ARTICLE
Exercise Enhances and Protects Brain Function
Carl W. Cotman and Christie Engesser-Cesar
Institute for Brain Aging and Dementia, University of California, Irvine
COTMAN, C.W., and C. ENGESSER-CESAR. Exercise enhances and protects brain function. Exerc. Sport Sci. Rev., Vol.
30, No. 2, pp. 7579, 2002. Physical activity, in the form of voluntary wheel running, induces gene expression changes in the brain.
Animals that exercise show an increase in brain-derived neurotrophic factor, a molecule that increases neuronal survival, enhances
learning, and protects against cognitive decline. Microarray analysis of gene expression provides further support that exercise enhances
and supports brain function. Keywords: running, BDNF, depression, estrogen, neuroplasticity, neuroprotection
INTRODUCTION
Exercise is known to impact nearly every system in the
body. Benefits of regular exercise include improved cardio-
vascular health, greater bone mineral density (BMD), and
decreased risk for cancer, stroke, and diabetes, yet many
people still choose not to participate. The extra incentive
many sedentary individuals need to begin exercising might be
found in new research showing that exercise is a means of
enhancing and protecting brain function. Unlike erythro-
cytes (red blood cells), which have a lifespan of 120 d, the
millions of neurons in the brain must last the 80 yrs of a
lifetime. Age-related neuron dysfunction and degeneration
cause cognitive decline and personality changes in some
cases. Many people turn to supplements, such as gingko
biloba, as a solution to cognitive impairments. Unfortu-
nately, no proof exists that any one supplement can maintain
brain function at an optimal level during the aging process.
One could imagine, though, that the brain can produce
molecules that nourish neurons and ensure overall brain
health. The ideal candidate molecule would have the ability
to protect neurons, to increase neuronal plasticity, to en-
hance learning, and to assist in the overall maintenance of
the brain. Such molecules do exist and fall into a class of
proteins called growth factors. Several specific growth fac-
tors, called neurotrophic factors, target neurons. (Neurons
are the key cells in the brain and trophin is the Greek word
for nutrition, hence the term neurotrophin.)
One neurotrophic factor, brain-derived neurotrophic fac-
tor (BDNF), is capable of mediating the beneficial effects of
Address for correspondence: Carl W. Cotman, Institute for Brain Aging and Dementia,
University of California Irvine, Irvine, CA 92697-4540 (E-mail: cwcotman@uci.edu).
Accepted for publication: December 27, 2001.
0091-6631/3002/7579
Exercise and Sport Sciences Reviews
Copyright 2002 by the American College of Sports Medicine
75
exercise on brain plasticity. BDNF is a member of a neuro-
trophic family that supports the health and functioning of
the primary neuronal type in the brain, glutamatergic neu-
rons. These neurons are the major projection neurons con-
necting cognitive, sensory, and motor brain regions. BDNF is
synthesized in the cell body and transported back and forth to
synapses, where neuronal communication occurs. In addition
to mediating synaptic efficacy, BDNF also promotes differ-
entiation, neurite (process) extension, and the survival of a
variety of neuronal populations in culture and in vivo. BDNF
is regulated by neuronal activity, and mechanisms that in-
duce BDNF, such as exercise, enhance learning.
EXERCISE INDUCES BRAIN-DERIVED NEUROTROPHIC
FACTOR (BDNF) GENE EXPRESSION
We developed an animal model to examine the effects of
exercise on the brain, specifically to see if exercise regulated
BDNF. We chose voluntary wheel running as it closely mimics
the choices humans have when exercising because animals
dictate the time, speed, and distance of running throughout the
experiment. Some rats voluntarily run up to an astounding 20
km in one night! At the beginning of the experiment, we
predicted that with physical activity the major sites of gene
induction in the brain would be in motor and sensory regions.
However, the brain region showing the earliest and most sus-
tained neurotrophic upregulation in response to exercise was the
hippocampus. The hippocampus is a brain region important in
learning and memory and is a target for early deterioration in
neurodegenerative diseases like Alzheimers disease (AD).
