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.

BACKGROUNDTopographic 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

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

PREVIOUS STUDIES

METHODOLOGY

DRUG GIVEN

(20 DAYS)

OPERANT TRAINING

(25-30 DAYS)

SPEAKER

IR BEAM

WATER SOURCE

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

0

20

-20

Rolipram causes map expansion at trained frequency

STRENGTH OF RESPONSE

Amphetamine and Rolipram have increased response strength for trained frequency

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SUMMARYAmphetamine 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

CONCLUSIONS1) 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. Amphetamine-

stimulated 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.

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