NUCLEUS ACCUMBENS PROCESSING OF REWARD-PREDICTIVE CUES

描述(申请人提供)：当吸毒者感觉到与毒品有关的条件性刺激(CS)时，他们经常发现自己参与了寻求药物的行为，即使在成功戒除一段时间后也是如此。因此，了解CS是如何促进药物和奖励行为的，对于了解成瘾和复发是至关重要的。在这项研究中，我们将重点放在条件性接近行为上：对CS的条件性运动反应通常会使受试者更接近预期的奖励。这些响应可以是灵活的，因为到达目标位置所需的特定方法操作在与CS的不同遭遇中可能有所不同。我们使用灵活条件化方法的大鼠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元素是伏隔核(NAC)，这是大脑中对成瘾行为有重大贡献的一个区域。这种贡献的一部分可能是由于它在灵活的途径反应中所起的关键作用：这些反应绝对依赖于NAC及其从腹侧被盖区接收到的多巴胺投射。然而，目前还不清楚NAC神经元是如何依赖多巴胺促进灵活的方法的。一种可能性(目标选择)是，一些NAC神经元根据CS预测的奖赏和目标位置在不同的可能目标中选择接近。其他NAC神经元可以发挥不同的功能(“接近门控”)，激活决定目标和接近动作的下游电路，而不是自己对目标选择做出贡献。要理解条件性接近行为，必须知道NAC神经元是否只服务于其中一项功能(如果是，是哪一项)，或者它们是否同时参与了这两项功能。为了验证目标选择和接近门控假说，我们使用多个CS、多个要接近的目标和/或多个结果来确定行为大鼠NAC神经元的CS诱发的放电反应是否编码了关于接近目标的信息、CS预测的结果，或者两者兼而有之。接下来，我们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)应用于我们在行为动物中记录的神经元，以确定多巴胺输入NAC如何影响这种编码。特别是，我们测试了长期存在的(但尚未直接测试的)假设，即多巴胺贡献了NAC神经元编码CS的奖赏预测成分。我们的技术使我们能够确定D1和D2类多巴胺受体对行为相关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，将加深我们对吸毒者通过与毒品有关的线索控制寻毒行为的理解。

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.