Institut für Humangenetik, Jena University Hospital, Am Klinikum 1, F4E20, 07747, Jena, Germany.
Institut für Neurologie, Jena University Hospital, Am Klinikum 1, F4E20, 07747, Jena, Germany.
Neuropharmacology. 2020 Jul;171:108112. doi: 10.1016/j.neuropharm.2020.108112. Epub 2020 Apr 23.
Depression is the leading cause of disability worldwide. Although most research into risk factors focuses on stress, dietary factors also have a strong link with depression. For instance, chronic vitamin B12-supplementation may reduce depression risk and helps to reverse the prodepressive effects of early life stress in animal models. However, it is still unclear whether a single acute dose of vitamin B12 is sufficient to induce antidepressant effects on molecular or behavioral levels. Based on pharmacological work and CRISPR-dCas9 epigenome editing in Neuro2A-cells we provide in vitro evidence for a link between vitamin B12, gene expression and DNA methylation of the antidepressant-associated gene Ntrk-2, which codes for the BDNF-receptor TRKB. Using stress-induction protocols in C57Bl/6 J mice combined with behavioral testing and subsequent molecular tissue analysis, we establish in vivo evidence for antidepressant effects of vitamin B12. Acute supplementation with vitamin B12, but not folic acid, selectively altered DNA methylation and gene expression of Ntrk-2 in vitro, albeit DNA methylation and Ntrk-2 gene expression do not correlate in vivo. Importantly, one acute vitamin B12 injection improved multiple behavioral measures in tests for antidepressant action and at the same time reversed the effects of chronic and acute stress on Ntrk-2 levels in vivo, however causality has not been proven at this stage. Taken together, acute vitamin B12 supplementation can reverse stress effects on Ntrk-2 gene expression and improve behaviors that are associated with depression-like behavior in mice. Our findings encourage further investigation of vitamin B12-supplementation as a novel model for antidepressant action.
抑郁症是全球范围内导致残疾的主要原因。尽管大多数风险因素的研究都集中在压力上，但饮食因素与抑郁症也有很强的关联。例如，慢性补充维生素 B12 可能会降低抑郁症的风险，并有助于逆转动物模型中早期生活应激的促抑郁作用。然而，目前尚不清楚单次急性剂量的维生素 B12 是否足以在分子或行为水平上产生抗抑郁作用。基于药理学工作和 CRISPR-dCas9 表观基因组编辑在 Neuro2A 细胞中的应用，我们提供了维生素 B12 与基因表达和抗抑郁相关基因 Ntrk-2 的 DNA 甲基化之间关联的体外证据，该基因编码 BDNF 受体 TRKB。通过在 C57Bl/6J 小鼠中使用应激诱导方案结合行为测试和随后的分子组织分析，我们在体内建立了维生素 B12 的抗抑郁作用的证据。急性补充维生素 B12，但不是叶酸，选择性地改变了体外 Ntrk-2 的 DNA 甲基化和基因表达，尽管 DNA 甲基化和 Ntrk-2 基因表达在体内没有相关性。重要的是，一次急性维生素 B12 注射改善了抗抑郁作用测试中的多种行为测量，同时逆转了慢性和急性应激对体内 Ntrk-2 水平的影响，但在现阶段还不能证明因果关系。总之，急性维生素 B12 补充可以逆转应激对 Ntrk-2 基因表达的影响，并改善与小鼠抑郁样行为相关的行为。我们的发现鼓励进一步研究维生素 B12 补充作为一种新型抗抑郁作用的模型。
