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

Award Number: R01NS097818
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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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 require astrocyte Ca2+ changes as an intermediate step and whether interneuron responses are altered in disease conditions. 1


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	5/11/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $332,500 )
2021	2021	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	3/11/2021	NON-COMPETING CONTINUATION	$332,500
														Subtotal = $332,500

Issue Date FY: 2020 ( Subtotal = $332,500 )
2020	2020	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	3/2/2020	NON-COMPETING CONTINUATION	$332,500
														Subtotal = $332,500

Issue Date FY: 2019 ( Subtotal = $516,618 )
2019	2019	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	3/4/2019	NON-COMPETING CONTINUATION	$332,500
2019	2019	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	7/23/2019	SUPPLEMENT FOR EXPANSION	$184,118
														Subtotal = $516,618

Issue Date FY: 2018 ( Subtotal = $332,500 )
2018	2018	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST # CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	2/5/2018	NON-COMPETING CONTINUATION	$299,250
2018	2018	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST # CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	5/9/2018	NON-COMPETING CONTINUATION	$33,250
														Subtotal = $332,500

Issue Date FY: 2017 ( Subtotal = $332,500 )
2017	2017	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST # CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	2/28/2017	NEW	$332,500
														Subtotal = $332,500

Grand Total All Awards = $1,846,618

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

Award Number: R01NS097818

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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