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

表征消退相关行为背景下 vmOFC->VTA 神经元的回顾性学习和联想信息记忆的行为表达

• 批准号: 10700484
• 负责人: Vijay Mohan K Namboodiri
• 金额: $ 4.89万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10700484
• 关键词: Animals; Behavior; Behavior Control; Behavioral; Brain; Calcium; Cues; Data; Evolution; Extinction; Image; Individual; Learning; Medial; Mediating; Memory; Memory impairment; Mental disorders; Mus; Nature; Neurons; Nucleus Accumbens; Outcome; Output; Pathway interactions; Population; Probability; Recording of previous events; Rewards; Structure; Testing; Theoretical model; Therapeutic; Training; Ventral Tegmental Area; excitatory neuron; expectation; experimental study; fitness; improved; in vivo calcium imaging; learning strategy; member; memory acquisition; memory encoding; neural circuit; neuronal circuitry; novel; optogenetics; prospective; prospective memory; recruit; response; sound; two-photon

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.

项目概要 动物学会预测奖励以最大限度地提高它们的适应性。奖励通常遵循环境线索和/或 动物执行的动作。动物如何学习和记住提示/动作与 显着的成果，例如奖励？一种可能性是他们记住了预期的联想，即如何 奖励通常会遵循特定的提示/行动吗？另一种可能性是他们记得回顾 关联，即特定提示/动作在奖励之前出现的频率如何？尽管这些可能性听起来可能 相似的是，它们实际上是分离的，并且可能具有不同的行为功能。共同的学习观 记忆是动物只能获得前瞻性联想。据此，众所周知，许多 大脑中的神经元编码前瞻性关联。然而，大脑是否也存储回顾性信息？ 协会未知。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 (vmOFC)，奖励学习的关键调节器，编码前瞻性和 提示和奖励之间的回顾性关联。与其他最近的发现一起，这表明 大脑在记忆中存储前瞻性和回顾性关联。然而，这些记忆如何 表现在学习过程中的神经元活动以及这些记忆是否由不同的编码 差异控制行为的神经回路尚不清楚。在此，我们建议对这一总体性问题进行调查 通过三个具体目标提出问题。首先，神经元如何获得代表未来和未来的活动？ 回顾性线索奖励关联？此类活动是在不同方向还是同一方向获得的 两个关联（即从提示向前到奖励和/或从奖励向后到提示）？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行为学习中单个神经元的活动获取。 这些实验将确定阻碍特定学习方向是否会阻碍形成 特定类型的记忆。其次，提示-行动-奖励学习能否差异化地招募潜在或 vmOFC 中基于动物训练历史的回顾性记忆？我们将通过以下方式解决这个问题 在行为训练期间使动物偏向于前瞻性或回顾性学习策略。自始至终 这样的学习，我们将记录相同vmOFC神经元的活动。这些实验将决定是否 不同的人在同一行为中可以获得不同的记忆。最后，做不同的vmOFC输出 腹侧被盖区 (VTA) 或伏隔核 (NAc) 的回路，两者都是学习的关键调节器， 编码不同的前瞻性或回顾性记忆来差异化地控制行为？我们将研究这个 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。