Functions of locus coeruleus norepinephrine neurons in decision making across multiple timescales

总结 去甲肾上腺素（NE）是由蓝斑（LC）中的少量神经元释放的神经递质， 大脑皮层有广泛的神经支配先前对人类和其他哺乳动物的研究导致了这一假设 LC-NE神经元调节多种形式的决策。本提案旨在全面测试这一点 通过研究执行多个决策任务的小鼠中的LC-NE神经元来验证这一假设。这些行为 研究包括两种类型的灵活决策：如何从几十秒的强化学习， 分钟的动态选择任务，以及如何根据感觉反馈快速改变运动程序， 几百毫秒到几秒该项目的目标是将已识别的LC-NE的动作电位 神经元对这两种类型的行为，并确定如何在多个皮层区域的神经元大群体 由NE输入调制以实现灵活的行为。 三个目标测试三个假设，解决不同的机械问题的功能， 新皮层中的去甲肾上腺素：1）LC-NE神经元在动态选择任务中调节强化学习; 2)去甲肾上腺素调节感觉驱动的运动程序转换; 3）LC-NE调节口面和 前额叶皮层用于有效的强化学习和运动程序切换。测量和 操作（激活和失活）NE神经元及其在新皮层中的靶点的活性， 在小鼠中进行良好控制的行为任务，将能够测试这三个假设。理解空间 皮质NE释放的时间动力学对于理解大脑中的灵活决策是必要的。 一般，以及依赖其功能的注意力，唤醒和情绪障碍。

SUMMARY Norepinephrine (NE) is a neurotransmitter released by a small number of neurons in the locus coeruleus (LC), with extensive innervation of the neocortex. Prior work in humans and other mammals led to the hypothesis that LC-NE neurons modulate multiple forms of decision making. This proposal aims to test this overall hypothesis by studying LC-NE neurons in mice performing multiple decision-making tasks. The behaviors to be studied include two types of flexible decision making: how to learn from reinforcement over tens of seconds to minutes in a dynamic choice task and how to rapidly change a motor program based on sensory feedback over hundreds of milliseconds to seconds. The goal of the project is to link action potentials from identified LC-NE neurons to both types of behavior, and determine how large populations of neurons in multiple cortical areas are modulated by NE input to achieve flexible behavior. Three aims test three hypothesis that address different mechanistic questions about the functions of norepinephrine in neocortex: 1) LC-NE neurons modulate reinforcement learning during a dynamic choice task; 2) norepinephrine regulates sensory-driven motor program switching; 3) LC-NE modulates orofacial and prefrontal cortex for effective reinforcement learning and motor program switching. Measurements and manipulation (activation and inactivation) of the activity of NE neurons and their targets in neocortex, during well-controlled behavioral tasks in mice, will enable testing these three hypotheses. Understanding the spatial and temporal dynamics of NE release in cortex will be necessary for understanding flexible decision making in general, and disorders of attention, arousal, and mood that rely on its function.