In vivo cortical neuron-astroglial functional coupling strengthens with acute stress but is impaired by chronic stress in mice

Abstract Exposure to acute, repeated, or chronic stress elicits a spectrum of cellular changes ranging from adaptive to maladaptive, including in the prefrontal cortex (PFC) where both neurons and astroglia undergo morphological, cellular and molecular remodeling. However, whether these alterations translate into altered cell activity and neuron-astroglia communication and how such changes evolve with recurrent stress or chronic stress exposure remains poorly understood. To address these questions, we used dual-color in vivo fiber photometry to longitudinally record PFC neuronal and astroglial calcium (Ca²⁺) signals in the same mice during a brief (tail pinch), sustained (immobilization) acute stress, repeated homotypic stress across weeks, and unpredictable chronic mild stress (UCMS), tracking of same cellular network across time. We found that acute stressors elicited coordinated increases in neuronal and astroglial Ca²⁺ activity and enhanced their Ca 2+ signal coupling. Repeated intermittent stress induced comparable per-cell-type responses but progressively strengthened coupling, suggesting adaptation. We also demonstrated that this trajectory is reversed under UCMS; neuronal Ca²⁺ reactivity to stress challenge was sensitized whereas astroglial reactivity was blunted. This was associated with a weakened intercellular coupling (-3.5 fold) and astroglia became progressively hyporesponsive to neuronal drive. UCMS-induced neuron-astroglia functional coupling impairment coincided with the onset of anhedonia- and anxiety-like behavioral deficits. These findings position impaired neuron-astroglial functional coupling as a potential substrate of stress-induced cortical dysfunction that may distinguish adaptive from maladaptive stress responses, offering a mechanistically tractable target for intervention in stress-related psychiatric disease such as depression, where dysfunction in both cell types has been consistently reported.