Dissection of Cell Type Specific Contributions to Motor Learning Circuits

Project Abstract Whether riding your bike down a narrow path or reaching for your favorite cookie in a small box, many of our daily actions require skilled and accurate movements. However, to achieve proficiency, these motor skills must first be learned through the process of motor learning. Much work on this subject has focused on the dynamics of heterogeneous populations of neurons in various parts of the motor system. However, whether specific types of neurons are recruited over learning and/or whether neurons change functionally over learning has not been thoroughly explored. Answering these questions is a key step in understanding how the motor circuit evolves over learning to allow for increased motor proficiency. Therefore, my long-term objective is to focus on (1) cell type specific contributions and (2) cell type intrinsic changes during motor learning. This will help instruct our thinking about motor diseases, especially those with motor learning deficits like autism spectrum disorder. In this proposal, I begin by examining the first area - the cellular determinants of motor learning. By focusing on the primary motor cortex, a central coordinator of the motor system and a region necessary for motor skill learning, I begin by asking whether different cell types are enriched over motor learning, a study in line with the first aim of the BRAIN 2025 report. In aim 1, during the mentored phase (K99), I present a novel approach that tags active cells during a forelimb task and allows for their isolation and single-cell transcriptional profiling. This has allowed me to examine cell type specific enrichment over learning. In aim 2, also during the mentored phase (K99), I begin to also explore the second area by examining potential changes within a specific cell type which I identified as enriched at late learning, FoxP2 expressing cells in layer VI of M1. These cells project to the motor thalamus, another region strongly implicated in motor learning, making them an interesting candidate for further study. I map the brain-wide projection pattern of these cells, examine their dynamics and engagement over learning, and perturb their activity. Finally, in aim 3, in the independent phase (R00), I continue to address both questions of cell type specific contribution and cell intrinsic changes but at a brain-wide level. By using Fos, I will identify regions engaged during learning and undergoing transcriptional changes. I will explore the role of several identified regions with functional manipulations and by identifying the active cell types over learning. I will then integrate both cell type and molecular changes by conducting in vivo single cell imaging of both calcium dynamics and Fos expression to explore the relationship between neuronal activity and induced transcriptional changes. Given my training in molecular biology and neuroscience, I am in a unique position to conduct this work at the intersection of both fields. I am fortunate to be at the Zuckerman Institute at Columbia University, a collaborative and immersive hub of neuroscience. Along with my mentor and co-mentor, Drs. Rui Costa and Elizabeth Hillman, whose expertise in systems neuroscience and behavior complement my background in molecular biology, I plan to continue my training in systems neuroscience approaches, transcriptomic data analysis, and lab management.