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

> **NIH NIH U01** · STATE UNIVERSITY OF NY,BINGHAMTON · 2020 · $270,760

## Abstract

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.

## Key facts

- **NIH application ID:** 10073648
- **Project number:** 1U01AA028710-01
- **Recipient organization:** STATE UNIVERSITY OF NY,BINGHAMTON
- **Principal Investigator:** Lisa M Savage
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $270,760
- **Award type:** 1
- **Project period:** 2020-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10073648

## Citation

> US National Institutes of Health, RePORTER application 10073648, 7/8 NADIA U01 Recovery of Adolescent Alcohol Disruption of Basal Forebrain-Cortical Projection Circuits (1U01AA028710-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10073648. Licensed CC0.

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