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MCDONNELL PROJECT

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Title: MCDONNELL PROJECT


1
  • MCDONNELL PROJECT

2
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.

3
BACKGROUNDTopographic Organization of Rat A1
Best frequency(kHz)
4
Cortical Map Plasticity
OBJECTIVES
-To examine the effects of d-amphetamine,
rolipram and nicotine in training induced
plasticity in A1
5
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
6
METHODOLOGY
DRUG GIVEN (20 DAYS)
OPERANT TRAINING (25-30 DAYS)
IR BEAM
WATER SOURCE
SPEAKER
Before drug
40
20
30
50
60
7
  • 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.

8
CORTICAL MAP REORGANIZATION
Rolipram causes map expansion at trained
frequency
20
0
-20
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10
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
19
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.

20
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)
21
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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