- A friend of mine wrote this paper, if anyone has time to read it, I
would like to know if this is factual for myself, her opinion seams
to be a little bias. hhaa
License to Run: Exercise Impacts Functional Plasticity in the Intact and Injured Central Nervous System by Using Neurotrophins
Department of Neurosurgery and Physiological Science, and Brain Injury Research Center, UCLA School of Medicine, Los Angeles, CA
Department of Neurosurgery and Physiological Science, and Brain Injury Research Center, UCLA School of Medicine, Los Angeles, CA, Fgomezpi@...
Exercise has been found to impact molecular systems important for maintaining neural function and plasticity. A characteristic finding for the effects of exercise in the brain and spinal cord has been the up-regulation of brain-derived neurotrophic factor (BDNF). This review focuses on the ability of exercise to impact brain circuitry by promoting neuronal repair and enhance learning and memory by increasing neurotrophic support. A paragon for the role of activity-dependent neurotrophins in the CNS is the capacity of BDNF to facilitate synaptic function and neuronal excitability. The authors discuss the effects of exercise in the intact and injured brain and spinal cord injury and the implementation of exercise preinjury and postinjury. As the CNS displays a capacity for plasticity throughout ones lifespan, exercise may be a powerful lifestyle implementation that could be used to augment synaptic plasticity, promote behavioral rehabilitation, and counteract the deleterious effects of aging.
Key Words: Cognition Oxidative stress Diet
Abstract and Full Text Links
The benefits of exercise on brain health have
been recognized for centuries. As early as 4
B.C. to A.D. 65, Seneca, Roman philosopher
and dramatist, prescribed exercise in his writings
as a means to obtain a healthy mind and body.1 Yet
it has only been in the past 2 decades that scientific
inquiry has stringently substantiated the effect of
exercise on CNS health. Both clinical2-4 and animal5-
7 studies have repeatedly demonstrated that
exercise benefits neuronal function. Exercise
improves learning and memory,3-5 counteracts the
mental decline that comes with age,2,8 and facilitates
functional recovery after brain and spinal
cord injury (SCI), disease,9-11 and depression.12,13
The brain and spinal cord display plasticity, a
capacity that enables these systems to achieve new
functions by modifying the constitutive elements
of their internal milieu and/or connectivity in
response to environmental constraints.14 Both the
brain and the spinal cord have a regenerative
potential that constitutes part of the plastic potential
of the young, adult, and senescent animal.15 A
major focus of research has been the attempt to
delineate the potential therapeutic capacity of
exercise in CNS injury. In fact, the major setback
limiting the rehabilitative implementation of exercise
can be poised in the following question: What
are the molecular mechanisms and signaling pathways
through which exercise promotes synaptic
plasticity, functional recovery, and learning and
memory? It is mainly through the use of animal
studies that the underlying mechanisms subserving
the ability of exercise to augment synaptic and
cognitive plasticity and promote neuronal repair
are beginning to be discerned.
The effects of exercise on the brain go beyond
simply increasing regional blood supply,16,17 nor
are they restricted to motor-sensory regions of the
brain expectant to be conjoined with a motor task.
Exercise can activate specific neural circuits to
modify the way that information is transmitted
across cells at the synapse, possibly by impacting
Copyright © 2005 The American Society of Neurorehabilitation 283
From the Department of Neurosurgery and Physiological Science,
and Brain Injury Research Center, UCLA School of Medicine,
Los Angeles, CA.
Address correspondence to Fernando Gomez-Pinilla, Department
of Physiological Science, 621 Charles E. Young Drive,
UCLA, Los Angeles, CA 90095. E-mail: Fgomezpi@....
Vaynman S, Gomez-Pinilla F. License to run: exercise impacts
functional plasticity in the intact and injured CNS by using
neurotrophins. Neurorehabil Neural Repair 2005;19:283295.
the action of specialized molecules. Characteristically,
animal studies have found that exercise elevates
the levels of neurotrophic factors in select
regions of the adult brain and spinal cord.
Neurotrophic factors have been categorically
described as factors that regulate the proliferation
and differentiation of cells in the developing
CNS.18 Among the trophic factors elevated by exercise
are insulin-like growth factor (IGF),19
fibroblast growth factor 2 (FGF-2),20,21 and brainderived
neurotrophic factor (BDNF).22 Although
other trophic factors have their roles in promoting
neuronal plasticity, an increase in BDNF and associated
plasticity molecules has been the thematic
epithet for the effects of exercise in the brain, especially
in the hippocampus, an area vital for supporting
learning and memory processes.23,24
BDNF MEDIATES THE EFFECTS
OF EXERCISE ON THE BRAIN
It must be emphasized that BDNF, unlike other
neurotrophins, seems to be especially susceptible
to regulation by activity, for both its expression
and release.25,26 This activity dependence provides
a means for behavioral implementations such as
exercise to easily modulate BDNF levels in the CNS.
Experiments using cultured hippocampal neurons,
in which the mRNAs for the precursor proteins
pro-BDNF and pronerve growth factor (pro-NGF)
were overexpressed, demonstrated that activity
applied here in the form of depolarization was
responsible for triggering the release of BDNF,
whereas NGF secretion remained constitutive.27
Like NGF, the expression of other neurotrophins,
NT-3 and NT-4, does not seem to be as susceptible
to regulation by activity.28 In fact, this lack of activity
dependence has enabled NT-3 to be used as a
control to study the effects of exercise on synaptic
plasticity.29-31 The activity dependence of BDNFwas
especially found to be prominent in hippocampal
neurons. The secretion of neurotrophins can be
either regulated or constitutive. In constitutive
secretion, neurotrophins are spontaneously
released shortly after being synthesized, thereby
enabling the neurotrophin to be continuously
available to cells that need it. In contrast, in the
regulated pathway, once synthesized, neurotrophins
are stored in secretory granules and
released in response to extracellular cues.32 Insertion
of BDNF into the hippocampus by using a
vaccina virus expression system showed that
BDNF is sorted into the regulated pathway,
whereas other neurotrophins are mainly sorted
into the constitutive pathway.27,32 Although other
neurotrophic factors, such as NGF23 and FGF-2,20
have been found to be induced in the hippocampus
by exercise, their up-regulation was curtailed
and less robust than that of BDNF. In conclusion,
the activity dependence of BDNF may enable it to
be particularly capable of mediating the benefits of
exercise on neuronal and cognitive plasticity.
Exercise-induced increase of BDNF in the hippocampus
may be archetypal for the benefits of
physical activity on overall CNS health. In addition
to the hippocampus, exercise induces the expression
of BDNF mRNA and protein in the cerebral
cortex, cerebellum, and the spinal cord.23,33-35 As
neuronal plasticity serves as the foundation for
learning and the basis of recovery of function,
neurotrophic factors such as BDNF, which are
intrinsically involved in mediating synaptic plasticity
and learning and memory mechanisms, may be
especially requisite in the reorganization and
regeneration of injured circuits. Exercise provides
a natural and noninvasive paradigm to activate this
plastic potential of the injured CNS by employing
BDNF and similar trophic support factors.
EXERCISE BENEFITS COGNITIVE
ABILITIES THROUGH BDNF
Learning and memory have been used as an
effective paradigm to understand how the nervous
system undergoes plasticity, that is, alters components
of its neuronal circuitry to effectuate changes
in synaptic transmission and functional outcome,
in response to behaviors such as exercise. In intact
animals, exercise has repeatedly been shown to
improve cognitive function, in particular, to facilitate
the acquisition of hippocampal-dependent
The role of neurotrophic factors, especially BDNF,
in mediating the effects of exercise on the brain
has been explored in regard to their ability to augment
cognitive function. It was first determined
that animals who learned the fastest and had the
best recall also had the highest levels of BDNF in
their hippocampi,17 suggesting that hippocampal
BDNF levels seem to be related to learning efficiency.
