Probing the origin and function of a novel subset of motor neurons

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Project Summary/Abstract: A fundamental question in vertebrate motion is how proper controlled motor output is achieved. A major concept in neuroscience that helps to explain controlled movement is the idea of corollary discharge. This idea asserts that copies of outgoing motor commands are sent back to the motor system and compared to actual sensory information to distinguish self-generated movements from externally-generated ones. In this way, smooth and corrective movements can be executed based on how predicted internal models of motor action match sensory input. While there is electrophysiological evidence for corollary discharge in several motor circuits, the neuroanatomical underpinnings of this physiological phenomenon is less well-described. In particular, neurons that have been identified as sources of corollary discharge to the cerebellum, a major integration and motor learning center, has been limited to regions rostral of the spinal cord. Preliminary data suggests that a subset of motor neurons in the spinal cord is derived from a novel progenitor domain that can project axon collaterals to both muscle and the cerebellum in mice. The goal of this proposal will be to examine the developmental origins and axonal projections of this motor neuron subset. The first aim will identify the functional motor pools, subtype, and development of the motor neurons demarcated by this novel motor neuron subset using a variety of genetic techniques combined with molecular marker analyses. The second aim will use a range of genetic, neuronal tracing, and optogenetic techniques to address whether motor neurons in the spinal cord, in particular those marked by this novel motor neuron subset, are sending axon collaterals to both muscle and the cerebellum. Confirmation of this second aim will provide a neuroanatomical basis for corollary discharge to the cerebellum from motor neurons. Altogether, the objective of this project is to understand the development and connectivity of a novel subset of motor neurons that may be communicating internal copies of motor commands for smooth motor output. Success in these aims will lay the foundation for a research program exploring the function and utility of these motor neurons in achieving proper motor control. Discovery of the circuits underlying controlled movement will help to refine computational models of motor execution and learning that could influence the fields of prosthetics and robotics. In addition, recognizing how motor circuits are wired and function in endogenous contexts will influence our understanding of the motor mechanisms damaged during spinal cord injury and neurodegenerative disease. In particular, research into how corollary discharge from these motor neurons is affected in amyotrophic lateral sclerosis or spinal motor atrophy models could provide new insights into the progression and phenotype of these motor neuron diseases.