# Protective effects of ovarian hormones: sex-specific differences in tlr4 expression after adolescent alcohol

> **NIH NIH F99** · UNIVERSITY OF MASSACHUSETTS AMHERST · 2021 · $9,840

## Abstract

PROJECT SUMMARY/ABSTRACT
Early onset of alcohol drinking is associated with an increased lifetime risk of alcohol use disorder (AUD) and
impairment of cognitive functions dependent on the prefrontal cortex (Jennison, 2004; Townshend and Duka,
2005). Understanding how alcohol impacts the developing adolescent brain can help us identify molecular and
cellular pathways to target for therapeutic intervention. Our lab has shown that just two weeks of voluntary
alcohol drinking in early adolescence (during pubertal maturation) leads to reduced myelinated fiber density in
the prefrontal cortex in males (Vargas et al., 2014), without measurable changes in female rats (unpublished).
This sex difference may reflect differential upregulation of toll-like receptor 4 (TLR4), as this receptor has been
shown to orchestrate a neuroinflammatory response (Blanco et al., 2010) and mediate myelin damage after
heavy or prolonged alcohol exposure (Alfonso-Loeches et al., 2012). In support of this hypothesis, my
dissertation research has confirmed that alcohol drinking upregulates TLR4 mRNA in the prefrontal cortex of
male, but not female adolescent rats (Aim 1). Gonadal hormones have been shown to have neuroprotective
and anti-inflammatory effects (Vegeto et al., 2003), however, their role in alcohol-mediated disruptions, like
upregulation of toll-like receptors, remains unknown. Therefore, in the F99 predoctoral phase of this proposal I
will test the role of circulating gonadal hormones in protecting females against these effects and identify the
glial population involved. After I am done with my dissertation, my goal for the K00 phase is to study how the
neuroimmune system adapts after alcohol exposure during adolescence, and how these neuroadaptations
may contribute to alcohol abuse and alcohol use disorder later in life. Specifically, I will use RNAseq,
transgenic animal models, primary cell cultures, and ChIP, along with mRNA and protein assays learned in the
F99 phase, to answer how epigenetic changes induced by alcohol, especially those targeting
neuroinflammatory genes, contribute to changes in biological function of different cell types and how this in turn
regulates behavior. My ultimate goal for this research is to gain insight into the epigenetic targets of alcohol,
which will help identify potential therapeutics for drug addiction and neurodegenerative disorders.

## Key facts

- **NIH application ID:** 10485334
- **Project number:** 3F99NS115272-02S1
- **Recipient organization:** UNIVERSITY OF MASSACHUSETTS AMHERST
- **Principal Investigator:** Andrea Silva-Gotay
- **Activity code:** F99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $9,840
- **Award type:** 3
- **Project period:** 2019-09-30 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10485334

## Citation

> US National Institutes of Health, RePORTER application 10485334, Protective effects of ovarian hormones: sex-specific differences in tlr4 expression after adolescent alcohol (3F99NS115272-02S1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10485334. Licensed CC0.

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