Recent studies indicate that the exerciseinduced
enhancement in learning and memory is
dependent on the increase in hippocampal BDNF
levels.31 Antibodies (TrkBIgG) that quench the
action of endogenous BDNF in the hippocampus
during exercise training were used in those stud-
284 Neurorehabilitation and Neural Repair 19(4); 2005
S. Vaynman and F. Gomez-Pinilla
ies. Blocking the action of BDNF during exercise
was found to be sufficient to abolish the exerciseinduced
enhancement of both learning and memory
on the Morris water maze task, a hippocampaldependent
task of spatial memory.31 Additionally,
there seems to be a strong quantitative relationship
between BDNF and learning and memory.17
Studies evaluating the importance of BDNF to
cognition indicate that exercise may activate the
neural circuitry necessary for the nervous system
to undergo learning and memory. Reminiscent of
the BDNF increases produced by physical activity,
actual learning and memory tasks,38 and long-term
potentiation (LTP), the electrophysiological correlate
believed to underlie learning and memory39,40
selectively increases BDNF mRNA levels in the hippocampus.
Studies have reported that BDNF
mRNA levels are increased in the hippocampi of
rats that have undergone 3 or 6 days of Morris
water maze training.16 Similarly, studies using
alternative hippocampal-dependent learning paradigms
such as contextual fear conditioning have
found increases in BDNF mRNA levels in the hippocampus.
41 The demarcation that BDNF holds
among its neurotrophic factors to regulation by
activity may similarly be occupied in regard to
memory processes. BDNF, but not NGF or NT-3,
seems to play a role in consolidating short-term
memories into long-term memories.42
The ability of exercise to induce BDNF takes on
an even greater significance when presented with
studies that illustrate that BDNF may be constitutive
for proper cognitive function. For example,
depleting the hippocampus of BDNF, by using
transgenic animals quenching endogenous BDNF
with function-blocking anti-BDNF antibodies, has
been demonstrated to impair spatial learning and
memory in rats on both the water maze and an
inhibitory avoidance task43-45 and reduce LTP.44,46
Exogenously reinstating BDNF into the depleted
hippocampus seems to ameliorate these deficits.
Exogenous BDNF application46 or transfection of
hippo- campal slices with a BDNF-expressing
adenovirus47 has been shown to restore the ability
to induce LTP. Clinical studies support the importance
of BDNF in learning and memory in
humans.48,49 A study conducted by Egan and colleagues
found that individuals expressing a specific
polymorphism in the BDNF gene exhibit
learning impairments.48 The possibility of using
chronic delivery of BDNF in human patients for
nervous system repair is problematic, in that it is
unable to cross the blood-brain barrier50 and
directly infusing it into the brain would be too
invasive. Therefore, using exercise as a physiological
means to increase BDNF levels makes it a
suitable candidate to be instated as a component of
EXERCISE ACTIVATES SIGNAL
The ability of physical activity to activate elements
of neuronal gene expression is fundamental
to the proficiency of exercise in inducing long-lasting
and/or permanent changes in the morphology
and function of the nervous system. Exercise
impacts downstream effectors of BDNF action on
gene expression by increasing the transcriptional
regulator cAMP response element binding protein
(CREB).30 CREB activation rapidly actuates de
novo transcription and translation of inducible
transcription factors, such as cFos and Jun, whose
transient expression leads to the more persistent
expression of their target genes. It is the expression
of these target genes that results in changes in
structural proteins, enzymes, ion channels, and
neurotransmitters that eventuate changes in the
structure and function of neuronal circuitry.51 The
functional outcome of CREB induction has been
applied to the field of learning andmemory. CREB
has been found to be an evolutionarily conserved
molecule requisite for the formation of long-term
memory (LTM).52-54 CREB has been described as a
molecular switch for the activation of transcription
necessary for LTM.54 Disrupting CREB function
with a dominant negative CREB protein impairs
odor memory in Drosophila55 and an LTM deficiency
CREB seems to be an important link in the
BDNF-mediated machinery responsible for
advancing the effects of exercise on learning and
memory. Blocking BDNF action during exercise
was sufficient to abrogate the exercise-induced
enhancement in learning and memory and prevent
exercise-induced increase in CREB mRNA levels
and the active form of CREB (p-CREB).31With exercise,
BDNF and CREB mRNA levels were significantly
and positively associated with each other as
well as with performance on the probe trial, illustrating
that animals with the highest BDNF expression
also had the highest CREB expression and the
best memory recall. Moreover, the effect of exercise
may be potentiated through CREB as it may
provide a self-perpetuating loop for BDNF action
during exercise, in that it regulates BDNF transcription56
and in turn is regulated by BDNF.57,58
Neurorehabilitation and Neural Repair 19(4); 2005 285
License to Run
EXERCISE USES BDNF TO
FACILITATE THE SYNAPSE
Exercise may benefit brain function by facilitating
transmission of nerve impulses at the synapse.
The most chronicled synaptic protein found to be
regulated by exercise under the action of BDNF is
synapsin I.17,30,31 Synapsin I tethers synaptic vesicles
to the actin cytoskeleton,59 thus providing for
a substantial and localized vesicular pool of vesicles
remote from the active zone that serves as a
reserve pool and proper neurotransmitter release;
inhibiting synapsin I reduces both the synaptic
vesicle reserve pool and neurotransmitter
release.60 The presence of an adequate vesicular
pool becomes apparent during high-frequency
stimulation, as without it vesicular rundown
occurs.61 The ability of BDNF to regulate synaptic
release proteins such as synapsin I may explain
why BDNF gene deletion in mice results in a
reduction in synaptic proteins, sparsely docked
vesicles, and impaired neurotransmitter release.62
In fact, blocking the action of BDNF produces synaptic
fatigue and decreases synapsin I levels.62 An
adequate vesicular release pool and adequate and
sustainable transmitter release provided by functional
levels of synapsin I may afford the level of
synaptic communication necessary for learning. A
recent clinical study conducted on familial epileptics
showed that a genetic mutation in the synapsin I
gene may be associated with learning difficulties.63
The action of exercise on presynaptic membrane
molecules such as synapsin I may contribute
to the observation that physical activity induces
perforated synapses, which characteristically have
multiple dendritic contacts.64,65 Synapsin I also regulates
neurite development,66,67 the formation and
maintenance of the presynaptic structure,68 axonal
elongation,69 and new synaptic formation.70 Synapses
with multiple dendritic contacts may not only
contribute to the efficacy of synaptic transmission
but may also represent newly formed conduits for
AND THE INJURED BRAIN
Similar to the developing nervous system,
which is structurally and functionally dynamic, the
injured CNS is undergoing processes of reorganization
and regeneration that may make it especially
responsive to being primed by external cues
such as physical activity. Exercise may potentiate
the intrinsic plasticity of the injured brain by
increasing expression of trophic support systems.
Animal studies have determined that exercise
may be therapeutic in the management of CNS
injury, by reducing the degree of initiatory damage,
limiting the amount of secondary neuronal
death, and supporting neural repair and behavioral
rehabilitation. These above-mentioned effects of
exercise have been accredited in part to neurotrophic
factors, such as BDNF. BDNF gene deletion
in mice increases the incidence of apoptosis,45
whereas the addition of BDNF in cultured rat
hippocampal neurons protects neurons against
excitotoxicity.71 Studies have shown that the powerful
role of BDNF in promoting neuronal survival
in the developing nervous system72 seems to
extend to injuries suffered by the adult brain. For
instance, BDNF is associated with improving cognitive
function and ameliorating neurological deficits
caused by ischemia.73-77
EXERCISE BEFORE OR
AFTER BRAIN INJURY
A pressing concern in need of being answered
about the implementation of exercise as a rehabilitative
intervention is what time period should
physical activity be applied to produce its
ameliorative effects on structural and functional
CNS damage. In animal studies, performing exercise
prior to brain trauma has been found to produce
prophylactic effects on attendant brain damage,
such as limiting the infarct size following
forebrain ischemia.78,79 Moreover, preinjury exercise
has been shown to have transoperative benefits
in animal models of stroke and Parkinson disease.
78,80 Obviously a preinjury exercise regimen
for humans may not be the most effective treatment
because the time of injury cannot be predicted.
