The Role of Hippocampal Microglial cGAS-STING Signaling Pathway in Postoperative Cognitive Dysfunction in Diabetic Mice

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OBJECTIVE: This study aimed to determine whether activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway within hippocampal microglia contributes to postoperative cognitive dysfunction (POCD) in a diabetic mouse model. Diabetes was induced using a high-fat, high-sugar (HFHS) diet combined with streptozotocin (STZ). METHODS: Diabetes was induced in C57BL/6J mice using an HFHS diet followed by STZ. POCD was modeled via tibial fracture surgery under general anesthesia. Cognitive function was assessed using the Open Field Test, Y-maze, and contextual fear conditioning. cGAS-STING pathway activation was evaluated by western blot for cGAS and STING expression. Microglial activation was assessed by co-localization of Iba-1 and CD68 by immunofluorescence, and the co-localization of STING with Iba-1 in the hippocampus was examined by immunofluorescence. Hippocampal neuroinflammation was quantified by enzyme-linked immunosorbent assay (ELISA) for interleukin-1beta (IL-1β) and tumor necrosis factor-alpha (TNF-α). Neuronal injury and apoptosis were evaluated by Nissl staining and western blot for cleaved caspase-3. RESULTS: Compared to non-diabetic controls, diabetic mice exhibited cognitive impairments, which were more pronounced in those that underwent surgery. This was accompanied by significant hippocampal neuronal loss, upregulated cleaved caspase-3 expression, and elevated IL-1β and TNF-α levels. Furthermore, diabetic mice that underwent surgery displayed increased expression of microglial activation markers (Iba-1 and CD68) and evidence of cGAS-STING pathway activation in the hippocampus. Immunofluorescence co-localization experiments further suggested a predominant association of this pathway with the microglial marker Iba-1. CONCLUSION: These findings suggest that surgery-associated overactivation of the microglial cGAS-STING pathway in the hippocampus may exacerbate neuroinflammation and neuronal injury, thereby contributing to cognitive decline in diabetic mice.

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