# Molecular regulation over the decline in long-distance corticospinal axon regenerative ability during development

> **NIH NIH R01** · WINIFRED MASTERSON BURKE MED RES INST · 2024 · $468,231

## Abstract

Corticospinal neurons (CSN) reside in the neocortex, and extend axons to specific segmental targets in the
spinal cord forming the corticospinal tract (CST). CSN critically control voluntary movement and are centrally
involved in recovery from paralysis originating from multiple causes, e.g., stroke, spinal cord injury (SCI), cerebral
palsy, etc.. CSN degeneration in amyotrophic lateral sclerosis (ALS), along with degeneration of spinal motor
neurons, causes spasticity and paralysis. Recovery in all these distinct causes of paralysis would ultimately
require long-distance CST regeneration, which remains an unattained goal in regenerative neuroscience.
Previous work using neonatal lesions has established CST regenerative ability declines from development into
adulthood. When the CST is damaged in early life, there is greater plasticity and regeneration as compared to
similar lesions in the adult. However, despite this work, we still do not know when long-distance regenerative
ability is lost during development. This is because a key limitation of these established neonatal lesion models
is that they massively disrupt the spinal environment and thereby interfere with the normal process of long-
distance CSN axon extension during development. This limits the ability of these lesion paradigms to assess the
ability of the CNS to support long-distance regeneration. We recently established a novel microsurgical approach
to axotomize the CST during development, while leaving the spinal environment relatively intact. We identified
that long-distance CST regenerative ability is lost at different times at distinct spinal levels– at postnatal day 4
(P4) the CST can fully regenerate when lesioned at thoracic T11, but fails to do so when lesioned at cervical C2.
Our results indicate that the loss of long-distance CST regenerative ability closely parallels the developmental
timeline of normal CST growth into the spinal cord, which suggests that the normal process of differentiation,
both in CSN and in the spinal cord, results in the loss of long-distance regenerative ability. This proposal
investigates the hypothesis that inhibition of differentiation to prolong the immature developmental state will
extend the time window when long-distance regeneration is possible. Specifically, we will manipulate the function
of RE1 silencing transcription factor (REST), a global repressor of neural differentiation, to test this hypothesis.
Building on this foundation, we will first manipulate REST function (both gain- and loss-of function) at distinct
spinal levels to investigate whether this affects the ability of these spinal segments to support long-distance CST
regeneration (Aim1). We will manipulate REST function in CSN to similarly investigate long-distance CST
regeneration (Aim 2). Finally, we will use single cell profiling to investigate potentially distinct molecular effects
of microlesions at distinct spinal levels on distinct CSN subsets depending on their develop...

## Key facts

- **NIH application ID:** 10803597
- **Project number:** 1R01NS131420-01A1
- **Recipient organization:** WINIFRED MASTERSON BURKE MED RES INST
- **Principal Investigator:** Vibhu Vinodchandra Sahni
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $468,231
- **Award type:** 1
- **Project period:** 2024-01-01 → 2028-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10803597

## Citation

> US National Institutes of Health, RePORTER application 10803597, Molecular regulation over the decline in long-distance corticospinal axon regenerative ability during development (1R01NS131420-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10803597. Licensed CC0.

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