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.

该项目解决了有关哺乳动物大脑中二氧化碳（LC-NE）发射机系统结构的主要未解决问题及其对CNS运动电路操作和运动的影响。 LC-NE系统在整个中枢神经系统中广泛项目，并已被证明可以调节在清醒各个阶段的认知和感觉信号处理。尽管它显着地支配了大脑的运动中心，但该系统在调节整个醒来状态的姿势，平衡，反射和目标方向运动中的作用在很大程度上没有探索。随着新方法的可视化LC神经元的可视化方法，将投影发送给CNS运动电路，将确定向运动中心的LC-NE输入的解剖结构和生理学。这些实验将提供信息，以推动我们对LC-NE系统如何在自适应行为的背景下对LC-NE系统如何影响运动信号处理和执行功能的思考。更广泛地相对于中枢神经系统中的许多发射器特异性途径，这种方法的大脑范围应用应用，并且该项目本身可以用作下一代神经科学家的训练平台。该项目还将通过高中生物医学学者计划以及通过Rutgers-Camden MARC计划的高中生研究以及从代表性不足的群体的大学生进行研究的培训。特别是，当前的项目重点介绍了Brain Semten nucleus nicleus coeruleus（LC）及其对Motornets Intact Network and Motornets的功能。 50多年来，LC在结构和功能上被认为是同质的，因此其主要发射器去甲肾上腺素（NE）可以均匀释放，并同时在整个大脑和脊髓的细胞和电路上起作用。然而，我们实验室和其他地方的最新研究提供了令人信服的证据，表明LC在设计中是模块化的，在整个中枢神经系统的感觉，运动和认知电路上隔离了输出渠道，并且在这些功能多样的投影领域中NE的差异释放的潜力。这些发现促使人们在思考LC操作方面发生了根本性的转变，并要求修改有关LC-NE系统对行为结果的影响，不仅涉及感觉和认知领域，而且还涉及运动产生。在这种情况下，我们所知的主要差距是LC-NE系统与CNS运动控制中心之间的解剖学和生理关系。研究者使用交叉遗传小鼠模型，逆行病毒载体追踪和体内电生理学的方法将使他们能够确定LC机动电路投影细胞是否表达独特的电生理特性，并维持有组织的树突状arbors和axon征材的有组织的网络，该网络对运动的终端和同步的辅助范围，对运动的辅助，同步，同步性，同步，辅助型号，同步，同步的固定型号，依从性。协调监管负责余额，姿势调整和执行自愿运动的行动。该奖项反映了NSF的法定任务，并被认为是值得通过基金会的知识分子优点和更广泛的影响评估标准通过评估来获得支持的。