Thursday, November 21, 2024 11/21/2024

11/11 Connectome-based fingerprinting of alcohol drinking in mice: mechanisms and biomarkers

Award Number: U01AA016658
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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SUMMARY In the current INIA period, we have developed multimodal brain MRI in mice, i.e. combining morphological, structural and functional data. Our data demonstrate circuitry-specific alterations of brain morphology, and reshaping of both structural and functional connectomes after 6 weeks excessive alcohol drinking. Our findings are consistent with the human literature and demonstrate our ability to characterize in-depth whole brain plasticity in a mouse model of alcohol drinking. We will build on these findings and methodologies to achieve three goals: Specific Aim 1. Longitudinal MRI biomarkers - Group level analysis: do alcohol effects on neurocircuitry depend on drinking history, and/or sex? We will continue to use the EOD-2BC model and C57BL/6 mice and incorporate female mice in longitudinal Experiment 1. We will acquire multimodal MRI images at four time points (baseline; 6 and 10 weeks drinking; 4 weeks withdrawal) and apply quantitative multiparametric analyses to investigate temporal and sex effects. Brains will be collected for histology, c-Fos analysis, metabolomics and transcriptomics (to be used in Aim 3). Specific Aim 2. Connectome/behavior individual signatures – Subject level analysis: can we classify and predict behavior and drug effects from MRI? We will move from group analysis to subject-level analysis and correlate multimodal MRI data with individual behavioral patterns using machine learning approaches. This is now feasible (GPR88 knockout mice/EOD-TBC,preliminary results). We will: Aim 2a. Identify connectome features that classify and predict alcohol drinking/withdrawal behavior. We will build a predictive multivariate model of the drinking trajectory at individual level, using longitudinal imaging data from Experiment 1. We will determine best MR-based connectome classifiers that discriminate drinking patterns and evaluate their respective causal influence on the negative affect of withdrawal. Aim 2b. Identify connectome features that predict drug treatment efficacy. We will study alcohol effects in male mice in longitudinal Experiment 2, which will include a drug treatment. We have selected a GPR-88 agonist, which reduces alcohol intake. We will expand the prediction model from Aim 2a to drug effects and include c-fos endpoints in the prediction (Kash/INIA-S). Specific Aim 3. Mechanisms: can we link connectome data with neuroimmune signaling? This aim will be synergistic with INIA partners, using notably molecular data from the same mice (see Aim 1). We will: Aim 3a. Develop hypothesis-driven analyses to identify MRI correlates for neuroadaptations in extracellular matrix (Lasek), microglia (Mangieri) and stress centers (AI, BNST, Kash). Aim 3b. Perform metabolomic profiling using HR-MAS (high resolution magic angle spinning) 1H-NMR at our site, for regions of interest based on our collaborative work. We will compare metabolic profiles of immune pathways with those obtained from mice undergoing the CIE-protocol (Kroenke-Cuzon/INIA-S). Aim 3c. Integrate transcriptomic brain mapping (Mayfield) with our MRI data to correlate altered gene expression and brain network remodeling in the EOD-TBC model. In conclusion, Specific Aim 1 will strengthen validity of our MRI-based fingerprinting approach in mice, address the yet poorly understood sex effect at whole brain level, and will be applicable to other mouse models of AUD. Specific Aim 2 will establish signatures of alcohol effects and drug treatments, with potential for diagnostic and patient stratification, confirm GPR88 as a target to treat AUD, and will be applicable to other INIA drugs. Specific Aim 3 will bridge our “mesoscale” data with molecular and cellular mapping INIA projects.


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: 2024 ( Subtotal = $255,960 )
2024	2024	UNIVERSITE DE STRASBOURG	4 RUE BLAISE PASCAL	STRASBOURG	ALSACE-CHAMPAGNE-ARDENNE-LORRAINE			FRA	Alcohol Research Programs	000	18	8/29/2024	NON-COMPETING CONTINUATION	$255,960
														Subtotal = $255,960

Issue Date FY: 2023 ( Subtotal = $255,960 )
2023	2023	UNIVERSITE DE STRASBOURG	4 RUE BLAISE PASCAL	STRASBOURG	ALSACE-CHAMPAGNE-ARDENNE-LORRAINE			FRA	Alcohol Research Programs	000	17	2/7/2023	NON-COMPETING CONTINUATION	$255,960
2023	2021	INSERM ADR STRASBOURG	5 RUE J MAYER	STRASBOURG				FRA	Alcohol Research Programs	001	15	5/25/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $255,960

