Identifying molecular markers of neuronal inhibition after opioids

Project summary/abstract Immediate Early Genes (IEGs) are commonly used as proxy markers for neuronal activity in the context of substance abuse research. Despite a wide-ranging catalog of activity-dependent IEGs, there is a notable absence of genetically encoded markers of neuronal inactivity. This paucity is particularly noticeable in the context of substances which principally exert inhibitory effects on target neuronal function, including opioids. There is, therefore, a critical need to determine the transcripts that are upregulated following strong neuronal inhibition. The overall objective in this application is to identify and characterize markers of inhibition within neurons in the nucleus accumbens. Our central hypothesis is that distinct inhibited neurons will undergo transcriptional changes that can be used to identify and one day manipulate these inhibited neurons. The rationale for the proposed research is that understanding how neurons respond to inhibition will provide new opportunities for developing experimental therapeutics to treating opioid use disorder. To attain the overall objectives, the following specific aims will be pursued: 1) Identification of Immediate Early Genes expressed following pharmacological inhibition of the nucleus accumbens (NAc); and 2) Identification of Immediate Early Genes expressed following pharmacological inhibition with fentanyl. The research proposed in this application is innovative because it applies cutting edge methods to identify immediate early genes that are expressed in inhibited neurons for the first time. These contributions will have significant impact because they are expected to build a foundation for unprecedented analysis of patterns of excitatory and inhibitory activity throughout the brain.