Dissecting spinal interneuron circuits controlling motor output

About This Grant

Project Summary: Movement emerges from the collective activity of neurons distributed across multiple structures in the nervous system, but the final responsibility for controlling motor output resides with neural circuits in the spinal cord. These circuits are comprised of networks of interneurons and motor neurons that together coordinate behaviorally relevant patterns of muscle contraction. Although substantial progress has been made in defining the overall landscape of cells in the spinal cord, resolving the synaptic connectivity and functional roles of spinal interneurons governing motor output remains a major challenge, particularly given their highly heterogeneous nature. Among the various classes of interneurons in the ventral spinal cord, V1 interneurons represent the largest inhibitory population and shape multiple aspects of limb movement, in part by directly innervating motor neurons (i.e. they are “pre-motor”). In recent work, we have used single-nucleus transcriptomics to define the molecular landscape of V1 interneurons, along with viral tracing strategies that identified over two dozen supraspinal brain regions that directly innervate the V1 population. These studies are consistent with the emerging view that spinal circuits are composed of diverse interneuron populations with distinct connectivity profiles and functional roles in motor output, and highlight the use of V1 interneurons as a valuable system for exploring general principles of interneuron connectivity and function. The main goals of this proposal are to (1) investigate the local connectivity of V1 interneurons, thereby providing a mesoscale circuit map of this genetically-defined class of interneurons, (2) leverage our knowledge of V1 heterogeneity to identify cell-type specific cis-regulatory elements that may be used for viral manipulation of V1 subsets, and (3) investigate the functional roles of V1 interneurons downstream of specific supraspinal motor systems. In pursuing these aims, this proposal tests the hypothesis that V1 interneurons are not uniformly pre-motor but have subtype-specific circuit architectures that reflect their molecular heterogeneity and exhibit additional functions beyond controlling locomotor speed and limb flexion. Together, these studies address a fundamental gap in knowledge concerning the connectivity, molecular characteristics, and functional roles of spinal interneurons, of relevance to spinal cord injury and developmental and neurodegenerative disorders of the motor system, all of which can profoundly impair motor function.