However, exercise therapy may be beneficial
for certain patient populations such as those
who have sustained a transient ischemic attack and
therefore have a high disposition to experience a
The implementation of exercise during the
postinjury phase requires paying attention to specific
protocols to be beneficial. In slow-degeneration,
nonsevere models of Parkinson disease, the
application of exercise during the incipient phase
of neuronal degeneration is neuroprotective, functioning
to attenuate neurochemical deficits and
provide a measure of behavioral recovery.82 These
effects of exercise have been reproduced in
286 Neurorehabilitation and Neural Repair 19(4); 2005
S. Vaynman and F. Gomez-Pinilla
human subjects. Physical therapy is effective in
increasing motor ability when implemented extant
to the diagnosis of Parkinson disease.83-86 In contradiction
to these findings, animal studies exploring
the use of exercise immediately following traumatic
brain injury (TBI) found that exercise can
exaggerate the extent of ischemic or TBI.87,88
The above-mentioned diametric findings bring
up the question of when postinjury physical activity
should be implemented to be beneficial. Post-
TBI, an energy crisis prevailing among surviving
cells may make them more vulnerable to secondary
activation.89-91 Studies suggest that postinjury,
there is less cellular ATP availability89,90,92 as an
immediate source of energy for cellular processes.
As exercise has been shown to increase the energy
demand in various parts of the brain such as the
hippocampus, motor cortex, and striatum,93 it is
possible that implementing physical activity during
this energetically compromised time may further
accelerate cellular dysfunction. In a TBI animal
model, premature exercise blocked the activitydependent
BDNF up-regulation and even impaired
the recovery of cognitive function.94 Moreover, the
immediate implementation of exercise following
TBI precluded the normal up-regulation of plasticity
molecules regulated by BDNF action, such as
CREB and synapsin I seen with exercise.94,95 However,
when exercise is delayed 14 days postinjury, it
increases BDNF and enhances cognitive function.95
In conclusion, exercise provides a therapeutic
tool for TBI by managing its time of application.
10,96,97 Especially because the traumatically
injured brain has not been responsive to exogenously
administered BDNF,98 it seems that exercise,
by activating the intrinsic milieu for the action
of trophic support, may be more propitious at
bequeathing the beneficial effects of BDNF on
restoring brain function. This understanding tempered
with the knowledge that the injured brain is
metabolically distressed should accede that there
exists a critical time window postCNS injury in
which the application of exercise may be therapeutically
AND THE INJURED SPINAL CORD
It is time to realize that the spinal cord, like the
brain, is capable of using experience to modify its
existing circuitry to affect behavior, in effect exhibiting
the essentials of what we call learning.
Although our conception of the spinal cord has
substantially matured beyond the Galenic view of
the spinal cord as a mantled bundle of nerves connecting
the brain to the body,99 it is in need of
The ability of exercise to enhance SCI recovery
may be extensively due to its adeptness at enhancing
sensory function,100,101 which seems to be
mediated by molecular systems dependent on
neurotrophic action.102 Voluntary wheel running
and forced treadmill exercise elevate the expression
of BDNF and molecules important for synaptic
function and neurite outgrowth in the spinal
cord and innervated skeletal muscle.34
The results of several studies in which BDNF
has been added to the neural milieu support the
possibility that these factors promote survival and
growth of brain and spinal cord neurons affected
by several types of insults.103,104 It has been shown
that BDNF administration after midthoracic complete
spinal cord transection improves the functional
recovery of hind limb stepping and that
these changes appear to be associated with
neuronal sprouting at the injury site.105,106
BDNF and NT-3 mRNA levels have been found
to be increased in the lumbar region of the spinal
cord and in the soleus muscle, whose innervating
motorneurons are located in the lumbar region.
The findings that 1) the soleus muscle contained
significant increase in BDNF mRNA levels without
concurrent increases in protein and 2) the spinal
cord protein levels far exceeded the small
increases in spinal BDNF mRNA levels have lead to
the suggestion that neuromuscular activity might
increase retrograde transport of BDNF from the
muscle.33 It is likely that peripheral sources of
neurotrophins are transported retrogradely from
the muscle via motorneuron axons to serve as
trophic sources for neurons in the spinal cord and
dorsal root ganglia.33 Using spinal cord isolation to
eliminate supraspinal and peripheral monosynaptic
input to the lumbar regions of the spinal
cord while retaining motorneuron-muscle connectivity
decreased the levels of BDNF and NT-3 mRNA
and protein levels in the isolated regions.107 Paralyzing
the soleus muscle with intramuscular botulin
toxin type A injection, thereby reducing activity of
this normally animated muscle, decreased BDNF
and synapsin I expression but increased NT-3 in
the lumbar spinal cord.107 Although classic treadmill
training has been shown to increase the production
of BDNF and NT-3 in the spinal cord and
skeletal muscle,34 this paradigm showed that there
is a differential effect of activity provided by exercise
on these 2 neurotrophins.
Neurorehabilitation and Neural Repair 19(4); 2005 287
License to Run
DO ALL FORMS OF
EXERCISE LEAD TO THE
Functional recovery seems to be highly task
specific. Possibly the most lucid representation of
this in action can be found in the study performed
by Nudo and colleagues.108 Squirrel monkeys who
had undergone unilateral microlesions to the hand
representation area of the cortex showed
behaviorally dependent changes in the damaged
hemisphere. Spontaneous recovery consisted of
the animal relying on the unimpaired limb and
resulted in a decrease of the hand representation
area.109 When the animals were forced to use the
impaired limb in a set of training tasks by restraining
the unimpaired limb, they showed a sparing of
the hand representation area of the cortex.108
Forced limb motor activity also adheres to the laws
of postinjury CNS vulnerability. When animals
were forced to rely on the unimpaired forelimb
immediately following the cortical injury for 14
days, neuroanatomical and functional losses were
A study conducted using 3 different exercise
paradigms, treadmill training, swim training, and
stand training, found that treadmill exercise was
the most propitious among the 3 for improving
sensory recovery after spinal cord contusion in
rats.102 Thus, it seems that rehabilitative strategies
that simulate walking are distinctively effective at
reclaiming locomotion. The beneficial effects of
exercise paradigms, such as running or walking,
on SCI may be attributed to the phasic sensory
input produced by repetitive foot contact with the
ground to result in the induction of activitydependent
events such as increased neurotrophin
levels in selective circuitry. As for the case of the
brain, BDNF is a prized candidate for use in spinal
cord therapies. BDNF localizes to synaptic vesicles
in the dorsal horn111 and modulates sensory input
within the spinal cord.112,113 BDNF acts to confer
tactile sensitivity to the spinal cord by transducing
tactile stimuli from slow-adapting mechanoreceptors
innervating Merkel cells within touch dome complexes
of the skin to the spinal cord.114 This may
explain why repetitive loading of the hind limb
provided during running but not standing or swimming
exercise paradigms produces increases in
BDNF levels.102 In fact, the recent findings from
Hutchinson and colleagues102 suggest that the best
predictor of tactile sensory recovery after SCI seems
to be spinal and peripheral expression of BDNF.
THE SPINAL CORD CAN
ALSO BENEFIT FROM LEARNING AND
Recent experiments have found that the upregulation
of BDNF by exercise in the spinal cord
may activate the select machinery employed by
BDNF to promote synaptic plasticity in brain
regions central to learning and memory. Hemisectioned
rats conditioned by 28 days of exercise,
initiated 1 week postinjury, showed significant
increase in BDNF levels in the lumbar region of the
hemicord ipsilateral to the lesion. Moreover, exercise
also augmented the consummate end products
of BDNF action on synaptic transmission and
gene transcription, that is, synapsin I and CREB.115
Like BDNF, these factors have been found to be
fundamental to promoting synaptic plasticity
underlying learning and memory.53,54,64 These findings
advocate for the existence of spinal cord
learning mechanisms that may be harnessed to
promote neuronal repair and functional recovery.
