Ethanol Effects on Neostriatal Function

描述(由Candiate提供)：这项建议的长期目标是通过评估乙醇对新纹状体长期可塑性和纹状体依赖的学习和记忆形式的影响，加深我们对导致酒精成瘾的神经机制的理解。最近的研究表明，新纹状体是从目标导向、自我控制的行为向刺激驱动的习惯转变的关键神经底物，即使结果不再令人满意，这种习惯也会持续下去。酗酒和酗酒可能涉及这种习惯性行为。新纹状体的不同区域与这些不同类型的行为控制有关，它们的特点是不同类型的长期突触可塑性。然而，关于乙醇这种被广泛滥用的药物如何影响这一关键结构中的突触可塑性，或者它如何改变纹状体依赖的学习和记忆，人们知之甚少。结合体外电生理学和体内行为分析，我希望阐明乙醇在改变新纹状体突触强度和纹状体依赖学习中所起的作用。提出了两个具体的目标：1)确定直接使用乙醇对新纹状体长期可塑性的影响。这将通过在精心准备的大鼠脑片中使用场电位和全细胞膜片钳记录来实现。2)确定体内酒精暴露对奖赏引导学习的影响。这将通过在工具性学习任务期间在体内向新纹状体局部注射同等剂量的乙醇来实现，并评估乙醇治疗对纹状体依赖学习和记忆的影响。从拟议的研究中获得的结果将通过阐明乙醇如何影响新纹状体突触可塑性所需的各种神经递质和神经调节剂，从而详细了解乙醇对神经回路中长期可塑性的影响，这些可塑性具体涉及习惯形成和成瘾。此外，这些研究将提供有价值的信息，说明体内乙醇暴露如何调节认知过程，导致对自愿行为的控制受损。完成这些目标还将有助于更好地理解乙醇如何篡夺自然奖赏引导学习的神经系统来产生强迫和成瘾行为，从而可能被证明在开发更有效的对抗酒精滥用和酒精中毒的策略方面有价值。

DESCRIPTION (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.