# Worms learning while intoxicated: determining the molecular mechanism and neuronal circuitry required for state dependent learning in Caenorhabditis elegans

> **NIH NIH F32** · VIRGINIA COMMONWEALTH UNIVERSITY · 2020 · $64,554

## Abstract

Abstract
Links between the neurobiology of learning and the neurobiology of addiction have been well documented. For
instance, human subjects recall memories more readily while intoxicated if the memory was acquired in an
intoxicated state. This is known as state dependent learning (SDL). SDL has been demonstrated in a wide
variety of organisms, but little is known of the molecular mechanisms and neurocircuitry associated with SDL.
In Caenorhabditis elegans (C. elegans), SDL is demonstrated by coupling the intoxicating effects of ethanol
with a specific learned behavior known as olfactory adaptation; animals recall their exposure while intoxicated
to an olfactory stimulus better if they are tested while intoxicated. C. elegans are an optimal model for studying
the molecular underpinnings of SDL, as they have a simple 302-neuron nervous system with invariant
neurocircuitry from animal to animal. The neurotransmitter dopamine is required for SDL, and animals with
mutations in dopamine synthesizing genes, cat-1 and cat-2, do not learn state-dependently. These results
suggest learning while intoxicated activates distinct SDL neurocircuitry that innervate and alter signaling of
olfactory adaptation neurons. The ultimate goal of this work is to discover the circuit required for state
dependency, and how this is regulated at the molecular level. Preliminary results show that a signaling peptide,
hen-1, and a receptor tyrosine kinase, scd-2, are required for SDL. The hen-1 expressing neuron ASE-R is
also required for SDL. The ASE-L neuron, which expresses almost all of the same genes as ASE-R with the
exception of hen-1, is not required for SDL. In specific aim 1 I will test the sufficiency of hen-1 and scd-2
expression in ASE-R and AIA neurons respectively. Other preliminary results show octopamine deficient
worms do not show SDL. The only neurons that release octopamine are RIC neurons. I will test constructs
lacking the RIC neuron via genetic ablation for SDL. I have also demonstrated that SDL emerges from
exposure to nicotine during olfactory learning in C. elegans. In specific aim 2 I will test for similarities in
molecular mechanisms and neurocircuitry between SDL that emerge from ethanol and nicotine. I will also
determine if SDL emerges in worms exposed to caffeine. Previously, a forward genetic screen was performed
to find animals that are incapable of learning state-dependently during ethanol intoxication. A mutation, dubbed
sdl-1, was isolated through selective screens. In specific aim 3 I will use genetic mapping and genomic
sequencing to determine the molecular identity of sdl-1 and determine how the gene containing this mutation
might promote SDL. Here, I hypothesize that SDL induced by ethanol intoxication has a distinct circuit
that inputs onto olfactory adaptation neurocircuitry. My aims identify the molecular mechanism and
neurocircuitry of this behavior by, 1) investigating hen-1/scd-2 and octopaminergic signals, 2) using other
substan...

## Key facts

- **NIH application ID:** 9992133
- **Project number:** 1F32AA028416-01
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Jonathan Houghton Lindsay
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $64,554
- **Award type:** 1
- **Project period:** 2020-09-30 → 2023-09-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9992133

## Citation

> US National Institutes of Health, RePORTER application 9992133, Worms learning while intoxicated: determining the molecular mechanism and neuronal circuitry required for state dependent learning in Caenorhabditis elegans (1F32AA028416-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9992133. Licensed CC0.

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