Cortico-striatal activity driving compulsive reward seeking

Abstract Addicted individuals compulsively seek drugs. Cortico-striatal projections have been implicated in persevering to seek rewards even when punished. The temporo-spatial determinants of the activity underlying the compulsive reward seeking however remains elusive. Here we trained mice in a seek-take chain, rewarded by optogenetic dopamine neuron self-stimulation (oDASS). Mice that persevered when seeking was punished, exhibited an increased AMPA/NMDA ratio selectively at orbitofrontal cortex (OFC) to dorsal striatum (DS) synapses. In addition, an activity peak of spiny projection neurons (SPNs) in the DS at the moment of signalled reward availability was detected. Chemogenetic inhibition of OFC neurons curbed the activity peak and reduced punished reward seeking, as did optogenetic hyperpolarization of SPNs time locked to the cue predicting reward availability, establishing a causal link. Taken together, we conclude that the strengthening of OFC-DS synapses drives SPNs activity when a reward predictive cue is delivered, thus encouraging reward seeking in subsequent trials.