Voluntary Exercise Induces a BDNF-Mediated Mechanism That Promotes Neuroplasticity

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Voluntary Exercise Induces a BDNF-Mediated
Mechanism That Promotes Neuroplasticity

• Fernando Gomez-Pinilla, Zeh Ting, Roland R. Roy,
  Raffaella Molteni, and V. Reggie Edgerton
• UCLA, Brain Research Institute (LA)

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Previous Findings
BDNF
Soleus
(Berchtold et al. 2001, 2002 Cotman and
Berchtold 2002, 2006 Gomez-Pinilla et al. 2002)
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Key Players

• BDNF modifies neuronal excitation and
  synaptic trasmission important in memory
  formation and plasticity
• trkB 1 transmembrane receptor for BDNF w/ tyr
  kinase activity
• Synapsin 1 phosphoprotein important for NT
  release
• GAP-43 important for axonal growth and NT
  release
• CREB well-known txn factor?regulates gene
  expression, specifically BDNF

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Background

• Botulinum toxin type A (BTX-A) purpose
  determine effects of reducing NM output of
  single muscle on neurotrophin response to motor
  activity
• Botulinum comes from Clostridium
• Blocks release of Ach from NM jxns, thus
  preventing muscular contraction
• Specifically degrades SNAP-25 (SNARE protein)

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Botox
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Hypothesis

• Exercise induces neuronal plasticity through BDNF
  and its receptor (trkB)
• Studying neuromuscular system (hindlimb)

Plasticity
BDNF
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Physical Parametrics

• Male Sprague-Dawley (rats) 3 months old
• Individually housed
• 12/12 hour light/dark
• Ad libitum food and wa-wa
• Exercise cage (30x40x20 cm) with wheel
• Adjustable resistance (1st day, no load100g
  thereafter)
• Carefully euthanized w/ pentobarb-Na and
  intracardial PBS and other goodies

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Results
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BDNF mRNA levels in spinal cord after 3 and 7
days of VE
Figure 1
correlation
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BDNF immunohisto-quimica
Figure 2
Sedentary
Exercise
Lumbar spinal cord
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Synapsin 1 (lumbar SC)
Figure 3
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GAP-43 (lumbar SC)
Figure 4 (A,B)
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CREB (lumbar SC)
Figure 4 (C,D)
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Soleus Muscle
Figure 5
BDNF mRNA
BDNF Protein
Synapsin 1 mRNA
TrkB mRNA
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Effect of BTX-A
Figure 6
Lumbar SC
Side ipsilateral to injection decreased BDNF
mRNA in sedentary and 7 days VE Contralateral
side no change in sedentary, significant
increase in 7 days VE
Soleus muscle
Ipsilateral BDNF mRNA reduced in both sedentary
and 7 days VE Contralateral no change sedentary,
175 increase with 7 days VE
Lumbar SC
Lumbar SC
Ipsilateral decrease in sedentary rats, but
maintained levels of synapsin 1 mRNA in 7 days
VE Contralateral no change in sedentary
synapsin 1 mRNA, significant increase in 7 days
VE
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Findings

• BDNF, TrkB, Synapsin 1, GAP-43, and CREB mRNA
  increased with exercise in lumbar SC (also
  Synapsin 1 protein)
• Direct relationship of mRNA levels to distance
  run (sed lt 3d VE lt 7d VE)
• Interestingly, exercise maintained levels of
  synapsin 1 mRNA on ipsilateral side of BTX-A
  injection in lumbar SC

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Findings (contd)

• In soleus muscle, BDNF mRNA and protein levels
  increased (higher after 3 days VE than 7 days VE)
• TrkB and Synapsin 1 mRNA levels increased after 3
  days VE and returned to control levels after 7
  days VE
• No change in GAP-43 mRNA seen in VE groups

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Findings (contd)

• Effect of BTX-A injection
• Decrease in BDNF mRNA in lumbar SC and soleus
  muscle on ipsilateral side in sedentary and VE
• Decrease in Synapsin 1 mRNA in lumbar SC on
  ipsilateral side in sedentary and VE
• Increase seen on contralateral side of soleus and
  lumbar SC in VE group (BDNF and Synapsin 1 mRNA)
• Interestingly, VE maintained levels of synapsin 1
  mRNA on ipsilateral side of BTX-A injection in
  lumbar SC

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Acknowledgements
Niel Burns
sustenance
Diet Mt Dew
Meeko