State-dependent modulation of learning (R01AA031471) – Project Grant to Virginia Commonwealth University

Abstract: Animals can modulate learning in response to differing internal and external environments. Layering context onto learned information can enhance the diversity and specificity of memories, and can allow efficient access to situation-specific behaviors. In state-dependent learning (SDL), information learned by an animal while IT is in a particular internal "state" is most effectively recalled when the animal is tested in the same internal state. Drug intoxication-induced SDL can be observed across diverse animal species, including humans. We will employ a model of ethanol intoxication-induced SDL that we have developed in the nematode caenorhabditis elegans to define the molecular mechanisms that are required for SDL to occur. The simple and highly conserved nervous system of c. Elegans provides an excellent model in which to study the molecular events that underlie SDL. When worms experience an attractive olfactory CUE in the absence of food, they can learn to associate the odorant with starvation and attenuate their response to IT in a process called olfactory learning (OL). We have shown that OL can become state-dependent; when animals undergo OL while they are intoxicated, they only express the learned behavior when they are tested in the same intoxicated state. We have shown that the internal intoxication state is encoded by a secreted peptide signal and its receptor during OL, but, surprisingly, this signal does not encode intoxication state during recall of OL. Here, we will identify the mechanisms by which state is encoded during recall of state-dependent OL. We will define the neural circuit in which SDL occurs and the inputs into IT that signal state during both learning and recall. We will distinguish between two explanations for the lack of expression of state-dependent OL when the animals are tested in a non-intoxicated state: forgetting (loss of the learned information) or failing to recall (the learned information remains, but the memory is only accessible when the animals are intoxicated). We will determine if other drugs besides ethanol can confer state-dependency on OL. Finally, we will probe the generalizability of SDL beyond OL by asking if learning paradigms that use other neural circuits and signaling systems can become state dependent. Successful completion of these aims will provide novel molecular insight into how context cues are added to learned information.

Action	Obligated	Date
Amendment	$381,149	Apr 17, 2026
Amendment	$420,027	May 14, 2025
Amendment	$440,027	Apr 16, 2024
Original award	$440,027	Apr 16, 2024

State-dependent modulation of learning

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