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

项目摘要 阿尔茨海默病（AD）患者表现出进行性记忆丧失、抑郁和焦虑， 伴随着受损的成年海马神经发生（AHN）。虽然年轻的成人出生的神经元（ABN） 已经显示在生理条件下的记忆和情感处理中起重要作用， 它们在退化的AD脑中的功能和治疗潜力在很大程度上仍不明确。一个长期存在的 问题一直集中在是否AHN可以增强，否则受损AD大脑恢复 认知和情感功能。我们最近的研究表明，刺激下丘脑乳头体上 细胞核（SuM）在健康野生型（WT）小鼠中发挥强大的神经原性作用。具体而言，慢性模式化 SuM的光遗传学刺激导致行为相关ABN的产生增加， 发展特性。重要的是，这些SuM增强的ABN的急性化学发生活化改善了 记忆力和减少焦虑行为。我们在5xFAD小鼠中进一步测试了该策略。引人注目的是， 模式化的SuM刺激恢复ABN的数量和发育特性， 这些SuM增强的ABN的小群体的活化（~500 ABN/DG，<0.05%总颗粒细胞/DG） 足以恢复记忆并减少AD小鼠的焦虑/抑郁样行为。这些发现强调 增强ABN（数量、质量和活性）在AD功能恢复中的治疗潜力。建筑 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，通过激活SuM增强的ABN介导的作用。目标1将 确定SuM增强的ABN的功能特性和SuM的分子调节剂- 介导的增强AD小鼠的神经发生。目标2将确定以下活动的依赖性贡献： SuM增强ABN对AD小鼠局部海马回路和全脑网络动力学的影响目标3将 确定SuM增强的ABN激活对小胶质细胞特性、AD病理学和海马神经元的影响。 在AD小鼠中发挥作用。

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.