Multiple Memory Systems in Action Selection

这项拟议的研究计划考察了参与学习的多个神经回路如何有助于做出决定，以及这一过程可能如何被成瘾药物颠覆。目前的几个模型表明，正常学习机制的异常参与导致了药物成瘾。特别是，有人认为，纹状体中药物促进的多巴胺反复释放会产生异常强烈的后天吸毒和吸毒习惯。这种习惯很难抑制，导致行为习惯逐渐缩小，对药物摄取的控制也大大减弱。为了更好地理解这一过程，我们将研究纹状体、海马体和额叶内侧皮质中涉及习惯形成和抑制的神经编码机制。我们还将研究当精神运动兴奋剂安非他明人工强化习惯时，神经表征是如何改变的。我们的方法有两个基本特征。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的任务。其次，我们在密切相关的情景之间进行比较，目的是分离出与不同认知需求特别相关的神经表征的各个方面。大鼠将执行两个径向迷宫任务，这两个任务在提供给动物的刺激中是相同的，只是获得奖励所需的策略不同。在“赢-留”任务(视觉刺激-反应)中，大鼠必须选择被照亮的手臂，而不考虑它最近的选择历史。学习这项任务已经被证明需要纹状体，纹状体内注射苯丙胺可以增强这一能力。在另一项任务(“Win-Shift”)中，老鼠必须避开最近访问过的手臂，而视觉提示是不相关的。这是一项空间工作记忆任务，需要完整的海马体功能。在视觉提示和空间策略之间的转换需要抑制习得的习惯，并且已经被证明涉及到大鼠的内侧额叶皮质。通过研究与视觉刺激反应习惯的获得、药物对习惯的增强和习惯的抑制有关的神经表征，我们的目标是获得关于习惯是如何编码的、以及过度强烈的习惯可能如何导致成瘾的趋同数据。同时，我们的目标是提供一种药物引起的行为灵活性丧失的行为模型，可供研究人员测试新的药物滥用疗法使用。更全面地了解额纹状体回路中的神经代表，以及它们是如何受到多巴胺的影响的，也将极大地有助于我们对精神分裂症、强迫症、抽动症、帕金森氏症以及药物滥用的理解。

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.