In conclusion, the use of exercise training may
activate mechanisms of motor skill learning in
patients with a moderate to profound loss of
ascending and descending spinal pathways by
using activity-dependent plasticity to increase
Particularly, our understanding of spinal cord
competence has been broadened by the finding of
a spinal central pattern generator (CPG) constituted
from interconnected spinal neurons. The
CPG is stimulated by supraspinal tracts that
descend from the locomotor regions in the
brainstem and the thalamus, but it relies on
proprioceptive and cutaneous inputs from the
periphery to continually adjust its activity.116 Studies
conducted in cats have found that when
supraspinal control is removed, by transecting the
thoracic spinal cord, the CPG in the lumbosacral
spinal cord is still capable of producing wellplanned
and coordinated treadmill locomotion.117
Studies in humans confirm animal studies, showing
the presence of the CPG in the lubrosacral spinal
cord.118,119 Advantageously, the existence of a
CPG allows for the possibility that exercise training
can be used to guide the performance of the CPG
and result in restoring some aspects of locomotion.
A robust body of data indicates that repetitive locomotor
activity can improve functional recovery following
different types of injuries to the spinal cord
in humans and animals.120-125
288 Neurorehabilitation and Neural Repair 19(4); 2005
S. Vaynman and F. Gomez-Pinilla
RUNNING OUT OF TIME:
The aging brain is beset by ever-accumulating
challenges to the neuronal milieu such as those
generated by oxidative damage and metabolic
changes.126,127 It is believed that these processes
contribute to the cellular and molecular abnormalities
that impose the dysfunction and eventual
death of neuronal populations in age-related
neurodegenerative diseases. Among these, oxidative
stress and lack of trophic support may engender
the pathology of various neurodegenerative
diseases. Aging is also accompanied by decreased
BDNF signaling in the brain. Studies conducted in
monkeys have shown that BDNF levels are
decreased during aging, especially in hippocampal
pyramidal and dentate granule cells.128 Conspicuously,
age-related decreases in hippocampal
BDNF levels consort with age-related impairments
in learning and memory in rats.129
Reigning supreme among the neurodegenerative
diseases afflicting the aging brain are Alzheimer
disease (AD), Parkinson disease (PD), and
stroke. The preclusion of normal BDNF expression
is a repeated characteristic in many disorders of
cognitive function that occur later in life, such
as schizophrenia,48 PD,130 dementia,131 and AD.132
For example, AD brains exhibit region-specific
decreases of BDNF in the hippocampus,133,134
which are also accompanied by decreases in the
expression of BDNF's cognate TrkB receptor.135
Regular exercise retards the accumulation of
cell damage and physiological dysfunction characteristic
of the aging process,136,137 especially attenuating
the oxidative stress and consort cognitive
decline in the brain. Rats that exercised regularly
during a 9-week period exhibited improved performance
on a learning and memory task accompanied
by reduced brain levels of membrane lipid
peroxidation and oxidative damage to DNA.36 This
result is especially prominent in older rats.138
The ability of exercise to improve cognitive
function, especially in age-compromised neural
integrity, may lie in its ability to interface metabolic
process altering oxidative stress by-products with
BDNF pathways. BDNF may be part of a system
that enhances neuronal plasticity and the resistance
to oxidative and metabolic insults. The ability
of BDNF to promote the survival of various cell
types throughout the CNS and PNS has been recurrently
reported in both the in vitro and in vivo literature.
103,139-141 Particularly, BDNF can protect CNS
neurons from oxidative stress142,143 such that BDNF
addition impacts mitochondrial activity.144 Other
neurotrophins such as NT-3 and NGF have been
shown to have antioxidant effects.143,145 However,
the benefits gained from NGF induction may be
limited given that there are few types of neurons in
the CNS that can maintain their survival in
response to NGF.146,147 In contrast, the cognate
TrkB receptor to BDNF is expressed abundantly
throughout the CNS,148 especially the hippocampus,
which exhibits a bountiful constitution of
both BDNF and the TrkB receptor.149,150 Considering
the evidence that other neurotrophins are less
susceptible to regulation by activity and those that
are, such as NGF, show transient and less robust
responses to activity than BDNF suggests that
BDNF may be the predominant neurotrophin
employed by exercise to perpetuate its effects on
the synaptic and cognitive plasticity of an animal
experienced over time.
LIFESTYLE CHOICES: A LACK
OF EXERCISE, A LACK OF BDNF
The issue of aging has particular relevance to
our present-day society. Our l ifestyle of
consummatory overindulgence and sedentary
adherence has created an authentic version of
"Logan's Run," a society that precludes us from
successful aging and where the only way out is to
start "running." The current trend to supersize
meals and minimize exercise has grown into an
obesity epidemic. The number of obese individuals
has been increasing in the past 40-year period.
Between the 19601962 and the 19881994 period,
the amount of U.S. adults fit into class I obesity
(BMI, 3034.9 kg/m2) increased to 66% (2.2%
increase per year).151 This rate seems to only be
increasing, as reported between 1991 and 1998,
the proportion of U.S. adults with a BMI > 30 kg/m2
rose 49% (7% increase per year).152 Unfortunately,
the younger generation is not immune. The number
of overweight children and adolescents has
likewise increased between the 19601962 and the
19881994 periods.151 Alarmingly, there was a
greater than 70% increase in the proportion of
obese individuals in the 18- to 29-year-old age
range between 1991 and 1998.152 The estimated
280,000 to 325,000 deaths accounted for by obesity
in 1991 is escalating.153 Moreover, obesity is a
comorbidity factor for the most prevalent of diseases
in our society, such as coronary heart disease
and diabetes.154,155 Coronary heart disease accounts
Neurorehabilitation and Neural Repair 19(4); 2005 289
License to Run
for the vast majority of deaths in the United States
in the 20th century,156 whereas diabetes has been
estimated to kill 193,000 Americans per year.157 A
sobering wakeup call should be the fact that the
increase in child obesity seems to coincide with
the increase in type II diabetes in youngsters, a disease
that has historically been relegated to the
adult and aging population.158 Between 1982 and
1994, there was an estimated 10-fold increase in
type II diabetes in adolescents, whereas in 1994
alone, 33% of all newly diagnosed cases occurred
in patients 10 to 19 years of age.159
Besides an improper diet, the lack of exercise
seems to be a leading culprit in sustaining this epidemic.
96 Accordingly, physical inactivity seems to
be the primary causal factor responsible for about
one third of deaths due to coronary heart disease,
colon cancer, and type II diabetes.160 If these statistics
are not sobering enough, it should be reiterated
that the effects of physical inactivity go
beyond affecting the body, but also are a cost to
the preservation of our cognitive faculties during
our aging process.
The damage imposed by diseases of metabolic
function characteristic of today's American society
may be especially conspicuous in the brain. As
BDNF is intimately connected with energy metabolism,
these metabolic disorders can affect BDNF
levels in the brain. Molecular systems related to
energy metabolism seem to interface with BDNFmediated
synaptic plasticity mechanisms subserving
cognition.161 Thus, the connection between
cognitive function and metabolism may be intimately
related, suggesting that behaviors such as
eating and physical activity, which modulate our
energy metabolism, may affect our ability to learn.
In fact, the mitochondrial powerhouse of the cell
driving the cellular energy production also
encodes 11 human mental retardation genes.162
Hypoglycemia and intermittent fasting both
increase BDNF levels, whereas hyperphagia and
high oxidative stress levels decrease BDNF levels.
163-165 In studies conducted with BDNF knockout
mice, BDNF has been shown to be important
for controlling glucose and insulin levels and body
weight,166 such that low levels of BDNF produce
hyperglycemia and obesity.167 Mice with reduced
BDNF levels are obese.168 Peripheral BDNF administration
can reduce body weight and normalize
glucose levels in diabetic rodents.169 Likewise,
BDNF administration into the brain has been
shown to reduce body weight and increase insulin
sensitivity.170,171 Importantly, the role that BDNF
holds in both metabolism and synaptic plasticity of
the CNS especially as related to learning and memory
processes underlines the importance of
implementing lifestyle changes such as exercise.
