Rabies screen reveals GPe control of cocaine-triggered plasticity

Identification of neural circuit changes that contribute to behavioural plasticity has routinely been conducted on candidate circuits that were preselected on the basis of previous results. Here we present an unbiased method for identifying experience-triggered circuit-level changes in neuronal ensembles in mice. Using rabies virus monosynaptic tracing, we mapped cocaine-induced global changes in inputs onto neurons in the ventral tegmental area. Cocaine increased rabies-labelled inputs from the globus pallidus externus (GPe), a basal ganglia nucleus not previously known to participate in behavioural plasticity triggered by drugs of abuse. We demonstrated that cocaine increased GPe neuron activity, which accounted for the increase in GPe labelling. Inhibition of GPe activity revealed that it contributes to two forms of cocaine-triggered behavioural plasticity, at least in part by disinhibiting dopamine neurons in the ventral tegmental area. These results suggest that rabies-based unbiased screening of changes in input populations can identify previously unappreciated circuit elements that critically support behavioural adaptations. A rabies virus-based monosynaptic tracing method is used to show that the external globus pallidus plays a critical role in cocaine-induced behavioural plasticity. Tracing a series of unexpected neural events Changes in neural circuit plasticity in response to cocaine experiences have been identified in previous studies, yet there are no unbiased methods for screening neural circuits that could potentially change following drug administration. Rob Malenka and colleagues conducted monosynaptic tracing of the rabies virus in mice in order to label and map changes in the neural ensembles connecting to neurons in the ventral tegmental area following the administration of cocaine, which was injected one day ahead of the rabies virus. The exercise revealed a previously unknown enhancement of activity between the globus pallidus externus and the ventral tegmental area, suggesting that this connectivity tracing strategy could be used to reveal underappreciated circuit changes in response to various behavioural experiences.