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Epigenetic Regulation Of Striatal Circuit Function For Action And Habit Learning

Award Number: R01DA046679
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2019
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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Epigenetic Regulation Of Striatal Circuit Function For Action And Habit Learning - PROJECT SUMMARY Growing evidence suggests addiction and other diseases of behavioral control result from the development of maladaptive habits. Indeed, an overreliance on habit is associated with the compulsive phenotype found in patients diagnosed with addiction and alcoholism, and comorbid conditions including obsessive-compulsive disorder and schizophrenia. Addictive substances and stress are thought to hijack the brain systems that normally support habit learning, causing habits to form faster and more strongly influence behavior than normal. This results in behavior that is insensitive to its consequences, even when those consequences are negative. Our ultimate goal is to expose the epigenetic-genomic-physiological-functional conduit that allows stress and exposure to addictive substances to promote these maladaptive habits. To achieve this, our specific goal here is to expose the multi-layered biological architecture required for mechanistic understanding of adaptive and maladaptive habits. Thus, this work will provide insight into how pathological states arise and what can be done to combat them. The striatum has long been known to function in habit learning. Where information is lacking is on how each striatal projection pathway, the direct- and indirect-projections to basal ganglia output nuclei, contribute and how their function might differ depending on the anatomically and functionally distinct medial and lateral striatal subdivisions. We will use a multi-faceted and integrative approach to expose the physiological and molecular changes that occur in each striatal subcircuit during goal-directed and habit learning. Our preliminary investigations have indicated that one major epigenetic repressor, HDAC3, functions in the striatum as a negative regulator of habit formation. Our hypothesis is that dorsal striatal HDAC3 functions as a molecular gate over habit, being engaged at the promoters of key neuronal activity genes to slow the transition to habit and being removed when conditions are ripe for habits to dominate. Thus, chronic stress and exposure to addictive substances might open this gate, creating an epigenetic landscape that biases future behavioral strategy towards habit, even with this is not adaptive, producing the compulsivity that marks many mental illnesses. Our proposed research begins to test this by investigating the molecular and cellular mechanisms that allows HDAC3 to regulate habit. This will enable future investigations into how disruptions in these mechanisms promote maladaptive behavior.


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 = $0 )
2025	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Drug Use and Addiction Research Programs	000	5	6/4/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $545,976 )
2023	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Drug Use and Addiction Research Programs	000	5	1/19/2023	NON-COMPETING CONTINUATION	$545,976
														Subtotal = $545,976

Issue Date FY: 2022 ( Subtotal = $545,976 )
2022	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Drug Use and Addiction Research Programs	000	4	1/21/2022	NON-COMPETING CONTINUATION	$491,377
2022	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Drug Use and Addiction Research Programs	001	4	3/21/2022	NON-COMPETING CONTINUATION	$54,599
														Subtotal = $545,976

Issue Date FY: 2021 ( Subtotal = $545,976 )
2021	2021	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Drug Use and Addiction Research Programs	000	3	2/5/2021	NON-COMPETING CONTINUATION	$545,976
														Subtotal = $545,976

Issue Date FY: 2020 ( Subtotal = $501,287 )
2020	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Drug Use and Addiction Research Programs	000	2	1/23/2020	NON-COMPETING CONTINUATION	$501,287
														Subtotal = $501,287

Issue Date FY: 2019 ( Subtotal = $517,352 )
2019	2019	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Drug Use and Addiction Research Programs	000	1	3/12/2019	NEW	$517,352
														Subtotal = $517,352

Grand Total All Awards = $2,656,567

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Epigenetic Regulation Of Striatal Circuit Function For Action And Habit Learning

Award Number: R01DA046679

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2019

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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