Issue Date FY: 2022 ( Subtotal = $255,960 )
2022	2022	UNIVERSITE DE STRASBOURG	4 RUE BLAISE PASCAL	STRASBOURG	ALSACE-CHAMPAGNE-ARDENNE-LORRAINE			FRA	Alcohol Research Programs	001	16	7/13/2022	COMPETING CONTINUATION	$255,960
2022	2021	INSERM ADR STRASBOURG	5 RUE J MAYER	STRASBOURG	NULL			FRA	Alcohol Research Programs	000	15	7/8/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $255,960

Issue Date FY: 2021 ( Subtotal = $253,236 )
2021	2021	INSERM ADR STRASBOURG	5 RUE J MAYER	STRASBOURG	NULL			FRA	Alcohol Research Programs	003	15	8/17/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$64,102
2021	2021	INSERM ADR STRASBOURG	5 RUE J MAYER	STRASBOURG				FRA	Alcohol Research Programs	004	15	9/20/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2021	2021	INSERM ADR STRASBOURG	5 RUE J MAYER	STRASBOURG				FRA	Alcohol Research Programs	001	15	6/8/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$253,236
2021	2020	ROYAL INSTITUTION FOR THE ADVANCEMENT OF LEARNING / MCGILL	845 RUE SHERBROOKE O	MONTREAL	PQ			CAN	Alcohol Research Programs	000	14	6/8/2021	NON-COMPETING CONTINUATION	$0
2021	2020	ROYAL INSTITUTION FOR THE ADVANCEMENT OF LEARNING / MCGILL	845 RUE SHERBROOKE O	MONTREAL	PQ			CAN	Alcohol Research Programs	002	14	8/17/2021	NON-COMPETING CONTINUATION	-$64,102
														Subtotal = $253,236

Issue Date FY: 2020 ( Subtotal = $253,236 )
2020	2020	ROYAL INSTITUTION FOR THE ADVANCEMENT OF LEARNING / MCGILL	845 RUE SHERBROOKE O	MONTREAL	PQ	H3A 0G4		CAN	Alcohol Research Programs	000	14	1/17/2020	NON-COMPETING CONTINUATION	$253,236
														Subtotal = $253,236

Issue Date FY: 2019 ( Subtotal = $253,236 )
2019	2019	ROYAL INSTITUTE FOR ADVANCEMENT OF LEARNING MCGILL	845 SHERBROOKE STREET WEST	MONTREAL	PQ	H3A 0G4		CAN	Alcohol Research Programs	000	13	1/29/2019	NON-COMPETING CONTINUATION	$253,236
														Subtotal = $253,236

Issue Date FY: 2018 ( Subtotal = $253,236 )
2018	2018	ROYAL INSTITUTION FOR THE ADVANCEMENT OF LEARNING / MCGILL UNIVERSITY	845 RUE SHERBROOKE O BUREAU 318	MONTREAL	PQ	H3A 0G4		CAN	Alcohol Research Programs	000	12	1/29/2018	NON-COMPETING CONTINUATION	$227,913
2018	2018	ROYAL INSTITUTE FOR ADVANCEMENT OF LEARNING MCGILL	845 SHERBROOKE STREET WEST	MONTREAL	PQ	H3A 0G4		CAN	Alcohol Research Programs	001	12	5/23/2018	NON-COMPETING CONTINUATION	$25,323
														Subtotal = $253,236

Issue Date FY: 2017 ( Subtotal = $253,236 )
2017	2017	ROYAL INSTITUTION FOR THE ADVANCEMENT OF LEARNING / MCGILL UNIVERSITY	845 RUE SHERBROOKE O BUREAU 318	MONTREAL	PQ	H3A 0G4		CAN	Alcohol Research Programs	001	11	6/19/2017	COMPETING CONTINUATION	$253,236
2017	2015	ROYAL INSTITUTION FOR THE ADVANCEMENT OF LEARNING / MCGILL UNIVERSITY	845 RUE SHERBROOKE O BUREAU 318	MONTREAL	PQ	H3A 0G4		CAN	Alcohol Research Programs	000	10	6/1/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $253,236

