Enhancing adult-born neurons to restore brain functions in Alzheimer's disease

增强成年神经元以恢复阿尔茨海默氏病的大脑功能

• 批准号: 10753894
• 负责人: Juan Song
• 金额: $ 72.56万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10753894
• 关键词: Acute; Adult; Affective; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease pathology; Alzheimer' s disease patient; Anatomy; Animal Diseases; Anxiety; Behavior; Behavioral; Brain; Cell Nucleus; Chronic; Cognitive; Development; Electrophysiology (science); Emotions; Exhibits; Fiber; Functional Magnetic Resonance Imaging; Genetic; Health; Hippocampus; Hypothalamic structure; Image; Impairment; Knock-in; Knowledge; Mediating; Memory; Memory Loss; Mental Depression; Microglia; Molecular; Mus; Nature; Neurons; Neurosciences; Pathway interactions; Pattern; Performance; Phagocytosis; Phosphoproteins; Photometry; Physiological; Play; Population; Production; Property; Proteomics; Recovery of Function; Role; Slice; Testing; Therapeutic; Wild Type Mouse; anxiety reduction; anxiety-like behavior; awake; behavior test; brain dysfunction; confocal imaging; functional restoration; granule cell; improved; in vivo; mouse model; neurogenesis; neuroinflammation; novel therapeutic intervention; optogenetics; overexpression; phosphoproteomics; receptor; young adult

Project Summary Patients with Alzheimer’s disease (AD) exhibit progressive memory loss, depression, and anxiety, accompanied by impaired adult hippocampal neurogenesis (AHN). Although young adult-born neurons (ABNs) have been shown to play an important role in memory and emotion processing under physiological conditions, their function and therapeutic potential in degenerated AD brains remain largely undefined. A long-standing question has been centering on whether AHN could be enhanced in otherwise impaired AD brains to restore cognitive and affective functions. Our recent study showed that stimulating hypothalamic supramammillary nucleus (SuM) exerts robust neurogenic effects in healthy wild-type (WT) mice. Specifically, chronic patterned optogenetic stimulation of SuM leads to increased production of behaviorally-relevant ABNs with enhanced developmental properties. Importantly, acute chemogenetic activation of these SuM-enhanced ABNs improves memory performance and reduces anxiety-like behavior. We further tested this strategy in 5xFAD mice. Strikingly, patterned SuM stimulation restores the number and developmental properties of ABNs and acute chemogenetic activation of a small population of these SuM-enhanced ABNs (~500 ABNs/DG, <0.05% total granule cells/DG) is sufficient to restore memory and reduce anxiety/depression-like behaviors in AD mice. These findings highlight the therapeutic potential of enhanced ABNs (number, quality, and activity) in functional restoration in AD. Building upon these findings, we propose the following aims to decipher the mechanisms underlying these beneficial effects mediated by activation of SuM-enhanced ABNs using two complementary AD mouse models. Aim 1 will determine the functional properties of SuM-enhanced ABNs and the molecular regulators underlying SuM- mediated enhancement of neurogenesis in AD mice. Aim 2 will determine activity-dependent contribution of SuM-enhanced ABNs to local hippocampal circuit and brain-wide network dynamics in AD mice. Aim 3 will determine the effects of SuM-enhanced ABN activation on microglia properties, AD pathology, and hippocampal function in AD mice.

项目摘要 阿尔茨海默氏病（AD）暴露的进行性记忆丧失，抑郁和动画的患者， 伴随着成人海马神经发生受损（AHN）。 已显示在生理条件下的记忆和情感处理中起着重要作用， 它们在退化的广告大脑中的功能和治疗潜力在很大程度上仍然不确定。长期存在 问题一直以其他质朴的广告大脑中的AHN为中心，以恢复 认知和情感功能。我们最近的研究表明，刺激下丘脑超肌 核（SUM）在健康的野生型（WT）小鼠中发挥强大的神经源作用。具体来说，长期图案 总和的光遗传学模拟导致行为相关的ABN的产生增加，并增强 发展特性。重要的是，这些衡量ABN的急性化学激活有所改善 记忆性能并降低类似动画的行为。我们进一步在5XFAD小鼠中测试了这一策略。令人惊讶的是， 图案总和模拟恢复ABN和急性化学生成的数量和发育特性 这些汇总ABN的少数人群的激活（〜500 ABN/DG，<0.05％的总颗粒细胞/DG） 足以恢复记忆并减少AD小鼠的动画/抑郁症行为。这些发现突出了 AD功能恢复中增强ABN的治疗潜力（数量，质量和活动）。建筑 根据这些发现，我们提出以下旨在破译这些有益的机制 使用两个完整的AD鼠标模型激活求和ABN的效果。目标1意志 确定加强ABN的功能特性和基于sum-的分子调节剂的功能特性 AD小鼠神经发生的介导的增强。 AIM 2将确定与活动有关的贡献 AD小鼠中局部海马电路和大脑网络动力学的求和性ABN。目标3意志 确定增强ABN激活对小胶质细胞特性，AD病理学和海马的影响 在AD小鼠中的功能。