# A comparative approach to uncovering the cellular and circuit basis of the role of the corticospinal tract in motor skill

> **NIH NIH K99** · HARVARD UNIVERSITY · 2024 · $130,815

## Abstract

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 ne...

## Key facts

- **NIH application ID:** 10887798
- **Project number:** 1K99NS133031-01A1
- **Recipient organization:** HARVARD UNIVERSITY
- **Principal Investigator:** Kelsey Marie Tyssowski
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $130,815
- **Award type:** 1
- **Project period:** 2024-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10887798

## Citation

> US National Institutes of Health, RePORTER application 10887798, A comparative approach to uncovering the cellular and circuit basis of the role of the corticospinal tract in motor skill (1K99NS133031-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10887798. Licensed CC0.

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