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 i dentify the molecular mechanism and neurocircuitry of this behavior by, 1) investigating hen-1/scd-2 and octopaminergic signals, 2) using other substances that may induce SDL, and 3) utilizing gene mapping to identify a novel gene associated with SDL.
Alcohol alters internal states, leading to changes in learning and memory mechanisms. Because of this, alcohol and other substances can cause a phenomenon known as state dependent learning, when the execution of a learned behavior is more effective when it is performed in the same internal state it was acquired. Here I use the model organism Caenorhabditis elegans as a means to identify the molecular mechanism and neurocircuitry of state dependent learning.
