An epigenetic mechanism of social isolation stress in adolescent female mice

IF 4.3 2区医学 Q1 NEUROSCIENCES

Neurobiology of Stress Pub Date : 2023-12-18 DOI:10.1016/j.ynstr.2023.100601

Pei Li, Zhen Yan

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Abstract

Social isolation during adolescence can increase the risk of mental disorders. Epigenetic changes induced by chronic social isolation may serve as a mechanism underlying emotional disturbances. To test this, we exposed female mice to a post-weaning 6-week social isolation (SI) stress. We found the significantly increased methylation of histone H3 at lysine 9 (H3K9), a histone mark linked to gene repression, as well as the increased H3K9 methyltransferases SUV39H1 and SETDB1, in prefrontal cortex (PFC) of SI females. To find out potential downstream genes affected by this epigenetic alteration, we examined genes linked to neuronal and synaptic functions. Activity-dependent genes, including Arc, c-Fos and Npas4, were significantly reduced in PFC of SI females, correlated with the increased H3K9me2 occupancy around Arc enhancer. Treatment of SI females with UNC0642, a selective inhibitor of H3K9 methylation, significantly attenuated the anxiety-like behavior and elevated Arc expression. These results have revealed an epigenetic mechanism and intervention avenue for anxiety induced by chronic social isolation.

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青春期雌性小鼠社会隔离压力的表观遗传机制

青少年时期的社会隔离会增加患精神疾病的风险。长期社会隔离所诱导的表观遗传变化可能是情绪障碍的一种潜在机制。为了验证这一点，我们将雌性小鼠置于断奶后 6 周的社会隔离（SI）应激中。我们发现，在社会隔离雌性小鼠的前额叶皮层（PFC）中，组蛋白 H3 在赖氨酸 9（H3K9）处的甲基化明显增加，而 H3K9 甲基转移酶 SUV39H1 和 SETDB1 的含量也有所增加。为了找出受这种表观遗传学改变影响的潜在下游基因，我们研究了与神经元和突触功能相关的基因。活动依赖基因，包括 Arc、c-Fos 和 Npas4，在 SI 雌性的 PFC 中显著减少，这与 Arc 增强子周围 H3K9me2 占有率的增加有关。用 H3K9 甲基化的选择性抑制剂 UNC0642 治疗 SI 雌鼠，可显著减轻焦虑样行为和 Arc 表达的升高。这些结果揭示了一种表观遗传学机制和干预长期社会隔离诱发焦虑的途径。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Neurobiology of Stress Biochemistry, Genetics and Molecular Biology-Biochemistry

CiteScore

9.40

自引率

4.00%

发文量

审稿时长

48 days

期刊介绍： Neurobiology of Stress is a multidisciplinary journal for the publication of original research and review articles on basic, translational and clinical research into stress and related disorders. It will focus on the impact of stress on the brain from cellular to behavioral functions and stress-related neuropsychiatric disorders (such as depression, trauma and anxiety). The translation of basic research findings into real-world applications will be a key aim of the journal. Basic, translational and clinical research on the following topics as they relate to stress will be covered: Molecular substrates and cell signaling, Genetics and epigenetics, Stress circuitry, Structural and physiological plasticity, Developmental Aspects, Laboratory models of stress, Neuroinflammation and pathology, Memory and Cognition, Motivational Processes, Fear and Anxiety, Stress-related neuropsychiatric disorders (including depression, PTSD, substance abuse), Neuropsychopharmacology.