Drugs of abuse hijack a mesolimbic pathway that processes homeostatic need

Abstract

AbstractAddiction prioritizes drug use over innate needs by “hijacking” brain circuits that direct motivation, but how this develops remains unclear. Using whole-brain FOS mapping andin vivosingle-neuron calcium imaging, we find that drugs of abuse augment ensemble activity in the nucleus accumbens (NAc) and disorganize overlapping ensemble responses to natural rewards in a cell-type-specific manner. Combining “FOS-Seq”, CRISPR-perturbations, and snRNA-seq, we identifyRhebas a shared molecular substrate that regulates cell-type-specific signal transductions in NAc while enabling drugs to suppress natural reward responses. Retrograde circuit mapping pinpoints orbitofrontal cortex which, upon activation, mirrors drug effects on innate needs. These findings deconstruct the dynamic, molecular, and circuit basis of a common reward circuit, wherein drug value is scaled to promote drug-seeking over other, normative goals.