PROJECT SUMMARY (Overall) We describe here the vision and plan for the second five-year period of support for a NIDA Center of Excellence, Neural circuit dynamics of drug action. This Center is dedicated to the development, application, and dissemination of brainwide and cellular-resolution analyses of altered states elicited by drugs of abuse. Our science will focus on identifying the causal circuit-level actions of drugs of abuse in modulating behavior relevant to assessment of context, risk and reward. In a manner that brings together the collaborating groups of the Center, we focus on clinically significant drugs with different molecular profiles but shared significance for understanding behaviors and perceptions relevant to social and nonsocial risk and reward. Specific agents employed include methamphetamine, MDMA, and ketamine, in the setting of validated human and rodent social and nonsocial behaviors. We will develop the brainwide technologies and engage in extensive outreach, training, and education to broaden impact, with the NIDA IRP and beyond. The Center includes four Research Projects (1: led by Dr. Karl Deisseroth, focusing on methamphetamine, MDMA and ketamine action in the cortex and across the brains of mice; 2: led by Dr. Lisa Giocomo, focusing on methamphetamine and ketamine action in entorhinal cortex and hippocampal formation of mice; 3: led by Dr. Robert Malenka and Dr. Boris Heifets, focusing on methamphetamine and MDMA action across the brain of mice; and 4: led by Dr. Leanne Williams and Dr. Brian Knutson, focusing on human structural and functional imaging relevant to methamphetamine, ketamine, MDMA, and risk/reward relationships. Broad and diverse interactions amongthese groups and external collaborators will be further enriched by the Center’s vital Training Core for disseminating these techniques to advance drug abuse research, a Technology Core for developing the next- generation technologies suitable for application to drug abuse research, and an Administrative Core for orchestrating these important interactions. This approach to the NIDA Center will allow us to capitalize on the unique strengths of our team, crossing scales from molecules and synapses, to circuits and behavior, reaching the scope of the intact human brain as we identify relevant structure-activity relationships within animal and human nervous systems.