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：Lisa Savage＆Ryan Vetreno 恢复青少年酒精的基础前脑皮质投射电路的破坏 项目摘要 青春期大量饮酒与大脑结构的持续变化有关 连通性和成人皮质介导的认知功能。关键的病理变化一致观察到 在青少年暴饮暴食的啮齿动物模型中 皮质神经生长因子（NGF），抑制胆碱能表型，并长期降低 功能性胆碱能基础前脑神经元（CBFN）的数量。胆碱能投射神经元 在基底核中，大细胞感应（NBM）为额叶皮层提供乙酰胆碱（ACH）， 包括内侧前额叶皮层（MPFC）和眶额皮质（OFC）。行为刺激的外排 在AIE之后，MPFC和OFC中的ACH均钝化，并且认知和行为丧失 灵活性。我们最近的数据表明，AIE引起的CBFN损失是由于表观遗传沉默引起的 胆碱能表型标记物，但可能通过NGF机制进行锻炼可以扭转这些 表观遗传变化和救助胆碱能神经元。这表明AIE最初是由 胆碱能神经元表型的表达减少，而不是神经元细胞死亡。因此， 应探讨机制以恢复AIE之后的CFBN病理。我们的总体假设是 AIE引起的皮质投影位点NGF的减少导致胆碱能的表观遗传沉默 具有NBM的表型，缩回和/或功能失调的皮质-NBM胆碱能的重新效果 连接组，导致皮质胆碱能张力和认知功能障碍的钝化。但是，适当 AIE的定时疗法（运动，NGF基因疗法，CRISPR/DCAS9-P300编辑） 通过胆碱能基因的振兴胆碱能的前脑回路，该电路将营救 皮质ACH并恢复AIE诱导的皮质依赖性行为损伤。我们的目标是映射和 AIE（AIM 1），恢复认知的拯救胆碱能前脑和皮质电路病理学 通过运动，NGF-基因治疗或胆碱能神经元的选择性化学刺激（AIM） 2），并通过CRISPR/DCAS9编辑确定NGF缺陷的核心作用 胆碱能表型基因的沉默（AIM 3）。安装证据支持 NGF是拯救弱势CBFN经历神经变性的课程，我们有强有力的证据 AIE引起的胆碱能病理可以逆转。了解胆碱能的机制 神经元恢复将有助于开发更有效的治疗认知功能障碍的疗法 与酒精相关的脑损伤和其他神经退行性疾病有关。