Given the ability of exercise to augment BDNF levels,
it is possible that exercise may be an effective
lifestyle implementation to abate if not combat the
effects of stress-related lifestyle choices. In particular,
it has been found that exercise can counteract
the decrease in hippocampal BDNF levels due to
the consumption of a high-fat diet.29 It should be
emphasized that other complementary lifestyle
changes such as dietary restriction172 and cognitive
stimulation173 can also be implemented to
counteract the stress-induced decrease in BDNF
expression and contribute to successful aging.
COMBINING EXERCISE WITH
The future of using exercise as an intervention
for the treatment of CNS trauma may be combined
with other protocols such as stem cells and pharmacological
manipulations. In addition to increasing
the regenerative processes, a prominent goal
in spinal cord repair has been to neutralize the
inhibitory CNS environment. Identified inhibitory
molecules are NogoA, Mag, tenascin-R, and
veriscan. The inhibitory action of NogoA has been
found to be suppressed by the IN-1 antibody.174
Since then, it has been demonstrated that the IN-1
antibody has cooperative effects when applied
with NT-3 or BDNF. Rats receiving the combination
treatment had a larger number of axons regenerated
for a great distance than those in rats who
received either treatment alone.175 Thus, in the
human patient, it is possible that the future may
combine physical training with pharmacological
interventions that down-regulate the inhibitory
cues of the CNS to optimize functional recovery
from brain and spinal cord trauma.
Exercise may be combined with stem cell grafts
to treat neurological disorders and SCI. Olfactory
ensheathing cells and embryonic stem cells have
been successfully used to promote the recovery of
the spinal tract in rats.176,177 Using the endogenous
ability of exercise to promote factors such as
BDNF, which have trophic, survival, and growthstimulating
properties, may help cell grafts survive
and integrate into existing circuitry. In fact, the
incorporation of motor training has been found to
enhance the survival and function of grafts of
290 Neurorehabilitation and Neural Repair 19(4); 2005
S. Vaynman and F. Gomez-Pinilla
transplanted tissue in stroke and Parkinsonian
It is becoming recognized that exercise has the
capacity to promote synaptic and functional plasticity
in the brain and spinal cord. In the intact
brain, exercise can enhance synaptic and cognitive
plasticity by using the aptitude of neurotrophic
factors such as BDNF. In the injured CNS, exercise
can facilitate functional recovery by harnessing the
intrinsic capacity of the intact nervous system that
uses BDNF-dependent synaptic plasticity. Especially
in the hippocampus, exercise has been
shown to effectuate synaptic plasticity and to
enhance learning through the action of BDNF.
Recent findings support the contention that the
spinal cord, like the hippocampus, uses a BDNFmediated
mechanism to facilitate learning.
Although the underlying mechanisms responsible
for the effects of exercise on synaptic plasticity,
functional recovery, and learning and memory are
still waiting to be delineated, the current findings
promote exercise as a potential rehabilitative therapy
for the injured CNS. In conclusion, exercise
should be considered as an important tool capable
of improving overall neural health and cognitive
ability and particularly as a regimen that can
sustain cognitive function throughout one's
This study was supported by NIH awards
NS45804 and NS39522.
1.Senecae LA. Liber I. In: L. D. Reynolds LD, ed. Ad Lucilium
Epistulae Morales, 2 vols. Oxford: Oxford University Press;
1965: Epistula X.
2.Kramer AF, Hahn S, Cohen NJ, et al. Aging, fitness, and
neurocognitive function. Nature 1999;400:418-9.
3.Suominen-Troyer S, Davis KJ, Ismail AH, Salvendy G.
Impact of physical fitness on strategy development in decision-
making tasks. Percept Mot Skills 1986;62:71-7.
4.Rogers RL, Meyer JS, Mortel KF. After reaching retirement
age physical activity sustains cerebral perfusion and cognition.
J Am Geriatr Soc 1990;38:123-8.
5.van Praag H, Christie BR, Sejnowski TJ, Gage FH. Running
enhances neurogenesis, learning, and long-term
potentiation in mice. Proc Natl Acad Sci U S A
6.Fordyce DE, Farrar RP. Enhancement of spatial learning in
F344 rats by physical activity and related learning-associated
alterations in hippocampal and cortical cholinergic
functioning. Behav Brain Res 1991;46:123-33.
7.Samorajski T, Delaney C, Durham L, Ordy JM, Johnson JA,
Dunlap WP. Effect of exercise on longevity, body weight,
locomotor performance, and passive-avoidance memory of
C57BL/6J mice. Neurobiol Aging 1985;6:17-24.
8.Laurin D, Verreault R, Lindsay J, MacPherson K, Rockwood
K. Physical activity and risk of cognitive impairment and
dementia in elderly persons. Arch Neurol 2001;58:498-504.
9.Bohannon RW. Physical rehabilitation in neurologic diseases.
Curr Opinion Neurol 1993;6:765-72.
10.Grealy MA, Johnson DA, Rushton SK. Improving cognitive
function after brain injury: the use of exercise and virtual
reality. Arch Phys Med Rehabil 1999;80:661-7.
11.Lindvall O, Kokaia Z, Bengzon J, Elmer E, Kokaia M.
Neurotrophins and brain insults. Trends Neurosci
12.Siuciak JA, Boylan C, Fritsche M, Altar CA, Lindsay RM.
BDNF increases monoamine activity in the rat brain following
intracerebroventricular or intraparenchymal administration.
Brain Res 1996;710:11-20.
13.Shirayama Y, Chen ACH, Nakagawa S, Russell DS, Duman
RS. Brain-derived neurotrophic factor produces antidepressant
effects in behavioral models of depression. J
14.Paillard J. Réflexions sur l'usage du concept de plasticité en
neurobiologie. J Psychol 1976;1:22-47.
15.Will B, Duconseille E, Cassel JC, Knoops B, Van den Bosch
de Aguikar Ph, Woerly S. Regeneration in brain and spinal
cord. In: Ferreti P, Geraudie J, eds. Cellular and molecular
basis of regeneration: from invertebrates to humans. New
York: John Wiley; 1998:379-410.
16.Kesslak JP, So V, Choi J, Cotman CW, Gomez-Pinilla F.
Learning upregulates brain-derived neurotrophic factor
messenger ribonucleic acid: a mechanism to facilitate
encoding and circuit maintenance? Behav Neurosci
17.Molteni R, Ying Z, Gomez-Pinilla F. Differential effects of
acute and chronic exercise on plasticity-related genes in the
rat hippocampus revealed by microarray. Eur J Neurosci
18.Calof AL. Intrinsic and extrinsic factors regulating vertebrate
neurogenesis. Curr Opin Neurobiol 1995;5:19-27.
19.Carro E, Trejo JL, Busiguina S, Torres-Aleman I. Circulating
insulin-like growth factor I mediates the protective effects
of physical exercise against brain insults of different etiology
and anatomy. J Neurosci 2001;21:5678-84.
20.Gomez-Pinilla F, Dao L, So V. Physical exercise induces
FGF-2 and its mRNA in the hippocampus. Brain Res
21.Gomez-Pinilla F, So V, Kesslak JP. Spatial learning and physical
activity contribute to the induction of fibroblast growth
factor: neural substrates for increased cognition associated
with exercise. Spatial learning and physical activity contribute
to the induction of fibroblast growth factor: neural substrates
for increased cognition associated with exercise.
22.Neeper SA, Gomez-Pinilla F, Choi J, Cotman C. Exercise and
brain neurotrophins. Nature 1995;373:109.
23.Neeper SA, Gomez-Pinilla F, Choi J, Cotman CW. Physical
activity increases mRNA for brain-derived neurotrophic factor
and nerve growth factor in rat brain. Brain Res
24.Russo-Neustadt AA, Beard RC, Huang YM, Cotman CW.
Physical activity and antidepressant treatment potentiate
the expression of specific brain-derived neurotrophic factor
Neurorehabilitation and Neural Repair 19(4); 2005 291
License to Run
transcripts in the rat hippocampus. Neuroscience
25.Lu B, Chow A. Neurotrophins and hippocampal synaptic
transmission and plasticity. J Neurosci Res 1999;58:76-87.
