Overall Local networks within the spinal cord represent an essential computational layer for the control of limb-driven motor behaviors, integrating descending and sensory inputs to coordinate dexterous motor output. Significant advances have been made in characterizing the developmental programs that specify the core cardinal interneuron types that make up these motor networks. This knowledge has been used to develop a battery of mouse genetic reagents for spinal circuit anatomical and functional dissection. To date, these genetic tools have been primarily used to study locomotion and spinal reflexes in the lumbar spinal cord. Given the wider range of dexterous motor behaviors that are produced by cervical circuits and the increased oversight of these behaviors by descending motor pathways, the mouse cervical spinal cord provides a unique and tractable mammalian model system for understanding how coordinated movements are generated by local motor networks and how these motor behaviors are regulated by the brain. The overall goal of this U19 Team-Research BRAIN Circuit Program proposal is two-fold: 1) the generation of a scalable, high-resolution atlas of forelimb-premotor interneurons in the cervical spinal cord that describes their connectivity, molecular phenotypes, electrophysiological properties, and functional contributions to forelimb behaviors, and 2) the development of testable predictive neural models that describe the network interactions that give rise to limb control. The functional interrogation and modeling of these circuits, based on real behavioral outcomes and detailed information about the cell types that generate these behaviors, will ensure that the overall project is greater than the sum of its parts. Specifically, the research plan will address two overarching questions: 1) How do rhythmic spinal networks control non-rhythmic movements, which represent the majority of forelimb motor behaviors, and 2) How are these spinal circuits modified to control more complex joint movements to achieve forelimb dexterity? To address these questions, the Spinal Cord Circuit Team (TeamSCC) will generate: (a) a pre-motor interneuron connectome that includes information on cell positions and synaptic weightings, (b) a comprehensive index of the physiological properties and molecular identities of genetically distinct neuronal subtypes within each cardinal interneuron class, (c) a functional description of spinal circuit control of natural forelimb motor behaviors, and (d) a working model of the motor network that describes how circuit connectivity and dynamics give rise to key elements of forelimb behavior. Ultimately, these data will be used to generate a searchable web-based portal with 3D visualization tools linked to the molecular, electrophysiological, functional, and network model databases. Together, this work will lead to a deeper understanding of the organization and function of cervical circuitry, which will be of great value to groups that are grappling with the issue of how motor centers in the brain communicate with sensorimotor circuits in the spinal cord to control movement.

Public Health Relevance

Overall Motor circuits in the cervical spinal cord control many essential behaviors, including skilled reaching and grasping, however, very little is known about the composition and structure of these circuits and how they produce these dexterous movements. The goal of the Spinal Cord Circuit Team (TeamSCC) is to generate comprehensive anatomical, molecular, and functional maps of circuits within the cervical spinal cord, which collectively will be used to develop and test predictive models of forelimb motor circuit function. Knowledge generated by these studies will inform ongoing studies of motor control and brain function, leading to a better understanding of the human motor system and how it is affected by neurological diseases and spinal injuries that compromise upper limb movements.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZNS1)
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Gnadt, James W
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Salk Institute for Biological Studies
La Jolla
United States
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