# Role of the transcriptional regulator Lmo4 in alcohol consumption and reward

> **NIH NIH R01** · UNIVERSITY OF TEXAS AT AUSTIN · 2020 · $352,125

## Abstract

Project Summary
Repeated exposure to alcohol leads to neuroadapative changes that underlie the transition from moderate to
excessive alcohol intake. Gene expression profiling studies in human alcoholics and rodents have led to the
identification of a multitude of ethanol-responsive gene networks and pathways. However, there is a gap in
knowledge in our understanding of how these networks are coordinated into a neuroadaptive response. One
potential mechanism could involve the recruitment of transcription factors and transcriptional co-regulators that
could modulate the expression of several downstream genes. However, very few studies have examined the
role of transcriptional co-regulators in alcohol use disorders. Our preliminary results implicate a novel role for
the transcriptional co-regulator Lim-Only 4 (LMO4) in regulating alcohol intake. LMO4 knockdown in the
basolateral amygdala (BLA) led to a significant decrease in alcohol consumption in the intermittent access
procedure and a significant deficit in conditioned place preference to alcohol suggesting a role for LMO4 in the
BLA in regulating both alcohol consumption and reward. Unbiased transcriptome analysis of the BLA from WT
and Lmo4gt/+ mice, which make 50% less Lmo4 than WT mice, using RNASeq revealed several genes that
were differentially expressed including the kappa opioid receptor (Oprk1). Weighted gene co-expression
network analysis (WGCNA) revealed extracellular matrix (ECM)-related genes as being dysregulated upon
LMO4 knockdown. These results led us to hypothesize that a LMO4-regulated transcriptional network in the
BLA regulates alcohol consumption. We propose the following specific aims to test this hypothesis. In Aim 1,
we will determine whether Oprk1 functions downstream of LMO4 in the BLA to regulate alcohol consumption.
We will use a combination of approaches including cell-type specific shRNA-mediated knockdown of Lmo4 and
Oprk1 in BLA pyramidal neurons and chromatin immunoprecipitation to address this question. In Aim 2, we will
determine whether LMO4 downregulation in the BLA causes abnormalities in the density of perineuronal nets
(PNNs), a highly specialized form of ECM in the brain. We will next determine whether enzymatic dissolution of
PNNs will reduce ethanol consumption. We will also determine whether a disintegrin and metalloproteinase
with thrombospondin motif (ADAMTS) 2 and sulfatase 2 (Sulf2) function downstream of LMO4 to regulate
alcohol consumption. Finally, in Aim 3, we will use a viral-based translational affinity purification strategy to
determine how the LMO4-regulated transcriptome changes with alcohol exposure. The proposed experiments
are significant because identification of transcriptional targets functioning downstream of LMO4 to regulate
alcohol consumption could lead to the identification of novel therapeutic targets to treat alcohol use disorders.

## Key facts

- **NIH application ID:** 9841868
- **Project number:** 5R01AA027293-02
- **Recipient organization:** UNIVERSITY OF TEXAS AT AUSTIN
- **Principal Investigator:** Rajani Maiya
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $352,125
- **Award type:** 5
- **Project period:** 2019-01-01 → 2020-05-17

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9841868

## Citation

> US National Institutes of Health, RePORTER application 9841868, Role of the transcriptional regulator Lmo4 in alcohol consumption and reward (5R01AA027293-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9841868. Licensed CC0.

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