Astrocytes in the paraventricular nucleus mediates inflammation-related depression in mice treated with lipopolysaccharide.

Abstract

BACKGROUND: Inflammation has been implicated in the pathogenesis of depression, yet the role of astrocytes in modulating these processes remains poorly understood. This study aimed to explore the involvement of paraventricular nucleus (PVN) astrocytes in inflammation-related depression, focusing on their impact on depression-like behaviors, neuronal activity, and immune responses. METHODS: We used the lipopolysaccharide (LPS)-induced depression model to evaluate depression-like behaviors in mice through sucrose preference, open field, and forced swim tests. Calcium dynamics in PVN astrocytes were measured with fiber photometry. Chemogenetic manipulation of astrocyte activity was achieved using AAV vectors encoding hM4Di and hM3Dq receptors. GFAP expression, c-Fos activation, and inflammatory cytokine levels were assessed by immunohistochemistry and ELISA. RESULTS: LPS treatment induced depressive-like behaviors in mice, which were accompanied by the activation of PVN astrocytes, as evidenced by increased GFAP expression and elevated calcium influx in these cells. Chemogenetic inhibition of PVN astrocytes reversed these depressive-like behaviors, as evidenced by improvements in sucrose preference, reduced anxiety, and decreased despair. Conversely, activation of PVN astrocytes alone was sufficient to induce depressive-like behaviors. Additionally, LPS treatment altered neuronal activity and disrupted immune regulation within the PVN. Notably, inhibition of PVN astrocytes attenuated the LPS-induced overactivation of neurons and alleviated the associated inflammatory dysfunction. CONCLUSIONS: Our findings underscore the role of PVN astrocytes in modulating depression-related behaviors through neuronal activity and inflammation regulation. These results provide insights into the cellular mechanisms of inflammation-induced depression and suggest targeting PVN astrocytes as a potential therapeutic strategy.