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VTA-NAc GABAergic communication underlying stress-induced reward deficits

Award Number: R01MH124998
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/10/2021
PERIOD OF PERFORMANCE END DATE: 04/30/2026

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VTA-NAc GABAergic communication underlying stress-induced reward deficits - Millions of Americans suffer from deficits in reward-seeking, in the context of psychiatric disorders, such as major depressive disorder, schizophrenia, and substance use disorders. Stress can both exacerbate these disorders and directly cause reward-seeking deficits. Mice subjected to chronic stress also develop reward-seeking deficits. However, it remains unclear how stress disrupts reward-seeking. Reward-seeking is a complex process that includes anticipatory motivation to obtain rewards, an assessment of the hedonic value of rewards, and learning to associate reward-predicting cues with rewarding outcomes. Communication between the ventral tegmental area (VTA) and the nucleus accumbens (NAc) plays a central role in these processes. Dopamine (DA) released from the VTA to the NAc supports components of reward-seeking, including anticipation and learning. Yet efforts to show that VTA-NAc DA deficits underlie stress-induced reward-seeking deficits have yielded mixed results. Recently, researchers have identified that inhibitory VTA GABA neurons are also key for setting expectations that both guide reward anticipation and associative learning. We have found that during acute stress, these VTA GABA neurons induce rhythmic NAc activity and that this activity predicts subsequent transient reductions in reward-seeking. Moreover, rhythmically stimulating NAc projecting VTA GABA neurons suffices to recapitulate both stress-induced NAc rhythmic activity and subsequent reward-seeking deficits. These data raise the possibility that chronic stress causes reward-seeking deficits via VTA-NAc GABA activity. Since VTA GABA neurons have known roles in anticipation and learning, these data also suggest that chronic stress might disrupt encoding of specific aspects of reward-seeking. This proposal tests these ideas and directly links chronic stress- induced VTA-NAc GABAergic activity to subsequent deficits in the encoding of reward-seeking. Specific Aim 1 will test whether two chronic stress disrupts specific aspects of reward-seeking using tasks that assess associative learning, anticipatory motivation and hedonic valuation and consider mice along the susceptible- resilient spectrum. Specific Aim 2 will use optogenetics and chronic in vivo multi-site electrophysiology in awake, behaving mice to test whether VTA-NAc GABAergic activity causes chronic stress-induced reward-seeking deficits by recording the in vivo firing activity of VTA-NAc GABA projections during chronic stress and subsequent reward-seeking. We will also determine whether chronic optogenetic stimulation of this pathways suffices to induce persistent reward-seeking deficits. Finally, Specific Aim 3 will use pathway-specific chemogenetic blockade to test whether blocking VTA-NAc GABAergic activity can prevent chronic stress-induced reward- seeking deficits. We will also use Cal-Light (calcium and light-activated gene expression) to express an inhibitory opsin in stress-activated VTA neurons. This technique will allow us to test whether inhibiting stress-activated neurons during reward-seeking can reverse the effects of chronic stress. With this approach, we will develop pathway and cell-type specific understanding of how chronic impairs reward-seeking with the goal of finding novel treatments for reward-seeking deficits.


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 = $479,447 )
2025	2025	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC.	1051 RIVERSIDE DR	NEW YORK	NY	10032	NEW YORK	USA	Mental Health Research Grants	000	5	4/23/2025	NON-COMPETING CONTINUATION	$479,447
														Subtotal = $479,447

Issue Date FY: 2024 ( Subtotal = $564,057 )
2024	2024	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC.	1051 RIVERSIDE DR	NEW YORK	NY	10032	NEW YORK	USA	Mental Health Research Grants	001	4	8/13/2024	SUPPLEMENT FOR EXPANSION	$80,062
2024	2024	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC.	1051 RIVERSIDE DR	NEW YORK	NY	10032	NEW YORK	USA	Mental Health Research Grants	000	4	5/14/2024	NON-COMPETING CONTINUATION	$564,057
2024	2024	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC.	1051 RIVERSIDE DR	NEW YORK	NY	10032	NEW YORK	USA	Mental Health Research Grants	002	4	9/2/2024	SUPPLEMENT FOR EXPANSION	-$80,062
														Subtotal = $564,057

Issue Date FY: 2023 ( Subtotal = $622,617 )
2023	2023	RESEARCH FOUNDATION FOR MENTAL HYGIENE INC	1051 RIVERSIDE DR	NEW YORK	NY	10032	NEW YORK	USA	Mental Health Research Grants	002	3	5/23/2023	SUPPLEMENT FOR EXPANSION	$95,115
2023	2023	RESEARCH FOUNDATION FOR MENTAL HYGIENE INC	1051 RIVERSIDE DR	NEW YORK	NY	10032	NEW YORK	USA	Mental Health Research Grants	001	3	5/22/2023	NON-COMPETING CONTINUATION	$507,652
2023	2023	RESEARCH FOUNDATION FOR MENTAL HYGIENE INC	1051 RIVERSIDE DR	NEW YORK	NY	10032	NEW YORK	USA	Mental Health Research Grants	000	2	4/10/2023	SUPPLEMENT FOR EXPANSION	$19,850
														Subtotal = $622,617

Issue Date FY: 2022 ( Subtotal = $540,520 )
2022	2022	RESEARCH FOUNDATION FOR MENTAL HYGIENE INC	1051 RIVERSIDE DR	NEW YORK	NY	10032	NEW YORK	USA	Mental Health Research Grants	000	2	4/20/2022	NON-COMPETING CONTINUATION	$540,520
														Subtotal = $540,520

Issue Date FY: 2021 ( Subtotal = $575,569 )
2021	2021	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC.	1051 RIVERSIDE DR	NEW YORK	NY	10032	NEW YORK	USA	Mental Health Research Grants	000	1	6/10/2021	NEW	$575,569
														Subtotal = $575,569

Grand Total All Awards = $2,782,210

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VTA-NAc GABAergic communication underlying stress-induced reward deficits

Award Number: R01MH124998

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/10/2021

PERIOD OF PERFORMANCE END DATE: 04/30/2026

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