Excitation-Inhibition Imbalance Underlies Perioperative Neurocognitive Disorders: A Single-Nucleus Transcriptomic Perspective in Mice Hippocampus

Perioperative neurocognitive disorders (PND), highly prevalent in geriatric surgical populations, constitute a major postoperative clinical challenge associated with prolonged hospital stays and adverse surgical outcomes. Although substantial research efforts have been devoted to investigating etiology, the precise molecular mechanisms of PND remains elusive, thereby hindering the development of effective therapeutic interventions. To address this gap, we conducted single-nucleus RNA sequencing on 119,109 hippocampal cells isolated from 18-month-old PND mice and age-matched controls, alongside performing complementary electrophysiological experiments. We noticed that hippocampal neuronal excitation-inhibition (E/I) imbalance serves as a key mechanism underlying PND, which is associated with dysregulated inhibitory control of excitatory plasticity in PND pathology. Furthermore, we identified PND-specific disease-associated astrocytes—distinct from those in other cognitive disorders and linked to E/I imbalance. We also observed significant changes in oligodendrocytes, oligodendrocyte precursor cells, microglia and border associated macrophages (BAM). These cell types played distinct roles in the pathological process of PND. Our study reveals that E/I imbalance, driven by dysregulated inhibitory control of excitatory plasticity, underpins the pathogenesis of PND, providing new insights for therapeutic interventions.