PROJECT SUMMARY/ABSTRACT Animals respond to changes in their external environment and promote pro-survival behavioral output. Shifts in an animal’s internal state, or a shift neuronal processing mediated through neuromodulation, drive these adaptive behavioral responses, affecting sensory and memory processing. State-dependent modulation can be harmful when it is related to drugs of abuse, particularly alcohol. This project aims to understand the mechanisms and circuit motifs that mediate state-dependent modulation of alcohol memory circuits. Understanding these circuit mechanisms will highlight how internal state, brought about by stress, mood, and physiological state, can affect drug abuse disorders, cravings, and relapse. Briefly, Drosophila melanogaster were conditioned with a spaced- training paradigm to associate an odor cue with an intoxicating dose of alcohol, and preference was tested the following day. Octopaminergic neurons, the invertebrate equivalent norepinephrine, were found to modulate olfactory reward memory circuits necessary for alcohol memory acquisition and retrieval in fruit flies. Thermogenetic inhibition of octopaminergic neurons showed that modulation occurred only when flies were in a food-deprived state, and this neuromodulation was necessary for the acquisition and retrieval of the alcohol memory. In-vivo calcium imaging will be used to assess the activity of the subset of octopamine neurons mediating this state-dependent modulation (satiated versus food-deprived states) and their downstream post- synaptic partners. Neuronal activity of the identified state-dependent octopaminergic circuit will be assessed during intoxication, naïve odor exposure, odor-alcohol pairings, and paired- or unpaired-odor re-cue. These experiments will highlight state-dependent mechanisms for memory processing, by which shifts in internal state can affect the acquisition and retrieval of memories related to drugs of abuse. The applicant will acquire training in calcium imaging and sophisticated data-analysis methods to follow-through on these experiments, with ongoing professional development training to help develop the applicant for the next stage of their career as a postdoctoral researcher. The applicant will continue to pursue mechanisms of state-dependent modulation and how that affects multi-sensory integration, to drive behavioral choices. In the postdoctoral phase, the applicant will gain proficiency in calcium imaging techniques, computational skills, and continued training in analytical methods to examine large-scale calcium imaging data sets. Additionally, the applicant will further their professional development and grow towards becoming an independent researcher at an academic institution.