# The role of brainstem projecting extended amygdala neurons in sudden unexpected death in epilepsy

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2024 · $491,027

## Abstract

Sudden unexpected death in epilepsy (SUDEP) is the most common cause of death in patients with refractory
epilepsy. Currently, it is impossible to predict or prevent SUDEP. However, SUDEPs that have occurred in
monitored settings were characterized by hypoventilation and apnea prior to cardiac dysfunction, implicating
seizure-related respiratory dysfunction as a critical factor. Human intracranial data suggests the amygdala as a
forebrain structure that may be important for respiratory control and involved in seizure-related respiratory
dysfunction. Understanding the neural circuit mechanisms involving amygdalar structures that underlies
seizure-related respiratory dysfunction that leads to hypoventilation and death is critical to advancing SUDEP
prevention options, which currently do not exist. Our long-term goal is to identify the neural circuits underlying
seizure-related respiratory dysfunction to predict and prevent sudden death. The main objective of the
proposed project is to delineate brainstem projecting extended amygdalar neurons involved in seizure-related
respiratory dysfunction and arrest. Preliminary data in a mouse model of SUDEP show that the extended
amygdalar structure the bed nucleus of the stria terminalis (BNST) represents a potential mediator underlying
seizure-related respiratory dysfunction. Our hypothesis is that BNST activation during seizures contributes to
seizure-related respiratory dysfunction, respiratory arrest, and death via downstream activation in the
parabrachial nucleus (PBN) of the pons. This hypothesis will be tested via the following specific aims in a
model of SUDEP: (1) Characterize the role of BNST and BNSTPBN activation in respiratory dysfunction in a
model of SUDEP. (2) Determine the effect of acute BNST inhibition on seizure-induced respiratory dysfunction
in a model of SUDEP. In Aim 1, we will use a viral approach to selectively identify and dissect BNST neurons
activated by seizures as well as determine the relationship between BNST activation and respiratory
dysfunction during seizures. In Aim 2, we will use in vivo optogenetic inactivation of the BNST to determine the
critical period of activity for respiratory depression and potential intervention. At the successful completion of
the proposed research, the expected outcomes are characterization of seizure-activated BNST-brainstem
circuitry and the temporal relationship of BNST activation to seizure-related respiratory dysfunction to
determine sufficiency and the timepoint necessary for acute BNST activation in this effect. The proposed
research is conceptually innovative through its focus on BNST circuitry in terms of SUDEP pathophysiology
and technically innovative through the use of cutting-edge systems neuroscience techniques applied to
SUDEP including fiber photometry, virally-mediated Targeted Recombination in Active Populations (TRAP) and
in vivo optogenetics. These results are expected to have a significant impact on our current understan...

## Key facts

- **NIH application ID:** 10930106
- **Project number:** 5R01NS133169-02
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** William Paul Nobis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $491,027
- **Award type:** 5
- **Project period:** 2023-09-15 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10930106

## Citation

> US National Institutes of Health, RePORTER application 10930106, The role of brainstem projecting extended amygdala neurons in sudden unexpected death in epilepsy (5R01NS133169-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10930106. Licensed CC0.

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