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

摘要 去甲肾上腺素(NE)是由蓝斑(LC)内少量神经元释放的一种神经递质。 新皮质有广泛的神经支配。先前在人类和其他哺乳动物身上的研究导致了这一假说 LC-NE神经元调节多种形式的决策。这项提案旨在全面检验这一点。 通过研究执行多项决策任务的小鼠的LC-NE神经元，提出了一种假设。应采取的行为 研究包括两种类型的灵活决策：如何从数十秒的强化中学习 动态选择任务中的几分钟，以及如何根据感觉反馈快速更改运动程序 几百毫秒到几秒。该项目的目标是将已识别的LC-NE的动作电位联系起来 神经元对这两种类型的行为，并决定如何在多个皮质区域的大量神经元 被NE输入调制以实现灵活的行为。 三个目标检验了三个假说，这些假说解决了关于脑细胞功能的不同机制问题 新皮质去甲肾上腺素：1)LC-NE神经元调节动态选择任务中的强化学习； 2)去甲肾上腺素调节感觉驱动的运动程序转换；3)LC-NE调节口腔和 用于有效强化学习和运动程序切换的前额叶皮质。测量和 新皮质去甲肾上腺素神经元及其靶点活动的调控(激活和失活) 在小鼠中控制良好的行为任务，将使这三个假说得到验证。了解空间 皮层去甲肾上腺素释放的时间动力学对于理解灵活决策是必要的。 一般，以及依赖其功能的注意力、觉醒和情绪障碍。

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.