Temporal cortex astrocytic Gi-GPCR signaling regulates learned threat responses

Astrocytes are increasingly recognized as dynamic modulators of brain circuit function, memory processing, and behavior. Emerging evidence suggests that astrocytic G-protein-coupled receptors (GPCRs) are key regulators of these processes through their influence on intracellular signaling and neuron-glia interactions. Here, we show that the repertoire of functionally expressed GPCRs in cortical astrocytes is broader than previously appreciated. Yet, how distinct GPCR pathways contribute to behavioral regulation remains unknown for most brain areas and behavioral contexts. We therefore investigated the role of astrocytic GPCR signaling in the temporal cortex, a region that integrates multimodal sensory information and learned fear associations. Using chemogenetic tools to selectively activate distinct GPCR pathways in astrocytes, we demonstrate that Gi-coupled GPCR signaling, but not Gs- or Gq-coupled signaling, enhances fear memory retrieval. In vivo fiber photometry revealed that temporal cortex astrocytes exhibit robust Ca2+ transients to neutral, conditioned auditory and aversive sensory stimuli. Notably, astrocytic Gi-GPCR activation attenuated cue-evoked Ca2+ transients during memory retrieval. Together, these findings identify astrocytic GPCR signaling as a pathway-specific regulator of fear memory retrieval and suggest that astrocytic Gi-GPCR signaling modulates the processing of sensory cues to drive defensive behavior.