# Therapeutic Targeting of Adult Hippocampal Neurogenesis in a Mouse Model of FASD

> **NIH NIH F31** · UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR · 2024 · $42,639

## Abstract

PROJECT SUMMARY
The overall goal of the proposed research is to determine the effect of pharmacological, genetic, or activity -
based intervention to restore the neurogenic response to enriched environment (EE) in a mouse model of
prenatal alcohol exposure (PAE). If successful, these studies may provide potential avenues of intervention for
hippocampal dysfunction associated with fetal alcohol spectrum disorder (FASD). The current proposal is
designed to test the overall hypothesis that increasing the survival of newborn neurons will reinstate the
neurogenic effect of enrichment in PAE mice. This proposal is premised on prior work demonstrating that
gestational exposure to moderate levels of alcohol have no effect on adult hippocampal neurogenesis when mice
are housed under standard conditions, but markedly impairs the ability of mice to mount a neurogenic response
to social and physical environmental enrichment. This impairment is not the result of reduced proliferation or size
of the progenitor pool, but results from impaired survival of newborn dentate granule cells (nDGCs) during the
activity-dependent stage of circuit integration. Using a well-characterized limited access voluntary drinking
paradigm, I will test our overarching hypothesis by addressing the following specific aims: Specific Aim 1: To
determine the therapeutic potential of fluoxetine (FLX) to restore EE-mediated neurogenesis in PAE mice.
For these studies, I will chronically administer the SSRI antidepressant, fluoxetine, (previously documented to
enhance the survival of nDGCs), during EE to determine its effects on the neurogenic response in PAE mice. In
addition, I will correlate the neurogenic response with behavioral assays of hippocampal function. Specific Aim
2: To determine the therapeutic potential of apoptotic inhibition, using inducible BAX knockout mice, to
restore EE-mediated neurogenesis in PAE mice. I will utilize a genetic approach to prolong the survival of
nDGCs in PAE-EE mice. Specifically, I will generate and characterize a triple transgenic mouse line,
NestinCreERT2:tdTomato:BAXf/f, to test whether selective deletion of the pro-apoptotic gene, BAX, within
hippocampal progenitors and their downstream progeny will facilitate EE-mediated neurogenesis in PAE mice.
Specific Aim 3: To determine the therapeutic potential of chemogenetic activation of nDGCs, to restore
EE-mediated neurogenesis in PAE mice. Here, I will utilize DREADD technology (designer receptors
exclusively activated by designer drugs) to selectively drive neuronal activity in nDGCs. Specifically, I plan to
generate and characterize a triple transgenic mouse line, NestinCreERT2:tdTomato:hM3Dq, and utilize the
DREADD agonist, deschloroclozapine (DCZ), to stimulate nDGCs in PAE-EE mice. These aims are in
accordance with the NIAAA’s mission to develop treatment strategies to address alcohol-related issues across
the lifespan. This proposed research also serves as an important framework for training ...

## Key facts

- **NIH application ID:** 10998022
- **Project number:** 1F31AA031920-01
- **Recipient organization:** UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
- **Principal Investigator:** Arasely M Rodriguez
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $42,639
- **Award type:** 1
- **Project period:** 2024-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10998022

## Citation

> US National Institutes of Health, RePORTER application 10998022, Therapeutic Targeting of Adult Hippocampal Neurogenesis in a Mouse Model of FASD (1F31AA031920-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10998022. Licensed CC0.

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