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: 10247815
• 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/10247815
• 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 UO1：丽莎·萨维奇和瑞安·维特雷诺 青少年酒精对基底前脑皮质投射回路破坏的恢复 项目概要 青春期大量饮酒与大脑结构的持续变化有关， 连接性和成人皮质介导的认知功能。持续观察到的关键病理变化 在青少年暴饮乙醇暴露（青少年间歇性乙醇；AIE）的啮齿动物模型中， 皮质神经生长因子（NGF）的减少，胆碱能表型的抑制，以及长期减少 功能性胆碱能基底前脑神经元（CBFN）的数量。胆碱能投射神经元 大细胞基底核复合体 (NbM) 内向额叶皮层提供乙酰胆碱 (ACh)， 包括内侧前额皮质（mPFC）和眶额皮质（OFC）。行为刺激的流出 AIE 后 mPFC 和 OFC 中的 ACh 都会减弱，认知和行为能力也会丧失 灵活性。我们最近的数据表明，AIE 引起的 CBFN 丢失是由于表观遗传沉默所致 胆碱能表型标记物，但运动可能通过 NGF 机制逆转这些 表观遗传变化并拯救胆碱能神经元。这表明 AIE 最初标记为 胆碱能神经元表型表达减少，而不是神经元细胞死亡。因此， 应探索 AIE 后 CFBN 病理恢复的机制。我们的总体假设是 AIE 诱导的皮质投射位点 NGF 减少导致胆碱能表观遗传沉默 具有 NbM、回缩和/或皮质 NbM 胆碱能神经支配功能障碍的表型 连接组，导致皮质胆碱能张力减弱和认知功能障碍。不过，适当地 AIE 之后的定时基于 NGF 的疗法（运动、NGF 基因疗法、CRISPR/dCas9-P300 编辑）将 通过胆碱能基因的复兴来重振胆碱能前脑回路，这将拯救 皮质 ACh 并恢复 AIE 引起的皮质依赖性行为损伤。我们的目标是绘制地图并 挽救 AIE 后出现的胆碱能前脑和皮质回路病理（目标 1），恢复认知 通过运动、NGF 基因治疗或胆碱能神经元的选择性化学遗传学刺激来发挥功能（目标 2)，并通过 CRISPR/dCas9 编辑确定 NGF 缺陷在 AIE 诱导的表观遗传中的核心作用 胆碱能表型基因的沉默（目标 3）。越来越多的证据支持神经保护作用 NGF 作为拯救经历神经退行性疾病的脆弱 CBFN 的一种方法，我们有强有力的证据 AIE 引起的胆碱能病理学是可以逆转的。了解胆碱能机制 神经元恢复将有助于开发更有效的疗法来治疗认知功能障碍 与酒精相关的脑损伤和其他神经退行性疾病有关。