Excitation-inhibition imbalance underlies perioperative neurocognitive disorders: a single-nucleus transcriptomic...

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 Western blotting and electrophysiological experiments. We propose 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-associated astrocytes and oligodendrocytes-distinct from those in other cognitive disorders and linked to E/I imbalance. These cell types played distinct roles in the pathological process of PND. Our study proposes that E/I imbalance, associated with dysregulated inhibitory control of excitatory plasticity, underlies the pathogenesis of PND, providing new insights for therapeutic interventions.