MCDONNELL PROJECT

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• MCDONNELL PROJECT

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ABSTRACT

• Plasticity mechanisms can alter the
  responses of neurons in the auditory cortex.
  Input-specific reorganization of primary auditory
  cortex (A1) can occur with daily episodic
  activation of nucleus basalis paired with tonal
  stimuli (Kilgard Merzenich, 1998). Previous
  experiments have shown that network level
  reorganization involves the release of cortical
  acetylcholine (ACh). We are currently engaged in
  a series of experiments to identify
  pharmacological agents that effectively stimulate
  input-specific cortical plasticity. CNS
  stimulants are known to increase ACh release
  therefore, we are examining the effects of
  amphetamine on training-induced plasticity in A1.
  After several weeks of tone detection training
  under the influence of amphetamine, nicotine and
  rolipram, standard microelectrode mapping
  techniques were used to obtain responses from
  trained animals and were subsequently compared to
  naive control animals. Our preliminary findings
  include 1) Rolipram causes an increase in the
  percent and response strength of A1 neurons that
  respond to the trained frequency. 2) Amphetamine
  causes an increase in the cortical sensitivity to
  untrained frequencies, and an increase in
  response strength specific to the trained
  frequency. 3)Nicotine shows an increase in
  response strength in trained and a trend in
  decreasing bandwidths in untrained
  frequencies.These findings provide support for
  the hypothesis that pharmacological manipulations
  combined with sensory training could be an
  effective tool in directing cortical plasticity
  for therapeutic benefit.

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BACKGROUNDTopographic Organization of Rat A1
Best frequency(kHz)
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Cortical Map Plasticity
OBJECTIVES
-To examine the effects of d-amphetamine,
rolipram and nicotine in training induced
plasticity in A1
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PREVIOUS STUDIES
Release of nucleus basalis mediated cortical Ach
release can be caused by Amphetamine too
Topically applied Cholinergic agonists can cause
cortical map expansion too
Rolipram increases cAMP levels to rise and is
responsible for persistence o f long-term
potentiation and increased long- term memory
retention
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METHODOLOGY
DRUG GIVEN (20 DAYS)
OPERANT TRAINING (25-30 DAYS)
IR BEAM
WATER SOURCE
SPEAKER
Before drug
40
20
30
50
60
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• Animal trained on a GO-NOGO task to detect a 4KHz
  tone for 25-30 days
• Each session for 2 hours, 300-400 sounds
  played/session
• Then any of amphetamine 0.5mg/kg 4 rats
• nicotine 0.5mg/kg 2
  rats
• rolipram 0.0375mg/kg
  2 rats injected subcutaneously for remaining 20
  days.
• High density electrode mapping done to obtain
  frequency-intensity tuning curves.

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CORTICAL MAP REORGANIZATION
Rolipram causes map expansion at trained
frequency
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STRENGTH OF RESPONSE
Amphetamine and Rolipram have increased response
strength for trained frequency
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SUMMARY
Amphetamine Nicotine Rolipram
Response strength Increase Increase Increase
Threshold Decrease No change No change
Bandwidths Increase Decrease No change
Latency Increase No change No change
Spontaneous Activity No change No change Increase
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CONCLUSIONS

1. Rolipram causes an increase in the percent and
   response strength of A1 neurons that respond to
   the trained frequency.
2. Amphetamine causes an increase in the cortical
   sensitivity to untrained frequencies, and an
   increase in response strength specific to the
   trained frequency.
3. Nicotine shows an increase in response strength
   in trained and a trend in decreasing bandwidths
   in untrained frequencies.

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RELEVANCE

• Pharmacological manipulations combined with
  sensory training could be an effective tool in
  directing cortical plasticity for therapeutic
  benefit.

FUTURE DIRECTIONS -training at other
frequencies to check for frequency specific
effects -administering other drugs (
acetylcholinesterase inhibitors, piracetam,
muscarinic agonists)
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SELECTED REFERENCES

• Kilgard MP, Merzenich MM. Cortical map
  reorganization enabled by nucleus basalis
  activity. Science. 279 1714-8.1998
• Arnold H Moore, Fadel James, Sarter Martin, Bruno
  P John. Amphetamine-stimulated cortical
  acetylcholine release role of the basal
  forebrain.Brain Research.89474-87.2001
• Penschuck S,Chen-Bee H Cynthia, Prakash Neal,
  Frostig D Ron. In vivo Modulation of cortical
  functional sensory representation shortly after
  topical cholinergic agent application.The Journal
  of Comparative Neurology. 45238-50.2002
• Barad M,Bourtchouladze R, Winder DG, Golan H,
  Kandel E. Rolipram, a type IV-specific
  phosphodiesterase inhibitor, facilitates the
  establishment of long-lasting long-term
  potentiation and improves memory. Proceedings of
  the National Academy of Sciences. 95(25)
  15020-5. 1998.
• Dinse HR, Ragert P, Pleger B, Schwenkreis P,
  Tegenthoff M. Pharmacological modulation of
  perceptual learning and associated cortical
  reorganization. Science. 30191-4.2003.

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