# Estrogen modulation of spinal cord microglia for respiratory neuroplasticity

> **NIH NIH F31** · UNIVERSITY OF MINNESOTA · 2024 · $45,686

## Abstract

PROJECT SUMMARY
Stimulation of beneficial neuroplasticity is a crucial component in promoting recovery from neurological diseases
or insults like spinal cord injury and stroke. Respiratory neuroplasticity, in the form of phrenic long-term facilitation
(pLTF), can be induced non-pharmacologically via acute intermittent hypoxia (AIH). However, it is abolished in
conditions of low circulating sex hormones or elevated systemic inflammation. At present, the interaction of sex
hormones, CNS inflammation, and mechanisms of neuroplasticity are not well understood. The long-term
objectives of this research are to understand the mechanism of microglial-mediated inflammation in cases of
reduced circulating estrogen. Our central hypothesis is that reduced levels of circulating estrogen provoke a
microglial-mediated increase in inflammatory cytokine gene and protein expression in the spinal cord,
accompanied by altered microglial morphology, which inhibits plasticity. The hypothesis will be tested through
two specific aims. 1: Define the inflammatory cytokine signature of the ventral cervical spinal cord of
female rats across estradiol states. The approach for this aim will involve assessment of inflammatory-related
gene and protein changes in the ventral cervical spinal cord of female rats using quantitative reverse transcription
polymerase chain reaction (qRT-PCR) and multi-color flow cytometry, respectively. Further, we will determine if
cytokine changes are driven by spinal microglia by assessing isolated microglia from ventral cervical spinal cords
of ovariectomized and naturally cycling female rats. 2: Determine the role of spinal cord microglia in
modulating the expression of phrenic neuroplasticity in states of reduced estradiol. The approach for this
aim will be to apply three dimensional Sholl analysis to cervical spinal cord segment images to allow
quantification of altered microglial morphology across low and high states of circulating estradiol. Multi-color flow
cytometry will be used to quantify microglial proliferation. Secondly, female rats will be treated with a CSF1R
inhibitor to transiently eradicate CNS microglial populations. AIH-induced pLTF will be measured via in vivo
phrenic neurophysiology. This proposed research will contribute to science by establishing the mechanistic role
and molecular signature of spinal microglia in inhibiting plasticity in states of low estradiol. These contributions
are expected to be significant in advancing neuroplasticity research because they will support the need to
account for sexual dimorphisms when designing and implementing novel neurotherapeutic interventions. The
proposed research is part of a fellowship training plan with extensive hands-on training and mentoring in technical
and professional research skills necessary to become an independent clinician-researcher. Primary research
activities and training will take place at the University of Minnesota Medical School with additional training at the
...

## Key facts

- **NIH application ID:** 10995580
- **Project number:** 1F31HL175931-01
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Azaline I Dunlap-Smith
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $45,686
- **Award type:** 1
- **Project period:** 2024-09-13 → 2027-09-12

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10995580

## Citation

> US National Institutes of Health, RePORTER application 10995580, Estrogen modulation of spinal cord microglia for respiratory neuroplasticity (1F31HL175931-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10995580. Licensed CC0.

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