Abstract
Background
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.
Methods
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.
Results
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.
Conclusions
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.
Keywords
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Article info
Publication history
Published online: June 17, 2019
Accepted:
May 30,
2019
Received in revised form:
May 29,
2019
Received:
February 11,
2019
Identification
Copyright
© 2019 Society of Biological Psychiatry.
ScienceDirect
Access this article on ScienceDirectLinked Article
- Angiotensin II Signaling and Fear Extinction: Translational Evidence and Novel Receptor TargetsBiological PsychiatryVol. 86Issue 12
- PreviewThere 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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