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Restoration and Further Assessment of the Actor-Critic Circuit and Connected Areas After Cocaine Self-Administration

Award Number: R01DA031695
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Restoration and Further Assessment of the Actor-Critic Circuit and Connected Areas After Cocaine Self-Administration - PROJECT SUMMARY Reward-guided decision-making and impulse control are disrupted after chronic cocaine use. These changes have been attributed to altered functions in brain circuits critical for computation of reward predictions, action policies, prediction errors and attention. ‘Reward prediction’ signals reflect the reward the animal expects to receive as a result of behavior or presentation of a stimulus. ‘Action policies’ are rules that govern behavior that are triggered by external stimuli or context, and are thought to underlie habits. Both reward predictions and action policies are modified when there are violations in predictions known as ‘reward prediction errors’. ‘Signed’ reward prediction errors reflect the valence associated with an error, strengthening or weakening the associability between cues, responses and outcomes. ‘Unsigned’ prediction errors reflect the surprise induced by errors which lead to increases in ‘attention’ so that learning can occur. We have uncovered neural correlates of these constructs and the relationship between them by recording from multiple brain areas as rats perform a reward- guided decision-making task in which we unexpectedly varied the delay to and size of reward across several trial blocks. We have shown that nucleus accumbens core (NAc) and anterior insula (AI) encode reward predictions, firing strongly for cues that predict more valued reward, whereas firing in dorsal lateral striatum (DLS) is highly associative, encoding action policies such as stimulus-response associations and contextual bias signals. We have also shown that midbrain dopamine (DA) neurons increase firing to unexpected reward and decrease firing to unexpected reward omission. During learning these signed prediction errors transfer to cues, with cues predicting more valued reward eliciting stronger firing. Unlike firing of DA neurons in ventral tegmental area (VTA), our work has shown that firing in basolateral amygdala (ABL) and anterior cingulate cortex (ACC) better reflects integrated unsigned prediction error signals and attention, increasing during unexpected up- and down-shifts in value at the time of the error and during cue sampling on subsequent trials. Here, we propose that activation of ACC increases attention and engages model-based mechanisms that govern goal-directed behavior and associated mechanisms in AI, NAc and VTA, and that chronic cocaine reduces the fidelity of reward prediction and prediction error signals, in part, by disrupting ACC function. Further, we propose that epigenetic changes in ACC, NAc and DLS after chronic drug use alter cue selectivity in a way that promotes fast, automatic behavior by altering the start point and rate of signals that drive actions. In this resubmission of my renewal application we propose to further model the normal circuit and behavior, and its disruption after cocaine-exposure by bi-directionally manipulating neural signals via optogenetics and epigenetic (histone deacetylase 5, HDAC5) manipulation. By performing these experiments, we will gain further insight into how the brain functions normally, how it is disrupted after chronic cocaine use, and determine if repairing neural signals in ACC and striatum might restore behavior and neural constructs in downstream regions.


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 = $342,465 )
2025	2025	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BUILDING	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Drug Use and Addiction Research Programs	000	13	2/27/2025	NON-COMPETING CONTINUATION	$342,465
														Subtotal = $342,465

Issue Date FY: 2024 ( Subtotal = $380,968 )
2024	2024	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BUILDING	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Drug Use and Addiction Research Programs	004	12	4/25/2024	NON-COMPETING CONTINUATION	$38,096
2024	2024	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BUILDING	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Drug Use and Addiction Research Programs	003	12	2/26/2024	NON-COMPETING CONTINUATION	$342,872
2024	2023	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BUILDING	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Drug Use and Addiction Research Programs	002	11	2/23/2024	COMPETING CONTINUATION	$0
2024	2023	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BUILDING	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Drug Use and Addiction Research Programs	001	11	2/22/2024	COMPETING CONTINUATION	$0
2024	2021	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BUILDING	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Drug Use and Addiction Research Programs	000	10	2/22/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $380,968

Issue Date FY: 2023 ( Subtotal = $380,812 )
2023	2023	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Drug Use and Addiction Research Programs	002	11	4/13/2023	COMPETING CONTINUATION	$380,812
2023	2021	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Drug Use and Addiction Research Programs	001	10	4/13/2023	NON-COMPETING CONTINUATION	$0
2023	2021	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Drug Use and Addiction Research Programs	000	10	1/5/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $380,812

