Spatiotemporal dynamics of locus coeruleus norepinephrine release in a learned behavior

项目摘要 蓝斑(LC)是一种小的脑干核团，是神经调节剂的主要来源 大脑中的去甲肾上腺素(NE)。LC从分布广泛的大脑区域和投射中接收信息 前脑、脑干、小脑和脊髓。LC神经元释放去甲肾上腺素调节基线 觉醒，并在各种感觉-运动和行为功能的背景下相关联。然而，尽管 它的全脑影响，以及行为过程中去甲肾上腺素的作用模式还知之甚少。一种流行的理论 建议NE起控制输出电路增益的作用，从而通过增强 或抑制对刺激的反应。然而，另一种理论表明，去甲肾上腺素在大脑皮层输出中释放 区域可重置网络活动，从而实现任务切换或学习新规则。这两个都不是 理论充分地解释了LC-NE系统在学习和行为中的许多观察到的作用。我建议 LC功能的一种新假设，即时空动力学和模块化电路使角色分离 学习过程中的行为执行和强化学习。在此，我建议 使用先进的双光子相结合的创新方法检验这一假说的多个特征 靶区去甲肾上腺素释放的成像和LC神经元和轴突的光遗传操作。在《目标1》中，我将 操纵小鼠LC神经元的活动，在这些小鼠中，它们执行仪器条件任务 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活动前杠杆按压促进高不确定性任务执行的假设 试验，和LC-NE活动加强后促进任务优化。在目标2中，我将评估解剖学 LC向运动皮质(MC)或前额叶皮质(PFC)投射的模块化，并监测快速运动 去甲肾上腺素在MC和PFC中的释放检验在MC前任务中NE优先释放的假设 执行并在全球范围内释放后的负面加固。在目标3中，我将检验假设 MC中网元释放与全局网元释放的差异集成分别促进了任务执行和学习。 我将利用光遗传学来测量沉默这些皮质靶点的NE活动对行为的影响 NE轴突的沉默。这些数据将为LC的作用的新理论提供必要的信息 并为理解LC-NE功能障碍在多种疾病中的作用提供了机制基础。 神经精神障碍。通过这个项目的完成，我将成为一名应用广泛的专家 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、海报和演示文稿进行沟通，并与我的 科学导师以及我的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 成为独立科学家的目标.

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.