# The role of lateral orbitofrontal cortex astrocytes in alcohol drinking

> **NIH NIH F31** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2024 · $38,142

## Abstract

PROJECT SUMMARY
Alcohol use disorder (AUD) is characterized by the progression from recreational drinking to uncontrollable and
excessive consumption resulting in a myriad of social and neurobiological complications. The mechanisms
underlying the dependence-induced escalation in drinking are not completely understood. However, a key brain
region disrupted in individuals with AUD is the orbitofrontal cortex (OFC). Studies from the Woodward laboratory
show that acute ethanol inhibits action potential firing of lateral orbitofrontal (lOFC) cortex pyramidal neurons.
This occurs via an astrocyte-dependent process involving activation of astrocytic D1/D5 dopamine receptors and
the release of glycine via reversal of the GlyT1 glycine transporter. Following chronic intermittent exposure (CIE)
to alcohol, lOFC neurons become hyperexcitable and are tolerant to acute ethanol. However, the effects of CIE
exposure on lOFC astrocytes and how this affects lOFC neuronal excitability are not completely understood. The
overarching hypothesis of this proposal is that CIE exposure impairs lOFC astrocyte function that contributes to
hyperexcitability of lOFC pyramidal neurons and the resulting dependence-induced escalation in drinking. This
hypothesis will be tested with two complementary aims. Aim 1 will test the hypothesis that CIE-induced increases
in lOFC neuronal excitability and loss of acute ethanol inhibition involves astrocytic calcium signaling. To test
this, male and female C57BL/6J mice will receive an intra-OFC infusion of an astrocyte-selective AAV encoding
either a plasma membrane calcium ATPase (PMCA) or a reporter construct (tdTomato). Following repeated
cycles of CIE exposure, slice electrophysiology will be used to measure current-evoked spiking of lOFC neurons
and the membrane potential of lOFC astrocytes. Training in viral infusion surgeries and astrocyte and neuron
slice electrophysiology will be achieved under this aim. Aim 2 will test the hypothesis that expressing PMCA in
lOFC astrocytes prevents the increases in drinking following CIE exposure. In the first study, male and female
C57BL/6J mice expressing either PMCA or tdTomato localized in lOFC astrocytes will undergo baseline sessions
of two-bottle choice ethanol drinking. Weekly sessions of CIE exposure will then be interleaved with test weeks
of drinking. The second study will follow the same CIE paradigm with the absence of homecage drinking and will
use mice expressing GCaMP6f in lOFC astrocytes and the red-shifted opsin ChrimsonR in lOFC neurons.
Training in astrocyte fiber photometry and optogenetics will be achieved under this aim. The proposed research
studies will be complemented by career development activities including manuscript preparation, data
presentation, networking, and training in the responsible conduct of research. These studies will provide novel
insight into the role of lOFC astrocytes in AUD and position me to pursue a productive career in alcohol research.

## Key facts

- **NIH application ID:** 10933451
- **Project number:** 5F31AA030913-02
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Abigail Riley Blasczyk
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $38,142
- **Award type:** 5
- **Project period:** 2023-09-19 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10933451

## Citation

> US National Institutes of Health, RePORTER application 10933451, The role of lateral orbitofrontal cortex astrocytes in alcohol drinking (5F31AA030913-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10933451. Licensed CC0.

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