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Dependence induced dysfunction of decision-making circuits

Award Number: R01AA026077
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: 09/10/2017
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Dependence induced dysfunction of decision-making circuits - Project Summary Aberrant cognitive function is a hallmark of alcohol use disorders (AUD), disrupting daily function and contributing to alcohol abuse and relapse. Identifying the nature of these deficits is challenged by a lack of understanding of involved cortical circuits and mechanisms. AUD shows altered orbital frontal (OFC) and pre-supplementary motor area (Pre-SMA) cortical function, regions implicated in cognitive functions necessary for decision-making. The mechanisms underlying behavioral and circuit dysfunction are not clear. OFC hypoactivity resulted in a loss of value-based control over goal-directed behavior; however additional cortical circuits have been implicated in behavioral flexibility, including Pre-SMA, whose rodent homologue is the secondary motor cortex (M2), and its output to DS. Increased Pre-SMA/M2 activity is correlated with behavioral inflexibility and impulsivity in AUD; however, no preclinical studies have examined effects of chronic alcohol exposure on M2 circuit function or its output to DS. The overarching hypothesis of this work is that AUD alters OFC and Pre-SMA/M2 circuit function and striatal output, resulting in inflexible behavior underlying dysfunctional decision-making. The current proposal addresses this through three Aims with experiments to be conducted in mice. Aim 1 examines the influence of chronic alcohol on OFC output to M2 contributing to behavioral flexibility. A series of ex vivo slice physiology and in vivo activity monitoring and manipulation experiments will test the hypothesis that chronic intermittent ethanol exposure and repeated withdrawal (CIE) decreases OFC-M2 transmission important for behavioral flexibility. In Aim 2, effects of chronic alcohol on M2 function and its contribution to ethanol self-administration will be examined. By examining effects of chronic ethanol on identified M2 cell type transmission ex vivo and the dynamics and functional contribution of such output to ethanol self-administration in vivo, this aim will address the hypothesis that CIE alters M2 transmission and results in hyperactivity of M2 excitatory populations to contribute to inflexible alcohol self-administration. Lastly, Aim 3 will examine effects of CIE on M2-DS output and control over ethanol-seeking. An integrative ex vivo and in vivo approach will be taken to address the hypothesis that CIE produces aberrant control over striatal processes through increased activation and output of motor-related circuits. Together, these aims will inform how CIE affects cortical circuits and alters their recruitment of striatum to disrupt goal-directed control, thereby identifying novel targets for AUD treatment. Identifying the mechanisms underlying chronic alcohol-induced alterations to cortico-cortical and cortico-striatal circuits is a critical step towards understanding how their disruption contributes to AUD.


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 = $0 )
2025	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Alcohol Research Programs	001	6	1/14/2025	COMPETING CONTINUATION	$983
2025	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Alcohol Research Programs	000	5	1/14/2025	NON-COMPETING CONTINUATION	-$983
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $440,061 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Alcohol Research Programs	000	8	7/1/2024	NON-COMPETING CONTINUATION	$440,061
														Subtotal = $440,061

Issue Date FY: 2023 ( Subtotal = $440,061 )
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Alcohol Research Programs	000	7	7/31/2023	NON-COMPETING CONTINUATION	$440,061
														Subtotal = $440,061

Issue Date FY: 2022 ( Subtotal = $427,263 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Alcohol Research Programs	001	6	9/16/2022	COMPETING CONTINUATION	$427,263
2022	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Alcohol Research Programs	000	5	9/7/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $427,263

Issue Date FY: 2021 ( Subtotal = $344,773 )
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Alcohol Research Programs	000	5	7/5/2021	NON-COMPETING CONTINUATION	$344,773
														Subtotal = $344,773

Issue Date FY: 2020 ( Subtotal = $337,168 )
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Alcohol Research Programs	000	4	6/12/2020	NON-COMPETING CONTINUATION	$337,168
														Subtotal = $337,168

Issue Date FY: 2019 ( Subtotal = $337,719 )
2019	2019	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Alcohol Research Programs	000	3	6/26/2019	NON-COMPETING CONTINUATION	$337,719
														Subtotal = $337,719

Issue Date FY: 2018 ( Subtotal = $338,244 )
2018	2018	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Alcohol Research Programs	000	2	6/15/2018	NON-COMPETING CONTINUATION	$338,244
														Subtotal = $338,244

Issue Date FY: 2017 ( Subtotal = $338,744 )
2017	2017	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Alcohol Research Programs	000	1	9/7/2017	NEW	$338,744
														Subtotal = $338,744

Grand Total All Awards = $3,004,033

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Dependence induced dysfunction of decision-making circuits

Award Number: R01AA026077

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: 09/10/2017

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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