NUCLEUS ACCUMBENS PROCESSING OF REWARD-PREDICTIVE CUES

项目摘要 当成瘾者遇到与药物相关的条件刺激时，他们通常会发现自己很吸引人 在寻求毒品的行为中，即使在一段时间的禁欲之后。了解CS如何能够促进 因此，寻求药物和奖励的行为对于理解成瘾和复发至关重要。在这 建议，我们专注于如何条件接近行为-条件运动反应的CS， 往往会使受试者更接近预期的奖励-是学习。我们将测试三个相关的假设。 首先，先前的研究表明，在丘脑核（NAc）中的NMDA受体激活是ac-fos的必需条件。 条件性接近反应的获取，表明NAc内的突触可塑性是负责 对于这种学习。我们实验室的研究表明，在已经学会反应的动物中， 许多NAc神经元被CS兴奋，兴奋先于接近运动启动，并预测 它的潜伏期，他们是因果关系的方法。因此，我们假设，突触可塑性内的 NAc在任务获得过程中引起CS诱发的兴奋，并且这种机制是学习的原因。 第二，NAc接受来自基底外侧杏仁核（BLA）的显著兴奋性投射， 条件性接近行为和CS诱发的NAc兴奋都需要经过训练的动物 神经元以前的研究表明，许多BLA神经元编码感觉显着性，因为它们在响应时放电 甚至在动物还没有学会它们的预测价值之前，另一方面， 在受试者开始学习对CS的接近反应之前，不要开始对CS进行射击。 因此，我们假设，在BLA-NAc突触的突触可塑性是需要的出现CS- 诱发NAc神经元的兴奋，这种机制是学习的原因。 最后，NAc CS诱发的兴奋也需要多巴胺，这是由腹侧投射提供的。 被盖区（VTA）。多巴胺神经元的刺激是强烈的强化，可能是因为它促进了 形成和维持刺激和积极结果之间的关联。我们假设NAc 提示诱发的兴奋是多巴胺神经元介导的可塑性的产物，因此， 多巴胺神经元足以维持线索诱发的兴奋（从而维持线索诱发的接近行为） 在接下来的比赛中 我们将用独特而强大的尖端技术组合来测试这些假设。我们将记录 在整个任务获得学习过程中，NAc和BLA中神经元的单位放电活动，同时 将NMDA拮抗剂注射到我们记录的同一结构中。我们也将使用这种方法， 与通过局部显微注射DREADD使NAc中的BLA末端化学遗传沉默的组合 激动剂进入NAc。最后，我们将使用对腹侧被盖区多巴胺神经元的光遗传学控制来研究 VTA-NAc多巴胺投射影响作为学习基础的NAc神经元活动。

Project Summary When addicts encounter conditioned stimuli (CSs) associated with drugs, they often find themselves engaging in drug-seeking behavior, even after a period of abstinence. Understanding how CSs become able to promote drug- and reward-seeking behavior is thus of primary importance to understanding addiction and relapse. In this proposal, we focus on how conditioned approach behavior – the conditioned locomotor response to the CS that often brings the subject closer to the predicted reward – is learned. We will test three related hypotheses. First, previous studies show that NMDA receptor activation in the nucleus accumbens (NAc) is required for ac- quisition of the conditioned approach response, suggesting that synaptic plasticity within the NAc is responsible for this learning. Studies from our laboratory have shown that in animals that have already learned the response, many NAc neurons are excited by CSs, that the excitations precede approach movement initiation and predict its latency, and that they are causal to approach. Therefore, we hypothesize that synaptic plasticity within the NAc gives rise to CS-evoked excitations during task acquisition, and that this mechanism is causal to learning. Second, the NAc receives a prominent excitatory projection from the basolateral amygdala (BLA), which, in trained animals, is required for both conditioned approach behavior and for the CS-evoked excitations of NAc neurons. Previous studies suggest that many BLA neurons encode sensory salience in that they fire in response to prominent stimuli even before the animal has learned their predictive value. NAc neurons, on the other hand, do not begin to fire in response to CSs until the subject begins to learn the approach response to the CS. Therefore, we hypothesize that synaptic plasticity at the BLA-NAc synapse is required for emergence of the CS- evoked excitations of NAc neurons, and that this mechanism is causal to learning. Finally, NAc CS-evoked excitations also require dopamine, which is provided by the projection from the ventral tegmental area (VTA). Stimulation of dopamine neurons is strongly reinforcing, possibly because it facilitates the formation and maintenance of associations between stimuli and positive outcomes. We hypothesize that NAc cue-evoked excitations are a product of dopamine neuron-mediated plasticity, and that therefore stimulation of dopamine neurons is sufficient to maintain cue-evoked excitations (and hence cue-evoked approach behavior) on subsequent encounters with the cue. We will test these hypotheses with a unique and powerful combination of cutting-edge techniques. We will record the unit firing activity of neurons in the NAc and BLA throughout task acquisition learning, while simultaneously injecting an NMDA antagonist into the same structure from which we record. We will also use this method in combination with chemogenetic silencing of BLA terminals in the NAc by local microinjection of a DREADD agonist into the NAc. Finally, we will use optogenetic control over VTA dopamine neurons to examine how the VTA-NAc dopamine projection impacts the NAc neuronal activity that underlies learning.