Human Informatics and Interaction Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1 Umezono, Tsukuba, Ibaraki 305-8568, Japan; Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan; Research Fellow of Japan Society for the Promotion of Science (DC2), 5-3-1 Kojimachi, Chiyoda-ku, Tokyo 102-0083, Japan.
Human Informatics and Interaction Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1 Umezono, Tsukuba, Ibaraki 305-8568, Japan; Faculty of Engineering, Information and Systems, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8573, Japan.
Brain Res. 2025 Jan 1;1846:149257. doi: 10.1016/j.brainres.2024.149257. Epub 2024 Oct 1.
Neonatal hypoxic ischemia (HI) occurs owing to reduced cerebral oxygen levels and perfusion during the perinatal period. Brain injury after HI triggers neurological manifestations such as motor impairment, and the improvement of impaired brain function remains challenging. Recent studies suggest that cortical myelination plays a role in motor learning, but its involvement in motor improvement after HI injury is not well understood. This study aimed to investigate the impact of myelination on motor improvement following neonatal HI injury. We employed a modified Rice-Vannucci model; the right common carotid artery of postnatal day 7 (P7) Wistar rats was isolated and divided, and the rats were then exposed to hypoxic condition (90 min, 8 % O2). A total of 101 rats (66 males) were divided into four groups: trained-HI (n = 38), trained-Sham (n = 16), untrained-HI (n = 31), and untrained-Sham (n = 16). The trained groups underwent rotarod-based exercise training from P22 to P41 (3 days per week). Structural analysis using magnetic resonance imaging and immunohistochemistry (n = 6 per group) revealed increased fractional anisotropy and myelin density in the primary somatosensory cortex of the trained-HI group. We further evaluated the effect of myelination promotion on rotarod performance by administering clemastine, a myelination-promoting drug, via daily intraperitoneal injections. Clemastine did not enhance motor improvement in untrained-HI rats. However, clemastine-administered trained-HI rats (n = 7) exhibited significantly improved motor performance compared to both saline-administered trained-HI rats (n = 11) and clemastine-administered untrained-HI rats (n = 7). These findings suggest that myelination may be a key mechanism in motor improvement after HI injury and that combining exercise training with clemastine administration could be an effective therapeutic strategy for motor improvement following HI injury.
新生儿缺氧缺血性脑损伤（HI）是由于围产期脑氧水平和灌注减少引起的。HI 后的脑损伤引发运动障碍等神经表现，改善受损脑功能仍然具有挑战性。最近的研究表明皮质髓鞘化在运动学习中起作用，但它在 HI 损伤后运动改善中的作用尚不清楚。本研究旨在探讨髓鞘化对新生儿 HI 损伤后运动改善的影响。我们采用改良的 Rice-Vannucci 模型；分离并结扎出生后第 7 天（P7）Wistar 大鼠的右侧颈总动脉，然后将大鼠暴露于缺氧环境（90min，8%O2）。共有 101 只大鼠（66 只雄性）分为四组：训练 HI 组（n=38）、训练假手术组（n=16）、未训练 HI 组（n=31）和未训练假手术组（n=16）。训练组从 P22 至 P41 进行基于转棒的运动训练（每周 3 天）。采用磁共振成像和免疫组织化学（每组 n=6）进行结构分析，结果显示训练 HI 组初级体感皮层的分数各向异性和髓鞘密度增加。我们通过每日腹腔注射氯苯那敏（一种促进髓鞘形成的药物）进一步评估促进髓鞘形成对转棒性能的影响。氯苯那敏并未增强未训练 HI 大鼠的运动改善。然而，氯苯那敏给药的训练 HI 大鼠（n=7）的运动性能明显优于生理盐水给药的训练 HI 大鼠（n=11）和氯苯那敏给药的未训练 HI 大鼠（n=7）。这些发现表明髓鞘化可能是 HI 损伤后运动改善的关键机制，将运动训练与氯苯那敏联合应用可能是 HI 损伤后运动改善的有效治疗策略。
