# Measuring and manipulating stress-responsive neuronal activity to improve post-stroke outcomes

> **NIH NIH P20** · WEST VIRGINIA UNIVERSITY · 2022 · $196,960

## Abstract

Stroke is a severe ischemic neurovascular injury, with high rates of incidence in the developed world, high 
mortality, and long-term disability for survivors. It is critical for the development of improved interventions that 
novel therapies take into account post-ischemic stroke (IS) temporality to target appropriate time windows 
for intervention. Hypothalamic-pituitary-adrenal (HPA) axis activation, which effectuates the neuroendocrine 
stress response, is elevated in the hyperacute phase post-IS, increasing corticotropin releasing hormone 
(CRH) and corticosteroid (CORT) signaling. Elevated stress and HPA activity pre-IS is associated with worse 
outcomes, and hypercortisolism in the subacute and chronic phases is both typical and deleterious. The 
hippocampus provides crucial negative feedback regulation of the HPA axis, and secondary post-IS damage 
to the hippocampus is common. Secondary damage to the hippocampus post-IS may depend on corticoiddependent 
signaling; this could set up a feed-forward loop whereby post-stroke potentiation of stress 
signaling propagates itself, promoting further excitotoxicity and neurodegeneration. 
A growing body of evidence suggests that targeting CRH signaling could reduce post-IS morbidity and 
mortality; this includes advanced anti-CRH antibody treatment and CRF1R antagonism. CNS control of HPA 
axis activation is likely a major contributor to CRH and corticoid elevation post-IS. The ventral hippocampus 
regulates CRH production and HPA activation through excitatory projections to the bed nucleus of the stria 
terminalis (BNST), which in turn sends inhibitory projections to CRH+ neurons in the paraventricular nucleus 
(PVN) of the hypothalamus. This circuit represents a viable target for temporally-modulated interventions 
after stroke. In this proposal we will investigate how BNST and PVN neuronal activity changes acutely poststroke, 
and how modulating the activity of key neuronal populations in these nuclei will be effective in 
improving functional outcomes and reducing neuronal damage in the hippocampus and throughout the brain 
after ischemia.

## Key facts

- **NIH application ID:** 10793141
- **Project number:** 5P20GM109098-08
- **Recipient organization:** WEST VIRGINIA UNIVERSITY
- **Principal Investigator:** Morgan Stuart Bridi
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $196,960
- **Award type:** 5
- **Project period:** 2023-02-21 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10793141

## Citation

> US National Institutes of Health, RePORTER application 10793141, Measuring and manipulating stress-responsive neuronal activity to improve post-stroke outcomes (5P20GM109098-08). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10793141. Licensed CC0.

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