Stress is a major risk factor for depression and exerts complex effects on brain function and behavior. In this study, we examined the neural mechanisms of stress responses in the prefrontal cortex (PFC), with particular focus on neuron/astrocyte interactions. Using dual-color fiber photometry, we simultaneously monitored neuronal and astrocytic activity during acute and chronic stress. Acute stressors, including tail pinch and immobilization, evoked coordinated increases in both neuronal and astrocytic activity. In contrast, prolonged exposure to unpredictable chronic mild stress (UCMS) produced heightened neuronal activity alongside astrocytic dysfunction. Notably, UCMS disrupted the correlation between neuronal and astrocytic signals, pointing to impaired cellular crosstalk. These findings highlight a critical role of disrupted neuron/astrocyte interactions in shaping maladaptive stress responses and suggest a potential mechanism contributing to stress-related neuropsychiatric disorders.