Zhou Kai, Zisiadis Georgios Alkis, Havermans Monique, Fragkopoulou Adamantia, Dominguez Cecilia, Ohshima Makiko, Osman Ahmed M, Rodrigues Carlos F D, Blomgren Klas
Henan Neurodevelopment Engineering Research Center for Children, Zhengzhou Key Laboratory of Pediatric Neurobehavior, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, China; Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
Brain Behav Immun. 2025 Jan;123:57-63. doi: 10.1016/j.bbi.2024.08.055. Epub 2024 Aug 30.
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 Cx3cr1Rosa26 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.
颅脑放疗可导致儿童脑肿瘤幸存者出现终身认知并发症，据推测海马神经发生减少是导致这一情况的原因。照射（IR）后，小胶质细胞清除死亡的神经祖细胞，并形成一种神经炎症微环境，这种微环境促使存活的祖细胞从神经元分化转向胶质细胞分化。最近，在各种脑损伤模型中，小胶质细胞的耗竭和再填充被证明可促进神经发生并改善认知缺陷。在本研究中，我们利用Cx3cr1Rosa26转基因小鼠模型，在幼年小鼠脑部进行全脑照射前耗尽小胶质细胞，并研究其对海马神经发生的短期和长期影响。在照射后的最初24小时内，小胶质细胞的缺失导致颗粒下区死细胞堆积，假手术组大脑中趋化因子C-C基序配体2（CCL2）水平高50倍，照射后高7倍。小胶质细胞的缺失以及随后10天内的再填充，既不影响增殖细胞或双皮质素阳性细胞的损失，也不影响颗粒细胞层生长的减少。我们的结果表明，促炎微环境在海马神经发生失调中不起作用，并表明观察到的神经发生减少完全是由于照射所致。
