Astrocytes are the primary cell type in the central nervous system, responsible for maintaining the stability of the brain's internal environment and supporting neuronal functions. Researches have demonstrated the close relationship between astrocytes and the pathophysiology and etiology of major depressive disorder. However, the regulatory mechanisms of astrocytes during depression remain unclear. The aim of this study is to examine the alterations of calcium signaling of astrocytes in the dorsal raphe nucleus (DRN), the calcium signaling alterations of neurons in both the DRN and medial prefrontal cortex (mPFC), and the alteration of depressive-like behaviors by activation of DRN astrocytes using chemogenetics in chronic social defeat stress (CSDS) mice. The results showed that the intensity of calcium signaling in DRN astrocytes was decreased and the frequency of calcium signaling was lower after CSDS. The activation of DRN astrocytes increased the calcium signaling of the neurons including CaMKII