NUCLEUS ACCUMBENS PROCESSING OF REWARD-PREDICTIVE CUES

描述（由申请人提供）：当成瘾者感知到与毒品有关的条件刺激（CSs）时，他们经常发现自己有寻求毒品的行为，即使在成功戒断一段时间后也是如此。因此，了解CSs如何促进药物和奖励寻求行为对于理解成瘾和复发至关重要。在这一提议中，我们关注的是条件接近行为：对CS的条件运动反应通常使受试者更接近预测的奖励。这些反应可以是灵活的，因为到达目标位置所需的具体方法行动可能因遇到CS而异。我们使用大鼠的灵活条件方法模型来研究这种行为背后的神经回路。这个回路的一个重要组成部分是伏隔核（NAc），这是一个对成瘾行为有重大影响的大脑区域。这种贡献的部分原因可能是由于它在灵活的接近反应中起着关键作用：这些反应完全取决于NAc和它从腹侧被盖区接收的多巴胺投射。然而，目前尚不清楚NAc神经元如何依赖多巴胺促进灵活的方法。一种可能性（“目标选择”）是一些NAc神经元根据CS预测的奖励和目标位置在不同可能的目标中选择接近。其他NAc神经元可能具有不同的功能（“接近门控”），激活下游回路，确定目标和接近动作，而不参与目标选择。为了理解条件趋近行为，有必要知道NAc神经元是否只服务于这些功能中的一种（如果是，是哪一种），或者它们是否参与这两种功能。为了验证目标选择和趋近门控假说，我们使用多个CSs、多个目标趋近和/或多个结果来确定行为大鼠中CS诱发的NAc神经元的放电反应是否编码有关趋近目标的信息，CS预测的结果，或两者兼有。接下来，我们确定多巴胺输入NAc如何影响这种编码，使用我们实验室开发的一种强大的新技术，将药理化合物（多巴胺拮抗剂和激动剂）应用于我们记录的行为动物的神经元。特别是，我们测试了长期存在（但尚未直接测试）的假设，即多巴胺有助于NAc神经元编码CSs的奖励预测成分。我们的技术允许我们建立D1和D2类多巴胺受体对行为相关的NAc神经元放电的不同潜在贡献。因此，这些实验将揭示NAc神经元促进对CSs的接近反应的特定电路机制。通过这样做，他们将加强我们对药物相关线索对成瘾者寻求药物行为的控制的理解。

DESCRIPTION (provided by applicant): When addicts perceive conditioned stimuli (CSs) associated with drugs, they often find themselves engaging in drug-seeking behavior, even after a period of successful abstinence. Understanding how CSs promote drug- and reward-seeking behavior is thus of primary importance to understanding addiction and relapse. In this proposal, we focus on conditioned approach behavior: the conditioned locomotor response to the CS that often brings the subject closer to the predicted reward. These responses can be flexible in that the specific approach actions required to reach the target location can vary across encounters with the CS. We use a rat model of flexible conditioned approach to investigate the neural circuitry underlying this behavior. An important element of this circuitry is the nucleus accumbens (NAc), a brain region that contributes significantly to addictive behavior. Part of this contribution is likely due to the critical role it plays in flexible approach responses: these absolutely depend on the NAc and the dopamine projection it receives from the ventral tegmental area. However, it is not yet understood how NAc neurons dopamine-dependently facilitate flexible approach. One possibility ("Target Selection") is that some NAc neurons selects among different possible targets to approach based on the reward predicted by the CS and the target location. Other NAc neurons could serve a different function ("Approach Gating") of activating downstream circuits that determine the target and the approach actions, without themselves contributing to target selection. To understand conditioned approach behavior, it is essential to know whether NAc neurons serve only one of these functions (and if so, which one) or whether they participate in both of them. To test the Target Selection and Approach Gating hypotheses, we use multiple CSs, multiple targets to approach, and/or multiple outcomes to determine whether the CS-evoked firing responses of NAc neurons in behaving rats encode information about the approach target, the outcome predicted by the CS, or both. Next, we determine how the dopamine input to the NAc influences this encoding, using a powerful new technique developed in our lab for applying pharmacological compounds (dopamine antagonists and agonists) to the neurons we record from in behaving animals. In particular, we test the long-standing (but not yet directly tested) hypothesis that dopamine contributes the reward-predictive component of NAc neurons' encoding of CSs. Our technique allows us to establish different potential contributions of D1 and D2 classes of dopamine receptors to behaviorally-relevant NAc neuronal firing. Thus, these experiments will reveal specific circuit mechanisms whereby NAc neurons promote approach responses to CSs. By doing so, they will enhance our understanding of the control over addicts' drug-seeking behavior by drug-associated cues.