Friday, March 14, 2025 3/14/2025

Project 7/8: INIA Stress and Chronic Alcohol Interactions: Cross-species studies of metabolic allostasis and altered striatal circuitry

Award Number: U01AA029967
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY Chronic heavy ethanol drinking and stress are associated with impaired cognitive flexibility, reflected in habitual and compulsive drinking. This proposal seeks to improve our understanding of the neural basis of these effects by combining ex vivo slice electrophysiological studies with non-invasive magnetic resonance spectroscopy (MRS) measurements on mouse and nonhuman primate (NHP) subjects over the course of experimental drinking procedures common across the INIA-Stress consortium. Electrophysiological recordings of brain slices have demonstrated that establishment of habitual behaviors, including heavy drinking, involve and increase in the excitatory to inhibitory tone of neural input (the E/I ratio) to medium spiny neurons (MSNs) of the mouse dorsolateral striatum (DLS), which in primates is termed the putamen. Specialized MRS techniques for quantifying -aminobutyric acid (GABA) and glutamate within specific brain regions have led researchers to propose that the glutamate/GABA ratio reflects E/I, in the context of chronic stress, however the MRS approach has yet to be validated with direct comparisons to electrophysiological recordings. In Aims 1 and 2, we propose to use electrophysiology and MRS to study mice undergoing chronic intermittent ethanol exposure, combined with forced swim stress (CIE-FSS mice). Our experiments will expand our understanding of striatal neurocircuit adaptations to stress and ethanol exposure by using chemogenetic and recombinant mouse strains to characterize changes in cortical (excitatory) and parvalbumin-expressing interneuron (inhibitory) input to DLS MSNs. In the same mice, metabolic allostasis will be characterized with dynamic MRS methods that monitor cerebral glucose metabolism and neurotransmitter synthesis to estimate the neural tricarboxcylic acid cycle rate (VTCA) in real time, to provide a biochemical context for interpreting glutamate/GABA ratios, which will also be measured in these mice. In Aim 3, parallel chemogenetic manipulations and electrophysiological recordings will be performed in NHP subjects following schedule-induced polydipsia and open-access drinking. These measures will be directly compared to MRS determinations of glutamate/GABA and VTCA within the putamen. Together, these results will support the development of non-invasive strategies to measure stress and ethanol-induced changes in striatal neurocircuitry associated with the establishment of heavy drinking behaviors. The cross-species approach will contribute reliability to the conclusions to be drawn, and enhance the translatability of this work to future application in human subjects.


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: 2025 ( Subtotal = $431,839 )
2025	2025	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Alcohol Research Programs	001	4	1/17/2025	NON-COMPETING CONTINUATION	$431,839
2025	2024	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Alcohol Research Programs	000	3	1/13/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $431,839

Issue Date FY: 2024 ( Subtotal = $479,315 )
2024	2024	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Alcohol Research Programs	001	3	5/16/2024	NON-COMPETING CONTINUATION	$47,930
2024	2024	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Alcohol Research Programs	000	3	1/18/2024	NON-COMPETING CONTINUATION	$431,385
														Subtotal = $479,315

Issue Date FY: 2023 ( Subtotal = $486,265 )
2023	2023	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Alcohol Research Programs	001	2	9/6/2023	NON-COMPETING CONTINUATION	$0
2023	2023	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Alcohol Research Programs	000	2	2/1/2023	NON-COMPETING CONTINUATION	$486,265
														Subtotal = $486,265

Issue Date FY: 2022 ( Subtotal = $484,797 )
2022	2022	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Alcohol Research Programs	001	1	3/22/2022	NEW	$0
2022	2022	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Alcohol Research Programs	000	1	3/11/2022	NEW	$484,797
														Subtotal = $484,797

Grand Total All Awards = $1,882,216

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Project 7/8: INIA Stress and Chronic Alcohol Interactions: Cross-species studies of metabolic allostasis and altered striatal circuitry

Award Number: U01AA029967

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

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