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Circuit-specific mechanisms of reward and aversion in ventral tegmental area dopamine neurons

Award Number: R01DA042889
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2017
PERIOD OF PERFORMANCE END DATE: 12/31/2027

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Circuit-specific mechanisms of reward and aversion in ventral tegmental area dopamine neurons - ABSTRACT Cue-driven behaviors are actions motivated by salient environmental stimuli. Maladaptive changes in cue- driven behaviors are fundamental to several neuropsychiatric disorders, including substance use disorder. Ventral tegmental area (VTA) dopamine (DA) neurons have often been assumed to homogeneously encode reward prediction errors. However, even within the nucleus accumbens (NAc), which is the major projection target of VTA DA neurons, DA release has been implicated in several behavioral functions, including reward, aversion, motivation, and incentive salience. This discrepancy might be, at least in part, due to the different methodologies used to record DA cell body activity versus DA release at the axon terminal level. Additionally, recent investigations suggest that VTA DA neurons might differentially contribute to reward and aversion dependent on their projection target and mediolateral position within the VTA. Here, we propose to further detail and define, in a circuit- and cell-type specific manner, the functional heterogeneity of the mesoaccumbal DA system. We will employ a three-pronged approach that leverages pharmacological manipulations, fiber photometry-based recordings of DA cell body activity and DA release, as well as in vivo electrophysiological recordings of DA neurons using Neuropixels and optogenetics. Our investigations will that takes the precise neuroanatomical position of DA neurons within the VTA and their corresponding NAc projection target into consideration. Experiments will be performed in head fixed mice during pharmacological manipulation or during reward seeking behavior as well as in freely behaving mice performing a two-armed bandit task. This will allow us to test whether DA dynamics mediated by different mechanisms in different locations (i.e., at the level of cell bodies versus terminals) underlie distinct behavioral functions. The primary goals are to (1) investigate how different doses of nicotine modulate DA release in distinct NAc subregions. Additionally, we will provide a systematic understanding of how nicotinic acetylcholine receptor function contributes to nicotine-induced DA release in different NAc subregions. (2) We will study how DA cell body activity and DA release in separate mesoaccumbal subcircuits contributes to reward learning and motivated behavior. (3) We will establish an in vivo electrophysiological approach that utilizes Neuropixels and optogenetics to record VTA DA neurons in a circuit- and cell-type specific manner in head fixed mice performing a reward seeking task. Together, we anticipate that these experiments will provide further evidence for our hypothesis that VTA DA neurons make specific contributions to reward learning and motivation in a projection-defined manner. Delineating the precise functions of separate mesoaccumbal DA subcircuits for reward learning and motivated behavior is a significant step in improving our understanding of their diverse roles in health and disease.


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 = $578,718 )
2026	2026	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	119 CALIFORNIA HALL	BERKELEY	CA	94720	ALAMEDA	USA	Drug Use and Addiction Research Programs	001	9	2/6/2026	NON-COMPETING CONTINUATION	$57,870
2026	2026	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Drug Use and Addiction Research Programs	000	9	1/27/2026	NON-COMPETING CONTINUATION	$520,848
														Subtotal = $578,718

Issue Date FY: 2025 ( Subtotal = $571,056 )
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Drug Use and Addiction Research Programs	000	8	12/18/2024	NON-COMPETING CONTINUATION	$513,950
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Drug Use and Addiction Research Programs	001	8	4/7/2025	NON-COMPETING CONTINUATION	$57,106
														Subtotal = $571,056

Issue Date FY: 2024 ( Subtotal = $563,615 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Drug Use and Addiction Research Programs	000	7	12/8/2023	NON-COMPETING CONTINUATION	$507,254
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Drug Use and Addiction Research Programs	001	7	4/25/2024	NON-COMPETING CONTINUATION	$56,361
2024	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Drug Use and Addiction Research Programs	003	6	4/29/2024	COMPETING CONTINUATION	$3
2024	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Drug Use and Addiction Research Programs	002	5	4/29/2024	NON-COMPETING CONTINUATION	-$3
														Subtotal = $563,615

Issue Date FY: 2023 ( Subtotal = $556,393 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Drug Use and Addiction Research Programs	000	6	3/30/2023	COMPETING CONTINUATION	$556,393
														Subtotal = $556,393

Issue Date FY: 2021 ( Subtotal = $343,229 )
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 220	BERKELEY	CA	94710	ALAMEDA	USA	Drug Use and Addiction Research Programs	000	5	3/24/2021	NON-COMPETING CONTINUATION	$343,229
														Subtotal = $343,229

Issue Date FY: 2020 ( Subtotal = $343,521 )
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 220	BERKELEY	CA	94710	ALAMEDA	USA	Drug Use and Addiction Research Programs	000	4	3/26/2020	NON-COMPETING CONTINUATION	$343,521
														Subtotal = $343,521

Issue Date FY: 2019 ( Subtotal = $353,250 )
2019	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 220	BERKELEY	CA	94710	ALAMEDA	USA	Drug Use and Addiction Research Programs	000	3	3/28/2019	NON-COMPETING CONTINUATION	$353,250
														Subtotal = $353,250

Issue Date FY: 2018 ( Subtotal = $353,250 )
2018	2018	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	2150 SHATTUCK AVE RM 313	BERKELEY	CA	94704	ALAMEDA	USA	Drug Use and Addiction Research Programs	001	2	4/26/2018	NON-COMPETING CONTINUATION	$35,325
2018	2018	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	2150 SHATTUCK AVE RM 313	BERKELEY	CA	94704	ALAMEDA	USA	Drug Use and Addiction Research Programs	000	2	3/23/2018	NON-COMPETING CONTINUATION	$317,925
														Subtotal = $353,250

Issue Date FY: 2017 ( Subtotal = $353,250 )
2017	2017	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	2150 SHATTUCK AVE RM 313	BERKELEY	CA	94704	ALAMEDA	USA	Drug Use and Addiction Research Programs	000	1	5/8/2017	NEW	$353,250
														Subtotal = $353,250

Grand Total All Awards = $4,016,282

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Circuit-specific mechanisms of reward and aversion in ventral tegmental area dopamine neurons

Award Number: R01DA042889

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2017

PERIOD OF PERFORMANCE END DATE: 12/31/2027

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