微胶质细胞耗竭与再生对颅脑照射影响海马神经发生的作用不明显

Microglia depletion and repopulation do not alter the effects of cranial irradiation on hippocampal neurogenesis

BRAIN BEHAVIOR AND IMMUNITY

影响因子:7.6

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

DOI: 10.1016/j.bbi.2024.08.055

摘要

颅脑放疗可能导致儿童脑肿瘤幸存者终生认知障碍，其机制之一被认为是海马神经发生的减少。放疗（IR）后，微胶质细胞清除死亡的神经祖细胞，并形成促炎微环境，促使幸存的祖细胞从神经元分化转变为胶质细胞。近年来，微胶质细胞的耗竭与再生被证明能促进神经发生并改善多种脑损伤模型中的认知缺陷。本研究利用Cx3cr1CreERt2-YFP/+Rosa26DTA/+ 转基因小鼠模型，在幼年小鼠脑中耗竭微胶质细胞后，进行全脑放疗，并观察其对海马神经发生的短期及长期影响。在IR后24小时内，微胶质细胞的缺失导致下颗粒区积累死亡细胞， sham脑中CCL2（C-C基序配体2）水平高出50倍，IR后高出7倍。微胶质细胞的缺失及其在10天内的再生既未影响增殖细胞或双皮质素阳性细胞的减少，也未影响颗粒细胞层的生长。研究结果反对促炎微环境在海马神经发生失调中的作用，表明神经发生的减少完全由IR引起。

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.