Angiotensin type 1a receptors on corticotropin‐releasing factor neurons contribute to the expression of conditioned fear1

Angiotensin II receptor type 1a (AT1aR) and corticotropin‐releasing factor (CRF) co‐localize in subsets of paraventricular nucleus (PVN) and central amygdala (CeA) neurons. Dense AT1aR and CRF expression is observed in the PVN and CeA of AT1aR‐GFP (green fluorescent protein) mice. Although generally associated with cardiovascular regulation, angiotensin II receptor type 1a (AT1aR) blockade in mouse models and humans has also been associated with enhanced fear extinction and decreased post‐traumatic stress disorder (PTSD) symptom severity, respectively. The mechanisms mediating these effects remain unknown, but may involve alterations in the activities of corticotropin‐releasing factor (CRF)‐expressing cells, which are known to be involved in fear regulation. To test the hypothesis that AT1aR signaling in CRFergic neurons is involved in conditioned fear expression, we generated and characterized a conditional knockout mouse strain with a deletion of the AT1aR gene from its CRF‐releasing cells (CRF‐AT1aR(−/−)). These mice exhibit normal baseline heart rate, blood pressure, anxiety and locomotion, and freeze at normal levels during acquisition of auditory fear conditioning. However, CRF‐AT1aR(−/−) mice exhibit less freezing than wild‐type mice during tests of conditioned fear expression—an effect that may be caused by a decrease in the consolidation of fear memory. These results suggest that central AT1aR activity in CRF‐expressing cells plays a role in the expression of conditioned fear, and identify CRFergic cells as a population on which AT1R antagonists may act to modulate fear extinction.