Characterizing the behavioral expression of retrospective learning and memory of associative information by vmOFC->VTA neurons in the context of extinction-related behaviors

项目摘要 动物学会预测奖励以最大化它们的适应性。奖励通常遵循环境线索和/或 动物所做的动作。动物是如何学习和记住线索/动作之间的联系的， 奖励等重大成果？一种可能性是，他们记住了预期的关联，即，如何 奖励是否经常跟随特定的提示/动作？另一种可能性是他们回顾性地记得 协会，即，在奖励之前多久会有一个特定的暗示/行动？虽然这些可能性听起来 相似的是，它们实际上是可分离的，并且可能具有不同的行为功能。共同的学习观 而记忆是动物只获得预期的联想。众所周知，许多 大脑中的神经元对预期的关联进行编码。尽管如此，大脑是否也储存了回顾性的信息， 协会是未知的。我们最近发现，小鼠中不同的神经元亚群 腹侧/内侧眶额皮层（ventral/medial orbitofrontal cortex，vmOFC）是奖赏学习的关键调节器， 提示和奖励之间的回溯关联。沿着其他最近的发现，这表明， 大脑在记忆中储存了前瞻性和回顾性的关联。然而这些记忆 表现在学习过程中的神经元活动中，以及这些记忆是否由不同的 差异控制行为的神经回路是未知的。在这里，我们建议调查这一总体 通过三个具体目标。首先，神经元是如何获得代表预期和 回溯性线索-奖励关联这种活动是在不同的方向上获得的，还是在相同的方向上获得的？ 两个关联（即，从提示到奖励和/或从奖励到提示的向后）？我们将解决 这个问题使用双光子钙成像来纵向跟踪相同神经元在几天内的活动， 行为学习这将使我们能够研究单个神经元在行为学习中的活动获取。 这些实验将确定是否阻止特定的学习方向可能会阻止形成 特定类型的记忆。第二，提示-行动-奖励学习是否能区别地招募潜在的或潜在的员工？ 根据动物的训练历史，在vmOFC中建立回顾性记忆？我们将通过以下方式解决这一问题： 在行为训练期间，使动物偏向于前瞻性或回顾性学习策略。在整个 在这种学习中，我们将记录相同vmOFC神经元的活动。这些实验将决定 不同的个体在同一行为中可以获得不同的记忆。最后，执行不同的vmOFC输出 到腹侧被盖区（VTA）或丘脑核（NAc）的回路，这两个都是学习的关键调节器， 编码不同的前瞻性或回顾性记忆，以区别地控制行为？我们会研究这个 使用投影特异性成像和光遗传学来测试这些不同电路的因果功能。 总的来说，这些实验将揭示OFC回路调节奖励学习的新机制。

PROJECT SUMMARY Animals learn to predict rewards to maximize their fitness. Rewards often follow environmental cues and/or actions performed by animals. How do animals learn and remember the associations between cues/actions and salient outcomes such as rewards? One possibility is that they remember prospective associations, i.e., how often does reward follow a specific cue/action? Another possibility is that they remember retrospective associations, i.e., how often does a specific cue/action precede reward? Though these possibilities may sound similar, they are in fact dissociable, and likely have different behavioral functions. The common view of learning and memory is that animals only acquire prospective associations. Accordingly, it is well known that many neurons in the brain encode prospective associations. Nevertheless, whether the brain also stores retrospective associations was unknown. We recently showed that different neuronal subpopulations in the mouse ventral/medial orbitofrontal cortex (vmOFC), a key regulator of reward learning, encode prospective and retrospective associations between a cue and reward. Along with other recent findings, this demonstrated that the brain stores both prospective and retrospective associations in memory. Nevertheless, how these memories manifest in neuronal activity during the course of learning and whether these memories are encoded by different neural circuits to differentially control behavior are unknown. Here, we propose to investigate this overarching question through three specific aims. First, how do neurons acquire activity representing prospective and retrospective cue-reward associations? Is such activity acquired in distinct directions or the same direction for the two associations (i.e., forward from cue to reward and/or backward from reward to cue)? We will address this question using two-photon calcium imaging to longitudinally track activity of the same neurons over days of behavioral learning. This will allow us to study activity acquisition of individual neurons over behavioral learning. These experiments will determine whether blocking specific directions of learning may block the formation of specific types of memories. Second, can cue-action-reward learning differentially recruit prospective or retrospective memories in vmOFC based on the training history of an animal? We will address this question by biasing animals to either a prospective or a retrospective learning strategy during behavioral training. Throughout such learning, we will record the activity of the same vmOFC neurons. These experiments will determine whether different individuals can acquire different memories during the same behavior. Lastly, do different vmOFC output circuits to the ventral tegmental area (VTA) or the nucleus accumbens (NAc), both key regulators of learning, encode distinct prospective or retrospective memories to differentially control behavior? We will study this question using projection-specific imaging and optogenetics to test the causal function of these different circuits. Overall, these experiments will uncover novel mechanisms by which OFC circuits regulate reward learning.