Department of Rehabilitation Science, Faculty of Health Sciences, Hokkaido University, Kita 12 Nishi 5, Kita-ku, Sapporo 060-0812, Japan.
Graduate School of Health Sciences, Hokkaido University, Kita 12 Nishi 5, Kita-ku, Sapporo 060-0812, Japan.
Brain Res. 2021 Jan 15;1751:147191. doi: 10.1016/j.brainres.2020.147191. Epub 2020 Nov 2.
The objective of this study was to examine the effect of epigenetic treatment using an histone deacetylases (HDAC) inhibitor in addition to aerobic exercise on the epigenetic markers and neurotrophic gene expressions in the motor cortex, to find a more enriched brain pre-conditioning for motor learning in neurorehabilitation. ICR mice were divided into four groups based on two factors: HDAC inhibition and exercise. Intraperitoneal administration of an HDAC inhibitor (1.2 g/kg sodium butyrate, NaB) and treadmill exercise (approximately at 10 m/min for 60 min) were conducted five days a week for four weeks. NaB administration inhibited total HDAC activity and enhanced acetylation level of histones specifically in histone H4, accompanying the increase of transcription levels of immediate-early genes (IEGs) (c-fos and Arc) and neurotrophins (BDNF and NT-4) crucial for neuroplasticity in the motor cortex. However, exercise enhanced HDAC activity and acetylation level of histone H4 and H3 without the modification of transcription levels. In addition, there were no synergic effects between HDAC inhibition and the exercise regime on the gene expressions. This study showed that HDAC inhibition could present more enriched condition for neuroplasticity to the motor cortex. However, exercise-induced neurotrophic gene expressions could depend on exercise regimen based on the intensity, the term etc. Therefore, this study has a novelty suggesting that pharmacological HDAC inhibition could be an alternative potent approach to present a neuronal platform with enriched neuroplasticity for motor learning and motor recovery, however, an appropriate exercise regimen is expected in this approach.
这项研究的目的是考察在有氧运动的基础上，使用组蛋白去乙酰化酶（HDAC）抑制剂进行表观遗传治疗对运动皮层中表观遗传标记和神经营养基因表达的影响，以寻找一种更丰富的脑预处理方法，用于神经康复中的运动学习。ICR 小鼠根据两个因素分为四组：HDAC 抑制和运动。每周五天进行腹腔内注射 HDAC 抑制剂（1.2 g/kg 丁酸钠，NaB）和跑步机运动（约 10 m/min，持续 60 min）。NaB 给药抑制了总 HDAC 活性，并特异性增强了组蛋白 H4 的乙酰化水平，伴随着即刻早期基因（IEG）（c-fos 和 Arc）和神经营养因子（BDNF 和 NT-4）转录水平的增加，这些基因对于运动皮层的神经可塑性至关重要。然而，运动增强了 HDAC 活性和组蛋白 H4 和 H3 的乙酰化水平，而不改变转录水平。此外，HDAC 抑制和运动方案之间没有协同作用对基因表达。本研究表明，HDAC 抑制可以为运动皮层提供更丰富的神经可塑性条件。然而，运动诱导的神经营养基因表达可能取决于运动方案的强度、期限等因素。因此，本研究具有创新性，表明药理学 HDAC 抑制可能是一种替代的有效方法，可以为运动学习和运动恢复提供一个富含神经可塑性的神经元平台，然而，在这种方法中需要一个适当的运动方案。