26.Schinder AF, Poo M. The neurotrophin hypothesis for synaptic
plasticity. Trends Neurosci 2000;23:639-45.
27.Mowla SJ, Pareek S, Farhadi HF, et al. Differential sorting of
nerve growth factor and brain-derived neurotrophic factor
in hippocampal neurons. J Neurosci 1999;19:2069-80.
28.Chen WP, Chang YC, Hsieh ST. Trophic interactions
between sensory nerves and their targets. J Biomed Sci
29.Molteni R, Wu A, Vaynman S, Ying Z, Barnard RJ, Gomez-
Pinilla F. Exercise reverses the harmful effects of consumption
of a high-fat diet on synaptic and behavioral plasticity
associated to the action of brain-derived neurotrophic factor.
30.Vaynman S, Ying Z, Gomez-Pinilla F. Interplay between
brain-derived neurotrophic factor and signal transduction
modulators in the regulation of the effects of exercise on
synaptic-plasticity. Neuroscience 2003;122:647-57.
31.Vaynman S, Ying Z, Gomez-Pinilla F. Hippocampal BDNF
mediates the efficacy of exercise on synaptic plasticity and
cognition. Eur J Neurosci 2004;20:2580-90.
32.Farhadi HF, Mowla SJ, Petrecca K, Morris SJ, Seidah NG,
Murphy RA. Neurotrophin-3 sorts to the constitutive secretory
pathway of hippocampal neurons and is diverted to the
regulated secretory pathway by coexpression with brainderived
neurotrophic factor. J Neurosci 2000;20:4059-68.
33.Gomez-Pinilla F, Ying Z, Opazo P, Roy RR, Edgerton VR.
Differential regulation by exercise of BDNF and NT-3 in rat
spinal cord and skeletal muscle. Eur J Neurosci
34.Gomez-Pinilla F, Ying Z, Roy RR, Molteni R, Edgerton VR.
Voluntary exercise induces a BDNF-mediated mechanism
that promotes neuroplasticity. J Neurophysiol 2002;88:2187-
35.Klintsova AY, Dickson E, Yoshida R, Greenough WT.
Altered expression of BDNF and its high-affinity receptor
TrkB in response to complex motor learning and moderate
exercise. Brain Res 2004;1028:92-104.
36.Radak Z, Kaneko T, Tahara S, et al. Regular exercise
improves cognitive function and decreases oxidative damage
in rat brain. Neurochem Int 2001;38:17-23.
37.Anderson BJ, Rapp DN, Baek DH, McCloskey DP, Coburn-
Litvak PS, Robinson JK. Exercise influences spatial learning
in the radial arm maze. Physiol Behav 2000;70:425-9.
38.Falkenberg T, Mohammed AK, Henriksson B, Persson H,
Winblad B, Lindefors N. Increased expression of brainderived
neurotrophic factor mRNA in rat hippocampus is
associated with improved spatial memory and enriched
environment. Neurosci Lett 1992;138:153-6.
39.Patterson SL, Grover LM, Schwartzkroin PA, Bothwell M.
Neurotrophin expression in rat hippocampal slices: a stimulus
paradigm inducing LTP in CA1 evokes increases in
BDNF and NT-3 mRNAs. Neuron 1992;9:1081-8.
40.Patterson SL, Pittenger C, Morozov A, et al. Some forms of
cAMP-mediated long-lasting potentiation are associated
with release of BDNF and nuclear translocation of
phospho-MAP kinase. Neuron 2001;32:123-40.
41.Hall J, Thomas KL, Everitt BJ. Rapid and selective induction
of BDNF expression in the hippocampus during contextual
learning. Nat Neurosci 2000;3:533-5.
42.Johnston AN, Rose SP. Memory consolidation in day-old
chicks requires BDNF but not NGF or NT-3; an antisense
study. Brain Res Mol Brain Res 2001;88:26-36.
43.Mu J, Li W, Yao Z, Zhou X. Deprivation of endogenous
brain-derived neurotrophic factor results in impairment of
spatial learning and memory in adult rats. Brain Res
44.Ma YL, Wang HL, Wu HC, Wei CL, Lee EH. Brain-derived
neurotrophic factor antisense oligonucleotide impairs
memory retention and inhibits long-term potentiation in
rats. Neuroscience 1998;82:957-67.
45.Linnarsson S, Bjorklund A, Ernfors P. Learning deficit in
BDNF mutant mice. Eur J Neurosci 1997;9:2581-7.
46.Patterson SL, Abel T, Deuel TA, Martin KC, Rose JC, Kandel
ER. Recombinant BDNF rescues deficits in basal synaptic
transmission and hippocampal LTP in BDNF knockout
mice. Neuron 1996;16:1137-45.
47.Korte M, Carroll P, Wolf E, Brem G, Thoenen H, Bonhoeffer
T. Hippocampal long-term potentiation is impaired in mice
lacking brain-derived neurotrophic factor. Proc Natl Acad
Sci U S A 1995;92:8856-60.
48.Egan MF, Weinberger DR, Lu B. Schizophrenia, III: brainderived
neurotropic factor and genetic risk. AmJ Psychiatry
49.Hariri AR, Goldberg TE, Mattay VS, et al. Brain-derived
neurotrophic factor val66met polymorphism affects human
memory-related hippocampal activity and predicts memory
performance. J Neurosci 2003;23:6690-4.
50.Eaton MJ, Staley JK, Globus MY, Whittemore SR. Developmental
regulation of early serotonergic neuronal differentiation:
the role of brain derived neurotrophic factor and
membrane depolarization. Dev Biol 1995;170:169-82.
51.Hughes PE, Alexi T, Walton M, et al. Activity and injurydependent
expression of inducible transcription factors,
growth factors and apoptosis-related genes within the central
nervous system. Prog Neurobiol 1999;57:421-50.
52.Dash PK, Hochner B, Kandel ER. Injection of the cAMPresponsive
element into the nucleus of Aplysia sensory
neurons blocks long-term facilitation. Nature 1990;345:718-
53.Bourtchouladze R, Frenguelli B, Blendy J, Cioffi D, Schutz
G, Silva AJ. Deficient long-term memory in mice with a targeted
mutation of the cAMP-responsive element-binding
protein. Cell 1994;79:59-68.
54.Yin JC, Del Vecchio M, Zhou H, Tully T. CREB as a memory
modulator: induced expression of a dCREB2 activator
isoform enhances long-term memory in Drosophila. Cell
55.Yin JC, Wallach JS, Del Vecchio M, et al. Induction of a dominant
negative CREB transgene specifically blocks longterm
memory in Drosophila. Cell 1994;79:49-58.
56.Tao X, Finkbeiner S, Arnold DB, Shaywitz AJ, Greenberg
ME. Ca2+ influx regulates BDNF transcription by a CREB
family transcription factor-dependent mechanism. Neuron
57.Finkbeiner S, Tavazoie SF, Maloratsky A, Jacobs KM, Harris
KM, Greenberg ME. CREB: a major mediator of neuronal
neurotrophin responses. Neuron 1997;19:1031-47.
58.Tully T. Regulation of gene expression and its role in longterm
memory and synaptic-plasticity. Proc Natl Acad Sci U S
59.Greengard P, Valtorta F, Czernik AJ, Benfenati F. Synaptic
vesicle phosphoproteins and regulation of synaptic function.
60.Hilfiker S, Pieribone VA, Czernik AJ, Kao HT, Augustine GJ,
Greengard P. Synapsins as regulators of neurotransmitter
release. Philos Trans R Soc Lond B Biol Sci 1999;354:269-79.
61.Pieribone V, Shupliakov O, Brodin L, Hilfiker-Rothenfluh S,
Czernik AJ, Greengard P. Distinct pools of synaptic vesicles
in neurotransmitter release. Nature 1995;375:493-7.
62.Pozzo-Miller LD, Gottschalk W, Zhang L, et al. Impairments
in high frequency transmission, synaptic vesicle docking,
and synaptic protein distribution in the hippocampus of
BDNF knockout mice. J Neurosci 1999;19:4972-83.
