Functional organization of locus coeruleus projections to CNS motor circuits

蓝斑投射到中枢神经系统运动回路的功能组织

• 批准号: 2128543
• 负责人: Barry Waterhouse
• 金额: $ 70万
• 依托单位: Rowan University School of Osteopathic Medicine
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2128543&HistoricalAwards=false
• 关键词: Functional; organization; locus; coeruleus; projections

This project addresses major unanswered questions about the structure of the locus coeruleus-norepinephrine (LC-NE) transmitter system in the mammalian brain and its influence on CNS motor circuit operations and movement. The LC-NE system projects broadly throughout the CNS and has been shown to regulate cognition and sensory signal processing across all stages of wakefulness. Although it prominently innervates motor centers of the brain, a similar role for the system in regulating posture, balance, reflex and goal-directed movement across the waking state is largely unexplored. With development of new methodology for visualization of LC neurons that send projections to CNS motor circuits, the anatomy and physiology of LC-NE inputs to motor centers will be determined. These experiments will provide information that will advance our thinking about how the LC-NE system exerts influences on not only motor activity but also sensory signal processing and executive function in the context of adaptive behaviors. More broadly there are brain-wide applications for this approach relative to a host of transmitter-specific pathways in the CNS and the project itself can be used as a training platform for a next generation of neuroscientists. The project will also facilitate training of high school students in research through the High School Biomedical Science Scholar program as well as of undergraduates from under-represented groups through the Rutgers-Camden MARC program.More specifically, the current project focuses on the innervation of CNS motor circuits by the brainstem nucleus locus coeruleus (LC) and its impact on motor network function. For more than 50 years LC was considered homogeneous in structure and function such that its primary transmitter norepinephrine (NE) could be released uniformly and act simultaneously on cells and circuits throughout the brain and spinal cord. However, recent studies from our laboratory and elsewhere have provided compelling evidence that LC is modular in design, with segregated output channels to sensory, motor, and cognitive circuitries throughout the CNS and the potential for differential release of NE in these functionally diverse projection fields. These findings have prompted a radical shift in thinking about LC operations and demand revision of theoretical constructs regarding the impact of the LC-NE system on behavioral outcomes involving not only sensory and cognitive domains but also movement generation. Within this context, a major gap in our knowledge is the anatomical and physiological relationship between the LC-NE system and CNS motor control centers. The investigators' approach using an intersectional genetic mouse model, retrograde viral vector tracing, and ex vivo electrophysiology will allow them to determine if LC-motor circuit projection cells express unique electrophysiological properties and maintain an organized network of dendritic arbors and axon collaterals that is specific to motor terminal fields and capable of supporting selective, synchronous release of NE in CNS motor centers for the purpose of coordinately regulating operations responsible for balance, postural adjustments, and execution of voluntary movements.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

该项目解决了关于哺乳动物大脑中蓝斑-去甲肾上腺素（LC-NE）递质系统的结构及其对CNS运动回路操作和运动的影响的主要未回答的问题。LC-NE系统广泛地投射在整个CNS中，并且已经显示出在觉醒的所有阶段调节认知和感觉信号处理。虽然它显著地支配大脑的运动中心，但该系统在调节姿势、平衡、反射和清醒状态下的目标导向运动中的类似作用在很大程度上未被探索。随着LC神经元（向CNS运动回路发送投射）可视化的新方法学的发展，将确定LC-NE向运动中枢的输入的解剖学和生理学。这些实验将提供信息，将推进我们的思考如何LC-NE系统不仅对运动活动，而且对感觉信号处理和执行功能的适应性行为的背景下施加影响。更广泛地说，这种方法相对于CNS中的许多递质特异性通路具有全脑应用，该项目本身可以用作下一代神经科学家的培训平台。该项目还将通过高中生物医学科学奖学金计划促进高中生的研究培训，以及通过Rutgers-Camden MARC计划促进来自代表性不足群体的本科生的研究培训。更具体地说，目前的项目侧重于脑干蓝斑核（LC）对CNS运动回路的神经支配及其对运动网络功能的影响。50多年来，LC被认为在结构和功能上是均匀的，使得其主要递质去甲肾上腺素（NE）可以均匀地释放，并同时作用于整个大脑和脊髓的细胞和回路。然而，最近的研究，从我们的实验室和其他地方提供了令人信服的证据表明，LC是模块化的设计，隔离输出通道的感觉，运动和认知电路在整个中枢神经系统和潜在的差异释放NE在这些功能不同的投影领域。这些研究结果促使了一个根本的转变，在思考LC操作和需求修改的理论结构的影响LC-NE系统的行为结果，不仅涉及感官和认知领域，但也运动生成。在这种情况下，我们的知识的一个主要差距是LC-NE系统和CNS运动控制中心之间的解剖和生理关系。研究人员使用交叉遗传小鼠模型，逆行病毒载体追踪和离体电生理学的方法将使他们能够确定LC-运动回路投射细胞是否表达独特的电生理学特性，并维持树突状动脉和轴突侧支的组织网络，该网络对运动终末场是特异性的，并能够支持选择性，在CNS运动中心同步释放NE，以协调调节负责平衡，姿势调整，该奖项反映了NSF的法定使命，并通过使用基金会的智力价值进行评估，更广泛的影响审查标准。