(provided by candidate): The long-term objective of this proposal is to further our understanding of neural mechanisms that lead to alcohol addiction, by assessing the effects of ethanol on long-term plasticity in the neostriatum and on striatum-dependent forms of learning and memory. Recent work has suggested that the neostriatum is the critical neural substrate underlying a transition from goal-directed, self-controlled actions to stimulus-driven habits that persist even when the outcome is no longer desirable. Alcohol abuse and alcoholism may involve such habitual behavior. Different regions in the neostriatum have been implicated in these distinct types of behavioral control, and they are characterized by distinct types of long-term synaptic plasticity. Yet little is known about how ethanol, a widely abused drug, affects synaptic plasticity in this critical structure, or how it can alter striatum-dependent learning and memory. Combining in vitro electrophysiology with in vivo behavioral analysis, I hope to elucidate the role played by ethanol in modifying synaptic strength in the neostriatum and striatum-dependent learning.
Two specific aims are proposed: 1) Determine the effect of direct application of ethanol on long-term plasticity in the neostriatum. This will be accomplished by using field potential and whole-cell patch-clamp recording in acutely prepared rat brain slices. 2) Determine the effect of ethanol exposure in vivo on reward-guided learning. This will be accomplished by local injection of comparable doses of ethanol into the neostriatum in vivo during instrumental learning tasks and assessing the impact of ethanol treatment on striatum-dependent learning and memory. The results obtained from the proposed studies will provide a detailed understanding of the effects of ethanol on long-term plasticity in neural circuits specifically implicated in habit formation and addiction, by elucidating how ethanol impacts the various neurotransmitters and neuromodulators necessary for synaptic plasticity in the neostriatum. In addition, these studies will provide valuable information as to how ethanol exposure in vivo can modulate cognitive processing, resulting in impaired control over voluntary behavior. Completion of these aims will also contribute to a better understanding of how ethanol usurps neural systems underlying natural reward guided learning to produce compulsive and addictive behavior, and thus may prove valuable in the development of more effective strategies for counteracting alcohol abuse and alcoholism.
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| Yin, Henry H (2010) The sensorimotor striatum is necessary for serial order learning. J Neurosci 30:14719-23 |
| Yu, Chunxiu; Gupta, Jay; Chen, Jiang-Fan et al. (2009) Genetic deletion of A2A adenosine receptors in the striatum selectively impairs habit formation. J Neurosci 29:15100-3 |
