Enhancing astrocytic GAT-3 in zona incerta diminishes fear memory generalization through remodeling neural network.

Subpopulations within the zona incerta (ZI) have been implicated in the encoding of post-traumatic stress disorder (PTSD)-associated phenotypes, including fear response and fear memory generalization. However, its neural integration mechanism underlying ZI-mediated regulation of these PTSD-related pathophysiological processes remains poorly elucidated. Here, we systematically investigated the role of astrocytes in encoding neural dynamics in an odor-cue related mouse model of PTSD. We observed aberrant astrocyte-neuron correlative dynamics in the ZI of the PTSD mice. Moreover, neuronal hypoactivity was positively correlated with downregulated GAT-3 expression in astrocytes. Targeted enhancement of GAT-3 functions in ZI astrocytes suppressed excessive neuronal firing evoked by conditioned cues, reduced aberrant increases in beta and gamma band oscillatory power elicited by neutral cues, and reversed the pathological beta-low gamma phase-amplitude coupling-a neural oscillatory mechanism critical for cue discrimination. Collectively, our findings demonstrate that astrocyte-driven neural integration underlies the pathogenesis of fear memory generalization in PTSD Targeted intervention of astrocytic GAT-3 remodels the integration of ZI neural network, which may serve as a potential therapeutic strategy to alleviate pathological fear memory generalization in PTSD.