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

7/8 NADIA U01 青少年酒精恢复对基底前脑皮质投射回路的破坏

• 批准号: 10473730
• 负责人: Lisa M Savage
• 金额: $ 27.36万
• 依托单位: STATE UNIVERSITY OF NY,BINGHAMTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10473730
• 关键词: ATAC-seq; Acetylcholine; Adolescence; Adolescent; Adult; Alcohol consumption; Alcohols; Alzheimer' s Disease; Animal Model; Anxiety; Attention; Behavior; Behavioral; Brain; Brain Injuries; Cells; Cholinergic Fibers; Chromatin; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Cognition; Cognitive; Complement; Complex; Coupled; Data; Decision Making; Development; Dissection; Epigenetic Process; Ethanol; Exercise; Exercise Therapy; Functional disorder; Genes; Goals; Growth Factor Gene; Impaired cognition; Impairment; Maintenance; Maps; Medial; Mediating; Mediator of activation protein; Modeling; Monkeys; NGFR Protein; NGFR gene; Nerve Degeneration; Nerve Growth Factors; Neurodegenerative Disorders; Neuroimmune; Neurons; Nucleus Basalis Magnocellularis; Pathologic; Pathology; Pattern; Phenotype; Prefrontal Cortex; Process; Prosencephalon; Rattus; Recovery; Research; Reversal Learning; Rodent Model; Role; Short-Term Memory; Signaling Molecule; Site; Source; Structure; Techniques; Testing; Viral; adolescent alcohol exposure; adolescent binge drinking; aged; alcohol exposure; basal forebrain; basal forebrain cholinergic neurons; base; cholinergic; cholinergic neuron; cognitive function; connectome; density; designer receptors exclusively activated by designer drugs; discounting; drinking; early adolescence; effective therapy; epigenetic regulation; epigenetic silencing; flexibility; frontal lobe; gene therapy; human model; innovation; knock-down; nerve supply; nestin protein; neuroimaging; neuron loss; phenotypic biomarker; restoration; tool; underage drinking

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.

C7/8 u01: Lisa Savage和Ryan Vetreno