# Combining Physiological, Genetic, and Computational Approaches with Naturalistic Climbing Behavior to Elucidate the Functional Elements of Descending Motor Control

> **NIH NIH DP2** · NORTHWESTERN UNIVERSITY · 2020 · $2,340,462

## Abstract

PROJECT SUMMARY
Many mammals are distinguished by the exceptional diversity and agility of their limb movement. These qualities
are critical to the fitness certain movements confer, and so to the evolutionary success of many species. While
brain regions important for limb control have been identified, the neural signal processing that ultimately governs
motor commands sent to muscles has remained stubbornly opaque. Mechanistic models of motor system
operation in real time during movement are thus lacking. This obscures the etiology of motor deficits caused by
neurological disease and stroke, which in turn stymies the development of effective treatments.
 A primary cause of this opacity of motor system processing is the ambiguity of the basic functional
elements comprising relevant neural circuits. An emerging view posits that these elements may be neuronal
subtypes defined by features like axonal target region, target cell identity, and gene expression. Yet the
fundamental question of what are the appropriate cellular features for defining functional units remains
unanswered. This ambiguity stems from a host of technical limitations. We expect that functionally salient
neuronal subtypes will make characteristic contributions to specific phases of movement. Yet traditional methods
for silencing neural activity to assess function lack the temporal resolution to discern such specific influence. We
also expect that functionally salient subtypes will exhibit distinct activity patterns and interactions with other
neuronal populations. But classical methods for measuring neural firing are typically blind to key cellular features.
Moreover, the behavioral paradigms used for motor system studies have not captured essential aspects of
natural mammalian movement, for which motor system organization may have been adapted over evolution.
 Fortunately though, systems neuroscience is currently being revolutionized by advances in physiological,
genetic, and computational techniques. I plan to leverage many of these advances and pursue an innovative
approach to resolve the basic functional elements within a model motor system population – the subcerebral
projection neurons (SPNs) found in motor areas of the neocortex. We will employ a naturalistic climbing paradigm
for mice engineered in my lab to overcome limitations of previous motor behavior paradigms. New genetically-
mediated targeting strategies will provide access to potential functional subtypes for activity measurement and
perturbation. We will novelly couple optogenetic probes, electromyography, and automated behavior
decomposition to distinguish precise phases of neuronal subtype influence. Large-scale, multi-area activity
recording, optogenetic identification, and machine learning will parse subtypes by their activity and interactions
with other neuronal populations. Our work will articulate an interdisciplinary approach applicable to the
fundamental question of functional units in other neural system...

## Key facts

- **NIH application ID:** 10002981
- **Project number:** 1DP2NS120847-01
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Joseph Andrew Miri
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $2,340,462
- **Award type:** 1
- **Project period:** 2020-09-30 → 2025-03-21

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10002981

## Citation

> US National Institutes of Health, RePORTER application 10002981, Combining Physiological, Genetic, and Computational Approaches with Naturalistic Climbing Behavior to Elucidate the Functional Elements of Descending Motor Control (1DP2NS120847-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10002981. Licensed CC0.

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