Spatiotemporal dynamics of locus coeruleus norepinephrine release in a learned behavior

学习行为中蓝斑去甲肾上腺素释放的时空动态

基本信息

批准号：
10463122
负责人：
Gabrielle Drummond
金额：
$ 4.68万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-15 至 2024-09-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10463122
关键词：
Address Aging Air Alzheimer&apos s Disease Anatomy Arousal Attention Attention deficit hyperactivity disorder Auditory Axon Behavior Behavioral Brain Brain Stem Brain region Cell Nucleus Cerebellum Cognition Communication Communities Data Etiology Event Exhibits Functional disorder Goals Image Immunohistochemistry Impaired cognition Kinetics Knowledge Learning Measures Mediating Mental Depression Mentors Monitor Motor Motor Cortex Movement Mus Negative Reinforcements Neuromodulator Neurons Neurosciences Norepinephrine Output Phase Population Positive Reinforcements Post-Traumatic Stress Disorders Prefrontal Cortex Process Prosencephalon Psychological reinforcement Publications Punishment Rewards Role Scientist Sensory Signal Transduction Source Specificity Spinal Cord Stimulus System Task Performances Techniques Testing Tissues Training Uncertainty Viral Water Work behavioral outcome brain dysfunction density flexibility functional outcomes genetic manipulation improved innovation insight learned behavior locus ceruleus structure nervous system disorder neuropsychiatric disorder neuroregulation norepinephrine system novel optogenetics posters response segregation sensor skills spatiotemporal student mentoring theories two-photon

项目摘要

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.

项目概要蓝斑 (LC) 是一个小的脑干核，是神经调节剂的主要来源大脑中的去甲肾上腺素（NE）。 LC 接收来自广泛大脑区域的输入并在整个过程中进行投射前脑、脑干、小脑和脊髓。 LC 神经元紧张性释放 NE 来调节基线唤醒，以及在各种感觉运动和行为功能的背景下的阶段性。然而，尽管人们对 NE 在整个大脑范围内的影响以及行为过程中的作用模式知之甚少。一种流行理论表明 NE 的作用是控制输出电路的增益，从而通过增强或抑制对刺激的反应。然而，另一种理论表明，皮质输出中的 NE 释放区域的作用是重置网络活动，从而实现任务切换或学习新规则。这些都不是理论充分解释了 LC-NE 系统在学习和行为中的许多观察到的作用。我建议 LC 功能的新假设，即时空动力学和模块化电路能够实现分离的角色用于学习行为期间行为执行和强化学习中的 LC。在此，我提议使用结合先进的 2 光子的创新方法来检查该假设的多个特征目标区域 NE 释放的成像以及 LC 神经元和轴突的光遗传学操作。在目标 1 中，我将操纵小鼠的 LC 神经元的活动，执行仪器条件任务，其中它们检测不同强度的音调，执行响应，并接收积极或消极的强化。我将检验以下假设：LC-NE 活动预压杆有利于高不确定性下的任务执行试验和 LC-NE 活动后强化有助于任务优化。在目标 2 中，我将评估解剖学 LC 投射到运动皮层 (MC) 或前额叶皮层 (PFC) 的模块化，并监测 MC 和 PFC 中的 NE 释放，以检验 NE 在 MC 前任务中优先释放的假设执行并释放全球后负强化。在目标 3 中，我将检验以下假设： MC 中的 NE 释放与全局中的 NE 释放的差异化集成分别促进了任务执行和学习。我将使用光遗传学测量这些皮质目标中沉默 NE 活动对行为的影响 NE 轴突沉默。这些数据将为 LC 作用的新理论提供重要信息。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疾病。通过完成这个项目，我将成为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、海报和演示来培养沟通技巧，并与我的互动并向我学习科学导师以及我的实验室和麻省理工学院以外的社区。这次培训将使我实现我的目标成为独立科学家的目标。