Issue Date FY: 2021 ( Subtotal = $353,410 )
2021	2021	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Drug Use and Addiction Research Programs	000	10	2/5/2021	NON-COMPETING CONTINUATION	$353,410
														Subtotal = $353,410

Issue Date FY: 2020 ( Subtotal = $353,772 )
2020	2020	UNIVERSITY OF MARYLAND	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Drug Use and Addiction Research Programs	000	9	1/23/2020	NON-COMPETING CONTINUATION	$353,772
														Subtotal = $353,772

Issue Date FY: 2019 ( Subtotal = $354,116 )
2019	2019	UNIVERSITY OF MARYLAND	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Drug Use and Addiction Research Programs	000	8	1/16/2019	NON-COMPETING CONTINUATION	$354,116
														Subtotal = $354,116

Issue Date FY: 2018 ( Subtotal = $319,864 )
2018	2018	UNIVERSITY OF MARYLAND	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Drug Use and Addiction Research Programs	000	7	1/17/2018	NON-COMPETING CONTINUATION	$287,877
2018	2018	UNIVERSITY OF MARYLAND	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Drug Use and Addiction Research Programs	001	7	4/26/2018	NON-COMPETING CONTINUATION	$31,987
														Subtotal = $319,864

Issue Date FY: 2017 ( Subtotal = $325,116 )
2017	2017	UNIVERSITY OF MARYLAND	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Drug Use and Addiction Research Programs	003	6	6/13/2017	COMPETING CONTINUATION	$30,166
2017	2017	UNIVERSITY OF MARYLAND	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Drug Use and Addiction Research Programs	001	6	1/11/2017	COMPETING CONTINUATION	$325,116
2017	2015	UNIVERSITY OF MARYLAND	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Drug Use and Addiction Research Programs	000	5	1/6/2017	NON-COMPETING CONTINUATION	$0
2017	2015	UNIVERSITY OF MARYLAND	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Drug Use and Addiction Research Programs	002	5	6/13/2017	NON-COMPETING CONTINUATION	-$30,166
														Subtotal = $325,116

Issue Date FY: 2015 ( Subtotal = $327,050 )
2015	2015	UNIVERSITY OF MARYLAND	4101 CHESAPEAKE BLDG	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Drug Use and Addiction Research Programs	000	5	4/13/2015	NON-COMPETING CONTINUATION	$327,050
														Subtotal = $327,050

Issue Date FY: 2014 ( Subtotal = $332,291 )
2014	2014	UNIVERSITY OF MARYLAND	4101 CHESAPEAKE BLDG	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Drug Use and Addiction Research Programs	000	4	4/17/2014	NON-COMPETING CONTINUATION	$332,291
														Subtotal = $332,291

Issue Date FY: 2013 ( Subtotal = $314,917 )
2013	2013	UNIVERSITY OF MARYLAND	4101 CHESAPEAKE BLDG	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Drug Use and Addiction Research Programs	000	3	4/19/2013	NON-COMPETING CONTINUATION	$295,235
2013	2013	UNIVERSITY OF MARYLAND	4101 CHESAPEAKE BLDG	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Drug Use and Addiction Research Programs	001	3	5/16/2013	NON-COMPETING CONTINUATION	$19,682
														Subtotal = $314,917

Issue Date FY: 2012 ( Subtotal = $301,275 )
2012	2012	UNIVERSITY OF MARYLAND	4101 CHESAPEAKE BLDG	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Drug Use and Addiction Research Programs	000	2	4/13/2012	NON-COMPETING CONTINUATION	$301,275
														Subtotal = $301,275

Issue Date FY: 2011 ( Subtotal = $292,500 )
2011	2011	UNIVERSITY OF MARYLAND	4101 CHESAPEAKE BLDG	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Drug Use and Addiction Research Programs	000	1	6/13/2011	NEW	$292,500
														Subtotal = $292,500

Grand Total All Awards = $4,378,556

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Restoration and Further Assessment of the Actor-Critic Circuit and Connected Areas After Cocaine Self-Administration

Award Number: R01DA031695

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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