In addition to their functions in healthy CNS, astrocytes exhibit an evolutionarily ancient response to CNS injury and disease commonly referred to as astrocyte reactivity that was long regarded as homogeneous and functionally passive [1, 8–10]. Instead, over the last twenty-five years, experimental studies using causation-testing transgenic manipulations and other technologies have revealed that astrocyte reactivity can lead to a diverse set of potential changes in astrocyte morphology, molecular expression and functions that can powerfully influence outcomes in all types of CNS disorders including traumatic injury [11–13], autoimmune inflammation [14–18], microbial infections [19–21], tumor formation [22, 23], exposure to environmental toxins [24, 25], peripheral metabolic disorders [26] and neurodegenerative diseases [27–29]. An extensive body of literature shows that reactive astrocytes can respond to diverse molecular signals that derive from many cell types including neurons, other glia, local stromal cells, microbes, serum proteins, as well as blood borne immune cells and molecules, from metabolic disorders in other tissues (Figure 1A); in response to such non-cell autonomous stimuli, astrocytes can produce a multitude of molecular signals that can influence many different neural
