Possible role of transcriptional regulation of 5-HT1A receptor in the midbrain on unadaptation to stress in mice
Possible role of transcriptional regulation of 5-HT1A receptor in the midbrain on unadaptation to stress in mice
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DOI：
10.1016/j.brainres.2022.147859
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发表时间：
2022-03-04
期刊：
影响因子：
2.9
通讯作者：
Takeda，Hiroshi
中科院分区：
文献类型：
--
作者：
Miyagishi，Hiroko;Tsuji，Minoru;Takeda，Hiroshi
适应压力的能力是一个生命体的基本防御功能，大脑中这种能力的干扰可能有助于情感疾病的发展。以前，我们报道过，小鼠暴露于不适应约束压力表现出情绪异常。此外，这种情绪异常缓解长期治疗与flesinoxan，5-羟色胺（5-HT）1A受体激动剂。5-HT 1A受体的表达受多种转录因子如核变形表皮自动调节因子（NUDR/Deaf-1）和双重阻遏结合蛋白1（Freud-1）下的5个主要阻遏物的调控。本研究旨在观察应激适应和非应激适应小鼠中脑和海马5-HT 1A受体及其转录因子的表达水平。将小鼠暴露于14天的重复适应性（1小时/天）或重复不适应性（4小时/天）束缚应激，或留在其饲养笼中（非应激组）。在Western印迹分析中，在应激适应小鼠的海马膜组分中观察到5 HT 1A受体蛋白的表达水平显著增加。与此相反，5-HT 1A受体蛋白在应激不适应小鼠的表达水平显着增加，在细胞质和膜部分的中脑。实时荧光定量PCR分析显示，应激不适应小鼠中脑5-HT 1A受体mRNA表达水平显著升高，Freud-1和NUDR mRNA表达水平显著降低。这些结果提示，由于Freud-1和NUDR的表达减少而引起的中脑5-HT 1A受体表达的增加可能在应激不适应小鼠的情绪异常中起关键作用。
The ability to adapt to stress is an essential defensive function of a living body, and disturbance of this ability in the brain may contribute to the development of affective illness. Previously, we reported that mice exposed to unadaptable restraint stress show emotional abnormality. Moreover, this emotional abnormality was alleviated by chronic treatment with flesinoxan, a serotonin (5-HT)1Areceptor agonist. 5-HT1Areceptor expression is regulated by several transcription factors such as nuclear deformed epidermal autoregulatory factor (NUDR/Deaf-1) and five prime repressors under dual repression binding protein 1 (Freud-1). The present study was designed to investigate the expression levels of 5-HT1Areceptor and its transcription factors in the midbrain and hippocampus of stress-adaptive and -unadaptive mice. Mice were exposed to 14 days of repeated adaptable (1 h/day) or repeated unadaptable (4 h/day) restraint stress, or were left in their home cage (non-stressed groups). In a western blot analysis, a significant increase in the expression levels of 5HT1Areceptor protein were observed in the hippocampal membrane fraction in stress-adaptive mice. In contrast, the expression levels of 5-HT1Areceptor protein in stress-unadaptive mice were significantly increased in both cytoplasmic and membrane fraction of the midbrain. Furthermore, real-time PCR analysis revealed that, in the midbrain of stress-unadaptive mice, the expression levels of 5-HT1Areceptor mRNA and Freud-1 or NUDR mRNA were significantly increased and decreased, respectively. These results suggest that increased expression of 5-HT1Areceptor due to decrease in the expression of Freud-1 and NUDR in the midbrain may play a pivotal role in the emotional abnormality of stress-unadaptive mice.