Diffusion magnetic resonance tractography-based evaluation of commissural fiber abnormalities in a heparan sulfate endosulfatase-deficient mouse brain
Diffusion magnetic resonance tractography-based evaluation of commissural fiber abnormalities in a heparan sulfate endosulfatase-deficient mouse brain
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DOI：
10.1016/j.mri.2022.01.017
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发表时间：
2022-02-24
影响因子：
2.5
通讯作者：
Arikawa-Hirasawa，Eri
中科院分区：
文献类型：
--
作者：
Tsuji，Yusuke;Kerever，Aurelien;Arikawa-Hirasawa，Eri
在大脑发育过程中，神经回路是通过许多基因的协调作用，通过细胞分化、细胞迁移、轴突引导和突触发生过程形成的。神经发育异常，尤其是连接缺陷，可能导致精神疾病，例如精神分裂症和自闭症。扩散张量成像的最新进展使我们能够检查大脑的宏观神经轨迹。在这项研究中，我们研究了缺乏硫酸乙酰肝素 6-O 内硫酸酯酶 Sulf1 和 Sulf2 (Sulf1/2) 的小鼠中连接左右大脑半球的连合纤维的异常情况，这两种酶是细胞外酶，可以从硫酸乙酰肝素中去除 6-O 硫酸盐，从而调节轴突导向因子的功能。我们之前证明Sulf1/2双敲除（DKO）小鼠胚胎的皮质脊髓束存在缺陷，并且其中一些DKO小鼠经历了胼胝体发育不全。然而，成人 DKO 大脑中连合纤维的异常尚未得到系统评估。在这项研究中，我们通过结合放射学和组织学分析来研究这些小鼠的连合纤维异常。首先，我们使用9.4T动物磁共振成像系统获得了成年大脑的扩散加权图像和三维T2加权图像，发现Sulf1/2 DKO小鼠具有较小的胼胝体和背侧海马连合。接下来，我们进行了髓磷脂染色和顺行追踪，揭示了背侧海马连合在头侧方向拉长。这些结果表明Sulf1/2在连合束的形成中发挥重要作用，并且与显微镜分析相关的扩散张量成像是阐明神经束异常的有力工具。缩写：AAV，腺相关病毒； AC，前连合； AD，轴向扩散率； AP，前后； CC，胼胝体； df，背侧穹窿； DHC，海马背侧连合； DKO，双重击倒； DS，背下托； DTI，扩散张量成像； DV，背腹侧； DWI，弥散加权图像； EGFP，增强型绿色荧光蛋白； f，穹窿； FA，分数各向异性； HSPG，硫酸乙酰肝素蛋白聚糖； MB，乳头体； MD，内侧扩散率； ML，内侧-外侧； PBS，磷酸盐缓冲盐水； PBT、含 0.1% Tween-20 的 PBS； PFA、多聚甲醛； PS，后枕； SC，上丘； RD，径向扩散率； VHC，腹侧海马连合； WI，加权成像； WT，野生型..* 通讯作者：顺天堂大学医学研究生院，老年疾病研究所，10 号楼，606 室，2-1-1 Hongo，Bunkyo-ku，Tokyo 113-8421，Japan。
During brain development, neural circuits are formed through cellular differentiation, cell migration, axon guidance, and synaptogenic processes by the coordinated actions of many genes. Abnormalities in neural development, especially connectivity defects, can result in psychiatric disorders, such as schizophrenia and autism. Recent advances in diffusion tensor imaging have enabled us to examine the brain’s macroscopic nerve trajectories. In this study, we investigated the abnormalities of the commissural fibers that connect the left and right cerebral hemispheres in mice lacking heparan sulfate 6-O endosulfatases, Sulf1 and Sulf2 (Sulf1/2), which are extracellular enzymes that remove 6-O sulfate from heparan sulfate and thereby modulate the function of axon guidance factors. We previously demonstrated that Sulf1/2 double knockout (DKO) mouse embryos harbored defects in their corticospinal tract and that some of these DKO mice experienced corpus callosum agenesis. However, abnormalities of the commissural fibers in the adult DKO brain have not been systematically assessed. In this study, we investigated commissural fiber abnormalities in these mice by the combined use of radiological and histological analyses. First, we acquired diffusion-weighted images and three-dimensional-T2 weighted images of adult brains using a 9.4 T animal magnetic resonance imaging system and found that Sulf1/2 DKO mice had a smaller corpus callosum and dorsal hippocampal commissure. Next, we performed myelin staining and anterograde tracing, revealing that the dorsal hippocampal commissure was elongated in a rostral direction. These results suggest that Sulf1/2 play an important role in the formation of commissural tracts and that diffusion tensor imaging associated with microscopic analysis is a powerful tool to clarify nerve tract abnormalities.Abbreviation: AAV, adeno-associated virus; AC, anterior commissure; AD, axial diffusivity; AP, anterior-posterior; CC, corpus callosum; df, dorsal fornix; DHC, dorsal hippocampal commissure; DKO, double knockout; DS, dorsal subiculum; DTI, diffusion tensor imaging; DV, dorsal-ventral; DWI, diffusion-weighted images; EGFP, enhanced green fluorescent protein; f, fornix; FA, fractional anisotropy; HSPG, Heparan sulfate proteoglycans; MB, mammillary body; MD, medial diffusivity; ML, medial-lateral; PBS, phosphate-buffered saline; PBT, PBS with 0.1% Tween-20; PFA, paraformaldehyde; PS, postsubiculum; SC, superior colliculus; RD, radial diffusivity; VHC, ventral hippocampal commissure; WI, weighted imaging; WT, wild-type..* Corresponding author at: Juntendo University Graduate School of Medicine, Research Institute for Diseases of Old Age, Building 10, Room 606, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.