# Project 7/8: INIA Stress and Chronic Alcohol Interactions: Cross-species studies of metabolic allostasis and altered striatal circuitry

> **NIH NIH U01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2022 · $484,797

## Abstract

PROJECT SUMMARY
Chronic heavy ethanol drinking and stress are associated with impaired cognitive flexibility, reflected in habitual
and compulsive drinking. This proposal seeks to improve our understanding of the neural basis of these effects
by combining ex vivo slice electrophysiological studies with non-invasive magnetic resonance spectroscopy
(MRS) measurements on mouse and nonhuman primate (NHP) subjects over the course of experimental
drinking procedures common across the INIA-Stress consortium. Electrophysiological recordings of brain slices
have demonstrated that establishment of habitual behaviors, including heavy drinking, involve and increase in
the excitatory to inhibitory tone of neural input (the E/I ratio) to medium spiny neurons (MSNs) of the mouse
dorsolateral striatum (DLS), which in primates is termed the putamen. Specialized MRS techniques for
quantifying -aminobutyric acid (GABA) and glutamate within specific brain regions have led researchers to
propose that the glutamate/GABA ratio reflects E/I, in the context of chronic stress, however the MRS
approach has yet to be validated with direct comparisons to electrophysiological recordings. In Aims 1 and 2,
we propose to use electrophysiology and MRS to study mice undergoing chronic intermittent ethanol exposure,
combined with forced swim stress (CIE-FSS mice). Our experiments will expand our understanding of striatal
neurocircuit adaptations to stress and ethanol exposure by using chemogenetic and recombinant mouse
strains to characterize changes in cortical (excitatory) and parvalbumin-expressing interneuron (inhibitory)
input to DLS MSNs. In the same mice, metabolic allostasis will be characterized with dynamic MRS methods
that monitor cerebral glucose metabolism and neurotransmitter synthesis to estimate the neural tricarboxcylic
acid cycle rate (VTCA) in real time, to provide a biochemical context for interpreting glutamate/GABA ratios,
which will also be measured in these mice. In Aim 3, parallel chemogenetic manipulations and
electrophysiological recordings will be performed in NHP subjects following schedule-induced polydipsia and
open-access drinking. These measures will be directly compared to MRS determinations of glutamate/GABA
and VTCA within the putamen. Together, these results will support the development of non-invasive strategies to
measure stress and ethanol-induced changes in striatal neurocircuitry associated with the establishment of
heavy drinking behaviors. The cross-species approach will contribute reliability to the conclusions to be drawn,
and enhance the translatability of this work to future application in human subjects.

## Key facts

- **NIH application ID:** 10409985
- **Project number:** 1U01AA029967-01
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Verginia Carmella Cuzon Carlson
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $484,797
- **Award type:** 1
- **Project period:** 2022-03-15 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10409985

## Citation

> US National Institutes of Health, RePORTER application 10409985, Project 7/8: INIA Stress and Chronic Alcohol Interactions: Cross-species studies of metabolic allostasis and altered striatal circuitry (1U01AA029967-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10409985. Licensed CC0.

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