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7/8 NADIA U01 Recovery of Adolescent Alcohol Disruption of Basal Forebrain-Cortical Projection Circuits

Award Number: U01AA028710
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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C7/8 UO1: Lisa Savage & Ryan Vetreno Recovery of Adolescent Alcohol Disruption of Basal Forebrain-Cortical Projection Circuits Project Summary Heavy alcohol consumption during adolescence is associated with persistent changes in brain structure, connectivity, and adult cortical-mediated cognitive function. Critical pathological changes consistently observed in rodent models of adolescent binge ethanol exposure (Adolescent Intermittent Ethanol; AIE) are a reduction of cortical nerve growth factor (NGF), suppression of the cholinergic phenotypes, and a long-term decrease in the number of functional cholinergic basal forebrain neurons (CBFNs). The cholinergic projection neurons within the nucleus basalis magnocellularis complex (NbM) provide acetylcholine (ACh) to the frontal cortex, including the medial prefrontal cortex (mPFC) and orbitofrontal cortex (OFC). Behaviorally-stimulated efflux of ACh in both the mPFC and OFC are blunted following AIE, and there is a loss of cognitive and behavioral flexibility. Our recent data demonstrate that AIE-induced loss of CBFNs is due to epigenetic silencing of cholinergic phenotypic markers, but exercise, potentially through a NGF mechanism, can reverse these epigenetic changes and rescue cholinergic neurons. This demonstrates that AIE is initially marked by a reduction of the expression of cholinergic neuronal phenotypes, rather than neuronal cell death. Thus, mechanisms should be explored to recover CFBN pathology following AIE. Our overarching hypothesis is that AIE-induced reductions of NGF in cortical projection sites leads to epigenetic silencing of cholinergic phenotypes with the NbM, retraction and/or dysfunctional re-innervation of the cortical-NbM cholinergic connectome, causing blunting of cortical cholinergic tone and cognitive dysfunction. However, appropriately timed NGF-based therapies (exercise, NGF gene therapy, CRISPR/dCas9-P300 editing) following AIE will reinvigorate cholinergic forebrain circuitry through the revitalization of cholinergic genes, which will rescue cortical ACh and recover AIE-induced impairments in cortical-dependent behaviors. Our goals are to map and rescue cholinergic forebrain and cortical circuit pathology seen following AIE (Aim 1), restore cognitive functioning by exercise, NGF-gene therapy, or selective chemogenetic stimulation of cholinergic neurons (Aim 2), and identify the central role of NGF deficits, through CRISPR/dCas9 editing, in AIE-induced epigenetic silencing of cholinergic phenotype genes (Aim 3). Mounting evidence supports the neuroprotective effects of NGF as a course to rescue vulnerable CBFNs undergoing neurodegeneration, and we have strong evidence that AIE-induced cholinergic pathology can be reversed. Understanding the mechanisms of cholinergic neuronal recovery will aid in the development of more effective therapies to treat cognitive dysfunction associated with alcohol-related brain damage and other neurodegenerative disorders.


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 = $385,559 )
2024	2024	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	4400 VESTAL PKWY E	BINGHAMTON	NY	13902	BROOME	USA	Alcohol Research Programs	000	5	8/6/2024	NON-COMPETING CONTINUATION	$234,360
2024	2024	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	4400 VESTAL PKWY E	BINGHAMTON	NY	13902	BROOME	USA	Alcohol Research Programs	001	5	8/8/2024	SUPPLEMENT FOR EXPANSION	$151,199
														Subtotal = $385,559

Issue Date FY: 2023 ( Subtotal = $426,559 )
2023	2023	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	4400 VESTAL PKWY E	BINGHAMTON	NY	13902	BROOME	USA	Alcohol Research Programs	001	4	8/29/2023	SUPPLEMENT FOR EXPANSION	$152,949
2023	2023	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	4400 VESTAL PKWY E	BINGHAMTON	NY	13902	BROOME	USA	Alcohol Research Programs	000	4	8/23/2023	NON-COMPETING CONTINUATION	$273,610
														Subtotal = $426,559

Issue Date FY: 2022 ( Subtotal = $273,610 )
2022	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	4400 VESTAL PKWY E	BINGHAMTON	NY	13902	BROOME	USA	Alcohol Research Programs	000	3	8/21/2022	NON-COMPETING CONTINUATION	$273,610
														Subtotal = $273,610

Issue Date FY: 2021 ( Subtotal = $273,610 )
2021	2021	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	4400 VESTAL PKWY E	BINGHAMTON	NY	13902	BROOME	USA	Alcohol Research Programs	000	2	8/23/2021	NON-COMPETING CONTINUATION	$273,610
														Subtotal = $273,610

Issue Date FY: 2020 ( Subtotal = $270,760 )
2020	2020	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	4400 VESTAL PKWY E	BINGHAMTON	NY	13902	BROOME	USA	Alcohol Research Programs	000	1	8/26/2020	NEW	$270,760
														Subtotal = $270,760

Grand Total All Awards = $1,630,098

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7/8 NADIA U01 Recovery of Adolescent Alcohol Disruption of Basal Forebrain-Cortical Projection Circuits

Award Number: U01AA028710

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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