Functional organization of locus coeruleus projections to CNS motor circuits

该项目主要研究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中枢神经系统运动神经回路操作和运动的影响。LC-NE系统广泛投射到整个中枢神经系统，并已被证明在清醒的所有阶段调节认知和感觉信号处理。尽管它显著地支配着大脑的运动中枢，但该系统在调节清醒状态下的姿势、平衡、反射和目标定向运动方面的类似作用在很大程度上还没有被探索过。随着向中枢运动回路投射的LC神经元可视化的新方法的发展，LC-NE向运动中枢的输入的解剖学和生理学将被确定。这些实验将提供信息，以推动我们思考LC-NE系统如何在适应行为的背景下不仅对运动活动产生影响，而且对感觉信号处理和执行功能产生影响。更广泛地说，相对于中枢神经系统中的许多特定递质通路，这种方法在整个大脑范围内都有应用，该项目本身可以作为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学者计划促进高中生的研究培训，并通过Rutgers-Camden MARC计划促进来自代表性不足群体的本科生的培训。更具体地说，目前的项目重点是脑干蓝斑(LC)对中枢运动神经回路的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同质的，其初级递质去甲肾上腺素(NE)可以被均匀地释放，并同时作用于大脑和脊髓的细胞和回路。然而，最近来自我们实验室和其他地方的研究提供了令人信服的证据，证明LC在设计上是模块化的，在整个中枢神经系统中有分离的输出通道到感觉、运动和认知回路，并且在这些功能不同的投影区中可能有不同的NE释放。这些发现促使人们对LC手术的思考发生了根本性的转变，并要求修改关于LC-NE系统对行为结果的影响的理论结构，这些影响不仅涉及感觉和认知领域，还涉及运动生成。在此背景下，我们认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体外电生理学的方法，将使他们能够确定LC马达回路投射细胞是否表现出独特的电生理特性，并维持一个特定于运动终末区域的树突树枝和轴突侧支的有组织网络，该网络能够支持中枢神经系统运动中心选择性的、同步的NE释放，目的是协调调节负责平衡、姿势调整和执行自愿运动的操作。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，认为值得支持。

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.