Microglia in Perioperative Neurocognitive Disorders: Pathogenic Mechanisms and Emerging Concepts of Microglial Heterogeneity.

Perioperative neurocognitive disorders (PND) comprise a spectrum of cognitive disturbances after anesthesia and surgery, affecting learning, memory, and executive function. Although systemic inflammation, surgical trauma, anesthetic exposure, and patient vulnerability have been implicated in PND, the mechanisms linking perioperative stress to persistent cognitive changes remain incompletely understood. Microglia, as resident immune cells of the central nervous system, are important regulators of neuroimmune interactions and may contribute to PND through alterations in inflammatory signaling, synaptic regulation, vascular function, metabolism, and epigenetic programs. In this Overview, we summarize current evidence regarding microglial involvement in PND across five interconnected domains: neuroinflammation, blood-brain barrier dysfunction, microglia-neuron communication, mitochondrial and metabolic regulation, and epigenetic remodeling. We further discuss emerging single-cell transcriptomic and multi-omic studies indicating that microglial responses are heterogeneous, dynamic, and context dependent rather than adequately described by the traditional M1/M2 framework. We propose that PND involves complex interactions among peripheral immune activation, neurovascular dysfunction, microglial state transitions, and neuronal vulnerability. Finally, we highlight current challenges in translating microglial mechanisms into clinical applications and discuss future directions for identifying biomarkers and developing context-specific perioperative neuroprotective strategies.