A Comparative Approach to Uncovering the Cellular and Circuit Basis of the Role of the Corticospinal Tract in Motor Skill - PROJECT SUMMARY The goal of the proposed research is to discover how variation in the number of corticospinal neurons (CSNs) causes variation in motor circuit function and dexterous behavior, thus linking cells, circuits, and behavior in the same system. The evolution of advanced cognitive and motor function is associated with cerebral cortex expansion, including expansion of CSN neuron number, and it has long been hypothesized that the expansion of CSNs in primates underlies their exquisite hand dexterity, such as that required for tool use. In support of this, lesioning studies have demonstrated a role for motor cortex, and CSNs in particular, in dexterous behaviors. However, CSN number has not been causally linked to dexterity, nor do we understand the basic principles of how expanding a cell population alters circuit activity and thus behavior. The experiments proposed here will test the hypothesis that animals with more CSNs have greater dexterity, thus synthesizing cellular, circuit-level, and behavioral discovery, thus achieving the Goal 7 of the BRAIN Initiative. Specifically, this research will compare subspecies of deer mice (Peromyscus maniculatus) that evolved in different habitats and have innate differences in dexterity as well as a difference in CSN number. First, it will use single-nucleus RNA-sequencing to characterize which population(s) of CSNs differ in abundance between subspecies and to identify candidate developmental mechanisms underlying CSN population expansion. (Aim 1). At the circuit level, this research will determine whether neural activity during a dexterity task and neural architecture, as assessed with viral tracing, differs between subspecies (Aim 2). Finally, in the candidate’s independent research program (R00 phase), she will use the tools and datasets generated in Aims 1 and 2 to manipulate CSNs to establish causal links between CSN number, neural activity, and dexterity (Aim 3). This project will take advantage of recent technological advances in high throughput experiments (e.g., single nucleus sequencing) and neural manipulation (e.g., virally delivered gene editing) to work in a non-traditional model system, affording the unique ability to capitalize on naturally evolved behavioral differences to elucidate general principles of how cellular and neural variation mediate behavioral variation. This research is part of a comprehensive training plan that combines training in comparative behavior, developmental and systems neuroscience, and computational analysis of datasets in these areas, as well as training in communication and mentoring. This plan will be mentored by Dr. Hopi Hoekstra at Harvard University, an expert in deer mouse comparative behavior, and Dr. Adam Hantman at the University of North Carolina Chapel Hill, an expert in the neuroscience of motor systems. Additional mentorship will come from an Advisory Committee in single cell sequencing analysis, developmental neuroscience, and analysis of neural recording data. Together, this opportunity will provide excellent training for an independent research career in a unique, interdisciplinary niche at the interface of molecular neuroscience, behavior, and evolutionary biology.
