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.