Sijia Chen, Shixin Ding, Yingting Pang, Yuxi Jin, Peng Sun, Yue Li, Min Cao, Yimiao Wang, Ze Wang, Tianqi Wang, Ying Zou, Yanli Zhang, Ming Xiao
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引用次数: 0
摘要
早期社会隔离(SI)会导致成年后情绪和行为的各种异常。然而,社会隔离对后代的负面影响仍不清楚。这项研究发现,父系早期社会隔离会导致 F1 年轻成年小鼠的社会记忆缺陷和焦虑样行为,并改变内侧前额叶皮层(mPFC)的髓鞘和突触。对 F1 后代进行 2 周的 SI 会加剧 mPFC 中的社会记忆障碍和髓鞘化不足。此外,在F1小鼠的mPFC中下调miR-124(一种髓鞘生成的关键抑制因子)或过度表达其靶基因Nr4a1可改善社交互动能力,并促进少突胶质细胞的成熟和髓鞘的形成。从机理上讲,父系 SI 小鼠精子中 miR-124 水平的升高会通过表观遗传传递给子代,从而改变 mPFC 少突胶质细胞中 miR-124/Nr4a1/ 糖皮质激素受体的表达水平。这反过来又阻碍了依赖髓鞘生成的社会行为的建立。这项研究揭示了一种新的机制,通过这种机制,miR-124介导了早期隔离应激的代际效应,最终损害了社会行为和神经发育的建立。
Dysregulated miR-124 mediates impaired social memory behavior caused by paternal early social isolation.
Early social isolation (SI) leads to various abnormalities in emotion and behavior during adulthood. However, the negative impact of SI on offspring remains unclear. This study has discovered that paternal early SI causes social memory deficits and anxiety-like behavior in F1 young adult mice, with alterations of myelin and synapses in the medial prefrontal cortex (mPFC). The 2-week SI in the F1 progeny exacerbates social memory impairment and hypomyelination in the mPFC. Furthermore, the down-regulation of miR-124, a key inhibitor of myelinogenesis, or over-expression of its target gene Nr4a1 in the mPFC of the F1 mice improves social interaction ability and enhances oligodendrocyte maturation and myelin formation. Mechanistically, elevated levels of miR-124 in the sperm of paternal SI mice are transmitted epigenetically to offspring, altering the expression levels of miR-124/Nr4a1/glucocorticoid receptors in mPFC oligodendrocytes. This, in turn, impedes the establishment of myelinogenesis-dependent social behavior. This study unveils a novel mechanism through which miR-124 mediates the intergenerational effects of early isolation stress, ultimately impairing the establishment of social behavior and neurodevelopment.
期刊介绍:
Psychiatry has suffered tremendously by the limited translational pipeline. Nobel laureate Julius Axelrod''s discovery in 1961 of monoamine reuptake by pre-synaptic neurons still forms the basis of contemporary antidepressant treatment. There is a grievous gap between the explosion of knowledge in neuroscience and conceptually novel treatments for our patients. Translational Psychiatry bridges this gap by fostering and highlighting the pathway from discovery to clinical applications, healthcare and global health. We view translation broadly as the full spectrum of work that marks the pathway from discovery to global health, inclusive. The steps of translation that are within the scope of Translational Psychiatry include (i) fundamental discovery, (ii) bench to bedside, (iii) bedside to clinical applications (clinical trials), (iv) translation to policy and health care guidelines, (v) assessment of health policy and usage, and (vi) global health. All areas of medical research, including — but not restricted to — molecular biology, genetics, pharmacology, imaging and epidemiology are welcome as they contribute to enhance the field of translational psychiatry.