title: Decreasing Striatopallidal Pathway Function Enhances Motivation by Energizing the Initiation of Goal-Directed Action.
abstract: Altered dopamine D2 receptor (D2R) binding in the striatum has been associated with abnormal motivation in neuropsychiatric disorders, including schizophrenia. Here, we tested whether motivational deficits observed in mice with upregulated D2Rs (D2R-OEdev mice) are reversed by decreasing function of the striatopallidal "no-go" pathway. To this end, we expressed the Gαi-coupled designer receptor hM4D in adult striatopallidal neurons and activated the receptor with clozapine-N-oxide (CNO). Using a head-mounted miniature microscope we confirmed with calcium imaging in awake mice that hM4D activation by CNO inhibits striatopallidal function measured as disinhibited downstream activity in the globus pallidus. Mice were then tested in three operant tasks that address motivated behavior, the progressive ratio task, the progressive hold-down task, and outcome devaluation. Decreasing striatopallidal function in the dorsomedial striatum or nucleus accumbens core enhanced motivation in D2R-OEdev mice and control littermates. This effect was due to increased response initiation but came at the cost of goal-directed efficiency. Moreover, response vigor and the sensitivity to changes in reward value were not altered. Chronic activation of hM4D by administering CNO for 2 weeks in drinking water did not affect motivation due to a tolerance effect. However, the acute effect of CNO on motivation was reinstated after discontinuing chronic treatment for 48 h. Used as a therapeutic approach, striatopallidal inhibition should consider the risk of impairing goal-directed efficiency and behavioral desensitization.
  
  
  
  Motivation involves a directional component that allows subjects to efficiently select the behavior that will lead to an optimal outcome and an activational component that initiates and maintains the vigor and persistence of actions. Striatal output pathways modulate motivated behavior, but it remains unknown how these pathways regulate specific components of motivation. Here, we found that the indirect pathway controls response initiation without affecting response vigor or the sensitivity to changes in the reward outcome. A specific enhancement in the activational component of motivation, however, can come at the cost of goal-directed efficiency when a sustained response is required to obtain the goal. These data should inform treatment strategies for brain disorders with impaired motivation such as schizophrenia and Parkinson's disease.
authors.affiliation: Department of Psychiatry and.
authors.forename: Fernanda
authors.identifier: 0000-0003-2488-6849
authors.initials: F
authors.lastname: Carvalho Poyraz
authors.affiliation: Department of Psychiatry and Barnard College, New York, New York 10027.
authors.forename: Eva
authors.identifier: 0000-0003-4796-5785
authors.initials: E
authors.lastname: Holzner
authors.affiliation: Department of Psychiatry and.
authors.forename: Matthew R
authors.identifier: 0000-0002-9570-7505
authors.initials: MR
authors.lastname: Bailey
authors.affiliation: Department of Psychiatry and.
authors.forename: Jozsef
authors.initials: J
authors.lastname: Meszaros
authors.affiliation: Department of Psychiatry and.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Kenney
authors.affiliation: Department of Psychiatry and Division of Integrative Neuroscience, New York State Psychiatric Institute, New York, New York 10032, and.
authors.forename: Mazen A
authors.initials: MA
authors.lastname: Kheirbek
authors.affiliation: Department of Psychiatry and Barnard College, New York, New York 10027 ck491@cumc.columbia.edu balsam@columbia.edu.
authors.forename: Peter D
authors.identifier: 0000-0001-7581-5499
authors.initials: PD
authors.lastname: Balsam
authors.affiliation: Department of Psychiatry and Department of Pharmacology, College of Physicians and Surgeons, Columbia University, New York, New York 10032, Division of Molecular Therapeutics and ck491@cumc.columbia.edu balsam@columbia.edu.
authors.forename: Christoph
authors.initials: C
authors.lastname: Kellendonk
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism; D003024:Clozapine / Q000031:analogs & derivatives / Q000494:pharmacology; D003214:Conditioning, Classical; D003216:Conditioning, Operant; D003342:Corpus Striatum / Q000166:cytology / Q000502:physiology*; D005106:Exploratory Behavior / Q000502:physiology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D005917:Globus Pallidus / Q000166:cytology / Q000502:physiology*; D006040:Goals; D053444:Inhibitory Postsynaptic Potentials / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009042:Motivation / Q000502:physiology*; D009434:Neural Pathways / Q000502:physiology*; D009474:Neurons / Q000502:physiology; D017448:Receptors, Dopamine D2 / Q000235:genetics; D012054:Reinforcement, Psychology
chemical_list: D017448:Receptors, Dopamine D2; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D003024:Clozapine; C079149:clozapine N-oxide; D002118:Calcium
keywords: DREADD; calcium imaging; indirect pathway; motivation; striatum