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BDNF

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  • Richard Hernon
    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.
    Message 1 of 1 , Jul 1, 2006
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      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
      Shoshanna Vaynman

      Department of Neurosurgery and Physiological Science, and Brain Injury Research Center, UCLA School of Medicine, Los Angeles, CA

      Fernando Gomez-Pinilla

      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 one’s 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
      http://nnr.sagepub.com/cgi/content/abstract/19/4/283

      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;19:283–295.
      DOI: 10.1177/1545968305280753
      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 pro–nerve 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
      learning tasks.29,31,36,37
      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
      neurorehabilitative therapy.
      EXERCISE ACTIVATES SIGNAL
      TRANSDUCTION MECHANISMS
      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
      in mice.53
      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
      communication.
      EXERCISE, NEUROTROPHINS,
      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
      secondary insult.81
      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 post–CNS injury in
      which the application of exercise may be therapeutically
      implemented.
      EXERCISE, NEUROTROPHINS,
      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
      reorganization.
      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
      SAME DESTINATION?
      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
      exacerbated.110
      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
      MEMORY MECHANISMS
      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
      rehabilitative gains.
      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:
      EXERCISE, NEUROTROPHINS,
      AND AGING
      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 1960–1962 and the 1988–1994 period,
      the amount of U.S. adults fit into class I obesity
      (BMI, 30–34.9 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 1960–1962 and the
      1988–1994 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.
      THERAPEUTIC CHALLENGES:
      COMBINING EXERCISE WITH
      OTHER INTERVENTIONS
      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
      models.178,179
      CONCLUSIONS
      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
      lifetime.
      ACKNOWLEDGMENT
      This study was supported by NIH awards
      NS45804 and NS39522.
      REFERENCES
      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
      1999;96:13427-34.
      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
      1994;17490-6.
      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
      Neurosci 2002;22:3251-61.
      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
      1998;112:1012-9.
      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
      2002;16:1107-16.
      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
      1997;764:1-8.
      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.
      Neuroscience 1998;85:53-61.
      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
      1996;726:49-56.
      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
      2000;101:305-12.
      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
      1999;6:79-85.
      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.
      Neuroscience 2004;123:429-40.
      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
      2001;13:1078-84.
      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-
      95.
      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
      1999;835:259-65.
      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
      2003;160:1242.
      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-
      21.
      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
      1995;81:107-15.
      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
      1998;20:709-26.
      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
      A 1997;94:4239-41.
      59.Greengard P, Valtorta F, Czernik AJ, Benfenati F. Synaptic
      vesicle phosphoproteins and regulation of synaptic function.
      Science 1993;259:780-5.
      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
      1996;105:365-73.
      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
      1995;65:1740-51.
      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.
      Stroke 2004;35:992-7.
      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
      1997;12:271-80.
      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
      Neurochem 2003;85:299-305.
      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
      2003;119:899-911.
      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.
      Neurorehabilitation 2000;14:165-74.
      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
      2001;18:977-91.
      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
      Neurotrauma 2003;20:409-20.
      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
      2004;1016:154-62.
      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
      2002;93:3-30.
      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
      2004;127:1403-14.
      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
      1993;10:359-67.
      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
      Neurol 1998;154:170-84.
      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
      Neurosci 1997;17:8476-90.
      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
      Neurosci 1999;19:5138-48.
      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
      1998;1:42-6.
      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
      2001;24:807-43.
      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
      1995;9:183-90.
      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
      1987;412:84-95.
      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
      1998;79:1329-40.
      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
      Neurosci 2004;27:145-67.
      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
      2001;918:191-6.
      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.
      Neuropsychobiology 2004;49:10-2.
      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
      1991;7:695-702.
      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
      1999;58:729-39.
      136.Kirkwood TB. Molecular gerontology. J Inherit Metab Dis
      2002;25:189-96.
      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)
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