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

蓝斑-去甲肾上腺素系统在灵活决策中的作用

• 批准号: 10818825
• 负责人: Benjamin B Scott
• 金额: $ 41.25万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-13 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10818825
• 关键词: Address; Affect; Behavior; Behavioral; Calcium; Cerebral cortex; Cognition; Cognition Disorders; Cognitive; Color; Complex; Computer Models; Data; Decision Making; Dependovirus; Development; Diagnosis; Disease; Enhancers; Environment; Foundations; Genetic Markers; Human; Image; Imaging Device; Immediate-Early Genes; Immunohistochemistry; Impulsivity; Individual; Injections; Knowledge; Link; Measurement; Measures; Mental disorders; Modeling; Mood Disorders; Motor Cortex; Nervous System; Neurodevelopmental Disorder; Neurons; Norepinephrine; Organism; Output; Pattern; Physiological; Physiology; Play; Population Dynamics; Process; Public Health; Rattus; Research; Resolution; Rodent; Role; Sensory; Signal Transduction; System; Testing; Training; Visual Cortex; Work; cell type; designer receptors exclusively activated by designer drugs; experimental study; flexibility; genetic effector; genetic manipulation; improved; in vivo; in vivo imaging; in vivo optical imaging; information processing; locus ceruleus structure; neural; neural circuit; neural model; neuroimaging; neuromechanism; neuropsychiatric disorder; norepinephrine system; novel; pharmacologic; predictive modeling; redshift; response; role model; selective expression; sensor; sensory cortex; sensory input; spectrograph; theories; tool

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.

项目摘要/摘要 灵活的决策，个人适应他们的决策策略，是人类的标志 认识。特别是，人类能够在冲动（快速但不准确）和审议之间转移 （准确但缓慢）基于情境需求的策略。观察到这种能力被破坏 神经精神疾病激发了对这种调节这种柔性的神经机制的研究 决策。先前的研究表明，基因座去甲肾上腺素（LC-NE）系统可能会发挥钥匙 在冲动和审议决策之间灵活切换方面的作用。但是，我们仍然缺乏精确的 电路级对NE-LC系统如何改变下游目标的信息处理的理解 效应决策。 为了解决知识的这一差距，我们建议利用灵活决策的大鼠模型来识别 NE-LC在灵活决策过程中如何改变信息处理。具体来说，我们旨在测试预测 在领先的计算模型中，自适应增益理论模型，该模型认为高音调会改变增益 大脑皮质神经元中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活性和NE的细胞分辨率成像 释放以确定NE信号的变化是否与冲动性变化相关 响应环境需求。在第二个目标中，我们将操纵LC中NE神经元的活性 使用化学药品并评估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释放的同时成像 确定NE音调是否预测了对决策相关感觉输入的皮质反应的强度。如果 成功，该项目将对NE信号如何调节柔性疾病进行电路级别的了解 制作。这种改善的理解将为识别神经机制提供关键的进步 决策，并将为理解这些机制如何受到影响为基础 神经精神疾病。