Initial experiments were designed to measure the effects of
acute exercise bouts on BDNF activity. In situ hybridization
measures of BDNF messenger RNA (mRNA) found a 20%
increased abundance of BDNF mRNA from control levels in
the hippocampus after 27 nights of running (Fig. 1) (6,7).
Increases in BDNF mRNA levels occur when running activ-

ity is above a minimum threshold level of approximately 500
md1. BDNF mRNA increases with greater distances run up
to a ceiling at several kmd1. Experiments looking at 3 wk
of exercise demonstrated that the effect of exercise on BDNF
mRNA levels was not merely a short-term, transient effect.
Indeed others have shown that increases in mRNA for BDNF
and its receptor trkB are observed in the hippocampus after
6 wk of voluntary wheel running (15). Recently, experiments
showed that the increase in abundance of BDNF mRNA is
paralleled by increases in BDNF protein levels (Fig. 1).
Maintenance of cerebral BDNF levels is important for
effective neural function and longevity (Table 1) (10). There
is strong evidence that BDNF is important in the ability of
synapses to encode change, as measured by long-term poten-
tiation (LTP). In LTP, patterns of synaptic stimulation lead
to a long-term potentiation of the synaptic response; there-
fore, LTP is regarded as synaptic analog of learning and
memory. LTP is impaired in BDNF-deficient mice, but can
be restored with BDNF infusion. This suggests that LTP
formation is BDNF dependent. In addition to its effects on
plasticity (LTP), BDNF demonstrates its neuroprotective
role by promoting survival of hippocampal, striatal, and sep-
tal neurons in culture and in vivo as well as by protecting the
TABLE 1
The neurotrophic factor, BDNF, participates in numerous functions in the
brain and is best known for its roles in neuroplasticity and neuroprotection
Neuroplasticity roles
Enhances synaptic transmission
Activity dependent regulation
Encodes LTP
Improves learning
Stimulates synaptic protein synthesis
Neurotrophic roles
Promotes survival in culture and in vivo
Promotes neurite extension
Promotes differentiation
Neuroprotective roles
Protects against ischemic insults
Protects against axotomy
76 Exercise and Sport Sciences Reviews
Figure 1. Voluntary running is an easily
monitored and quantifiable method of ex-
ercise. A. Animals have access to running
wheels for a defined length of time. During
this time computers record the distance an-
imals run. B. Enzyme-linked immunosor-
bent assay quantification of BDNF protein
levels (pgmL1) in hippocampal lysate af-
ter 5 d of running shows an increase in
protein in the running (EX) animals com-
pared with sedentary (SED) animals. Error
bars represent SEM (* P 0.0244). C and
D. Coronal sections depicting in situ hybrid-
ization of BDNF mRNA in the rat hippocam-
pus after 6 d of voluntary running wheel
activity (C) and sedentary animals (D). Note
the increase in mRNA in the dentate gyrus
(DG) and CA1-CA3 regions of the hippocam-
pus and in the cortex (ctx) after exercise.
brain against insults such as ischemia and axotomy. Indeed,
as predicted, animals that exercised showed improved learn-
ing (14) and increased resistance to stroke (2).
BDNF ENHANCES NEURONAL FUNCTION BY
PROMOTING SYNAPTOGENESIS AND NEUROGENESIS
In addition to BDNF, other genes in the brain are likely to
be affected by exercise. It is also probable that BDNF inter-
acts with pathways that trigger changes in genes causing
synaptic change. High-density oligonucleotide microarrays
allow the simultaneous analysis of the activity of ~5000
genes. Tong et al. (13) discovered that in addition to BDNF,
exercise induces changes in other genes known to be associ-
ated with neuronal activity, synaptic structure, and neuronal
plasticity (Fig. 2). Thus, gene expression profiles suggest that
exercise has the ability to enhance brain plasticity and en-
coding in a manner that may translate directly into structural
change of neurons or synapses. Neuronal connections can be
strengthened and made more efficient through enhanced
synaptic capacity and the addition of new neurons.
