Astrocyte activation contributes to exertional heatstroke-induced learning and memory impairment in mice

Exertional heatstroke (EHS) is a life-threatening medical condition with a high mortality rate, characterized by dysfunction of the central nervous system, including memory impairment. Astrocytes have been reported to be closely related to learning and memory process. However, the role of astrocytes in EHS has not been elucidated. In this study, an EHS mouse model was established to recapitulate the physical state of human in severe environment of high temperature and humidity. EHS mice showed significant memory decline in novel location recognition and shuttle box tests. To investigate the underlying mechanisms, RNA sequencing of the hippocampal tissue was performed, and the results indicated that astrocytes and neuroinflammation-related signaling pathways were activated in EHS mice. The activation of astrocytes was confirmed by the increased protein and mRNA levels of GFAP. The production of pro-inflammatory factors, including IL-6, IL-1βand TNF-α, was also increased. Furthermore, we used fluoxetine (Flu) to suppress astrocyte activation. Flu significantly improved learning and memory impairment of EHS mice and reversed the upregulation of GFAP. Therefore, our data suggest that EHS triggers hippocampal astrocyte activation accompanied by a astrogliosis-associated neuroinflammatory response with elevated pro-inflammatory cytokine expression, contributing to learning and memory impairment in mice. Flu serves as a potential therapeutic drug in EHS-induced learning and memory disorder.