Astrocyte glucocorticoid signaling mediates cognitive impairment induced by early-life stress

Abstract

AbstractEarly-life stress can have lifelong consequences, enhancing stress susceptibility and resulting in behavioural and cognitive deficits. While the effects of early-life stress (ELS) on neuronal function have been well-described, we still know very little about the contribution of nonneuronal brain cells to the cellular and behavioural adaptations following ELS. Here, using a rodent model of ELS, we report that astrocytes play a key role in mediating the impact of stress on amygdala-dependent behaviour and synaptic plasticity during adolescence. We report that ELS induces generalisation of fear, associated with increased levels of circulating corticosterone and activation of glucocorticoid receptors in astrocytes. In addition, we identify astrocyte glucocorticoid receptors as targets, mediating ELS-induced cognitive and synaptic impairments. This work establishes astrocytes as key elements in amygdala-dependent memory, and as central mediators of the effects of stress on cognitive function via stress hormone signalling pathways.SummaryELS impairs lateral amygdala-dependent cognition and synaptic plasticity during adolescence.Stress-induced behavioural changes were associated with astrocyte dysfunction in the lateral amygdala.Genetic disruption of astrocyte function in the lateral amygdala replicated the cognitive and synaptic impairments induced by stress.ELS induced a latent increase in blood glucocorticoid levels during adolescence.Ablating glucocorticoid signalling in astrocytes rescued cognitive impairments induced by ELS.