title: Endocannabinoid Modulation of Orbitostriatal Circuits Gates Habit Formation.
abstract: Everyday function demands efficient and flexible decision-making that allows for habitual and goal-directed action control. An inability to shift has been implicated in disorders with impaired decision-making, including obsessive-compulsive disorder and addiction. Despite this, our understanding of the specific molecular mechanisms and circuitry involved in shifting action control remains limited. Here we identify an endogenous molecular mechanism in a specific cortical-striatal pathway that mediates the transition between goal-directed and habitual action strategies. Deletion of cannabinoid type 1 (CB1) receptors from cortical projections originating in the orbital frontal cortex (OFC) prevents mice from shifting from goal-directed to habitual instrumental lever pressing. Activity of OFC neurons projecting to dorsal striatum (OFC-DS) and, specifically, activity of OFC-DS terminals is necessary for goal-directed action control. Lastly, CB1 deletion from OFC-DS neurons prevents the shift from goal-directed to habitual action control. These data suggest that the emergence of habits depends on endocannabinoid-mediated attenuation of a competing circuit controlling goal-directed behaviors.
authors.affiliation: Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA; Department of Psychology, Neuroscience Graduate Program, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Gremel
authors.affiliation: Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Jessica H
authors.initials: JH
authors.lastname: Chancey
authors.affiliation: Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Brady K
authors.initials: BK
authors.lastname: Atwood
authors.affiliation: Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Guoxiang
authors.initials: G
authors.lastname: Luo
authors.affiliation: Department of Brain and Cognitive Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Rachael
authors.initials: R
authors.lastname: Neve
authors.affiliation: Department of Bioengineering, Stanford University, Stanford, CA 94305, USA.
authors.forename: Charu
authors.initials: C
authors.lastname: Ramakrishnan
authors.affiliation: Department of Bioengineering, Stanford University, Stanford, CA 94305, USA.
authors.forename: Karl
authors.initials: K
authors.lastname: Deisseroth
authors.affiliation: Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: lovindav@mail.nih.gov.
authors.forename: David M
authors.initials: DM
authors.lastname: Lovinger
authors.affiliation: Champalimaud Neuroscience Programme, Champalimaud Institute for the Unknown, Lisbon 1400-038, Portugal. Electronic address: rui.costa@neuro.fchampalimaud.org.
authors.forename: Rui M
authors.initials: RM
authors.lastname: Costa
mesh_terms: D000818:Animals; D003024:Clozapine / Q000031:analogs & derivatives / Q000494:pharmacology; D003216:Conditioning, Operant; D003342:Corpus Striatum / Q000502:physiology*; D063388:Endocannabinoids / Q000502:physiology*; D055785:Gene Knockdown Techniques; D006184:Habits; D008297:Male; D051379:Mice; D009433:Neural Inhibition / Q000502:physiology; D009434:Neural Pathways / Q000187:drug effects / Q000502:physiology; D017397:Prefrontal Cortex / Q000502:physiology*; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000502:physiology*
chemical_list: D063388:Endocannabinoids; D043884:Receptor, Cannabinoid, CB1; D003024:Clozapine; C079149:clozapine N-oxide