title: GABAAα1-mediated plasticity in the orbitofrontal cortex regulates context-dependent action selection.
abstract: An essential aspect of goal-directed action selection is differentiating between behaviors that are more, or less, likely to be reinforced. Habits, by contrast, are stimulus-elicited behaviors insensitive to action-outcome contingencies and are considered an etiological factor in several neuropsychiatric disorders. Thus, isolating the neuroanatomy and neurobiology of goal-directed action selection on the one hand, and habit formation on the other, is critical. Using in vivo viral-mediated gene silencing, we knocked down Gabra1 in the orbitofrontal prefrontal cortex (oPFC) in mice, decreasing oPFC GABAAα1 expression, as well as expression of the synaptic marker PSD-95. Mice expressing Green Fluorescent Protein or Gabra1 knockdown in the adjacent M2 motor cortex served as comparison groups. Using instrumental response training followed by action-outcome contingency degradation, we then found that oPFC GABAAα1 deficiency impaired animals' ability to differentiate between actions that were more or less likely to be reinforced, though sensitivity to outcome devaluation and extinction were intact. Meanwhile, M2 GABAAα1 deficiency enhanced sensitivity to action-outcome relationships. Behavioral abnormalities following oPFC GABAAα1 knockdown were rescued by testing mice in a distinct context relative to that in which they had been initially trained. Together, our findings corroborate evidence that chronic GABAAα1 deficiency remodels cortical synapses and suggest that neuroplasticity within the healthy oPFC gates the influence of reward-related contextual stimuli. These stimuli might otherwise promote maladaptive habit-based behavioral response strategies that contribute to-or exacerbate-neuropsychiatric illness.
authors.affiliation: 1] Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA [2] Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA [3] Graduate Program in Neuroscience, Emory University, Atlanta, GA, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Swanson
authors.affiliation: 1] Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA [2] Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA.
authors.forename: Amanda G
authors.initials: AG
authors.lastname: Allen
authors.affiliation: 1] Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA [2] Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA [3] Graduate Program in Molecular and Systems Pharmacology, Emory University, Atlanta, GA, USA.
authors.forename: Lauren P
authors.initials: LP
authors.lastname: Shapiro
authors.affiliation: 1] Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA [2] Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA [3] Graduate Program in Neuroscience, Emory University, Atlanta, GA, USA [4] Department of Psychiatry and Behavioral Science, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Gourley
mesh_terms: D000818:Animals; D001288:Attention / Q000502:physiology; D003072:Cognition Disorders / Q000235:genetics; D003216:Conditioning, Operant / Q000502:physiology*; D003657:Decision Making / Q000502:physiology*; D000076122:Disks Large Homolog 4 Protein; D005108:Extinction, Psychological / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D051528:Guanylate Kinases / Q000378:metabolism; D066298:In Vitro Techniques; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009473:Neuronal Plasticity / Q000502:physiology*; D017397:Prefrontal Cortex / Q000166:cytology / Q000502:physiology*; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D012054:Reinforcement, Psychology; D016708:Synaptophysin / Q000378:metabolism
chemical_list: D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; C546241:Gabra1 protein, mouse; D008565:Membrane Proteins; D011963:Receptors, GABA-A; D016708:Synaptophysin; D049452:Green Fluorescent Proteins; D051528:Guanylate Kinases; C045073:Cre recombinase; D019426:Integrases