UC San Diego

Astrocytes, the most numerous brain glia, play crucial roles in maintaining brain homeostasis, supplying energy, and mediating the injury response, as well as regulating neuronal synapse formation and function. Astrocytes are highly dynamic, sensing and responding to a large variety of factors and neuronal activity, changing their function and morphology in response to extrinsic events. This dissertation investigates the extent of this dynamism under physiological conditions, interrogating how astrocytes mature, affect synaptic plasticity, and change in old age. I used astrocyte-ribotag to isolate murine astrocyte-enriched mRNA in vivo, RNA sequencing to identify and quantify mRNA, and validated relevant astrocyte gene expression changes. Together these data provide a comprehensive mRNA-seq database of developing, plastic, and adult cortical astrocytes, as well as adult and aged astrocyte gene expression across the visual cortex, motor cortex, hypothalamus, and cerebellum.

Chapter 2 identifies astrocyte genes altered by aging across brain regions, and regionally unique aging changes. Aging astrocytes show minimal alteration in basic function, but upregulate genes that eliminate synapses, and partially resemble reactive astrocytes. I find that alterations to astrocytes in aging create an environment permissive to synapse elimination and neuronal damage, potentially contributing to aging-associated cognitive decline.

In Chapter 3, I demonstrate that adult astrocytes are highly regionally distinct, implying widely different functionality depending on brain region. In aging, astrocytes exhibit an order of magnitude different level of gene expression changes based upon regional identity. In Chapter 4, I find that astrocyte identity is in flux in postnatal development, with key functional changes pegged to developmental stage and circuit-level changes, and I further used this data to identify markers of astrocyte maturity. Astrocytic gene expression was altered in visual cortex by plasticity paradigms, though there were few common changes across different plasticity paradigms. These data demonstrate that astrocytes are not static; however, the magnitude of their adaptation is highly variable, both on the level of what population/region is being surveyed, and what provokes a response. Overall, this dissertation demonstrates that astrocytic dynamism is prominent during changes in the brain, from regional changes, to circuit changes in development and plasticity, and in aging.