Inflammation associated microglial expansion disrupts hippocampal glial network communication, driving postoperative neurocognitive impairment

Background: Postoperative neurocognitive impairment (PNCI) significantly affects the recovery and long-term outcomes of elderly patients, with central nervous system (CNS) inflammation serving as the key pathogenic driver of its development. As the resident immune cells of the CNS, microglia play a crucial role in regulating perioperative inflammation and maintaining homeostasis. However, the contribution, phenotypic heterogeneity, and communication network of perioperative microglia in the development of PNCI remain insufficiently characterized.

Methods: 18-month-old mice underwent surgery and developed PNCI. The hippocampi of mice in both control and surgery groups were dissected 24 h postoperatively for single-cell RNA Sequencing. Immunofluorescence coupled with fluorescence in situ hybridization was used to verify the number of subpopulations and the expression levels of target RNA transcripts in the hippocampus. Cognitive function tests were conducted to evaluate the effects of the TNF inhibitor etanercept in PNCI model.

Results: Eight microglial subpopulations and six astrocytic subpopulations were identified in the hippocampus. Postoperatively, the percentage of microglial subpopulations underwent dramatic changes, with inflammation associated microglia (IAM) increasing more than 14-fold and transition state microglia (TSM) increasing more than 33-fold. These alterations were accompanied by a marked enhancement of intercellular communications among glial cells, particularly driven by the activation of TNF signaling pathway in IAM. This pathway, along with its associated regulatory network, critically modulated the function of astrocytes and endothelial cells, thereby playing a pivotal role in CNS inflammation and the subsequent development of PNCI. Notably, administration of TNF inhibitor etanercept attenuated IAM activation and glial network communication in the hippocampus, which was associated with improved cognitive performance in PNCI mice.

Conclusion: These results highlight the pivotal role of TNF signaling activation in IAM and its associated glial cell communication as the fundamental mechanism driving hippocampal CNS inflammation, which subsequently contributes to the onset and progression of PNCI.

Supplementary Information: The online version contains supplementary material available at 10.1186/s12974-025-03566-5.

Glial network communication; Inflammation associated microglia; Postoperative neurocognitive impairment; Single cell RNA sequencing; Tumor necrosis factor.