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

• Published in: Biological psychiatry (1969) Vol. 86; no. 12; pp. 899 - 909
• Main Authors: Yu, Zhe, Swiercz, Adam P., Moshfegh, Cassandra M., Hopkins, Lauren, Wiaderkiewicz, Jan, Speth, Robert C., Park, Jeanie, Marvar, Paul J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.12.2019
• Subjects: Amygdala; Angiotensin II; AT2R; Mouse; Pavlovian fear conditioning; PTSD; PTSD; Pavlovian fear conditioning; Amygdala; Mouse; Angiotensin II; AT2R; ATR
• ISSN: 0006-3223; 1873-2402
• DOI: 10.1016/j.biopsych.2019.05.027

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.