title: Connections of the Mouse Orbitofrontal Cortex and Regulation of Goal-Directed Action Selection by Brain-Derived Neurotrophic Factor.
abstract: Distinguishing between actions that are more likely or less likely to be rewarded is a critical aspect of goal-directed decision making. However, neuroanatomic and molecular mechanisms are not fully understood.
  
  
  
  We used anterograde tracing, viral-mediated gene silencing, functional disconnection strategies, pharmacologic rescue, and designer receptors exclusively activated by designer drugs (DREADDs) to determine the anatomic and functional connectivity between the orbitofrontal cortex (OFC) and the amygdala in mice. In particular, we knocked down brain-derived neurotrophic factor (Bdnf) bilaterally in the OFC or generated an OFC-amygdala "disconnection" by pairing unilateral OFC Bdnf knockdown with lesions of the contralateral amygdala. We characterized decision-making strategies using a task in which mice selected actions based on the likelihood that they would be reinforced. Additionally, we assessed the effects of DREADD-mediated OFC inhibition on the consolidation of action-outcome conditioning.
  
  
  
  As in other species, the OFC projects to the basolateral amygdala and dorsal striatum in mice. Bilateral Bdnf knockdown within the ventrolateral OFC and unilateral Bdnf knockdown accompanied by lesions of the contralateral amygdala impede goal-directed response selection, implicating BDNF-expressing OFC projection neurons in selecting actions based on their consequences. The tyrosine receptor kinase B agonist 7,8-dihydroxyflavone rescues action selection and increases dendritic spine density on excitatory neurons in the OFC. Rho-kinase inhibition also rescues goal-directed response strategies, linking neural remodeling with outcome-based decision making. Finally, DREADD-mediated OFC inhibition weakens new action-outcome memory.
  
  
  
  Activity-dependent and BDNF-dependent neuroplasticity within the OFC coordinate outcome-based decision making through interactions with the amygdala. These interactions break reward-seeking habits, a putative factor in multiple psychopathologies.
authors.affiliation: Department of Pediatrics, Emory University, Atlanta, Georgia; Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, Georgia; Department of Yerkes National Primate Research Center, Emory University, Atlanta, Georgia; Department of Graduate Program in Neuroscience, Emory University, Atlanta, Georgia.
authors.forename: Kelsey S
authors.initials: KS
authors.lastname: Zimmermann
authors.affiliation: Department of Pediatrics, Emory University, Atlanta, Georgia; Department of Yerkes National Primate Research Center, Emory University, Atlanta, Georgia.
authors.forename: John A
authors.initials: JA
authors.lastname: Yamin
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, Georgia; Department of Yerkes National Primate Research Center, Emory University, Atlanta, Georgia; Department of Graduate Program in Neuroscience, Emory University, Atlanta, Georgia.
authors.forename: Donald G
authors.initials: DG
authors.lastname: Rainnie
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, Georgia; Department of Yerkes National Primate Research Center, Emory University, Atlanta, Georgia; Department of Graduate Program in Neuroscience, Emory University, Atlanta, Georgia; Department of Howard Hughes Medical Institute, Bethesda, Maryland.
authors.forename: Kerry J
authors.initials: KJ
authors.lastname: Ressler
authors.affiliation: Department of Pediatrics, Emory University, Atlanta, Georgia; Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, Georgia; Department of Yerkes National Primate Research Center, Emory University, Atlanta, Georgia; Department of Graduate Program in Neuroscience, Emory University, Atlanta, Georgia. Electronic address: shannon.l.gourley@emory.edu.
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Gourley
mesh_terms: D000679:Amygdala / Q000166:cytology / Q000502:physiology; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000502:physiology*; D003216:Conditioning, Operant / Q000502:physiology; D003342:Corpus Striatum / Q000166:cytology / Q000502:physiology; D003657:Decision Making / Q000502:physiology*; D005108:Extinction, Psychological / Q000502:physiology; D006040:Goals; D006184:Habits; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009434:Neural Pathways / Q000166:cytology / Q000502:physiology; D056347:Neuroanatomical Tract-Tracing Techniques; D017397:Prefrontal Cortex / Q000166:cytology* / Q000502:physiology*; D020813:Receptor, trkB / Q000502:physiology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D020813:Receptor, trkB
keywords: Action; Amygdala; Habit; Orbital; Outcome; Striatum