Neural circuit dynamics of drug action

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Overall Summary We will develop a NIDA Center, Neural circuit dynamics of drug action, 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, rat, and mouse social and nonsocial behaviors. We will both 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 brain of mice and rats; 2: led by Dr. Lisa Giocomo, focusing on methamphetamine and ketamine action in entorhinal cortex and hippocampal formation of mice and rats; 3: led by Dr. Robert Malenka, focusing on methamphetamine and MDMA action across the brain of mice; and 4: led by Dr. Leanne Williams and Brian Knutson, focusing on human structural and functional imaging relevant to methamphetamine, ketamine, MDMA, and risk/reward relationships. Broad and diverse interactions among these 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.