Project Summary/Abstract Circuits in the brain control motor output to generate the precise behaviors required for survival. Dysfunction of these circuits results in devastating movement disorders such as Parkinson’s disease and amyotrophic lateral sclerosis. It is important to understand how the brain normally controls behavior by understanding what features of motor output are encoded in individual neurons and how these representations are organized across a neuronal population. This K99/R00 proposal will support Dr. Helen Yang in her pursuit to understand motor control and allow her to acquire new skills in connectomics and modeling that will open up innovative avenues of exploration of this problem. The experiments will be initiated during the mentored period (carried out in Dr. Rachel Wilson’s lab in the Department of Neurobiology at Harvard Medical School) and continue in Dr. Yang’s own lab upon securing an independent position. Dr. Yang’s long-term career goal is to understand robustness and flexibility in motor control by exploring neural circuit architecture and encoding across timescales, with the hope of providing insight into movement disorders and for the development of prosthetics and robotics that recapitulate features of the brain’s control of motor action. Dr. Yang’s current research has identified a number of descending neurons (DNs) whose activity is correlated with specific features of walking behavior. DNs project from the brain to the nerve cord and are a key bottleneck in the brain’s control of motor output. As such, understanding their encoding and organization will reveal fundamental principles of motor control. Utilizing approaches including the monitoring and manipulation of neural activity, behavior tracking, connetomics, and modeling, Specific Aim 1 will investigate how DNs control turns during walking, and Specific Aim 2 will investigate how DNs control forward walking. During the mentored phase of this proposal, Dr. Yang will focus on 3 specific DNs, but she will expand her studies to additional DNs in the independent phase and examine how turning and forward DNs function together to control walking. Flexibility is a critical feature of motor actions, but how neuronal circuits implement it is still poorly understood. Specific Aim 3, carried out during the independent phase, will investigate flexibility in walking by studying how patterns of DN activity and recruitment change across behavioral contexts and internal states. Overall, the experiments in this proposal should significantly advance understanding of how the brain controls motor output and pave the way for Dr. Yang to secure an independent position in academia.

Project Narrative Precise control of behavior is a fundamental function of the nervous system, and its dysfunction leads to devastating movement disorders such as Parkinson’s disease and amyotrophic lateral sclerosis. However, the nature of the neural code by which the brain controls behavior—which features of the motor output are encoded and the organizational logic of these representations—remain incompletely understood. The experiments outlined in this proposal will provide novel insights into what information the brain conveys to nerve cord, informing studies of movement disorders and the development of prosthetics and robotics that recapitulate features of the brain’s control of motor action.