PMID- 26786312 OWN - NLM STAT- MEDLINE DCOM- 20170810 LR - 20220309 IS - 1873-2402 (Electronic) IS - 0006-3223 (Print) IS - 0006-3223 (Linking) VI - 81 IP - 4 DP - 2017 Feb 15 TI - Connections of the Mouse Orbitofrontal Cortex and Regulation of Goal-Directed Action Selection by Brain-Derived Neurotrophic Factor. PG - 366-377 LID - S0006-3223(15)00956-7 [pii] LID - 10.1016/j.biopsych.2015.10.026 [doi] AB - 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. CI - Copyright (c) 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved. FAU - Zimmermann, Kelsey S AU - Zimmermann KS AD - 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. FAU - Yamin, John A AU - Yamin JA AD - Department of Pediatrics, Emory University, Atlanta, Georgia; Department of Yerkes National Primate Research Center, Emory University, Atlanta, Georgia. FAU - Rainnie, Donald G AU - Rainnie DG AD - 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. FAU - Ressler, Kerry J AU - Ressler KJ AD - 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. FAU - Gourley, Shannon L AU - Gourley SL AD - 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. LA - eng GR - P51 OD011132/OD/NIH HHS/United States GR - T32 DA015040/DA/NIDA NIH HHS/United States GR - R21 DA034808/DA/NIDA NIH HHS/United States GR - R01 MH101477/MH/NIMH NIH HHS/United States GR - R03 DA036737/DA/NIDA NIH HHS/United States GR - P30 NS055077/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20151118 PL - United States TA - Biol Psychiatry JT - Biological psychiatry JID - 0213264 RN - 0 (Brain-Derived Neurotrophic Factor) RN - EC 2.7.10.1 (Receptor, trkB) SB - IM CIN - Biol Psychiatry. 2017 Feb 15;81(4):282-284. PMID: 28089025 MH - Amygdala/cytology/physiology MH - Animals MH - Brain-Derived Neurotrophic Factor/*physiology MH - Conditioning, Operant/physiology MH - Corpus Striatum/cytology/physiology MH - Decision Making/*physiology MH - Extinction, Psychological/physiology MH - *Goals MH - Habits MH - Male MH - Mice MH - Mice, Inbred BALB C MH - Mice, Inbred C57BL MH - Neural Pathways/cytology/physiology MH - Neuroanatomical Tract-Tracing Techniques MH - Prefrontal Cortex/*cytology/*physiology MH - Receptor, trkB/physiology PMC - PMC4871791 MID - NIHMS752581 OTO - NOTNLM OT - Action OT - Amygdala OT - Habit OT - Orbital OT - Outcome OT - Striatum COIS- All authors report no biomedical financial interests or potential conflicts of interest. EDAT- 2016/01/21 06:00 MHDA- 2017/08/11 06:00 PMCR- 2018/02/15 CRDT- 2016/01/21 06:00 PHST- 2015/02/11 00:00 [received] PHST- 2015/10/27 00:00 [revised] PHST- 2015/10/27 00:00 [accepted] PHST- 2016/01/21 06:00 [pubmed] PHST- 2017/08/11 06:00 [medline] PHST- 2016/01/21 06:00 [entrez] PHST- 2018/02/15 00:00 [pmc-release] AID - S0006-3223(15)00956-7 [pii] AID - 10.1016/j.biopsych.2015.10.026 [doi] PST - ppublish SO - Biol Psychiatry. 2017 Feb 15;81(4):366-377. doi: 10.1016/j.biopsych.2015.10.026. Epub 2015 Nov 18.