Typically, healthy neurons have synaptic connections
with thousands of cells. These connections are essential to
the successful coordination of all brain activity, including
cognition. To promote neural health, synapses need to main-
tain synaptic protein levels. Decreases in the presynaptic
vesicle proteins synaptobrevin, synaptophysin, and synapto-
tagmin correlate with cognitive decline in the brains of those
with AD (12). Given the loss of function likely to be found
with decreased synaptic proteins, any means of upregulating
synaptic proteins would be a significant finding. We suggest,
and literature supports our prediction, that BDNF interacts
with a pathway that triggers changes in synaptic proteins.
BDNF acts to increase levels of these important synaptic
proteins. BDNF mutants have low levels of the synaptic
vesicle proteins, synaptophysin and synaptobrevin, and mice
with a mutation in the BDNF receptor, trkB, have decreased
levels of synaptophysin and synaptotagmin. In addition, mice
www.acsm-essr.org

with a mutation in BDNF have a decreased number of docked
synaptic vesicles. Interestingly, infusion of BDNF to the
brain of normal mice results in an increase in the number of
docked vesicles (10). This suggests that low BDNF levels may
result in impaired neuronal communication, whereas in-
creased BDNF levels may improve neuronal communication.
As mentioned earlier, microarray analysis shows that ex-
ercise induces changes in a number of genes that regulate
synapses (Fig. 2) (13). Genes whose expression was upregu-
lated include those associated with membrane trafficking,
vesicle recycling, and synaptic plasticity. For example, syn-
aptotagmin, the synaptic vesicle protein believed to be the
calcium sensor necessary to trigger release of the neurotrans-
mitter, was upregulated. In addition, VESL/homer, genes that
have been implicated in synaptic growth, and COX-2, a gene
believed to be involved in activity-dependent synaptic plas-
ticity, were both upregulated after exercise. These data and
others are important because they indicate voluntary exercise
enhances synaptic function. Additional research is needed to
link these changes directly to BDNF.
Neuronal connections can also be selectively strengthened
by the recruitment of new neurons formed from neurogenesis,
the process whereby neural stem cells proliferate and differ-
entiate into neurons and glial cells. Until recently, stimuli to
induce neurogenesis were unknown. However, an increased
number of new neurons were recently discovered in the
hippocampus of mice living in an enriched environment
where animals are exposed to stimulation such as social
interaction, learning, and exercise in running wheels. Further
experiments then looked at which component of the en-
riched environment exercise or learningwas more im-
portant for stimulating neurogenesis. Mice were placed in
conditions of swimming, swimming with learning, voluntary
wheel running, or an enriched environment. Increased neu-
rogenesis was seen only in the voluntary wheel running group
and the enriched environment group (14), suggesting that
running alone is sufficient to increase neurogenesis, allowing
for the possibility of strengthening neuronal connections.
ESTROGEN IS CRITICAL TO MAINTAINING BDNF LEVELS
For various reasons, many women agonize over decisions
regarding estrogen replacement. On one hand, estrogen
Volume 30 Number 2 April 2002
Figure 2. Exercise-induced gene
expression changes in rat hip-
pocampi. After 3 wk of running,
gene expression changes were de-
tected using Affymetrix high-den-
sity oligonucleotide microarray
chips (Affymetrix, Inc., Santa Clara,
CA). Various significant changes in
gene expression can be broadly
classified into categories regulating
plasticity, metabolism, immune
function, and degeneration pro-
cesses. For details see (13).
reduces bone loss and protects against the onset of demen-
tia, whereas on the other hand, it may increase the risk of
breast cancer. In the brain, estrogen deficits are known to
affect neuronal function, survival, and synaptogenesis neg-
atively, as well as to decrease the availability of BDNF in
the hippocampus. We sought to determine whether estro-
gen deprivation and replacement interacted in any way
with exercise to influence BDNF gene and protein regu-
lation. Although a few days of running can offset BDNF
losses from short-term estrogen deprivation, it cannot off-
set BDNF mRNA and protein decreases after long-term
estrogen deprivation (1). However, long-term estrogen
replacement combined with exercise increases BDNF pro-
tein levels even more than estrogen replacement alone,
providing more evidence that exercise initiates pathways
that protect against functional losses (Fig. 3). Interest-
ingly, the amount of voluntary running is dependent on
estrogen, such that those without estrogen were signifi-
cantly less active than those with estrogen. Restoring
estrogen returned activity to normal levels. Controlled
clinical studies are still needed, but it appears that the
benefits of hormone replacement in women may include
increased exercise participation and induction of BDNF.
