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 UO1：丽莎·萨维奇和瑞安·维特雷诺 青少年酒精对基底前脑-皮质投射环路破坏的恢复 项目摘要 青春期大量饮酒与大脑结构的持续变化有关， 连接性和成人皮质调节的认知功能。持续观察到严重的病理变化 在青少年狂欢酒精暴露的啮齿动物模型中(青少年间歇性乙醇；AIE)是一种减少 皮质神经生长因子(NGF)的抑制，胆碱能表型的抑制，以及长期 功能性胆碱能基底前脑神经元(CBFN)数量。胆碱能投射神经元 在基底核内，大细胞复合体(NBM)向额叶皮质提供乙酰胆碱(ACh)， 包括内侧前额叶皮质(MPFC)和眶前叶皮质(OFC)。行为刺激的外流 AIE后，mPFC和OFC中的ACh都被钝化，认知和行为能力下降 灵活性。我们最近的数据表明，AIE诱导的CBFN的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，可以逆转这些 表观遗传学改变和挽救胆碱能神经元。这表明AIE最初由一个 减少胆碱能神经元表型的表达，而不是神经元细胞死亡。因此， 应探讨AIE后CFBN病理恢复的机制。我们最重要的假设是 AIE诱导皮质投射部位NGF减少导致胆碱能表观遗传沉默 皮质-NBM胆碱能神经再支配的表型与NBM、退缩和/或功能障碍 连接体，导致皮质胆碱能张力减退和认知功能障碍。然而，适当地， AIE后基于NGF的定时治疗(运动、NGF基因治疗、CRISPR/dCas9-P300编辑)将 通过激活胆碱能基因来重振胆碱能前脑回路，这将挽救 大脑皮层ACh和恢复AIE诱导的皮质依赖行为损伤。我们的目标是绘制地图和 抢救AIE后出现的胆碱能前脑和皮质环路病理(目标1)，恢复认知 通过运动、NGF基因治疗或选择性胆碱能神经元化学刺激发挥功能(目的 2)，并通过CRISPR/dCas9编辑，确定NGF缺陷在AIE诱导的表观遗传学中的核心作用 胆碱能表型基因沉默(目标3)。越来越多的证据支持药物的神经保护作用 NGF作为抢救正在经历神经变性的脆弱CBFN的一个疗程，我们有强有力的证据 AIE诱导的胆碱能病理是可以逆转的。对胆碱能机制的认识 神经元的恢复将有助于开发更有效的治疗认知功能障碍的方法 与酒精相关的脑损伤和其他神经退行性疾病有关。