Individual Variation in Dopamine Encoding of Incentive Salience

描述(由申请人提供)：使人上瘾的食物和药物从不与显著的、离散的和背景刺激分开使用。联想记忆的形成允许将这些刺激与无条件的奖励效应联系起来，从而使这些线索获得预测未来强化的能力。这些条件性刺激(CS)本身往往成为人们所需要的，每个人在这种情况下发生的程度也不同。最近的证据表明，CS的吸引力和激励意义的大小可能与大脑中的多巴胺(DA)信号有关。我们一直在老鼠身上使用一种被称为自动整形的条件任务来研究这一点。在这项任务中，一个可扩展/可伸缩的杠杆是预测报酬的CS。通过重复试验，大鼠产生条件性反应(CR)；特定的条件反应在不同人群中表现不同。例如，一些大鼠靠近控制杆CS并与之互动，而不是接近食物递送的位置(“手势追踪器”)，而另一些大鼠则相反(“目标追踪器”)。在腹侧纹状体被称为伏隔核核心(NACC)的区域拮抗DA受体可以减少这种杠杆定向行为，同时保持目标定向小球提取的完整性。因此，NACC中的DA信号被假设为选择性地将激励显著的属性编码到水平CS。这项拟议的研究使用电化学技术快速扫描循环伏安法(FSCV)来研究DA信号在潜在动机和奖励学习中的个体差异性。这项技术允许检测清醒行为大鼠中DA浓度的实时变化。在两个目标中，研究将询问(1)将激励意义归因于离散的奖赏配对线索(如杠杆)的个体变异性是否被腹侧和背侧纹状体中的DA信号差异编码；(2)在目标1中研究的行为表现和DA信号的变异性如何受到环境背景的调节，这些环境环境预测了奖赏的可获得性或缺乏，从而为在自动整形任务中追求奖赏创造了条件。通过了解奖励预测刺激如何激励我们寻求强化的可变性，我们可以更好地使用针对特定个体量身定做的新型认知-行为和药物治疗技术来治疗成瘾障碍。

DESCRIPTION (provided by applicant): Addictive foods and drugs are never administered in isolation from salient discrete and contextual stimuli. The formation of associative memories allows for the linking of these stimuli to unconditioned rewarding effects, such that these cues obtain the ability to predict future reinforcement. These conditioned stimuli (CS) often become desired themselves and individuals vary in the degree to which this occurs. Recent evidence suggests the magnitude by which a CS is attractive and attributed with motivational meaning may be a function of dopamine (DA) signaling in the brain. We have been studying this in the rat using a conditioning task known as autoshaping. In this task an extendable/retractable lever is the CS that predicts reward. With repeated trials rats develop a conditioned response (CR); the specific CR performed varies across a population. For example, some rats approach and interact with the lever CS instead of approaching the location of food delivery ("sign-trackers"), while other rats do the opposite ("goal-trackers"). Antagonizing DA receptors in a region of the ventral striatum known as the nucleus accumbens core (NAcC) reduces this lever-directed behavior, while leaving goal-directed pellet retrieval intact. Therefore, DA signaling in the NAcC is hypothesized to selectively encode the attribution of incentive salience to the lever CS. The proposed research investigates individual variability in DA signaling underlying motivation- and reward-learning using the electrochemical technique Fast Scan Cyclic Voltammetry (FSCV). This technique allows for detecting real-time alterations in DA concentration in the awake-behaving rat. In two aims, the studies will ask (1) whether individual variability in the propensit to attribute motivational meaning to discrete reward-paired cues, such as the lever, is differentially encoded by DA signaling in the ventral and dorsal striatum; and (2) how variability in behavioral performance and DA signaling investigated in Aim 1 are modulated by environmental contexts that are predictive of reward availability or lack-there-of, therefore "setting the occasion" for pursuit of reward in the autoshaping task. By understanding variability in how reward-predictive stimuli motivate us to seek reinforcement we can better treat addictive disorders with novel cognitive-behavioral and pharmacotherapeutic techniques that are tailored to specific individuals.