# Hippocampal-thalamo-prefrontal circuitry damage and therapeutic intervention in a model of FASD

> **NIH NIH R01** · UNIVERSITY OF DELAWARE · 2022 · $397,545

## Abstract

ABSTRACT
Fetal alcohol spectrum disorders (FASD) are estimated to affect 3-5% of the US population (1). Prenatal alcohol
exposure (AE) leads to significant perturbations of brain circuitry and persisting cognitive deficits (2, 3) that include
abnormalities in executive functioning (EF) and working memory (4, 5). These abnormalities stem from orchestrated
structural changes in several key brain regions including the prefrontal cortex (PFC) and hippocampus (HPC). While
HPC and PFC have long been implicated in effective cognitive functioning, the role of the thalamic nucleus reuniens
(Re), that controls information flow between these structures, has only recently been appreciated. The Re serves as a
functional bridge between PFC and the HPC which are crucial for EF (6-9). Our preliminary data using a rat model of
binge AE during the third trimester revealed persistent structural damage of Re, highly correlated to behavioral deficits
consistent with fronto-hippocampal damage. The proposed research will test the hypothesis that binge AE during the
third trimester produces neuronal loss as well as dendritic and synaptic reorganization in the Re and mPFC,
which ultimately produces dysfunctional connectivity among mPFC-Re-HPC circuitry that is associated with
EF deficits. In addition,
we will evaluate if mPFC-Re-HPC dysfunction is mitigated via a therapeutic strategy,
wheel-running (WR) followed by environmental complexity (EC), which has been successful in alleviating the
deleterious AE effects on other behaviors disrupted in FASD(10-14)
.Using our combined expertise in experience-
dependent brain plasticity, developmental alcohol exposure and in vivo electrophysiology in freely moving rats during
memory tasks, we aim to reveal AE vulnerability of the PFC-Re-HPC circuit and determine the cellular components
and factors involved in plasticity of this circuit.
integrity of the Re and PFC in a binge third trimester
Aim 1
will establish the contributions of alcohol dose on structural
AE rat model.
Aim 2
working spatial memory deficits. Connectivity-behavior relationships will be
will test the hypothesis that AE induces
determined within the same animals via
virus labeling to test the hypothesis that AE disrupts the structural connectivity between the Re, HPC and PFC. In
addition, we will test the prediction that behavioral intervention (WR/EC) reduces AE-related deficits in behaviors that
are dependent on the integrity of the PFC-Re-HPC circuit by enhancing neuroplasticity. We will assess whether
neuroplasticity is critically dependent on increased expression of neurotrophic factors in the structural components of
the circuitry. Finally,
Aim 3
will determine whether AE-induced Re damage leads to reduced oscillatory synchrony
between the dorsal HPC and PFC during a spatial working memory task and if WR/EC can reinstate mPFC-HPC
synchrony.
and in vivo
Significance and Innovation
: The proposed research is innovative. It will use viral neural circuit mapping
m...

## Key facts

- **NIH application ID:** 10470201
- **Project number:** 5R01AA027269-04
- **Recipient organization:** UNIVERSITY OF DELAWARE
- **Principal Investigator:** ANNA Y KLINTSOVA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $397,545
- **Award type:** 5
- **Project period:** 2019-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10470201

## Citation

> US National Institutes of Health, RePORTER application 10470201, Hippocampal-thalamo-prefrontal circuitry damage and therapeutic intervention in a model of FASD (5R01AA027269-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10470201. Licensed CC0.

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