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Notch-dependent microcircuit regulation of alcohol reward memory

Award Number: R01AA024434
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/20/2016
PERIOD OF PERFORMANCE END DATE: 07/31/2026

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Notch-dependent microcircuit regulation of alcohol reward memory - PROJECT SUMMARY: Alcohol is the widely abused drug in the world, yet our understanding of the molecular mechanisms by which it regulates brain function and behavior is rudimentary. Many of the molecules implicated in alcohol-induced behaviors have broad roles in regulating diverse processes such as cell signaling, transcription, and neuronal plasticity. The complexity of these processes has led to confusion about alcohol’s molecular underpinnings, which has been further compounded by lack of the ability to manipulate gene expression with precise temporal and spatial control within a well-defined neural circuit. The temporal and spatial specificity for manipulating gene expression afforded in the fruit fly, Drosophila melanogaster, provides the ability to define where and when and where alcohol is acting in the brain to influence both naive and learned behavior. Our unbiased forward genetics approach in Drosophila has revealed the importance of the Notch signaling pathway in regulating formation of memories of a sensory cue associated with the intoxicating properties of alcohol. Notch is a highly conserved cell-signaling mechanism that involves cell-to-cell contact and initiates a transcriptional cascade important for determining cell fate and function. Notch signaling also plays a key role in multiple forms of cancer and immune disorders, as well as cardiovascular, kidney, liver, respiratory and neurodegenerative disease. We recently demonstrated that rewarding doses of alcohol activate Notch signaling in memory-encoding neurons, and this affects expression of novel Notch transcriptional targets such as dopamine receptors. What remains to be understood are the mechanisms through which alcohol activates Notch, and how this ultimately affects dynamics of memory circuits, both acutely and with chronic alcohol use. We hypothesize that Notch plays an important role in activity-dependent transcription required for memory formation and thus ultimately shapes future reward seeking. The goal of the proposed work is to use a genes-to-circuits-to-behavior approach to provide a causal Notch-dependent mechanism through which alcohol-induced cellular activity can guide a transcriptional cascade that influences future alcohol seeking. This increased molecular understanding of the lasting sensory memories for intoxication will ultimately inform more effective targets for pharmacological treatment of alcohol use disorder.


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 = $353,350 )
2025	2025	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Alcohol Research Programs	000	10	8/11/2025	NON-COMPETING CONTINUATION	$353,350
														Subtotal = $353,350

Issue Date FY: 2024 ( Subtotal = $355,950 )
2024	2024	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Alcohol Research Programs	000	9	7/12/2024	NON-COMPETING CONTINUATION	$355,950
														Subtotal = $355,950

Issue Date FY: 2023 ( Subtotal = $355,950 )
2023	2023	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Alcohol Research Programs	000	8	8/2/2023	NON-COMPETING CONTINUATION	$355,950
														Subtotal = $355,950

Issue Date FY: 2022 ( Subtotal = $353,350 )
2022	2022	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Alcohol Research Programs	002	7	8/26/2022	NON-COMPETING CONTINUATION	$353,350
2022	2021	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Alcohol Research Programs	001	6	12/29/2021	COMPETING CONTINUATION	$5,317
2022	2020	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Alcohol Research Programs	000	5	12/29/2021	NON-COMPETING CONTINUATION	-$5,317
														Subtotal = $353,350

Issue Date FY: 2021 ( Subtotal = $367,003 )
2021	2021	BROWN UNIVERSITY IN PROVIDENCE IN THE STATE OF RHODE ISLAND AND PROVIDENCE PLANTATIONS	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Alcohol Research Programs	000	6	9/2/2021	COMPETING CONTINUATION	$367,003
														Subtotal = $367,003

Issue Date FY: 2020 ( Subtotal = $353,986 )
2020	2020	BROWN UNIVERSITY IN PROVIDENCE IN THE STATE OF RHODE ISLAND AND PROVIDENCE PLANTATIONS	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Alcohol Research Programs	000	5	7/24/2020	NON-COMPETING CONTINUATION	$353,986
														Subtotal = $353,986

Issue Date FY: 2019 ( Subtotal = $354,485 )
2019	2019	BROWN UNIVERSITY IN PROVIDENCE IN THE STATE OF RHODE ISLAND AND PROVIDENCE PLANTATIONS	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Alcohol Research Programs	000	4	7/23/2019	NON-COMPETING CONTINUATION	$354,485
														Subtotal = $354,485

Issue Date FY: 2018 ( Subtotal = $685,182 )
2018	2018	BROWN UNIVERSITY IN PROVIDENCE IN THE STATE OF RHODE ISLAND AND PROVIDENCE PLANTATIONS	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Alcohol Research Programs	000	3	7/18/2018	NON-COMPETING CONTINUATION	$356,282
2018	2018	BROWN UNIVERSITY IN PROVIDENCE IN THE STATE OF RHODE ISLAND AND PROVIDENCE PLANTATIONS	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Alcohol Research Programs	001	3	9/12/2018	SUPPLEMENT FOR EXPANSION	$328,900
														Subtotal = $685,182

Issue Date FY: 2017 ( Subtotal = $368,161 )
2017	2017	BROWN UNIVERSITY IN PROVIDENCE IN THE STATE OF RHODE ISLAND AND PROVIDENCE PLANTATIONS	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Alcohol Research Programs	000	2	7/17/2017	NON-COMPETING CONTINUATION	$368,161
														Subtotal = $368,161

Issue Date FY: 2016 ( Subtotal = $356,039 )
2016	2016	BROWN UNIVERSITY	POST OFFICE BOX 1929	PROVIDENCE	RI	02912	PROVIDENCE	USA	Alcohol Research Programs	000	1	7/21/2016	NEW	$356,039
														Subtotal = $356,039

Grand Total All Awards = $3,903,456

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Notch-dependent microcircuit regulation of alcohol reward memory

Award Number: R01AA024434

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/20/2016

PERIOD OF PERFORMANCE END DATE: 07/31/2026

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