# Developmental Alcohol exposure and cerebro-cerebellar circuits

> **NIH NIH R21** · UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR · 2024 · $181,094

## Abstract

Project Summary / Abstract
Cognitive and executive function deficits are among the most devastating consequences of fetal
alcohol exposure. Currently available treatments against these deficits have limited efficacy. Our
long-term goal is to identify specific functional mechanisms underlying the cognitive deficits
associated with FASD. Our objective is to use circuit tracing and slice electrophysiology to determine
the long-term impact of third trimester-equivalent alcohol exposure (TTAE) on components of the
cerebro-cerebellar system involved in executive function. Our working hypotheses are that 1) TTAE
reduces glutamatergic input from the orbitrofrontal cortex—a brain region implicated in FASD-linked
executive function deficits—to the cerebellar cortex via pontine nuclei neurons and 2) TTAE
decreases glutamatergic output from the cerebellum to the orbitofrontal cortex via the deep cerebellar
nuclei and the thalamus. Our rationale for using circuit mapping is to characterize the effects of TTAE
on the function of reciprocal orbitofrontal cortex↔cerebellum connections. This proof-of-principle R21
proposal will establish a strong foundation for an R01 grant application to extend this work. In Aim 1,
we will determine the effects of TTAE on the function of the cerebro-cerebellar system feed-forward
limb. We will use anterograde transsynaptic labeling, slice electrophysiology, and optogenetics to test
the hypothesis that TTAE persistently reduces glutamatergic transmission at synapses between
pontine nuclei neurons (that receive input from the orbitofrontal cortex) and cerebellar granule cells
(lobule VI) while also reducing feed-forward disynaptic inhibition at pontine nuclei neuron→Golgi
cell→cerebellar granule cell synapses. In Aim 2, we will determine the effects of TTAE on the function
of the cerebro-cerebellar system feedback limb. We will use an intersectional approach consisting of
anterograde viral tracing coupled with retrobead labeling to test the hypothesis TTAE persistently
reduces monosynaptic glutamatergic and disynaptic GABAergic transmission at synapses between
deep cerebellar nuclei neurons—that receive input from lobule VI Purkinje neurons—and thalamic
neurons that project to the orbitofrontal cortex. The research proposed in this application is innovative
because it will systematically characterize, for the first time, the developmental effects of ethanol on
interactions among key components of the cerebro-cerebellar network. The proposed research is
significant because it will elucidate novel functional neurobiological mechanisms underlying fetal
alcohol exposure-induced executive function deficits, and identify specific biological targets for
interventions to ameliorate these deficits.

## Key facts

- **NIH application ID:** 10825519
- **Project number:** 5R21AA030639-02
- **Recipient organization:** UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
- **Principal Investigator:** Carlos Fernando Valenzuela
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $181,094
- **Award type:** 5
- **Project period:** 2023-04-10 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10825519

## Citation

> US National Institutes of Health, RePORTER application 10825519, Developmental Alcohol exposure and cerebro-cerebellar circuits (5R21AA030639-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10825519. Licensed CC0.

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