# Notch-dependent microcircuit regulation of alcohol reward memory

> **NIH NIH R01** · BROWN UNIVERSITY · 2024 · $355,950

## Abstract

PROJECT SUMMARY:
Alcohol is the widely abused drug in the world, yet our understanding of the molecular mechanisms by which it
regulates brain function and behavior is rudimentary. Many of the molecules implicated in alcohol-induced
behaviors have broad roles in regulating diverse processes such as cell signaling, transcription, and neuronal
plasticity. The complexity of these processes has led to confusion about alcohol’s molecular underpinnings,
which has been further compounded by lack of the ability to manipulate gene expression with precise temporal
and spatial control within a well-defined neural circuit. The temporal and spatial specificity for manipulating gene
expression afforded in the fruit fly, Drosophila melanogaster, provides the ability to define where and when and
where alcohol is acting in the brain to influence both naive and learned behavior. Our unbiased forward genetics
approach in Drosophila has revealed the importance of the Notch signaling pathway in regulating formation of
memories of a sensory cue associated with the intoxicating properties of alcohol. Notch is a highly conserved
cell-signaling mechanism that involves cell-to-cell contact and initiates a transcriptional cascade important for
determining cell fate and function. Notch signaling also plays a key role in multiple forms of cancer and immune
disorders, as well as cardiovascular, kidney, liver, respiratory and neurodegenerative disease. We recently
demonstrated that rewarding doses of alcohol activate Notch signaling in memory-encoding neurons, and this
affects expression of novel Notch transcriptional targets such as dopamine receptors. What remains to be
understood are the mechanisms through which alcohol activates Notch, and how this ultimately affects dynamics
of memory circuits, both acutely and with chronic alcohol use. We hypothesize that Notch plays an important
role in activity-dependent transcription required for memory formation and thus ultimately shapes future reward
seeking. The goal of the proposed work is to use a genes-to-circuits-to-behavior approach to provide a causal
Notch-dependent mechanism through which alcohol-induced cellular activity can guide a transcriptional cascade
that influences future alcohol seeking. This increased molecular understanding of the lasting sensory memories
for intoxication will ultimately inform more effective targets for pharmacological treatment of alcohol use disorder.

## Key facts

- **NIH application ID:** 10898059
- **Project number:** 5R01AA024434-09
- **Recipient organization:** BROWN UNIVERSITY
- **Principal Investigator:** Karla R. Kaun
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $355,950
- **Award type:** 5
- **Project period:** 2016-08-20 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10898059

## Citation

> US National Institutes of Health, RePORTER application 10898059, Notch-dependent microcircuit regulation of alcohol reward memory (5R01AA024434-09). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10898059. Licensed CC0.

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