Region-Specific Homeostatic Identity of Astrocytes Is Essential for Defining Their Response to Pathological Insults

The transformation of astrocytes into reactive states constitutes a biological response of the central nervous system under a variety of pathological insults. Astrocytes display diverse homeostatic identities that are developmentally predetermined and regionally specified. Upon transformation into reactive states associated with neurodegenerative diseases and other neurological disorders, astrocytes acquire diverse reactive phenotypes. However, it is not clear whether their reactive phenotypes are dictated by region-specific homeostatic identity or by the nature of an insult. To address this question, region-specific gene expression profiling was performed for four brain regions (cortex, hippocampus, thalamus, and hypothalamus) in mice using a custom NanoString panel consisting of selected sets of genes associated with astrocyte functions and their reactivity for five conditions: prion disease, traumatic brain injury, brain ischemia, 5XFAD Alzheimer's disease model and normal aging. Upon transformation into reactive states, genes that are predominantly associated with astrocytes were found to respond to insults in a region-specific manner. Regardless of the nature of the insult or the insult-specificity of astrocyte response, strong correlations between undirected GSA (gene set analysis) scores reporting on astrocyte reactivity and on their homeostatic functions were observed within each individual brain region. The insult-specific gene expression signatures did not separate well from each other and instead partially overlapped, forming continuums. The current study demonstrates that region-specific homeostatic identities of astrocytes are important for defining their response to pathological insults. Within region-specific populations, reactive astrocytes show continuums of gene expression signatures, partially overlapping between individual insults.