Sawada Kazuhiko, Ryoke Rie, Nonaka Hiroi, Kawashima Ryuta, Sumiyoshi Akira
Department of Nutrition, Faculty of Medical and Health Sciences, Tsukuba International University, Tsuchiura, Ibaraki 300-0052, Japan
Institute of Development, Aging and Cancer, Tohoku University, Sendai, Miyagi 980-8575, Japan.
eNeuro. 2025 Aug 7;12(8). doi: 10.1523/ENEURO.0135-25.2025. Print 2025 Aug.
Lipopolysaccharide (LPS) is a bacterial endotoxin that induces innate immune responses. The present study aimed to elucidate alterations in cerebral cortical surface morphology induced by neonatal exposure to LPS using gyrencephalic ferrets. Male ferret pups received a subcutaneous injection of LPS (500 µg/g of body weight) on Postnatal Day (P)6 and P7. Furthermore, EdU and BrdU were administered on P5 and P7, respectively, to label postproliferative and proliferating cells that were exposed to LPS in the late stage of cortical neurogenesis. On P20 when the primary sulci and gyri had formed, MRI-based morphometry revealed an anterior shift in sulcal infolding in the medial and dorsolateral cortices of LPS-exposed ferrets. Immunofluorescence analysis showed that LPS increased the density of BrdU-labeled cells and reduced their apoptosis, as indicated by cleaved caspase-3 (cCasp3) immunostaining, in the outer stratum of the lateral sulcus located on the parietal association cortex. Furthermore, cCasp3 immunostaining of EdU-labeled cells was enhanced in the presylvian and lateral sulci located in the prefrontal and parietal association cortices, respectively, but was reduced in the coronal sulcus and gyrus located on the primary motor cortex in LPS-exposed ferrets. This study is the first to elucidate the effect of bacterial components on cerebral cortical sulcogyrogenesis, which is involved in the pathogenesis of neurodevelopmental disorders. Such altered sulcal topology may be attributed to a region-related effect on cortical neuron apoptosis in the medial and dorsolateral cortices caused by neonatal LPS exposure.
脂多糖（LPS）是一种可诱导先天免疫反应的细菌内毒素。本研究旨在利用脑沟回发达的雪貂，阐明新生期暴露于LPS所诱导的大脑皮质表面形态变化。雄性雪貂幼崽在出生后第（P）6天和第7天接受皮下注射LPS（500μg/g体重）。此外，分别在P5和P7给予EdU和BrdU，以标记在皮质神经发生后期暴露于LPS的增殖后细胞和增殖细胞。在P20，当主要的脑沟和脑回形成时，基于MRI的形态学测量显示，暴露于LPS的雪貂的内侧和背外侧皮质的脑沟折叠出现向前移位。免疫荧光分析表明，LPS增加了BrdU标记细胞的密度，并减少了其凋亡，如位于顶叶联合皮质的外侧沟外层中裂解的半胱天冬酶-3（cCasp3）免疫染色所示。此外，在暴露于LPS的雪貂中，位于前额叶和顶叶联合皮质的嗅前沟和外侧沟中，EdU标记细胞的cCasp3免疫染色增强，但在位于初级运动皮质的冠状沟和脑回中则减弱。本研究首次阐明了细菌成分对大脑皮质沟回形成的影响，这与神经发育障碍的发病机制有关。这种改变的脑沟拓扑结构可能归因于新生期LPS暴露对内侧和背外侧皮质中皮质神经元凋亡的区域相关影响。
