Connections of the Mouse Orbitofrontal Cortex and Regulation of Goal-Directed Action Selection by Brain-Derived Neurotrophic Factor

• Type of Material: Article
• Authors: Kelsey S. Zimmermann, Emory University; John A. Yamin, Emory University; Donald Rainnie, Emory University; Kerry Ressler, Emory University; Shannon L Gourley, Emory University
• Language: English
• Date: 2017-02-15
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2016 Society of Biological Psychiatry
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.biopsych.2015.10.026
• Title of Journal or Parent Work: Biological Psychiatry
• ISSN: 0006-3223
• Volume: 81
• Issue: 4
• Start Page: 366
• End Page: 377
• Grant/Funding Information: This work was supported by T32DA015040, P51OD11132, P30NS055077, DA034808, DA036737, Children’s Healthcare of Atlanta, the Brain and Behavior Research Foundation when Dr. Gourley was the Foundation’s Katherine Deschner Family Investigator, and an NIMH BRAINS award to Dr. Gourley (MH101477).
• Keywords: NUCLEUS-ACCUMBENS; Striatum; CORTICES; Neurosciences; Amygdala; RAT; HIPPOCAMPAL-NEURONS; PRELIMBIC CORTEX; BASOLATERAL AMYGDALA; RHESUS-MONKEY; Psychiatry; BDNF; Orbital; Action; Science & Technology; Life Sciences & Biomedicine; REINFORCER DEVALUATION; Neurosciences & Neurology; PREFRONTAL CORTEX; Outcome; Habit
• Research Categories: Biology, Neuroscience; Psychology, Behavioral

Abstract

Background 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. Methods 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. Results 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. Conclusions 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.