Archival Report| Volume 86, ISSUE 12, P899-909, December 15, 2019

Angiotensin II Type 2 Receptor–Expressing Neurons in the Central Amygdala Influence Fear-Related Behavior

  • Author Footnotes
    1 ZY and APS contributed equally to this work.
    Zhe Yu
    1 ZY and APS contributed equally to this work.
    Department of Pharmacology and Physiology, The George Washington University, Washington, D.C.
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  • Author Footnotes
    1 ZY and APS contributed equally to this work.
    Adam P. Swiercz
    1 ZY and APS contributed equally to this work.
    Department of Pharmacology and Physiology, The George Washington University, Washington, D.C.
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  • Cassandra M. Moshfegh
    Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska
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  • Lauren Hopkins
    Department of Pharmacology and Physiology, The George Washington University, Washington, D.C.
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  • Jan Wiaderkiewicz
    Department of Psychology, University of Illinois at Chicago, Chicago, Illinois
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  • Robert C. Speth
    Department of Pharmacology and Physiology, College of Medicine, Georgetown University, Washington, D.C.

    Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, Florida
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  • Jeanie Park
    Division of Renal Medicine, Emory University School of Medicine, Atlanta Veterans Administration Hospital, Atlanta, Georgia
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  • Paul J. Marvar
    Address correspondence to Paul J. Marvar, Ph.D., Department of Pharmacology and Physiology, The George Washington University, 2300 I St. NW, Washington, DC 20037.
    Department of Pharmacology and Physiology, The George Washington University, Washington, D.C.

    Department of Psychiatry and Behavioral Sciences, The George Washington University, Washington, D.C.

    GW Institute for Neuroscience, The George Washington University, Washington, D.C.
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  • Author Footnotes
    1 ZY and APS contributed equally to this work.



      The renin-angiotensin system has been implicated in posttraumatic stress disorder; however, the mechanisms responsible for this connection and the therapeutic potential of targeting the renin-angiotensin system in posttraumatic stress disorder remain unknown. Using an angiotensin receptor bacterial artificial chromosome (BAC) and enhanced green fluorescent protein (eGFP) reporter mouse, combined with neuroanatomical, pharmacological, and behavioral approaches, we examined the role of angiotensin II type 2 receptor (AT2R) in fear-related behavior.


      Dual immunohistochemistry with retrograde labeling was used to characterize AT2R-eGFP+ cells in the amygdala of the AT2R-eGFP-BAC reporter mouse. Pavlovian fear conditioning and behavioral pharmacological analyses were used to demonstrate the effects of AT2R activation on fear memory in male C57BL/6 mice.


      AT2R-eGFP+ neurons in the amygdala were predominantly expressed in the medial amygdala and the medial division of the central amygdala (CeM), with little AT2R-eGFP expression in the basolateral amygdala or lateral division of the central amygdala. Characterization of AT2R-eGFP+ neurons in the CeM demonstrated distinct localization to gamma-aminobutyric acidergic projection neurons. Mice receiving acute intra–central amygdala injections of the selective AT2R agonist compound 21 prior to tests for cued or contextual fear expression displayed less freezing. Retrograde labeling of AT2R-eGFP+ neurons projecting to the periaqueductal gray revealed AT2R-eGFP+ neuronal projections from the CeM to the periaqueductal gray, a key brain structure mediating fear-related freezing.


      These findings suggest that CeM AT2R-expressing neurons can modulate central amygdala outputs that play a role in fear expression, providing new evidence for a novel angiotensinergic circuit in the regulation of fear.


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      Linked Article

      • Angiotensin II Signaling and Fear Extinction: Translational Evidence and Novel Receptor Targets
        Biological PsychiatryVol. 86Issue 12
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          There is an alarming paucity of new clinical studies for novel treatments for fear-based disorders and in particular posttraumatic stress disorder (PTSD). In the last 2 decades there has been a paradigm shift in exploring pharmacotherapeutics that are not simply static anxiolytics to be taken daily for symptom alleviation but that might instead act at key mechanisms of recovery like fear extinction. Such compounds may enhance natural extinction or be used specifically as adjunctive treatments for extinction-based therapies (e.g., exposure therapy).
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