Role of Cholecystokinin in the Dentate Gyrus

项目摘要 哺乳动物（包括人类）存在活跃的成年神经发生，这表明了惊人的结构可塑性 以及成熟神经系统的再生能力。成体颗粒细胞（GCs）来源于桡动脉 齿状回（DG）内的神经干细胞（rNSCs）已被证明在特定形式中发挥关键作用， 记忆。记忆力受损，通常与阿尔茨海默病（AD）相关，与受损的 AD小鼠模型和人类患者中的rNSC行为和海马神经发生，可能是由于缺乏 允许的生态位环境以支持神经发生。因此，确定关键的利基组成部分， 维持神经干细胞和促进可持续的神经发生将使开发新的策略， 增强内源性NSC的功能修复。 越来越多的人类研究证据为基因的改变提供了巨大的支持。 胆囊收缩素（CCK）系统在AD患者中的作用尽管这些有希望的发现，CCK的功能作用， 健康和AD大脑仍然未知。我们的目标是探索内源性CCK在 在正常和AD小鼠中调节神经原生态位和神经发生。这一建议是建立在一系列 我们最近的发现具体地说，我们发现刺激DG CCK中间神经元增加CCK水平， DG提供了一个允许的生态位环境，以支持rNSC增殖和增殖的 通过CCK对齿状回星形胶质细胞的营养作用促进其细胞增殖， 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原性龛 和神经炎症，其与rNSC的活化减少和增殖的细胞因子的产生相关。 子代，提示CCK在DG中的抗炎作用。有趣的是，5xFAD小鼠表现出营养不良的CCK 神经突和减少的齿状核proCCK表达，这与反应性星形胶质细胞相关，受损 神经发生和记忆缺陷这些数据表明，AD病理可能与齿状CCK相互作用 interneurons影响与DG相关的各种功能方面。这些有趣的发现引发了 按照我们想要追求的方向。目的1是验证齿状回星形胶质细胞介导CCK-1的假说。 NSC和神经发生通过星形胶质细胞的神经胶质传递的依赖性调节;目的2 是为了验证这一假设，即减少齿状CCK损害神经干细胞的增殖和神经发生，通过反应， 星形胶质细胞介导的干扰素-γ信号传导到NSC上;目的3是检验增加齿状回的假设， CCK可恢复5xFAD小鼠受损的神经原生态位、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.