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Propranolol Decreases Fear Expression by Modulating Fear Memory Traces

  • Sofia Leal Santos
    Affiliations
    Department of Psychiatry, Columbia University Irving Medical Center, New York, New York

    Division of Systems Neuroscience, Research Foundation for Mental Hygiene Inc/New York State Psychiatric Institute, New York, New York

    Life and Health Sciences Research Institute, School of Medicine, University of Minho, Braga, Portugal

    ICVS/3B’s - PT Government Associate Laboratory, Braga, Portugal
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  • Author Footnotes
    1 MS and AMZ contributed equally to this work.
    Michelle Stackmann
    Footnotes
    1 MS and AMZ contributed equally to this work.
    Affiliations
    Neurobiology and Behavior Graduate Program, Columbia University, New York, New York
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  • Author Footnotes
    1 MS and AMZ contributed equally to this work.
    Andrea Muñoz Zamora
    Footnotes
    1 MS and AMZ contributed equally to this work.
    Affiliations
    Division of Systems Neuroscience, Research Foundation for Mental Hygiene Inc/New York State Psychiatric Institute, New York, New York
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  • Alessia Mastrodonato
    Affiliations
    Department of Psychiatry, Columbia University Irving Medical Center, New York, New York

    Division of Systems Neuroscience, Research Foundation for Mental Hygiene Inc/New York State Psychiatric Institute, New York, New York
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  • Allegra V. De Landri
    Affiliations
    Division of Systems Neuroscience, Research Foundation for Mental Hygiene Inc/New York State Psychiatric Institute, New York, New York

    Columbia College, Columbia University, New York, New York
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  • Nick Vaughan
    Affiliations
    Columbia College, Columbia University, New York, New York
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  • Briana K. Chen
    Affiliations
    Neurobiology and Behavior Graduate Program, Columbia University, New York, New York
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  • Marcos Lanio
    Affiliations
    Medical Scientist Training Program, Columbia University Irving Medical Center, New York, New York

    Neurobiology and Behavior Graduate Program, Columbia University, New York, New York
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  • Christine A. Denny
    Correspondence
    Address correspondence to Christine A. Denny, Ph.D.
    Affiliations
    Department of Psychiatry, Columbia University Irving Medical Center, New York, New York

    Division of Systems Neuroscience, Research Foundation for Mental Hygiene Inc/New York State Psychiatric Institute, New York, New York
    Search for articles by this author
  • Author Footnotes
    1 MS and AMZ contributed equally to this work.

      Abstract

      Background

      Posttraumatic stress disorder can develop after a traumatic event and results in heightened, inappropriate fear and anxiety. Although approximately 8% of the U.S. population is affected by posttraumatic stress disorder, only two drugs have been approved by the Food and Drug Administration to treat it, both with limited efficacy. Propranolol, a nonselective β-adrenergic antagonist, has shown efficacy in decreasing exaggerated fear, and there has been renewed interest in using it to treat fear disorders.

      Methods

      Here, we sought to determine the mechanisms by which propranolol attenuates fear by utilizing an activity-dependent tagging system, ArcCreERT2 x eYFP mice. 129S6/SvEv mice were administered a 4-shock contextual fear conditioning paradigm followed by immediate or delayed context reexposures. Saline or propranolol was administered either before or after the first context reexposure. To quantify hippocampal, prefrontal, and amygdalar memory traces, ArcCreERT2 x eYFP mice were administered a delayed context reexposure with either a saline or propranolol injection before context reexposure.

      Results

      Propranolol decreased fear expression only when administered before a delayed context reexposure. Fear memory traces were affected in the dorsal dentate gyrus and basolateral amygdala after propranolol administration in the ArcCreERT2 x eYFP mice. Propranolol acutely altered functional connectivity between the hippocampal, cortical, and amygdalar regions.

      Conclusions

      These data indicate that propranolol may decrease fear expression by altering network-correlated activity and by weakening the reactivation of the initial traumatic memory trace. This work contributes to the understanding of noradrenergic drugs as therapeutic aids for patients with posttraumatic stress disorder.

      Keywords

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