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Excitation-inhibition shift in hippocampal of perioperative neurocognitive disorders: a single-cell landscape glance of pathological phenotype

ABSTRACT: Perioperative neurocognitive disorders (PND) are a common complication in elderly patients. PND seriously worsens the outcome of surgery, leads to a decline in the quality of life of patients after surgery, and increases the consumption of medical and social resources. However, at present, the pathogenesis of PND is unclear and the treatment is limited, so a comprehensive study on the pathogenesis of PND is urgently needed. We analyzed the hippocampus of 18-month-old PND mice by single-nucleus RNA sequencing, and obtained a landscape of cell type classification and phenotype. We revealed that PND induced abundant changes of crosstalk between inhibitory neurons and excitatory neurons. Through multi-dimensional analysis and electrophysiological experiments, We propose disturbance of neuronal excitation-inhibition (E/I) balance in hippocampus is a crucial mechanism of PND. More, by analyzing the trajectories of PND disease development, we suggest that PND-specific disease-associated astrocytes are different from known cognitive disease-associated astrocytes. We also showed changes of oligodendrocyte, OPCs and CNS associated macrophages in PND. Overall, our study propose that the excitation-inhibition imbalance which rely on crosstalk changes between excitatory and inhibitory neurons forms the basis of perioperative neurocognitive disorders.

ORGANISM(S): Mus musculus

PROVIDER: GSE279516 | GEO | 2026/09/08

REPOSITORIES: GEO

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Project description:BACKGROUND: Perioperative neurocognitive disorder (PND) is a key complication affecting older individuals after anesthesia and surgery. Failure to translate multiple pharmacological therapies for PND from preclinical studies to clinical settings has necessitated the exploration of novel therapeutic strategies. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) treatment has emerged as a promising therapeutic strategy for treating neurodegenerative diseases and has the potential to translate basic science into clinical practice. In this study, we investigated the effects and underlying mechanism of hUC-MSCs on PND in aged mice.METHODS: hUC-MSCs were isolated from an infant umbilical cord and identified using flow cytometry and differentiation assays. We established PND model by undergoing aseptic laparotomy under isoflurane anesthesia maintaining spontaneous ventilation in 18-month-old male C57BL/6 mice. hUC-MSCs were slowly injected into mice by coccygeal vein before anesthesia. Cognitive function, neuroinflammation, neuroplasticity, endogenous neurogenesis and brain-derived neurotrophic factor (BDNF) were assessed. To determine the mechanisms underlying by which hUC-MSCs mediate their neuroprotective effects in PND, K252a, an antagonist of BDNF receptor, was administered intraperitoneally before surgery. Hippocampal BDNF/TrkB/CREB signaling pathway and metabolomic signatures were evaluated.RESULTS: hUC-MSC treatment ameliorated the learning and memory impairment in aged mice with PND. The downstream effects were the suppression of neuroinflammatory responses and restoration of neurogenesis and neuroplasticity dysregulation. Interestingly, the level of mature BDNF, but not that of proBDNF, was increased in the hippocampus after hUC-MSC treatment. Further analysis revealed that the improved cognitive recovery and the restoration of neurogenesis and neuroplasticity dysregulation elicited by exposure to hUC-MSCs were, at least partially, mediated by the activation of the BDNF/TrkB/CREB signaling pathway. Untargeted metabolomic further identified lipid metabolism dysfunction as potential downstream of the BDNF/TrkB/CREB signaling pathway in hUC-MSC-mediated neuroprotection for PND.CONCLUSIONS: Our study highlights the beneficial effects of hUC-MSC treatment on PND and provides a justification to consider the potential use of hUC-MSCs in the perioperative period.

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Excitation-inhibition shift in hippocampal of perioperative neurocognitive disorders: a single-cell landscape glance of pathological phenotype

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