PROJECT SUMMARY Chronic pain is a major health crisis in the United States, affecting >100 million Americans and millions more worldwide. In addition, the use of opioids to treat chronic pain has been a major driver in the opioid epidemic that has swept over the country. Development of new classes of therapeutics that have a similar or higher efficacy relative to opioids for treating pain but lack the addictive liability of prescription opioids could have profound effects both for treating pain patients and for reducing the burden of the national opioid crisis. A significant barrier in achieving this goal is that we have little understanding of the brain circuits and pathways that contribute to the suffering caused by chronic pain. Our goal is to identify the neural circuit elements underlying pain affective perception, decode how their neural computations evolve during chronic pain, and attempt to normalize these pathological dynamics with precise circuit-based optical interventions. Here, we will achieve this goal by visualizing critical opioid circuits within the neocortex using automated large-scale single-neuron resolution imaging, optogenetic manipulations, and machine-vision behavior analysis. By achieving this goal, we will generate new dynamic frameworks for modeling the emergence of chronic pain. These frameworks will inform our translational targeting strategies using contemporary circuit disruption technologies with the ultimate goal of promoting endogenous opioid peptide release only in the desired brain region, circuit, and synapses relevant to pain processing, with temporal on-demand control. Therefore, successful implementation of our strategy could unleash technologies for disrupting cortical and/or sub-cortical circuit-specific pathologies that alleviate the suffering of chronic pain patients. The proposed research is well suited to the goals of the NIH New Innovator Award program. The innovative combination of these technical and high-risk strategies has the potential to transform our understanding of how chronic pain modulates brain networks and how to tightly-control them. Our projects encompass a number of significant advances, both in concept and in techniques that might fundamentally change the approach toward the rationale design of analgesics aimed at altering the neural circuits underlying the negative affective perception of pain. My interdisciplinary background in pain neurobiology, opioid pharmacology, and systems neuroscience, together with my demonstrated success in identifying the structure- function logic of neural circuits is the precise combination of skills that make me well suited to fully execute a project of this ambition. The NIH Director’s New Innovator Award would provide an invaluable jumpstart to my early career and support the continued trajectory of my research program into deconstructing the brain’s pain systems for the development of non-traditional strategies to treat the unpleasant affect and suf...