Gamma Oscillation Disruption Induced By Microglial Activation Contributes to Perioperative Neurocognitive Disorders in Aged Mice

Perioperative neurocognitive disorder (PND) is a prevalent postoperative complication of the central nervous system (CNS) in elderly patients. Advanced age is an independent risk factor for developing PND. Microglia are essential immune cells in the CNS and play a critical role in neuroinflammation. The activation of microglia is closely linked to PND, although the precise mechanism remains unclear. Gamma oscillations (30-100 Hz) are associated with higher cognitive functions, including attention. The aim of this study was to investigate the mechanism by which microglial activation in PND disrupts gamma oscillations. The study utilized 18-month-old male C57BL/6 J mice and established a PND model through exploratory laparotomy. The results of both Contextual Fear Conditioning (CFC) and Morris Water Maze (MWM) experiments demonstrated that exploratory laparotomy could lead to hippocampus-dependent neurocognitive dysfunction in aged mice. We observed that exploratory laparotomy induced the transformation of microglia in the hippocampus of aged mice into an activated phenotype characterized by enlarged cell bodies and shortened processes. This transformation was accompanied by a significant increase in the expression levels of pro-inflammatory factors in hippocampal tissue, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6). Specific depletion of microglia in aged mice, achieved by drinking water supplemented with the colony-stimulating factor 1 receptor (CSF1R)/c-Kit kinase inhibitor PLX3397 for seven consecutive days, resulted in a reduction of postoperative hippocampal neuroinflammation and a significant improvement in cognitive dysfunction. Similarly, perioperative inhibition of microglial activation with minocycline resulted in cognitive improvement. Additionally, we found that the expression levels of hippocampal parvalbumin (PV) and glutamate decarboxylase 67 (GAD67) were significantly reduced following exploratory laparotomy, which was accompanied by disturbed gamma oscillations. Depletion of microglia restored the expression levels of PV and GAD67 and significantly improved the disturbances in gamma oscillations. These findings suggest that the activation of hippocampal microglia and the associated neuroinflammatory response following surgery play a crucial role in PND. The underlying mechanism may be related to disturbed gamma oscillations and a reduction in the inhibitory function of PV interneurons.

Gamma oscillations; Microglia; Neuroinflammation; Parvalbumin (PV); Perioperative Neurocognitive Disorders (PND).