EXERCISE-INDUCED BDNF MEDIATES RECOVERY
FROM DEPRESSION
The finding that BDNF levels are upregulated with exer-
cise has potential significance for depression, an important
clinical field of research. Exercise is often recommended to
individuals suffering from depression as a means of improving
their psychological well-being. In general, research supports a
correlation between improvement in depression and partic-
ipation in either aerobic or anaerobic exercise. Patients who
remain active after clinical interventions report less depres-
sion than those who return to sedentary lifestyles. Overall
exercise was found to have positive effects on depression for
both clinical and healthy participants. Experiments showing
that antidepressants increase BDNF mRNA in animals link
BDNF to depression. Interestingly, in animal models of de-
pression, BDNF itself has antidepressant effects (11). Our
finding that exercise increases BDNF mRNA levels suggests
Exercise Enhances and Protects Brain Function 77
Figure 3. Estrogen and exercise cooperatively interact to upregulate BDNF levels in the brain. A. Hippocampal BDNF protein is increased after estrogen
manipulation and exercise treatment; however, exercise potentiation of BDNF protein is dependent upon estrogen. OVX, ovariectomized; OVX/ER,
estrogen-replacement; ex, exercise; sed, sedentary. Error bars represent SEM (*, P 0.05; **, P 0.0001). B. Estrogen increases BDNF directly, through
enhancing availability of BDNF, and indirectly, by stimulating voluntary running. Both effects raise important considerations for women deciding upon
hormone replacement.

a possible physiological reason for the benefits of exercise in
depressed persons. We investigated the combined effect of
exercise and antidepressants in our voluntary running model.
Hippocampal BDNF mRNA level was increased with either
exercise or the antidepressant tranylcypromine. The combina-
tion of exercise with antidepressant administration produced
additive increases in BDNF mRNA abundance (Fig. 4) (9).
Antidepressant treatment in humans may take up to 2 wk to
reach maximal effectiveness. A similar period is required for
antidepressant-triggered increases in BDNF mRNA levels.
However, when combined with exercise, antidepressants may be
effective more quickly. Our research showed that when antide-
pressant treatment was combined with exercise, BDNF mRNA
was increased in as little as 2 d. Thus, exercise may decrease the
time required for antidepressants to be effective, a finding that
is potentially clinically significant (9).
Another implication of research on BDNF and exercise
comes from the finding that if exercise is terminated abruptly,
BDNF levels initially fall below normal before returning to
control levels by 30 d (15). The decrease in BDNF after a
sudden withdrawal of access to wheel running may correlate
with the depression often reported by athletes whose training
has been unexpectedly interrupted by injury.
Exercise and Antidepressants Together Improve
Stress Response
Exposure to stress causes a decrease in BDNF mRNA levels
in the hippocampus, which may be linked to depression. We
investigated whether exercise and antidepressants could
counteract stress-induced decreases in BDNF mRNA (8).
Animals underwent a forced swim test (a stressful event) after
1 wk of treatment with tranylcypromine, 1 wk of voluntary
exercise, or a combination of these two interventions. An-
tidepressant administration or exercise alone prevented the
BDNF decrease caused by the acute stress. The combination
of exercise with antidepressant led to significantly greater
increases in hippocampal BDNF mRNA levels than did ei-
ther treatment alone. It is possible that select antidepressants
and exercise converge at a cellular level to promote brain

Figure 4. Exercise and select antidepressants influence BDNF levels. A. Total BDNF mRNA levels in the dentate gyrus of the hippocampus after 1 wk of
treatment with antidepressant, exercise, or the combination of both (expressed as percentage of control values). The combined intervention (exercise with
antidepressant) potentiates the effect of either treatment alone. Error bars represent SEM (* P 0.05). CTR, control; TC, antidepressant tranylcypromine;
EX, exercise. B. Exercise and select antidepressants converge upon a shared molecular pathway to influence BDNF levels. Combined treatment potentiates
the effect and reduces the time required for a response to treatment.

