LAUSR

Significance Persistent alterations to neural circuitry may help to explain why opiate abuse liability is higher among individuals with a history of chronic exposure. In this study, we employ a unique combination of computational approaches to understand how opiate-induced reorganization of network connectivity is supported by transcriptional and structural features of the brain. We identify a persistent reduction in FOS correlation network strength following opiate dependence and determine that correlated gene expression is predictive of opiate-induced changes in network connectivity. Further, we identify brain regions that influence the transition between opiate-naïve and opiate-dependent states. These findings establish a link between gene expression and changes in brain connectivity in response to opioids. Opioid addiction is a chronic, relapsing disorder associated with persistent changes in brain plasticity. Reconfiguration of neuronal connectivity may explain heightened abuse liability in individuals with a history of chronic drug exposure. To characterize network-level changes in neuronal activity induced by chronic opiate exposure, we compared FOS expression in mice that are morphine-naïve, morphine-dependent, or have undergone 4 wk of withdrawal from chronic morphine exposure, relative to saline-exposed controls. Pairwise interregional correlations in FOS expression data were used to construct network models that reveal a persistent reduction in connectivity strength following opiate dependence. Further, we demonstrate that basal gene expression patterns are predictive of changes in FOS correlation networks in the morphine-dependent state. Finally, we determine that regions of the hippocampus, striatum, and midbrain are most influential in driving transitions between opiate-naïve and opiate-dependent brain states using a control theoretic approach. This study provides a framework for predicting the influence of specific therapeutic interventions on the state of the opiate-dependent brain.