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

Abstract

Although generally associated with cardiovascular regulation, angiotensin II receptor type 1 (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 AT1R 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.

Angiotensin type 1a receptors in the paraventricular nucleus of the hypothalamus control cardiovascular reactivity and anxiety-like behavior in male mice

“…time that specific deletion of AT 1a from PVN neurons decreases hypothalamic CRH mRNA expression as well as anxiety-like behavior as assessed in the EPM. These results conflict with those of a recent report demonstrating that selective deletion of AT 1a from CRH cells had no effect on anxiety-like behavior in the EPM (31). While these discrepancies may be explained by differences in mouse strains, testing environment, and the degree of AT 1a inhibition, it is clear that within the brain AT 1a interacts with cells that produce CRH (3,33), and there is strong preclinical and clinical evidence that preventing this interaction may influence the etiology of stress-related disorders (9,14,36,59).…”

“…Such neurons are known to produce CRH, and, indeed, mRNAs for CRH and AT 1a colocalize in cells residing in the PVN (3). More recently, genetic reporting for AT 1a was used in conjunction with IHC to demonstrate that AT 1a -expressing neurons in the PVN colocalize with CRH immunoreactivity (31). In regard to functionality, acute injection or chronic infusion of exogenous ANG II into the brain increases CRH mRNA in the PVN (3,12), indicating that AT 1a stimulation in the PVN may regulate CRH expression.…”

Amygdala-Dependent Molecular Mechanisms of the Tac2 Pathway in Fear Learning

“…However, changes in freezing during the fear expression test after photostimulation of amygdala-Tac2-YFP-ChR2 during fear acquisition suggests that it may enhance fear memory consolidation. This opens many new questions for future experiments, such as examining the CeA-Tac2 projections to other areas related to fear memories including the paraventricular nucleus of the hypothalamus and bed nucleus of the stria terminalis, as well as investigating interactions with other neuropeptide systems involved in fear learning such as angiotensin II, oxytocin, or opiods (Andero, 2015;Bealer and Flynn, 2003;Hurt et al, 2015;Marvar et al, 2014).…”

Elastase-2 Knockout Mice Display Anxiogenic- and Antidepressant-Like Phenotype: Putative Role for BDNF Metabolism in Prefrontal Cortex

“…ANGII, acting through its receptors (AGTR1 and AGTR2), can regulate several behavioral responses. For instance, animals lacking AGTR1 receptors, display a facilitated extinction of conditioned fear [9]. On the other hand, animals lacking AGTR2 did not show any changes in step-down test, in the case used to evaluate learning behavior [10], but AGTR2-KOs displayed an anxiogenic phenotype in the elevated plus maze and light-dark box, attenuated by captopril, an inhibitor of ACE [11,12].…”