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.

项目概要 阿尔茨海默病 (AD) 患者表现出进行性记忆丧失、抑郁和焦虑， 伴随着成年海马神经发生（AHN）受损，尽管年轻的成年神经元（ABN）。 已被证明在生理条件下的记忆和情感处理中发挥重要作用， 长期以来，它们在退化 AD 大脑中的功能和治疗潜力在很大程度上仍不清楚。 问题一直集中在是否可以增强 AHN 来恢复受损的 AD 大脑 我们最近的研究表明，刺激下丘脑乳头上区。 Nucleus (SuM) 在健康野生型 (WT) 小鼠中发挥强大的神经源作用，特别是慢性模式小鼠。 SuM 的光遗传学刺激导致行为相关 ABN 的产生增加，并增强 重要的是，这些 SuM 增强的 ABN 的急性化学遗传学激活得到改善。 令人惊讶的是，我们在 5xFAD 小鼠中进一步测试了这种策略。 模式化 SuM 刺激可恢复 ABN 的数量和发育特性以及急性化学遗传学 激活一小部分 SuM 增强的 ABN（~500 ABN/DG，<0.05% 颗粒细胞总数/DG） 足以恢复 AD 小鼠的记忆并减少类似焦虑/抑郁的行为。 增强 ABN（数量、质量和活性）在 AD 功能恢复中的治疗潜力。 根据这些发现，我们提出以下目标，以破译这些有益的机制 使用两种互补的 AD 小鼠模型激活 SuM 增强的 ABN 介导的效应。 确定 SuM 增强的 ABN 的功能特性和 SuM- 的分子调节剂 目的 2 将确定 AD 小鼠神经发生的活动依赖性增强。 SuM 增强 ABN 对 AD 小鼠局部海马回路和全脑网络动态的影响。 确定 SuM 增强的 ABN 激活对小胶质细胞特性、AD 病理学和海马的影响 AD 小鼠中的功能。