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Alcohol dependence induced aberrant persistence of reward-seeking and its corticostriatal determinants.

Award Number: F31AA027439
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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Project Summary Dysfunctional decision-making is found in alcohol dependence and is hypothesized to involve a shift from initial goal-directed decision-making to habitual/compulsive control. Top-down, cortical control is essential for goal- directed decision-making. The pre-SMA/SMA is one such cortical circuit and its activity is disrupted in AUD. How alcohol dependence affects goal-directed decision-making and the associated cortical neural mechanisms remains unclear. Goal-directed decision-making is derived from sensitivity to changes in the value of the consequence (i.e. do I want it) as well as sensitivity to feedback on the decision itself (i.e., was it successful). While research has focused on the ability for alcohol dependence to induce insensitivity to value change, the effects of dependence on sensitivity to decision feedback has been neglected. This is a crucial component of AUD; research into the cortical mechanisms of feedback sensitivity will inform how alcoholics shift from goal- directed to compulsive control. To assess the role of premotor corticostriatal circuits in alcohol dependence, we have adapted an operant task in rodents to dissociate value sensitivity from feedback on the decision. Our preliminary data in mice show chronic alcohol exposure leads to the aberrant persistent use of decision feedback; CIE exposed mice continue to adjust their behavior to get reward even under circumstances when control mice do not. Furthermore, chronic alcohol exposure increases the excitability of secondary motor cortex (M2) pyramidal neurons, which we have shown to be involved when using feedback during decision-making. Our central hypothesis is that chronic alcohol exposure increases M2 output into DS, leading to the aberrant persistent use of feedback during decision-making. We will address this hypothesis by 1) determining how chronic alcohol exposure affects M2 population activity and output to control decision-making and by 2) manipulating M2 projection neuron activity to establish a causal link between alcohol dependence-induced changes in M2 activity and persistent feedback control. We will utilize the well- validated chronic intermittent ethanol vapor exposure to model alcohol dependence, and sophisticated behavioral analyses combined with in vivo calcium fiber photometry and in vivo chemo- and optogenetics in order to understand how chronic alcohol exposure affects activity within M2 during goal-directed decision- making. The pre-SMA/SMA, M2’s human homologue, is associated with response inhibition and is disrupted in AUD. Since the pre-SMA/SMA is accessible to treatments like TMS, the impact of this work will be to identify a novel and therapeutically targetable corticostriatal pathway by which chronic alcohol exposure disrupts goal- directed decision-making.


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	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Alcohol Research Programs	001	2	1/19/2023	NON-COMPETING CONTINUATION	$0
2023	2019	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Alcohol Research Programs	000	1	1/19/2023	NEW	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Alcohol Research Programs	000	2	7/5/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $37,593 )
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Alcohol Research Programs	000	2	7/27/2020	NON-COMPETING CONTINUATION	$37,593
														Subtotal = $37,593

Issue Date FY: 2019 ( Subtotal = $37,089 )
2019	2019	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Alcohol Research Programs	000	1	8/13/2019	NEW	$37,089
														Subtotal = $37,089

Grand Total All Awards = $74,682

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Alcohol dependence induced aberrant persistence of reward-seeking and its corticostriatal determinants.

Award Number: F31AA027439

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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