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Updated: Jul 8, 2026
A Mouse Model of Orthopedic Surgery to Study Postoperative Cognitive Dysfunction and Tissue Regeneration
Published on: February 27, 2018
The Role of Hippocampal Microglial cGAS-STING Signaling Pathway in Postoperative Cognitive Dysfunction in Diabetic
Jiaqi Ning1, Mengjie Chen1, Jiaxi Liu1
1Department of Anesthesiology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, 100010 Beijing, China.
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.
Insights
Surgery exacerbates cognitive decline in diabetic mice by activating the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway in the hippocampus. This pathway activation in microglia contributes to neuroinflammation and neuronal injury, worsening postoperative cognitive dysfunction (POCD).
Area of Science:
- Neuroscience
- Immunology
- Endocrinology
Background:
- Postoperative cognitive dysfunction (POCD) is a significant concern, particularly in diabetic patients.
- The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is implicated in innate immunity and inflammation.
- Microglia, the resident immune cells of the brain, play a critical role in neuroinflammation.
Purpose of the Study:
- To investigate the role of the microglial cGAS-STING pathway in the hippocampus in the development of POCD in a diabetic mouse model.
- To determine if diabetes and surgery synergistically activate this pathway and contribute to cognitive deficits.
Main Methods:
- Diabetes was induced in mice using a high-fat, high-sugar diet and streptozotocin.
- Postoperative cognitive dysfunction was modeled via tibial fracture surgery under anesthesia.
- Cognitive function, microglial activation, cGAS-STING pathway activation, neuroinflammation, and neuronal injury were assessed using behavioral tests, western blot, immunofluorescence, and ELISA.
Main Results:
- Diabetic mice exhibited cognitive impairments, which were worsened by surgery.
- Surgery in diabetic mice led to increased hippocampal neuroinflammation (IL-1β, TNF-α), neuronal injury (cleaved caspase-3), and microglial activation (Iba-1, CD68).
- The cGAS-STING pathway was upregulated in the hippocampus, predominantly associated with microglia (Iba-1), suggesting its activation contributes to the observed pathology.
Conclusions:
- The study demonstrates that surgery-associated activation of the microglial cGAS-STING pathway in the hippocampus exacerbates neuroinflammation and neuronal injury.
- This pathway activation is a key mechanism contributing to cognitive decline in diabetic mice following surgery.
- Targeting the microglial cGAS-STING pathway may offer therapeutic potential for preventing POCD in diabetic individuals.
