MCT-2 can
suppress lactate-induced neurogenesis, and the expres-
sion of MCT-2 on mature neurons is a potential target for
lactate-mediated metabolic and signal transduction (Lev-
Vachnish et al. 2019). It has been suggested that lactate
may regulate NMDA receptor activity via MCT-2 to enhance
neuroplasticity (Yang et al. 2014). Therefore, the lactate
released after exercise can promote the function of neu-
rotrophic factors and enhance neurogenesis. However, it
has been reported that high lactate levels can be detected
in the cerebrospinal fluid of AD patients, suggesting that
lactate may be a risk factor for cerebral amyloidosis (Red-
jems-Bennani et al. 1998). In another study, the β-hy-
droxybutyric acid level was found to be upregulated after
long-term exercise. β-Hydroxybutyric acid can activate the
Bdnf promoter I, leading to BDNF transcription, and in-
crease the levels of TrkB receptor-dependent neurotrans-
mitters (Sleiman et al. 2016). Therefore, exercise may
modulate the metabolism, thereby regulating the expres-
sion of lactate and β-hydroxybutyric acid, which is bene-
ficial to brain health (El Hayek et al. 2019; Sleiman et al.
2016).
These findings implicate that physical exercise can
enhance hippocampal neurogenesis by regulating the
levels of adiponectin, FNDC5/irisin, CTSB, Gpld1, lactate
and β-hydroxybutyric acid (Figure 1B). But how exercise-
induced peripheral effects affect brain remodeling requires
more research. Additionally, Table 1 briefly summarizes
the independent variables on exercise-induced effects
regarding brain remodeling.
Conclusions
In summary, physical exercise can delay or even reverse
the effects of aging on the brain, improve cognitive decline,
and reduce the vulnerability to some neurological dis-
eases. Exercise can reduce the pathological damage on AD,
PD, depression and stroke, leading to brain rehabilitation.
The regulation of neurotrophic factors, such as BDNF,
IGF-1, and VEGF, plays a pivotal role in exercise-induced
brain remodeling. Exercise also can promote BDNF
expression, facilitate chromatin remodeling of the Bdnf
10 J. Liang et al.: Exercise promotes brain remodeling

Table : Independent variables on exercise-induced effects on Future work should clarify the relationships between
brain remodeling. changes in the brain and peripheral levels of these sub-
stances following exercise. Therefore, physical exercise
Independent Mechanisms Effects
can not only promote fitness but also enhance brain
variables
remodeling by regulating epigenetic information, pro-
Epigenetics Histone modification ↑ acetylation
moting neuroplasticity, and modulating the expression of
factors ↑ phospho-acetylation
neurotrophic factors.
DNA methylation and ↓ bdnf promoter IV CpG
Chromatin remodeling methylation
miRNAs ↓ miRNA- ↑ Author contributions: All the authors have accepted
miRNA- responsibility for the entire content of this submitted
Neuroplasticity Synaptic plasticity ↑ SYN ↑ PSD- ↑ MAP- manuscript and approved submission.
↑ tau protein
Research funding: Our work was supported by the National
↑ synaptic transmission
↑ LTP Science Foundation of China (81630038, 81971433,
Dendritic remodeling ↑ dendritic length ↑ 81971428, 81771634, 81842011, 81330016, 81801629), the
spine density National Key R&D Program of China (2017YFA 0104200),
↑ neurons density the grants from the Ministry of Education of China
Hippocampal ↑ NPCs proliferation and
(IRT0935), the grants from the Science and Technology
neurogenesis differentiation
Bureau of Sichuan Province (2016TD0002), the grant from
↑ CBF
Trophic factors Neurotrophic factors ↑ BDNF ↓ p receptor the clinical discipline program (Neonatology) from the
↑ IGF- ↑ BrdU-labeled Ministry of Health of China (1311200003303), and the
cells ↑ HN Fundamental Research Funds for the Central Universities.
↑ VEGF ↑ angiogenesis Conflict of interest statement: The authors declare that the
Circulating Hormonal substances ↑ Adiponectin ↑FNDC/
research was conducted in the absence of any commercial
factors irisin
↑ CTSB ↑ doublecortin or financial relationships that could be construed as a
Metabolic substances ↑ Gpld ↑ lactate potential conflict of interest.
↑ β-hydroxybutyric acid

↑, increased. ↓, decreased. BDNF, brain-derived neurotrophic factor;

SYN, synapsin-I; PSD-, postsynaptic density-; MAP-,
microtubule associated protein ; AD, Alzheimer’s disease; LTP, long-
term potentiation; NPCs, neural progenitor cells; CBF, cerebral blood
flow; IGF-, insulin-like growth factor ; BrdU, bromodeoxyuridine;
HN, hippocampal neurogenesis; VEGF, vascular endothelial growth
factor; FNDC, fibronectin type III domain-containing protein ; CTSB,
cathepsin B; Gpld, glycosylphosphatidylinositol phospholipase D.
gene, and alter the methylation status of the Bdnf promoter
IV. Altered BDNF expression is associated with synapsin
I, 5-HT, CAMKII, MAPK, and NMDA receptors, which all
may be involved in exercise-induced neuroplasticity.
IGF-1/IGF-1R upregulation after exercise modulates
neuronal precursor proliferation, and neuronal differenti-
ation. Exercise can regulate the dendritic morphology via
the caveolin-1/VEGF signaling pathway. Exercise-induced
effects are involved in the regulation of cell cycle dy-
namics, leading to the proliferation of neural progenitor
cells in the dentate gyrus. Additionally, the regulation of
histone modifications and miRNAs play a critical role in
brain remodeling after exercises. Furthermore, exercise-
induced changes in peripheral levels of molecules such as
adiponectin, FNDC5/irisin, CTSB, Gpld1, lactate and β-hy-
droxybutyric acid are also related to brain remodeling.
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