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; 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.

项目摘要 动物学会预测奖励以最大程度地提高其健身。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/行动之间的关联 明显的结果，例如奖励？一种可能性是他们记得潜在的协会，即如何 奖励通常会遵循特定的提示/动作吗？另一种可能性是他们记得回顾 协会，即特定的提示/行动在奖励之前多久一次？尽管这些可能性可能听起来 类似，它们实际上是可解散的，并且可能具有不同的行为函数。学习的共同观点 记忆是动物只能获得前瞻性关联。因此，众所周知 大脑中的神经元编码前瞻性关联。然而，大脑是否还存储回顾性 关联是未知的。我们最近表明，小鼠中不同的神经元亚群 腹侧/内侧轨道额皮质（VMOFC），奖励学习的关键调节剂，编码潜在的和 提示与奖励之间的回顾性关联。除了最近的其他发现，这表明 大脑将前瞻性和回顾性关联存储在记忆中。然而，这些记忆如何 在学习过程中表现出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。在这里，我们建议调查这个总体 通过三个特定目标提问。首先，神经元如何获得代表前瞻性和 回顾性提示奖励协会？是在不同的方向上获得的这种活动还是相同的方向 这两个协会（即，从提示到奖励和/或从奖励到提示向后的提示）？我们将解决 这个问题使用两光子钙成像进行纵向跟踪相同神经元的活动。 行为学习。这将使我们能够在行为学习中研究单个神经元的活动。 这些实验将确定阻止特定的学习方向是否会阻止形成 特定类型的记忆。第二，可以提示奖励学习差异化招募潜在的或 基于动物的训练史，在VMOFC中回顾性回忆？我们将通过 在行为训练期间，将动物偏向前瞻性或回顾性学习策略。自始至终 这样的学习，我们将记录相同的VMOFC神经元的活性。这些实验将确定是否 不同的人可以在同一行为期间获得不同的记忆。最后，执行不同的VMOFC输出 通往腹侧对盖区域（VTA）或伏隔核的电路（NAC），这两个都是学习的关键调节剂， 对差异控制行为编码不同的前瞻性或回顾性记忆？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的问题。 总体而言，这些实验将发现OFC电路调节奖励学习的新型机制。