The Influence of IGF-1 on Astrocytic Regulation of Learning and Memory PROJECT SUMMARY/ABSTRACT The goal of this R15 project is to engage student researchers in the laboratory while examining the role of insulin-like growth factor-1 in regulating astrocyte function in the aging brain. Our focus will be on examining the ability of astrocytes to release signals to neurons when they experience a loss of IGF-1, and ultimately what the loss of IGF-1 signaling within astrocytes does to learning and memory. We have developed two novel mouse models of inducible IGF- 1 deficiency in astrocytes: one model reduces the receptor so we can identify how IGF-1 regulation of astrocytes influences cognition, and the other reduces the ligand production within astrocytes to determine if IGF-1 released from these cells to nearby cells is important for cognition. We will utilize these models, as well as in vitro astrocyte cultures where we pharmacologically and genetically manipulate IGF-1 signaling to explore how reduced IGF-1 after development influences glutamate/glutamine cycling, ATP release, growth factor release, as well as several aspects of cognition. We hypothesize that IGF-1 continues to support the beneficial aspects of astrocyte function even after development. Overall, this hypothesis would suggest that the age-related loss of IGF-1 would be detrimental to the functions of astrocytes in the aging brain, and ultimately to the overall function of the aging brain. This research will address the significant knowledge gap that exists related to how aging influences astrocyte function and whether growth factors continue to play a role in maintaining glial function long after development. Importantly, it will engage student scientists in the NIH emphasis areas of geroscience and neuroscience.