# Interrogating stress-relieving neural circuits to alleviate cardiovascular disease

> **NIH NIH R35** · UNIVERSITY OF FLORIDA · 2020 · $733,362

## Abstract

Project Summary
Stressful life events are linked to the etiology of cardiovascular disease (CVD), which is the leading cause of
death in the U.S. The mechanisms by which stress causes pathophysiology contributing to CVD are poorly
understood and effective therapeutics that relieve stress and improve cardiovascular health are lacking. A
premise of this proposal is that exploration of the neural circuits controlling the perception of stress may provide
insight towards mechanisms underlying CVD and interventions aimed at its reversal. Causally-linking patterns
of neural activity to stress and the development of CVD in humans is challenging. However, preclinical studies
using laboratory mice that implement modern neuroscience and genetic technologies to excite or inhibit specific
neural circuits make causally-linking neural activity and indices of stress responsiveness achievable. Using
genetically-modified mice, we revealed that the activity of neurons that express genes encoding particular
angiotensin receptor subtypes is coupled to cardiovascular, neuroendocrine and behavioral responses to stress.
Specifically, we discovered that neurons expressing the angiotensin type-2 (AT2R) and Mas receptor (MasR)
densely populate cortical and limbic brain regions controlling the perception of psychological stress and that
excitation of these neurons decreases blood pressure, heart rate, circulating levels of corticosterone and anxiety-
like behavior. In the periphery, we discovered that the nodose ganglion is densely populated by neurons
expressing the angiotensin type 1a receptor (AT1R). These neurons function as primary baroreceptor afferents
and excitation of these neurons lowers blood pressure, heart rate and energy expenditure. Collectively, these
observations have led to the overall hypothesis that excitation of particular neuronal populations that
express the AT1R, AT2R or MasR alters the perception of stress to protect against CVD. Experiments will
use the Cre-LoxP system in mice with a cadre of modern neuroscience techniques and classical systems
physiology to confirm or refute this hypothesis. Initial experiments utilize Cre-diver mice with virally-mediated
gene transfer and in vivo optogenetics to determine whether the excitation or inhibition of neurons that express
AT1R, AT2R, or MasR attenuates or exacerbates stress responding. Subsequent experiments use a model of
stress-induced pathophysiology to evaluate how the structure and function of neurons that express the AT1R,
AT2R or MasR is altered by disease. The final experiments attempt to alleviate stress-induced pathophysiology
with optogenetic, genetic or pharmacological manipulations that alter the excitability of neurons that express the
AT1R, AT2R or MasR. We anticipate that the proposed research will reveal, at a detailed and mechanistic level,
neural circuits that provide stress relief, thereby guiding development of novel therapeutics for CVD.

## Key facts

- **NIH application ID:** 9893161
- **Project number:** 1R35HL150750-01
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Eric Gerald Krause
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $733,362
- **Award type:** 1
- **Project period:** 2020-02-05 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9893161

## Citation

> US National Institutes of Health, RePORTER application 9893161, Interrogating stress-relieving neural circuits to alleviate cardiovascular disease (1R35HL150750-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9893161. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*