Transcript 1) Rolipram causes an increase in the percent and response

MCDONNELL PROJECT
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.
BACKGROUND
Topographic Organization of Rat A1
Best frequency(kHz)
Cortical Map Plasticity
OBJECTIVES
-To examine the effects of d-amphetamine, rolipram
and nicotine in training induced plasticity in A1
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
METHODOLOGY
OPERANT TRAINING
(25-30 DAYS)
DRUG GIVEN
(20 DAYS)
IR BEAM
WATER
SOURCE
SPEAKER
Before drug
20
30
40
50
60
• 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.
CORTICAL MAP REORGANIZATION
Rolipram causes map expansion at trained
frequency
20
0
-20
STRENGTH OF RESPONSE
Amphetamine and Rolipram have increased
response strength for trained frequency
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SUMMARY
Amphetamine
Nicotine
Rolipram
Response
strength
Threshold
Increase
Increase
Increase
Decrease
Bandwidths
Increase
No
change
Decrease
Latency
Increase
Spontaneous
Activity
No change
No
change
No
change
No
change
Increase
No
change
No
change
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.
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)
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. Amphetaminestimulated cortical acetylcholine release: role of the basal forebrain.Brain
Research.894:74-87.2001
• 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.
452:38-50.2002
• 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. 301:91-4.2003.
Supported by a grant from the