# CRH Dysregulation of Brainstem Autonomic Circuits Increases SUDEP Risk

> **NIH NIH R01** · TUFTS UNIVERSITY BOSTON · 2024 · $590,755

## Abstract

Project Summary
The overarching objective of this proposal is to investigate a novel mechanism for sudden unexpected death in
epilepsy (SUDEP). Our laboratory recently made the unexpected discovery that mice genetically engineered for
hyperactive stress circuits exhibit an increased incidence of SUDEP, a finding that was verified to be
translationally relevant from observed neuroendocrine abnormalities in patients that died of confirmed or
suspected SUDEP. Given that both stress and SUDEP link to disruption of central circuits responsible for the
regulation of cardiorespiratory function, we propose that exaggerated activity of central stress circuits on
downstream brainstem autonomic control centers represents a novel mechanism contributing to increased
SUDEP risk. Corticotropin releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus
(PVN) are at the apex of the stress axis and project directly to brainstem regions critical for autonomic regulation,
including the nucleus of the solitary tract (PVN-NTSCRH). PVN-NTSCRH has a well-established role in integrating
cardiorespiratory responses to stress, making them a likely driver of cardiorespiratory dysfunction related to
central stress axis hyperexcitability and, potentially, SUDEP. In fact, our preliminary data demonstrate that
chemogenetic activation of PVN-NTSCRH increases SUDEP incidence. The current application will build on the
expertise of, Drs. Jamie Maguire and Carie Boychuk, to test the hypothesis that HPA axis hyperexcitability in
chronically epileptic mice increases the risk for SUDEP through increased PVN-NTSCRH drive, exaggerating
cardiac vagal output during homeostatic challenges. We will investigate this hypothesis by examining whether
there is increased PVN-NTSCRH drive associated with SUDEP risk and whether excessive activation of this
pathway is sufficient to increase SUDEP incidence. We will interrogate potential, novel pathophysiological
mechanisms mediating the impact of hyperactive stress circuits on SUDEP risk by examining the impact on
cardiac vagal output. Finally, we will investigate whether environmental factors associated with hyperactive
stress circuits, such as chronic stress, can impact cardiac vagal function and SUDEP risk. This application has
the potential to uncover a novel mechanism contributing to SUDEP risk, which may also be relevant to other
forms of sudden death.

## Key facts

- **NIH application ID:** 10749913
- **Project number:** 5R01NS102937-07
- **Recipient organization:** TUFTS UNIVERSITY BOSTON
- **Principal Investigator:** Jamie Lynn Maguire
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $590,755
- **Award type:** 5
- **Project period:** 2022-12-09 → 2027-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10749913

## Citation

> US National Institutes of Health, RePORTER application 10749913, CRH Dysregulation of Brainstem Autonomic Circuits Increases SUDEP Risk (5R01NS102937-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10749913. Licensed CC0.

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