Astrocytic glucocorticoid receptors in the ventral hippocampus modulate anxiety-like behaviors

Abstract

Stress exposure is associated with the development of anxiety disorders, and astrocytes have emerged as critical mediators of stress responses and anxiety pathogenesis. While astrocytic dysfunction has been implicated in these processes, the specific molecular mechanisms remain elusive. In this study, we demonstrate a crucial role for astrocytic glucocorticoid receptors (GRs) in the ventral hippocampus (vHPC) in modulating anxiety-like behaviors. We found that chronic restraint stress specifically reduced the GR expression in the vHPC, with no significant changes observed in the amygdala or dorsal hippocampus. Consistent with this finding, chronic corticosterone administration was found to induce anxiety-like behaviors in mice, accompanied by a significant reduction in the GR expression in the vHPC. The GR reduction, while prominent and functionally significant in astrocytes, is not exclusive to them in the vHPC under these stress conditions. Targeted deletion of GRs in astrocytes resulted in the development of anxiety-like behaviors in mice. Notably, selective ablation of astrocytic GRs specifically within the vHPC region produced similar behavioral phenotypes. RNA sequencing analysis of the vHPC from astrocytic GR-depletion mice identified potential molecular mechanisms underlying the pathomechanisms of astrocytic GRs in anxiety. These findings establish a novel pathway through which astrocytic GRs in the vHPC regulate anxiety-like behaviors, providing new insights into the neurobiological basis of stress-related anxiety disorders and identifying potential therapeutic targets.