Loss of the brain’s functional ability is a common symptom of neurodegeneration across diverse phyla. While the genetic and molecular mechanisms underlying mammalian neurodegeneration have been studied in-depth, very little is known about the evolutionary origin of these mechanism and their implication in loss of nervous system function in invertebrate species. In this project, I will build on previous research findings advancing the marine colonial tunicate Botryllus schlosseri as a model for evolutionary neuroscience. In this organism, there are two pathways of neurodegeneration: a complete degeneration of the nervous system occurs weekly as part of the asexual budding cycle, and a gradual decline in brain function is observed over years as individual colonies age. My goal is to develop and deploy the experimental approaches to identifying the specific gene products and cellular mechanisms regulating neurogenesis and neurodegeneration across phylogeny. Leveraging fine-scale knowledge of organism biology, morphology, and life history and cutting-edge bioinformatic tools and techniques, I will 1) Compare the genetic and cellular basis of neurodegeneration across two distinct pathways with different developmental origins, with specific attention to the role of immunocytes in neuronal cell death; 2) Evaluate the roles and functions of identified genes of interest in cyclical and age-induced neurodegeneration processes in order to better understand the evolutionary origin of neurodegenerative diseases; and 3) Explore the potential of transplanted neural stem cells to mitigate neurodegeneration in colony brains. Leveraging the organism’s unique and assayable life cycle as well as gene expression profiles with analogues associated with neurodegenerative diseases in humans, we will obtain new insight regarding the evolutionary processes and pathways regulating brain development, health and regeneration across phylogeny and test hypothesis with the power to inform nascent regenerative medicine and biomedical research applications.