Abstract
In this review, we synthesize recent conceptual and experimental advances in neuroscience, highlighting selected studies that delineate the roles of reactive microglia and astrocytes in the contexts of developmental inflammatory stress, neurodegenerative diseases, and cellular senescence. Since the characterization of disease-associated glial phenotypes in 2017, building on earlier pioneering discoveries, we focus here on disease-associated microglia (DAM) and disease-associated astrocyte (DAA) to reassess their contributions to glio-inflammation. It is now recognized that the stress-induced glial states are far from uniform; however, the ontogeny, molecular determinants, and functional consequences of this heterogeneity remain incompletely understood, particularly in psychiatric disorders, Alzheimer’s disease, and amyotrophic lateral sclerosis. Accordingly, we compare the glial heterogeneity and its underlying mechanisms across translational mouse models and human neuropathology, considering their evolutionary and physiological contexts. While this review does not aim to be exhaustive, we propose an integrative framework that redefines glial stress responses through the combined lenses of inflammation, transcriptomics, mitochondrial dynamics, lipid metabolism, epigenomic regulation, and cellular senescence. Finally, we outline emerging frontiers for AI-enabled multi-omic physiological and pathological approaches, emphasizing their potential to illuminate glial state transitions and accelerate therapeutic discovery in the near future.