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

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

Animal trained on a GO-NOGO task to detect a 4KHz tone for days Each session for 2 hours, sounds played/session Then any of amphetamine 0.5mg/kg – 4 rats nicotine 0.5mg/kg – 2 rats rolipram mg/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

STRENGTH OF RESPONSE Amphetamine and Rolipram have increased response strength for trained frequency

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SUMMARY AmphetamineNicotineRolipram Response strength Increase ThresholdDecreaseNo change BandwidthsIncreaseDecreaseNo change LatencyIncreaseNo change Spontaneous Activity No change Increase

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: Arnold H Moore, Fadel James, Sarter Martin, Bruno P John. Amphetamine- stimulated cortical acetylcholine release: role of the basal forebrain.Brain Research.894: 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: 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): Dinse HR, Ragert P, Pleger B, Schwenkreis P, Tegenthoff M. Pharmacological modulation of perceptual learning and associated cortical reorganization. Science. 301: Supported by a grant from the