Rabies screen reveals GPe control of cocaine-triggered plasticity

Identification of neural circuit changes contributing to behavioral plasticity has routinely been conducted on candidates that were preselected based on past results. Here we present an unbiased method for identifying experience-triggered circuit-level changes in neuronal ensembles. Using rabies virus monosynaptic tracing we mapped cocaine-induced global input changes onto ventral tegmental area (VTA) neurons. Cocaine increased rabies labeled inputs from the globus pallidus externus (GPe), a basal ganglia nucleus previously not known to participate in behavioral plasticity triggered by drugs of abuse. We demonstrated that cocaine increased GPe neuron activity, which accounted for the increase in GPe labeling. Inhibition of GPe activity revealed its vital role in two different forms of cocaine-triggered behavioral plasticity, at least in part via GPe-mediated disinhibition of VTA dopamine neuron activity. These results suggest that rabies-based unbiased screening of changes in input populations can identify previously unappreciated circuit elements that critically support behavioral adaptations.