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Author Notes:

Correspondence should be addressed to Dr. Shannon L. Gourley, Yerkes National Primate Research Center, 954 Gatewood Drive NE, Atlanta, GA 30329. Email: shannon.l.gourley@emory.edu

S.L.G. and J.R.T. designed research;

S.L.G., K.S.Z., and A.G.A. performed research;

S.L.G. and J.R.T. analyzed data;

S.L.G., K.S.Z., A.G.A., and J.R.T. wrote the paper.

We thank Alexia Kedves, Tendi Hungwe, and Courtni Andrews for valuable assistance and the Duman laboratory for providing Bdnf+/− mice used here.

We also thank Dr. Glenn Schafe for critical comments on this manuscript and Dr. R. Jude Samulski at the University of North Carolina Viral Vector Core.

S.L.G. and K.S.Z. contributed equally to this work.

Subjects:

Research Funding:

This work was supported by National Institutes of Health Grants DA011717, DA027844 (J.R.T.), and MH101477 (S.L.G.), the Children's Center for Neuroscience Research (S.L.G.), and the Connecticut Department of Mental Health and Addiction Services (J.R.T.).

The Emory Viral Vector Core is supported by National Institute of Neurological Disorders and Stroke Core Facilities Grant P30NS055077.

The Yerkes National Primate Research Center is supported by P51OD011132.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Neurosciences
  • Neurosciences & Neurology
  • cue
  • dorsal striatum
  • neurotrophin
  • operant
  • orbital
  • progressive ratio
  • LONG-TERM POTENTIATION
  • HIGH-FREQUENCY STIMULATION
  • ACTIVATED PROTEIN-KINASE
  • NEUROTROPHIC FACTOR
  • PREFRONTAL CORTEX
  • SYNAPTIC-TRANSMISSION
  • NUCLEUS-ACCUMBENS
  • DENDRITIC GROWTH
  • COCAINE-SEEKING
  • ORBITAL CORTEX

The Medial Orbitofrontal Cortex Regulates Sensitivity to Outcome Value

Tools:

Journal Title:

Journal of Neuroscience

Volume:

Volume 36, Number 16

Publisher:

, Pages 4600-4613

Type of Work:

Article | Final Publisher PDF

Abstract:

An essential component of goal-directed decision-making is the ability to maintain flexible responding based on the value of a given reward, or “reinforcer.” The medial orbitofrontal cortex (mOFC), a subregion of the ventromedial prefrontal cortex, is uniquely positioned to regulate this process. We trained mice to nose poke for food reinforcers and then stimulated this region using CaMKII-driven Gs-coupled designer receptors exclusively activated by designer drugs (DREADDs). In other mice, we silenced the neuroplasticity-associated neurotrophin brain-derived neurotrophic factor (BDNF). Activation of Gs-DREADDs increased behavioral sensitivity to reinforcer devaluation, whereas Bdnf knockdown blocked sensitivity. These changes were accompanied by modifications in breakpoint ratios in a progressive ratio task, and they were recapitulated in Bdnf+/− mice. Replacement of BDNF selectively in the mOFC in Bdnf+/− mice rescued behavioral deficiencies, as well as phosphorylation of extracellular-signal regulated kinase 1/2 (ERK1/2). Thus, BDNF expression in the mOFC is both necessary and sufficient for the expression of typical effort allocation relative to an anticipated reinforcer. Additional experiments indicated that expression of the immediate-early gene c-fos was aberrantly elevated in the Bdnf+/− dorsal striatum, and BDNF replacement in the mOFC normalized expression. Also, systemic administration of an MAP kinase kinase inhibitor increased breakpoint ratios, whereas the addition of discrete cues bridging the response–outcome contingency rescued breakpoints in Bdnf+/− mice. We argue that BDNF–ERK1/2 in the mOFC is a key regulator of “online” goal-directed action selection. SIGNIFICANCE STATEMENT Goal-directed response selection often involves predicting the consequences of one's actions and the value of potential payoffs. Lesions or chemogenetic inactivation of the medial orbitofrontal cortex (mOFC) in rats induces failures in retrieving outcome identity memories (Bradfield et al., 2015), suggesting that the healthy mOFC serves to access outcome value information when it is not immediately observable and thereby guide goal-directed decision-making. Our findings suggest that the mOFC also bidirectionally regulates effort allocation for a given reward and that expression of the neurotrophin BDNF in the mOFC is both necessary and sufficient for mice to sustain stable representations of reinforcer value.

Copyright information:

© 2016 the authors.

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