Hans Berger Department of Neurology, Jena University Hospital, Am Klinkum 1, D-07747 Jena, Germany.
Hans Berger Department of Neurology, Jena University Hospital, Am Klinkum 1, D-07747 Jena, Germany; Section of Translational Neuroimmunology, Jena University Hospital, Am Klinkum 1, D-07747 Jena, Germany; Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany.
Exp Neurol. 2021 Apr;338:113591. doi: 10.1016/j.expneurol.2020.113591. Epub 2020 Dec 30.
Sepsis associated encephalopathy (SAE) is a major complication of patients surviving sepsis with a prevalence up to 70%. Although the initial pathophysiological events of SAE are considered to arise during the acute phase of sepsis, there is increasing evidence that SAE leads to persistent brain dysfunction with severe cognitive decline in later life. Previous studies suggest that the hippocampal formation is particularly involved leading to atrophy in later stages. Thereby, the underlying cellular mechanisms are only poorly understood. Here, we hypothesized that endogenous neural stems cells and adult neurogenesis in the hippocampus are impaired following sepsis and that these changes may contribute to persistent cognitive dysfunction when the animals have physically fully recovered. We used the murine sepsis model of peritoneal contamination and infection (PCI) and combined different labeling methods of precursor cells with confocal microscopy studies to assess the neurogenic niche in the dentate gyrus at day 42 postsepsis. We found that following sepsis i) gliogenesis is increased, ii) the absolute number of radial glia-like cells (type 1 cells), which are considered the putative stem cells, is significantly reduced, iii) the generation of new neurons is not significantly altered, while iv) the synaptic spine maturation of new neurons is impaired with a shift to expression of more immature and less mature spines. In conclusion, sepsis mainly leads to depletion of the neural stem cell pool and enhanced gliogenesis in the dentate gyrus which points towards an accelerated aging of the hippocampus due to septic insult.
脓毒症相关性脑病（SAE）是存活脓毒症患者的主要并发症，其患病率高达 70%。尽管 SAE 的初始病理生理事件被认为发生在脓毒症的急性期，但越来越多的证据表明，SAE 导致持续性脑功能障碍，在后期生活中出现严重认知能力下降。先前的研究表明，海马结构特别参与其中，导致后期出现萎缩。因此，潜在的细胞机制还知之甚少。在这里，我们假设脓毒症后海马中的内源性神经干细胞和成人神经发生受损，并且当动物在身体上完全恢复后，这些变化可能导致持续性认知功能障碍。我们使用了腹膜污染和感染（PCI）的小鼠脓毒症模型，并结合了前体细胞的不同标记方法与共聚焦显微镜研究，以评估脓毒症后 42 天齿状回中的神经发生龛。我们发现，脓毒症后：i）神经胶质发生增加，ii）被认为是潜在干细胞的放射状胶质样细胞（type 1 细胞）的绝对数量显著减少，iii）新神经元的生成没有明显改变，而 iv）新神经元的突触棘成熟受损，表现为表达更多不成熟和较不成熟的棘。总之，脓毒症主要导致神经干细胞池耗竭和齿状回中的神经胶质发生增强，这表明由于脓毒症的侵袭，海马加速衰老。
