Early-life stress induces persistent astrocyte dysfunction resulting in fear generalisation

Early-life stress can have lifelong consequences, enhancing stress susceptibility and resulting in behavioral and cognitive deficits. While the effects of early-life stress on neuronal function have been well-described, we still know very little about the contribution of non-neuronal brain cells. Investigating the complex interactions between distinct brain cell types is critical to fully understand how cellular changes manifest as behavioral deficits following early-life stress. Here, using male and female mice we report that early-life stress induces anxiety-like behavior and fear generalisation in an amygdala-dependent learning and memory task. These behavioral changes were associated with impaired synaptic plasticity, increased neural excitability, and astrocyte dysfunction. Genetic perturbation of amygdala astrocyte function by either silencing these cells or reducing astrocyte network function was sufficient to replicate cellular, synaptic, and fear memory changes associated with early-life stress. These data provide mechanistic links between early-life stress and astrocyte dysfunction. Our data reveal a role of astrocytes in tuning emotionally salient memory with astrocyte dysfunction resulting in fear generalisation. Further understanding of how astrocytes are affected by stress might offer new insights into the long-term impact of early-life stress on affective states.