78 Exercise and Sport Sciences Reviews www.acsm-essr.org

health. The impact of exercise on reducing brain stress re-
sponses is an exciting area for future research.
COGNITIVE EFFECTS OF EXERCISE IN THE AGING
ADULT
Exercise increases BDNF, aids in treatment of depression,
is affected by estrogen levels, and may induce neurogenesis,
but why should this motivate the general populace to exer-
cise? The answer is really twofold. First, gross characteriza-
tions of diseased brains include cortical atrophy and decreas-
ing synaptic connections, both of which are correlated with
cognitive impairments. Secondly, as previously mentioned,
BDNF is a neuroprotective factor capable of sustaining neu-
ron viability. The conclusion then, on a systems level, is
amazingly simple; exercise results in upregulated BDNF lev-
els, which should lead to less cortical atrophy and hence
improved cognitive function, as supported by animal models.
Our argument that exercise can mediate brain function is
supported by research from trials with people aged 60 75 yrs.
A group of people who underwent aerobic exercise (walking)
was compared with a group who underwent anaerobic exer-
cise (stretching) (4). The aerobic group showed improve-
ments in neuropsychological measures of executive control,
linking the enhanced ability to increased physical fitness.
The argument that improvements might be due to decreased
depression levels leading to increased information-processing
efficiency is countered by the lack of effect in anaerobic
exercisers. If depression levels were a factor, improvements
would have been expected in both groups of exercisers.
Exercise may also be a physiological stimulus capable of
initiating protective brain mechanisms. Two studies examining
activity levels of adults indicate that physical activity and en-
riched environments may help decrease the risk of cognitive
impairments. Comparisons of clinical evaluations, spaced by 5
yrs, of 4615 adults aged 65 yrs and older revealed that high levels
of physical activity corresponded with decreased incidence of
cognitive impairments (5). This result was particularly signifi-
cant in women. A similar study examining retrospective surveys
from 193 possible or probable participants with AD and 358
healthy controls aged 20 60 yrs concluded that those with AD
participated in fewer activities during middle adulthood than
did healthy controls (3). Activities examined were categorized
as passive, intellectual, and physical, suggesting that participants
with more active lifestyles were living in more enriched envi-
ronments and were less likely to have AD. Additional clinical
studies are needed, because nearly all of the research to date has
been retrospective.
SUMMARY
Exercise is a universal activity capable of inducing change
throughout the body. Recently, several exciting findings in the
basic sciences have extended this concept to include the brain
as an organ that directly benefits from exercise. Changes in gene
expression in the hippocampus, a brain region critical for learn-
ing and memory, suggest that physical activity initiates modifi-
cations in molecular mechanisms supporting the health and
Volume 30 Number 2 April 2002
enhancing the plasticity of the brain. BDNF availability is
critical for many of these mechanisms. Animal models have
shown that exercise reduces the extent of damage after brain
injury; furthermore, human studies suggest that exercise can
delay the onset of AD. No other behavioral or pharmaceutical
intervention can make such claims. Although some may exert
neuroprotective or neuroplasticity effects, no other intervention
has yet been shown to successfully influence both of these
endpoints. Understanding the fundamental mechanisms by
which exercise can impact brain molecular mechanisms and
function will allow for the optimization of human cognitive
health and improve exercise compliance.
Acknowledgments
We thank Cheryl A. Cotman for her artwork. This work was supported by
the National Institute on Aging Grant AG13411 and the Christopher
Reeve Paralysis Foundation.
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