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Updated: Jun 11, 2025
Chronic Social Defeat Stress in Early Adolescent Male Mice
Published on: January 24, 2025
Dysregulated miR-124 mediates impaired social memory behavior caused by paternal early social isolation
Sijia Chen1,2, Shixin Ding1,2, Yingting Pang1,3
1Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, 211166, China.
Abstract:
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.
Insights
Paternal early social isolation (SI) impairs offspring social behavior and memory by altering brain development. Epigenetic transmission of miR-124 impacts myelin formation and social interaction in young mice.
Area of Science:
- Neuroscience
- Epigenetics
- Developmental Biology
Background:
- Early social isolation (SI) is known to cause adult behavioral abnormalities.
- The intergenerational impact of paternal SI on offspring neurodevelopment and social behavior remains largely unexplored.
Purpose of the Study:
- To investigate the effects of paternal early SI on the social behavior and neurodevelopment of F1 offspring.
- To elucidate the underlying molecular mechanisms, focusing on epigenetic modifications and brain alterations.
Main Methods:
- Mice models were used to study the effects of paternal early SI on F1 offspring.
- Analysis included behavioral tests (social memory, anxiety), and molecular analysis of the medial prefrontal cortex (mPFC), including myelin, synapses, and gene/microRNA expression (miR-124, Nr4a1).
- Epigenetic transmission via sperm was investigated.
Main Results:
- Paternal early SI induced social memory deficits and anxiety-like behavior in F1 offspring.
- Alterations in myelin and synapses were observed in the mPFC of affected offspring.
- Down-regulation of miR-124 or over-expression of its target Nr4a1 in the mPFC improved social interaction and oligodendrocyte maturation.
- Elevated miR-124 in sperm from SI fathers was epigenetically transmitted, affecting miR-124/Nr4a1/glucocorticoid receptor pathways in offspring mPFC oligodendrocytes, impairing myelinogenesis-dependent social behavior.
Conclusions:
- Paternal early SI epigenetically impacts offspring neurodevelopment and social behavior through miR-124 mediated pathways.
- This study reveals a novel mechanism for intergenerational transmission of stress effects, impacting social behavior and myelin formation.
- Targeting the miR-124/Nr4a1 pathway offers potential therapeutic avenues for social behavior deficits stemming from early life stress.
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