# Prenatal alcohol exposure and corticostriatal mediation of behavioral flexibility

> **NIH NIH R01** · UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR · 2020 · $335,439

## Abstract

Abstract
There is growing evidence that moderate exposure to alcohol during development can lead to behavioral and
cognitive deficits that can persist throughout the lifespan. Cognitive impairments associated with Fetal Alcohol
Spectrum Disorders (FASD) include abnormalities in learning and memory, executive control and social
behaviors and are often characterized by a hyper-focus on one particular task or aspect of a task, to the
detriment of other important behaviors. We have recently shown that moderate prenatal alcohol exposure
(PAE) can impair executive control in adulthood and that behavioral impairments are accompanied by
significant alterations in coherence in the orbitofrontal cortex during choice. Both behavioral deficits and
cortical alterations are found when GluN2B subunit containing N-Methyl-D-Aspartate receptors (NMDAR) are
lost in the OFC. Given preliminary data that GluN2B is significantly reduced in the OFC after PAE, we propose
to investigate whether impairments in behavioral flexibility are driven by alterations in cortical coherence
mediated by alterations in NMDAR expression and function and whether these deficits can be rescued. We
propose to integrate a well-established voluntary drinking paradigms for moderate PAE with touch-screen
behavioral assays, in vivo and ex vivo electrophysiology and optogenetic stimulation. First, we will express
channel rhodopsin (ChR2) in the cortex of PAE and SAC mice and examine whether direct stimulation will
rescue behavioral flexibility impairments in PAE mice. Next, given evidence that GluN2B is downregulated
after PAE and that his subunit contributes to establishing cortical coherence, we will investigate whether
behavioral deficits in the model are mediated by alterations in GluN2B subunit expression and recruitment
required to induce plasticity and support behavioral flexibility. Finally, we will examine whether changes in
connectivity between OFC and dS drives asynchrony and perseveration. We will use retrograde expression to
fluorescently tag OFC-dS neurons and characterize function of NMDAR via ex vivo slice physiology. Then we
will utilize retrograde expression of ChR2 to test if stimulation restricted to OFC-dS neurons is sufficient to
rescue the behavioral deficits. Taken together the completion of these aims will elucidate the mechanisms of
cognitive impairment in FASD and provide an important tool for developing more effective therapies for
executive dysfunction.

## Key facts

- **NIH application ID:** 9856393
- **Project number:** 5R01AA025652-03
- **Recipient organization:** UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
- **Principal Investigator:** Jonathan L Brigman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $335,439
- **Award type:** 5
- **Project period:** 2018-02-15 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9856393

## Citation

> US National Institutes of Health, RePORTER application 9856393, Prenatal alcohol exposure and corticostriatal mediation of behavioral flexibility (5R01AA025652-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9856393. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*