Recent advances in single-cell transcriptomic methods have revealed an incredible diversity of neuronal subtypes. This presents a challenge for understanding substance use disorders because these subtypes can only be identified in post mortem brain tissue, but substance use disorders occur only in living humans. One of the key unsolved problems is how to link these numerous transcriptomically-defined neuronal subtypes to their functional roles in drug addiction in the intact brain. In this proposal, we take first steps toward bridging this gap. First, we will use innovative optogenetic and electrophysiological techniques to record neuronal activity from genetically identified cell types in the nucleus accumbens during oral opioid self-administration in mice. We will also take the converse approach, using innovative optical methods to label neuronal subpopulations that are active during different phases of opioid self-administration, then identifying their transcriptomic profiles post mortem using a novel in situ sequencing method. We also describe plans to extend these techniques for compatibility with advanced in vivo multiphoton imaging and single-cell transcriptomic and epigenomic studies. We expect this project will open new lines of exploration in substance use disorders and contribute broadly to understanding the relationship between neuronal gene regulation and functional roles in opioid addiction, which may identify new therapeutic targets.
This project aims to identify the relationships between genetically-defined subpopulations of cells in the brain and the functional roles they play in opioid self-administration. This is likely to provide insight into the neural basis of drug addiction and identify possible therapeutic targets for future studies.