Molecular Adaptations to Social Defeat Stress and Induced Depression in Mice
Molecular Adaptations to Social Defeat Stress and Induced Depression in Mice
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DOI：
10.1007/s12035-017-0586-3
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发表时间：
2018-04-01
影响因子：
5.1
通讯作者：
Merkulova, Tatiana
中科院分区：
文献类型：
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作者：
Bondar, Natalya;Bryzgalov, Leonid;Merkulova, Tatiana
慢性压力是导致重度抑郁症的一个危险因素。社会失败压力是一种有效的小鼠抑郁症模型。然而，在抑郁样状态的发展过程中，人们对基因活动的动态知之甚少。我们分析了不同持续时间（10天和30天）的社会失败应激对C57BL/6小鼠行为模式和前额叶皮层转录组的影响。10天的社会失败压力暴露导致了高水平的社会回避，没有抑郁相关行为的迹象。大多数动物暴露在30天的社会失败压力下，表现出明显的抑郁特征，包括更高水平的社会回避，在强迫游泳测试中增加不动，以及快感缺乏行为。对转录组变化的监测显示，在第10天，基因表达发生了广泛的变化。令人惊讶的是，只有少数基因的表达受到胁迫第30天的影响，显然是由于大多数早期应激诱导的变化逆转到原始基础状态。此外，我们发现糖皮质激素敏感基因在应激第10天明显是受刺激的目标，但这些基因在应激第30天停止对皮质酮水平升高的反应。30天应激改变的基因大部分下调，与染色质修饰和神经可塑性相关的基因（如GTPases rho家族的鸟嘌呤核苷酸交换因子）最多。小鼠在短期和长期社会压力下的分子反应截然不同。早期应激反应与社会回避和许多基因的上调和下调有关，包括与信号转导和细胞粘附途径相关的基因。一些基因的下调，特别是组蛋白修饰甲基转移酶基因的下调，是对长期压力的一种典型反应，这种压力会诱发抑郁症状。总之，我们的数据表明，在社会压力条件下抑郁症的发展与对诱导应激的过度活跃分子反应的抑制有关，涉及基因对糖皮质激素分子的调控抗性，可能通过染色质重塑机制。
Chronic stress is a risk factor for major depression. Social defeat stress is a well-validated murine model of depression. However, little is known about the gene activity dynamics during the development of a depression-like state. We analyzed the effects of social defeat stress of varying duration (10 and 30 days) on the behavioral patterns and prefrontal-cortex transcriptome of C57BL/6 mice. The 10-day exposure to social defeat stress resulted in a high level of social avoidance with no signs of depression-associated behavior. Most animals exposed to 30 days of social defeat stress demonstrated clear hallmarks of depression, including a higher level of social avoidance, increased immobility in the forced swimming test, and anhedonic behavior. The monitoring of transcriptome changes revealed widespread alterations in gene expression on the 10th day. Surprisingly, the expression of only a few genes were affected by the 30th day of stress, apparently due to a reversal of the majority of the early stress-induced changes to the original basal state. Moreover, we have found that glucocorticoid-sensitive genes are clearly stimulated targets on the 10th day of stress, but these genes stop responding to the elevated corticosterone level by the 30th day of stress. The majority of genes altered by the 30-day stress were downregulated, with the most relevant ones participating in chromatin modifications and neuroplasticity (e.g., guanine nucleotide exchange factors of the Rho-family of GTPases). Very different molecular responses occur during short-term and long-term social stress in mice. The early-stress response is associated with social avoidance and with upregulation and downregulation of many genes, including those related to signal transduction and cell adhesion pathways. Downregulation of a few genes, in particular, genes for histone-modifying methyltransferases, is a signature response to prolonged stress that induces symptoms of depression. Altogether, our data show that the development of depression under social stress conditions is correlated with suppression of the overactive molecular response to induced stress, involving gene regulatory resistance to glucocorticoid molecules, potentially via a chromatin remodeling mechanism.