292 Neurorehabilitation and Neural Repair 19(4); 2005
S. Vaynman and F. Gomez-Pinilla
63.Garcia CC, Blair HJ, Seager M, et al. Identification of a mutation
in synapsin I, a synaptic vesicle protein, in a family
with epilepsy. J Med Genet 2004;41:183-6.
64.Jones TA, Chu CJ, Grande LA, Gregory AD. Motor skills
training enhances lesion-induced structural plasticity in the
motor cortex of adult rats. J Neurosci 1999;19:10153-63.
65.Jones TA, Bury SD, Adkins-Muir DL, Luke LM, Allred RP,
Sakata JT. Importance of behavioral manipulations and
measures in rat models of brain damage and brain repair.
ILAR J 2003;44:144-52.
66.Melloni RH Jr, Apostolides PJ, Hamos JE, DeGennaro LJ.
Dynamics of synapsin I gene expression during the establishment
and restoration of functional synapses in the rat
hippocampus. Neuroscience 1994;58:683-703.
67.Zurmohle U, Herms J, Schlingensiepen R, Brysch W,
Schlingensiepen KH. Changes in the expression of synapsin
I and II messenger RNA during postnatal rat brain development.
Exp Brain Res 1996;108:441-9.
68.Sato K, Morimoto K, Suemaru S, Sato T, Yamada N. Increased
synapsin I immunoreactivity during long-term potentiation
in rat hippocampus. Brain Res 2002;872:219-22.
69.Akagi S, Mizoguchi A, Sobue K, Nakamura H, Ide C. Localization
of synapsin I in normal fibers and regenerating
axonal sprouts of the rat sciatic nerve. Histochem Cell Biol
70.Ferreira A, Chin LS, Li L, Lainer LM, Kosik KS, Greengard P.
Distinct roles of synapsin I and synapsin II during neuronal
development. Mol Med 1998;4:22-8.
71.Mattson MP, Lovell MA, Furukawa K, Markesbery WR.
Neurotrophic factors attenuate glutamate-induced accumulation
of peroxides, elevation of intracellular Ca2+ concentration,
and neurotoxicity and increase antioxidant enzyme
activities in hippocampal neurons. J Neurochem
72.Barde YA. Neurotrophins: a family of proteins supporting
the survival of neurons. Prog Clin Biol Res 1994;390:45-56.
73.Almli CR, Levy TJ, Han BH, Shah AR, Gidday JM, Holtzman
DM. BDNF protects against spatial memory deficits following
neonatal hypoxiaischemia. Exp Neurol 2000;166:99-114.
74.Schabitz WR, Schwab S, Spranger M, Hacke W.
Intraventricular brain-derived neurotrophic factor reduces
infarct size after focal cerebral ischemia in rats. J Cereb
Blood Flow Metab 1997;17:500-6.
75.Schabitz WR, Sommer C, Zoder W, Kiessling M,
Schwaninger M, Schwab S. Intravenous brain-derived
neurotrophic factor reduces infarct size and counterregulates
Bax and Bcl-2 expression after temporary focal
cerebral ischemia. Stroke 2000;31(9):2212-7.
76.Schabitz WR, Berger C, Kollmar R, et al. Effect of brainderived
neurotrophic factor treatment and forced arm use
on functional motor recovery after small cortical ischemia.
77.Yamashita K, Wiessner C, Lindholm D, Thoenen H,
Hossmann KA. Post-occlusion treatment with BDNF
reduces infarct size in a model of permanent occlusion of
the middle cerebral artery in rat. Metab Brain Dis
78.Wang RY, Yang YR, Yu SM. Protective effects of treadmill
training on infarction in rats. Brain Res 2001;922:140-3.
79.Stummer W, Weber K, Tranmer B, Baethmann A, Kemski O.
Reduced mortality and brain damage after loco motor activity
in gerbil forebrain ischemia. Stroke 1994;25:1862-9.
80.Cohen AD, Tillerson JL, Smith AD, Schallert T, Zigmond MJ.
Neuroprotective ef fects of poor l imb use in 6-
hydroxydopamine-treated rats: possible role of GDNF. J
81.Kleim JA, Jones TA, Schallert T. Motor enrichment and the
induction of plasticity before and after brain injury.
Neurochem Res 2003;28:1757-69.
82.Tillerson JL, Caudle WM, Reveron ME, Miller GW. Exercise
induces behavioral recovery and attenuates neurochemical
deficits in rodent models of Parkinson's disease. Neuroscience
83.Bilowit DS. Establishing physical objectives in the rehabilitation
of patients with Parkinson's disease; gymnasium
activities. Phys Ther Rev 1956;36:176-8.
84.Palmer SS, Mortimer JA,Webster DD, Bistevins R, Dickinson
GL. Exercise therapy for Parkinson's disease. Arch Phys
Med Rehabil 1986;67:741-5.
85.Hirsch EC. Nigrostriatal system plasticity in Parkinson's disease:
effect of dopaminergic denervation and treatment.
Ann Neurol 2000;47:S115-20; discussion S120-1.
86.Toole T, Hirsch MA, Forkink A, Lehman DA, Maitland CG.
The effects of a balance and strength training program on
equilibrium in Parkinsonism: a preliminary study.
87.Risedal A, Zeng J, Johansson BB. Early training may exacerbate
brain damage after focal ischemia in the rat. J Cereb
Blood Flow Metab 1999;19:997-1003.
88.Humm JL, Kozlowski DA, Bland ST, James DC, Schallert T.
Use-dependent exaggeration of brain injury: is glutamate
involved? Exp Neurol 1999;157:349-58.
89.Lee SM, Wong MD, Samii A, Hovda DA. Evidence for energy
failure following irreversible traumatic brain injury. Ann N
Y Acad Sci 1999;893:337-40.
90.Signoretti S, Marmarou A, Tavazzi B, Lazzarino G, Beaumont
A, Vagnozzi R. N-acetylaspartate reduction as a measure
of injury severity and mitochondrial dysfunction following
diffuse traumatic brain injury. J Neurotrauma
91.Zanier ER, Lee SM, Vespa PM, Giza CC, Hovda DA.
Increased hippocampal CA3 vulnerability to low-level
kainic acid following lateral fluid percussion injury. J
92.Lifshitz J, Friberg T, Neumar RW, et al. Structural and functional
damage sustained by mitochondria after traumatic
brain injury in the rat: evidence for differentially sensitive
populations in the cortex and hippocampus. J Cereb Blood
Flow Metab 2003;23:219-31.
93.Vissing J, Andersen M, Diemer NH. Exercise-induced
changes in local cerebral glucose utilization in the rat. J
Cereb Blood Flow Metab 1996;16:729-36.
94.Griesbach GS, Gomez-Pinilla F, Hovda DA. The
upregulation of plasticity related proteins following TBI is
disrupted with acute voluntary exercise. Brain Res
95.Griesbach GS, Hovda DA, Molteni R, Wu A, Gomez-Pinilla
F. Voluntary exercise following traumatic brain injury:
brain-derived neurotrophic factor upregulation and recovery
of function. Neuroscience 2004;125:129-39.
96.Booth FW, Chakravarthy MV, Gordon SE, Spangenburg EE.
Waging war on physical inactivity: using modern molecular
ammunition against an ancient enemy. J Appl Physiol
97.Vitale AE, Sullivan SJ, Jankowski LW, Fleury J, Lefrancois C,
Lebouthillier E. Screening of health risk factors prior to
exercise or a fitness evaluation of adults with traumatic
brain injury: a consensus by rehabilitation professionals.
Brain Injury 1996;10:367-75.
98.Blaha GR, Raghupathi R, Saatman KE, McIntosh TK. Brainderived
neurotrophic factor administration after traumatic
brain injury in the rat does not protect against behavioral or
histological deficits. Neuroscience 2000;99:483-93.
99.Clarke E, O'Malley CD. The human brain and spinal cord.
San Francisco: Norman; 1996.
