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Central Ghrelin Resistance Permits the Overconsolidation of Fear Memory

  • Elia S. Harmatz
    Affiliations
    McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge

    Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge
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  • Lauren Stone
    Affiliations
    McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge

    Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge
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  • Seh Hong Lim
    Affiliations
    McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge

    Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge

    Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, Massachusetts
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  • Graham Lee
    Affiliations
    McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge

    Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge
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  • Anna McGrath
    Affiliations
    McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge

    Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge
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  • Barbara Gisabella
    Affiliations
    McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge

    Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge
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  • Xiaoyu Peng
    Affiliations
    McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge

    Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge
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  • Eliza Kosoy
    Affiliations
    McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge

    Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge
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  • Junmei Yao
    Affiliations
    McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge

    Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge
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  • Elizabeth Liu
    Affiliations
    McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge

    Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge
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  • Nuno J. Machado
    Affiliations
    McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge

    Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge

    Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal

    Faculty of Medicine, University of Coimbra, Coimbra, Portugal
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  • Veronica S. Weiner
    Affiliations
    McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge

    Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge
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  • Warren Slocum
    Affiliations
    McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge

    Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge
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  • Rodrigo A. Cunha
    Affiliations
    Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal

    Faculty of Medicine, University of Coimbra, Coimbra, Portugal
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  • Ki A. Goosens
    Correspondence
    Address correspondence to Ki A. Goosens, Ph.D., McGovern Institute for Brain Research, Massachusetts Institute of Technology, 43 Vassar Street, Cambridge, MA02139;
    Affiliations
    McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge

    Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge
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Published:November 28, 2016DOI:https://doi.org/10.1016/j.biopsych.2016.11.009

      Abstract

      Background

      There are many contradictory findings about the role of the hormone ghrelin in aversive processing, with studies suggesting that ghrelin signaling can both inhibit and enhance aversion. Here, we characterize and reconcile the paradoxical role of ghrelin in the acquisition of fearful memories.

      Methods

      We used enzyme-linked immunosorbent assay to measure endogenous acyl-ghrelin and corticosterone at time points surrounding auditory fear learning. We used pharmacological (systemic and intra-amygdala) manipulations of ghrelin signaling and examined several aversive and appetitive behaviors. We also used biotin-labeled ghrelin to visualize ghrelin binding sites in coronal brain sections of amygdala. All work was performed in rats.

      Results

      In unstressed rodents, endogenous peripheral acyl-ghrelin robustly inhibits fear memory consolidation through actions in the amygdala and accounts for virtually all interindividual variability in long-term fear memory strength. Higher levels of endogenous ghrelin after fear learning were associated with weaker long-term fear memories, and pharmacological agonism of the ghrelin receptor during the memory consolidation period reduced fear memory strength. These fear-inhibitory effects cannot be explained by changes in appetitive behavior. In contrast, we show that chronic stress, which increases both circulating endogenous acyl-ghrelin and fear memory formation, promotes profound loss of ghrelin binding sites in the amygdala and behavioral insensitivity to ghrelin receptor agonism.

      Conclusions

      These studies provide a new link between stress, a novel type of metabolic resistance, and vulnerability to excessive fear memory formation and reveal that ghrelin can regulate negative emotionality in unstressed animals without altering appetite.

      Keywords

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