Issue Date FY: 2016 ( Subtotal = $50,635 )
2016	2016	MCGILL UNIVERSITY	361 UNIVERSITY STREET	MONTREAL, QUEBEC				CAN	Alcohol Research Programs	001	10	8/25/2016	SUPPLEMENT FOR EXPANSION	$50,635
2016	2015	MCGILL UNIVERSITY	361 UNIVERSITY STREET	MONTREAL, QUEBEC				CAN	Alcohol Research Programs	000	10	8/25/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $50,635

Issue Date FY: 2015 ( Subtotal = $121,522 )
2015	2015	MCGILL UNIVERSITY	361 UNIVERSITY STREET	MONTREAL, QUEBEC				CAN	Alcohol Research Programs	000	10	8/28/2015	NON-COMPETING CONTINUATION	$121,522
														Subtotal = $121,522

Issue Date FY: 2014 ( Subtotal = $121,521 )
2014	2014	MCGILL UNIVERSITY	361 UNIVERSITY STREET	MONTREAL, QUEBEC				CAN	Alcohol Research Programs	000	9	8/5/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$121,521
2014	2013	GIE-CERBM	1 RUE LAURENT FRIES BP 10142	ILLKIRCH				FRA	Alcohol Research Programs	001	8	8/5/2014	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $121,521

Issue Date FY: 2013 ( Subtotal = $116,510 )
2013	2013	INSTITUT/GENETIQUE/BIOLOGIE MOLEC/CELL	BP 10142	ILLKIRCH				FRA	Alcohol Research Programs	000	8	8/13/2013	EXTENSION WITH OR WITHOUT FUNDS	$116,510
														Subtotal = $116,510

Issue Date FY: 2012 ( Subtotal = $125,280 )
2012	2012	INSTITUT/GENETIQUE/BIOLOGIE MOLEC/CELL	BP 10142	ILLKIRCH				FRA	Alcohol Research Programs	000	7	7/24/2012	NON-COMPETING CONTINUATION	$125,280
														Subtotal = $125,280

Issue Date FY: 2011 ( Subtotal = $125,280 )
2011	2011	INSTITUT/GENETIQUE/BIOLOGIE MOLEC/CELL	BP 10142	ILLKIRCH				FRA	Alcohol Research Programs	000	6	9/2/2011	COMPETING CONTINUATION	$125,280
2011	2011	GIE-CERBM	1 RUE LAURENT FRIES BP 10142	ILLKIRCH				FRA	Alcohol Research Programs	001	6	9/9/2011	COMPETING CONTINUATION	$0
														Subtotal = $125,280

Issue Date FY: 2010 ( Subtotal = $110,879 )
2010	2010	INSTITUT/GENETIQUE/BIOLOGIE MOLEC/CELL	BP 10142	ILLKIRCH				FRA	Alcohol Research Programs	000	5	9/1/2010	NON-COMPETING CONTINUATION	$110,879
														Subtotal = $110,879

Issue Date FY: 2009 ( Subtotal = $111,998 )
2009	2009	INSTITUT/GENETIQUE/BIOLOGIE MOLEC/CELL	BP 10142	ILLKIRCH				FRA	Alcohol Research Programs	000	4	9/1/2009	NON-COMPETING CONTINUATION	$111,998
														Subtotal = $111,998

Issue Date FY: 2008 ( Subtotal = $111,998 )
2008	2008	GIE-CERBM	1 RUE LAURENT FRIES BP 10142	ILLKIRCH				FRA	Alcohol Research Programs	000	3	9/4/2008	NON-COMPETING CONTINUATION	$111,998
														Subtotal = $111,998

Issue Date FY: 2007 ( Subtotal = $111,998 )
2007	2007	GIE-CERBM	1 RUE LAURENT FRIES BP 10142	ILLKIRCH				FRA	Alcohol Research Programs	000	2	9/8/2007	NON-COMPETING CONTINUATION	$111,998
														Subtotal = $111,998

Issue Date FY: 2006 ( Subtotal = $115,344 )
2006	2006	GIE-CERBM	1 RUE LAURENT FRIES BP 10142	ILLKIRCH				FRA	Alcohol Research Programs	000	1	9/28/2006	NEW	$115,344
														Subtotal = $115,344

Grand Total All Awards = $3,257,025

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11/11 Connectome-based fingerprinting of alcohol drinking in mice: mechanisms and biomarkers

Award Number: U01AA016658

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

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