100.Edgerton VR, de Leon RD, Tillakaratne N, Recktenwald MR,
Hodgson JA, Roy RR. Use-dependent plasticity in spinal
stepping and standing. Adv Neurol 1997;72:233-47.
Neurorehabilitation and Neural Repair 19(4); 2005 293
License to Run
101.Trimble MH, Kukulka CG, Behrman AL. The effect of treadmill
gait training on low-frequency depression of the soleus
H-reflex: comparison of a spinal cord injured man to normal
subjects. Neurosci Lett 1998;246:186-8.
102.Hutchinson KJ, Gomez-Pinilla F, Crowe MJ, Ying Z, Basso
DM. Three exercise paradigms differentially improve sensory
recovery after spinal cord contusion in rats. Brain
103.Koliatsos VE, Clatterbuck RE, Winslow JW, Cayouette MH,
Price DL. Evidence that brain-derived neurotrophic factor is
a trophic factor for motor neurons in vivo. Neuron
104.Xu XM, Guenard V, Kleitman N, Aebischer P, Bunge MB. A
combination of BDNF and NT-3 promotes supraspinal
axonal regeneration into Schwann cell grafts in adult rat
thoracic spinal cord. Exp Neurol 1995;134:261-72.
105.Jakeman LB, Wei P, Guan Z, Stokes BT. Brain-derived
neurotrophic factor stimulates hindlimb stepping and
sprouting of cholinergic fibers after spinal cord injury. Exp
106.Bregman BS, McAtee M, Dai HN, Kuhn PL. Neurotrophic
factors increase axonal growth after spinal cord injury and
transplantation in the adult rat. Exp Neurol 1997;148:475-94.
107.Gomez-Pinilla F, Ying Z, Roy RR, Hodgson J, Edgerton VR.
Afferent input modulates neurotrophins and synaptic plasticity
in the spinal cord. J Neurophysiol 2004;92:3423-32.
108.Nudo RJ, Wise BM, SiFuentes F, Milliken GW. Neural substrates
for the effects of rehabilitative training on motor
recovery after ischemic infarct. Science 1996;272:1791-4.
109.Friel KM, Heddings AA, Nudo RJ. Effects of postlesion experience
on behavioral recovery and neurophysiologic reorganization
after cortical injury in primates. Neurorehabil
Neural Rep 2000;14:187-98.
110.Kozlowski DA, James DC, Schallert T. Use-dependent exaggeration
of neuronal injury after unilateral sensorimotor
cortex lesions. J Neurosci 1996;16:4776-86.
111.Michael GJ, Averill S, Nitkunan A, et al. Nerve growth factor
treatment increases brain-derived neurotrophic factor
selectively in TrkA-expressing dorsal root ganglion cells
and in their central terminations within the spinal cord. J
112.Kerr BJ, Bradbury EJ, Bennett DL, et al. Brain-derived
neurotrophic factor modulates nociceptive sensory inputs
and NMDA-evoked responses in the rat spinal cord. J
113.Mendell LM, Johnson RD, Munson JB. Neurotrophin modulation
of the monosynaptic reflex after peripheral nerve
transection. J Neurosci 1999;19:3162-70.
114.Carroll P, Lewin GR, Koltzenburg M, Toyka KV, Thoenen H.
A role for BDNF in mechanosensation. Nat Neurosci
115.Ying Z, Roy RR, Edgerton VR, Gomez-Pinilla F. Exercise
restores levels of neurotrophins and synaptic plasticity following
spinal cord injury. Exp Neurol 2005;193:411-9.
116.Wolpaw JR, Tennissen AM. Activity-dependent spinal cord
plasticity in health and disease. Annu Rev Neurosci
117.Rossignol S. Neural control of stereotypic limb movements.
In: Rowell LB, Sheperd, JT, eds. Handbook of physiology.
New York: Oxford University Press; 1996:173-216.
118.Dobkin B, Harkema S, Requejo PS, Edgerton VR. Modulation
of locomotor-like EMG activity in subjects with complete
and incomplete spinal cord injury. J Neurol Rehabil
119.Rossignol S. Locomotion and its recovery after spinal injury.
Curr Opin Neurobiol 2000;10:708-16.
120.Lovely RG, Gregor RJ, Roy RR, Edgerton VR. Effects of training
on the recovery of full-weight-bearing stepping in the
adult spinal cat. Exp Neurol 1986;92:421-35.
121.Barbeau H, Rossignol S. Recovery of locomotion after
chronic spinalization in the adult cat. Brain Res
122.Barbeau H, McCrea DA, O'Donovan MJ, Rossignol S, Grill
WM, Lemay MA. Tapping into spinal circuits to restore
motor function. Brain Res Rev 1999;30:27-51.
123.de Leon RD, Hodgson JA, Roy RR, Edgerton VR. Locomotor
capacity attributable to step training versus spontaneous
recovery after spinalization in adult cats. J Neurophysiol
124.Edgerton VR, Roy RR. Paralysis recovery in humans and
model systems. Curr Opin Neurobiol 2002;12:658-67.
125.Edgerton VR, Tillakaratne NJT, Bigbee AJ, de Leon RD, Roy
RR. Plasticity of the spinal circuitry after injury. Annu Rev
126.Forster MJ, Dubey A, Dawson KM, Stutts WA, Lal H, Sohal
RS. Age-related losses of cognitive function and motor skills
in mice are associated with oxidative protein damage in the
brain. Proc Natl Acad Sci U S A 1996;93:4765-9.
127.Navarro A, Sanchez Del Pino MJ, Gomez C, Peralta JL,
Boveris A. Behavioral dysfunction, brain oxidative stress,
and impaired mitochondrial electron transfer in aging mice.
Am J Physiol Regul Integr Comp Physiol 2002;282:R985-92.
128.Hayashi M, Mistunaga F, Ohira K, Shimizu K. Changes in
BDNF immunoreactive structures in the hippocampal formation
of the aged macaque monkey. Brain Res
129.Schaaf MJ, Workel JQ, Lesscher HM, Vreugdenhil E, Oitzl
MS, de Kloet ER. Correlation between hippocampal BDNF
mRNA expression and memory performance in senescent
rats. Brain Res 2001;915:227-33.
130.Howells DW, Porritt MJ, Wong JY, et al. Reduced BDNF
mRNA expression in the Parkinson's disease substantia
nigra. Exp Neurol 2000;166:127-35.
131.Ando S, Kobayashi S, Waki H, et al. Animal model of
dementia induced by entorhinal synaptic damage and partial
restoration of cognitive deficits by BDNF and carnitine. J
Neurosci Res 2002;70:519-27.
132.Tsai SJ, Hong CJ, Liu HC, Liu TY, Hsu LE, Lin CH. Association
analysis of brain-derived neurotrophic factor Val66Met
polymorphisms with Alzheimer's disease and age of onset.
133.Phillips HS, Hains JM, Armanini M, Laramee GR, Johnson
SA, Winslow JW. BDNF mRNA is decreased in the hippocampus
of individuals with Alzheimer's disease. Neuron
134.Connor B, Young D, Yan Q, Faull RL, Synek B, Dragunow
M. Brain-derived neurotrophic factor is reduced in Alzheimer's
disease. Brain Res Mol Brain Res 1997;49:71-81.
135.Ferrer I, Marin C, Rey MJ, et al. BDNF and full-length and
truncated TrkB expression in Alzheimer disease. Implications
in therapeutic strategies. J Neuropathol Exp Neurol
136.Kirkwood TB. Molecular gerontology. J Inherit Metab Dis
137.Radak Z, Naito H, Kaneko T, et al. Exercise training
decreases DNA damage and increases DNA repair and resistance
against oxidative stress of proteins in aged rat skeletal
muscle. Pflugers Arch 2002;445:273-8.
138.Goto S, Radak Z, Nyakas C, et al. Regular exercise: an effective
means to reduce oxidative stress in old rats. Ann N Y
Acad Sci 2004;1019:471-4.
139.Nonomura T, Hatanaka <br/><br/>(Message over 64 KB, truncated)