Astrocytic oxytocin receptors mediate behavioral stress response through Gαi signaling in the central amygdala

Anticipated reactions to stressful situations are vital for the survival and well-being of organisms, and abnormal reactions are involved in stress-related disorders. The neuropeptide oxytocin is a key modulator ensuring well-adapted stress responses. Oxytocin acts on both neurons and astrocytes, but the molecular and cellular mechanisms mediating stress response remain poorly understood. Here, we focus on the amygdala, a crucial hub that integrates and processes sensory information through oxytocin-dependent mechanisms. Using an acute stress paradigm in mice, genetic and pharmacological manipulations combined with molecular, morphological, electrophysiological and behavioral approaches, we reveal that oxytocinergic modulation of the freezing response to stress is mediated by transient, Gαi-dependent retraction of astrocytic processes, followed by enhanced neuronal sensitivity to extracellular potassium in the amygdala. Our findings elucidate a pivotal role for oxytocin-dependent signaling in astrocytes that is required for proper anticipated behavioral response to stressful situations.