title: 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.
authors.affiliation: Interdepartmental Neuroscience Program, Division of Molecular Psychiatry, Department of Psychiatry, Yale University, New Haven, Connecticut 06508, USA.
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Gourley
authors.forename: Anastasia
authors.initials: A
authors.lastname: Olevska
authors.forename: Jessica
authors.initials: J
authors.lastname: Gordon
authors.forename: Jane R
authors.initials: JR
authors.lastname: Taylor
mesh_terms: D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D051356:Cortactin / Q000378:metabolism*; D003599:Cytoskeleton / Q000187:drug effects* / Q000378:metabolism; D003657:Decision Making / Q000187:drug effects; D000076122:Disks Large Homolog 4 Protein; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D051528:Guanylate Kinases / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D051356:Cortactin; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D018765:Dopamine Uptake Inhibitors; D008565:Membrane Proteins; D051528:Guanylate Kinases; D003042:Cocaine