# Network mechanisms of impaired adult hippocampal neurogenesis in a mouse model of prenatal alcohol exposure

> **NIH NIH R01** · UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR · 2024 · $340,875

## Abstract

PROJECT SUMMARY/ABSTRACT
The overall goal of this proposal is to establish the relevance of adult hippocampal neurogenesis as a potential
therapeutic target for fetal alcohol spectrum disorder (FASD), utilizing a well-characterized mouse model of
prenatal alcohol exposure (PAE). The significance for adult hippocampal neurogenesis as a potential therapeutic
target in fetal alcohol spectrum disorder (FASD) is based on preclinical rodent models that demonstrate long-
lasting deficits in neurogenesis following developmental alcohol exposure, the critical role of neurogenesis in
many hippocampal-dependent behaviors that are also disrupted in clinical FASD, and recent evidence that
neurogenesis continues throughout life in the human hippocampus. Using voluntary drinking paradigms to model
PAE in mice, our laboratory previously demonstrated marked impairment of the neurogenic response to enriched
environment (EE) that is associated with disruption of neurochemical, morphological and electrophysiological
indices of EE-mediated network activity. Experiments outlined in this proposal are designed to test the overall
hypothesis that impaired EE-mediated neurogenesis is relevant for deficits in behavior and hippocampal
network mechanisms in PAE, and can be restored using genetic and/or pharmacological therapeutic
approaches. This hypothesis will be tested by addressing the following specific aims.
Specific Aim 1: To determine whether impaired EE-mediated neurogenesis is directly correlated with
impaired pattern discrimination learning in PAE mice. We will utilize two complex neurogenesis-dependent
cognitive tasks in which pattern discrimination/separation is tested in both contextual and spatial domains.
Behavioral performance will be correlated with impaired neurogenesis in PAE-EE mice, and with immediate early
gene expression as a readout of network activation.
Specific Aim 2: To determine whether impaired EE-mediated neurogenesis in PAE mice leads to
compensatory remodeling of afferent synaptic input to aDGCs. We will utilize neuroanatomical approaches
including rabies-based retrograde tracing to determine whether dendritic complexity and/or the distribution of
monosynaptic afferent inputs to aDGCs are selectively altered in PAE-EE mice.
Specific Aim 3: To determine whether sensitivity to EE-mediated neurogenesis in PAE mice is restored
by genetic and/or pharmacological intervention. We will utilize a genetic gain-of-function approach to
augment the survival of aDGCs in an attempt to restore EE-mediated neurogenesis in PAE mice. In addition, we
will test whether the neurogenic antidepressant, fluoxetine (FLX), restores EE-mediated neurogenesis and
behavior in PAE. If so, causal relationships between neurogenesis and FLX-mediated behavioral improvement
will be tested by selective, genetic silencing of aDGCs.

## Key facts

- **NIH application ID:** 10893495
- **Project number:** 5R01AA027462-05
- **Recipient organization:** UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
- **Principal Investigator:** Lee Anna Cunningham
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $340,875
- **Award type:** 5
- **Project period:** 2020-08-05 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10893495

## Citation

> US National Institutes of Health, RePORTER application 10893495, Network mechanisms of impaired adult hippocampal neurogenesis in a mouse model of prenatal alcohol exposure (5R01AA027462-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10893495. Licensed CC0.

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