Multiple Memory Systems in Action Selection

拟议的研究计划将研究参与学习的多个神经回路如何有助于做出决定，以及这一过程如何被成瘾药物破坏。 目前的几个模型表明，正常学习机制的异常参与有助于药物成瘾。 特别是，有人认为，纹状体中多巴胺的反复药物增强释放产生了异常强烈的寻求药物和服用药物的学习习惯。 这种习惯很难抑制，导致行为范围逐渐缩小，并大大削弱了对药物摄入的控制。为了更好地理解这一过程，我们将研究纹状体、海马和内侧额叶皮层中涉及习惯形成和抑制的神经编码机制。 我们还将研究当习惯被精神兴奋剂安非他明人为地强化时，神经表征是如何改变的。我们的方法有两个基本特点。 首先，我们将电生理学方法应用于行为和神经解剖学特征相对较好理解的任务。 其次，我们在密切相关的情况下进行比较，旨在隔离与不同认知需求具体相关的神经表征方面。 大鼠将执行两个径向迷宫任务，它们在呈现给动物的刺激中是相同的，不同的只是获得奖励所需的策略。 在“赢-留”任务（视觉刺激-反应）中，大鼠必须选择被照亮的手臂，而不管其最近的选择历史。 学习这项任务已经被证明需要纹状体，并且可以通过纹状体内注射安非他明来增强。 在另一个任务（“胜利转移”）中，大鼠必须避开最近访问的手臂，视觉提示是无关紧要的。这是一项空间工作记忆任务，需要完整的海马功能。 在视觉提示和空间策略之间转换需要抑制习得的习惯，并且已被证明涉及大鼠内侧额叶皮层。通过检查与视觉刺激反应习惯的获得，与习惯的药物增强，与习惯的抑制相关的神经表征，我们的目标是获得关于习惯如何编码的收敛数据，以及过度强烈的习惯如何导致成瘾。与此同时，我们的目标是提供一个药物诱导的行为灵活性丧失的行为模型，可用于研究人员测试新的药物滥用疗法。 更全面地了解额叶-纹状体回路中的神经表征，以及它们如何受到多巴胺的影响，也将极大地有助于我们理解精神分裂症、强迫症、图雷特综合征、帕金森病以及药物滥用。

The proposed research program examines how multiple neural circuits involved in learning contribute to making a decision, and how this process may be subverted by addictive drugs. Several current models suggest that the abnormal engagement of normal learning mechanisms contributes to drug addiction. In particular, it has been argued that repeated drug-enhanced release of dopamine in the striatum produces unusually strong learned habits of drug-seeking and drug- taking. Such habits are hard to suppress, resulting in a progressive narrowing of behavioral repertoire, and greatly diminished control over drug intake. To better understand this process, we shall examine neural coding mechanisms involved in habit formation and inhibition, in striatum, hippocampus and medial frontal cortex. We shall also investigate how neural representations are altered when habits are artificially strengthened by the psychomotor stimulant drug amphetamine. Our approach has two essential features. Firstly we apply electrophysiological methods to tasks whose behavioral and neuroanatomical characteristics are relatively well understood. Secondly we perform comparisons between closely related situations, aiming to isolate aspects of neural representations that are specifically associated with distinct cognitive demands. Rats will perform two radial maze tasks that are identical in the stimuli presented to the animal, differing only in the strategies required to obtain rewards. In the 'win-stay' task (visual stimulus- response) the rat has to choose the arm that is illuminated, regardless of its recent history of choices. Learning this task has been shown to require the striatum, and can be enhanced by intra-striatal injections of amphetamine. In the other task ('win-shift'), the rat has to avoid the most- recently-visited arm, and the visual cue is irrelevant. This is a spatial working-memory task, that requires intact hippocampal function. Shifting between the visually-cued and spatial strategies requires suppression of the learned habit, and has been shown to involve the rat medial frontal cortex. By examining neural representations associated with acquisition of a visual stimulus-response habit, with drug enhancement of a habit, and with suppression of a habit, we aim to gain convergent data on how habits are encoded, and how excessively strong habits may contribute to addiction. At the same time we aim to provide a behavioral model of drug-induced loss of behavioral flexibility, that could be used by investigators testing novel drug abuse therapies. A fuller understanding of neural representations in frontal- striatal circuits, and how they are affected by dopamine, would also greatly contribute to our understanding of schizophrenia, obsessive-compulsive disorder, Tourette's syndrome, and Parkinson's Disease, as well as drug abuse.