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3/8: INIA Stress and Chronic Alcohol Interactions: Norepinephrine and corticostriatal circuit regulation of cognitive effort after chronic alcohol and stress

Award Number: U01AA025481
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/ABSTRACT Chronic alcohol use disrupts a number of cognitive functions, including attention, memory, flexibility, and other aspects of executive control. This is exacerbated by both exogenous stress and stress associated with alcohol use and withdrawal. We hypothesize that a key factor relating widespread cognitive dysfunction to problematic alcohol use is cognitive effort, which is needed to sustain diverse cognitive functions, particularly under conditions of heavy demand. In particular, we hypothesize that a history of chronic alcohol and stress disrupts the willingness and ability to exert cognitive effort, and conversely, that pre-alcohol limitations in cognitive effort predict future problematic alcohol use. There is strong interest in the neural basis of cognitive effort, but to our knowledge, no studies have examined the relationship between cognitive effort and alcohol at either a behavioral or neural level. Here we will investigate a neural circuit critical for cognitive effort and impacted by stress and alcohol use. This circuit is formed by the locus coeruleus norepinephrine (LC-NE) system, its strong projections to the anterior cingulate cortex (ACC), and ACC projections to the dorsomedial striatum (DMS). Unique to this proposal is 1) the integration of these systems into a unified circuit and 2) the investigation of this circuit in the integrated framework of cognitive effort, alcohol, and stress. We will measure the impact of chronic intermittent ethanol (CIE) and/or forced swim stress (FSS) on willingness and ability to perform two cognitively-demanding tasks (extradimensional set shifting and cognitive effort discounting in a sustained attention task) in mice. We will identify CIE/FSS associated changes in ACC noradrenergic regulation using RNAscope and probe them with CRISPR-mediated NE receptor knockdown (Aim 1). We will record neural dynamics in this network during cognitive performance after CIE/FSS (Aim 2), and manipulate the activity of this circuit using optogenetics to reversibly disrupt or rescue cognitive effort (Aim 3). Finally, we will collaborate with INIA Neuroimmune investigators to identify the impact of the phosphodiesterase inhibitor apremilast on cognitive function after CIE/FSS and characterize its effect in this circuit (Aim 4). Studies will integrate individual and sex differences to capitalize on heterogeneity in behavior and its relationship to underlying neural function. Cognitive effort is a novel and powerful framework for investigating the impact of alcohol and stress on cognition. Our studies have the potential to unite diverse findings related to the cognition and AUD. By identifying changes in neural circuitry underlying CIE/FSS-induced changes in cognitive effort, there is significant potential for identifying broadly-influential treatments for AUD that strengthen cognitive abilities to serve as a bulwark against the combined influences of alcohol and stress.


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: 2024 ( Subtotal = $460,847 )
2024	2024	UNIVERSITY OF MASSACHUSETTS	COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Alcohol Research Programs	000	8	1/18/2024	NON-COMPETING CONTINUATION	$414,763
2024	2024	UNIVERSITY OF MASSACHUSETTS	101 COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Alcohol Research Programs	002	8	7/17/2024	NON-COMPETING CONTINUATION	$0
2024	2024	UNIVERSITY OF MASSACHUSETTS	101 COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Alcohol Research Programs	001	8	5/16/2024	NON-COMPETING CONTINUATION	$46,084
														Subtotal = $460,847

Issue Date FY: 2023 ( Subtotal = $465,254 )
2023	2023	UNIVERSITY OF MASSACHUSETTS	COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Alcohol Research Programs	000	7	2/2/2023	NON-COMPETING CONTINUATION	$465,254
														Subtotal = $465,254

Issue Date FY: 2022 ( Subtotal = $446,161 )
2022	2022	UNIVERSITY OF MASSACHUSETTS	COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Alcohol Research Programs	006	6	6/15/2022	COMPETING CONTINUATION	$249,728
2022	2022	UNIVERSITY OF MASSACHUSETTS	COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Alcohol Research Programs	001	6	2/16/2022	COMPETING CONTINUATION	$446,161
2022	2022	UNIVERSITY OF MASSACHUSETTS	COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Alcohol Research Programs	007	6	8/25/2022	COMPETING CONTINUATION	$0
2022	2022	UNIVERSITY OF MASSACHUSETTS	COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Alcohol Research Programs	002	6	3/22/2022	COMPETING CONTINUATION	$0
2022	2021	UNIVERSITY OF MASSACHUSETTS	COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Alcohol Research Programs	005	5	6/15/2022	SUPPLEMENT FOR EXPANSION	-$249,728
2022	2021	UNIVERSITY OF MASSACHUSETTS	COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Alcohol Research Programs	004	5	5/13/2022	NON-COMPETING CONTINUATION	$0
2022	2020	UNIVERSITY OF MASSACHUSETTS	COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Alcohol Research Programs	003	4	4/26/2022	NON-COMPETING CONTINUATION	$0
2022	2019	UNIVERSITY OF MASSACHUSETTS	COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Alcohol Research Programs	000	3	11/30/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $446,161

Issue Date FY: 2021 ( Subtotal = $632,946 )
2021	2021	UNIVERSITY OF MASSACHUSETTS	COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Alcohol Research Programs	001	5	4/13/2021	SUPPLEMENT FOR EXPANSION	$313,946
2021	2021	UNIVERSITY OF MASSACHUSETTS	COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Alcohol Research Programs	000	5	2/18/2021	NON-COMPETING CONTINUATION	$319,000
														Subtotal = $632,946

Issue Date FY: 2020 ( Subtotal = $319,000 )
2020	2020	UNIVERSITY OF MASSACHUSETTS	COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Alcohol Research Programs	000	4	2/17/2020	NON-COMPETING CONTINUATION	$319,000
														Subtotal = $319,000

Issue Date FY: 2019 ( Subtotal = $319,000 )
2019	2019	UNIVERSITY OF MASSACHUSETTS	COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Alcohol Research Programs	000	3	1/30/2019	NON-COMPETING CONTINUATION	$319,000
														Subtotal = $319,000

Issue Date FY: 2018 ( Subtotal = $319,000 )
2018	2018	UNIVERSITY OF MASSACHUSETTS	COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Alcohol Research Programs	001	2	5/21/2018	NON-COMPETING CONTINUATION	$31,900
2018	2018	UNIVERSITY OF MASSACHUSETTS	COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Alcohol Research Programs	000	2	1/24/2018	NON-COMPETING CONTINUATION	$287,100
														Subtotal = $319,000

Issue Date FY: 2017 ( Subtotal = $319,000 )
2017	2017	UNIVERSITY OF MASSACHUSETTS	70 BUTTERFIELD TERRACE	AMHERST	MA	01003	HAMPSHIRE	USA	Alcohol Research Programs	000	1	2/1/2017	NEW	$319,000
														Subtotal = $319,000

Grand Total All Awards = $3,281,208

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3/8: INIA Stress and Chronic Alcohol Interactions: Norepinephrine and corticostriatal circuit regulation of cognitive effort after chronic alcohol and stress

Award Number: U01AA025481

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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