小胶质细胞的耗竭和重生不会改变颅辐射对海马神经发生的影响
Microglia depletion and repopulation do not alter the effects of cranial irradiation on hippocampal neurogenesis
影响因子:7.60000
分区:医学1区 Top / 神经科学1区 精神病学1区 免疫学2区
发表日期:2025 Jan
作者:
Kai Zhou, Georgios Alkis Zisiadis, Monique Havermans, Adamantia Fragkopoulou, Cecilia Dominguez, Makiko Ohshima, Ahmed M Osman, Carlos F D Rodrigues, Klas Blomgren
摘要
颅骨放射疗法会导致儿童脑肿瘤幸存者的终生认知并发症，并且假设海马神经发生降低会为此做出贡献。辐照后（IR），小胶质细胞透明死神经祖细胞，并引起神经炎性的微环境，从而促进了从神经元到神经胶质分化的祖细胞的转变。最近，在各种脑损伤模型中，小胶质细胞的耗竭和再催化可促进神经发生和改善认知缺陷。在这项研究中，我们利用CX3CR1CREERT2-YFP/+ ROSA26DTA/+转基因小鼠模型在少年小鼠脑中耗尽了小胶质细胞，然后才使它们遭受全脑IR，并研究了短期和长期对海马神经发生的影响。在IR之后的最初24小时内，小胶质细胞的缺乏导致粒状区域中死细胞的积累，而在假大脑中，趋化因子C-C-C-C-C-C-C-C-C-C-C-C-C-C-C-C-C-C-C-C-C-C-C-C-C-C-C-C-C-C-C-C-C-C-C-C-C-C-C-C-C-C-C-C-C-C-C-C-C CCL2（CCL2）在假大脑中，IR后高7倍。小胶质细胞的缺乏以及随后在10天内的重生，既没有影响增殖或双铁蛋白阳性细胞的丧失，也没有影响颗粒细胞层的生长降低。我们的结果反对促炎性微环境在海马神经发生失调中的作用，并表明观察到的神经发生的降低完全是由于IR引起的。
Abstract
Cranial radiotherapy can cause lifelong cognitive complications in childhood brain tumor survivors, and reduced hippocampal neurogenesis is hypothesized to contribute to this. Following irradiation (IR), microglia clear dead neural progenitors and give rise to a neuroinflammatory microenvironment, which promotes a switch in surviving progenitors from neuronal to glial differentiation. Recently, depletion and repopulation of microglia were shown to promote neurogenesis and ameliorate cognitive deficits in various brain injury models. In this study, we utilized the Cx3cr1CreERt2-YFP/+Rosa26DTA/+ transgenic mouse model to deplete microglia in the juvenile mouse brain before subjecting them to whole-brain IR and investigated the short- and long-term effects on hippocampal neurogenesis. Within the initial 24 h after IR, the absence of microglia led to an accumulation of dead cells in the subgranular zone, and 50-fold higher levels of the chemokine C-C motif ligand 2 (CCL2) in sham brains and 7-fold higher levels after IR. The absence of microglia, and the subsequent repopulation within 10 days, did neither affect the loss of proliferating or doublecortin-positive cells, nor the reduced growth of the granule cell layer. Our results argue against a role for a pro-inflammatory microenvironment in the dysregulation of hippocampal neurogenesis and suggest that the observed reduction of neurogenesis was solely due to IR.