# Adolescent intermittent ethanol induction of neuroimmune signaling disrupts the mature phenotype of surviving hippocampal neuroprogenitors

> **NIH NIH K99** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2022 · $125,519

## Abstract

PROJECT SUMMARY
Adolescent binge drinking hijacks the developing brain, resulting in long-lasting increases in neuroinflammation
which are paralleled by decreases in hippocampal neurogenesis and deficits in learning and memory-related
tasks. Unlike adult alcohol exposure, the cellular and behavioral effects of adolescent binge drinking do not
recover following periods of abstinence, suggesting that alcohol exposure across adolescence permanently
disrupts the brain’s developmental trajectory. However, while prior research has focused on the underlying
mechanisms driving this loss and restoration of newborn hippocampal neurons, no research has investigated
how adolescent intermittent ethanol (AIE) impacts the ability of surviving hippocampal neuroprogenitor cells
(NPCs) to appropriately integrate into adult hippocampal circuitry. Newborn neurons assimilate into dentate
circuitry in an activity dependent manner which is sensitive to shifts in the balance between neuronal excitation
and inhibition as well as neuroinflammatory signaling. Any disruption in this integration could have profound
consequences on learning and memory functions as granular cells are a gatekeeper for downstream activation
of hippocampal circuitry. To test the impact of adolescent alcohol on network integration of developing
neurons, we will use a reporter mouse line (DCX-CreERT2/tdtomato) which was developed to specifically tag
and then fate-map NPCs across their lifespan. This technique will allow us to track how alcohol impacts the
ability of adolescent maturing neurons to effectively integrate into mature dentate circuitry. By combining this
transgenic model with 5-ethynyl-2'-deoxyuridine, we will test whether adolescent alcohol exposure induces
adult innate immune gene expression preferentially in adolescent-maturing NPCs and glia, and we will also
test whether AIE impairs formation of dendritic arborization in adolescent-maturing NPCs (AIM 1/K99). We will
then test whether adolescent alcohol impairs the electrophysiological properties of these adolescent-maturing
NPCs in adulthood (AIM 2/K99). As it remains unclear whether maturational changes in adolescent maturing
neurons mediate cognitive-behavioral deficits, we will test whether AIE disrupts immediate early gene
expression in adolescent-maturing NPCs following reversal learning in the Morris water maze, novel object
recognition memory, and social dominance behaviors in adulthood (AIM 3/K99). Finally, while preliminary data
suggest that anti-inflammatory interventions can reverse neurogenic and behavioral deficits after AIE in both
sexes, whether anti-inflammatory pharmacological interventions (e.g., indomethacin) can similarly restore
morphological and physiological maturation, circuit integration, and innate immune gene expression in
adolescent-maturing NPCs in adulthood is unknown (AIM 4/R00). Collectively, these experiments will provide
critical insight into the impact of adolescent alcohol on the resulting phenoty...

## Key facts

- **NIH application ID:** 10591757
- **Project number:** 1K99AA030089-01A1
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Victoria Alice Macht
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $125,519
- **Award type:** 1
- **Project period:** 2022-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10591757

## Citation

> US National Institutes of Health, RePORTER application 10591757, Adolescent intermittent ethanol induction of neuroimmune signaling disrupts the mature phenotype of surviving hippocampal neuroprogenitors (1K99AA030089-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10591757. Licensed CC0.

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