Functional organization of locus coeruleus projections to CNS motor circuits

Rowan University School Of Osteopathic Medicine, Stratford NJ

Investigators

Abstract

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.