# Spreading Depolarizations and Neuronal Vulnerability

> **NIH NIH R01** · UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR · 2021 · $326,384

## Abstract

PROJECT SUMMARY
This project addresses fundamental mechanisms that contribute to the progression of acute brain injuries,
including stroke and trauma. Our long-term goal is to develop interventions that can be applied at late
time points, and which ultimately will be translatable to clinical studies to improve survival, and quality of
life of survivors. The project focuses on the phenomenon of Spreading Depolarization (SD), which has
recently emerged as a key contributor to the delayed progression of acute brain injuries. Recent clinical
recordings now imply that repetitive SD waves cause progression of damage for many days in stroke and
trauma patients. The challenge now is to understand how to block damaging SDs, or alternatively how to
support injured brain tissue to survive deleterious effects of SD. This project therefore addresses key
gaps in knowledge about mechanisms linking SD to injury. We will use brain slices and animal models to
identify fundamental mechanisms that underlie damaging effects of SD, and approaches to support
compromised tissues to recover from repeated SD episodes. Our central hypothesis is that agents that
selectively reduce the duration of individual SD events will reduce episodic glutamate and Ca2+-mediated
neuronal injury that occurs episodically with each SD event. Furthermore, preserving the propagation of
SDs through peri-infarct tissues will maintain beneficial effects of SD required for brain recovery. We will
test whether limiting glutamate transients and/or activation of NMDA-type glutamate receptors specifically
during the late phase of SD will support neuronal recovery after SD. Specific Aim 1 tests the hypothesis
that pathophysiological glutamate pulses are strictly limited to SD, and extended in metabolic
compromised tissues, due to presynaptic release and disruption of astrocytic regulation in metabolically
compromised slices. Specific Aim 2 tests the hypothesis that targeting the vulnerable phase of SD will
promote neuronal recovery metabolically compromised tissues. Neuronal Ca2+ loading will be evaluated,
and pharmacological interventions used to identify approaches to improve recovery of Ca2+ loading,
without impairing beneficial mechanisms. Specific Aim 3 makes key tests of these mechanisms in an in
vivo setting. Combined imaging and electrophysiological methods will be used throughout each aim, with
cellular mechanisms characterized in brain slices (Aims 1&2) and then tested in vivo (Aim 3). Genetically-
encoded sensors for glutamate and calcium will complement other single-neuron electrophysiological and
imaging approaches. Pharmacological approaches will be will be tested to identify mechanisms and
interventions that reduce deleterious effects of SD in metabolically compromised tissues. Successful
completion of these aims should identify fundamental mechanisms linking SD to cellular injury in
compromised tissues, and provide the basis for rational approaches that can be developed for
interventio...

## Key facts

- **NIH application ID:** 10083239
- **Project number:** 5R01NS106901-04
- **Recipient organization:** UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
- **Principal Investigator:** Claude W Shuttleworth
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $326,384
- **Award type:** 5
- **Project period:** 2018-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10083239

## Citation

> US National Institutes of Health, RePORTER application 10083239, Spreading Depolarizations and Neuronal Vulnerability (5R01NS106901-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10083239. Licensed CC0.

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