# Compulsive Alcohol Drinking and Cortical Extracellular Matrix

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2020 · $376,241

## Abstract

Several criteria for diagnosis of alcohol use disorder (AUD) involve drinking despite negative consequences,
meaning the decision to drink despite the loss of a job, damage to relationships, or increased risk of harm to
oneself. One region of the brain that controls the decision to drink under conditions of risk is the insular cortex.
Changes in neuronal function in the insula caused by excessive drinking may drive the transition to this risky,
or aversion-resistant alcohol drinking. Our preliminary data indicates that specialized extracellular matrix
structures, known as perineuronal nets (PNNs), may be involved in aversion-resistant drinking. PNNs in
cortical regions primarily surround fast-spiking GABAergic interneurons that express the calcium-binding
protein parvalbumin (PV). These neurons are important for cognition and tightly control the firing of
excitatory cortical projection neurons. The overarching goals of this proposal are 1) to examine the cellular and
molecular changes in PNNs on PV neurons in the insula after extended binge-like alcohol consumption by
mice, and 2) to determine the behavioral consequences of manipulating PV neurons and PNNs on PV neurons
in the insula on aversion-resistant drinking. In Specific Aim 1, we will examine the structure of PNNs at
different time points after binge drinking using immunocytochemical methods, measure changes in the
expression of PNN genes and proteins, and measure the activity of the proteases (MMP and ADAMTS
metalloproteinase family) that regulate the remodeling of PNNs. In Specific Aim 2, we will measure changes in
synaptic density and volume on PV neurons with and without PNNs after binge drinking using
immunocytochemical methods and super-resolution microscopy. In addition, we will measure excitability and
synaptic changes on these neurons after binge drinking using electrophysiological methods. Together, these
two Specific Aims will provide important knowledge regarding the changes that occur in PNNs and their
associated synapses after extended periods of binge alcohol drinking. In the third Specific Aim of this proposal,
we will disrupt PNNs on PV neurons by knocking down the expression of two specific PNN proteins encoded by
the genes Acan and Bcan using viral-delivered short hairpin RNAs. Viruses will be injected directly into the
insula of mice expressing Cre recombinase in PV neurons (PV-Cre) for localized cell-type specific gene
knockdown. These mice will be tested for consumption of ethanol alone and an aversive solution of ethanol
containing quinine to determine the effect of PNN disruption on aversion-resistant drinking. Finally, we will
directly manipulate the activity of insular PV neurons by viral delivery of designer receptors exclusively
activated by designer drugs (DREADDs) to determine the role of these neurons in aversion-resistant ethanol
consumption. These studies will provide information on the cellular and molecular changes that occur on PV
neurons in the insula t...

## Key facts

- **NIH application ID:** 9996437
- **Project number:** 5R01AA027231-02
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Amy Wolven Lasek
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $376,241
- **Award type:** 5
- **Project period:** 2019-08-15 → 2024-07-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9996437

## Citation

> US National Institutes of Health, RePORTER application 9996437, Compulsive Alcohol Drinking and Cortical Extracellular Matrix (5R01AA027231-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9996437. Licensed CC0.

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