# The role of microglia in cortical remyelination

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $398,690

## Abstract

Cortical
disability
lesions,
microglia
survey
is
oligodendrocyte
recovery
We
dynamics
replacement
identified
treatment.
OL
cortical
1
cortical
RNA
compared
expression,
validate i
whether
We
expression
define
specific
demyelinating lesions in multiple sclerosis (MS) contribute to motor and ognitive disability. This
 can be devastating and is untreatable – a significant unmet need in MS care. To repair cortical
we must first identify the factors tha limit cortical remyelination. Here we propose to study the role of
(MG) in cortical remyelination. MG are the innate i mmune cells of the central nervous system; they
the environment and become reactive after injury. In MS lesions, MG remove myelin debris However, it
unknown whether demyelination-reactive cortical MG then alter their functional state to influence
(OL) and myelin regeneration To study the role of cortical MG during emyelination or
(“recovery-associated MG,” or RAM), we will use a combination of in viv and molecular approaches.
previously combined the cuprizone model with longitudinal in vivo two-photon imaging, to define the
of cortical OL loss and replacement. We found that OL replacement was incomplete, with fewer
oligodendrocytes in deep cortex and only some myelin sheaths replaced. Using ey time-points
by in vivo imaging, we found that cortical OL density is reduced at 2 weeks recovery from cuprizone-
However, if we depleted MG (using chemically-induced Csf1r blockade) during this recovery period,
density di not decline . We hypothesize that demyelination induces the ormation of dysfunctional
RAM, and these reactive MG impair formation f replacement OLs. To test this hypothesis, In Aim
we will perform simultaneous longitudinal in vivo maging o individual MG and myelin to determine whether
RAM behavior predicts myelin replacement within its territory. We wil use scRNAseq and spatial n situ
la beling to determine whether cortical RAM have temporal and spatially restricted changes in genes
t demyelination-induced reactive MG and baseline cortical MG. These studies will
de fine gene
morphological, and functional changes of activated cortical RAM in cortex, and whic we will then
 n MS cortica l lesion tissue. In Aim 2 we will leverage th resolution of in vivo imaging to determine
 the absence o MG during recovery changes the fate of baseline OLs, newly formed OLs or OPCs.
will als determine, with single cell RNAseq, whether cortical emyelination induces differential gene
 changes in cortical OPCs that coul impair thei ability to regenerate OLs. Together, these aims will
the remyelination-specific role o cortical MG. Based on these findings, we will target and manipulate
RAM features that promote OL regeneration and
remyelinati on.
c
t
.
. r
o
k
d f
o
i f
l i
o
h
e
f
o d
d r
f

## Key facts

- **NIH application ID:** 10861341
- **Project number:** 1R01NS132793-01A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Jennifer Lauren Orthmann-Murphy
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $398,690
- **Award type:** 1
- **Project period:** 2024-04-16 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10861341

## Citation

> US National Institutes of Health, RePORTER application 10861341, The role of microglia in cortical remyelination (1R01NS132793-01A1). Retrieved via AI Analytics 2026-05-31 from https://api.ai-analytics.org/grant/nih/10861341. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*