Taranov Aleksandr, Bedolla Alicia, Iwasawa Eri, Brown Farrah N, Baumgartner Sarah, Fugate Elizabeth M, Levoy Joel, Crone Steven A, Goto June, Luo Yu
Department of Molecular and Cellular Biosciences, College of Medicine, University of Cincinnati, Cincinnati, OH 45229, USA.
Division of Pediatric Neurosurgery, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
bioRxiv. 2024 Jan 23:2024.01.22.575277. doi: 10.1101/2024.01.22.575277.
The brain's neuroreparative capacity after injuries such as ischemic stroke is contained in the brain's neurogenic niches, primarily the subventricular zone (SVZ), which lies in close contact with the cerebrospinal fluid (CSF) produced by the choroid plexus (ChP). Despite the wide range of their proposed functions, the ChP/CSF remain among the most understudied compartments of the central nervous system (CNS). Here we report a mouse genetic tool (the ROSA26iDTR mouse line) for non-invasive, specific, and temporally controllable ablation of CSF-producing ChP epithelial cells to assess the roles of the ChP and CSF in brain homeostasis and injury. Using this model, we demonstrate that ChP ablation causes rapid and permanent CSF volume loss accompanied by disruption of ependymal cilia bundles. Surprisingly, ChP ablation did not result in overt neurological deficits at one-month post-ablation. However, we observed a pronounced decrease in the pool of SVZ neuroblasts following ChP ablation, which occurs due to their enhanced migration into the olfactory bulb. In the MCAo model of ischemic stroke, neuroblast migration into the lesion site was also reduced in the CSF-depleted mice. Thus, our study establishes an important and novel role of ChP/CSF in regulating the regenerative capacity of the adult brain under normal conditions and after ischemic stroke.
大脑在诸如缺血性中风等损伤后的神经修复能力存在于大脑的神经源性微环境中,主要是脑室下区(SVZ),它与脉络丛(ChP)产生的脑脊液(CSF)紧密接触。尽管人们提出了ChP/CSF的多种功能,但它们仍然是中枢神经系统(CNS)中研究最少的部分之一。在这里,我们报告一种小鼠基因工具(ROSA26iDTR小鼠品系),用于对产生脑脊液的ChP上皮细胞进行非侵入性、特异性和时间可控的消融,以评估ChP和CSF在脑内稳态和损伤中的作用。使用这个模型,我们证明ChP消融会导致脑脊液体积迅速且永久性减少,并伴有室管膜纤毛束的破坏。令人惊讶的是,ChP消融在消融后一个月并未导致明显的神经功能缺损。然而,我们观察到ChP消融后SVZ神经母细胞池明显减少,这是由于它们向嗅球的迁移增强所致。在缺血性中风的大脑中动脉闭塞(MCAo)模型中,脑脊液减少的小鼠中神经母细胞向损伤部位的迁移也减少。因此,我们的研究确立了ChP/CSF在正常条件下和缺血性中风后调节成体大脑再生能力方面的重要且新颖的作用。