Project Summary Astrocytes are glial cells involved in the regulation of neuronal synaptic formation, maturation, and plasticity. The period in development when neural circuits are shaped by experience is termed the critical period. In the visual critical period, the development of normal vision depends on proper visual input. This period is characterized by increased plasticity, whereas in adulthood plasticity is decreased and changes to the circuitry are restricted. Plasticity alterations have been shown to contribute to neurological diseases, such as glioma and schizophrenia. Astrocytes secrete different proteins that induce synapse formation or maturation, in an age-dependent manner. Experience-induced neuronal activity elicits transcriptional changes in astrocytes in the visual cortex, including the expression of immediate early gene c-fos. Fos, the c-fos coded protein, acts as a transcription factor and it has been shown to have cell-type specific targets. In astrocytes, c-fos expression is induced upon visual stimulus in the visual cortex. Further, astrocytes upregulate c-fos mRNA throughout development and into adulthood, and c-fos is downregulated when visual input is decreased. Previous findings have shown age- and experience- dependent astrocyte transcriptional changes; however, the astrocyte upstream regulators of these gene expression changes remain poorly understood. I hypothesize that astrocytes regulate experience-dependent plasticity through the expression of Fos and its subsequent regulation of astrocyte-specific late response genes leading to synapse stabilization. With my dissertation, I will elucidate the regulation of astrocyte experience- dependent transcriptional changes via Fos, and its modulatory effect on plasticity, i.e., synapse stabilization in the adult visual cortex. Preliminary data in Aim 1 suggest Fos is an experience-dependent and upstream transcriptional regulator of astrocytes’ response to neuronal activity. These data demonstrate my expertise on molecular techniques, bioinformatics, and mouse surgery. A functional approach that answers whether Fos deletion in astrocytes results in increased plasticity in the adult visual cortex, will further elucidate its role as an experience-dependent astrocyte transcriptional regulator. For the F99 phase, I propose in vivo imaging to assess the functional effects of Fos deletion in astrocytes. For the K00 phase, I will focus on disease models to assess how astrocyte transcriptional dysregulation results in functional and plasticity alterations that contribute to disease. The carefully designed training plan targets gaps in my scientific training and professional development that will ultimately allow me to advance confidently toward my goal of becoming an independent principal investigator and mentor leading a research team. I will work with my Sponsors to continue acquiring the proposed skills, and to enable me to find the right environment and mentors to further my care...