# Clinically unscreened vasculo-glial-neuronal coupling is critical for physiological brain function

> **NIH NIH R01** · AUGUSTA UNIVERSITY · 2021 · $332,500

## Abstract

While much effort has been devoted to the understanding of mechanisms linked to activity-evoked changes in
cerebral blood flow (CBF) namely, functional hyperemia and neurovascular coupling, less is understood about
the processes controlling basal CBF and resting neuronal activity. Considering that chronic brain hypoperfusion
contributes to cognitive impairments our group is interested in studying the cellular mechanisms by which
changes in steady-state vascular tone, and thus perfusion, affect resting neuronal function. Our central
hypothesis is that constitutive mechanisms defining physiological vasculo-glial-neuronal coupling (VGNC) are
impaired in disease. Using a multidisciplinary approach we will address the following three aims: Aim1: Test the
hypothesis that aberrant astrocytes Ca2+ signaling in disease impairs VGNC. Astrocytes constitutively
integrate perfusion status to the brain and, through the release of gliotransmitter signals, adjust resting neuronal
activity accordingly. Impairments in VGNC places the brain at risk for glutamate excitotoxicity, inflammation and
oxidative stress. Using GLAST-CreERT2; R26-lsl-GCaMP3 mice (in vivo and in vitro) we will measure astrocytic
Ca2+ events in response to parenchymal arteriole vascular reactivity changes evoked by ↑or↓ in lumen
flow/pressure in brain slices from control and cerebral hypoperfused (bilateral common carotid artery stenosis)
mice. A pharmacological approach will be used to define key signal mechanisms (i.e. P2Y1 and TRPV4 channel)
mediating VGNC. Aim2. Test the hypothesis that changes in vascular reactivity are directly associated
with changes in resting cortical pyramidal neuron activity. Optimal energy balance requires that the degree
of neuronal activity be properly matched with blood perfusion. Using in vivo and in vitro approaches, we will
determine how pressure/flow parenchymal arteriole diameter changes impact resting neuronal activity in control
mice and in models of vascular disease using Angiotensin II-dependent hypertension and cerebral
hypoperfusion. In vitro: measurements of arteriolar diameter, neuronal membrane potential, firing rates and
synaptic currents are obtained before, during and after a hemodynamic challenge (e.g. ↑or↓ flow/pressure)
evoked to pressurized PA. In vivo: resting neuronal activity in response to systemic-evoked changes in blood
pressure will be assessed. Aim3. Test the hypothesis that changes in vascular reactivity recruit, via an
astrocyte Ca2+-dependent pathway, GABAergic interneurons to regulate cortical neuronal networks.
Using simultaneous parenchymal arteriole diameter changes with electrophysiological neuronal activity
recordings we will determine the effect pressure/flow-evoked parenchymal arteriole vascular reactivity changes
has on cortical GABAergic interneuron function and neuronal networks. Specifically, we will identify the
GABAergic interneuron subtype driving neuronal network responses during VGNC, whether interneuron
responses...

## Key facts

- **NIH application ID:** 10117289
- **Project number:** 5R01NS097818-05
- **Recipient organization:** AUGUSTA UNIVERSITY
- **Principal Investigator:** JESSICA A FILOSA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $332,500
- **Award type:** 5
- **Project period:** 2017-03-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10117289

## Citation

> US National Institutes of Health, RePORTER application 10117289, Clinically unscreened vasculo-glial-neuronal coupling is critical for physiological brain function (5R01NS097818-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10117289. Licensed CC0.

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