The societal and economic burden of substance abuse and addiction is vast and ever-increasing. To address this requires developing innovative therapeutics, an approach necessitating a deep understanding of addictive behavior and its neurobiological basis. Fortunately, the last decade has witnessed a surge of breakthrough technologies with significant promise for advancing the understanding of the neurobiological basis of normal and pathological behavior. Our goal will be to leverage the unique NIH intramural environment to establish a pioneering, and collaborative, translational research program. This program will implement state-of-the-art biobehavioral molecular imaging approaches integrated alongside cutting-edge neuromodulatory (e.g. chemogenetic, optogenetic), molecular, pharmacological, transgenic, and bioinformatic methods for identifying behaviorally-relevant neurobiological mechanisms associated with substance abuse and addiction. Special emphasis will be placed on reverse-translating findings from clinical research to animals. In addition, clinical relevance of mechanisms studied in animals will be determined in humans via bioinformatic, genetic and postmortem tissue examination. One of the labs core areas of focus will be on development and application of novel molecular imaging strategies for assessment of whole-brain and cellular-level molecular dynamics simultaneously with behavior in animal models of substance abuse and addiction. Another major core focus involves development of novel theranostic neuromodulation technologies that can be used for clinical treatment of addiction and other disease state.