Short‐term running exercise alters DNA methylation patterns in neuronal nitric oxide synthase and brain‐derived neurotrophic factor genes in the mouse hippocampus and reduces anxiety‐like behaviors
Short‐term running exercise alters DNA methylation patterns in neuronal nitric oxide synthase and brain‐derived neurotrophic factor genes in the mouse hippocampus and reduces anxiety‐like behaviors
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DOI：
10.1096/fj.202100630r
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发表时间：
2021-08
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影响因子：
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通讯作者：
Yuki Tomiga;Kazuya Sakai;Song-Gyu Ra;Masaki Kusano;Ai Ito;Y. Uehara;Hirokazu Takahashi;K. Kawanaka;H. Soejima;Y. Higaki
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作者：
Yuki Tomiga;Kazuya Sakai;Song-Gyu Ra;Masaki Kusano;Ai Ito;Y. Uehara;Hirokazu Takahashi;K. Kawanaka;H. Soejima;Y. Higaki
跑步锻炼对大脑健康有有益的影响。然而，相对短期的跑步运动（STEx）对行为的影响及其潜在的信号通路知之甚少。在这项研究中，我们评估了STEx对脑源性神经营养因子（BDNF）和神经元型一氧化氮合酶（nNOS，由NOS 1编码）的调节可能涉及表观遗传修饰机制的可能性，这些分子是焦虑调节的重要分子，如DNA甲基化。将C57 BL/6 J雄性小鼠分为久坐（SED，n = 12）和STEx（EX，n = 15）组;用小鼠进行STEx，持续11天。STEx减少了焦虑样行为，STEx减少了海马中Nos 1 α和增加了BDNF外显子I和IV mRNA水平。有趣的是，行为参数与Bdnf外显子I和IV以及腹侧海马区的Nos 1 α mRNA水平相关，而与背侧海马区无关。然而，STEx对过氧化物酶体增殖物激活受体-γ共激活因子1α（Pgc-1α）或纤连蛋白III型结构域5（Fndc 5）mRNA水平没有影响，这是相对长期的运动诱导的BDNF上游调节因子。与基因表达变化平行，我们首次发现STEx下调了海马中Bdnf启动子IV和上调了Nos 1 DNA甲基化水平，并且这些模式在背侧和腹侧区域之间部分不同。这些发现表明，跑步锻炼对情绪调节的有益影响可能是由表观遗传机制的改变控制的，特别是在腹侧海马。即使在相对较短的运动时间后，这些影响也会发生。
Running exercise has beneficial effects on brain health. However, the effects of relatively short‐term running exercise (STEx) on behavior, and its underlying signaling pathways, are poorly understood. In this study, we evaluated the possibility that the regulation by STEx of brain‐derived neurotrophic factor (BDNF) and neuronal nitric oxide synthase (nNOS, encoded by NOS1), which are important molecules for anxiety regulation, might involve mechanisms of epigenetic modification, such as DNA methylation. C57BL/6J male mice were divided into sedentary (SED, n = 12) and STEx (EX, n = 15) groups; STEx was conducted with the mice for a duration of 11 days. STEx reduced anxiety‐like behaviors, and STEx reduced Nos1α and increased Bdnf exon I and IV mRNA levels in the hippocampus. Interestingly, behavioral parameters were associated with Bdnf exon I and IV and Nos1α mRNA levels in the ventral, but not dorsal, hippocampal region. However, STEx had no effect on peroxisome proliferator‐activated receptor‐γ coactivator 1α (Pgc‐1α) or fibronectin type III domain‐containing 5 (Fndc5) mRNA levels, which are relatively long‐term exercise‐induced upstream regulators of BDNF. In parallel with gene expression changes, we found, for the first time, that STEx downregulated Bdnf promoter IV and upregulated Nos1 DNA methylation levels in the hippocampus, and these patterns were partially different between the dorsal and ventral regions. These findings suggest that the beneficial effects of running exercise on mood regulation may be controlled by alterations in epigenetic mechanisms, especially in the ventral hippocampus. These effects occur even after a relatively short‐term period of exercise.