The Role of the Locus Coeruleus-Norepinephrine System in Flexible Decision-Making

项目摘要/摘要 灵活的决策，即个体调整他们的决策策略，是人类的标志 认知力。特别是，人类能够在冲动(快速，但不准确)和深思熟虑之间转换 (准确，但缓慢)基于情景需求的策略。观察到这种能力在以下方面被破坏 神经精神障碍激发了对调节这种类型的灵活性的神经机制的研究 做决定。以往的研究表明，蓝斑-去甲肾上腺素(LC-NE)系统可能起关键作用 在冲动和深思熟虑的决策之间灵活切换的作用。然而，我们仍然缺乏一个准确的， 电路级理解NE-LC系统如何改变下游目标中的信息处理以 影响决策。 为了解决这一知识差距，我们建议利用灵活决策的RAT模型来识别 NE-LC如何改变灵活决策过程中的信息处理。具体地说，我们的目标是测试预测 一个领先的计算模型，自适应增益理论模型，它假设高NE音调改变了增益 大脑皮层神经元的信息处理导致冲动决策。我们的建议 分为三个目标。在第一个目标中，我们将使用LC-NE活动和NE的细胞分辨率成像 释放以确定NE信号的变化是否与生物体的冲动变化相关 回应环境诉求。在第二个目标中，我们将操纵LC中去甲肾上腺素神经元的活动 使用化学遗传学并评估LC-NE系统的人工激活和沉默是否足以驱动 冲动的变化。在第三个目标中，我们将使用神经元动力学和NE释放的同步成像 确定去甲肾上腺素是否能预测皮层对与决策相关的感觉输入的反应强度。如果 成功后，该项目将实现对NE信令如何调节灵活分离的电路级别的理解 制作。这一更好的理解将在识别神经机制方面取得关键进展。 并将为了解这些机制在 神经精神障碍。

PROJECT SUMMARY/ABSTRACT Flexible decision making, in which individuals adapt their decision strategies, is a hallmark of human cognition. In particular, humans are able to shift between impulsive (fast, but inaccurate) and deliberative (accurate, but slow) strategies based on situational demands. Observations that this capacity is disrupted in neuropsychiatric disorders motivates the study of the neural mechanisms that regulate this type of flexible decision making. Previous studies suggest that locus-coeruleus norepinephrine (LC-NE) system may play a key role in flexibly switching between impulsive and deliberative decision making. However, we still lack a precise, circuit-level understanding of how the NE-LC system alters information processing in downstream targets to effect decision making. To address this gap in knowledge, we propose to utilize a rat model of flexible decision making to identify how NE-LC alters information processing during flexible decision making. Specifically, we aim to test predictions of a leading computational model, the adaptive gain theory model, which posits that high NE tone alters the gain of information processing in neurons of the cerebral cortex leading to impulsive decision making. Our proposal is separated into three aims. In the first aim, we will use cellular resolution imaging of LC-NE activity and NE release to determine whether changes in NE signaling correlate with changes in impulsivity as organisms respond to environmental demands. In the second aim, we will manipulate the activity of NE neurons in the LC using chemogenics and evaluate whether artificial activation and silencing of LC-NE system is sufficient to drive changes in impulsivity. In the third aim, we will use simultaneous imaging of neuronal dynamics and NE release to determine whether NE tone predicts the strength of cortical responses to decision-related sensory inputs. If successful, this project will achieve a circuit-level understanding of how NE signaling regulates flexible discission making. This improved understanding will provide a critical advance in identifying the neural mechanism of decision making and will provide a foundation for understanding how these mechanisms may be affected in neuropsychiatric disorders.