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Striatal Microcircuit Dynamics of Ethanol Habits

Award Number: R01AA024845
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/15/2016
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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Striatal Microcircuit Dynamics of Ethanol Habits - Project Summary We recently demonstrated that dorsolateral striatum fast-spiking interneurons (FSIs) are necessary for compulsive alcohol drinking, which is a cardinal feature of alcohol use disorder. This proposal seeks to understand the impact of ethanol on this critical interneuron population at molecular, neural circuit, and behavioral levels to advance novel therapeutic strategies targeting compulsive alcohol use. While chronic intermittent ethanol exposure exerts little effect on excitatory inputs to FSIs and FSI intrinsic excitability, it dramatically downregulates inhibitory synaptic control of FSIs – positioning FSIs to activate without regulation to underlie pathological compulsive drinking behavior. Our substantial preliminary data points to a framework wherein ethanol acutely potentiates GABAergic input to FSIs and, following repeated intermittent exposure to ethanol, GABAergic inputs are homeostatically downregulated by a degradation of the extracellular matrix that surrounds FSIs, the so-called perineuronal nets that stabilize inhibitory input onto FSIs. Thus, we herein hypothesize that this dramatic loss of GABAergic input to FSIs is mediated by a degradation of perineuronal nets. This will be tested with three interrelated yet fully independent experimental aims using cutting-edge approaches. Aim 1 will examine circuit-specific synaptic mechanisms governing the acute ethanol potentiation of GABAergic input to FSIs using molecular tools and whole-cell patch clamp electrophysiology. Aim 2 will determine the fate of GABAergic inputs to FSIs that are downregulated by chronic intermittent ethanol using a suite of advance cellular and molecular imaging techniques. Aim 3 will explore the causal interaction of acute ethanol potentiation of GABAergic input and the perineuronal net-mediated downregulation of these inputs following chronic intermittent ethanol exposure using a powerful combination of slice electrophysiology, perineuronal net imaging, in vivo chemogenetics, and compulsive alcohol drinking analyses. This multilevel, orthogonal experimental approach positions this project to yield vertical advances toward novel therapeutics targeting compulsive alcohol consumption and insight to myriad neuropsychiatric disorders involving dorsal striatal dysfunction.


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: 2026 ( Subtotal = $440,826 )
2026	2026	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Alcohol Research Programs	000	9	2/27/2026	NON-COMPETING CONTINUATION	$440,826
														Subtotal = $440,826

Issue Date FY: 2025 ( Subtotal = $439,281 )
2025	2025	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Alcohol Research Programs	000	8	5/12/2025	NON-COMPETING CONTINUATION	$439,281
														Subtotal = $439,281

Issue Date FY: 2024 ( Subtotal = $434,646 )
2024	2024	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Alcohol Research Programs	001	7	5/16/2024	NON-COMPETING CONTINUATION	$43,464
2024	2024	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Alcohol Research Programs	000	7	2/21/2024	NON-COMPETING CONTINUATION	$391,182
														Subtotal = $434,646

Issue Date FY: 2023 ( Subtotal = $475,118 )
2023	2023	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Alcohol Research Programs	000	6	3/15/2023	COMPETING CONTINUATION	$475,118
														Subtotal = $475,118

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Alcohol Research Programs	000	5	7/21/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $540,790 )
2020	2020	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Alcohol Research Programs	000	5	3/23/2020	NON-COMPETING CONTINUATION	$540,790
														Subtotal = $540,790

Issue Date FY: 2019 ( Subtotal = $579,375 )
2019	2019	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Alcohol Research Programs	000	4	3/26/2019	NON-COMPETING CONTINUATION	$347,625
2019	2019	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Alcohol Research Programs	001	4	6/20/2019	SUPPLEMENT FOR EXPANSION	$231,750
														Subtotal = $579,375

Issue Date FY: 2018 ( Subtotal = $347,625 )
2018	2018	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Alcohol Research Programs	000	3	3/29/2018	NON-COMPETING CONTINUATION	$312,862
2018	2018	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Alcohol Research Programs	001	3	5/24/2018	NON-COMPETING CONTINUATION	$34,763
														Subtotal = $347,625

Issue Date FY: 2017 ( Subtotal = $318,195 )
2017	2017	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Alcohol Research Programs	001	2	7/27/2017	NON-COMPETING CONTINUATION	$31,820
2017	2017	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Alcohol Research Programs	000	2	3/23/2017	NON-COMPETING CONTINUATION	$286,375
														Subtotal = $318,195

Issue Date FY: 2016 ( Subtotal = $317,340 )
2016	2016	UNIVERSITY OF MARYLAND BALTIMORE PROFESSIONAL SCHOOLS	220 ARCH ST OFFICE LEVEL 2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Alcohol Research Programs	000	1	7/15/2016	NEW	$317,340
														Subtotal = $317,340

Grand Total All Awards = $3,893,196

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Striatal Microcircuit Dynamics of Ethanol Habits

Award Number: R01AA024845

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/15/2016

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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