Voluntary Exercise Induces a BDNF-Voluntary Exercise Induces a BDNF-Mediated Mechanism That Promotes Mediated Mechanism That Promotes

NeuroplasticityNeuroplasticity

Fernando Gomez-Pinilla, Zeh Ting, Roland R. Roy, Fernando Gomez-Pinilla, Zeh Ting, Roland R. Roy, Raffaella Molteni, and V. Reggie EdgertonRaffaella Molteni, and V. Reggie Edgerton

UCLA, Brain Research Institute (LA)UCLA, Brain Research Institute (LA)

Previous FindingsPrevious Findings

BDNF

(Berchtold et al. 2001, 2002; Cotman and Berchtold 2002, 2006; Gomez-Pinilla et al. 2002)

Soleus

Key PlayersKey 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 factorregulates gene expression, specifically BDNF

BackgroundBackground

• 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)

BotoxBotox

HypothesisHypothesis

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

BDNF Plasticity

Physical ParametricsPhysical 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 load…100g thereafter)

• Carefully euthanized w/ pentobarb-Na+ and intracardial PBS and other goodies

ResultsResults

BDNF mRNA levels in spinal cord BDNF mRNA levels in spinal cord after 3 and 7 days of VEafter 3 and 7 days of VE

Figure 1

+ correlation

BDNF immunohisto-quimicaBDNF immunohisto-quimica

Sedentary ExerciseLumbar spinal cord

Figure 2

Synapsin 1 Synapsin 1 (lumbar SC)(lumbar SC)Figure 3

GAP-43 GAP-43 (lumbar SC)(lumbar SC)Figure 4 (A,B)

CREB CREB (lumbar SC)(lumbar SC)

Figure 4 (C,D)

Soleus MuscleSoleus Muscle

BDNF mRNA BDNF Protein

TrkB mRNA Synapsin 1 mRNA

Figure 5

Effect of BTX-AEffect of BTX-ASide ipsilateral to injection: decreased BDNF

mRNA in sedentary and 7 days VE

Contralateral side: no change in sedentary, significant increase in 7 days VE

Lumbar SC

Soleus muscleIpsilateral: BDNF mRNA reduced in both

sedentary and 7 days VE

Contralateral: no change sedentary, 175% increase with 7 days VE

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

Lumbar SCLumbar SC

Figure 6

FindingsFindings

• 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 < 3d VE < 7d VE)

• Interestingly, exercise maintained levels of synapsin 1 mRNA on ipsilateral side of BTX-A injection in lumbar SC

Findings (cont’d)Findings (cont’d)

• 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

Findings (cont’d)Findings (cont’d)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

AcknowledgementsAcknowledgements

Diet Mt Dew

Niel Burns

Meeko

sustenance