# Effects of Developmental Ethanol Exposure on Cerebellar Microglia and Purkinje Cells

> **NIH NIH F31** · UNIVERSITY OF ROCHESTER · 2022 · $46,753

## Abstract

Project Summary
 Fetal alcohol spectrum disorders (FASD) are the most common cause of non-heritable, preventable
mental disability, occurring in almost 5% of births in the U.S. There is no known cure for FASD, and its
mechanisms remain unclear. A wide range of cognitive, behavioral, and physical impairments have been
reported in FASD, including deficits in behaviors related to the cerebellum. These changes in behavior may arise
from ethanol's effects on the cellular level. The sole output of the cerebellum, Purkinje cells, as well as microglia,
the immune cells of the Central Nervous System, are both impacted by developmental ethanol exposure.
Reduced numbers of both neurons and microglia, as well as alterations in Purkinje cell excitability and firing have
been reported. After developmental ethanol exposure, microglia display a phenotype associated with immune
activation and release pro-inflammatory factors. Peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists
can block this immune activation and have been shown to attenuate some of the inflammatory responses in
microglia and reduce Purkinje cell loss in rodents. This suggests that microglia may be a therapeutic target in
FASD. Microglia are known to shape neuronal circuit development and connectivity in the cerebellum, which is
linked to microglial structural dynamics. How ethanol affects these dynamics and how that impacts microglia-
Purkinje cell interactions is unknown. Additionally, it is not yet known when these changes occur and how they
are maintained or progressively altered into adulthood. Elucidating how ethanol-induced changes in microglia
mediate some of the pathological changes in cerebellar Purkinje cells may be critical for understanding the onset
of FASD pathology. Furthermore, modulating microglial survival and activity during ethanol exposure through a
PPAR-γ agonist may provide some answers and potential therapies for these diseases. Thus, I hypothesize that
ethanol induces neuroimmune changes in cerebellar microglia that alter their dynamics and interactions with
Purkinje cells, and reducing microglia-mediated inflammation through a PPAR-γ agonist mitigates the
pathological effects of ethanol. To test this hypothesis, I will pursue two aims using a mouse model of FASD.
The first will investigate how developmental ethanol and a PPAR-γ agonist affects microglial phenotype over
time using in vivo two-photon imaging of microglial dynamics, immunohistochemistry, and quantitative real time
PCR. The second will determine if Purkinje cell and microglia interactions are affected throughout life by
developmental ethanol exposure and PPAR-γ agonist administration with two-photon imaging,
immunohistochemistry, and electron microscopy. These experiments will elucidate the effects of cerebellar
microglia on Purkinje cells in the cerebellum after developmental ethanol exposure and assess microglia as a
potential target to mitigate disease pathology in a mouse model of FASD.

## Key facts

- **NIH application ID:** 10533906
- **Project number:** 1F31AA030445-01
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** MaKenna Cealie
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $46,753
- **Award type:** 1
- **Project period:** 2022-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10533906

## Citation

> US National Institutes of Health, RePORTER application 10533906, Effects of Developmental Ethanol Exposure on Cerebellar Microglia and Purkinje Cells (1F31AA030445-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10533906. Licensed CC0.

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