How the brain and spinal cord transform neuronal activity into coordinated movement is a central question in neuroscience. Corticospinal neurons, the principle output of motor cortex, project to the spinal cord, where they shape motor output by synapsing on a diversity of spinal interneurons. Corticospinal neurons also send axon collaterals to the striatum, where they synapse on two populations of neurons with opponent roles in motor control. Intuitively, cortical projections the spinal cord and the striatum should be coordinated in the cell types they target, in order to direct coherent motor output. Experimentally addressing this possibility been restricted by an inability to map, measure, and manipulate interconnected circuits defined by their synaptic targets. Our narrow understanding of how these motor control circuits are coordinated has undoubtedly limited clinicians’ ability to treat movement disorders that originate in brain dysfunction, particularly Parkinson’s disease and dystonia. In this proposal, I will use recently developed technologies to uncover the anatomical and functional organization of cortical outputs to the basal ganglia and the spinal cord, and how these circuits are coordinated during movement. This proposal is organized in three Aims split across a K99 training phase and an R00 independent phase. In the first Aim, I will combine anatomical and electrophysiological tools to map the organization of synapses made by corticospinal neurons in both the spinal cord and the striatum. Experiments in this Aim will uncover a circuit through which these motor control structures are coordinated. In Aim 2, I will use two-photon imaging methods to define the logic by which corticospinal neurons, and their cellular targets in basal ganglia, encode salient features of movement. Finally, in Aim 3, I will combine anatomical, electrophysiological, and behavioral tools to determine how corticospinal neurons with collaterals in the striatum influence circuits in the spinal cord to shape motor output. Critically, experiments in all three Aims will capitalize on innovative technology developed and mastered at Columbia University, as well as interactions with expert collaborators. This work will be conducted in the newly developed and thriving Zuckerman Mind Brain Behavior Institute under the supervision of Drs. Rui Costa and Mark Churchland. Their technical and professional mentorship, along with that of expert collaborators in the Institute, will ensure I am fully equipped to lead a successful research program as an independent investigator. The experiments outlined in this proposal will become the foundation for my research program as an independent investigator and will have profound basic science and clinical implications for our understanding of motor control.

The voluntary control of movement emerges from neuronal activity distributed across many motor controls structures – notably motor cortex, the basal ganglia, and spinal cord. We understand little of how these structures are coordinated, undermining our ability to treat associated movement disorders like Parkinson’s disease and dystonia. In this proposal I will test the idea that the logic of output of cortical projections to basal ganglia and spinal motor centers is coordinated through innervation of defined neuron types that provide cohesion in motor action.