Role of Cholecystokinin in the Dentate Gyrus

项目摘要 哺乳动物，包括人类，存在活跃的成体神经发生，这表明了显著的结构可塑性。 以及成熟神经系统内的再生能力。成体出生的放射状颗粒细胞(GC) 齿状回(Dg)内的神经干细胞(RNSCs)已被证明在特定形式中起着关键作用。 对记忆的记忆。记忆受损，通常与阿尔茨海默病(AD)有关，与 AD小鼠模型和人类患者的RNSC行为和海马神经发生，可能是由于缺乏 允许的利基环境，以支持神经发生。因此，确定关键的利基组件能够 维持神经干细胞和促进可持续的神经发生将使新策略的发展成为可能 增强内源性神经干细胞的功能修复。 来自人类研究的越来越多的证据为人类的改变提供了巨大的支持 阿尔茨海默病患者的CCK系统尽管有这些令人振奋的发现，CCK在 健康和阿尔茨海默病的大脑仍不清楚。我们的目标是探索内源性CCK在 调节正常和阿尔茨海默病小鼠的神经源性生态位和神经发生。这项建议是建立在一系列 我们最新的发现。具体地说，我们发现刺激DG CCK中间神经元增加CCK水平。 DG提供了一个允许的利基环境来支持RNSC的增殖和增殖的生产 CCK对齿状星形胶质细胞谷氨酸能神经元的营养促进作用 神经胶质传递。相反，减少齿状CCK通过诱导反应性星形胶质细胞破坏神经源性生态位 和神经炎症，这与rNSCs的激活和增殖的产生减少有关 子代，提示CCK在DG中具有抗炎作用。有趣的是，5xFAD小鼠表现出营养不良的CCK 神经突起和与反应性星形胶质细胞相关的齿状体内proCCK表达减少 神经发生和记忆缺陷。这些数据提示AD病理可能与齿状CCK相互作用 中间神经元影响与DG相关的各种功能方面。这些有趣的发现引发了 遵循我们想要追求的方向。目的1是验证齿状星形胶质细胞介导CCK的假说。 星形胶质细胞谷氨酸能神经传递对神经干细胞的依赖性调节和神经发生；目标2 是为了验证这样一种假设，即减少齿状CCK通过反应性损害NSC的增殖和神经发生 星形胶质细胞介导干扰素-γ信号传导到神经干细胞；目标3是测试增加齿状突 CCK可恢复5xFAD小鼠受损的神经源性生态位、神经发生和记忆。

Project Summary The existence of active adult neurogenesis in mammals, including humans, suggests striking structural plasticity and regenerative capacity within the mature nervous system. Adult-born granule cells (GCs) derived from radial neural stem cells (rNSCs) within the dentate gyrus (DG) have been shown to play a critical role in specific forms of memory. Impaired memory, commonly associated with Alzheimer’s disease (AD), correlates with impaired rNSC behavior and hippocampal neurogenesis in AD mouse models and human patients, likely due to lack of permissive niche environment to support neurogenesis. Therefore, identifying critical niche components capable of maintaining NSCs and promoting sustainable neurogenesis will enable development of novel strategies to enhance functional repair from endogenous NSCs. Increasing evidence from human studies have provided tremendous support for the alterations of cholecystokinin (CCK) system in AD patients. Despite these promising findings, the functional role of CCK in heathy and AD brains remains unknown. Our goal is to explore the unprecedented role of endogenous CCK in regulating neurogenic niche and neurogenesis in normal and AD mice. This proposal is built upon a series of our recent findings. Specifically, we found that stimulating DG CCK interneurons to increase CCK level in the DG provides a permissive niche environment to support rNSC proliferation and production of proliferating progeny through the trophic effects of CCK on dentate astrocytes in promoting their glutamatergic gliotransmission. In contrast, reducing dentate CCK disrupts neurogenic niche by inducing reactive astrocytes and neuroinflammation, which correlates with decreased activation of rNSCs and production of proliferating progeny, suggesting an anti-inflammatory role of CCK in DG. Interestingly, 5xFAD mice exhibit dystrophic CCK neurites and reduced dentate proCCK expression, which correlates with reactive astrocytes, impaired neurogenesis, and memory deficits. These data suggest that AD pathology may interact with dentate CCK interneurons to impact various functional aspects associated with DG. These interesting findings sparked the following directions we would like to pursue. Aim 1 is to test the hypothesis that dentate astrocytes mediate CCK- dependent regulation of NSCs and neurogenesis through glutamatergic gliotranmission from astrocytes; Aim 2 is to test the hypothesis that reduced dentate CCK impairs NSC proliferation and neurogenesis through reactive astrocytes mediated interferon-γ signaling onto NSCs; Aim 3 is to test the hypothesis that increasing dentate CCK restores impaired neurogenic niche, neurogenesis, and memory in 5xFAD mice.