Inhibiting Rho kinase promotes goal-directed decision making and blocks habitual responding for cocaine.

The prelimbic prefrontal cortex is necessary for associating actions with their consequences, enabling goal-directed decision making. We find that the strength of action-outcome conditioning correlates with dendritic spine density in prelimbic cortex, suggesting that new action-outcome learning involves dendritic spine plasticity. To test this, we inhibited the cytoskeletal regulatory factor Rho kinase. We find that the inhibitor fasudil enhances action-outcome memory, resulting in goal-directed behavior in mice that would otherwise express stimulus-response habits. Fasudil transiently reduces prelimbic cortical dendritic spine densities during a period of presumed memory consolidation, but only when paired with new learning. Fasudil also blocks habitual responding for cocaine, an effect that persists over time, across multiple contexts, and depends on actin polymerization. We suggest that Rho kinase inhibition promotes goal-oriented action selection by augmenting the plasticity of prelimbic cortical dendritic spines during the formation of new action-outcome memories.