Cytoskeletal Determinants of Stimulus-Response Habits

Abstract

Both humans and rodents can learn to associate specific actions with their outcomes, but with repeated performance or exposure to pathological stimuli, such as drugs of abuse, behaviors assume stimulus-elicited, or "habitual," qualities. Psychostimulants remodel dorsal striatal neurons, critical determinants of decision-making strategies, but cytoskeletal mechanisms associated with drug-induced habit formation are largely unknown. We first show that cocaine can bias decision-making strategies toward stimulus-response habits by interfering with learning about the predictive relationship between a response and its outcome. In the dorsomedial, but not ventral, striatum, cocaine decreases PSD95 expression and phosphorylation of cortactin, a cytoskeletal regulator that interacts with, and is phophorylated by, the Abl2 (Arg) kinase. Based on this pattern, we inhibited Abl-family kinase signaling in the dorsomedial striatum, impairing new response-outcome learning. Consistent with evidence that the dorsomedial striatum promotes response-outcome decision-making while the dorsolateral compartment promotes stimulus-response habits, inhibition of Abl-family kinases in the dorsolateral striatum reinstates goal sensitivity in over-trained "habitual" mice. These findings provide a structural mechanism by which even acute exposure to drugs of abuse can reorganize behavioral response strategies and promote outcome-insensitive stimulus-response habits.