# Brain Angiotensin II as a Mediator of Fear Memory and Cardiovascular Dysfunction

> **NIH NIH R01** · GEORGE WASHINGTON UNIVERSITY · 2020 · $507,051

## Abstract

Summary
Post-traumatic stress disorder (PTSD) is a debilitating neuropsychological disorder that develops as a result of exposure to
physical or psychological trauma. Emerging evidence suggests that PTSD is a strong predictor of cardiovascular disease
(CVD). Recent clinical studies suggest that blockade of the renin-angiotensin system (RAS)—crucial to blood pressure
control and fluid homeostasis—reduces the severity of PTSD symptoms. We have also demonstrated in a preclinical
mouse model of PTSD (Pavlovian fear conditioning) that angiotensin type 1 receptor (AT1R) inhibition attenuates
conditioned fear responses and facilitates the extinction of conditioned fear. Both AT1Rs and angiotensin type 2 receptors
(AT2Rs) are expressed in the amygdala, a brain region critical for fear learning and extinction. Whether different brains
AT receptor subtypes play a role in stress disorders such as PTSD is largely unknown, as is their impact on cardiovascular
dysfunction in fear. Our preliminary studies suggest, however, that activation and inhibition of brain AT2Rs have
opposing effects on the expression of fear memory in a preclinical mouse model of PTSD. Utilizing a multi-disciplinary
approach that combines physiological, molecular, analytical and behavioral neuroscience, this proposal will investigate
the role of endogenous brain angiotensin II, its receptors (AT1R and AT2R) and downstream signaling pathways in fear
memory and cardiovascular events associated with conditioned fear. Our working hypothesis is that the expression and
activity of brain angiotensin II and its receptors (AT1R / AT2R) are differentially and dynamically regulated during the
consolidation and recall of fear memory, and that these changes contribute to the balance of excitatory (“fear-on”) and
inhibitory (“fear-off”) signals required for the storage and retrieval of conditioned fear memories. The goals of this
proposal are two-fold: (1) Identify signaling pathways and gene networks that are both regulated by brain AT1R/AT2R
activation and implicated in the excitatory and inhibitory signaling necessary and sufficient for fear learning and retrieval;
(2) Determine the spatio-temporal contributions of AT1Rs and AT2Rs in key limbic and hypothalamic structures on the
expression of conditioned fear memories and cardiovascular alterations. We have 2 specific aims. Specific Aim 1: To
demonstrate that angiotensin II-induced activation of brain AT1Rs is necessary and required for the maintenance and
reconsolidation of fear memory and the conditioned cardiovascular responses. Specific Aim 2: To demonstrate that
activation of brain AT2Rs both stimulates fear-off neurons and reduces fear memory and adverse cardiovascular changes
during fear conditioning. These studies will further elucidate the mechanism(s) by which the renin-angiotensin system
acts as an important and novel mediator of PTSD pathology, and will provide new targets and opportunities for
pharmacological interventions in PTSD and ...

## Key facts

- **NIH application ID:** 9844969
- **Project number:** 5R01HL137103-03
- **Recipient organization:** GEORGE WASHINGTON UNIVERSITY
- **Principal Investigator:** Paul J Marvar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $507,051
- **Award type:** 5
- **Project period:** 2018-01-15 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9844969

## Citation

> US National Institutes of Health, RePORTER application 9844969, Brain Angiotensin II as a Mediator of Fear Memory and Cardiovascular Dysfunction (5R01HL137103-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9844969. Licensed CC0.

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