# A novel experimental model of chronic stress and hypertension for studying dementia-related neurovascular dysfunction in the hippocampus

> **NIH NIH R03** · UNIVERSITY OF VERMONT & ST AGRIC COLLEGE · 2021 · $156,000

## Abstract

Project summary
Small vessel diseases of the brain (SVDs) together with Alzheimer’s disease (AD) are the major causes of
dementia. The prevalence of AD and related dementias is increasing worldwide, and the development of effective
treatments is hampered by an inadequate understanding of the underlying pathophysiological mechanisms.
Psychological/social stress and associated hypertension are major drivers of brain vascular dysfunction, which
leads to impaired blood perfusion and compromised blood brain barrier (BBB) integrity in specific brain regions,
notably including the hippocampus. However, developing an animal model that captures the pathophysiological
aspects of the continuous, relentless stress experienced by humans has proven difficult. Here, we propose to
characterize a novel experimental model – the PVN-BDNF model – that addresses this problem and allows
investigation of chronic stress-related neuro-glial-vascular dysfunction in the hippocampus, a highly relevant
brain region in AD pathophysiology. This model uses viral vectors to drive long-term overexpression of brain-
derived neurotrophic factor (BDNF) in the paraventricular nucleus of the hypothalamus (PVN). Although BDNF
in the hippocampus has traditionally been considered beneficial owing to its role in learning and memory, BDNF
in the PVN plays a central, but less-appreciated, role in stimulating both major stress pathways – the sympathetic
nervous system and the hypothalamic-pituitary-adrenal (HPA) axis – resulting in chronically elevated blood
pressure and plasma glucocorticoid levels. High plasma glucocorticoid levels in turn downregulate hippocampal
BDNF levels; thus, the PVN-BDNF model recreates the imbalance in hypothalamic (increased) and hippocampal
(decreased) BDNF expression characteristic of neuroendocrine stress responses. Hypertension and elevated
glucocorticoids exert detrimental effects on cerebrovascular function by impeding communication within the
neurovascular unit (NVU), a functionally and structurally complex system in which glial cells (mainly astrocytes)
relay information between neurons and the surrounding vasculature to support neuronal and synaptic function.
Accordingly, disruption of NVU mechanisms results in impaired BBB function, perturbed microvascular
architecture and diminished vasodilator responses to neuronal activity. Using novel imaging and analytic tools,
we will characterize NVU dysfunction in PVN-BDNF model mice by analyzing BBB integrity, microvascular
architecture, astrocytic and endothelial Ca2+ signaling events, and neuronal activity-dependent vasodilator
responses.

## Key facts

- **NIH application ID:** 10194742
- **Project number:** 1R03AG072016-01
- **Recipient organization:** UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
- **Principal Investigator:** Benedek Erdos
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $156,000
- **Award type:** 1
- **Project period:** 2021-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10194742

## Citation

> US National Institutes of Health, RePORTER application 10194742, A novel experimental model of chronic stress and hypertension for studying dementia-related neurovascular dysfunction in the hippocampus (1R03AG072016-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10194742. Licensed CC0.

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