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

项目总结 动物学会预测奖励，以最大限度地保持自己的健康。奖励通常跟随环境线索和/或 动物所做的动作。动物是如何学习和记忆线索/动作和 显著的结果，如奖励？一种可能性是，他们记住了预期的联想，即如何 奖励通常遵循特定的提示/动作吗？另一种可能性是他们记得追溯 关联，即，特定的提示/动作在奖励之前多久出现一次？尽管这些可能性听起来可能 相似的是，它们实际上是可分离的，而且可能具有不同的行为功能。对学习的普遍看法 而记忆是，动物只能获得预期的联想。因此，众所周知，许多人 大脑中的神经元编码未来的关联。尽管如此，大脑是否也存储了追溯 这种联系是未知的。我们最近在小鼠身上发现了不同的神经元亚群 腹侧/内侧眶前叶皮质(VmOFC)是奖赏学习的关键调节因素，它编码预期和 回溯线索和奖励之间的联系。与其他最近的发现一起，这证明了 大脑在记忆中存储着前瞻性和追溯性的联系。然而，这些记忆是如何 在学习过程中表现在神经元活动中，以及这些记忆是否由不同的 对行为进行差异化控制的神经回路尚不清楚。在这里，我们建议调查这一最主要的 通过三个具体目标提问。首先，神经元如何获得代表未来和未来的活动？ 回溯线索--奖赏关联？这种活动是以不同的方向获得的，还是以相同的方向获得的 这两个关联(即，从提示向前到奖励和/或从奖励到提示向后)？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过程中的活动获得。 这些实验将确定阻止特定学习方向是否会阻止 特定类型的记忆。第二，提示-行动-奖励学习能否差异化地招募预期或 基于动物训练史的vmOFC中的回顾记忆？我们将通过以下方式解决这个问题 在行为训练中使动物偏向前瞻性或回溯性学习策略。贯穿始终 这样的学习，我们就会记录到相同的vmOFC神经元的活动。这些实验将决定是否 不同的人可以在相同的行为中获得不同的记忆。最后，执行不同的vmOFC输出 通向腹侧被盖区(VTA)或伏隔核(NAC)的电路，这两个都是学习的关键调节因素， 编码不同的前瞻性或回溯性记忆，以区别控制行为？我们将对此进行研究 使用投影特定成像和光遗传学来测试这些不同电路的因果功能的问题。 总体而言，这些实验将揭示OFC回路调节奖赏学习的新机制。

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.