Department of Biomedical Science, Program in Biomedical Science and Engineering, College of Medicine, Inha University, Incheon, Korea.
Department of Physiology and Biophysics, College of Medicine, Inha University, Incheon, Korea.
J Neuropathol Exp Neurol. 2024 Nov 1;83(11):927-938. doi: 10.1093/jnen/nlae092.
This study investigated the behavioral and molecular changes in the telencephalon following needle stab-induced injury in the optic tectum of adult zebrafish. At 3 days post-injury (dpi), there was noticeable structural damage to brain tissue and reduced neuronal proliferation in the telencephalon that persisted until 30 dpi. Neurobehavioral deficits observed at 3 dpi included decreased exploratory and social activities and impaired learning and memory (L/M) functions; all of these resolved by 7 dpi. The injury led to a reduction in telencephalic phosphorylated cAMP response element-binding protein and O-GlcNAcylation, both of which were restored by 30 dpi. There was an increase in GFAP expression and nuclear translocation of NF-κB p65 at 3 dpi, which were not restored by 30 dpi. The injury caused decreased O-GlcNAc transferase and increased O-GlcNAcase levels at 3 dpi, normalizing by 30 dpi. Glucosamine (GlcN) treatment at 3 dpi significantly restored O-GlcNAcylation levels and L/M function, also reducing GFAP activation. Glucose treatment recovered L/M function by 7 dpi, but inhibition of the hexosamine biosynthetic pathway by 6-diazo-5-oxo-L-norleucine blocked this recovery. These findings suggest that the O-GlcNAc pathway is a potential therapeutic target for addressing L/M impairment following traumatic brain injury in zebrafish.
本研究调查了成年斑马鱼视神经顶盖刺伤后，端脑的行为和分子变化。在损伤后 3 天（dpi），脑组织出现明显的结构损伤，端脑的神经元增殖减少，这种情况一直持续到 30dpi。在 3dpi 观察到的神经行为缺陷包括探索和社交活动减少，以及学习和记忆（L/M）功能受损；所有这些在 7dpi 时都得到了改善。损伤导致端脑磷酸化 cAMP 反应元件结合蛋白和 O-GlcNAcylation 减少，这些在 30dpi 时得到恢复。在 3dpi 时，GFAP 表达增加，NF-κB p65 核转位，这些在 30dpi 时没有恢复。损伤导致 3dpi 时 O-GlcNAc 转移酶减少和 O-GlcNAcase 水平增加，30dpi 时恢复正常。3dpi 时用葡萄糖胺（GlcN）处理可显著恢复 O-GlcNAcylation 水平和 L/M 功能，同时减少 GFAP 激活。7dpi 时葡萄糖处理恢复了 L/M 功能，但 6-二氮-5-氧-L-正亮氨酸抑制己糖胺生物合成途径阻断了这种恢复。这些发现表明，O-GlcNAc 途径是治疗斑马鱼创伤性脑损伤后 L/M 损伤的潜在治疗靶点。
