PROJECT SUMMARY Many of the 54,000 opioid-related deaths in 2017 were due to respiratory depression. The specific mechanisms by which opioids depress breathing are not fully understood. Current hypotheses focus on single areas within the respiratory network, such as the pons or pre-Bötzinger complex. However, perturbation of these areas has not fully predicted the actions of opioids to depress breathing. Based on preliminary data and model simulations we have developed the following hypothesis: opioid administration induces reconfiguration of the respiratory network in a dose-dependent manner. This reconfiguration involves alterations in the pattern of discharge of some neurons (discharge identity), loss of synchrony among interconnected inspiratory neuron networks in the ventral respiratory column (VRC) and altered functional connectivity within and between respiratory areas in the brainstem. This project has three Specific Aims: 1) Determine the influence of opioids on functional network interactions between neurons in the nucleus tractus solitarius (NTS), raphe, pontine, and VRC that regulate motor output to respiratory muscles, 2) Determine the role of opioids in modulating synchrony within inspiratory neuron circuits in the VRC, 3) Generate a network-scale model of the brainstem circuits that control breathing in the presence of opioids. We anticipate this project will lead to: a) identification of elements of the respiratory control network that participate in opioid-mediated reconfiguration, b) delineation of functional relationships between E-T/NBM in the pons, raphe, NTS area and VRC neurons that contribute to depression of breathing by opioids, c) the role of impaired synchrony in inspiratory neuron networks in reduced motor drive produced by opioids, and d) new predictive model will be produced featuring the network-scale mechanisms that contribute to opioid depression of breathing. This new knowledge will provide a critical step in understanding the network scale mechanisms of action of opioids to depress breathing.