Spatiotemporal dynamics of locus coeruleus norepinephrine release in a learned behavior

项目摘要 蓝斑（LC）是一个小的脑干核团，是神经调质的主要来源 去甲肾上腺素（NE）在大脑中。LC从广泛的大脑区域接收输入，并在整个过程中投射 前脑脑干小脑和脊髓LC神经元紧张性释放NE调节基线 唤醒，以及在各种感觉-运动和行为功能的背景下的阶段性。但尽管 它的全脑效应，NE在行为过程中的作用模式知之甚少。一个流行的理论是 表明NE的作用是控制输出电路的增益，从而通过提高任务绩效来调节任务绩效。 或抑制对刺激的反应。然而，另一种理论认为，在皮层输出中NE的释放 区域的作用是重置网络活动，使任务切换或学习新规则成为可能。这两种 这些理论充分解释了LC-NE系统在学习和行为中的许多观察到的作用。我提议 LC功能的一个新假设，即时空动力学和模块电路使分离的角色成为可能 在学习行为过程中的行为执行和强化学习。在此，我提议 使用结合先进的双光子技术的创新方法来研究这一假设的多个特征 靶区域中NE释放的成像以及LC神经元和轴突的光遗传学操纵。在目标1中，我将 操纵小鼠LC神经元的活动，执行工具条件任务， 检测不同强度的听觉音调，执行响应，并接受积极或消极的强化。 我将检验LC-NE活动预杠杆压力促进高不确定性任务执行的假设 强化后LC-NE活性促进任务优化。在目标2中，我将评估 LC投射到运动皮层（MC）或前额叶皮层（PFC）的模块化，并监测LC投射到运动皮层（MC）或前额叶皮层（PFC）的快速动力学。 NE在MC和PFC中的释放，以检验NE在MC前任务中优先释放的假设 执行并在负强化后全局释放。在目标3中，我将检验以下假设： MC中NE发布与全局NE发布的差异集成分别促进了任务执行和学习。 我将使用光遗传学方法测量沉默这些皮质靶点中NE活性对行为的影响。 NE轴突的沉默。这些数据将提供必要的信息，一个新的理论的作用，LC在 认知，并为理解LC-NE功能障碍在一系列疾病中的作用提供机制基础。 神经精神障碍通过这个项目的完成，我将成为一个广泛应用的专家。 一系列系统神经科学技术，实践项目管理和指导学生，提高我的 通过出版物，海报和演示文稿的沟通技巧，并与我的互动和学习 以及我实验室和麻省理工学院以外的社区。这次培训将使我能够实现我的 成为独立的科学家。

Project Summary The locus coeruleus (LC), a small brainstem nucleus, is the primary source of the neuromodulator norepinephrine (NE) in the brain. The LC receives input from widespread brain regions and projects throughout the forebrain, brainstem, cerebellum, and spinal cord. LC neurons release NE tonically to regulate baseline arousal, and phasically in the context of a variety of sensory-motor and behavioral functions. However, despite its brain-wide effects, the modes of NE action during behavior are poorly understood. One prevailing theory suggests that NE acts to control the gain of output circuits, thereby modulating task performance by enhancing or dampening responses to stimuli. However, another theory suggests that NE release in cortical output regions acts to reset network activity, enabling task-switching or learning of new rules. Neither of these theories adequately explains the many observed roles of the LC-NE system in learning and behavior. I propose a new hypothesis of LC function, that spatiotemporal dynamics and modular circuits enable dissociated roles for the LC in behavioral execution and reinforcement learning during learned behaviors. Here, I propose to examine multiple features of this hypothesis using innovative approaches combining advanced 2-photon imaging of NE release in target regions and optogenetic manipulation of LC neurons and axons. In Aim 1, I will manipulate the activity of LC neurons in mice performing an instrumentally conditioned task in which they detect auditory tones of variable intensity, execute a response, and receive positive or negative reinforcement. I will examine the hypothesis that LC-NE activity pre-lever press facilitates task execution on high uncertainty trials, and LC-NE activity post-reinforcement facilitates task optimization. In Aim 2, I will assess the anatomical modularity of LC projections to motor cortex (MC) or prefrontal cortex (PFC), and monitor the fast kinetics of NE release in MC and PFC to examine the hypothesis that NE is preferentially released in MC pre-task execution and released globally post-negative reinforcement. In Aim 3, I will examine the hypothesis that differential integration of NE release in MC versus globally facilitates task execution and learning, respectively. I will measure the impact on behavior of silencing NE activity in these cortical targets using optogenetic silencing of NE axons. These data will provide essential information for a new theory of the role of LC in cognition, and provide a mechanistic basis for understanding the role of LC-NE dysfunction in a range of neuropsychiatric disorders. Through the completion of this project, I will become an expert in applying a wide range of systems neuroscience techniques, practice project management and mentoring students, improve my communication skills through publications, posters, and presentations, and interact with and learn from my scientific mentors as well as the community outside my lab and MIT. This training will enable me to achieve my goal of becoming and independent scientist.